>> WELCOME TO THE PEOPLE ONLINE, ON THE PHONE, IN THE AUDIENCE.
COULD WE CHECK IN TO SEE WHO IS ON THE PHONE? IS JOAN STILL ON?
>> HI, I'M HERE. >> THANK YOU, JOAN.
SUSAN COOLEY? >> STILL HERE, YES.
>> DEB ULSZER? NOT YET.
ELLEN BLACKWELL? IS THERE ANYONE ON THE PHONE WHOSE NAME I
DIDN'T CALL? >> HI, LAURIE, YES, I'M HERE.
>> THANK YOU, ELLEN. WE HAVE AN ACTION PACKED AFTERNOON, AND TO
START US OFF IF YOU REMEMBER WE WERE GOING TO HAVE FOR EACH OF THE COMMITTEE MEETINGS,
ONE OF THE SUBCOMMITTEES THINKS THROUGH AND ORGANIZES THE SESSION, WE'RE STARTING WITH
THE RESEARCH WORKING GROUP. I'M GOING TO TURN IT OVER TO YOU, ANGELA,
TO INTRODUCE THIS SESSION. >> ALL RIGHT.
SO TODAY'S SESSION IS GOING TO FOCUS ON THE PATH FROM IDENTIFYING TARGETS TO THE EVOLUTION
TO TREATMENTS. LOOKING AT THINGS FROM A BASIC SCIENCE STAND
POINT HAS NOT BEEN COVERED IN THE PAST NUMBER OF YEARS, AND SO I'M GOING TO REALLY JUST
RELY LARGELY ON BRAD AND ALLAN TO LEAD OUR SESSION TODAY.
MY JOB IS REALLY ONLY AS A TIME KEEPER. SO I CAN'T SEE THEM.
IT WILL BE HARD TO NUDGE THEM WITHOUT BUTTING IN IF WE RUN LONG.
I WANT TO THANK THEM, AND IN THE FINE STYLE OF NO GOOD DEED GOES UNPUNISHED, THEY GOT
HANDED A JOB RIGHT OFF THE BAT AS NEW SUBCOMMITTEE MEMBERS.
SO REALLY THANK THEM FOR THEIR LEADERSHIP IN THIS SESSION.
>> WELL, THANK YOU VERY MUCH, ANGELA. MY NAME IS ALLAN LEVEY, I WANT TO THANK BRAD
AND RICHARD HODES DESERVES RECOGNITION. TOGETHER WE WORKED TO HELP ORGANIZE THE SITUATION
THIS AFTERNOON, I WANT TO THANK IN ADVANCE THE SPEAKERS.
SO AS LAURIE JUST AS ANGELA JUST MENTIONED, EXCUSE ME, WHAT WE WANT TO DO IS FRAME A LITTLE
BIT WHAT WE'RE GOING TO TALK ABOUT THIS AFTERNOON. TO REMIND EVERYBODY ON THE SLIDE HERE, WITH
THE NATIONAL PLAN, THE FIRST BULLET POINT TO REMIND EVERYBODY IS PREVENT AND EFFECTIVELY
TREAT ALZHEIMER'S DISEASE BY 2025, SOMETHING NONE OF US NEED REMINDING ABOUT.
THERE'S A LOT OF URGENCY AND WE HAVE A WAYS TO GO.
BUT THAT'S WHAT WE WANT TO TALK ABOUT, SOME OF THE BIOLOGICAL PROGRESS AND WHERE WE ARE
IN THE ROAD MAP IN THIS DOMAIN. AND AS WE TALKED ABOUT THIS MORNING WITH THE
FRAMEWORK FOR VISUALIZING ALL THE EFFORTS UNDERWAY, WE HAVE THE NATIONAL SUMMITS THAT
HAVE OCCURRED THAT REALLY HELP DRIVE THE RECOMMENDATIONS THAT CAN BE USED THEN TO INSPIRE SCIENCE ACROSS
THE COUNTRY, TO MOVE FORWARD. AND SO DR. HODES THIS MORNING MENTIONED WE
HAVE THE UPCOMING A.D. SUMMIT IN TWO MONTHS WHICH WE'RE LOOKING FORWARD TO.
THERE ARE A VARIETY OF THEMES AND AREAS OF EMPHASIS THAT SCIENTISTS ACROSS THE COUNTRY
HAVE BEEN PLANNING MAKING RECOMMENDATIONS HAVE BEEN ADVOCATING FOR.
AND WHAT WE'LL TALK ABOUT THIS AFTERNOON IS SOME OF THE PROGRESS THAT'S BEEN MADE ALONG
THE WAY. AND JUST TO FRAME FOR THOSE WHO DON'T THINK
ABOUT THIS ON A REGULAR BASIS, SORT OF HOW I THINK WE AS A RESEARCH COMMUNITY HAVE BEEN
THINKING ABOUT ALZHEIMER'S DISEASE AND RELATED DEMENTIAS, AND HERE I REALLY MEAN RELATED
DEMENTIAS AS MUCH AS ALZHEIMER'S DISEASE. BUT THIS IS A POPULAR SLIDE IN THE SCIENTIFIC
COMMUNITY WHICH SHOWS ON THE Y AXIS THE DEGREE OF CHANGE IN DIFFERENT THINGS WE MEASURE.
SO DOWN AT THE BOTTOM IS TYPICALLY NORMAL, AS THE LINE GOES UP THINGS ARE CHANGING FROM
NORMAL TO ABNORMAL. AND THEN ACROSS THE X AXIS WE'RE LOOKING AT
TIME. SO IMAGINE AN INDIVIDUAL OVER TIME, THERE'S
A DEVELOPMENT IN THE BRAIN, FIRST OF AMYLOID PLAQUES, WHICH YOU SEE IN THE RED CURVE THERE.
AND THEN ON THE FAR RIGHT IS OF COURSE THE MOST IMPORTANT ELEMENT, WHICH IS CLINICAL
FUNCTION. SO WHEN DOES A PERSON BECOME SYMPTOMATIC?
AND WHETHER THIS IS SYMPTOMATIC WITH MEMORY LOSS, SYMPTOMATIC WITH HALLUCINATIONS, IT
MIGHT OCCUR IN DLB OR ANOTHER PROBLEM WITH VASCULAR OR FTD, IT'S WHEN WE FIRST BECOME
AWARE OF THE CLINICAL SYMPTOMS OF THE DISEASE. AND THE RULE THAT WE'RE LEARNING FOR THIS
WHOLE FAMILY OF DISEASES FROM THE TREMENDOUS RESEARCH ADVANCES OVER THE LAST DECADE HAS
BEEN THAT ALL THESE PATHOLOGIES ARE VERY HETEROGENEOUS, WHICH WE'RE GOING TO TALK ABOUT, AND THEY
ALL BEGIN BEFORE SYMPTOMS TYPICALLY. AND SO IT PROVIDES OPPORTUNITIES AND CHALLENGES
THAT WE'RE GOING TO TALK ABOUT TOWARDS TREATMENT. SO THE COMMUNITY HAS LARGELY BEEN FOCUSED
ON THE DEVELOPMENT OF THE AMYLOID PLAQUES AND THEN NEUROFIBRILLARY TANGLE, DR. HODES
TALKED ABOUT THE PROGRAM AIMED AT DISCOVERING OTHER TARGETS, USING GENOME WIDE INFORMATION
WE'RE LEARNING ABOUT, AT A GENOMIC LEVEL, RNA LEVEL, PROTEIN, LIPIDOMICS, METABOLOMICS
LEVEL, HOW DO WE USE A BROADER BASE OF INFORMATION ABOUT WHAT HAPPENS IN THE BRAIN TO INFORM
TREATMENTS, WHETHER THAT'S A DRUG TREATMENT OR BEHAVIORAL TREATMENT.
