Confirmation Number:261476 Event Started: 9/23/2004 3:45:01 PM Event Ended: 1/1/0001 12:00:00 AM

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GOOD MORNING AND WELCOME TO THE 97th MEETING OF THE RECOMBINANT DNA ADVISORY COMMITTEE. WE ARE GOING TO BEGIN THIS MORNING BY INTRODUCING THREE NEW RAC HERE TODAY. DOCTORS DEWHURST ABELE DA AND VIAL AND I WILL ASK EACH OF THEM TO SAY A VIEW WORDS ABOUT THEMSELVES. DR. DEWHURST.

I'M WITH THE UNIVERSITY OF ROW CHESTER IN THE DEPARTMENT OF MYOBIOLOGY AND MIEWNOLOGY. I WORK WITH VACCINES THAT INCLUDE AID KNEE AND HER PES RELATED VECTORS.

DOCTOR A BALANCE DA.

I'M PRO FEARS OF MEDICINE AT THE UNIVERSITY OF PENNSYLVANIA J A PULMONARY AND CRITICAL CARE PHYSICIAN. I HAVE BEEN INVOLVED IN GENE THERAPY FOR OVER TEN YEARS. MOST OF THE CLINICAL EXPERIENCE IS WITH CANCER GENE THERAPY SPECIFICALLY FOCUSING ON ITEMERS OF THE LUNG, LUNG CANCERS AND THIEL THELIOMA.

I WORK AT THE MAYO CLINIC IN THE DEPARTMENT OF IMMUNE. MY DOCTOR IS IN CANCER GENE THERAPY AND MY AREAS ARE EXPERTISE ARE BIOVECTORS AND MOLECULAL MIEWN YO IMMUNE YO THERAPY FOR CANCER.

WE GO ON TO THE MINUTES OF THE JUNE 8-99 -- I FORGOT SOMETHING. DOCTOR ROSE IS GOING TO DISCUSS CONFLICT OF TRW US. DR. ROSE.

THANK YOU, DIANE. I WANT TO GO OVER. [PLEASE STAND BY, LOSS OF AUDIO. [

WITH AN INFORMATION YOUR PERSONAL, PROFESSION PROFESSION AND FINANCIAL INTERESTS USE TO ASSESS WHETHER ANY REAL OR APPARENT CONFLICTS OF INTEREST THAT CAN COMPROMISE YOUR ABILITY TO BE OBJECTIVE IN GIVING ADVICE DURING THE COMMITTEE MEETINGS. WE WAIVE CONFLICTS OF INTEREST FOR AGAIN GENERAL MATTERS BECAUSE WE BELIEVE YOUR ABILITY TO BE OBJECTIVE WILL NOT BE AFFECTED ABOUT YOUR INTERESTS IN SUCH MATTERS WE RELY IN A GREAT DEGREE ON YOU TO BE ATTEND DANT DURING MEETINGS TO THE POSSIBILITY. IF THIS HAPPENS, WE ASK YOU TO REDUCE YOURSELF FROM THE DISCUSSION AND -- RECUSE FROM THE DISCUSSION AND LEAVE THE ROOM AND YOU ARE REQUIRED TO RECUSE YOURSELF FROM PRELIMINARY PROTOCOL CAL REVIEW PROCESS IF YOU HAVE A REAL OR APPARENT CONFLICT OF INTEREST. IF YOU HAVE ANY QUESTIONS, PLEASE LET US KNOW OR TALK TO THE COMMITTEE MANAGEMENT OFFICE. THANK YOU.

NOW, WE WILL GO ON TO THE MINUTES OF THE JUNE MEETING. DR. HESLOP.

I WOULD LIKE TO [ INDISCERNIBLE ] I HAVE A COUPLE OF MINE 84 CHANGES AND WOULD LIKE TO MOVE THAT WITH THOSE CHANGES THE MINUTES BE ACCEPTED.

THANK YOU, DO I HAVE A MOTION TO ACCEPT THE MINUTES?

YOU.

SECOND?

ALL IN FAVOR? ANY -- OH, HAVE TO GO AROUND THE ROOM. I BETTER EDUCATE MYSELF AGAIN. MS. KWAN.

EYE.

DOCTOR VIAL AYE.

DOO LUCA. WARA, YES.

BOHN AYE. DEWHURST AND NOW WE WILL MOVE TOWARDS AN UPDATE ON THE RAC GENE TRANSFER CLINICAL TRIAL DESIGN WORKING GROUP WHICH DOCTOR DEMETS HAS LED FOR US OVER THE PAST I THINK IN EXCESS OF 6 MONTHS. AND WE HAVE THREE PRESENTATIONS THIS MORNING. THE FIRST IS BY DOCTOR DEMETS WHOM I BELIEVE WILL GIVE US AN OVERVIEW OF PROGRESS AND WHAT WE CAN EXPECT.

OH, YOU'RE AT THE MIKE. DR. DEMETS.

GOOD MORNING. THANK YOU. FOR OVER THE PAST PROBABLY CLOSER TO A YEAR OR 15 MONTHS, FROM THE TIME WE GOT OURSELVES FIRST FORMED AND ORGANIZED THE -- RAC DESIGN WORKING GROUP HAS BEEN FORMED AND THE MEMBERSHIP IN THIS GROUP IS MYSELF AS A COCHAIR ALONG WITH NANCY KING, A FORMER MEMBER OF THE RAC, KERRY KLEIN AND GARY LOW FROM THE RAC. SOME EXTERNAL TO 2308INGS. DAVE HAIRINGTON. SUSAN ELLENBERG. LAWRENCE FRIEDMAN. GREG PODSAKOFF CYNTHIA RAVING. MARCEL SALI VE AND JAMES WILLIAMS AND CHERYL MCDONALD AND ALEX FROM THE INSTITUTE. WE GOT TOGETHER BY CONFERENCE CALL IN NOVEMBER OF 2003 AND SORT OF ORGANIZED YOURSELVES. WE REALIZED WE NEEDED TO HAVE FACE TO FACE MEETINGS. WE MET IN FEBRUARY OF 2004 AND DECIDED TWO OR THREE THINGS THAT WE NEED TO ACCOMPLISH. FIRST, WE WANTED TO PREPARE A DRAFT OF SOME BASIC DESIGN PRINCIPLES THAT WE THOUGHT WOULD BE WORTH CONSIDERING FOR ANY PROTOCOL AND IN THE GENE TRANSFER AREA AND TWO, WE REALIZED THAT WE DIDN'T HAVE A LOT OF DATA ON OURSELVES HOW WE HAVE BEEN PERFORMING AS A RAC IN REVIEWING AND ALSO IN HOW THE CONSENT FORMS HAVE REFLECTED THE KINDS OF THINGS WE HAVE BEEN TALKING ABOUT. WE ALSO REALIZED IN ORDER TO ACHIEVE THAT WE WOULD NEED SOME HELP SO WE WERE FORTUNATE ENOUGH TO HAVE TWO SUMMER INTERNS WORKING WITH US. ONE OF WHOM YOU WILL HEAR IN A BIT, TIFFANY SCHARSCHMIDT, A SECOND YEAR MEDICAL STUDENT AND DANIEL LIPTON AN UNDER GRAD. NOW, THIS IS SORT OF OUR FIRST OFFICIAL PRELIMINARY REPORT. WHAT WE HAVE IS A DRAFT GUIDELINES WHICH I WILL COMMENT ON IN A BIT. TIFFANY AND UNDER THE DIRECTION OR SUPER VISION OF DR. LO HAS REVIEWED SOME OF THE REVIEW OF THE RAC AND DANIEL LIPTON AND CHERYL -- WORKED WITH CHERYL MCDONALD AND HAVE A REPORT ON REVIEW OF THE INFORMED CONSENTS. DANIEL IS AN UNDERGRAT WAIT ATTENDING CLASSES AS HE SHOULD AND CHERYL AS YOU NO IS NO LONGER WITH THE RAC. SO THAT I'M GOING TO GIVE A LITTLE OVERVIEW AND TERRY KWAN WILL GIVE US A SUMMARY. WE NEED TO INTEGRATE THE THREE REPORTS. WE HAVEN'T DONE THAT. I THINK WE NEED SOME SUBSTANTIAL STAFF SUPPORT AND JEN PUT FROM THE WORKING GROUP -- INPUT FROM THE WORKING GROUP BUT THAT IS SORT OF THE NEXT STEP. TO GO BACK TO THE DRAFT DESIGNS JUST FOR A FEW MINUTES. IT IS NOT POSSIBLE WITH THE VARIED DISEASES AND THE VARIED GOALS OF THE PROTOCOLS THAT WE SEE THAT YOU CAN COME UP WITH A SINGLE RECIPE. THIS IS THE DESIGN THAT YOU SHOULD FOLLOW. IT IS JUST NOT FOLLOW. BUT WHAT WE DID DECIDE IS THAT THERE ARE SOME PRINCIPLES OR ISSUES THAT YOU CAN CONSIDER. AND PROBABLY SHOULD INCLUDE THOSE KIND OF -- ADDRESS THOSE KIND OF ISSUES AND SO THE DRAFT DESIGN DOCUMENT ADDRESSES FIVE OR SIX OF THOSISH FEWS WHICH I WILL -- OF THOSE ISSUES WHICH I WILL OUTLINE. WE ARE YOU DOING THIS. WHAT IS THE RATIONALE. AND MORE IMPORTANTLY, WHAT IS THE GOAL. SPECIFICALLY WHAT IS THE GOAL OR OBJECTIVES OF THE PROTOCOL. AS WE HAVE SEEN AND WHETHER HEAR, SOMETIMES THAT IS NOT CLEAR. WHAT OUTCOMES, WHAT MEASURING STICK ARE YOU GOING USE TO ASSESS THAT OUTCOME. THESE ARE BASIC PRINCIPLES BUT I THINK IF YOU REFLECT ON SOME OF OUR DISCUSSIONS THAT IS NOT ALWAYS CLEAR. WHAT POPULATION ARE YOU GOING TO STUDY AND WHY THAT POPULATION. AND THEN AN ISSUE WHICH YOU HAVE HEARD ME COMMENT ON ON NUMEROUS OCCASIONS, THE BASIC DESIGN IS DESIGN STATISTICAL DESIGN AND SAMPLE SIZE JUSTIFICATION. WHAT ANALYSIS PLAN IS IN PLACE AND PARTICULARLY WHAT MONITORING PLAN IS IN PLACE. AND FINALLY, HOW WILL THE DATA THAT YOU ACCUMULATED BE USED IN DESIGNING THE NEXT TRIAL AND THE NEXT RESEARCH STEP. SO THIS DOCUMENT OUTLINES THOSE ISSUES AND GIVES SOME DISCUSSION OF WHAT -- WHAT -- WHY THEY WERE IMPORTANT, WHY THEY SHOULD BE ADDRESS BUD AGAIN YOU CANNOT PROVIDE A SINGLE ANSWER TO THESE THAT EVERYBODY CAN USE AND JUST SORT OF COPY AND PEACE. THAT IS NOT -- AND PASTE. THAT IS NOT POSSIBLE. THERE ARE SIMILARITIES OF COURSE, BUT THEY MAY NOT BE EXACTLY THE SAME. I'M SURE YOU CAN'T READ THIS BUT I JUST READ ONE IT IS A TABLE AND I LISTED ON IT THE REPORT. YOU HEARD ME COMMENT ON WHY AND BEFORE ME WHY FIVE PATIENTS. WHY NOT SIX. WHY NOT FOUR. SO THIS TABLE WHICH IS NOT LABELED, IF YOU HAD A SAMPLE SITE OF FIVE WHICH IS A NUMBER THAT WE HAVE HEARD BEFORE AS A SAMPLE SIZE AND ALL CONSISTS OF DIFFERENT SAMPLE SIZE JUST FOR COMPLETENESS AND OVER HERE IS A NUMBER OF EVENTS WITH THEED A VERTS EVENTS, SERIOUS ADVERSE EVENTS, A DEATH AND THEN WHAT I HAVE PROVIDED HERE IS THE CONFIDENCE. SO SUPPOSE YOU HAD A SAMPLE SIZE OF FIVE AND YOU SOUGHT NO SERIOUS ADVERSE EVENTS. WHAT HAVE YOU LEARNED. YO YOU HAVE LEARNED -- YOU HAVE A SUSPICION THAT THE EVENT RATE IS SOME WHERE BETWEEN 0 AND 50 SO WHEN YOU SAY THAT -- DOING SAFETY WITH FIVE PATIENTS, WELL, TO SOME EXTENT YOU ARE. YOU DON'T THINK BASED ON THAT EXPERIMENT OF FIVE PATIENTS AND NO SERIOUS EVENTS THAT THE EVENT RATE IS 75% BUT YOU COULD BE SOME WHERE BETWEEN 0 AND 50. YOU LEARN SOMETHING BUT YOU DON'T LEARN AS MUCH AS MAYBE IS IMPLIED IN SOME OF THE IX PAIR MRNTS. SO THIS DC EXPERIMENTS. SO THIS TABLE LAYS THAT OUT MORE CLEARLY AND HOPEFULLY IF WE GIVE IT A LABEL AND FANCY IT UP IN OUR REPORT IT WILL BE USEFUL AND GIVE FOLKS A CHANCE TO THINK ABOUT WHAT THEY ARE GOING TO ACHIEVE FROM THE STUDY THAT THEY ARE PRESENTING TO US OR NOT. SO THAT SURVEY AS I SAID A HIGH LEVEL OVERVIEW OF WHAT THE DRAFT REPORT. IT IS AVAILABLE IN DRAFT FORM. IT NEEDS WEAVING AND INTO THE OTHER TWO COMPONENTS. AND WORD SMITHING AND MADE MORE FRIENDLY BUT WE WILL RELY ON STAFF HELP TO GET US TO THAT STAGE. I'M NOW GOING TO TURN TO THE TWO SUMMER PROJECTS. ONE THAT DNA DAN LIPTON WAS PERSON WHO WENT TO THE CONSENT FORMS PROTOCOLS OVER THE PAST TWO YEARS WE SELECTED AND WENT BACK THAT FAR. THOUGHT THAT WAS A PRETTY GOOD SAMPLE. CHERYL MCDONALD WAS VERY INVOLVINGED AND JUST A BIT TERRY KWAN IS GOING TO DISCUSS IN A BRIEF WAY THE RESULTS OF THAT EXERCISE. SO DANIEL AND CHERYL REVIEWED I THINK IT WAS 43 PROTOCOLS OVER THE PAST TWO YEARS. AND THEY ASKED QUESTIONS ABOUT THE FOLLOWING 11 CONSENT FORM DESCRIPTIONS AND DID THESE CONSENT FORMS ADEQUATELY ADDRESS THESE ISSUES. THE QUESTIONS WERE WERE THE OB JEBLGTIVES OF THE STUDY CLEARLY EXPLAINED IN THE CONSENT FORM. WAS IT CLEAR WHAT THE RESEARCH THERAPY WAS AND WHAT THE VARIABLE STANDARD CARE THERAPY WAS. DID IT DESCRIBE THIS IS GENE TRANSFER PROCEDURE AND WHAT WAS INVOLVINGED AND WHAT WAS ENTAILED. IF IT WAS A DOSE ESCALATION OF SOME KIND WAS WHAT EXPLAINED ADEQUATELY. DID THEY TALK ABOUT POTENTIAL BEN AND IF SO HOW WAS IT EXPLAINED. DID THEY DISCUSS THE FUTURE RISKS AND DISCOMFORTS THERE MIGHT BE TO THE PROCEDURES. WHAT CONDITIONS ARE EXPLAINED THAT WOULD TERMINATE THE TRIAL EARLY. BE FINANCIAL COST IMPLICATIONS FOR PARTICIPATING. ARE THERE DISCUSSIONS OF PI FINANCIAL CONFLICTS. PHYSICIAN CONTACT INFORMATION, IF NECESSARY, AND HOW WITH EMERGENCY SITUATIONS -- WOULD EMERGENCY SITUATIONS BE DEALT WITH. AT ANY RATE THOSE WERE THE 11 QUESTIONS THAT CHERYL AND DANIEL PUT FORWARD AND -- WHEN THEY WENT THROUGH THESE 43 PROTOCOLS. I THINK I'M GOING TO ASK TERRY IF SHE CAN WEIGH IN HERE AND SORT OF SUMMARIZE THE RESULTS WHICH IN SOME WAYS ARE VERY SIMILAR AS A AS A RESULTS FOR EACH OF THESE 11 QUESTIONS.

RIGHT. I WOULD ASK THAT THE OTHER REAL ADVANTAGE OF HAVING -- GETTING A LIPTON -- OF HAVING DANIEL LIPTON WITH US IS THAT HE IS NOT A SCIENCE MAJOR. HE IS AN UNDERGRADUATE STUDENT, HIGH CALIBER, A POLITICAL SCIENCE MAJOR. AND THE ABILITY TO HAVE SOMEBODY THAT IS WELL ABOVE THE 8th GRADE READING LEVEL, WHICH WE SUGGEST FOR INFORMED CONSENT DOCUMENTS, WELL EDUCATED, BUT NOT DEEPLY INVOLVED IN THE SCIENCES GO OVER THESE INFORMED CONSENT DOCUMENTS WITH A FRESH EYE, I THINK WAS VERY ENLIGHTENING. I SHOULD ALSO NOTE THAT THE PROTOCOL SELECTED BECAUSE WE HAD TO SELECT OUT OF MORE THAN 600 PROTOCOLS SUBMITTED TO THE RAC OVER THE YEARS, THEY WERE CHOSEN FROM THOSE THAT WERE SUBMITTED FROM DECEMBER 2000 THROUGH 2003 AND THAT IS HOW WE CAME OUT WITH THE 44 PROTOCOLS OF WHICH THERE WERE 43 UNIQUE DOCUMENTS. THE OTHER NOTE IS THAT THESE PROTOCOLS WERE SUB SMITED PRIOR -- SUBMITTED PRIOR TO THE INFORMED CONSENT GUIDANCE BEING PUT UP ON THE WEB THAT WAS THE WORK DONE BY NANCY KING. SO THESE DO NOT HAVE THE ADVANTAGE OF HAVING THAT INSTRUMENT AVAILABLE TO THEM. OVERALL, WITH THE 11 QUESTIONS IN -- AND THIS IS JUST A ROUGH CUT -- THE INITIAL SUBMITTALS, THE RESULTS IN TERMS OF JUST A SATISFACTORY, UNDERSTANDABLE, REASONABLE, HOVERED AROUND 50% POINT. THEN THE OTHER PIECE OF NEWS IS DANIEL WAS ALSO ABLE TO REVIEW THE REVISED CONSENT DOCUMENTS THAT CAME IN FOR PROTOCOLS THAT ACTUALLY HAD SUBMITTED UNDER THE APPENDIX MC1 GUIDANCE THAT THEY HAD ACTUALLY BEGUN TO RECRUIT RESEARCH SUB SUBJECTS. AND AGAIN, THERE WERE NOT A LARGE NUMBER. AND THERE WAS -- THERE WERE IMPROVEMENTS IN ALL OF THE 11 AREAS. BUT THEY REALLY STILL WERE WELL BELOW WHAT SHOULD BE EXPECTED BY RESEARCH SUBJECTS IN TERMS OF UNDERSTANDABILITY. THEY PROBABLY WENT UP HOVERING AROUND THE 60-70% RANGE. NOW, THIS IS JUST THE ROUGH CUT AND WE WILL HAVE TO LOOK AT THE DETAILS AND WHAT HAS HELPED AND WHAT HA IS NOT HELPED SO I THINK ONE CONCLUSION WE CAN DRAW WAS CERTAINLY HELP AND GUIDANCE ON THE INFORMED CONSENT WAS NEEDED. AND SECONDLY, THAT FOLLOWING FULL REVIEW BY THE RAC, THERE WAS A RESULTING IMPROVEMENT. AND THIRD, WE COULD DO A LOT BETTER.

THANK YOU. THE NEXT STAR PROJECT I WANT -- SORT OF PROJECT I WANT TO SHARE WITH YOU IS THE ONE THAT WAS PUT TOGETHER WITH DR. LO. SHE HAS A NICE SLIDE PRESENTATION TO SHARE WITH YOU SO I WOULD LIKE TO INTRODUCE TIFFANY TO YOU AND WE WILL LOOK FORWARD TO HER SUMMARY OF HER SUMMER PROJECT.