HOW DO WE BEGIN TO USE WHAT WE'RE UNDERSTANDING THE DISEASE IS ACTUALLY DRIVEN BY IN A SMART
WAY TO MONITOR. SO, WITH THAT, WE'VE ALSO KNOWN THAT WE'RE
MOVING THE NEEDLE ON WHERE WE ENROLL PEOPLE IN CLINICAL TRIALS.
IT'S ONLY RECENTLY WE'VE BEGUN TO THINK ABOUT GETTING PEOPLE INVOLVED IN CLINICAL TRIALS
AT AN EARLIER STAGE. MANY OF THE FAILURES THAT WE'VE KNOWN WE'VE
HAD HAVE REALLY RESULTED FROM TRIALS WHERE PEOPLE HAVE ONLY BEEN SYMPTOMATIC OR EVEN
MODERATELY SYMPTOMATIC WHEN THEY WERE ENGAGED IN TRIALS FOR THE FIRST TIME.
I'M GOING TO TURN IT OVER TO MY CO CHAIR, DR. HYMAN NOW, TO FINISH THE REST OF OUR INTRODUCTORY
REMARKS.
>> THANK YOU. AND WELCOME, EVERYBODY.
I'D ALSO LIKE TO THANK THE SPEAKERS, OF COURSE, THAT WILL BE COMING.
YOU KNOW, WE'RE REALLY DELIGHTED TO DO THIS. I THINK THE CHALLENGES THAT ALLAN DISCUSSED
ARE HIGHLIGHTED A LITTLE BIT IN THIS SLIDE. SORT OF THE SHAPE OF THIS SLIDE REALLY REFERS
TO THE CHALLENGES AND FLIP SIDE OF THAT IS THE OPPORTUNITIES FOR NOT JUST ALZHEIMER'S
DISEASE WHICH ARE ILLUSTRATED BY TANGLES, FRONTOTEMPORAL DEMENTIA, LOSS OF NEURONS IN
SPECIFIC AREAS OF THE BRAIN, LEWY BODY DEMENTIA, ACCUMULATE OF LEWY BODIES IN SPECIFIC AREAS
OF THE BRAIN, MORPHOLOGYICALLY YEARS BEFORE, THE DIFFICULTY MAKING A DIAGNOSIS EARLY IN
DISEASE AND NEED FOR BIOMARKERS AND THEN WHEN TO INTERVENE AND WHO TO INTERVENE IN, AND
HOW THE CHALLENGES OF DESIGNING THIS EXPERIMENTAL THERAPEUTIC TRIALS, I THINK THOSE PLAY OUT
ACROSS ALL THE DISEASES THAT WE'RE LOOKING AT.
AND IT REALLY ALSO LEADS TO CONCEPTUALLY THE IDEAS THAT WE'RE SORT OF CHALLENGED WITH.
SO EVEN THOUGH THE THEMES THAT WE'RE GOING TO PRESENT HERE I THINK ARE GOING TO USE ALZHEIMER'S
AS AN EXEMPLAR, IT SHOULD REALLY BE VIEWED AS SORT OF AN ACROSS THE BOARD FOR ALL THE
ILLNESS GROUPS WE'RE LOOKING AT. THIS MAPS OUT ALSO SOME OF THE CHALLENGES
YOU HAVE IN TERMS OF THINKING ABOUT WHAT KINDS OF THERAPEUTICS MIGHT BE USEFUL AND ALSO THE
TIME SCALE IN WHICH YOU MIGHT BE ABLE TO TEST THESE THINGS.
AND SO FOR EXAMPLE, FROM THE VERY FIRST PLAQUES TO DEMENTIA MIGHT BE 15, 20 YEARS.
RANDY BATEMAN WILL BE TALKING ABOUT THAT LATER ON THIS AFTERNOON.
AND SO HOW DO YOU DESIGN AN EXPERIMENT WHICH YOU MAKE AN INTERVENTION AND THEN WAIT 15
YEARS OR SO TO FIGURE OUT WHETHER OR NOT IT WORKED?
I MADE A COMMENT EARLIER THAT WE HAVE, YOU KNOW, SO MANY MINUTES BETWEEN NOW AND 2025,
WHICH IS OUR GOAL. IT TURNS OUT THAT THE IPHONE HAS A LITTLE
CALCULATOR ON IT. IT'S 3 1/2 MILLION MINUTES, SO I DON'T WANT
TO WASTE ANY OF THEM. BUT I DO WANT TO USE AT LEAST ONE OF THEM
TO THINK A LITTLE BIT ABOUT THE CHALLENGES OF DEVELOPING TREATMENTS, AND THEN PASS IT
ON TO OUR COLLEAGUES AT NIA AND ALSO REPRESENTATIVE FROM PHARMA, ERIC, FROM ABBVIE, TO REALLY
THINK ABOUT HOW WE CAN MUSTER OUR JOINT EFFORTS TO OVERCOME THOSE CHALLENGES.
SO INHERENT IN THE SLIDE THAT ALLAN SHOWED, THERE'S DIFFERENT PHASES OF DISEASE, YOU CAN
INTERVENE BEFORE IT STARTS, THAT'S A PREVENTION TRIAL.
YOU CAN INTERVENE IN A DISEASE IN A DISEASE MODIFYING MODE, THAT DEPENDS WHAT YOU DEFINE
AS DISEASE. IF IT'S ACCUMULATION OF TANGLES AND PLAQUES,
YOU NEED HAVE SOME MARKER REGARDLESS OF CLINICAL SYMPTOMS.
IF YOU WANT TO INTERVENE IN DISEASE IN TERMS OF MOVING THE NEEDLE IN HOW RAPIDLY IT PROGRESSES
CLINICALLY, WELL, THEN PEOPLE SORT OF HAVE TO HAVE SOMETHING YOU CAN MEASURE TO START
WITH TO SEE WHETHER OR NOT THAT'S CHANGED. SO THAT MOVES YOU TO A DIFFERENT POINT IN
THE DISEASE PROCESS WHEN YOU'RE INTERVENING. AND CERTAINLY SYMPTOMATIC TREATMENT, YOU NEED
SYMPTOMS TO CHANGE THOSE. AND SO THAT MOVES YOU TO A DIFFERENT PLACE
ON THAT MODEL. SO ALREADY EVEN JUST VERY BROADLY CONCEPTUALLY
WE WERE MAYBE TALKING ABOUT FOUR OR FIVE DIFFERENT TYPES OF CLINICAL TRIALS THAT YOU HAVE TO
THINK ABOUT DESIGNING, AND FOUR OUR FIVE TYPES OF TARGETS THAT YOU MIGHT HAVE TO THINK ABOUT
HOW TO VALIDATE AND HOW TO EXAMINE. AND THEN NEXT, I THINK THAT WE HAVE TO FACE
THE OBVIOUS, WHICH IS THAT THESE ARE PEOPLE WHO HAVE DISEASES, AND THAT NO TWO PEOPLE
ARE THE SAME. I WAS VISITING WITH ALLAN ABOUT TWO INDIVIDUALS
WHO WE HAD THE OPPORTUNITY TO CARE FOR OVER THE LAST FEW YEARS.