GOOD MORNING. I JUST WANTED TO THANK YOU ALL AGAIN FOR WELCOMING ME BACK. IT WAS A PLEASURE WORKING WITH THE SUBCOMMITTEE AND DOING RESEARCH WITH THEM OVER THE SUMMER. JUST TO REMIND YOU MY NAME IS TIFFANY SHARK SMITS I'M CURRENTLY A -- SHACK SMITS. I WANTED TOING THANK AND ACKNOWLEDGE ALL THE PEOPLE OF GREAT HELP TO ME IN PUTTING THE PROJECT TOGETHER AND IN SUPPORTING ME ALONG THE WAY. THAT INCLUDES ALL THE MEMBERS OF THE SUBCOMMITTEE. IN PARTICULAR DR. DEMETS, DR. LO. DANIEL LIPTON WHO I CON CONSULTED WITH. VIA THE PHONE QUITE A LOT THIS SUMMER AS WELL AS DR. CHERYL MCDONALD. I WELCOME YOU STOP ME AT ANY POINT IF YOU HAVE CLARIFYING QUESTIONS BUT IF YOU WOULDN'T MIND HOLDING SUBSTANTIVE COMMENTS TO THE END JUST SO I CAN GET THROUGH THE PRESENTATION I APPRECIATE IT. JUST TO REMIND YOU SOME OF THE RESEARCH QUESTIONS THAT THE SUBCOMMITTEE WANT NEED TAKE A LOOK AT WERE A NUMBER. FIRSTLY, HOW FREQUENTLY RAC MEMBERS RAISED DESIGN KENS EITHER IF THE WRITTEN REVIEW OR IN THE PUBLIC DISCUSSION OF PROTOCOLS. AND WHICH WERE THE MOST COMMON DESIGNS CONCERNED THAT WERE MENTIONED. AND THEN SECONDLY OF THOSE WHICH ONES APPEAR IN THE FINAL RAC LETTER TO INVESTIGATORS INDICATING THAT THEY WERE NOT FULLY RESOLVED DURING THE COURSE OF PUBLIC DISCUSSION. I JUST WANTED TO FIRST MAYBE GIVE YOU A CHANCE TO TAKE A -- FREQUENTLY SOME OF THESE THINGS COME UP DURING RAC REVIEW SEEING THAT YOU ARE THE ONES RAISING THE ISSUES I HAVE SELECTED A NUMBER OF CATEGORIES HERE SO FIRST IF I COULD GET A SHOW OF HAPPENS FOR COMMENTS REGARDING BIOSTATISTICAL ANALYSIS. HOW MANY OF YOU THINK THOSE COME UP 25% OR LESS OF THE TIME? OKAY. AND ABOUT 50%? AND GREATER THAN 75%? OKAY. ISSUES OF DOES ESCALATION. AGAIN, LESS THAN 25 25%? OKAY. 50%? AND 75 OR GREATER PERCENT? THANKS. SELECTION OF SUBJECTS. LESS THAN 25%? 50%? ANDGREATER THAN 75%? GREAT. AND FINALLY, CONCERNS RELATED TO SELECTION OF SAFETY ENDPOINTS. LESS THAN 25%? 50%? AND 75%? GREAT. WELL,ION KEEP THOSE GUESSES IN MIND. I'LL GIVE YOU SOME IMMEDIATE FEEDBACK HERE TO SHOW YOU WHAT THE RESULTS WERE OF MY STUDTY. A NUMBER OF THESE WERE ACTUALLY SOME OF THE MORE FREQUENTLY RAISED ISSUES AND I WILL GO IN MORE DEPTH IN EXPLAINING WHAT THOSE ENTAILED. LIKE DANIEL I WAS LOOKING AT A SUSUB SET OF PROTOCOLS THAT WERE REVIEWED PUBLICLY, NOT JUST UB SUBMITTED TO THE RAC BUT CAME HERE FOR DISCUSSION BETWEEN DISEASE OF 2002 AND 2003. OF 2000 AND 2003. THOUGH TOTALED 44 IN ALL. TWO PAIRS JUNT WIND JOINT REVIEW BY THE COMMITTEE DUE TO SIMILARITIES. SO THAT LEFT ME WITH 43 DATE PA POINTS. THE OVERALL OF THE MAJORITY OF THE PROTOCOLS WERE EARLY STAGE DEVELOPMENT. 70% PHASE 1. A HANDFUL OF PHASE IS, PHASE 2 AND ONLY ONE PHASE ABOUT 2 . AS MIGHT BE EXPECTED OF PROTOCOLS THIS EARLY IF DEVELOPMENT A NUMBER OF THE CONCERNS RELATED TO SAFETY. THERE WERE SOME ABOUT DOING REGIMENS AND TO SOME EXTENT THERE WAS A QUESTION ABOUT EVIDENCE OF BIOACTIVITY. ALSO 82% OF THE PROTOCOLS EMPLOYED A DOSE ESCALATION DESIGN AND I CAN DISCUSS LATE WHARE SPECIFIC ISSUES THAT RAISES BUT IT IS OF NOTE HERE AS A COMMENT TO THE DESIGN OF THE PROTOCOLS. NOW, I'M SURE YOU ARE ALL VERY FAMILIAR WITH THE -- MEMBERS OF THE YD YENS I WANTED TO JUST TO REVIEW THE POINTS OF THE RAC REVIEW THAT WERE MOST PERTINENT TO THE STUDY THAT I WAS CONDUCTING. PROTOCOLS ARE FIRST SUBMITTED TO THE COMMITTEE AND THEN, OF COURSE, HAVE TO BE SELECTED SPECIFICALLY FOR PUBLIC REVIEW AT WHICH POINT A SUB SET OF MEMBERS, THREE OR FOUR WILL LOOK AT THEM CLOSELY AND SUBMIT WRITTEN COMMENTS TO THE INVESTIGATOR THAT THEY CAN RESPOND TO. BUT THE PROTOCOL WHEN THE INVESTIGATOR COMES HERE FOR POST DISCUSSION WHETHER WRITTEN CONCERNS ARE ADDRESSED BUT ALSO OTHER RAC MEMBERS ARE FREE TO ADD THEIR OWN COMMENTS. THOSE ISSUES THAT REMAIN OUTSTANDING AT THE END OF THE PUBLIC DISCUSSION ARE CONVEYED TO THE INVESTIGATOR AND THE FINAL RAC RECOMMENDATIONS. EACH OF THESE STEPS HAVE VERY CONVENIENTLY FOR ME A SORT OF WRITTEN [ INDISCERNIBLE ] IS I WAS ABLE TO LOOK AT WHAT THE REVIEW PROCESS WAS FOR THESE PROTOCOLS. BEFORE I WAS ABLE TO EVEN LAUNCH INTO THE PROJECT I HAD TO IDENTIFY WHAT DESIGN ISSUES WE WERE INTERESTED IN AND WITH THE HELP OF THE SUBCOMMITTEE AND REVIEW OF LITERATURE ABOUT TRIAL DESIGN I WAS ABLE TO PUT TOGETHER PERSPECTIVELY A DAY THAT CAPTURE FORM WITH KEY DESIGN ISSUES WHICH I THEN TESTED AND REFINED ON A SUBSET OF PROTOCOLS UNTIL I WAS COMFORTABLE THAT I HAD A CONSISTENT METHODOLOGY AND WAS IN FACT CAPTURING THE DESIGN ISSUES RAISED HERE BY THE RAC. WHAT I DID WAS ALSO GROUP THE ISSUES INTO MAJOR CATEGORIES WITH SPECIFIC SUBCATEGORIES SO THAT EACH INDIVIDUAL COMMENT WOULD THEN BE CATEGORIZED AS ONE OF THEM. AN EXAMPLE ISSUES OF DOES ESCALATION AS I MENTIONED EARLIER. MORE SPECIFIC CATEGORIES WIN THAT INCLUDED THE STARTING DOSE OR THE ESCALATION ALGORITHM. SO WHAT I DID IN OUR VEE VIEW OF THESE -- REVIEW OF THESE DOCUMENTS WAS AS I MENTIONED IDENTIFIED WHEN ISSUES ARE RAISED BY ONE OR MORE COMMITEE MEMBERS EITHER DURING THE WRITTEN REVIEW OR HERE DURING PUBLIC DISCUSSION AS WELL AS WHAT ISSUES REMAINED SOME WHAT UNRESOLVED IN THE FORM OF FINAL RAC RECOMMENDATIONS AND THE ASSIGNMENT TO THE CATEGORIES I MENTIONED WERE MADE BY MYSELF IN AGREEMENT WITH DR. LO. I WOULD LIKE TO SHARE WITH YOU NOW THE RESULTS. JUST TO REMIND YOU ANY NUMBERS OR PERCENTAGES COME OUT OF THE TOTAL ADDED UP FOR YOU, TOO. THIS SLIDE IN THE NEXT IS A SORT OF LIST IN DESCENDING ORDER OF THE MAJOR CATEGORIES. SEE LEXINGTON OF SUB JEBS -- SELECTION OF SUB GECKS WAS THE THE MOST FREQUENT FOLLOWED BY ISSUES RELATED TO DOSE ESCALATION, SELECTION OF SAFETY END POINTS BIO YO LOGIC OUTSOMES AND OVERALL STUDY DESIGN. SOME WHAT LESS FREQUENTLY RAISED WERE ISSUES PERTAINING TO THE DATA SAFETY MONITORING BOARD, SELECTION OF EFFICACY OUTCOMES. BIOSTATISTICAL ANALYSIS SPECIFICALLY OF ADVERSE EDEBTS OR EFFICACY OUTCOMES AND THEN IN ONLY ONE CASE COMMENTS RELATED TO DOSE OR PHASE TWO STUDY. AS I MENTIONED, THERE IS VERY SORT OF PARTICULAR SUBCATEGORIES THAT EACH OF THESE I WANTED TO JUST GO INTO A BIT IN DEPTH WITH YOU ABOUT THE MAJOR AND MOST FREQUENT CATEGORIES. STARTING WITH SELECTION OF SUBJECTS. COMMENTS BY THE COMMITTEE SOME OF THEM WERE JUST CLARIFYING COMMENTS OR REQUESTS FOR MORE SPECIFIC INCLUSION OR EX-CLUE N. NEARLY OR GREATER THAN HALF OF THE PROTOCOLS SOLICITED CHENS BY THE COMMITTEE ERATED TO SUBJECTS OF INCREASED RISK. ALSO THE APPROPRIATENESS OF THE SUBJECSUBJECT POPULATION WITH REGARD TO THE USE OF THERAPY AND THE USE OF OTHER THERAPIES CON COMMITTANTLY OR FOLLOWING THE GENE THERAPY INVOLVED IN THE PROTOCOL. AN SCAM OF A COMMENT -- AN EXAMPLE OF A COMMENT RELATE THE TO PATIENTS AT WICK THE PRESENCE OF IN FLAM TAR TOY TRACK CHANGES IN OTHER HUMAN STIEWDZ DID IS WERE TRANSGENESES ARE INJECTED INTO THE. ARE IN CLOSE PROXIM TOIT THE VENTTRY CALS. DOES ESCALATION. ISSUES RAISED HERE IN AGAIN MORE NAN THREE QUARTERS OF PROTOCOLS. SOME WERE CLARIFYING FOR REQUESTING MORE INFORMATION. BUT IN PARTICULAR, SPECIFIC KENTS RELATED TO THE TIME INTERVALS BETWEEN PATIENTS OR COHORTS AS WELL AS PARTICULAR COMMENTS RELATED TO THE ESCALATION ALOE GIG IMTHAT WAS BE -- ALGORITHM THAT WAS GENTLEMENING USED. GENERAL AND ALL THE COMMENTS OF DOSE ESCALATION ADVOCATED A MORE AAH SHUS APPROACH TO BE TAKE BIN THE INVESTIGATOR. FOR THE THIRD AND FOURTH CO-HARTS ONE PATIENT ENROLLED AT A TIME. STOP THE TRAIL IF THERE IS ONE PARTICIPANT DEATH DUE TO EXCESSIVE BLEEDING RATHER THAN APPLYING THE THREE DEATH RULE.

SELECTION OF SAFETY ENDPOINTS WAS RAISED WITH EQUAL FREFREQUENCY. SPECIFICALLY THE COMMITTEE RECOMMEND AID DICKSAL TEST -- ADDITIONAL TESTS, THEY WERE CONCERNED ABOUT ADVERSE EVENTS AND RECOMMENDED MODIFICATIONS OF THE PROTOCOL OTHER THAN ADDITIONAL ASSAY TO REDUCE THE RISK TO SUB GECKS SUB! UBJECTS. GENE EXPRESSION IN TISSUES THAT COME IN CONTACT WITH THE TRANSAGAIN POSES A POTENTIAL RISK TO CITIES TANS SIGHT OH VERY TIME. CON JUNKTY VOLE SCRAPINGS SHOULD BE TESTED.

BIOLOGIC OUTCOMES WAS AN ISSUE IN 64% OF THE PROTOCOLS REVIEWED. AGAIN, THE COMMITTEE WOULD OFTEN REQUEST FURTHER DISCUSSION FOR CONSIDERATION OF THE ISSUES HERE BUT WOULD ALSO FREQUENTLY RECOMMEND ADDITIONAL TESTS OR ASSAYS OR MODIFICATIONS OF THE PROTOCOL. A COMMENT RELATED TO AN ADDITIONAL ASSAY FOR A BIOLOGIC END POINT. PLACE KA AS WELL AS WHITE BLOOD CELLS SHOULD BE ANALYZED FOR THE PRESENCE OF VECTOR SEE AGAINSTS. ANY TUMORS THAT DEVELOP IN THE RESEARCH PARTICIPANTS SHOULD BE TESTED FOR THE PRESENCE OF VECTOR SEQUENCES. OVERALL STUDY DESIGN WAS THE FINAL CATEGORY. I WANT WANTED GO TO GO A BIT MORE INTK ELINDEPTH.

W THE SUBCATEGORIES WITHIN THIS INCLUDED COMMENTS RELATE ID TO THE RATIONALE OF THE SAMPLE SIZE SELECTION AS DR. DEMETS ALOU ALLUDED TO EARLIER. THE USE OF PLACEBO IN THE TRIAL AND APPROPRIATE PHASE DESIGNATION OF THE TRIAL. A COMMENT PERTAINING TO SAMPLE SIZE RATIONALE. WHY 12 PATIENTS? SAMPLE SIZE IS DETERMINED BY STATISTICAL CONSIDERATION, AFFORDABILITY, FEASIBILITY AND SO FORTH. IT SEEMS Q3 PUT SOME PRESIX ON WHAT WE WILL LEARN FROM THE NUMBER OF PATIENTS PAY IN THIS STUDY. WE SHOULD BEGIN TO QUANTIFY WHAT IT IS WE ARE GOING TO LEARN. AS I MENTIONED I ALSO EXAMINED THE FREQUENCY WITH WHICH ISSUES APPEARED IN THE FINAL RAC RECOMMENDATIONS. AND A NUMBER OF THE CATEGORIES WERE SIMILAR TO THOSE VERY FREQUENTLY RAISED IN THE REVIEW PROCESS. AGAIN, THESE NUMBERS ARE OUT OF 4 # 2 SO IN 50% OF PROTOCOLS THE COMMENTS PERTAINING TO THE SELECTION OF SUBJECTS AGAIN APPEARED IN FINAL RECOMMENDATIONS. ALSO FREQUENTLY SELECTION OF SAFETY END POINTS, BIOLOGIC OUTCOMES AND DOSE ESCALATIONS. SUBJECT SAFETY IS OBVIOUSLY, YOU KNOW, OF PREMIER IMPORTANCE IN ANY SORT OF PHASE ONE TRIAL AND IS OF GREAT INTEREST TO THIS COMMITTEE SINCE ITS INITIATION AND WITH THAT IN MIND I WANTED TO GO TRY AND LOOK AT THAT MORE SPECIFICALLY AS IT RELATES TO DESIGN ISSUES IN THE REVIEW PRO VEES. EC. DID I IT COMPOSING A VARIABLE OF 15 SUBCATEGORIES WITH EACH OF WHICH PERTAIN PARTICULARLY TO SUBJECT SAFETY. SOME THAT WERE INCLUDED WERE TIME INTERVALS BETWEEN CO-HORSTS. ADDITIONAL SAFETY ACE ASSAYS OR END POINTS. NEED FOR DSMB AND EXCLUSION OF SUBJECTS AT RISK. THIS IS 5 OF THE 15 THAT WERE INCLUDED THERE. PROTOCOL SOLICITED COMMENTS BELONGING TO ANY ONE OF THESE SUBCATEGORIES THAT WAS SUFFICIENT FOR IN CLIEWTION AND WHAT I FOUND WAS -- IN INCLUDION WHAT I FOUND WAS OVERWHELMING FREQUENCY IN 92% OF -- 93% OF PROTOCOLS THESE DID COME UP IN THE RAC REVIEW PROCESS AND 67% ANY APPEARED IN THE FINAL RAC LETTER. IN INTERPRETING THE RESULTS OF THE TRIALS OF COURSE, IT IS IMPORTANT TO TAKE A LOOK AT CERTAIN LIMITATIONS. WITH THE SMALL DATA SETS AND ALSO WITH CERTAIN UNKNOWNS, NOT ABLE TO -- [ INDISCERNIBLE ] FOLLOWING THE RAC REVIEW NOR RECOMMENDATIONS OF THE FDA OR LOCAL IRB. THERE WAS NO COMPARISON GROUP TO PHASE ONE AND PHASE TWO GENE PROTOCOLS OTHER THAN THERAPY TO ASSESS HOW COMMENTS TO DESIGN MIGHT BE DIFFERENT OR SIMILAR TO GENE THERAPY. I THINK HOWEVER, THERE ARE DEFINITELY CERTAIN LESSONS OR POSSIBLE NEXT STEPS THAT CAN BE TAKE FRNT RESULTS I DESCRIBED HERE. OB SEE JUSLY CONCERNS ABOUT THE DESIGN ARE COMMONLY RAISED AND ARE A FREQUENT PART OF THE RAC REVIEREVIEW PROCESS AND THEY FOCUS PARTICULARLY ON SAFETY. YOU KNOW, IDENTIFYING AND THE COCONFIRMING THIS FACT AS WELL AS BEING ABLE TO CHARACTERIZE A BIT BETTER WHAT THE DESIGN ISSUES ARE WILL HOPEFULLY FORM THE BASIS FOR THE DOCUMENT OR POINTS TO CONSIDER PUT TOGETHER BY THE SUBCOMMITTEE FOR THE BENEFIT OF INVESTIGATORS. AS I ALSO MENTIONED, THERE ARE MANCONCERNS THAT REMAIN OUTSTANDING AT THE END OF PUBLIC DISCUSSION AND TO A CERTAIN EXTENT THAT IS THE CASE BECAUSE THERE MAY NOT BE CLEAR ANSWER THAT'S RAC CAN IMMEDIATELY PROVIDE TO INVESTIGATORS. NOT ALWAYS BUT THERE ARE CERTAINLY ISSUES COMMON TO THE FIELD AS A WHOLE AND TOSS EXTENT THAT IS TRUE IT SEEMS THEY SHOULD BE A SUBJECT FOR FURTHER DISCUSSION AND CRABATIOCRABATION INVOLVING THE RAC -- CO-LABATION LOVING THE RAC. THE GOAL WOULD BE TO BOTH ADVANCE THE FIELD OF GENE THERAPY AS WELL, ASTIN TO PROTECT THE -- AS WELL, ASTIN TO PRO SECT THE SAFETY OF SUB GECKS IN ALL THESE TRIALS. I WOULD LIKE TO THANK YOU AGAIN AND WOULD PLEASE LIKE TO WELCOME ANY QUESTIONS AT THIS TIME.

ARE THERE QUESTIONS ON THE -- ARE THERE QUESTION RS ON THE RAC -- FROM THE RAC MEMBERS FOR TIFFANY OR ANY OF US THAT HAVE BEEN INVOLVED?

AS I SAID, OUR CHALLENGE IS TO TAKE A REPORT THAT DANIEL WROTE, WHICH IS PRETTY COMPLETE AND A REPORT THAT TIFFANY HAS JUST SHARED WITH YOU AND THE DRAFT THAT I AND MY STATISTICAL COLLEAGUES PUT TOGETHER DURING THE COURSE OF THE SPRING AND WEAVE THESE INTO A COMPREHENSIVE DOCUMENT. I THINK IT IS PRETTY CLEAR FROM WHAT WE HAVE READ AND LEARNED SO FAR THAT WE CAN IMPROVE. WE NEED TO IMPROVE. AND NICE TO HAVE A LITTLE QUANTITIATION AND JUST UNDERLINE OUR IMPRESSIONS BUT WE DO, I THINK, HAVE SOME DATE IT. IT IS LIMITED AS -- TIFFANY POINTED OUT TO US BUT I THINK WILL GIVE US A PLACE TO START AND SO THE CHALLENGE, OF COURSE, IS TO WAVING THIS ALL TOGETHER AS -- WEAVING THIS ALL TOGETHER AS A READABLE PRESENTABLE DOCUMENT. I THINK WE HAVE ACCOMPLISHED A LOT SINCE WE BEGAN THIS AS AN IDEA I THINK IT WAS ALMOST ONE YEAR AGO. SO AT ANY RATE, OTHER QUESTIONS? DIANE.

IF NOT, DOCTOR DEMETS THANK YOU AND OTHER MEMBERS OF THE SUB KITEEE FOR AN -- SUBCOMMITTEE FOR AN OUTSTANDING JOB AND TIFFFY I WANT TO THANK YOU IN PARTICULAR FOR THE HARD WORK YOU DID THIS SUMMER AND FOR BEING ABLE TO COME HERE TODAY AND PRESENT IT TO US AND A THANK YOU TO DAN LIPTON AS WELL FOR THE WORK THAT HE DID. NOW, DOCTOR DEMETS, WHAT IS THE NEXT STEP AND WHAT IS THE TIMELINE FOR IT?

I HAVE HAD AT LEAST ONE E-MAIL CORE CORRESPONDENCES WITH DR. ROSE. INITIALLY WE WERE GOING TO RELY ON CHERYL AND ALEX TO HELP US BRING THIS HOME AND SINCE THEY ARE NOT HERE TO HELP US I WROTE TO STEVE A FEW WEEKS AGO AND SAY WE NEED HELP. ALL OUR SCHEDULES ARE SUCH THAT IT WILL BE DIFFICULT FOR US TO DO THIS WITHOUT A LITTLE STAFF HELP AND SO WE HAD NOT RESOLVED THAT ISSUE. I'M SURE THAT AS PART OF THE RECRUITMENT PROCESS BUT ANYWAY, WE DON'T HAVE PEOPLE EYE IDENTIFIED TO DO IT BUT OUR PLAN IS CERTAINLY OVER THE FALL TO TAKE THE DOCUMENTS AND PUT TOGETHER IN A WAY THAT THEY ARE COHESIVE AND COHEIR RENT. I DON'T KNOW HOW MUCH PROGRESS WE WILL MAKE UNTIL WE CAN IDENTIFY WHEN WE HAVE SOME HELP BUT CLEARLY WE WOULD LIKE TO GET THIS COMPLETED OVER THE COURSE OF THE FALL. I MAY BE ABLE WITH NANCY KING'S HELP TO GET SOME OF THAT DONE BUT AGAIN, IT IS TIME LIMITED, OF COURSE.

COMPLETELY GUNNED UNDERSTOOD.

AND THEN IF WE GET A DRAFT WE WANT TO CIRCULATE IT TO THE WORKING GROUP TO GET THEIR INPUT. THAT HAS NOT YET HAPPENED. BUT THEN TO THE RAC ITSELF FOR COMMENTS.

WILL IT BE POSSIBLE FOR DAN LIPTON TO CONTINUE TO PARTICIPATE ACTIVELY IN THE SUBCOMMITTEE? THEY PUT IN SO MUCH WORK TO DATE.

AND TIFFANY.

I CAN'T SPEAK FOR THEM. PERHAPS TIFFANY CAN COMMENT. OB SEOUSLY THEY ARE -- OBVIOUSLY THEY ARE BUSY STUDENTS. I'M SURE WE CAN GET -- I THINK WE CAN GET SOME OF THEIR TIME AS -- THEY'RE NOT GOING TO BE THE WRITERS AND DRAFTERS BUT MAYBE THEY CAN BE THE REVIEWERS OF SOME OF THE WORK WE DO.

DAVID, I HAVE A QUICK QUESTION. IN LOOKING AT THE CATEGORIES AND THE BIOSTATISTICAL DESIGN ISSUES AND SOME OF THE THINGS THAT WERE BROUGHT UP, HAVE YOU FORM LATED ANY SORT OF GENERAL OVERALL FEELINGS ABOUT IN PHASE I TRIALS IN GENE TRANSFER IS THERE AN OVERARCHING IDEA GENERATING IN YOUR MIND WITH RESPECT TO NUMBERS AND HOW PHASE 1 COULD BE DONE EFFICIENTLY TO PROVIDE AS MUCH USEFUL INFORMATION? IS THERE ANYTHING THAT SORT OF -- YOU HAVE BEEN BRINGING THIS UP FOR AWHILE. YOU HAVE THE DATA NOW TO LOOK AT IT. HAS IT LED YOUR THINKING ANY WAR THAT YOU CARE TO -- ANY WAR THAT YOU CARE TO SHARE WITH US?

WELL, I THINK THAT SOME OF THE TRIALS WE HAVE SEEN THE -- YOU KNOW, THE CLASSICAL PHASE ONE DOSE ESCALATION PROBABLY WORKS WITH SOME VARIATION. FOR OTHERS, AS WE HAVE SEEN, IT IS JUST -- IT IS JUST NOT USEFUL OR APPROPRIATE OREL OR RELEVANT. BUT ALL PHASE ONES HAVE THE SAME CHARACTERISTIC. YOU LEARN A LITTLE BIT AND YOU GO ON TO THE NEXT STEP. WHAT PART OF WHAT I WAS TRYING TO ACCOMPLISH IS TO REMIND PEOPLE OR GET THEM TO THINK THAT YOU LEARN SOMETHING BUT YOU DON'T LEARN EVERYTHING SO YOU SAY WE'RE GOING TO STUDY SAFETY IN THIS STU DID I, THAT IS TRUE, BUT IN IS VERY LIMITED WAY. THAT WOULD BE A STEP FORWARD, I THINK, JUST TO GET THAT APPRECIATION. BUT I BELIEVE THAT THE WHOLE PHASE ONE DESIGN FIELD WILL NEED TO BE EVALUATED AS WE GET FURTHER AND FURTHER INTO GENE TRANSFER AND IT WILL PROBABLY BE METHODOLOGIES SPECIFIC, PERHAPS DISEASE SPECIFIC. THERE WILL BE SOME COMMONALITY. WE AREN'T QUITE THERE YET BUT IF WE BEGIN TO REALIZE THAT WE CAN'T JUST COPY AND PASTE WE WILL PROBABLY BE BETTER OFF AND I CAN'T TELL YOU, YOU KNOW, HOW COMPLICATED THAT IS GOING TO BE. BUT I DO BELIEVE WE NEED TO BEGIN THAT PROCESS IN THINKING THROUGH THE FIRST PRINCIPLES WHAT DO WE WANT TO LEARN, WHAT DO WE LEARN AND HOW IT WILL BE MOST EFFICIENT AND IT WILL PROBABLY TAKE SOME MORE IS A TAISTATISTICAL THINKING. THAT IS WHERE I SEE US IS TO TRY TO GET THE PROBLEM STATED AND GET INTEREST IN IT AND FOR SOME AREA IS WE'RE PROBABLY GOING TO BE OKAY SOME AREAS WE HAVE TO START OVER THE PRINCIPLE IS.

IN THE GROUPS THAT NORMALLY THINK ABOUT THIS WHAT WE CALL THE CLINICAL TRIAL DESIGN SPECIALITIES WHAT SORT OF DIALOGUE IS DOING ON IN THAT COMMUNITY ABOUT NOT ONLY GENE TRANSFER BUT LOOKING AT TRIAL DESIGN IN GENERAL GOING FORWARD, THINGS THAT CHANGE WITH RESFOAKT MONITORING AND THINGS THAT CHANGE WITH RESPECT TO SOME OF THE STATISTICAL METHODS OF WHICH THIS ARE NOW MORE BEING USED IN ANALYSIS OF THE TRIALS? HOW IS THIS PLAYING OUT IN THE COMMUNITY IN GENERAL WITH RESPECT TO TRIAL DESIGN THAT YOU HAVE SEEN? YOU SIT ON A LOT OF BOARDS. YOU CONSULT WITH A LOT. HAVE YOU SEEN ANY AND WHERE -- IN YOUR VISION TO YOU THINK THE COMMUNITY IS MOVING?

WELL, THERE TENDS TO BE CLUSTERS OF ACTIVITY IN BIOSTATISTICS AS IN ANY OTHER FIELD. CERTAINLY THE '70S WAS AN ERA WHERE WE LEARNED HOW TO ANALYZE SUSURVIVAL DATE THAT DATA IN GREAT DETAIL. TEASE THESE DAYS THE BIOSTATISTICAL COMMUNITY IS GENTLEMEN INTO GENOMICS AND SEQUENCING AND MORE AT THE BASIC LEVEL. I DON'T THINK MANY -- WHEN YOU GO TO THE NATIONAL MEETINGS YOU DON'T HEAR OR SEE TOO MANY SESSION RS OR PAPERS CHIRCHG THINKING ABOUT IN THE EARLY PHASE GENE TRANSFER. I DON'T THINK IT IS CLEAR ON THE HORIZON YET. ONE OF THE THINGS THAT MAY COME OUT OF OUR DISCUSSIONS OR RECOMMENDATIONS IS TO FIBBED WAYS TO MAKE THIS -- FIND WAYS TO MAKE THIS VISIBLE TO THAT COMMUNITY AND GET THEM TO THINK ABOUT IT AND ALSO FOR THOSE DOING GENE TRANSFER AS THEY BEGIN TO SEEK HELP AND COUNSEL THEN THEY WILL WE A LYZE THAT OKAY, WE CAN APPLY SOME OF THE THINGS WE KNOW BUT TO SOME WE DON'T KNOW IT WILL BEGIN TO GERMINATE NEW THINKING ABOUT IT IN. RIGHT NOW IT IS NOT A HOT TOPIC IN THE FIELD. WE NEED TO FIND WAYS TO GET TO THINK ABOUT IT AND THE WHOLE FIELD OF PHASE ONE AND PHASE TWO IS OLD AND THOUGHT ABOUT A LOT AND THERE ARE DESIGNS OUT THERE THAT, FOR EXAMPLE, FIGURE OUT HOW TO SPEED UP THE DOSE ESCALATION IN A FASTER WAY BUT STILL BE CONSCIOUS AND SO WORK IN THAT AREA. AND SO PEOPLE HAVE BEEN THINKING ABOUT THAT BUT EVEN THAT FIELD IS NOT PROBABLY AS RICH AND DEEP IT IS A SHOULD HAVE BEEN OUTSIDE OF GENE TRANSFER SO NOW WHEN WE TALK ABOUT GENE TRANSFER WE HAVE TO GET IN EVEN FURTHER. I THINK WE CAN DO A LOT TO STIM ULATE THE COMMUNITY.

A GENERAL COMMENT. I WOULD LIKE TO SEE MAYBE A LITTLE MORE EMPHASIS OR CONSIDERATIONS OF ISSUES RELATED TO RECOMBINANT DNA, RECOMBINANT DNA, IN OTHER WORDS, THE STRUCTURE AND CONSEQUENCES OF THE RECOMBINANT DNA THAT IS BEING ADMINISTERED IN THE FIRST THIRD OF APPENDIX M THE SECTION DEVOTED TO THAT AND I THINK WE OFTEN -- WITH SOME OF THOSE ISSUES WE OFTEN PUNT TO THE FDA OR SUB CONSCIOUSLY PUNT TO THE FDA OH, THEY'RE GOING TO LOOK AT IT BUT WE'RE THE RECOMBINANT DNA ADVISORY COMMITTEE AND I THINK MAYBE WE SHOULD LOOK MORE AT THOSE SORTS OF ISSUES IN REVIEWS AND REVIEWS OF REVIEWS. THE -- WHEN I THINK BACK TO THE TWO EVENTS THAT WE TALK ABOUT OR BOTH RECOMBINANT DNA EVENTS OR INVOLVED RECOMBINANT DNA EVENTS THE GAL SINGER ISSUES WITH THE VECTORS THERE WERE RECOMBINANT DNA ISSUES THERE AND ALSO IN THE SIDS THE RECOMBINANT DNA ISSUES THERE, SO I -- I WOULD JUST LIKE TO PUT IN A LITTLE PLUG FOR MORE CONSIDERATION OF THE STRUCTURE THE ONSEQUENCES.

I'M MISSING -- MS. KWAN.

YES, I THINK THAT OUR GOAL WOULD HAVE BEEN NICE TO REALLY PRODUCE A GUIDANCE DOCUMENT TO BE PUT UP ON THE WEBSITE THE WAY WE DID FOR INFORMED CONSENT BUT JUST OBSERVING THE CONVERSATIONS WHEN WE MET AS A WORKING GROUP AND THERE WERE A NUMBER OF OTHER BIOSTATISTICKIANS IN THE ROOM I THINK THAT WOULD BE HARD TO DO BECAUSE AS DR. DEMETS HAS POINTED OUT, WHAT TO RECOMMEND HAS NOT BEEN PRODUCED BY THE BIOSTATISTICS COMMUNITY. AND REALLY HIS SUGGESTION THAT WE NEED TO SOMEHOW LIGHT A FIRE UNDER THE BIOSTATICE TIGS AND SAY SOMETHING NEEDS TO START THINKING ABOUT THIS AND REE CREATE SOME MODELS. THAT SEEMS TO BE. [ INAUDIBLE ] BECAUSE MOST OF THE MODELS BEING USED WERE LIFTED FROM HIV OR LIFTED FROM CANCER RESEARCH. WHICH FOR NOW KIND OF WORES TO THE EXTENT THAT IT IS NOT PARTICULARLY WELL FITTING SHOE BUT THAT IS ALL THAT PEOPLE HAVE. THE OTHER ISSUE THAT CAME UP AND THIS IS PROBABLY MORE COMMON IN -- IN THE DRUG RELATED FIELDS IS SOME OF THE TARGETED RESEARCH SUBJECTS ARE SO FEW IN NUMBER THAT YOU CAN CREATE A BEAUTIFUL DESIGN AND THEN YOU WOULD NEVER BE ABLE TO FIND ENOUGH PEOPLE TO RECUTE INTO IT. SO THAT SUGGESTED TO ME AS A LAY PERSON SITTING IN ON THE CONVERSATION THAT BEFORE WE CAN RECOMMEND THINGS TO PEOPLE SOMEBODY HAS TO IN CENT ONE TO RECOMMEND.

ONE ENCOURAGING COMMENTS. RESPONDED. THEY DON'T ALWAYS HAVE NICE SIMPLE ELOQUENT ANSWERS BUT THEY DO PAY ATTENTION AND THEY DO RESPOND TO THIS THAT IF WE LIGHT THE FIRE I THINK THEY WILL COME AND WORK ON DRK WORK TON BUT RIGHT NOW THEY ARE JUST NOT SUFFICIENTLY AWARE IN SUFFICIENT NUMBERS.

THANK YOU VERY MUCH, DR. DELETS AND THE GROUP. WE ARE GOING TO MOVE ON NOW TO THE DATA MANAGEMENT REPORT. DOCTOR SIMARI WILL BEGIN.

FIRST LIKE TO REVIEW THE FULL REVIEW OF THE HUMAN GENE TRANSFER TRIALS THAT WERE SUBMITTED FOR THIS MEETING. THERE WERE 20 SUBMISSION PS TOTAL. 19 WERE NOT SELECTED FOR INDEPTH REVIEW AND PUBLIC DISCUSSION. ONE WILL BE DISCUSSED LATER THIS MORNING PROTOCOL 669. A GENERAL EVERVIEW OF THOSE NOT SELECTED 13 OF THE TRIALS NOT SELECTED WERE FOR CANCER. THREE OF THESE ARE VACCINE STUDIES AND NONTHERAPEUTIC. ONE IS FOR DIABETIC INURE ON PATHY AND INFECTIOUS DISEASE AND PERIPHERAL ARTERY DISEASE. FOUR ADENOVIRAL AND TWO POSITION AND ONE EMPLOYED A REST FREE THROW VIRAL AND RUN EMPLOYED RNA TRANSFER AND ONE USED AN ADENOASSOCIATED AND ONE HUGHES USED A HER PES VIRUS VECTOR. 20 TRIALS SUBMIED IN THE QUARTER AND ONE SELECTED FOR PUBLIC REVIEW. IN TERMS OF ADVERSE EVENTS IT HAS BEEN A TYPICALLY BUSY QUARTER FOR ADVERSE EVENTS AND I APPRECIATE WE ALL APPRECIATE THE OBA STAFF FOR PUTTING TOGETHER THE REPORT AND REVIEW. THERE WERE A TOTAL OF 168SAEs REPORTED TO THE OBA WITHIN THIS QUARTER. OF THOSE 25 WERE A EVENTS AND OF THE A EVENTS 12 WERE NEW OR INITIAL REPORTS AND DATA MANAGEMENT TEAM REVIEWED EACH OF THE INITIAL REPORTS OF THE A EVENTS IN SOME DETAIL. SOME THAT WE ARE FOLLOWING. SOME OF WHICH LOOKING INTO SIMILAR EVENTS IN THE PROTOCOLS. THERE WAS ONE THAT WE THOUGHT MIGHT BE NOTED IN THE PUBLIC CONTEXT. AND THAT INVOLVED PROTOCOL NUMBER 530. THE TITLE OF THAT PROTOCOL IS IN RANDOMIZED PHASE TWO SKID OF /11 RATE BIOLOGIC WITH 5FU AND RADIATION TREATMENT FOR LOCALLY ADVANCED PANCREATIC CANCER AND THERE WAS A -- AN EVENT IN AN INDIVIDUAL THAT DEVELOPED PANCREATITIS FIVE DAYS FOLLOWING DELIVERY OF THE STUDY AGENT THAT WAS -- THAT RESOLVED BUT WAS DEEMED PROBABLY RELATED TO THE ADMINISTRATION PROCEDURE OR THE -- OR THE -- OR THE AGENT. IN THE SHORT PERIOD OF TIME FOLLOWING THAT -- THAT ANNOUNCEMENT THOOR DISCLOSURE, THERE WERE TWO OTHER EVENTS. ONE ANOTHER ANOTHER CLINICAL PANCREATITIS THAT FOLLOWED ONE DAY FOLLOWING DELIVERY OF THE STUDY AGENT AND THERE WAS -- THAT ALSO WAS SELF-RESOLVING AND THERE WAS ALSO AN EPISODE OF BILLARY SEM CERUS AND SAY SOMASOME MYKOEL LOAN ENGITES. WE RACED IN BECAUSE OF THE TEMPORAL RELATIONSHIP TO THE STUDY OF THE DRUG ADMINISTRATION AS WELL AS IT BEING BOTH DEEMED POSSIBLY OR PROBABLY RELATED TO THE AGENT AND SOMETHING THAT WE WILL CONTINUE TO FOLLOW. I THINK OF THE NEW ADVERSE EVENTS THAT WAS THE ONLY ONE THAT WE THOUGHT WAS OF INTEREST IN A GENERAL SENSE.

THANK YOU.

THANK YOU, DR. SIMARI. EXCUSE ME. DR. LO.

CAN I ASK A FOLLOW-UP QUESTION?

SURE.

AFTER NOTING THE THREE POSSIBLE AND PROBABLE EPISODE T PANCREATITIS DO YOU KNOW WHETHER THE INVESTIGATOR MODIFIED THE INFORMED CONSENT FORM AFTERWARDS TO NOTE FIE FUTURE PRO SPECTIVE ENROLLEES THAT THIS WAS A POSSIBLE ADVERSE EVENT RELATED TO THE GENE TRANSFER?

AS PART OF THE DATE FA MANAGEMENT REVIEW WE DO GET THAT DATA AND AS FAR AS I'M AWARE THAT HAS NOT BEEN DONE. PAN CREE YAO TIGHTS WAS LIFT THE AS A -- PANCREA.

I.

GOOD MORNING.

GOOD MORNING.

GOOD MORNING. ALL THE ADVERSE EVENTS THAT COME IN TO OBA WHEN WE REVIEW THE AMENDMENTS AS FAR AS THE DATA MANAGEMENT IF SOMETHING COMES IN THAT WOULD BE NOTED AT THAT POINT. THESE EVENTS CAME IN AFTER THE CUTOFF DATE FOR THE STATISTICAL ANALYSIS OF THE AEs BUT WE THOUGHT THEY WERE WORTH MENTIONING AT THIS POINT SO I WILL LOOK FOR THAT FOR THE NEXT MEETING.

THANK YOU.

OTHER COMMENTS FROM THE PUBLIC OR FROM THE RAC? ALL RIGHT. DURING THIS CYCLE 97 97 AMEND AND 10 RESPONSES TO APPENDIX M WERE RECEIVED. OF THE 97, 40 REPRESENTED CHANGES IN SITES OR IN PRINCIPAL INVESTIGATORS. WE SELECTED FOUR TO PRESENT PUBLICLY. THE FIRST IS PROTOCOL 4 # 53 AN OPEN LABEL TWO PART DOSE ESCALATION STUDY TO DETERMINE THE TOLL LEERABILITY OF INTERFUHR RAN BETA GENE TRANSFER IN THE TREATMENT OF RECURRENT OR PRO GUESSIVE GLIO GLASS TOE MA AND TIFFANY MENTIONED THIS PARTICULAR PROTOCOL DURING HER PRESENTATION. THE PROTOCOL FTC CLOSED PRIOR TO ACCRUAL BY THE SPONSOR BIOGEN DUE TO THE RESTRICTIVE POPULATION OF DPLEE GLIOMA PATIENTS THAT DO NOT HAVE TUMORS. BECAUSE OF AN SAE RELATED TO AN INFLAMMATORY RESPONSE IN ANOTHER PROTOCOL THE SAE AND THE SECOND PROTOCOL WAS RELATED TO AN INFLAMMATORY RESPONSE IN THE VENICE VENICE VENICE VENTRICULAR REGION RAC RECOMMENDED THAT NOT BE ACCRUED IN THE TUMOR WAS ADJACENT TO THE VENICETY CAL. FOLLOWING THAT RECOMMENDATION THE IN INCLUDION EXCLUSION WERE MODIFIED BY THE INVESTIGATORS AND SUBSEQUENTLY AS I STATED THE PROTOCOL WAS CLOSED BECAUSE OF DIFFICULTY ACCRUING. THE SECOND PROTOCOL PROTOCOL 468 INVOLVES GENE TRANSFER TO PROMOTE ANGIOGENESIS IN PATIENTS WITH ADVANCED HEART FAILURE. THE PROTOCOL -- THE PRINCIPAL INVESTIGATOR REQUESTED OF THE FDA REMOVAL OF THE 15 YEAR FOLLOW-UP. THEY REQUESTED THAT ACTIVE ASSESSMENTS IN THE POST ADMINISTRATION FOLLOW-UP PERIOD THE TO PROTOCOLS WERE PLACED ON CLINICAL HOLD FOLLOWING THE REPORT OF TWO WITH LIEU LEUKEMIA AFTER GENE TRANSFER IN FRANCE. THE TWO U.S. PROTOCOLS NOW ARE REOPENED AND THIS REOPENING FOLLOWED AS WE HAVE DISCUSSED THOROUGHLY FURTHER FOLLOW-UP AND UNDERSTANDING OF OF THE FRENCH EX-SKID EXPERIENCE. AND I'M GOING TO JUST BRIEFLY SUMMARIZE THE TWO PROTOCOLS FOR YOU. PROTOCOL 494 GENE FRANCE FEAR OF THE GENE GDNA INTO CD # 34 POSITIVE AMOUNT OF POETIC CELLS OF INFANTS OR CHILDREN WITH EX-LINK SKID. THE SUBMITTED PROPOSAL REQUESTS THAT THE UNDERLYING PREMISE FOR GENE THERAPY AS AN AIL AIL TERN TAIV TO HAPPEN LOW IDENTICAL TRANSPLANT NATIONAL UNDERLYING PREMISE BE MEDICAL INDICATION RATHER THAN AGE RESTRICTION TO INFANTS LESS THAN -- OR GREATER THAN I'M SORRY, SIX MONTHS OF AGE ZWLA IS THAT EVIDENCE OF ACTIVE INFECTION OR OTHER HIGH RISK CLINICAL FEATURES THAT WOULD EITHER PREVENT THE INFANT FROM UNDERGOING A HAPLO IDENTICAL TRANSPLANT OR WOULD SIGNIFICANTLY INCREASE THE RICK OF THE HAPLO TRANSPLANT TO THIS INFANT BE UTILIZED RATHER THAN AGE AS THE IN INCLUDION CRITERIA. THAT IS THE STRUCTURE OF THE PROTOCOL AS IT MOVES FORWARD. PROTOCOL 516. WHICH INVOLVES EX-VEE YO RETROVIRAL GENE TRANSFER FOR TREATMENT OF EX-LINK SKID THE FDA CLINICAL HOLD WAS REMOVED AND THE FIRST SUBJECT WAS ENROLLED IN JANUARY 2004. GENE TRANSFER OCCURRED ON JANUARY 302004. APPARENTLY THE CHILD LEE PAINED STABLE. -- REMAINED STABLE. GENE MARKINGS SHOWED 0.5% T-CELLS MARKED 5 5 MONTHS POST GENE TRANSFER. THE FOURTH TROAT KOEL IS 588 -- PROTOCOL IS 588. A PHASE ONE STUDY OF INTRAARE AARE TICK KRALL RETAINING THE RECEPTOR FC FUSION GENE IN UHM TOYED ARTHRITIS. THIS WAS THE FIRST PROTOCOL INVOLVING JOINT INJECTION REVIEWED BY THE RAC. IT WAS REVIEWED IN THE SEPTEMBER '03 MEETING. TWO AMENDMENTS WERE RECEIVED. THE FDA ALLOWED THE PROTOCOL TO PROCEED AS OF JANUARY 7, 2004. AND THE PROTOCOL WAS INITIATED IN MARCH OF 2004 WITH THE FIRST SUBJECT ENROLLED ON MARCH 16, 2004. AND I PRESENT THIS TO YOU AS A REFLECTION OF THE RAPIDITY OF THE MOVEMENT OF PROTOCOLS ONCE THEY ARE REVIEWED BY THE RAC AND THE SKI MA IN PLACE FOR REVIEW OF AMENDMENTS AS WELL AS THE COORD COORDINATION BETWEEN THE RAC AND THE FDA. THANK YOU VERY MUCH. IF THERE ARE QUESTIONS OR COMMENTS?

DOCTOR SIMARI.

THE QUESTION THAT WAS RAISED ABOUT FOLLOW-UP, I KNOW WE CAN'T TALK ABOUT THE INDIVIDUAL TRIALS, BUT IS THERE SOMETHING -- IS THERE -- THERE ARE CHANGES AT THE FDA REGARDING LONG-TERM FOLLOW-UP THAT WOULD BE OF GENERAL INTEREST TO THE GENERAL COMMUNITY?

WHAT I CAN SAY RIGHT NOW IS AS YOU KNOW, WE HAD THE WORKSHIP IN JUNE ON LONG-TERM FOLLOW-UP AND THE FDA PAYS CLOSE ATTENTION TO WHAT INVESTIGATOR SPONSORS SAID TO US. WE ARE CURRENTLY DISCUSSING THIS INTERNALLY. WE WILL MOST LIKELY WRITE A GUIDANCE IN THE FUTURE. I MEAN I CAN'T REALLY GO INTO ANY DETAILS BUT AT PRESENT OUR POLICY, OUR CURRENT POLICY STILL STANDS THAPD IS -- AND THAT IS THAT WE REQUIRE ALL OF OUR GENE TRANSFER PROTOCOL GENE TRANSFE TOHAVE -- SUBMIT A PROTOCOL FOR LONG-TERM FOLLOW-UP FOR 15 YEARS. AND UNTIL, YOU KNOW, WE HAVE A GUIDANCE OUT THAT DIFFERS, THAT IS WHAT WE CURRENTLY HAVE IN PLACE.

THANK YOU VERY MUCH FOR THE CLARIFICATION FOR US. MRS. KWAN.

THIS IS PROBABLY NOT AS MUCH INTEREST TO THE SIGH ENFIF PARTICULAR MEMBERS WITH YOU -- SH D. SIGH ENTIFF FICK MEMBERS BUT TO TRY TO PLAY CONTEXT TO IT WE HAD EXTENSIVE DISCUSSIONS ABOUT WHAT HAPPENED TO THE TWO KIDS IN THE SKID TRIALS WAY BACK WHEN. I WOULD BE INTERESTED TO KNOW, THEY DEVELOPED LIEU LEUKEMIA. THEY WERE TREAT FORD LEUKEMIA, WHAT IS THEIR PRESENT CONDITION AND HOW MIGHT THAT INFORM OUR DECISION-MAKING IN THE FUTURE AS IT RELATES TO IF THEY HADN'T BEEN TREATED AT ALL WHAT CONDITION MIGHT THEY BE IN.

TERRY, WE ARE ACTUALLY IN THE PROCESS OF TRYING TO PUT TOGETHER AN UPDATE ON THE EX-SKID TRIALS FOR THE DELAWARE RAC MEETING WHERE WE WANT TO BE INVITING THE INVESTIGATORS AND OTHER PARTIES WHO WERE INVOLVED IN THE TRIALS IN HAPLO IDENTICAL BONE MARROW TRANSPLANTATION TO COME AND GIVE AN UPDATE TO THE RAC AS TO WHAT THE CONDITIONS OF THOSE TWO PARTICULAR CHILDREN AS WELL AS THE FIELD, THE INTEGRATION ANALYSIS, THAT HAS BEEN GOING ON AND WHERE THINGS STAND IN GENERAL. SO WE ARE MOVING FORWARD WITH THAT. AS PART OF HOPEFULLY THE DECEMBER RAC MEETING SCHEDULING, YOU KNOW, OF GETTING PEOPLE TO COME IS OBVIOUSLY SOMETHING WE ARE WORKING ON. WE ARE AWARE OF THAT AND WE ACTUALLY -- PART OF THAT IS FOR THE RAC TO REVISIT THE RECOMMENDATIONS THAT CAME OUT OF THE FEBRUARY 2003 MEETING IN LIGHT OF THE NEW DATA IN LIGHT OF THE HAPLO IDENTICAL DATA.

JUST FOR THE RECORD, OUR ANALOGIES -- OUR KNOWLEDGE IS THAT THOSE TWO CHILDREN ARE FIND FINE.

THAT IS MY UNDERSTANDING AS WELL.