IDENTICAL TWIN WOMEN, WHO UP THROUGH THEIR LATE 80s STILL CAME TO CLINIC WEARING THE
SAME THING EVERY TIME. IT WAS KIND OF FUN.
AND, YOU KNOW, THEY HAD OBVIOUSLY SPENT THEIR WHOLE LIVES BEING MIRROR IMAGES OF EACH OTHER.
YOU KNOW, GENETICALLY IDENTICAL, YOU KNOW, AS FAR AS WE KNOW.
AS FAR AS SCIENCE CAN TELL. AND YET ONE OF THEM HAD SEVERE IMPAIRMENT.
THE OTHER COGNITIVELY OKAY. AND AT AUTOPSY THE BRAINS, ONE HAD TANGLES
AND PLAQUES, THE OTHER HAD TANGLES AND PLAQUES. AND SO WHAT WAS DIFFERENT?
THIS IS A FUNDAMENTAL MYSTERY. BUT IT HIGHLIGHTS THE KIND OF HETEROGENEITY
OF CLINICAL PRESENTATION WE HAVE TO TAKE INTO ACCOUNT, WHEN WE'RE DESIGNING A CLINICAL TRIAL.
AND THOSE ARE TWO PEOPLE WHO PRESUMABLY HAD THE SAME DISEASE.
IF YOU ADD IN HETEROGENEITY HIGHLIGHTED BY SO MANY OF US REALLY IN THE LAST COUPLE OF
YEARS, SOME PEOPLE ALSO HAVE SOME STROKES AND JUST BECAUSE YOU HAVE THE BAD LUCK TO
HAVE ALZHEIMER'S DISEASE DOESN'T MEAN YOU DON'T ALSO HAVE LEWY BODIES OR DON'T ALSO
HIT YOUR HEAD, OR SINCE I'M FROM BOSTON I'M ALLOWED TO SAY THIS, IF YOU'D BEEN A RED SOX
FAN THAT ALSO HAS ITS, YOU KNOW, DIFFICULTIES WITH COGNITION AS TIME GOES ON.
SO, YOU KNOW, IT'S COMPLICATED, BOTH BY THE HETEROGENEITY OF DISEASE AND THEN ALSO BY
THE DIFFERENT PHASES OF DISEASE. AND SO WHEN WE'RE THINKING ABOUT HOW TO DESIGN
CLINICAL TRIALS TO SAY, YES, WE'VE ACCOMPLISHED SOMETHING, WELL, DEFINING THAT SOMETHING IS
REALLY CRITICAL. AND WE THINK OF THAT IN TERMS OF GIVING THE
RIGHT THERAPY TO THE RIGHT PERSON AT THE RIGHT TIME, IN DISEASE.
THIS IS PLAYED OUT THROUGH ALL OF MEDICINE, AND IT'S CHALLENGING FOR ALL OF MEDICINE.
YOU CAN THINK OF CANCER AND ATHEROSCLEROSIS AS OTHER CHRONIC DISEASES, IN WHICH YOU HAVE
TO CHOOSE THE RIGHT PATIENT WITH THE RIGHT MEDICINE AT THE RIGHT TIME.
I THINK WE'RE JUST BEGINNING TO HAVE THE FUNDAMENTAL UNDERSTANDING THAT WE NEED TO DISSECT HETEROGENEITY
AND UNDERSTAND HOW TO DESIGN THOSE SORTS OF TRIALS.
AND OF COURSE, THE OTHER CHALLENGE THAT WE HAVE IN TERMS OF THERAPEUTICS AND THAT I HOPE
ERIC WILL ADDRESS SPECIFICALLY, IS THAT WE ALSO JUST HAVE TO SEE THAT THERE'S RECENTLY
BEEN SOME VERY HIGH PROFILE WELL DESIGNED TRIALS THAT FAILED IN THEIR ATTEMPT TO CHANGE
THE DISEASE. AND, YOU KNOW, WHAT HAVE WE LEARNED FROM THOSE
AND HOW CAN WE DO BETTER THE NEXT TIME. AND ALSO HOW CAN WE KEEP THE MOMENTUM TO KEEP
TRYING, BECAUSE AT SOME POINT $500 MILLION TRIALS, IF THEY ARE DOOMED TO FAILURE OR IF
THAT'S THE PERCEPTION, THEN THAT GETS TO BE A TOUGH SELL.
AND YET THE URGENCY AND THE NEED AND THE PUBLIC HEALTH NEED IS SO HUGE THAT WE HAVE TO THINK
SERIOUSLY ABOUT STRATEGIES TO KEEP THE MOMENTUM FORWARD, TO CONTINUE GOING.
SO FROM THOSE PERSPECTIVES, WE'VE ASKED ELIEZER AND LAURIE FROM NIA TO ADDRESS CHALLENGES,
GET PRE CLINICAL PROGRESS, CREATE A CLINICAL TRIAL PIPELINE NIMBLE AND FLEXIBLE AND WILL
SUCCEED AND THEN ERIC KARRAN FROM ABBVIE, INDUSTRY PERSPECTIVE ON HOW TO KEEP ENERGY
AND ENTHUSIASM, NEW IDEAS FLOATING THROUGH. THERE ARE OBVIOUS PARTNERS, IMPORTANT.
AND THEN WE'VE ASKED CYNTHIA AND MARION TO TALK ABOUT THE PATIENT SIDE OF THIS.
WHAT'S IT LIKE TO PARTICIPATE IN A CLINICAL TRIAL?
HOW CAN WE THINK ABOUT HOW TO MAKE THAT EXPERIENCE BETTER AND HOW TO KEEP THAT EXPERIENCE BE
ONE THAT'S FULL OF HOPE IN ADDITION TO THE INEVITABLE CHALLENGES OF JUST GETTING TO AN
INFINITE NUMBER OF APPOINTMENTS AND HAVING MORE AND MORE SCANS AND MORE AND MORE BLOOD
AND MORE AND MORE BIOFLUIDS AND EVERYTHING ELSE, WHICH THE SCIENTISTS WHO DRAWS UP THE
CARTOON OF THE CLINICAL TRIAL, WELL, LET'S GET ANOTHER MRI SCAN IN SIX WEEKS, THAT'S
INFORMATIVE, WE SAY, YET THE SUBJECT HAS TO GET IN THE CAR, DRIVE THROUGH BOSTON TRAFFIC,
PARK IN OUR PARKING LOT AND MAKE THEIR WAY TO WHITE 12, IMPOSSIBLE TO FIND EVEN IF YOU
WORKED THERE FOR 25 YEARS. AND SO WE REALLY APPRECIATE THEIR INPUT AND
THEIR PERSPECTIVE. SO WITH THAT, I WANT TO TURN IT OVER, ELEAZER.