ALL RIGHT. OTHER QUESTIONS? THEN I JUST HAVE ONE FINAL COMMENT BEFORE WE MOVE INTO PROTOCOL REVIEW. BEGINNING ON MONDAY, IS A SYMPOSIUM WAS HELD HER SPONSORED BY THE RAC AND BY OBA REGARDING SAFETY CONSIDERATIONS IN RECOMBINANT DNA WITH PATHOGENIC RYPATHOGEN -- RESEARCH WITH PATHOGENIC VUDZ. IRUS. I THANK ALL OF THE MEMBERS MO HAVE PARTICIPATE THE ACTIVELY BOTH IF DEFINK THE SEMINAR, IN BEING THERE, AND IN PARTICIPATING IN THE SCUKTS ON AS WELL AS OBA STAFF FOR ALL THE HARD WORK YOU PUT INTO IT. THE GROUP IS GOING TO PUT TOGETHER DRAFT POINTS TO CONSIDER PORE INSTITUTIONAL BIOSAFETY COMMITTEES AND THESE DRAFT POINTS THEN WILL BE REVIEWED BY THE RAC AND PUBLICLY DURING THE DECEMBER MEETING. THE DEVELOPMENT OF THE POINTS TO CONSIDER WE BELIEVE IS THE BEGINNING OF AN ONGOING FORWARD MOVING PROCESS THAT IS NECESSARY TO MAINTAIN THE ISSUES THAT THE IBCs CURRENTLY USE IN THEIR DELIBERATIONS SCIENTIFICALLY AS UP TO DATE AS IS POSSIBLE. THE POINTS TO CONSIDER THAT WILL BE DEVELOPED AND HOPEFULLY ENDORSED BY THE RAC WILL BE MEANT TO BE A RESOURCE FOR IBCs, NOT ONLY FOR THE SPECIFIC INFECTIOUS AGENTS THAT WERE DISCUSSED TUESDAY MORNING AT THE BEGINNING OF THE SYMPOSIUM BUT THESE POINTS TO CONSIDER ARE ALSO TO PROVIDE A FRAMEWORK FOR THE DELIBERATIONS OF IBCs REGARDING CONTAINMENT ISSUES THAT ARE NECESSARY FOR RESEARCH WITH EMERGING INFECTIOUS AGENTS. CLEAR THAT THE RESEARCH ON EMERGING INFECTIOUS AGENTS MUST CONTINUE IN IT COUNTRY AND SO THE -- IN THIS COUNTRY AND SO THE CHALLENGE THAT IS PUT FORTH TO THE RAC IS TO PROVIDE POINTS TO CONSIDER OR GUIDANCE SO THAT THIS RESEARCH CAN BE DONE IN A AS SAFE A MANNER AS IS POSSIBLE. AND BY SAFE WE THE RAC MEAN NOT ONLY FOR THOSE WHO ARE IN THE LABORATORY AT THE MOMENT, BUT FOR SOCIETY AS A WHOLE. AND AS I -- AS I MENTIONED PUBLIC HEALTH DEPENDS ON THIS RESEARCH AND THEREFORE THE RESEARCH MUST BE CARRIED OUT IN WHAT OBA AND THE OFFICE OF THE DIRECTOR TERMS THE CULTURE OF RESPONSIBILITY AND IT IT IS A CULTURE THAT THE POINTS WILL ADDRESS AND INFORM. SO WE WILL BE REVIEWING THOSE HOPEFULLY IN A FINAL FORM EARLY IN THE DECEMBER MEETING.

CAN WE TAKE A FIVE MINUTE BREAK?

WELL, I WAS GOING TO SUGGEST THAT WE PROCEED WITHOUT A BREAK. DR. DURING IS HERE. WE ARE 20 MINUTES EARLY BUT THAT IS PERFECTLY ACCEPTABLE. SO WE'RE TRYING TO LINE PEOPLE UP ON THE PHONE AND THEN WE WILL MOVE RIGHT AHEAD. I'M AFRAID IF WE TAKE A BREAK IT WON'T BE FIVE MINUTES.

THAT'S FINE.

DR. DURING, WE ARE READY TO BEGIN. DR. MATT DURING FROM CORNEL UNIVERSITY IS JOINING US AGAIN TODAY TO DISCUSS PROTOCOL 669, WHICH INVOLVES HIPPOCAMPAL NPY GENE TRACTOR IN SUB GECKS WITH IN TRACTABLE MEALIAL EPILEPSY.

I'M HERE.

THANK OU. -- INTRACTABLE MESIAL TEMPORAL LOBE EPILEPSY.

THIS WILL IS THE DISPLAY HERE. SHOULD BE SEEING IT NOW. IT SHOULD BE MIRRORING.

OKAY. SORRY ABOUT THE DELAY. MEMBERS OF THE RAC AND CHAIRMAN AND MEMBERS THE RAC AND MEMBERS OF THE PUBLIC WHO ATTEND TODAY, I'M GOING TO PRESENT THE PROTOCOL WHICH I BELIEVE IS THE FIRST EPILEPSY PROTOCOL TO COME BEFORE THE RAC AND I HAVE SEVERAL PIs UNFORTUNATELY THAT COULD NOT ATTEND TODAY. AT UCLA IN ISRAEL, CLOSE TO THE JEWISH HOLIDAYS TO DIFFICULT FOR HIM TO GET BACK. JOHN AT UCLA AND THE CURRENT INVESTIGATOR IN THE PRECLINICAL STUDIES. I THINK BECAUSE I WILL GET IT OUT OF THE WAY QUICKLY BECAUSE IT CAME AS AN ISSUE EARLY ON THAT THIS TRIAL ABOUT LE SPONSORED BY NEUROLOGIX WHICH HAS SPECIFICKENT LEGUAL PROPERTY AND -- INTELLECTUAL PROPERTY AND INTEREST IN THE AV AND BRAIN SPACE AND I'M A FOUNDER AND CONSULTANT IN THAT COMPANY. FOOD I WILL PRESENT THREE COME POE THENS. QUICKLY RUN THROUGH THE BURDEN AND WHY EPILEPSY IS A POTENTIALLY GOOD CANDIDATE FOR GENE THERAPY. TALK A LITTLE BIT ABOUT THE PRECLINICAL DATA AND THEN DISCUSS THE CLINICAL PROTOCOL BRIEFLY AND THEN RACE AND ADDRESS SOME OF THE POINTS THAT THE RAC MEMBERS AND DOCTOR MARC DICHTER THE AD HOC REVIEWER RAISED. I ALWAYS THINK ABOUT TEMPORAL LOBE EPILEPSY AS A CINDERELLA DISEASE. YOU HEAR ABOUT MANY OTHER NEUROLOGIC DISEASES AND CONSIDERING THE BURDEN TO THE SOCIETY AND INDIVIDUALS THAT HAVE EPILEPSY IT IS VERY MUCH UNDERSTATED. IT IS COMMON. 2.5 MILLION PEOPLE WITH EPILEPSY IN THE U.S. AND A SIGNIFICANT PERCENTAGE OF THAT, 30% ARE RESISTANT TO DRUGS. IN FACT, THAT MEANS EVEN WITH THE BEST DRUGS AND COMBINATIONS OF DRUGS THEY CONTINUE TO HAVE SEIZE ZIEWRS IMPACTING DA MAT TECHILY ON THEIR QUALITY OF LIFE. HALF OF THEM THIS MESIAL TEMPORAL LOBE EPILEPSY MESIAL TEMPORAL LOBI WON'T GO INTO A FULL DISCUSSION ON ALL OF THE TYPES OF EPILEPSY BUT BEST TO THINK OF EPILEPSY AS A FAMILY OF DISORDER OF WHICH MESIAL TEMPORAL LOBE EPILEPSY IS THE MOST COMMON FORM. THE COST TO SEE SIGHTY THERE IS CONSIDERABLE. THESE RT CONCERNS THAT PATIENTS SUBJECTS WITH EPILEPSY HAVE AND I THINK NOT SURPRISLY THE MAJORITY CAN'T DRIVE. THEY CAN'T WORK. EMBARRASSMENT. DEPENDENCE ON DRUGS. MOOD, DRESS AND SAFETY. IT AS DISEASE WITH SIGNIFICANT MORBIDITY. THIS SLIDE IS A LITTLE HARD TO FOLLOW. I REALLY PUT UP TO EMPHASIZE THE POINT THAT WE -- THAT THE MAJORITY OF PATIENTS WITH OR IS SIGNIFICANT PERCENTAGE OF PATIENTS WITH TEMPORAL LOBE EPILEPSY WILL BECOME INTRACTABLE. AFTER DIAGNOSED WITH A DISEASE AND ON ONE DRUG HOW LONG DOES IT TAKE FOR THE DRUG TO STOP WORK AND OVER TIME ALMOST ALL OF THEM WILL ACTUALLY BECOME RESISTANT AND IN TRACTABLE. WHAT HAPPENED THEN IS OF THAT GROUP AND I APOLOGIZE FOR THE QUALITY OF A A COUPLE OF THE SLIDES HERE OF THAT GROUP WE KNOW THAT THEY DO POTENTIALLY THEY FAIL WITH DRUGS SO WHAT OTHER OPTIONS AVAILABLE TO THEM AND ONE OF THE BIG DEVELOPMENTS AND GROWING AREAS IN MEDS IS EPILEPSY SURGERY AND THERE HAS ONLY BEEN A HANDFUL OF REALLY WELL CONDUCTED STUDIES ON EPILEPSY SURGERY AND HALF OF THOSE AS YOU CAN SEE HERE IS BAY SEL NERVE STIMULATION. THERE WILL HAVE BEEN FOUR TRIALS AND THREE TRIALS IN SURGERY. THE FIRST TWO, THE MESIAL PEOPLE TORAH RAL WAS WHETHER YOU DO A LARGE RESECTION OF THE TEMPORAL LOBE WITH THE SMALL AND THE SECOND TRIAL WAS IF YOU EXCLUDE RESECTING THE TEMPORAL AND THE THIRD TRIAL IS REALLY THE ONLY CONTROLLED TRIAL COMPARING SURGERY TO STENTED DRUG TREATMENT. AND BASICALLY THE RESULT OF THESE TRIALS JUST VERY QUICKLY IS THAT NERVE STIM YOU LAKES IN ABOUT A THIRD OF THE PATIENTS LEADS TO 50% SEE DURE REDUCTION. IT IS NOT -- SEIZURE REDUCTION. NOT A GREAT BENEFIT COMPARED TO WHEN YOU RESECT THE MEDIAL TEMPORAL LOBE APPROXIMATELY 30% OF THE PATIENTS WERE ACTUALLY SEIZURE FREE AT ONE YEAR AND ONLY 8% OF THOSE THAT CONTINUED ON DRUG TREATMENT WERE SEIZURE FREE. EPILEPSY SURGERY THE TEMPORAL LIE BECK TOREMY IS A DRAMATICALLY EFFECTIVE FORM OF TREATMENT. THE PROBLEM THAT WE HAVE IS THAT WHEN YOU LOOKED AT THOSE EARLIER NUMBERS AND THE ESTIMATES ARE OF ALL THE PEOPLE WITH IN TRACTABLE MESIAL TEMPORAL LOBE EPILEPSY PERHAPS 1,000 TO 2,000 AMERICANS COULD BENEFIT FROM THAT SEARCHRY. WHEW IS IT SO FEW? REASONS AREN'T PARTICULARLY CLEAR. PART OF IT MAY BE PEOPLE UNAWARE OF HOW SERIOUS AND POOR THE OUTCOME IS OF THE AND ALSO A GENERAL ANXIETY AND RELUCTANCE TO HAVE AN OPERATION WHICH REMOVE MOVES A SIGNIFICANT PORTION OF THE BRAIN AND, OF COURSE, IT IS EXPENSIVE. A SUMMARY STATEMENT THAT PETE ENGEL AT UCL CHAIRED FROM THE AMERICAN ACADEMY OF NIEWRLG AND AMERICAN ASSOCIATION OF NIEWRL SURGEONS QUOTED THERE WHAT THEY SAID AND IT IS CRITICAL THAT THERE ACTUAL LI NEEDS TO BE INVESTMENT AND APPROACHES WHICH MORE COST-EFFECTIVE AND ALTERNATIVE SURGICAL STRATEGIES. AND THAT IS IS WHERE WE COME TODAY. SO I THINK ONE ALTERNATIVE APPROACH, SURGICAL APPROACH THAT IS IS GENE THERAPY. AND WHAT MAKES IT A POTENTIALLY GOOD CANDIDATE, I BELIEVE, IS THAT IT IS A FOCAL PATHOLOGY BY DEFINITION MESIAL TEMPORAL LOBE EPILEPSY INVOLVES THE TEMPORAL LOBE. IT IS SPECIFIC AND LOCALIZED TO THE TEMPORAL LOBE. AFTER MEDICAL TREATMENT FAILS. WE ALREADY DISCUSSD THAT AND BECAUSE INSUFFICIENT NUMBER OF RESECTIVE SURGERY IS BEING DONE THERE IS A CLEARLY LARGE UNMET NEED. THE SUCCESS OF THE SURGERY AND LEADING SYMPTOMS. 70% SEIZURE FREE IS ABOUT RIGHT SUPPORTS THE RATIONALE THAT IF YOU COULD ACTUALLY DO GENE TRANSFER AND JUST ALTER THE PHYSIOLOGY IN THAT PART OF THE BRAIN NORMALLY REMOVED YOU SHOULD BE ABLE TO MATCH OR COME CLOSE TO MATCHING THE SUCCESS WITH RESECTIVE SURGERY. OKAY. TISSUE RESECTION IS THE MOST! T EXTREME FORM. IF THE CELL IS NOT THERE IT IS OOBVIOUSLY NOT GOING TO BE FUNCTIONING. THERE ARE AND AND SET ITIC AGENTS. TO DAMPEN DOWN THE TEMPORAL LOBE ALL THOSE DRUGS WOULD ACTUALLY DAMEN DOWN ALL CORTEX AND BRAIN STEM AND, OF COURSE, THE SUBJECT WOULD BE IN A STUPORAL COMA AT THAT TIME. INFUSING A DRUG DIRECTLY IN THE HIPPO CAMPUS WOULD DO IT. THERE IS MANY POTENTIAL GENES THAT YOU COULD DELIVER THAT COULD ACTUALLY LEAD TO THE SCIENCING OR QUIETING OF THE BRAIN REGION. WE DID WE SELECT NPY FOR THE STUDY? THIS IS A REVIEW BY TOMORROW MATS HAWKFIELD, ONE OF PIONEERS, IF I COULD HAVE A POINTER. OKAY. THE MOST OF YOU IN THE AUDIENCE THE RAC MEMBERS KNOW THAT IN THE PARKINSON'S TRIAL WE ARE PUTTING A GENE IN WHICH ANNIBLES US TO RELEASE A FAST NEUROTRANSMITTER. AND SNAP THE VESICLES AND GOES ACROSS AND BIAS RECEPTORS IS INVOLVED IN CON DUBS OF ION CHANNELS AND HYPE HYPER POE POLAR RISE THE CELL. WITH HAPPENS WHEN CELLS MOST OF THE GABA CELLS AND THE MAJORITY OF THE CELLS IN THE BRAIN CONTAIN NOT JUST CLASSICAL FUHR ROW TRANSKNITERS BUT WHAT WE CALL NEUROPEPPEPTIDES. THEY COME IN TO PLAY WHEN IT THE INCREASED FURTHER. ONCE YOU GET ABOVE 5-10-HERTZ YOU START GETTING THE NEUROPEPTIDE RELEASE AND AS YOU GO FEW FAST FIRING OR BURST FIRING THERE IS A PREPONDERANCE OF NEUROPEPTIDE RELEASED. RELEASED EXTRA AND DOESN'T HAVE THE SAME RAPID UPTAKE MECHANISMS THAT THE NEUROTRANSMITTERS HAS SO IT TENDS TO STAY IN THE SPACE ANDY FUSE AND HAVE PRO FOUND REACTIONS OVER A LONGER PERIOD OF TIME. MAKES THEM ATTRACTIVE AGENTS WHEN TRYING TO THINK ABOUT A GLOBAL WAY TO DAMPEN DOWN AN ACTIVITY. NEUROPEPTIDE Y IS INTERESTING BECAUSE IT EXPRESSED ITSSELF IN THE BRAIN AS WELL AS IN HUMAN EPILEP TICK TISSUE AND THERE ARE CHANGES IN RELEASE OF NPY IN EPILEPSY. AND THERE IS ACTUALLY AN ALTERED AND NPY MEDIA NEUROTRANSMISSION. MOTHEROVER, NPY SIGNIFICANTLY INHIBITS SYNAPTIV ZEES SURE ACTIVITY IN ANIMALS AND IN THE HUMAN BRAIN SLICES AS WELL THAT I WILL SHOW YOU. THE MAJORITY OF ACTIONs ARE MEDIATED THROUGH TWO CLASSES OF RECEPTORS. WHILE ONE MEDIATE EXCITERY ACTIONs THESE ARE COUNTE WAGED. WHAT HAPPENS TO NPY IN EPILEPSY? HERE THESE ARE TWO MODELS THAT ARE COMMONLILY USED IN THE RESEARCH LAN TO MODEL TEMPORAL LOBE EPILEPSY. CAUSES SEE ZEE SEE SEIZURES AND REORGANIZATION OF HIPPO CAMPAL STRUCTURE. YOU CAN SEE THAT THE RNA LEVEL AMOUNT INCREASED NOT JUST IN THE GRAN ULE CELLS HERE. SO THIS IS ACTUALLY A CORE RHONEAL SECTION THROUGH THE DORSAL SUPERIOR SECTION OF THE RIGHT HIPPOCAMPAL SEC. THIS IS THE CORTEX LYING ON TOP. THE TOP OF BRAIN HERE. THE BOTTOM OF BRAIN HERE. THIS IS THE CROSS SECTION THROUGH THE BRAIN CLASSICAL STRUCTURE OF THE HIPPOCAMP US INVOLVES THIS STRUCTURE AND THE PRY PERICELLS THAT COME ACROSS HERE CONTRIBUTION THERE IS TOO MUCH FOR US TO COVER THE WHOLE CIRCUIT BUT THESE ARE THE PRINCIPAL CELL GROUPS. YOU CAN SEE THAT WITH THESE SEIZURE MOODLES YOU CAN INCREASE AN IX PRE OBJECTION OF NPY. YOU ALSO GET AN INCREASE IN THE RELEASE ON THE BASAL BAY SITUATIONS WHEN YOU DEPOT DEPOT LAR RISE WITH POTASSIUM. AND IN THE HUMAN HIPPO CAMPUS YOU LOSE NEUROPEPTIDE YSMT. I WILL SHOW YOU THE HUMAN HIPPOCAMPUS CELL IN A MINUTE. IS A RESPONSE OF THE MEW MAN EPILEP PARTICULAR BRAIN TO CONTROL AND DAMPEN DOWN AUK CONTINUITY. IT AS WAY WHEN YOU IS SEIZURES THE BRAIN HAS AN ADAPTIVE RESPONSE TO TRY AND DAMPEN DOWN EXCITABILITY. AGAIN, THIS IS LOOKING AT THE RECEPTORS BRIEFLY. THE Y1 RECEPTOR IN THIS CONTEXT THE BAD RECEPTOR BECAUSE WE DON'T WANT ANY MORE EXCITATION, WE WANT INHIBITION AND DAMPENING DOWN AND WITH EPILEPSY THE Y1 RECEPTOR LUCKILY DECREASES. THIS IS TRUE ALSO IN THE HUMAN BRAIN. WE WILL SHOW YOU THAT IN A SECOND. THE Y2 RECEPTORS. HERE IS THE RNA LEVEL. HERE IS THE APPROACHING LEVEL. THE Y2 YOU SEE A MARKED INCREASE IN THE Y2 RECEPTOR EXPRESSION PARTICULARLY IN THE DEN DRAOIT GRAN ULE CELLS. THIS IS EVEN MORE DRAMATIC PERHAPS IN THE HUMAN HIPPO CAMPUS. THE Y1 RECEPTOR IS A SLIGHT DECREASE IN Y1 RECEPTOR EXPRESSION BUT A MARKED INCREASE INY Y2 EXPRESSION IN TEMPORAL EPILEPSY. IF YOU PUT IN A GENE FOR PROP TEEN YOU WANT TO -- PROTEIN YOU WANT TO MAKE SURE THE RECEPTORS ARE THERE. IN EPILEPSY THE RECEPTORS THAT MEDIATE THE INHIBITOR ACTIONS ARE NOT ONLY THERE BUT MARKEDLY IN CREED SUGGESTING THIS IS A GOOD CANDIDATE. BEFORE I MOVE ON TO THAT IS IF THAT IF YOU TAKE THE HUMAN HIPPOCAMPAL SLICES FROM THE OPERATING PATIENTS AND ACTUALLY BATHE INFUSE NPY ON NOT SLICES AND THEN LOOK AT PHYSIOLOGY OF THAT SLICE YOU SEE A MARKED DECREASE IN THE EPILEP TICK TIVITY. TALK ABOUT A LITTLE BIT OF DATA FROM THE LAB OF AND AND MA IN MILAN AND SHE DEVELOPED THE TRANTS GENIC LINE OF RATS THAT OVEREXPRESSED NPY AND CAN SEE HERE THE NPY EXPRESSION ON THE SLIDE OVER HERE. AND SHE LOOKED AT VARIOUS SEIZURE MODELS. AND I APOLOGIZE THAT THIS SLIDE I COULDN'T CHANGE THE FONT SO I WILL TELL YOU THE DATA. WHAT SHE LOOKED AT WAS USING SEVERAL DIFFERENT MODELS AND LOOKED AT THE ONSET OF SEIZURES, THE NUMBER OF SEE IT ZIEWRS, THE TIME TO SET IT SEE URES AND WHAT SHE SHOWED WAS THAT A SIGNIFICANT -- A SIGNIFICANT INCREASE IN THE LATENCY, IN OTHER WORDS, THE TIME TO ZEE ZEE SEIZURES WAS INCREASED AND NUMBER WAS DECREASE. KINDLING. YOU CAN SEE HERE THAT PARTICULARLY THESE LATER STAGE TO HERE WE ARE TALKING ABOUT WHEN YOU KINDLE AN ANIMAL WHAT WE ARE DOING IS PUTTING ELECTRICAL STIMULATOR AND TURNING UP THE CURRENT REPEATEDLY UNTIL YOU DEVELOP THIS HYPER EXCITEABLE STATE. SORT OF AKIN TO KINDLING A FIRE AND THAT IS WHERE THE NAME CAME FROM BUT THE SMALL REPETITIVE STIMULATIONS IN THE BRAIN ULTIMATELY LEAD TO AN EPILEPSYIC STATE. GOES FROM LIGHT SEIZURES TO MORE SEVERE. STAGE FOUR AND FIVE EQUIVALENT TO GENERALIZED AND YOU CAN SEE IN THE TRANSGENIC RATS IT WAS MA MAJOR DELAY. A NUMBER OF STIM YOU LAKES IRED TO REACH THAT STAGE OF SEIZURE. A LOT NOR STIMULATIONS NEEDED TO GET TO THE STAGE FOUR AND STAGE FIVE PROCEDURE. AFTER DISCHARGE WAS THE AMOUNT OF ELECTRICAL ACTIVITY THAT OCCURS AFTER EACH STIMULATION. IF YOU KNOCK OUT THE Y2 RECEPTOR YOU ACTUALLY PREDISPOSE AGAIN THIS IS PUBLISHED DATA. AND THEN IF YOU ACTUALLY BLOCK Y1 RECEPTORS YOU INHIBIT SEIZURES AS WELL. CONSISTENT WITH Y1 ABOUT FAIL TATEING THE THE SEIZURE STRAIN. ONE OF THE MEMBERS OF RAC ASKED ABOUT THE DRUGS THAT COULD BE USED IN EPILEPSY. THESE DRUGS UNFORTUNATELY HAVE TO BE INFUSE INSIDE THE BRAIN DIRECTLY AND THERE IS NO GOOD SYSTEMICALLY ACTIVE PEPTIDE NEUROAGONIST OR AND ANTAGONIST AVAILABLE TO MOVE TO THE CLINIC. Y2 AGONISTS SIMILARLY GIVEN. INTRAHIPPOCAMPALLY. ALSO SHOWS EPILEP TICK ACTIVITY. AGAIN, THIS DATA IS PUBLISHED. MOVED TO THE GENE TANS FEAR AND THE GUTS OF TODAY'S INTEREST. WE STARTED OFF IN COLLABORATION WITH ANNA MARIA LOOKING AT AN AV VIRUS OF SERO TYPE # 2 2 # 2 AND THAT IS JUST EXPRESSION DATE THAT THAT SHE HAS GOT. YOU CAN SEE THAT THE RNA WITH AB2 TYPICALLY SPHERES OR TRANSFUSES THE GRAN ULE CELL THERE BUT PREDOMINANTLY FOUND IN THE HIGHER CELLS. ALSO SHOWN HERE. TRAFFIC AND TRANSPORTED DOWN THROUGH THE FIVE FIBERS. SO THE FIVE HES ACTUALLY -- FIBERS YOU CAN SEE FIBER STANDING THAT GETS A LONG WAY FROM WHERE THE RNA IS EXPRESSED AND SOME EVEN CROSS THE MIDLINE. THE SPREAD FOR THE AB2 WERE THE SORTS OF INJECTION VOLUMES AND TITERS ARE ONLY 1-2-MILLIMETERS. THE TRAN SECTION EFFICIENCY WAS NOT AS GREAT AS WE WOULD LIKE TO WE MOVED TO A COMAIR RICK AND HALF DERIVED FROM AB2 AND HALF FROM AB1. YOU CAN SEE HERE THAT THE EXPRESSIOEXPRESSION PATTERN IS MOREAU BUST AND INCLUDES GRAN ULE AS WELL, PARIETAL AND EVEN DOWN TO THE SEBECULU M AS WELL. YOU CAN SEE HOW MUCH MORE DRAMATIC THAT IS. AGAIN, THIS IS PUBLISHED WORK. HERE OPPOSED TO ONE TO TWO WE ARE GETTING OUT TO TWO TO THREE MILLLY MEET AND GETTING MARKED SPREAD AND ALSO GETTING THE FIBER STANDING CROSS ON THE CONTRALATERAL SIDE. NOT SEEING CELL BODIES BUT GET FIBERS GOING ACROSS THE MIDLINE. OKAY. THIS IS JUST WHAT HAPPENS TO THE RECEPTORS WHEN YOU DO THIS. THIS WORK ISN'T PUBLISHED. THIS IS NEW WORK. LOOKING AT A NUMBER OF BRAINS LOOKING AT Y1 AND Y2. WHAT IS IMPORTANT IS THAT THERE IS VERY LITTLE CHANGE IN Y1 WHEN YOU PUT THE NPY VECTOR IN BUT INTERESTINGLY, Y2 RECEPTORS APPEAR TO BE ABRIKULATEED WITH THE NPY. WE BELIEVE THAT IF ANYTHING, WE ARE NOT GOING TO LOSE THE ACTUAL CHANGE IN Y1 AND Y2 BY OVEREXPRESSING NPY SO IT IS IMPORTANT THAT YOU DON'T HAVE A RECEPTOR SYSTEM THAT IS DRAMATICALLY DOWNREGULATED HERE. ONE OF THE FIRST STUDIES WE LOOKED AT WAS A MODEL THAT WE INFUSED THE EPILEPTIC AGENT AND LOOKED AT SEIZURE ACTIVITY OVER THE ENSUING THREE HOURS. WHAT WE SAW IS THE NUMBER OF SEIZURES THAT WE SEE THE ONSET OF SEIZURES, THIS IS REALLY THE TIME IT TAKES TO START ZEE SEIZURES, THE TOTAL NUMBER AND TOTAL DURATION OF VEKT TORAL ACTIVACTIVITY AND DESPITE POOR TRANSGREX WE GET A HAAR BORING OF THE THE SEE ZAUR ACTIVITY -- SEIZURE ACTIVITY. OKAY. SO HERE WE NOW LOOKING AT I AGENTS. PRIMARILY LOOK THE AT THIS STAGE BASED ON WHETHER OR NOT ANIMALS MOVE TOWARDS FULL EPILEPSY, THE MOST EXTREME WITH THE CONTINUEOUS AND LONG LASTING. YOU CAN SEE THAT DESPITE FAIRLY FOCAL TRANSDUCTION WE ARE GETTING COMPLETE ABOLITION. THERE IS NO STATUS OF EPILEPSY IN ANY OF THE NPY RATS SO WE ARE NOT NECESSARILY STOPPING COMPLETELY THE EARLY STAGE SEIZURES BUT WE ARE COMPLETING THE COMPLETE GENERALIZATION IN STATUS EPILEPSY. FINALLY USED THE KINDLING MODEL AND SIMILAR TO THE TRAN GENIC RATS WE ARE SEEING A MARKED INCREASE, A DOUBLING EVEN MORE THAN DOUBLING OF THE NUMBERS OF STIM YOU LAKES REQUIRED TO -- STIM YOU LAKES -- STIMULATIONS REQUIRED TO REACH THE LATE STAGE SEIZURES.

WE HAVE USED MANY OTHER VECTORS FOR INJURY. HERE AGAIN WE SEE SIMILAR INJURY REGARDLESS OF WHETHER PUTTING AB NPY, AB EMPTY VECTOR OR JUST THE SALINE CRYSTAL VIOLET STAINS. JUST LOOKING AT DEGENERATING CELL E. ESSENTIALLY AS WE HAVE SEE IN MANY OTHER STUDIES PREVIOUSLY THERE IS NOTHING UNIQUE OR SPECIAL ABOUT THE VIRUS IN TERMS OF INFLAMMATION OR TIRR RESPONSE. NPY IS ONE OF THE MAJOR AREA OF INTEREST IS NOT TO MUCH IN THE HIPPO CAMPUS BUT IN THE HYPOTHALAMUS. IT IS THE MOST POTENT STIMULOUS TO APPETITE SO THERE WAS IMPORTANT SHOW THERE WAS NO CHANGE IN WEIGHT GAIN AND EFFECTS OF ANXIETY AND LOW COMMOTION AND NO EFFECTS IN LOCAL FIELD TESTS. THIS IS IN THE SUBMISSION. ANXIETY IS ANOTHER AFFECTED BY NPY. WE DIDN'T SEE A CHANGE IN ANXIETY OR FEAR CONDITIONING OR THE MEMORY TEST THE MARS WATER MAZE. OKAY. I'M SORRY THE SLIDE IS PROBABLY NOT TOO READABLE AND IT IS A COMPLICATED ONE AND I THINK IT REENFORCES FOR THOSE OF YOU WHO ARE NOT FAMILIAR WITH HAPPENS WHEN SOMEONE HAS IN INTRACTABLE EPILEPSY WHAT DO THEY HAVE TO GO TO BEFORE THEY END UP BECOMING CONSIDERED A SURGICAL CANDIDATE? I'M GOING TO BRIEFLY RUN THROUGH THIS AND AGAIN I'M SORRY THAT IT IS HARD TO READ. BUT OF SUBJECTS WITH EPILEPSY WHO GET REFERRED IN THIS TRIAL WE ARE LOOKING AT SUBJECTS OF 18-40 THEY HAVE TO HAVE A HITS HISTORY AND SEE SEIZURE, HAVE TO BE CONSISTENT WITH TEMPORAL LOBE EPILEPSY. EPILEPSY IS A REFLECTION OF THAT PART OF THE BRAIN ACTIVEIATED IN THE SEIZURE. IF YOU HAVE JERKING OF A SPECIFIC ARM YOU KNOW YOU HAVE A FOCAL ACTIVITY OF THE CORTEX THAT REGULATES OR CONTROLS OF MOVEMENT OF THAT ARM. THERE IS IS A SPECIFIC TYPE OF SIMOLOGY WHICH RELATES TO ACTIVE YAKS OF TEMPORAL LOBE AND ECAN LOOK AT. TYPICALLY ASSOCIATED WITH THESE UNUSUAL AURAS. AFTEREN THE MOTOR. PATIENTS MAY PICK AT THEIR CLOSE CLOTHES AND DO REPEATED. YOU CAN SEE THEM TALK AND THEY ARE NOT AWARE THEY ARE HAVING A SEIZURE. DON'T ALWAYS LOSE CON CONSCIOUSNESS BUT THEY ALSO DO. THEN BECOMES A SECONDARY GENERALIZED SEIZURE WHEN THE FULL CORTEX IS INVOLVED. THESE PATIENTS WHO HAVE THIS TYPICAL TYPE OF PATTERN AND THE TYPICALLY HAD THE SEE IT ZIEWRS THAT THEY -- SEIZURES THAT THEY START DURING CHILDHOOD THEY WILL ACTUALLY THEN FAIL DRUGS AS I MENTIONED BEFORE OVER HALF OF THESE PATIENTS OR APPROXIMATELY HALF BECOME RESISTANT TO ONE DRUG AND THEN SUBSEQUENTLY TO THE SECOND DRUG. BY THE TIME THEY FAILED TWO GOOD TRIALS OF TWO DRUGS THE ADDED ADVANTAGE OF HAVING A THURD DRUG ADDED ON IS LIMITED INDEED, AND SO THE PATIENTS GET REFERRED EARLY ON FOR SURGICAL EVALUATION. THERE IS A MAJOR CLINICAL TRIAL GOING ON AT UCLA RIGHT NOW TO CONSIDER A PATIENTS RIGHT AT EARLY STAGES SHOULD THEY GET SURGERY THAT THE STAGE EVEN WITHIN 6 MONTHS OF THE DIAGNOSIS BECAUSE THERE A FEELING THEY COULD BENEFIT AT EARLY TIME POINT. THE CURRENT PRACTICE IS TO GO THROUGH PHASE ONE EVALUATION. COME INTO THE HOSPITAL AND HAVE TELEMETRY SET UP AND SCALP EEGs AND 24 HOUR VIDEO AND CONTINUOUSLY MONEY FORKED TO CAPTURE THE -- MONITORED TO CAPTURE THE SPONGE SPONTANEOUS SEIZURES THAT OCCUR AND THEN COUPLED TO THE IMAGING STUDIES AND PIT STUDIES LOOKING AT THE METABOLISM OF THE BRAIN AS WELL AS PSYCH PSYCH AT PSYCH AT RICK YOU CAN DETERMINE THAT THERE IS ONE MEDIAL TEMPORAL LOBE THAT HAS THE. AND THERE IS SUFFICIENT DATA FOR THE SURGEONS THEN TO COME ALONG AND PASS WHERE THAT SUBJECT CAN CONSENT TO THE INTRAMEDIAL TEMPORAL LOBE! TOMY. COMING THROUGH THE EVALUATION END HUP UP HERE. A SUBGROUP THAT DATA IS NOT FULLY DEFINITIVE. THEY REQUIRE FURTHER IMAGING AND THIS INCLUDES SPECK FUNCTION PRI AND OTHER SPORTS OF MRI EVALUATIONS. MAINLY IMPAGING TYPE STUDIES AND THAT WILL SICK UP A SUB SET WHERE PICK UP A SUB SET BUT THERE WILL BE A RESIDUAL GROUP THAT REQUIRES PHASE TWO EVALUATION WHICH IS AN INTRACRANIAL RECORDING. ALL OF THE NONIN NONININVASIVE TESTS HAVEN'T BEEN SUFFICIENT TO PROVIDE THE EPILEPSY TEAM THAT THAT PARTICULAR PART OF THE TEMPORAL LOBE WHERE THE PROBLEM IS AND THEY REQUIRE THIS INTRACRANIAL RECORDING WITH SUBDURE RAL STRIPS OR INTRACRANIAL DIP ELEG ODE OR A COMBINATION OF BOTH. THIS IS A SUBGROUP THAT WE PROPOSED TO STUDY IN THE TRIAL. THE SUBJECTS THAT COME IN WITH ELEELECTRODES WILL BE MONITORED AS THEY WERE IN PHASE ONE IN THE HOSPITAL FOR A COUPLE OF WEEKS TRYING TO CAPTURE SPONGE TANE SESEIZURES. ONCE IT IS IDENTIFIED THEN THE EOOH LEG ELECTRODES ARE MODIFIED. WE ARE PIG PIGGYBACKING ON A CLINICAL INDICATED PROCEDURE. THERE IS NO ADDITIONAL SURGICAL INTERVENTION.

TALKING WAY TOO LONG. OKAY. IT'S REBELLING. OKAY. SO IF THEY CONSENT TO THE TRIAL AT THAT STAGE, THOSE PATIENTS WHO WE BELIEVE GOOD CANDIDATES NOW NOR TEMPORAL RESECTION WILL UNDERGO GENE TRANSFER. THE ONES WHO DON'T UNDERGO WILL GO STRAIGHT TO PHASE THREE AND THE PATIENTS THAT UNDERGO GENE TRANSFER HAVE A SIX MONTH TEE LAY WHILE WE EVALUATE THE EFFECTS AND SAFETY OF THE GENE TRANSFER. SEVERAL MIGHT BE SURGICAL CANDIDATES. MAYBE BECAUSE IT IS NOT EXTRA TEMPORAL OR LATERAL REGIONS OR PERHAPS SOME BILATERAL CASES ZWLA IS THE CURRENT STUDY DESIGN. OKAY. BASELINE IN ADDITION TO ALL THE SORT OF GENERAL VITAL SIGNS AND NURL EVALUATIONS AND SAFETY AND MONITORING WE ARE COLLECTING SEVERAL ENDPOINTS INCLUDING SEIZURE LOGS, LIVERPOOL SEVERITY MODIFIED SCALES. CALL OF LIFE SCALE. VAIR 86MRI. REPEATING ONE AT THREE MONTHS AND AGAIN WITH THE PIT AT SIX MONTHS.

OKAY. SO IMPORTANT POINT TO EMPHASIZE HERE IS THAT THE BASE STANDARD OF CARE IS NOT OBVIATE THE BY THE CLINICAL PROTOCOL BUT BUILT INTO THE DESIGN. THE SUBJECTS MEET THE CRITERIA OF THE TEMPORAL LOBECTOMY. WE KNOW FROM THE CONTROLLED STUDY THAT I MENTIONED BEFORE THAT LONG-TERM OUTCOME AND QUALITY OF LIFE ESSENTIALLY IDENTICAL IF SURGERY IS DELAYED UP TO ONE YEAR BUT THERE IS A SMALL RIVALING RISK AND DOCTOR MARC DICHTER POINTED THIS OUT AS WELL. A SMALL RISK OF CERTAIN UNCONTROLLED SEIZURES. SMALL BUT WORTH MENTIONING. THE QUALITY OF LIFE DATA. PUBLICED IN THE "NEW ENGLAND JOURNAL." YOU CAN SEE THAT DRAMATICALLY AFTER SURGERY THE HIGHER NUMBERS RELATE TO BETTER QUALITY OF LIFE. THE QUALITY OF LIFE DRAMATICALLY IMPROVED AND PERSISTED TO 36 MONTHS AT THREE YEARS. THE MEDICAL GROUP WERE RANDOMIZED TO ACTUALLY JUST RECEIVE DRUGS. STENTED DRUG THERAPY YOU CAN SEE THE QUALITY OF LIFE GOT WORSE OVER THE FIRST 9-12 MONTHS BUT AS SOON AS THEY HAD SURGERY THEY ULTIMATELY REJOINED THE GROUP THAT ACTUALLY GOT SEARCHRY TO BEGIN WITH. SO THERE DOESN'T SEEM TO BE ANY LONG-TERM PROBLEMS ASSOCIATED WITH DELAYING RESECTIVE SURGERY EVEN AFTER ONE YEAR. POTENTIAL ADVANTAGES TO THE NPY GREEN TRANSER OVER -- GENE TRANSFER OVER RECEPTIVE SURGERY IF YOU REMOVE THE SIGNIFICANT PART OF THE BRAIN YOU WILL ACTUALLY HAVE A SIGNIFICANT RISK OF HAVING NEUROLOGICAL DEFICITS. THERE IS A LOT OF DEBATE ABOUT HOW SEVERE AND FREQUENT THE IMPAIRMENT IS. THE HIPPO CAM CAMPUS IS A CRITICAL STRUCTURE FOR LEARNING AND MEMORY. THEY ALL UNDERGO THE TEST IN WHICH SUB JEBS HAVE AN INTRAKA RO TID INFUSION WHICH ESSENTIALLY PUTS TO SLEEP ONE THEM SPHERE AT A TIME AND DURING THAT TIME THEY HAVE A TET FOR MEMORY AND LANGUAGE AND THEY WILL BE -- THE PRIMARILY REASON FOR THAT IS TO SAY CAN THE CONTRACTUAL HEMISPHERE OW SPORT MEMORY AND LANGUAGE FUNCTIONS. IF YOU PROPOSE TO TAKE OUT THE HIPPOCAMPUS WHICH IS CRITICAL THEN, OF COURSE, THE SURGERY COULD BE CONTRA INDICATED. THERE IS EVEN DESPITE HAVING DONE THAT TEST THE MAJORITY OF PATIENTS WILL IS SOME DIPS BASED ON HOW CAREFULLY YOU LOOK FOR IT. THIS IS JUST A SUMMARY OF THE COMPLICATIONS FROM THE PUBLISHED STUDIES. THESE ARE THE MAJOR PUBLICATIONS, MAJOR COMPLICATIONS I SHOULD SAY. A COUPLE OF DEATHS THAT WEREN'T SEIZURE RELATED BUT IF YOU LOOK HERE AT LIST. THESE AREN'T TRIVIAL. THEM HI PA RESIS IN -- HEMI PA RESIPARESIS AND THERE ARE SIGNIFICANT EVENTS WITH RESECTING TEMPORAL LOBE. THE CURRENT PROTOCOL IS DESIGNED TO MINIMIZE RISK AND THAT IS WHY WE DESIGNED THE TRIAL THE WAY WE DID. NO NUT INTERVENTION OR -- NO FURTHER INTERVENTION OR PROCEDURE NECESSARY. PHASE ONE IS NONINVASIVE. I MENTIONED THIS. AND I'M JUST HERE I THINK THERE WILL BE SUBJECTS IN PHASE TWO WHO DO HAVE HIPPOCAMPALER IS ROW SIS ALTHOUGH THE MAJORITY OF THE PATIENTS WILL BE PICKED UP ON MRI. I CAN SHOW YOU AN MRI WHAT IT LOOKS LIKE BUT THERE ARE PATIENTS WHO DO -- WHO DO REQUIRE INTRACRANIAL ELEG ELECTRODE RECORDING EVEN IF THE PIP HIPPOCAMPUS HAS OTHER MINOR CHANGES. THE OTHER ATTRACTIVE PART OF THE STUDY THAT IS 6 MONTHS POST-GENE TRANSFER THE STANDARD SURGICAL PROCEDURE AS ROUTINELY PERFORMED AT UCLA WILL BE CARRIED OUT. THIS WAS AN IMPORTANT POINT BECAUSE IT WAS RAISED BY DR. BOHN AND DOCTOR DICHTER IS THROUGH PHASE TWO IF YOU IDENTIFY THE SEE CECE STEWS COME FROM -- SEIZURES COULD FROM WHAT SECTION WHAT HAPPENS IF THEY CHANGE THEIR MIND. RESECTIVE SURGERY IS A PROCEDURE THAT REQUIRES INFORMED CONSENT AND IT AN ELECTIVE PROCEDURE. WE ARE MODIFYING THE PROTOCOL TO THIS. THE COMMITTEE MEMBERS SAID WE DIDN'T DISCUSS THIS APPROPRIATELY BEFORE AND THIS IS EXTREMELY HELPFUL AND THE PROTOCOL HAS BEEN MODIFIED ACCORDINGLY. THE RISK DISCUSSION REALLY IS IS -- IS REALLY REFLECTING ON THE COMMENTS THAT WERE RACED BY MEMBERS OF THE RAC AND BY DR. DICHTER AND I WILL GO THROUGH EACH ONE ONE AT A TIME. THE FIRST ONE IS THE CON FLIBLTCONFLICTOF INTERESTISH SWHIEW ISSUE WITH MYSELF AND NEUROLOGIX SPONSORING THE STUDTY. I'M A FOUNDER AND CONSULTANT. I WILL HAVE NO INVOLVEMENT IN PATIENT RECRUITMENT OR PATIENT CARE OR DATA COLLECTION. THAT WILL BE STATED AND I APOLOGIZE IT IS NOT STATED ON THE CONSENT FORM BUT IT WILL BE COMPLETELY DISCLOSED NOT JUST TO THE REGULATORY BODIES TO INSTITUTIONAL CARE AS WELL AS ANY POTENTIAL OR PRO SPECTTIVE SUBJECT GUSHES DR. FRIED AND STERN INTEREST NO RELATIONSHIP WITH NEUROLOGIX WHATSOEVER. TOXICITY DEATH ON THE SPECIFIC CONSTRAINT. WE WILL BE PROVIDING ADDITIONAL SAFETY DATE DATA TO SUPPORT THE SUB MID TO THE FDA. WE ARE LOOKING AT RODENTS WITH HIGH TITER WITH THE SWITCH IN THE PROMOTER TO SHOES THOSE OF YOU WHO WERE NT AWARE WE DID A LOT OF THE PRECLINICAL DATA HAS BEEN USING THE ADENOINURE RACE AND SINCE THAT TIME WE SHIFTED TO A CBA. WE DON'T BELIEVE THERE IS ENORMOUS DIFFERENCE IN THE PROMOTERS IN TERMS OF PROMOTER STRENGTH. BUT IT AS SLIGHT CHANGE AND SO I THINK IT IS IMPORTANT THAT WE DO ANIMALS AND WE ACCEPT THE RAC COMMENTS THAT IT IS IMPORTANT TO HAVE SPECIFIC DATA ASSOCIATED WITH THE CON CONSTRUCT EVEN THOUGH IT IS A PROMOTER ISSUE. WE HAVE A COLLABORATION WITH DOCTOR MOLE LOW. JUST STARTING. SANTA CRUZUSING THE SAME VIRUS. SO WE WILL BE PROVIDING PRIMARY DAY DATA. I DON'T HAVE THE DATA TO PRESENT TODAY. I THINK WE HAD SUFFICIENT DATA ON EFFICACY AND TOXICITY THAT IT WAS WORTH COMING TO THE RAC AT THIS STAGE. HIPPOCAMPAL SCLEROSIS. I DO ADDRESS THIS IN THE COMMENTS BUT JUST TO EMPHASIZE A COUPLE OF POINTS. FIRST THAT WE HAVE ACTUALLY USED AB IN HUMAN TISSUE OBTAINED FROM THE PATIENTS AND WE PUBLISHD THAT 7 YEARS AGO NOW. AND THE IMPORTANT POINT HERE IS THAT THE EXPRESSION PATTERN WE SKASAW, THE DEGREE OF EXPRESSION WAS EQUICK LEAPT TO WHAT WE SAW IN THE RAT BRAIN WITH THOSE SPECIFIC VIRUSES AND TITERS AT THAT TIME. WE COME A LONG WAY SINCE '97 BUT THERE WERE NO SURPRISES IN TIMES OF ACTUALLY LOOKING AT THAT HUMAN TISSUE WHEN WE PUBLISHD THAT STUDY AT THAT TIME. WE HAVE AN ON GOING COLLABORATION. THE MODELS ARE NOT TRIVIAL. IT IS EASY TO ACUTELY GENERATE SEIZURES BUT TO GENERATE SPONTANEOUS SEE SEIZURE MOD SEL HARD NOT SO MUCH IN TERMS OF - WHAT IS DIFFICULT IS THE 24 HOUR VIDEO AND EG MONITORING OF THE ANIMALS. IT IS HARD ENOUGH DOING IT IN HUMAN SUBJECTS BUT IMAGINE IT IS HARD TO DO IN ANIMALS. ONLY A FEW GROUPS DO THIS WELL. WE STARTED COLLABORATION WITH DR. PITKANEN IN FIN FINLAND AND USING HER MODEL WHERE SHE HAS SHOWED THE SAME CHANGES IN THE HUMAN BRAIN APPARENT WILL THE RAT MODEL AND THAT STUDY WE WILL ALSO BE LOOKING AT. THE NEXT MAJOR COMMENT AND REGARDING THE PROTOCOL WAS THAT EVEN SHE WE HAVE WHERE EVEN THOUGH WE HAVE A BUILT IN RESCUE PROCEDURE WE ARE NOT GOING OUT AND EVERY SPECIFIC CELL CARRYING THE GENE AND WE GOT SOME QUESTIONS REGARDING TO THE SPREAD AND DOING AS WELL. IT IS IMPORTANT TO EMPHASIZE THIS STUDY HERE IN WHICH MICHAEL WEST PUBLISHED SOME TIME AGO BACK THIS # 1990 THE COMPARISON IN THE HIPPOCAMPAL VOLVOLUMES OF RATS VERSUS THE HUMAN HIPPOCAMPUS YOU CAN SEE ALMOST 100 TIMES GREATER VOLUME TO WE ARE TALKING ABOUT AN ENORMOUS INCREASE IN THE HIPPOCAMPUS IN HUMANS. IF YOU LOOK AT OUR ANIMAL EXPERIMENTS AND LOOK AT THE DOSES AND TITERS AND THE VOLUMES WE ARE GIVING, IT IS EQUIVALENT TO CLOSE -- THE VOLUMES ARE A LITTLE BIT SIGNIFICANTLY HIGHER THAT THE RAT STUDIES AND WE ARE CLOSE TO WHERE WE ARE IN TERMS OF TOTAL NUMBER OF GENOMIC PARTICLES PER VOLUMES TRANSDUCED. THE AREA INCLUDES I'M JAY SENT COURT CAL -- ADJACENT COURT CAL REGIONS. NOT ONLY MOVING ON BLOCK THE HIPPOCAMPUS BUT REMOVING PARTICULA TISSUE WHICH IS ADJACENT. WE BELIEVE BASED ON YOUR EXPRESSION DATA IN RATS AND THIS IS JUST TO SHOW HOW KNOW CAL IT IS. THIS IS AB2 AND THIS IT IS THE NP VIRUS AND THE FOCAL TO THE DORSAL AND IN. WE ARE NOT GETTING MASS MASSIVE SPREAD THROUGHOUT THE BRAIN. SUBJECTS UNDERGOING PHASE TWO ARE ATYPICAL AND WILL BE FEW. THIS IS A COMMENT RAISED BY DR. DICHTER. AN IMPORTANT ONE. WE -- THE GARDEN VARIETY SUBJECT PATIENT WITH MESIAL TEMPORAL LOBE EPILEPSY TYPICALLY DON'T REQUIRE PHASE TWO BECAUSE THE IMAGING AND SURFACING EEG IS DEFINE FIVE AND THAT WE CAUSED. THE PHASE TWO PATIENTS ARE MORE COMPLICATED AND ONLY A MINORITY OF REALLY THE PERFECT SUBJECT HERE. THE SUBJECTS WILL BE RARE AND THAT MADE US CONSIDER IF THERE WAS A PROBLEM WITH RECRUITMENT WE MAY WANT TO CONSIDER BROADENING ELIGIBILITY TO INCLUDE THOSE WHO FAILED THE WATR TEST THAT I MENTIONED. THESE GROUPS MAY BE THE IDEAL GROUP FOR GENE THERAPY AS OPPOSED TO TEMPORAL LOBE RESECTION BECAUSE IF THE PATIENTS HAVE BILATERAL DISEASE YOU CAN'T DISSECT BOTH. WE KNOW IF WE GO IN ON THE CONTRALATERAL SIDE AND WE MAY BE SABLE TO GO IN AND DO GENE TRANSFER BILATERALRY. WE WE EXPECT THE EFFECTS ON COGNITIVE FUNCTION TO BE LESS THAN RESECTIVE SURGERY. A SUBJECT GROUP ULTIMATELY TORE GENE TRANSFER. THE REASON WE IS HAVEN'T INCLUDED THESE SUBJECTS IS BECAUSE WE WANTED TO MAINTAIN AND KEEP THE RISK OF THE PROCEDURE BUILT INTO THE STUDY DESIGN AND I THINK BASED ON THE NUMBER OF APPROXIMATELY ONE TO TWO SUBJECTS THAT COME TO PHASE TWO EVALUATION EACH MONTH AT UCLA SO BASED ON THE NUMBERS AND BASED ON THE PERCENTAGE OF THOSE THAT TEALLY END UP HAVING MESIAL TEMPORAL LOBE EPILEPSY WE DO THINK WE CAN RECRUIT THE 6 SUBJECTS IN THE 12-18 MONTH TIME FRAME BASED ON THE PAST EXPERIENCE AND HISTORICAL EXPERIENCE AT UCLA. SUBJECTS SELECTING WE DISCUSSED ELECTING TO FOREGO TEMPORAL RECESSION. THEY ARE TOLD ARE. THAT IS THE FEE DOLT POSITION AND THEY ARE UNDERGOING THE RICKS OF THE PHASE TWO NOT BECAUSE PHASE TWO CONFER IS INFORM BENEFIT BUT BECAUSE IF PHASE TWO IS SUCCESSFUL THEY ACCRUE THE BENEFITS ASSOCIATED WITH RESECTIVE SURGERY. THEREFORE, WHAT WOULD MAKE SOMEONE DEFER SURGERY? IT COULD BE MANY REASONS BUT PROBABLY THE MOST LIKELY IS THAT THIS HE HAVE PERCEIVED SIGNIFICANT BENEFIT AND LIKE ANY NO MAJOR ADVERSE EVENTS. THE IMPORTANT POINT TO EMPHASIZE IS THAT THESE ARE NOT THE SUBJECTS THAT ARE MOST LIKELY GOING TO NEED RES CUES. THE PATIENTS WITH COMPLICATIONS AREN'T GOING TO BE THE ONES THAT SAY NO, WE DON'T WANT RESECTIVE SURGERY NOW. LARGELY FROM A SAFETY ISSUE. ANY FUNCTIONAL STUD SKI A BONUS BUT THERE ARE NOT THAT CRITICAL. IF SAFETY IS NO LONGER A CRITICAL ISSUE THEN IT IS NOT A HUGE PROBLEM BY THE PATIENTS NO LONGER UNDERGOING RESECTION. WE BELIEVE THAT THESE SUBJECTS ARE NO LONGER PROTOCOL VIOLATORS BUT WILL BE FOLLOWED PRO SPECTIVELY BY THE INVESTIGATORS. END IT THERE AND JUST SAY THAT THIS IS A LARGE COLLABORATIVE TEAM WORKING ON THIS PROJECT. DRIVE BAIN LONG STANDING TRW AND MASSACHUSETTS RENA AT MARIO NEGLECTRY INSTITUTION IN MILAN WHO HAS A LONG STANDING RESEARCH HISTORY AND STUDTY THE PHYSIOLOGY IN EPILEPSY AND AND DA WHO WORKED ON THE PROJECT AS PART OF A PL DID THESIS AND SEVERAL OTHER INVESTIGATORS WITH HAVE LONG STANDING INTEREST IN NPY OR EPILEPSY. THANK YOU VERY MUCH.