>> ALL RIGHT. THANK YOU.
THANK YOU VERY MUCH, BRAD, FOR THE INTRODUCTION AND FOR INVITING ME TO BE HERE AND FOR HAVING
THE OPPORTUNITY TO TELL YOU A LITTLE BIT ABOUT WHAT WE'RE DOING AT NIA TO ADVANCE NATIONAL
PROGRAM PARTICULARLY AS IT RELATES TO PRE CLINICAL PROGRAMS AND TRANSLATIONAL PROGRAMS.
THE WORK THAT I'M GOING TO TELL YOU ABOUT TODAY IS REALLY THE RESULT OF SOME ABSOLUTELY
BRILLIANT COLLEAGUES THAT I HAVE AT THE NIA THAT HAVE BEEN WORKING ON THESE FOR MANY YEARS,
AND I HAVE ON THE SLIDE THEIR NAMES, FOR GENETICS PROGRAM MARILYN MILLER, FOR THE TARGET DISCOVERY
AND VALIDATION SUSANNA, FOR DRUG DISCOVERY LARRY ROFALI, FOR CLINICAL DRUG DEVELOPMENT
YOU'LL HEAR FROM LAURIE. THIS IS IN COLLABORATION, WORKING TOGETHER
WITH THE COMMUNITY, WITH BOTH ACADEMIC, PRIVATE AND NON PROFIT PARTNERS AND WITH THE SUPPORT
OF DR. HODES AND DR. BERNARD. REALLY, AS I SAID, THIS IS A HUGE EFFORT FROM
MANY DIFFERENT PEOPLE. SO, YEAH, AS DR. HYMAN MENTIONED, REALLY THE
CHALLENGE WITH ALZHEIMER'S DISEASE AND ADRDs, AS WE HAVE LEARNED IN THE LAST FEW YEARS,
IS THAT THESE ARE NOT JUST SIMPLE DISORDERS THAT COULD BE COMPARED OR DIVIDED ALONG VERY,
VERY SPECIFIC LINES, BUT WHAT WE HAVE LEARNED IS THAT ALZHEIMER'S COULD COALESCE WITH OTHER
NEURODEGENESIS DISORDERS LIKE LEWY BODY DISEASE, FRONTOTEMPORAL, VASCULAR DEMENTIA, A LOT OF
HETEROGENEITY IS PROBABLY RELATED TO OVERLAP. EVEN THOUGH WE THINK ABOUT ALZHEIMER'S AS
A DISEASE OF A BETA AND TAU, GDP 43 COULD ALSO ACCUMULATE IN ALZHEIMER'S.
LIKIZE IN LEWY BODY, WE CAN CAN FIND A BETA, TO YOU, AND FRONTOTEMPORAL, A DISEASE OF TAU
OR TDP 43, NOW WE'RE FINDING ACCUMULATION OF OTHER PROTEINS.
OF COURSE, THESE OVERLAPPING IN THE CONTEXT OF VASCULAR DISEASE.
SO REALLY A RATHER COMPLEX PROCESS. BUT THINKING ABOUT IT IN A VERY OVERSIMPLIFIED
MANNER, SUMMARIZING THE WORK OF MANY PEOPLE IN THE LAST TWO DECADES, WHAT WE UNDERSTAND
NOW IS THAT THE ACCUMULATION OF THESE PROTEINS, A BETA, TAU, TDP 43, ET CETERA, IS PROBABLY
RESULT OF DYSREGULATION IN THE PROCESS OF SYNTHESIS AGGREGATION AND CLEARING OF THE
PROTEINS, RESULTING IN AGGRESSIVE ACCUMULATION IN THE CELLS AND OUTSIDE THE CELLS, FORMING
THESE AGGREGATES WE DENOMINATE OLIGOMERS AND FIBERS, AND PROBLEM GATING OR JUMPING FROM
CELL TO CELL, AND ALSO TRIGGERING INFLAMMATORY AND PATHOLOGICAL PROCESS.
SO IN THIS CONTEXT, YOU CAN IMAGINE, WE'RE TRYING TO DEVELOP THERAPEUTICS FOR DISORDERS,
WELL, THE LOGICAL WAY TO GO IS PROBABLY EITHER TO DEVELOP DRUGS THAT WILL REDUCE THE PRODUCTION
OF THESE PROTEINS OR THAT WILL REDUCE THE AGGREGATION AND TRANSMISSION OF THESE PROTEINS,
OR THAT WILL INCREASE THE CLEARANCE OF THESE PROTEINS.
AND I THINK TREMENDOUS EFFORT HAS BEEN DONE IN ALL REGARDS, IN TERMS OF CLEARANCE OF THESE
PROTEINS. WE CAN TARGET TRAFFICKING, TRANSPORT, AUTOPHAGY,
THERAPEUTICS, PROTECT THE VASCULATURE, IF YOU CAN SEE FOR SOME SPECIFICALLY FOR ALZHEIMER'S
DISEASE, NOT INCLUDING THE OTHER ADRDs BECAUSE OF TIME CONSTRAINTS, BUT JUST SIMPLY THINKING
ABOUT ALZHEIMER'S DISEASE, THERE ARE SO MANY POINTS IN THE PROCESS ALL THE WAY FROM APP,
AMYLOID PROTEIN PROCESSING, SYNAPTIC DAMAGE, AXONAL PATHOLOGY, WHICH WE COULD INTERVENE
EITHER AS YOU CAN SEE IN THE TOP WITH BETA AND GAMMA INHIBITORS, WITH DRUGS THAT WILL
TARGET ApoE OR DRUGS THAT WOULD TARGET INFLAMMATORY PROCESS, OLIGOMERS, CYTOKINE PROCESS, TAU,
ET CETERA. IT'S A RATHER COMPLEX CASCADE, AND MANY POINTS
OF ENTRY. AS YOU CAN IMAGINE, THE PIPELINE THAT HAS
BEEN DEVELOPED FOR ALZHEIMER'S DISEASE, AND THIS IS A BEAUTIFUL REVIEW PAPER WRITTEN FOR
ALZHEIMER'S AND DEPARTMENT IN 2017, WE HAVE HUNDREDS OF DRUGS NOW WITH HUNDREDS OF DIFFERENT
TARGETS THAT HAVE BEEN DEVELOPED. THIS PARTICULAR REVIEW HAS OVER 120 DRUGS,
SOME DISEASE MODIFYING, 70% DISEASE MODIFYING, A GOOD CHANCE SYMPTOMATIC, ANOTHER RELEVANT
TO IMMUNOTHERAPY, LOOKING AT MANY DIFFERENT TARGETS, NOT ONLY A BETA PATHWAYS, TAUS, SYNUCLEIN,
ET CETERA, BUT EVEN THOUGH WE HAVE A VERY LARGE PIPELINE IN THE TOP OF THE CONE IN ALZHEIMER'S
DISEASE, WITH A NUMBER OF OVER 100 DRUGS BEING TESTED, ONLY VERY FEW, BASICALLY A COUPLE,
HAVE MADE IT TO THE FINISH LINE. AND THIS IS REALLY HUGE CHALLENGE, ESPECIALLY
IF YOU COMPARE TO THE INDUSTRY AVERAGE, WHICH IS AT LEAST FOUR TIMES LARGER.
SO WHAT IS THE PROBLEM? WHY IS IT THAT WE HAVE THIS?
AS ALLAN AND BRAD WERE TALKING ABOUT BEFORE, TOO LITTLE DRUG, TOO LATE IN THE INTERVENTION?
INSUFFICIENT DOSE, LACK OF BLOOD BRAIN BARRIER PENETRATION OR THE WRONG TARGET?
A BETA, TAU, ET CETERA, MAY BE THE WRONG TARGET OR WE'RE TARGETING MOLECULES AT THE WRONG
TIME OR WE'RE MISSING THE APPROPRIATE BIOMARKERS. I MEAN, THERE ARE A NUMBER OF QUESTIONS AS
TO WHY THIS COULD BE GOING WRONG. SO AS A MATTER OF FACT IN OUR ALZHEIMER'S
SUMMIT IN 2012 AND 2017 WE HAD A LOT OF DISCUSSIONS ABOUT THIS AND MANY OF THE RECOMMENDATIONS
IN THOSE SUMMITS WERE RELEVANT TO THIS TOPIC AND INCLUDED THIS IDEA OF EMPLOYING NEW RESEARCH
PARADIGMS AND SYSTEM BIOLOGY AND OPEN SCIENCE, THIS IS SOMETHING THAT IS VERY IMPORTANT,
NOW THIS IDEA OF MAKING ALL THESE DATA PUBLICLY AVAILABLE, DEVELOPING, IT WAS MENTIONED EARLIER
BY LAURA, AN ECOSYSTEM WHERE DATA COULD BE SHARED, RESEARCH ACCELERATED, DEVELOPING COMPUTATIONAL
SCHOOLS AND INFRASTRUCTURE, MULTI DISCIPLINARY TEAMS, AS I SAID, OPEN SCIENCE, AND MORE PRE
COMPETITIVE PUBLIC AND PRIVATE POINTS. SO WE TOOK THAT VERY MUCH TO HEART, AND AGAIN
A LOT OF THE WORK THAT THE COMMUNITY HAS DONE IN COLLABORATION WITH MY COLLEAGUES THAT I
ACKNOWLEDGED AT THE BEGINNING HAVE RESULTED IN THIS PARADIGM I PRESENT WHERE WE HAVE A
MUCH BETTER INTEGRATION AMONG OUR DIFFERENT PROGRAMS WHERE IN THE CENTER OF OUR PROGRAMS
ARE THESE PUBLIC/PRIVATE PARTNERSHIPS, AND THEN WE HAVE GENETICS PROGRAMS, DISCOVERY
PROGRAMS, RESEARCH TOOLS, ANIMAL MODELS, WE'RE LOOKING AT COMPLEX BIOLOGY OF RESILIENCE,
TRANSLATIONAL CAPABILITIES, AND CLINICAL DRUG DEVELOPMENT CAPABILITIES THAT LAURIE IS GOING
TO TALK TO YOU ABOUT. AND AS OVERARCHING TOPIC AMONG ALL OF THEM
IS THIS IDEA AGAIN OF OPEN SCIENCE, AND OPEN AND CONSISTENT OF THIS SCIENCE.
AND WHAT I'M GOING DO IN THE NEXT FEW MINUTES THAT I HAVE IS DESCRIBE TO YOU ALL THESE DIFFERENT
PROGRAMS AND HOW THEY ARE INTEGRATED AND HOW THEY ARE WORKING TOGETHER.
IN A NUTSHELL, I'VE BEEN AT NIH A YEARANDAHALF, I'M STILL LEARNING ALL OF THESE THINGS, IT'S
REALLY QUITE REMARKABLE WHAT HAS BEEN ACCOMPLISHED, AND I'M VERY EXCITED ABOUT IT.
BUT IN A NUTSHELL, WE HAVE ESSENTIALLY TRANSLATIONAL PROGRAMS AND INFRASTRUCTURE THAT ENABLES THOSE
TRANSLATIONAL PROGRAMS. SO WHAT WE HAVE HERE IN THE DIAMOND PIPELINE
DIAGRAM, GOING ALL THE WAY FROM TARGET DISCOVERY TO LEAD DEVELOPMENT AND THEN TO CLINICAL DEVELOPMENT,
WELL, PRECLINICAL AND CLINICAL DEVELOPMENT. WE HAVE THE INFRASTRUCTURE THAT ALLOWS THOSE
PROGRAMS TO DEVELOP. I'M GOING TO DESCRIBE SOME OF THESE PROGRAMS,
BUT IN TERMS OF INFRASTRUCTURE, WE HAVE ADSP, MPD AND RESILIENCE, AND THEN FOLLOWING IN
THAT PIPELINE WE HAVE MODEL AD, DEVELOPING NEW ANIMAL MODELS OF THE DISEASE AND THEN
LAURIE IS GOING TO TALE BUT THE INFRASTRUCTURE THAT ENABLES LATER STAGE CLINICAL TRIALS.
ADSD IS QUITE IMPORTANT IN THIS PROCESS OF NEW TARGET DISCOVERY.
THIS IS OUR ALZHEIMER'S DISEASE SEQUENCING PROGRAM.
AT THE MOMENT WE'RE SEQUENCING ABOUT 30,000 PEOPLE WHOLE GENOME SEQUENCING, AND BASICALLY
THE IDEA OF THIS PROGRAM IS TO DISCOVER ALL THE GENETIC VARIANTS OF ALZHEIMER'S DISEASE.
WE HAVE HAD SOME REALLY VERY EXCITING RESULTS, RECENTLY PUBLISHED BY THE GROUP OF JERRY SCHAUMBURG
AND OTHERS, WHERE A NUMBER OF GENES INVOLVING THE ENDOSOMAL LYSOSOMAL PATHWAYS AS I'M ILLUSTRATING
HERE, BASICALLY THE INTRACELLULAR TRAFFICKING OF ORGANELLES ARE AFFECTED, REPRESENTING NEW
TARGETS FOR DRUG DEVELOPMENT. HOWEVER, HERE WE HAVE TO BE THOUGHTFUL, GOING
BACK TO THE SUMMIT, ONE OF THE THINGS THAT WE LEARNED IS THAT IT'S PROBABLY WE SHOULD
NOT BE THINKING ONLY ABOUT SINGLE TARGETS BUT WE KNOW SINGLE GENES BELONG TO NETWORKS
OF GENES, AND THAT MIGHT EXPLAIN THE COMPLEXITY OF THE DISEASE SO THE QUESTION IS ALSO TO
GO FOR A SIMPLE TARGET TO NETWORK APPROACH FOR DRUG DEVELOPMENT, AND THIS IS EXACTLY
WHERE AMP ADs, AND ALLAN HERE IS PART OF THIS PUBLIC/PRIVATE PARTNERSHIP.