DR. DURING, THANK YOU VERY MUCH. WE WILL GO FORWARD WITH THE PUBLIC REVIEW AND I WILL ASK OUR REVIEWERS TO BE CERTAIN TO SUMMARIZE EACH OF THEIR WRITTEN COMMENTS OR CONCERNS AND TO TELL US HOW IT WAS RESOLVED, IF IT WAS AND IF IT WAS NOT RESOLVED TO MAKE THAT CLEAR. WE'RE GOING TO BEGIN WITH THE AD HOC REVIEWER. DR. MARC DICHTER FROM THE UNIVERSITY OF PENNSYLVANIA. DR. DICHTER. YES, YES, I'M HERE. THE WEBCAST IS A LITTLE BEHIND YOU BECAUSE I WAS WATCHING THAT. IS THAT RIGHT?

A SLIGHT DELAY.

BECAUSE DR. DURING IS STILL TALKING.

NOT SUCH A SLIGHT DELAY.

OKAY. HOW DO YOU WANT ME TO PROCEED WITH THE EVALUATION IN GENERAL NOR RELATION TO HOW THE GROUP HAS RESPONDED TO MY CRITIQUE?

I NEED TO ASK YOU TO PUBLICLY STATE EACH OF THE WRITTEN COMMENTS OR CONCERNS THAT YOU SUBMITTED TO THE RAC AND THEN TO SAY AS YOU GO FROM POINT TO POINT WHETHER THAT POINT WAS RESOLVED BY DR. DURING'S PRESENTATION AS WELL AS HIS WRITTEN RESPONSE. IT IT WAS RESOLVED, HOW WAS IT RESOLVED AND IF IT WAS NOT RESOLVED, TO PLEASE BE CLEAR WITH US THAT IT WAS NOT RESOLVED TO YOUR SASKATCHEWAN. IS TO JOB SATISFACTION.

TOCAI.

IS THAT DRK.

THANK YOU.

I DIDN'T RELY ALYZE THAT WAS THE FORM MAT. MY COMMENTS I HAVE THE SONS FROM DR. DURING IN FRONT OF ME WHICH I THINK CONTAINS ALL OF MY COMMENTS.

IT DOES.

I WILL START WITH THAT. FIRST, LET PEE STATE THAT I THOUGHT -- LET ME STATE THAT I THOUGHT THAT THIS WAS A VERY INTERESTING AND IMPORTANT AND VERY WELL DONE PROTOCOL. I WATCHED THE TELECAST IN DR. DURING'S PRESENTATION AND I BASICALLY AGREED WITH EVERYTHING THAT HE PRESENTED VIS-A-VIS THE EPILEPSY PROBLEM. I -- KIND OF APPRECIATE THAT HE APPRECIATES THAT MY -- SOME OF MY COMMENTS ABOUT THE COMPLEXITY OF THE ISSUES AND SOME OF THE NUANCES OF THE PROTOCOL AND INFORMED CONSENT WERE USEFUL AND AS FAR AS I CAN TELL THEY WERE ALL CORRECTED AND I WILL GO THROUGH IT POINT BY POINT. SO, I WAS FAVORABLY IMPRESSED BY THE INITIAL PROPOSAL, THE -- THE CRITIQUE I HAD FOCUSED ON TWO ISSUES. ONE WHICH I'M AN EXPERT IN WHICH IS THE ISSUE OF THE EPILEPSY AND THE BIOLOGY OF EPILEPTIC TISSUE AND A FEW QUESTIONS RELATED TO VIRUS SPREAD AND VECTOR SPREAD WHICH I RAISED BUT WOULD BE HAPPY TO REDETER TO EXPERTS IN THAT AREA ON THE COMMITTEE. THE FIRST ISSUE OF THE POTENTIAL RISK OF SUD DONE UNEXPLAINED DEATH. THIS IS A VERY IMPORTANT BUT CLOUDY ISSUE. PEOPLE WITH EPILEPSY ARE OCCASIONALLY FOUND DEAD IN BED OR DIE SUDDENLY FOR UNEXPLAINED REASONS. WE DON'T KNOW BECAUSE OF -- WE DON'T KNOW WHY THOSE OCCUR WHEN THEY ARE CARDIAC EVENTS OR SOMETHING SEPARATE. THEY ARE USUALLY NOT SEIZURES. AT LEAST NOT THE TRADITION AT THE PATIENTS HAS. BECAUSE OFTEN THEY ARE FOUND IN UNMESSED UP BEDS. JUST LYING THERE QUIETLY DEAD AND WHERE YA'S THE NORMAL SEIZURES WOULD HAVE CAUSED THEM TO MESS UP THE BED COVERS OR DO SOMETHING, YOU KNOW SHES CLEARLY UNUSUAL. ALTHOUGH THEY COULD BE A DIFFERENT KIND OF SEE SEIZURE THE PATIENT HAD. SINCE THERE IS A RISK OF THIS DELAYING SURGERY BY 6 MONTHS POTENTIALLY INCREASES THE PATIENT'S VERY, VERY SMALL RISK OF THIS HAPPENING SO I THOUGHT THAT WAS WORTH INCLUDEING THAT IF THE INFORMED CONSENT AND IN THE CONSIDERATION I THINK DR. DURING ADDRESSED THAT IN SAYING THEY WOULD DO THAT. THE APPROPRIATE CANDIDATE ISSUE DR. DURING SPOKE DURING THE END OF HIS TALK. AN IMPORTANT ISSUE WHICH HE ADDRESSED IN RESPONSE VERY WELL. THAT IS THE EASY PATIENTS WHO HAVE CLEAR TEMPORAL LOBE DISEASE ARE THE ONES THAT DON'T REQUIRE PHASE TWO EVALUATION. THE ONES WHO DO REQUIRE FACE TWO ARE MORE COMPLICATED PATIENTS AND PERCENTAGE OF THOSE PATIENTS IN WHO YOU FIND UNI LAT LATERAL PIP HOECAMPUS. ONE IS APPEARING TO BE THE DISEASE ORGAN WOULD BE IN TEDDED TO BE MOVE -- INTENDED TO BE REMOVED TO THAT WILL EXPAND THE PATIENT SUBJECT POPULATION A BIT BUT THEY ROW COG NICE THIS AND I THINK IT IS BUILT INTO THE -- RECOGNIZE THAT AND THAT IS BUILT INTO THE PROTOCOL AND THAT IS FINE. IN ADDITION, I THOUGHT THERE OUGHT TO BE BECAUSE THE CRITERIA FOR HOW TO SELECT AND CANDIDATES ARE NOT EUROPEAN FORM ACROSS EPILEPSY CENTERS IT WOULD BE WORTH MAKING SURE THAT THE PROTOCOL SPECIFIED IN ADVANCE WHAT TIE TEARIA WOULD BE USED TO SELECT THE PATIENTS AND ALTHOUGH I HAVEN'T SEEN THE FINAL PIECE IT IS APPARENT THAT THAT ISSUE IS GOING TO BE ADDRESSED AND BE MORE SPECIFIC.

ARE YOU SATISFIED WITH THE RESPONSE TO THAT PORTION OF YOUR COMMENT?

YES. -- WELL, YES -- I YES, GUESS YES BUT. I THINK THE SONS THAT THEY ARE GOING TO A-- THE RESPONSE THAT THEY ARE GOING TO ADDRESS THIS. I THINK IN THE PROTOCOL THEY NEED TO ADDRESS IT FORMALLY AND I DIDN'T SEE A DOCUMENT THAT WOULD ADDRESS THAT. MY ASSUMPTION IS THIS WOULD BE AN ISSUE FOR THEIR INTERNAL IRB AS MATCH IS THE RAC. IS THAT A QUALIFIED, YES?

ALMOST A FULL YES.

OKAY. GOOD. THE NEXT ISSUE IS NUMBER FOUR, WHAT HAPPENS IF THE SEIZURES DISAPPEAR AND AGAIN THE INVESTIGATORS ARE AWARE OF THIS. IT IS A -- IT IS A MAJOR KIND OF MORAL AS WELL AS MEDICAL CON NUMBER DRCONUNDRUM LET'S SAY THE EXPERIMENT IS SUCCESSFUL BEYOND THE WILDEST DREAMS AND EACH OF THE PATE SHENTS STOP HAVING SEIZURES. IT IS A THEORETICAL POSSIBILITY. WOULD WOULD MAKE THEM COME IN AND HAVE A TEMPORAL LOBECTOMY MONTHS LATER, IF IT WERE ME I WOULD NOT. I WOULD EXPECT THAT MANY OF THE PATIENTS WOULD FEEL THE SAME WAY AND THERE IS NO -- THERE IS NO WAY OF CO-ERSING OR FORCING AN INDIVIDUAL TO HAVE NEUROSURGERY BECAUSE THEY SIGNED UP SIX MONTHS AGO FOR A PROTOCOL. I THINK THE INVESTIGATORS ARE AWARE OF THIS. I THINK IT IS SOMETHING THAT WE ALL HAVE TO BE AWARE IS A POSSIBLE POTENTIAL OUTCOME AND IN M MANY SENSES IT WOULD BE A POSITIVE OUTCOME ASSUMING THERE ARE NO DILL TEAROUS' DILL LA TEAROUS EFFECT BUT IT NEEDS TO BE ADDRESSED AND I THINK IT WAS. I WOULD GUESS THEY WERE RELUCTANT TO ADDRESS THIS ISSUE FOR FEAR OF APPEARING TO BE TOO OPOPTIMISTIC IN THE PHASE OF AN EARLY SAFETY TRIAL. I HOPE THAT MEANS IT IS ADEQUATELY ADDRESSED. NUMBER FIVE WAS THE ISSUE OF WHETHER OR NOT THE DATA FROM THE RACs ARE SUFFICIENT. THE INFECTION LIKE TOY TO SPREAD. DR.-- LIKELY TO SPREAD. ALTHOUGH THEY DON'T [ INDISCERNIBLE ] THEY GOING TO BE LOOKED AT THEM AND DR. DURING MENTIOND THAT IN MISS REMARKS TOWARDS THE END. I DON'T KNOW HOW FAR RAC WANTS TO PURSUE THAT. THAT IS WAIT FOR THE DATA OR ASSUME THAT THE DATA WE HAVE IS SUFFICIENT. I'M MORE INTERESTED IN THE DATA FROM THE 7 SUBJECTS WHO HAVE ALREADY HAD THE AAV FROM PASH KIPARKINSON'S DISEASE. IT IS SAME VECTOR WITH A DIFFERENT GENE AND ALTHOUGH IT AS DIFFERENT PART OF THE BRAIN AND A DIFFERENT PATIENT POPULATION AT LEAST FROM THE PERSPECTIVE OF THE GENE TRANSFER ISSUES IN FLAMATION AND SPREAD, WHATEVER INFORMATION IS AA. AVAILABLE FROM THAT GROUP PATIENTS WOULD BE USEFUL AND I THINK DR. DURING SAID THEY WILL PROVIDE AS MUCH OF THAT INFORMATION AS THEY HAVE AVAILABLE. MOVING ON TO NUMBER 6. BY THE WAY, THE RESPONSES THAT I GOT WERE WELL ORGANIZED AND EASY FOR ME TO AND ANALYZE AND I WANT TO COMMEND THE PRINCIPAL INVESTIGATORS FOR THAT. THE ISSUE OF THE NORMAL RATS VERSUS EPILEP IT ITTIC RATS. IT IS SOMETHING THAT THE AUTHORS BROUGHT UP EARLIER AND IT IS WORTH DOING. I DON'T THINK IT IT IS A PROBLEM THAT WOULD DERAIL THIS PROTOCOL. I'M SATISFIED WITH THAT RESPONSE. THE -- MY ISSUE NUMBER 7 WAS SOMETHING THAT WAS ALSO RAISED BY OTHER REVIEWERS AND THEY ARE -- THEY RESPONDED ADEQUATELY THAT IS THAT THE STUDY IS A SAFETY TRIAL AND NOT AN EFFICACY TRIAL SO THEY HAVE TO BE CAREFUL WHAT HIGH POT CEASE THEY ARE THEY -- HIGH POT THAT SIS THEY ARE PRO SOSING. THE DOSE WAS INCORRECTLY REPORTED. THAT CAME UP IN MY COMMENTS. AND IT WAS APPARENTLY A TYPE POE GRAPH IBLGAL ERROR LEAVING OUT THE NUMBER. THERE WAS A MIXTURE THERE SO THAT WAS ADEQUATELY TAKEN CARE OF. NUMBER NINE. IT WAS MORE OF A SCIENTIFIC ISSUE THE GLEIAL CELLS TRAN SECTED AND APPARENTLY THEY ARE NOT AND I'M SATISFIED WITH THAT EXPLANATION. NUMBER TEN WAS A SCIENTIFIC ISSUE ABOUT WHETHER OR NOT THERE COULD BE INHIBITION OF THE INURE NEURONS BY THE OVER EXPRESS OBJECTION OF NPY. THIS WAS A MINE DWROR POINT VIS-A-VIS THE HUMAN PROTOCOL. 11 WAS SIMILAR TO WHAT WE SK USED BEFORE TO GET THE DATA FROM THE HUMAN PARKINSON'S TRIAL SINCE THAT IS THE OTHER HUMAN TRIAL WITH VECTOR AND THAT IS ADDRESS THE. NUMBER 12 IS THE ISSUE OF WHETHER THE AV NPY VECTOR TRAN SECTED JUST NEURONS OR A SUBSET. IT IS NO THERE IT NO SUBTYPE SPESPECIFICITY OF THE TRANSINVESTIGATION AND THAT IS FINE. B WAS OF THE ANIMAL ISSUE WHICH WAS ADDRESSED. THREE -- C WAS AGAIN WHAT I DID WAS -- GOING -- WE I WAS -- WHEN I WAS GOING THROUGH THE PROTOCOL SPECIFICALLY AS OPPOSED TO THE MATERIAL I HAD FONT EARLIER I GOT THE PROTOCOL I GUESS LATER SOME OF THE SAME ISSUES CAME UP BECAUSE THEY WERE MORE FORMALLY STATED IN THE IRB PROTOCOL SO I ENDED UP MAKING STATEMENTS TO BOTH. C WAS THE ISSUE OF THE -- THE STRICT ABOUT THE CRITERIA THAT UCLA EPIEPILEPSY GROUP TO USE TO OFFER UNI LATERAL RESECTION. D WAS AGAIN THE VIRAL VECTOR ISSUE WHICH HAS BEEN FIXED. E WAS A MINOR ISSUE OF THE WORD EXTENSIVE AND HOW THE PIs USED IT VERSUS HOW I INTERPRETED IT AND I THINK THAT HAS BEEN ADEQUATELY ADDRESSED. THAT IS THE EXTENT OF MY COMMENTS AND THEY WERE ALL VERY ADEQUATELY ADDRESSED. I THINK THE ONE THING THAT REQUIRES A LITTLE BIT MORE DETAIL ALTHOUGH THE INTENTION TO ADDRESS IT WAS CLIERLY STATED WAS THE SPECIFICITY IN THE PROTOCOL ABOUT THE HOW THE PATIENTS WOULD BE SELECTED OR PATIENTS THE UCLA ARE SELECTED FOR UNI LATERAL TEMPORAL LOBECTOMY.

WE WILL MOVE ON TO DOCTOR MARTHA BOHN FOR YOUR SECOND REVIEW.

I ALSO FELT THIS WAS A VERY STRONG PROPOSAL BECAUSE OF THE IN INCLUDION OF A NICE RESCUE APPROACH. AND THE IMPORTANCE OF HAVING A RESCUE APPROACH IN GENE DELIVERY TO THE NERVOUS SYSTEM.

I'M HAVING A HARD TIME HEARING?

I'M OKAY.

YOU CAN'T HEAR ME?

I THANK DR. DURING FOR HIS CLEAR PRESENTATION WHICH ADDRESSED MOTT OF MY POINTS. -- MOST OF MY POINTS SO I WILL GO THROUGH THESE. HE -- DR. DURING HAS CLARIFIED THE QUESTION OF CON FLIBLTHS OF INTEREST BETWEEN THIS PROTOCOL AND HIS ROLL IN NEUROLOGIX WHICH WAS A CONCERN OF A NUMBER OF THE REVIEWERS. WHAT IS THE PROBLEM?

OH A.

GO AHEAD.

SO I -- THERE WERE SOME STATEMENTS IN THE ABSTRACTS WHICH I THOUGHT WERE MISLEADING FOR THE PATIENTS IN THAT IT WAS -- IT IS CLEAR TO US THAT THE LONG-TERM GOAL OF THIS IS TO DELIVER THE GENE AND THEN IF IT IS EFFICACIOUS NOT TO HAVE TO GO THROUGH THE MEDIAL TEMPORAL LOBE LOBECTOMY BUT THE WAY IS CAME ACROSS IN THE ABSTRACTS IT WASN'T CLEAR THAT THIS PROTOCOL DOES INVOLVE AT LEAST THE WAY IT IS WRITTEN THE LOBECTOMY AND DR. DURING HAS AGREED TO CLARIFY THAT. IT WAS ALSO NOT CLEAR IN THE ABSTRACTS THAT THE VECTOR WOULD BE ADMINISTERED BY THE DEPTH ELECTRODE AND THAT IS ALSO EASY TO CLARIFY. ME MAJOR CONCERN ON THE PRECLINICAL DATA PRESENTED WAS THAT THE DATA WERE ALL PERFORMED WITH THE DIFFERENT VECTOR CONTAINING THE NSE PROMOTER AND AEV2 RATHER THAN THIS KY MARE RICK AAZ12SERO TYPE IN WHICH NPY WAS DRIVEN BY THE CPA PROMOTER. IT WAS STATED THIS MORNING THAT THESE TOXICITY DATA WOULD BE GATHERED WITH THE VECTOR TO BE USED IN CLINICAL TRIALS AND I THINK THAT IS ABSOLUTELY ESSENTIAL AND IT WILL BE VERY INFORMATIVE TO HAVE THOSE DATA IN THE NONHUMAN RIMATE.