THERE ARE SIX ACADEMIC TEAMS, INCLUDING EMORY, PHIL, DOUG, MENTIONED HERE.
THE PARTNERS INCLUDE NINDS, FDA, ABBVIE THAT WE HAVE REPRESENTED TODAY, AND FNIH, AND BASICALLY
IN A NUTSHELL THE IDEA OF AMP AD, THE SIX CENTERS ARE LOOKING BIOMICS, PROTEIN, GENES,
EPIGENETICS, CREATING NETWORKS MADE PUBLICLY AVAILABLE TO THE SYNAPSE AMP AD PORTAL KNOWLEDGE.
THIS PROGRAM IS CLOSE TO ITS FIRST FIVE YEARS, THERE HAVE BEEN PREMIUM ACCOMPLISHMENTS, ALMOST
ALL THE DELIVERABLES AND MILESTONES ACCOMPLISHED, OVER 100 CANDIDATE TARGETS HAVE BEEN NOMINATED,
I'M SHOWING A LIST OF THEM HERE. MANY OF THESE GENES ARE RELEVANT TO INFLAMMATORY
PATHWAYS, ENDOSOMAL LYSOSOMAL PATHWAYS. BGF WAS NOMINATED BY THE SIX TEAMS, EVERYBODY
CAME TO THE SAME CONCLUSION THIS PARTICULAR GENE THAT IS NEURONAL GENE INVOLVED IN NEUROTRANSMISSION
AND NEUROPROTECTION IS QUITE RELEVANT, IN EACH ONE OF THE TARGETS, YOU CAN SEE HERE
ALL THE PROTEIN AND NETWORKS THAT THIS GENE RESPONDS TO AND IS RELEVANT TO.
NOW, THE INTERESTING THING ABOUT AMP AD, IT'S DETECTING NEW TARGETS AND NETWORKS AND DEVELOP
THEM WITH PARTNERS BUT ALSO DISCOVERED NEW BIOMARKERS, THIS IS WORK OF ALLAN HERE, WHERE
HE HAS USED THESE OMICS APPROACH OF AMP AD TO DISCOVERY NEW BIOMARKERS FOR ALZHEIMER'S
DISEASE. SO THIS IS QUITE EXCITING.
NOW, SIMILAR TO AMP AD, WE HAVE ALSO DEVELOPED MOVE AD, THE COUNTERPART STRATEGY, FOR VASCULAR
DEMENTIA, AND AGAIN THIS IS ALSO PUBLIC/PRIVATE PARTNERSHIP WITH NINDS, MULTIPLE GROUPS, DOING
OMICS STUDY, DATA IS PUBLICLY AVAILABLE, AND AGAIN IT'S A SIMILAR STRUCTURE BUT FOR VASCULAR.
AND THIS ACTUALLY LINKS TO THE TRANSLATIONAL RESEARCH INITIATIVES DEVELOPED BY NINDS IN
COLLABORATION WITH NIA, I ASKED NINDS TO PROVIDE ME WITH THE NINDS PIPELINE FOR ADRD, AND AS
YOU CAN SEE HERE NINDS HAS DEVELOPED THE BCID FOR DRUG DEVELOPMENT AND BIOMARKERS FOR VASCULAR
DISEASE, BUT ALSO WE HAVE A NUMBER OF OTHER CONSORTIUMS AND FTD, LEWY BODY DISEASE, ET
CETERA, THAT GOES ALONG THIS DRUG DEVELOPMENT PIPELINE THAT DR. HODES DESCRIBED BEFORE.
ANOTHER VERY IMPORTANT ENABLING INFRASTRUCTURE ON THIS PIPELINE THAT WE HAVE RECENTLY DEVELOPED
AND WE JUST AWARDED TWO CENTER GRANTS IS TO DEVELOP NEW, THE NEXT GENERATION ALZHEIMER'S
MODEL, BASED ON ALL THE NEW GENETIC DATA THAT I MENTIONED TO YOU FROM ADSP, FROM THE WORK
THAT HAS BEEN DONE IN AMP AD, WE CALL THESE MODEL AD CONSORTIUM.
THE IDEA HERE IS TO CREATE ANIMAL MODELS, AVAILABLE TO EVERYBODY IN THE FIELD, ALL THE
DATA AVAILABLE TO EVERYBODY IN THE FIELD. AGAIN ALL THE DATA GOES TO SAGE PORTAL, AND
THESE ARE THE TWO TEAMS, ONE IS UCI, FRANK LAPERL, BRUCE LAMB AND THE JACKSON LAB GROUP,
AND AGAIN THE IDEA IS NOT TO DEVELOP CONVENTIONAL MODELS BUT RATHER TO USE GENETIC DATA AND
DEVELOP MORE THE MORE GARDEN VARIETY TYPE OF ALZHEIMER'S MODELS WITH THE LATE ONSET
ALZHEIMER'S GENES AND AGAIN A LOT OF THESE DATA AND ALSO A LOT OF THE DATA ON THE EXPERIMENTAL
STUDIES AND THE ANIMAL MODELS IS NOW BEING DEPOSITED IN THE SYSTEM WHERE WE'RE TRYING
TO HAVE GREATER TRANSPARENCY ON THE PRECLINICAL DATA THAT BE GENERATED AND, AGAIN, THAT EVERYBODY
HAS ACCESS TO THE DATA. NOW, I JUST WANT TO TAKE A FEW MINUTES TO
TALK ABOUT ANOTHER ASPECT, SO I ALREADY TALKED ABOUT ADSP, AMP AD, MOVE, MODEL AD, THAT GOES
ALONG THIS PATHWAY. WE HAVE SOME DRUG DEVELOPMENT PRECLINICAL
PROGRAMS INCLUDING NIA DRUG DISCOVERY PROGRAM, NIA DRUG DEVELOPMENT PROGRAM AS WELL AS SVIR
AND BLUEPRINT COLLABORATION WITH NINDS, AND A NUMBER OF DRUG TARGETS HAVE BEEN DEVELOPED
ALONG THIS AREA. WE HAVE, FOR EXAMPLE, BDNF GENE DELIVERY FOR
ALZHEIMER'S DISEASE. WE HAVE DRUG THAT ENHANCE GLUTAMATE CLEARANCE
IN THE BRAIN THAT ARE NEUROPROTECTIVE, ANTI INFLAMMATORY, BY TARGETING SELECTIVE KINASE
PATHWAYS. ALSO OF COURSE ANTI TAU ANTIBODIES, ET CETERA.
I'M JUST SHOWING SOME EXAMPLES OF SOME OF THESE PROGRAMS THAT ARE IN PRECLINICAL STAGES,
PRE IND FOR PHASE 1 OR PHASE 1 OR MOVING TO PHASE 2.