I HAD A QUESTION ABOUT HOW THE RESECTED TISSUE WOULD BE HANDLED AND STUDIED IN ADDITION TO DETERMINING THE NPY EXPRESSION IN PCR AND IMMUNOCYTIC AND IS RESPONSE THAT THEY WILL BE ANALYZED FOR CELL INFILTRATION AND INFLAMMATION AND MAY ALSO BE USED FOR ETROKE EELECTROFOYS YOELECTROPHYSIOLOGICAL STUDIES. I THINK THIS IS AN IMPORTANT ASPECT OF THE PROTOCOL AND ONE OF THE FEW PROTOCOLS WHERE ONE HAS CNF TISSUE AVAILABLE TO LOOK AT WHAT REALLY IS THE EFFECT OF THE GENE DELIVERY AND WHICH CELLS ARE INFECTED AND TO HAVE A SHORT-TERM GLIMPSE OF GENE TRANSFER EFFECTS IN THE NERVOUS SYSTEM. I ALSO BROUGHT UP THE ISSUE THAT MARC DICHTER JUST DISCUSSED AT LENGTH ABOUT WITH THE PATIENTS WOULD -- WHETHER THE PATIENTS WOULD HAVE AN OPTION OF CANCELLING THE LOBECTOMY SHOULD THEY INFER THAT THEY HAVE A BENEFIT OF THE NPY GENE DELIVERY. I THINK THAT HAS BEEN ADDRESSED VERY WELL AND I AGREE THAT THAT WOULD BE A POSITIVE JUT COME. MY QUESTION -- OUTCOME. MY QUESTION REMAINS WHETHER THE PROTOCOL WOULD THEN ADD MORE PATIENTS SO THAT YOU HAVE THE DATA NECESSARY TO SUPPORT THE PROPOSAL AS STATED OR WHETHER THE POE POSAL WOULD ACTUALLY -- THE PROPOSAL WOULD ACTUALLY BE CHANGED. IF YOU HAVE SAMPLE NO. THREE, WHERE YOU WANT ALL THESE JUT COME DATA, WOULD YOU ADD MORE -- MORE -- MORE INDIVIDUALS WHERE MORE SUBJECTS TO THE TRIAL? MY -- ANOTHER CONCERN WAS OR QUESTION WAS WHETHER IF ALTHOUGH IT IS NOT SOMEONE -- ALTHOUGH IT IS NOT ANTICIPATED THAT THE NPY GENE DELIVERY WOULD INCREASE THE FREQUENCY OF SEIZURES, THERE IS ONE HAS TO CONSIDER THE POSSIBILITY THAT THERE WOULD BE DELITERIOUS JUT COMES OF THE GENE TRANSFER AND THE QUESTION WOULD BE WHAT THE CRITERIA WOULD BE FOR AN EARLY LOBEECTOMY. AND THAT HAS BEEN ADDRESSED THAT THE CLINICAL INVESTIGATORS COULD -- COULD MAKE A DETERMINATION OF AN ARELY RESCUE STRATEGY -- AN AIRY RESCUE STRATEGY SHOULD THAT OCCUR. I ALSO ASKED THE QUESTION OF WHETHER THE VECTOR WOULD BE -- MIGHT BE TRANSPORTED TO THE CONTRALATERAL HIPPOCAMPUS WHERE THE RESCUE STRATEGY DOES NOT APPLY. IT IS CLEAR THAT AEV IS TRANSPORTED AND TIEROR GRADELY AND RETROGRADELY. SOME OF THE RAT DATA SHOWED THAT. IT WILL BE INTERESTING TO SEE TO WHAT EXTENT WITH COMPARABLE DOSES IN THE MO ARMOSETS THIS DOES OCCUR. THE RESPONSE WOULD BE THAT THE RESCUE STRATEGY COULD BE APPLIED TO THE CONTRALATERAL BRAIN AS I UNDERAND IT IT SO THERE IS THAT SAFEGUARD. IS IS IT LIKELY THAT HIPPOCAMPAL SKA SCLEROSIS WILL INTERFERE WITH VECTOR INFECTION AND DISTRIBUTION. I GUESS I'M NOT FULLY CLEAR. PERHAPS YOU CAN FULLY ELUCIDATE WHAT YOUR FEELING IT ON THIS, DR. DURING.

AND LET ME JUST FINISH AND MAYBE WE CAN COME BACK TO THAT. I ASKED ABOUT THE 48 NUKE LEE TIDE DELEGES IN CDA PRO POTER. IT WAS CLARIFIED THIS IS THE SAME PROMOTER BEING USE IN THE PARKINSON'S TRIAL. CORRECT ME IF I'M WRONG BUT I THINK THAT TRIAL IS AV2. IT WOULD BE NICE TO HAVE AN SCRUM DATE ONMY PROBLEMS -- J. UP A DATE ON ANY PROBLEMS WITH THAT STUDY IN THAT IS A DIFFERENT SERO TYPE VECTOR. I HAD A QUESTION ON PBS AS THE OPTIMAL VEHICLE FOR VECTOR DELIVERY AND HOW THE INVESTIGATORS WOULD DETERMINE THE PERCENT OF PACKAGED PARTICLES IN THE VECTOR STOCKS AND WHETHER AGGREGATION OF THE PARTICLES WOULD BE -- COULD BE MINIMIZED AT THE HIGH DOSES TO BE DELIVERED. I DON'T THINK THE ANSWERS FULLY INFORMATIVE ON THAT RESPECT. PERHAPS YOU COULD LET US KNOW WHETHER YOU DO LOOK AT THESE VECTORS BY EM TO DETERMINE THE PERCENT PACKAGED PARTICLES. OTHER PROTOCOLS SEEM TO HAVE SOME KIND OF CARRIER TO MINIMIZE ABSORPTION OF THE AAV AND -- AEV AND ALSO AGGREGATION. I HAD A QUESTION ON THE VEKT -- WHY ONLY TWO VECTOR DOSES AND A VOLUME THAT WAS SIX TIMES HIGHER AND TEN TIMES MORE CONCENTRATED THAN IN THE PARK KIPARKINSON'S TRIAL. I THINK THAT HAS BEEN ADDRESSED THAT YOU ARE TRYING TO TARGET A MUCH LARGER AREA OF THE BRAIN AND HIT MANY MORE NEURONS THAN THE SUBTHAT WILL SUBTHALAMIC NUCLEUS. I QUESTION WHETHER THE NTERVAL IS LONG ENOUGH TO ASSESS POSSIBLE DILL TEAROUS AFFECTS AND THAT IS THE SAME QUESTION APPLIES TO THE TWO-WEEK INTERVAL BETWEEN SUBJECTS. THE ANSWER AGAIN IS BASED ON THE PROTOCOL IN THE PARKINSON'S TRIAL. I MIGHT SUGGEST THAT THE SYSTEM IS SO MUCH DIFFERENT ONE MIGHT WANT TO HAVE A LITTLE BIT LONGER DELAY BETWEEN DOES CO-HART HORTS -- COHORTS. AND I HAD SOME QUESTIONS ON THE STATISTICAL ANALYSIS OF THE RODENT DATA AND THOSE -- THAT CONCERN WAS ADDRESSED. AND THEN FINALLY I HAD SOME COMMENTS ON THE -- THE CONSENT FORM AND THE INVESTIGATOR'S HAVE SUCCESSFULLY MODIFIED THE CONSENT FORM TO CLARIFY SOME OF THISH SHIES BROUGHT UP BY BOTH MYSELF AND DOCTOR POWERS. -- BY BOTH MYSELF AND DR. POWERS.

DR. DURING, WOULD YOU LIKE TO RESPOND TO SOME OF THE REMAINING QUESTIONS THAT DR. BOHN HAS POSED?

RIGHT. THANKS VERY MUCH, DR. BOHN AND I VERO BEACH APPRECIATE YOUR COMCOMPREHENSIVE REVIEW. IT IS HELPFUL IN TEMPERATURES OF SHAPING THE PROTOCOL. THE MAJOR UNANNED THE FIRST IS NUMBER 11 OF THE HIPPOCAMPAL SCLEROSIS DEALING WITH THE GENE TRANSFER. CAN YOU HEAR ME OKAY. I THINK AS YOU -- IT IS ADDRESSED THE MAJOR ET OF THE SUBJECTS WITH THE SEVERE HIPPOCAMPAL SKA LOW SIS, IF -- SCLEROSIS. I WANT TO SHOW JU SOMETHING. CAN WE TURN -- SHOW YOU SOMETHING. CAN WE TURN THE --

THIS IS AN MRI. CORE OHAL MR I AND THE PATIENT IS FACING YOU. THE RIGHT-HAND SIDE AND LEFT-HAND SIDE AND CUT THRAOI SECTION AND THE TEMPORAL LOBE MERE. MEDIAL TEMPORAL LOBE. ALL OF YOU WILL NOTICE THAT EVEN ON THIS THIS IS THE HIPPO CAMAPUS THIS STRUCTURE. YOU CAN SEE THE AFORE MUST AND FULLY DEFINED AND CLEARLY ATROPHIED. THAT IS THE STANDARD OF THE SUBJECTS. THOSE PATIENTS DON'T REQUIRE PHASE TWO EVALUATION. THEY ALMOST --

I'M NOT HEARING DRDZ DURING.

IS THAT YOU, MAC?

THAT IS BETTER.

MUCH BETTER.

CAN YOU HEAR ME OKAY?

YEAH.

CAN YOU SEE THE IMAGE?

ME?

YEAH.

WITH DELAYED.

OKAY. SO BASICALLY THE IMPORTANT POINT HERE IS THAT THESE ARE THE SUBJECTS -- THE GARDEN VARIETY THAT DR. DICHTER DISCUSSD THAT COME TO SURGERY AFTER PHASE ONE AND ARE NOT THE SUBJECTS THAT REQUIRE INTRACRANIAL ELECTRODES. THE SUBJECTS WE WILL BE STUDYING HERE -- WE CAN HAVE THE LIGHTS BACK ON. THE JUBT T SUBJECTS WE ARE STUDYING WILL HAVE AND TOMORROW MIXLY A -- ANNA TOMORROWICLY RELATIVELY NORM TAL. THEY WON'T HAVE THE SAME DRAMATIC DEGREE OF SCLEROSIS THAT WE SEE HERE. EVEN WITH SCLEROSIS THERE IS STILL A LOT OF CELLS THAT PERSIST AND AS WE PUBLISHED IN THE EPILEPSY PAPER THOSE ARE EXACTLY THE HIPPOCAMPAL SLICES WE STUDIED WERE THE EARLY AGAIN TION AB VIRUS IN '87 OR '86 AND WE WERE ABLE TO GET TRANSDUCKS. WE TRANS-- TRANSDUCTION. THE TRANSGENE. THE EARLIER SLIDES I SHOW YOUKED UP THE UP REGULATION PY OF THOSE. WE DO NOTE THAT CRITICAL ISSUE IS THAT THE SCLA ROTIC HIPPOCAMPUS DOES EX-PREBS THE Y2 RECEPTOR AND HAVE A SUFFICIENT TARGET CELL POPULATION TO TRANSDUCE WHERE OUR PRIMARY GOAL OF GETTING THE GENE IN AND GETTING THE NPY PROTEIN ACT [ INDISCERNIBLE ] IS ALL INTACT. THERE IS NO BE TEXT MODEL THAT -- PROSECUTOR TEXT MOD THAT WILL REFLECTS THE HUMAN CONDITION AS WE DID DISCUSS IT S. THAT WE ARE STUDYING IN COLLABORATION WITH DR. PITKANEN THE CHRONICALLY EPILEPTIC RATS. THEY HAVE MANY OF THE SAME PATH THOUGH LOGICAL CHANGES THAT WE OBSERVED THIS THIS BRAIN HERE AND THAT WILL BE A HIGHER LFL OF COMFORT THAT WE WILL BE ABLE TO GET GOOD TRANSDUCTION AND EFFICACY. I HOPE THAT IS ADEQUATE. IT ANY OTHER QUESTIONS? ANYTHING ELSE ON THAT?

MY OTHER QUESTIONS WERE ON THE VECTOR QUALITY CONTROL.

RIGHT, WE HAD -- WE HAVE A VERY STANDARD QUITE A -- I THINK WE -- WE PRIDE OUR RELEASE KY TEARIA SHEETS ON HOW WE CHARACTERIZE OUR VIRUS. AT THIS STAGE WE DON'T HAVE EM AS A SPECIFIC CRITERIA RELEASE LOT CRITERIA ALTHOUGH WE HAVE DONE EM ON SOME OF THE STOCKS. WE HAVE MODIFIED THE PLACE PLASMAS TO KEEP THAT DOWN. AND WHY WE -- WHEN WE FIRST GENERAT RATED AB NOW WE HAVE THE NEW HELPERS WITH THE RATIO OF [ INDISCERNIBLE ] FULLY INTACT IS ROUGHLY ONE ONE TO ONE. WE GET THAT INFORMATION IN PART THROUGH THE PHYSICAL AND GENOMIY TITER SO THE ASSUMPTION IS THAT DIFFERENCE RELATES TO EMPTY SO YOU DON'T HAVE TO DO AN EM TO SEE WHAT THE GENOMIC TITER IS. AND INFECTIOUS TIT ERR AND THAT A FAIRLY COMPREHENSIVE. THEEING A GENTLEMAN SAGES ISSUE WE OURSELVES HAVE NOT HAD A PROBLEM WITH KLUM PING OR AGGREGATION SUFFICIENT TO INTERFERE WITH TRANSDUCTION OR INFECTIVITY OF THE VIRUS AND I KNOW THERE HAS BEEN A LOT OF WORK AT TRYING TO OPTIMIZE THE BUFFERS AND MEDIANS BUT WE HAVE BEEN HAPPY WITH OUR EXPERIENCE WITH THE MEDIUM WE ARE USING RIGHT NOW.

AND WHAT ABOUT WHETHER THE NUMBER OF -- THE NUMBER OF INDIVIDUALS ENROLLED WOULD CHANGE IN YOU -- IF IT IS -- IF THERE IS AN EFFICACIOUS EFFECT?

I THINK -- THIS IS A -- THAT YOU KNOW, A SAFETY STUDY ANDED BIG QUESTION QUESTION IS CAN WE ADEQUATELY ASSESS SAFETY WITHOUT HAVING TO REMOVE THE TEMPORAL LOBE. AND IT IS THAT, YES, WE CAN. WE WILL OBTAIN THAT DATA REGARDLESS OF WHETHER OR NOT THE PATIENTS WERE TO. I THINK THE WEAKNESSES AND IT WOULD BE NICE TO HAVE MORE SUBJECTS FOR SCIENTIFIC ADD-ONS SAY STUDYING THE SLICES. I THINK ETHICALLY THE QUESTION IS -- TWO ISSUES. YOU COULDN'T FORCE THOSE TO HAVE -- WAS IT JUSTIFIABLE THEN TO EXTEND THE STUDY AND I THINK I PERSONALLY PREFER TO MOVE AT THAT STAGE FORWARD TOWARDS A PHASE TWO STUDY IF WE HAVE SAFETY ON SIX PATIENTS BECAUSE I THINK WE CAN CAD QATLY ADDRESS THE SAFETY ISSUE WITHOUT HAVING TEMPORAL RESECTION.

I THINK THE ANALYSIS OF THE TEMPORAL LOBE IS VERY IMPORTANT TO THE DESIGN OF THIS PROTOCOL. YOU KNOW, THE -- THE INFORMATION THAT YOU ARE GOING TO OBTAIN FROM THAT. FEARS T PERCENT MALTLY, I WOULD LIKE TO -- PERSONALLY, I WOULD LIKE TO SEE THE STUDY AS PROPOSED COMPLETED SO THAT IF INDIVIDUALS OPTED OUT OF THE STUDY AND DIDN'T HAVE THE LOBECTOMY YOU WOULD STILL HAVE THE --

RIGHT.

-- HAVE ALL THE INFORMATION THAT HAD BEEN PROPOSED.

TO TWO THINGS THERE. ONE IS THE STUDY DESIGN HAS BEEN MODIFIED AS I MENTIONED SO THAT IT IS NO LONGER OPTING OUT. THAT IS ONE. IT THERE IS SIGNIFICANT BENEFIT SO THEY WILL STILL COMPLETE THE STUDY IT IS JUST THE END POINT IS NO LONGER SURGICAL RESECTION. THAT WAS DESIGNED AS A RISK PROCEDURE FOR THOSE PATIENTS WHO WOULD NOT BENEFIT AND SO IT IS AN AD ON SAFETY COMPONENT BUT IT ISN'T ACTUALLY A DEFINITIVE DETERMINANT OF THE SAFETY AND TOLL LETTERABILITY. -- TOLERABILITY.

I THINK IF OTHER MEMBERS OF THE RAC WHO FUNDAMENTAL STRONGLY ABOUT THIS ISSUE WE WOULD BE PREPARED TO EBBS TEND THE STUDY. THE PROBLEM THAT WE HAVE HERE, OF COURSE, IS I THINK DR. DICHTER EXPLAINED IS THAT RECRUITMENT WILL NOT BE SIMPLE AND WILL TAKE TIME AND I THINK 6 SUBJECTS AT THIS STAGE SHOULD PROVIDE US SUFFICIENT SAFETY DATA.

I'M NOT SURE YOU WERE HERE EARLY THIS MORNING WHEN DR. DEMETS PUT UP THE TABLE ABOUT WHETHER YOU WOULD GET STAFFTY INFORMATIOSAFETY INFORMATION FROM FIVE INDIVIDUALS, RIGHT. SO WITH THREE INDIVIDUALS IN A GROUP, I'M NOT SURE HOW MEANINGFUL THAT SAFETY DATA ARE. AND HAVING MORE INFORMATION ON WHETHER THERE IS INFILTRATIONS OF CELLS, ET CETERA IN THE, YOU KNOW, THE TISSUE THAT IS REMOVED DOES ADD SIGNIFICANTLY TO THE STRENGTH OF YOUR PROPOSAL. AT THAT TIME' -- THAT IS WHAT I'M SAYING.

I MEAN I THINK WE WOULD BE HAPPY TO IN THAT CONTEXT EXTEND THE STUDY. I MEAN THE LIKELIHOOD THAT ANY ONE PATIENT IS NOT GOING HAVE RESECTIVE SEARCHRY WOULD BE A VERY POSITIVE OUTCOME IN A SENSE AND I THINK I DON'T WANT TO ARGUE SOMETHING THAT I THINK IS EXTREMELY LOW PROVABILITY EVENT BUT I THINK WE WOULD BE HAPPY TO EXTEND THE STUDY. THE PROBLEM IS IT COULD BE A SITUATION THERE IS NO END AND IF IT WORKED EXTREMELY WELL, THEY THEN WE COULD END UNDER WITH AN OPEN-ENDED PROBLEM THAT ANY PATIENT WANTS TO HAVE RESECTIVE SURGERY. THERE HAS TO BE A LIMIT IN TERMS OF THE NUMBERS WE ENROLL HERE. I DON'T THINK YOU CAN DEFINE -- THE MOMENT YOU ACKNOWLEDGE THAT IT IS A POSSIBILITY PATIENTS MAY NOT CONSENT TO HAVE A RESECTION YOU HAVE TO ACKNOWLEDGE YOU MAY NEVER COLLECT A CERTAIN [ INDISCERNIBLE ]

WHAT ABOUT THE DURATION OF TIME THAT THE PROTOCOL CURRENTLY ALLOWS BETWEEN COHORTS? I BELIEVE IT IS AT ONE MONTH AS WELL AS THE INTERVAL BETWEEN SUBJECTS WHICH CURRENTLY IS AT TWO WEEKS? DR. BOHN HAD A QUESTION ABOUT THAT AS WELL.

IT IS AN EXTREMELY GOOD COMMENT. THE -- THE --ED FDA OBVIOUSLY IS INTERESTED IN THIS QUESTION OF COURSE, BECAUSE THEY WOULD LIKE TO SEE THAT YOU DON'T ENROLL A SECTION PATIENT OR MOVE UP DOSE COHORTS UNTIL YOU REACHED A PEAK EXPRESSION AND LIKELY TO SEE ANY ADVERSE ACUTE EVENT THAT YOU WILL SEE. WE HAVE SHOWN THAT WITH AB2 AND THAT EXPRESSION PEAKS WITHIN 2002 TO THREE WEEKS AND WE SHOWED TWO WEEKS AT MAXIMUM AND THERE WAS NO SIGNIFICANT DIFFERENCE AND THAT IS WHERE WE GOT IN THE TWO WEEK INTERVAL AND ACTUAL ENROLLMENTS HAVE BEEN SLOWER THAN THAT. WE PUT THAT AS AS MINIMUM M THE PARKINSON'S TRIAL AND ENROLLED PATIENTS NO EARLIER THAN A MONTH BETWEEN PAY SHENS AND AT RE PATIENTS AND TWO MONTHS BETWEEN THE COULD HORTS. I -- COHORTS. I THINK WE WOULD BE HAPPY TO REVISE THOSE -- TO THOSE MINIMUMS BECAUSE THEY ARE NOT PRACTICAL IN TERMS OF RECRUITMENT ANYWAY. THEY ARE ACCELERATED WHICH IS INCONSISTENT WITH THE POPULATION GROUP AND I THINK YOU POINT IS VALID THAT WE WOULD BE HAPPY TO EXTEND THOSE TIMES AND DOUBLE EACH OF THOSE TIME OF POINTS I THINK IS REASONABLE.

OKAY. THANK YOU.

THEN WE ARE GOING TO MOVE ON TO DR. DEWHURST'S REVIEW.

I WAS ALSO IMPRESSED BY THE PROTOCOL AND PIGGY BACKING ON AN EXISTING PROCEDURE. AND IT IS OBVIOUSLY A VERY IMPORTANT AND THOUGHTFULLY CON STRUBTED PROPOSAL. -- CON STRUBLTHED PRO -- CONSTRUCTED PROPOSAL. MY QUESTIONS RELATED O TO A NUMBER AREAS THAT HAD BEEN DISCUSS.

SPEAK DIRECTLY INTO THE SPEAKER PHONE FOR ME, PLEASE.

THE ANSWER IS NO, HE CAN'T SPEAK INTO THE SPEAKER PHONE BUT WE WE CAN WORK ON GETTING THE MIKE UP.

OKAY. THE FIRST TWO QUESTIONS I HAD RELATED TO POTENTIAL CONFLICTS OF INTEREST AND THOSE HAVE EELLY ALREADY BEEN ADDRESSED FINANCIAL AND OTHER COME CONFLICTS. I HAD A QUESTION ABOUT THE CBA PRO POTPROMOTER AND THAT HAS BEEN DISCUSSED AT CONSIDERABLE LENGTH SO I AM GOING TO MOVE ON FROM THAT. I HAD A QUESTION ABOUT THE ABILITY TO PHARMACOLOGICALLY LIMIT THE RECEPTORS AND AS DR. DURING POINTED OUT IN HIS PRESENTATION THOSE MOLECULES ARE NOT A FEASIBLE APPROACH AT THE PRESENT TIME AND WOULD HAVE BROADLY SYSTEMIC EFFECTS IF THEY WERE AVAILABLE. THE FIFTH POINT I RAISED RELATES TO THE NATURE OF THE MODELS IN WHICH THE PRECLINICAL DATA HAS BEEN GENERATED AND SO THE CRITICAL ISSUE HERE REALLY RELATES TO THE PLANNED STUDIES WITH DR. PITKANEN AND THAT IS THE USE OF A MODEL SYSTEM THAT PERHAPS MORE ACCURATELY REPRESENTS THE HUMAN CONDITION. THAT IS THE CHRONIC MODEL THAT DOLLARS DURING DR.-- THAT DR. DURING DISCUSS TAD HE POE POSES TO GENERATE DATA IN. I WOULD LIKE DR. DURING'S RESPONSE REALLY ON THE POSSIBILITY FOR EXAMPLE IF THE STUDIES WITH DR. PITKANEN REVEAL THAT THE APPROACH IS LESS EFFECTIVE IN THIS CHRONIC MODEL EXACTLY HOW WOULD THAT INFLUENCE GOING FORWARD HERE? AND WHAT WOULD THE PLAN BE IN THAT DISAPPOINTING EVENT WHETHER IT RESULTS TO BE -- WERE THE RESULTS TO BE LESS POSITIVE THAN THE INITIAL PRECLINICAL DATA IN THE KINDLING AND KINITE MODELS? I THEN HAD A QUESTION REALLY ABOUT THE DURATION OF THE PRECLINICAL STUDIES REPORT THEED.