SOME OF THESE PROGRAMS HAVE BEGUN TO MOVE FROM PHASE 1 TO PHASE 2, PHASE 3, AND ACTUALLY
LAURIE IS GOING TO TELL YOU A LOT MORE ABOUT ALL THESE DRUGS THAT ARE NOW IN CLINICAL DEVELOPMENT.
BUT WE HAVE A NUMBER OF REALLY VERY EXCITING PROGRAMS AND I THINK AS DR. HODES MENTIONED
EARLIER SOME OF THEM ARE REALLY QUITE UNIQUE AND HAVE BEEN DEVELOPED, MOSTLY WITH NIA SUPPORT.
SO THESE ARE SOME OF THE RECENT FUNDING OPPORTUNITIES THAT WE HAVE OUT THERE FOR THESE PROGRAMS,
INCLUDING THE BIOLOGY OF RESILIENCE IN ALZHEIMER'S DISEASE, CLOSING THE GAP ON THE DRUG DISCOVERY,
AS DR. HODES MENTIONED, SCIR OPPORTUNITIES, BIOINFORMATICS, SEX DIFFERENCES, ET CETERA.
THERE ARE MORE COMING UP. IF YOU LOOK AT OUR PORTFOLIO FUNDING OPPORTUNITIES
IN THE LAST COUPLE YEARS, IT'S ABSOLUTELY MIND BOGGLING.
WE HAVE ALMOST 140 OUT THERE RIGHT NOW. THIS IS REALLY QUITE AN ABSOLUTELY GOLDEN
PERIOD TO BE INVOLVED IN THIS KIND OF RESEARCH. AND AS BRAD MENTIONED AT THE END OF HIS CONVERSATION,
AND ALSO I'M CLOSING, THIS IS ONE OF MY LAST SLIDES, WHAT WE ALSO NEED TO DO, WHAT IS NEXT?
WELL, OF COURSE WE NEED TO, AS I MENTIONED BEFORE, RECOGNIZE THIS PIPELINE AND TRY TO
INTEGRATE ALL THESE DIFFERENT ASPECTS OF THE PIPELINE WITH BETTER PROGRAMS, AND ENABLING
INFRASTRUCTURE IN AN OPEN SCIENCE ECOSYSTEM WHICH IS WHAT HOPEFULLY I ILLUSTRATE IS THE
TAKEHOME MESSAGE OF WHAT I SHOW YOU. WHAT IS NEXT, TESTING THE RIGHT TARGET WITH
THE RIGHT DRUG AT THE RIGHT TIME. AND THIS CONCEPT OF ATTAINING GOALS OF PRECISION
MEDICINE ILLUSTRATED SO NICELY IN THIS REVIEW PAPER BY SPERLING, JACK AND POLISON, THE MAIN
THEME OF OUR SUMMIT. DR. HODES ALREADY INTRODUCED TO YOU WE WILL
BE TALKING ABOUT THE COMPLEX BIOLOGY, BUT ALSO ENABLING PRECISION MEDICINE, TRANSLATIONAL
TOOLS, EMERGING THERAPEUTICS, UNDERSTANDING THE IMPACT OF ENVIRONMENT AND DISEASE AND
PREVENTION. THIS IS MONITORING.
AGAIN, AS I MENTIONED BEFORE, VERY IMPORTANTLY, OPEN SCIENCE RESEARCH ECOSYSTEM TO ACCELERATE
ALZHEIMER'S DEVELOPMENT SO WE HOPE TO SEE YOU ALL THERE.
WE'RE VERY EXCITED ABOUT THIS. AGAIN, THANK YOU FOR THE OPPORTUNITY.
>> OKAY. WELL, THANK YOU, ELEAZER.
OKAY. SO I'M GOING TO PICK UP WHERE ELEAZER LEFT
OFF TALKING ABOUT THE NIA SUPPORTED INITIATIVES THAT ENABLE THE CLINICAL INTERVENTIONS.
YOU ALL HAVE SEEN THIS BEFORE BUT WE'RE TALKING ABOUT A CONTINUUM OF A.D. AND RELATED DEMENTIA,
WHERE THE DISEASE IS DEVELOPING, NO OVERT SYMPTOMS.
AND SO WE WANT TO ACTUALLY HAVE TREATMENTS THAT WORK ACROSS THE SPECTRUM.
WE'D LIKE TO PREVENT BUT WE KNOW FOLKS ARE GOING TO GET THE DISEASE EVEN IF WE HAVE PREVENTIONS
THAT ARE IN EFFECT LIKE WE DO FOR CARDIOVASCULAR SO WE WANT TO TREAT ACROSS THE SPECTRUM.
THIS IS FROM THE PAPER ELEAZER JUST MENTIONED, TESTING THE RIGHT DRUG, THE RIGHT TARGET,
AT THE RIGHT TIME. WE WANT TO DELAY THE ONSET OF A.D. PATHOLOGY.
SECONDARY, WE WANT TO DELAY THE ONSET OF COGNITIVE IMPAIRMENT IN INDIVIDUALS WHO HAVE EVIDENCE
OF PATHOLOGY BEGINNING. THERE'S TERTIARY PREVENTION AND TREATMENT
WHERE WE WANT TO DELAY ONSET OR PROGRESSION OF DEMENTIA IN INDIVIDUALS WHO DO HAVE THE
DISEASE. YOU SAW THIS SLIDE IN MORE DETAIL HERE FROM
JEFF CUMMINGS, THE DRUGS IN CLINICAL DEVELOPMENT FOR A.D. AS OF 2017, 105 AGENTS CURRENTLY
IN DEVELOPMENT AT VARIOUS STAGES, PHASE 1 TO PHASE 3.
70% OF THOSE ARE WHAT WE CALL DISEASE MODIFYING, TRYING TO GET AT THE UNDERLYING PATHOLOGY.
AND THEN THE REST ARE FOR EITHER THE COGNITIVE SYMPTOMS OR NEUROPSYCHIATRIC SYMPTOMS.
AND WHAT I'M GOING TO TRANSITION TO, WHAT IS NIA DOING?
THESE ARE THE NIA SUPPORTED CLINICAL INTERVENTIONS. REALLY TALKING ABOUT EITHER TREATING OR PREVENTING
COGNITIVE OR NEUROPSYCHIATRIC SYMPTOMS HERE. THIS IS THE CURRENT NIA A.D. PORTFOLIO.
WE HAVE ALMOST 80 TRIALS NOW, FOCUS ON TREATING OR PREVENTING SYMPTOMS.
HALF ARE NON PHARMACOLOGIC, THE OTHER HALF PHARMACOLOGIC.
AND FOR OUR PHARMACOLOGIC WE HAVE MOST IN WHAT WE CALL EARLY STAGE DEVELOPMENT, PHASE
1 AND PHASE 2, AND WE HAVE LOWER NUMBER WHICH MAKES SENSE IN PHASE 3 AND WE ALSO SEPARATED
OUT, WE HAVE TRIALS LOOKING AT JUST THE NEUROPSYCHIATRIC SYMPTOMS, TREATING NEUROPSYCHIATRIC SYMPTOMS.
THIS IS THE SAME INFORMATION SHOWING BREAKDOWN IN NUMBERS.