THE "SCIENCE" ARTICLE AND THE REEE TEXT OF THE GENE THERAPY. OVERALL I THOUGHT THE RESPONSE PROVIDE THE WAS SOLID. ONE THING I PERSONALLY DON'T UNDERSTAND AND THIS IS JUST MY OWN IGNORANCE PERHAPS BUT I WOULD FIND IT HELPFUL IF DR. DURING DO COULD EX-PLANK TO ME WHY THE DRUGS FAILED. ONE OF THE THINGS I AM IMPRESSED BY WHEN YOU SHOWED WAS THE FACT THAT THE DRUGS FAILED LATE THAT THE PATIENTS. THEY TWO TEN YEARS AND THEN THE DRUG FAILS AND I WONDER IF THERE WAS AN UNDERSTANDING OF WHY THAT IS AND IF THAT HAS ANY RELEVANCE TO THE USE OF A GENE THERAPY OR OTHER APPROACH IN TERMS OF DURABILITY OF EFFECT? THE 7th POINT I RAISED RELATES TO PREEXISTING ANTIBODIES PARTICULARLY DIRECTED AGAINST THE AAV VECTOR. DR. DURING MADE A RESPONSE ESSENTIALLY STATING I GUESS A COUPLE OF THING. ONE IS THAT THERE IS REALLY NO AUK TEPT SEPTEMBERED CERTIFIED TEST FOR AAV AND THE TIE BODIES WHICH -- ANTIBODIES WHICH, OF COURSE, IS SUGGEST AND THERE IS NO DATA TO SUGGEST THAT NEUTRALIZING ANTIBODIES WOULD HAVE AN EFFECT ON GENE TRAN FEAR. HAVING SAID THAT ALSO IN RERESUEING THE LITERATURE I NOTICE THERE WAS A RECENT PAPER FROM THE LAB THAT RELATES TO THIS QUESTION AND THERE WAS AN EXTENSIVE DISCUSSION IN THE ARTICLE WHICH HAS BEEN MADE AVAILABLE HERE AND THAT SCULLINGS RELATED TO THE FACT THAT CSH -- THAT DISCUSSION RELATED TO THE FACT IT IS DIFFICULT TO EXTRAPOLATE WHAT THE HUMAN LEVELS OF ANTIBODIES ARE SO I WOULD LIKE DR. DURING'S COMMENT ON WHETHER OR NO THERE IS VALUE ON TRYING TO MEASURE THE PATIENT ANTIBODY LEVELS TO CORRELATE THAT WITH SAFETY OR EFFICACY OR EVEN TO CONSIDER THE USE OF SUCH ASSAYS AS POTENTIAL EX-CLUE OBJECTION -- EXCLUSION. I HAD A QUESTION OF ABOUT THE REPO DEUCEABLE AND RELIABILITY AND THOSE WERE THOROUGHLY ADDRESSED. A QUESTION WITH STUDY EX-CLUE OBJECTIONS FOR IMMUNE DIE PITCH SHENT INDIVIDUAL T AND -- DEFICIENT AND THAT WAS A SUFFICIENT RESPONSE AND THE WAY IN WHICH THE SIR RINGS WITH BOW STAITERAISLIZED AND THAT WAS SPONGED TO. A QUESTION ABOUT FUNDING WHICH HAS BEEN A I DRESSED. A QUESTION ABOUT MANUFACTURING. THAT I WAS JUST STRUCK BY THE FACT THAT THE VECTOR IS BEING PREPARED AT ONE SITE IN A DIFFERENT COUNTRY AND THEN SHIPPED OVER HERE. BUT THERE IS REALLY -- NOTHING IN PRINCIPLE WRONG WITH THAT AND DR. DURING HAS A VERY APPROPRIATE RESPONSE. MINOR OMISSIONS IN THE APPENDIX M WHICH WILL BE INCLUDED AND THEN I HAD TWO SUGGESTIONS ON THE CONSENT FORM. ONE TO EXTEND THE CONTR EPS TOMALES AS WELL AS FEMALES AND THERE WAS AN APPROPRIATE RESPONSE AND A MINEON CMOANT ON TERMINOLOGY IN THE -- COMMENT ON TERMINOLOGY IN THE CONSENT FORM AND THE RESPONSE IS APPROPRIATE. I GUESS RESPOND TO A COUPLE OF THE POINTS I MADE, PLEASE.

THANK YOU VERY MUCH FOR YOUR COMMENTS. THE FIRST COMMENT WAS WHAT WOULD HAPPEN IF WE DIDN'T GET YEAH, IT IS -- IT IS -- THIS -- I GUESS THE QUESTION EELLY RELATES TO HOW -- REAMLY RELATES TO. FIRST, THERE IS TWO ISSUES. IS THAT LIKELY TO HAPPEN. I THINK THE ANSWER TO THAT IS PRETTY STRONGLY NO BECAUSE THIS IS A MODEL THAT ALL DRUGS WHICH PREVIOUS TO THE EYE CUTE MODELS HAVE -- ACUTE MODELS HAVE SHOWN EFFICACY AND THERE WASN'T ANY SURPRISES YET. IT WAS DEVELOPED TO SEE ARE ANY OF THESE DRUGS ABLE TO PREVENT EELECTROGENESIS. AFTER THE EVENT AND THE MATURE ACTS OF THE SEMATURE -- MATURATION OF THE SEIZURE. MOST OF THE CURRENT DRUGS IF NOT ALL FAILED. AND INTRINSICALLY THOSE DRUGS DON'T STOP THE MATURATION BUT THEY DO DECREASE THE SPONTANEOUS SEIZURE. WE WILL NOT BE TESTING TO SEE WHETHER OR NOT THE NPY PREVEEPT VENTS THE MATURATION OF THE SEIZURE. THE QUESTION IS WILL IT IMPACT ON THE UPON UPON STAINOUS AND SEIZURES AND IF IT DOESN'T WORK WE WOULD HAVE TO THINK IS THERE SOMETHING NIEWRNL UNUSUAL ABOUT THE EXPRESSION AND RESEM CENTERS BECAUSE EVERYTHING WE KNOW ABOUT PHYSIOLOGY SUGGESTS IN YOU PUT WATER ON FIRE TH THEFIRE GOES OUT. IF IT DOESN'T GO OUT, WAS IT REALLY WATER. WE WOULD WANT TO DO ADDITIONAL SUD DID IS AND KNOW WE IT DOESN'T WORK IF IT IT DOESEN AND BE HAPPY TO SHARE THE DATA AND WE INTEND TO PRESENT THAT DATA AND PUBLISH IT AS NECESSARY. I THINK THE KEY HERE IS THAT EVERYTHING WE KNOW ABOUT NPY FUNCTION IN THE HIPPOCAMPUS PREDICTS IT WILL HAVE AN EFFECT ON THE TYPE AND WE HAVE TO MAKE SURE WE DO THE STUDY WELL. THE SECOND QUESTION IS THE LONGEVITY OF THE STUDIES. I THINK WE -- I THINK WE ADEQUATELY ADDRESSED THE LONGEVITY OF THE STUDIES. ARE YOU HAPPY WITH THAT.

IA.

THE NEXT ONE OF THE THE AND DIE BODY IMMUNOLOGICAL.

ONE QUESTION FOR MY OWN EDUCATION IS WHY THE DRUGS FAIL IN THE PATIENTS IN TEN YEARS.

THIS IS I MUCH PREFER DR. DICHTER TO RESPOND TO THAT. THIS IS AN AREA WHERE A LOT OF CLINICAL NEUROLOGISTS ARE LOOKING AT. THEY FAIL REMARKABLY QUICKLY. EVEN WIN THE FIRST YEAR 20-25% FAIL AND THEN WIN FIVE YEARS AND THIS RELATES TO WHEN THEY ACTUALLY HAVE A SEE SEIZURE. THEY POTENTIALLY FAIL EARLIER BUT THEY MAY NOT HAVE REPEATED SEIZURES TO WHEN DO YOU DEFINE THE FAILURE RATE. WHY AND WHAT IS IT ABOUT THE PROBLEM THAT THESE DRUGS HAVE ALL -- NONE OF THESE DRUGS HAVE POTENTIALLY VERY, VERY POTENT BECAUSE THEY ARE ALWAYS TO DEVELOP A GOOD END YOU HAVE TO A HAVE A BROAD THERAPEUTIC INDEX. A DRUG THAT YOU CAN TAB AND INCREASE THE AMOUNT AND SOMEONE IS NOT GOING TO FALL OVER IN A COMA AND COLLAPSE. THE MOST POTENT COMPOUNDS YOU CANNOT USE IT BECAUSE IT WOULD BE ABOVE THE THERAPEUTIC INDEX. YOU HAVE TO DEVELOP THE DRUGS TO MODULATE AND THAT ISN'T SUFFICIENT TO TREAT A DISEASE THAT HAS FIES YO LOGIC CAL AND ANNAND AND ANATOMORROW TOMICAL. YOU HAMPERED WITH THE DOSES. GIVE TOO MUCH AND YOU GET SIDE EFFECTS AND YOU HAVE TO DEVELOP THAT DRUG THAT IS NOT THE MOST WALKING AROUND AND FUNCTIONING REASONABLY WELL. WHAT YOU ARE TRYING TO DO IS COMPLETE PLI DAMPEN DOWN THE ACTIVITY. THAT IS WHY THE SUNRY WORKS WELL AND A MOBILE MOW CENTRALIZED DELIVERY DO THE -- DRUG THAT WOULD DO I THINK I HOPE THAT WAS SUFFICIENT. OUT THERE AND IF YOU LOOK AT THE HUMAN ANTIBODY DATA THE BEST STUDIES PUBLISHED NEUTRAL LYZING ANTIBODIES TO ADENOVIRUS AND FOUND THAT 30% OF SUB JEBS HAD AV AND 30% ADENOVIRUS. DESPITE THAT THEY HAD NO PROBLEMS WITH SUBSEQUENT GENE TRANSFER AND WITH AV THE TITERS THAT HE WAS FINDING, THE MAJORITY WAS ABOUT 30% OF THE POPULATION HAD TITERS THAT THE THRESHOLD WAS 100 TO 1 GO DROPPED TO 15% IF YOU DROP DOWN TO 200 TO 1 AND THERE WERE A FEW SCATTERED PAY SHENS WITH THE HIGHEST TITERS AROUND 700 OR SO. CONTRASTING THAT TO THE STUDY IN WHICH THEY HAD TITERS OF 51,000 THE RELEVANCE OF THAT STUDY IS IS QUESTIONABLE. IT IS TWO ORDERS ABOVE OR AT LEAST AN ORDER ABOVE THE MAGNITUDE OF ANTIBODY TITERS THAT WE HAVE EVER SEEN CLINICALLY. THE CLOSEST STUDY TO THE CLINICAL SITUATION IS THE STUDY IN WHICH THEY IMMUNIZED AND HAD TITERS TO TWO PROTOCOLS IN WHICH THE LOW DOSE GROUP HAD ANTIBODY TITERS AROUND 4 OR 500 WHICH IS MORE CRITICAL AND THE HIGH DOAT HAS 1200 WHICH IS IS LITTLE HIGHER THAN WHAT YOU HAVE SEEN CLINICALLY USING SIMILAR STRATEGIES. AT THE LOW DOSE THIS HAD NO EFFECT AT ALL ON GENE TRANSFER [ INDISCERNIBLE ] I THINK FROM THAT -- I THINK THERE IS -- I THINK THERE IS THE DRAMATIC EFFECTS PUBLISHED BY THE FLORIDA GROUP ARE PROBABLY NOT REFLECTTH THE HUMAN SITUATION AND THE STUDY I THINK WITH PROBABLY PREDICTS THINKS A LITTLE MORE CLOSELY SUGGESTS THAT AT THE COMMON TITERS WOO OULD NOT EX-PECS TO SEE MUCH EFFECT. THERE IS AN AREA WHICH IS TOO MUCH CONTROVERSY IN THE LITERATURE AND INTO CONSISTENT PATTERN AND WORTHY OF ATIGSAL THOUGHT. WE DON'T THINK THAT THE TATE THAT SUGGESTS THERE IS A STRONG ENOUGH RATIONALE TO INTERFERE WITH THE RECRUITMENT O PROCESS.

SOKY SEE CERTAINLY THAT THAT MAY BE NO BASIS FOREX INCLUDING PATIENTS FROM THE STUDY ON THE BASIS OF AN AND ANTIBODY TEST BUT TO THE KYMERIC1 VECTOR. IT WOULD SEEM THAT I HAD WONDERED ABOUT WHETHER OR NOT IN A MANUFACTURING SETTING WHETHER IT WOULD LEAD TO LOT TO LOT VARIATION IN MANUFACTURING AND THE RESPONSE IS THAT THERE APPEARS TO BE NONE SO I WOULD TAKE THAT AT FACE VALUE. THE SECOND ISSUE THAT I HAD RAISED WAS A CLARIFICATION IF ABOUT THE GENETIC SEQUENCES IN CORN RATED INTO THE VECTOR AND I THINK MATT RESPONDED ADEQUATELY TO THAT AND IT IS BASED ON SUB201. THE FINAL COMMENT I WOULD HAVE WOULD BE TO URGE THE INVESTIGATORS TO LOOK AT THE ANTIBODY STATUS NOT TO EXCLUDE OR INCLUDE ANYBODY ON THE BASIS OF THEIR ANTIAV TITERS BUT THIS IS AN OPPORTUNITY WHERE WE COULD ACTUALLY STUDY THE -- EFFECT OF PREEXISTING IMMUNITY ON GENE TRANSDUCTION BECAUSE IN SOME CASES IN THIS TRIAL YOU MAY HAVE THE OPPORTUNITY TO STUDY TIESH SHOES AND YOU -- TISSUES AND YOU COULD DO A PLOT OF GENE TRANSDUCTION VERSUS ANTIBODY TITE HES SO I THINK IT WOULD BY IMPORTANT TO FOLLOW UP ON THE COMMENT THAT THE DATA SHOULD BE COLLECTED AND ANALYZED AND I'LL STOP THERE.

THANK YOU. I AGREE THAT IS AN EXCELLENT POINT.

ANY COMMENTS FROM THE RA MEMBERS? YES. DR.-- I NOTICE IN YOUR PROTOCOL CAL THAT YOU WERE GOING TO MONITOR THE PATIENTS ONE MONTH, THREE AND SIX MONTHS AFTER INJECTION. HOW WOULD YOU SUGGEST THAT THAT SEEMS -- NOT QUITE AN INTENSIVE MONITORING. AT LEAST BY PHONE I WOULD THINK SINCE THE EFFECTS MAY BE PROLONGED THAT YOU WOULD WANT TO LOOK AT THE PATIENTS EVERY MONTH. I DON'T MEAN AN M RI EVERY MONTH BUT CERTAINLY AN EVALUATION OF SEIZURES AND ANY TYPE OF CLINICAL EVALUATION.

THE SEIZURE LOG IS KEPT FREQUENTLY AND THERE IS A TWO WEEK WHICH ACTUAL AND I'M SORRY I DIDN'T INCLUDE THAT. I JUST HAD THE MAJOR FOLLOW UP END POINTS ON THE SLIDE. I AGREE WITH THAT POINT.

DR. SIMARI.

I WOULD LIKE TO FOLLOW-UP ON COMMENTS THAT DR. BOHN MADE REGARDINGTY SHIEWR AND I'M TRYING TO UNDERSTAND. I APPRECIATE YOIR INKJET TRODUCTION REGARDING THE DISEASE PROCESS. WHAT IS THE LIKELIHOOD OF SOMEONE REMAINING SEIZURE FREE OVER A 6 MONTH PERIOD WITH A PLACEBO TREATMENT OR IN A CONTROL GROUP OF THE SURGICAL STUDIES? I PRESENT THE ONE YEAR DATA WHICH IS SIMILAR. DIFFERENT THAN THE OF 6 MONTHS AND 12 MONTHS IS NOT MUCH. AND I DON'T KNOW IF -- THE ONE YEAR THAT ONLY 8% DIDN'T HAVE SEIZURES AND AT MY RECOLLECTION IS THAT IT WOULD BE -- IT IS -- IT WOULD BE SOME WHERE BETWEEN 8-# 25% THAT ARE AT 6 MONTHS DID NOT IS ZEE SEIZURES OR REMAINED SEIZURE FREE. A SMALL PERCENTAGE. MAYBE EVEN AS MUCH AS 25% WHO COULD BE SEIZURE FREE AFTER 6 MONTHS AND THAT IS A POSSIBILITY.

ALTHOUGH THERE MIGHT BE AN ADDITIONAL PLACEBO?

IT IS INTERESTING. EPILEPSY IS NOT AS PRONE TO PLACEBO EFFECTS AND THIS FORM OF EPILEPSY AS MANY OTHER NEUROLOGICAL DISEASES WHERE AN EPILEPTIC EVENT IS A DRAMATIC EVENT. WE ARE EXCLUDING PATIENTS WITH SIGH QUPSYCHOGENIC SEIZURES. THERE IS A SMALL EFFECT IN EPILEPSY AS OPPOSED TO OTHER NURL CONDITIONS. IT WILL BE BON AND BEYOND MEDICAL TREATMENT AND MAY NOT BE REACTIVE TO THE GENE TRANSFER AND WE HAVE TO DO A CONTROLLED SUBSEQUENT PHASE TWO STUDY.

I ECHODR. BOHN'S COMMENTS THAT THE TISSUE WILL BE HELPFUL TO SORT OUT THAT ANALOGY AND I REMAIN CONFUSED BY THE TERM RES KARESCUE STRATEGY. I DON'T KNOW HOW TO PUT THAT IN THE -- DR. DURING?

I THINK IT IS -- IT IS -- IF FOR EXAMPLE WE HAD AN EXIT SUD SKI AND THERE WAS ZERO WHICH WOULD POTENTIALLY WANT US NEED TO LIKE CAREFULLY AT WAS AND SHOWN THAT THAT IT DOES MY OWN FEELING IS THAT IF THE I HATE HIGH BOTH HIGH BOTH SIZING. WE O I HAVE TO SHARE THE DATA BUT NO POINT SPENDING A LOT OF TIME ON SOMETHING THAT IS

I MADE ONE OF THE COMMENTS ABOUT THE RAT MODELS. THE RAT EPILEPSY MODELS AND I -- I CAN'T HEAR DOLLARS GS RESPONSES TO THE QUESTIONS. I MAY BE REPEATING WHAT HE SAID. I'M SORRY WR BUT MY VIEW IS THAT THE UTILITY OF THE EPILEPSY MODEL WAS MORE FOR ISSUES OF SPREAD OF THE VIRUS OF TRANSSECTION OF ALTERED BRAIN ISSUE IN AN EPILEPSY MODEL RATHER THAN EFFICACY IN THE MODEL BECAUSE THE MODELS THAT WE HAVE AVAILABLE AND THE ONES THAT THE DOCTOR USED ARE NOT REALLY ADEQUATE MODELS OF THE HUMAN CONDITION IN THE SENSE THAT THE SEIZURES ARE MUCH, MUCH MORE DA VEER AND PROBABLY NOT LOCALIZED TO THE HIPPOCAMPUS. THERE IS SOME QUESTION WHETHER THE HIPPOCAMPUS ARE INVOLVED IN THE SEIZURES AT ALL OR ONLY TOWARD THE END OF THE ZEE ZIEWRS IN THE MODELS. A NEGATIVE EFFICACY STUDY WOULD NOT BE GREATLY DISCOURAGING IN THE RAT MODEL. IT MIGHT BE MILDLY OF NOTE. BUT IN MY OPINION TO DO THE STUDIES WAS FOR THE ISSUES OF SAFETY AND VIRAL SPREAD IN ALTERED BRAIN TISSUE WHERE A LOT OF DATA EXISTS IN THE NORMAL BRAIN TISSUE SO I WOULD NOT RECOMMEND ALTERING NECESSARILY THE SCIENTIFIC CONCEPT OF THIS TRANSVECTION BASED ON A NECK NEGATIVE EFFICACY STUDY IN THE RAD MODELS -- RAT MODELS BECAUSE THEY ARE NOT ADEQUATE OF THE HUMAN CONDITION. AND ESSENTIAL ESSENTIAL CON TRAINT ON THE PIS IF THAT IS WHAT THE COMMITTEE INTENT WAS.

THANK YOU VERY MUCH FOR YOUR COMMENT. I WILL READ A SECTION FROM THIS SECOND RECOMMENDATION. RAC SUPPORTS THE PI INTENT TO COMPLETE PRECLINICAL STUDIES IN A CRON IB CHRONIC EPILEPSY RAT MODEL AND PRY MAT FOR A AND TRANSGENE PRIOR TO.

IT IS PERFECT BUT IT WAS THE SUBSEQUENT DISCUSSION ABOUT THE ISSUE OF WHAT HAPPENS IF IT TURNS OUT NOT TO BE EFFICACIOUS THAT CAUSE MID PREVIOUS COMMENT.

I THINK THAT WAS AN IMPORTANT CLARIFICATION. THANK YOU VERY MUCH. ANY OTHER COMMENTS FROM THE RAC OR THE PUBLIC? DR. DURING?

JUST I -- I JUST WANT TO THANK PARTICULARLY DR. DICHTER WHO SPENT A LOT OF TIME AND EVERY MEMBER OF THE COMMITTEE WHO DID A COMPREHENSIVE. IT IS DIFFICULT KNOWING AT WHAT STAGE IN THE EASTBOUND EVOLUTION APPROACH TO PRESENT. MY FEELING IS THAT I HOPE THAT THE COMMITTEE FELT THAT THIS WAS APPROPRIATELY MATURE PD AND A REASONABLE TIME TO DISCUSS THIS EVEN THOUGH WE DON'T HAVE ALL THE SAFETY DATA IN HAND AND WE CERTAINLY APPRECIATE THE INPUT. TANK YOU VERY MUCH ALL THE MEMBERS.

AND THANK YOU, DR. DURING. THIS IS I THINK LOW PRESSURE THE PERFECT STAGE FOR A -- ALMOST THE PERFECT STAGE TO COME TO THE RAC BECAUSE IT IS NOT SO MATURE THAT THERE IS NO ROOM LEFT FOR INPUT BUT MATURE ENOUGH TO GIVE US SUBSTANCE TO COMMENT ON. I APPRECIATE THE THOROUGH REVIEW AND DISCUSSION. LET'S GO AHEAD AND VOTE. DOCTOR POWERS.

WE NEED A FIRST AND A SECOND.

WE NEED A FIRST AND A SECOND. WHO WOULD LIKE TO GIVE US A FIRST FOR THIS PROTOCOL?

I RECOMMEND WE ACCEPT THE RECOMMENDATIONS AS STATED.

THANK YOU, I WAS GOING TO TRY TO SHUFFLE THEM THROUGH. SECOND.

DOCTOR GELHRTER. OKAY. NOW, LET'S VOTE.

POWERS, YAE.

NEWNEMEROW AYE. BARKLEY AYE. DURED AYE. DA LUCA, YES.

AIL BELL DA AYE.

DEMETS? YES.

ROSEING BERG.

AYE.

AND DOCTOR JOHNSON?

AYE. THANK YOU, SIR. ALL RIGHT. ON THAT NOTE OUR BUSINESS IS COMPLETE. AND I WOULD LIKE TO THANK EVERYONE FOR THEIR PARTICIPATION THIS MORNING AND LOOK FORWARD TO OUR NEXT MEETING IN DECEMBER. THANK YOU VERY MUCH.

THIS MEETING IS HERE BY ADJOURNED.