THESE NUMBERS AND CATEGORIES CAN BE FOUND ON I DROP.
AND WHAT I THOUGHT I WOULD DO NOW IS HIGHLIGHT THE PHARMACOLOGIC AND NONPHARMACOLOGIC TREATMENT,
WHAT ARE WE DOING, AND I'LL TALK ABOUT OUR INFRASTRUCTURE.
THESE ARE THE TARGETS IN NIA'S PHARMACOLOGIC CLINICAL TRIALS PORTFOLIO.
THERE'S LIPOPROTEINS, NEUROTRANSMITTER RECEPTORS, METABOLISM AND BIOINNERGENICS, AND I'LL HIGHLIGHT
A COUPLE. ONE I'M SURE A LOT OF PEOPLE HEARD OF, A LATE
STAGE INTERVENTION, ANTI AMYLOID TREATMENT IN ASYMPTOMATIC ADRA FOR TRIAL.
AND SO THIS IS A SECONDARY PREVENTION, IF WE GO BACK TO THE OTHER SLIDE, CLINICALLY
NORMAL OLDER ADULTS WHO HAVE EVIDENCE OF AMYLOID BETA PATHOLOGY ON PET SCREENING, AND SO RANDOMIZED
DOUBLE BLIND PLACEBO CONTROLLED, USING IMMUNOTHERAPY VERSUS PLACEBO, 240 WEEKS, THE TRIAL HAS OVER
1000 PARTICIPANTS, OBSERVATIONAL ARM FOR THOSE INDIVIDUALS CONSIDERED A BETA NEGATIVE, SCREEN
FAILS, THE LEARN STUDY SUPPORTED BY THE ALZHEIMER'S ASSOCIATION.
THERE'S AN ETHICS COMPONENT LOOKING AT DISCLOSURE OF AMYLOID STATUS, WHAT EFFECT MIGHT THAT
HAVE. TAU IMAGING AS YOU HEARD ABOUT ACCELERATING
AMP AD, PROJECT A IS LOOKING AT BIOMARKERS IN SOME SECONDARY PREVENTION TRIALS AND SO
TAU IMAGING WAS ADDED THROUGH THE AMPAD PARTNERSHIP. ENROLLMENT COMPLETED DECEMBER 15, A4, 7000
PARTICIPANTS WERE SCREENED. THIS IS SHOWING A SLIDE FROM RISA SPERLING,
THEY HAVE NOT SHOWN COGNITIVE SYMPTOMS, RIGHT BEFORE THAT.
CAN WE SLOW THE TRAJECTORY SO PEOPLE AMYLOID POSITIVE BUT TREATED HAVE SLOWER PROGRESSION
INTO ULTIMATE COGNITIVE DECLINE. AGAIN, WE'RE LOOKING AT DETERMINING WHETHER
IF YOU DECREASE A BETA BURDEN CAN YOU SLOW THE RATE IN CLINICALLY NORMAL OLDER INDIVIDUALS
AT RISK FOR PROGRESSING, TESTING HYPOTHESIS ALTERING ACCUMULATION WILL IMPACT DOWNSTREAM
NEURODEGENERATION AND COGNITIVE DECLINE. ON A DIFFERENT TARGET IS ANOTHER ONE I WANT
TO BRING UP THAT'S BEEN PART OF OUR PRECLINICAL AS WELL AS CLINICAL DEVELOPMENT PROGRAM AT
NIA, LM 11 A 31, A MODULATOR OF A NEUROTROPHIN RECEPTOR, MAY PREVENT ACTIVATION OF DEGENERATIVE
PROCESS AND PROTECT NERVE CELLS AND CONNECTIONS. THIS HAS BEEN LED BY DR. FRANK LONGO.
THE PRECLINICAL DRUG DEVELOPMENT AND STUDIES COMPOUND SUPPORTED BY NIA AD TRANSLATIONAL
PROGRAM ELEAZER HIGHLIGHTED, PHASE 2 IN THE CLINICAL TRIALS PROGRAM, THIS IS THE PHASE
2. SO IT'S A PHASE IIA, DOUBLE BLIND PLACEBO
CONTROLLED, RANDOMIZED, LOOKING AT EXPLORATORY ENDPOINTS.
THREE ARMS, 40 PATIENTS IN EACH, INCLUDING PLACEBO, TWO DOSES, TWICE DAILY FOR 26 WEEKS,
FDG, GLUCOSE, ADDITIONALLY MEASURES LOOKING AT COGNITION, BIOMARKERS AND MRI.
SUCCESSFUL COMPLETION WILL HOPEFULLY PROVIDE DOSE AND ENDPOINT STATISTICAL AND POWER BASIS
FOR DESIGNING A FULL PHASE IIB III TESTING OF THIS COMPOUND.
NOW I'M GOING TO SKIP TO THE NON PHARMACOLOGIC. THESE ARE REALLY THE MODALITIES CURRENTLY
IN OUR NON PHARMACOLOGIC CLINICAL TRIALS PORTFOLIO, RANGING FROM EXERCISE, DIET, COGNITIVE TRAINING,
COMBINATION OF THOSE. USING TECHNOLOGY, CARE MANAGEMENT, MEDICATION
MANAGEMENT FOR THIS. THIS IS FOCUSED ON TREATING OR PREVENTING
SYMPTOMS. THIS IS DONE IN THE COMMUNITY, CAN SLOW DECLINE,
BRAIN ATROPHY AND DELAY ONSET OF ALZHEIMER'S DEMENTIA IN THOSE WITH MILD COGNITIVE IMPAIRMENT,
RECRUITING SEDENTARY OLDER VOLUNTEERS WITH MCI TO PARTICIPATE IN A YEAR LONG PROGRAM,
ONE GROUP DOES HIGH INTENSITY AEROBIC EXERCISE, THE OTHER STRETCHING, COGNITIVE TESTING, BIOMARKERS,
PROVIDING CRITICAL DATA, IMPROVING COGNITION IN THOSE WITH MCI.
ANOTHER STUDY THAT JUST STARTED I WANT TO HIGHLIGHT IS DIETARY INTERVENTION, MIND DIET
INTERVENTION TO PREVENT ALZHEIMER'S DISEASE AT RUSH UNIVERSITY, A HYBRID OF A MEDITERRANEAN
DIET AND DASH HEART HEALTHY DIET ON COGNITIVE DECLINE, OXIDATION, DIABETES, HYPERTENSION,
THERE ARE TWO GROUPS, ONE GETTING MIND DIET PLUS CALORIE RESTRICTION, THE OTHER A USUAL
DIET AND CALORIE RESTRICTION, 600 OLDER ADULTS WITHOUT COGNITIVE IMPAIRMENT WHO ARE AT RISK
BECAUSE THEY ARE OVERWEIGHT OR OBESE, AND HAVE A SUBOPTIMAL DIET.
AND NOW I WANT TO TOUCH ON THE NEUROPSYCHIATRIC SYMPTOMS.
WE SEPARATE THESE OUT BECAUSE AS PEOPLE KNOW THE NEUROPSYCHIATRIC SYMPTOMS ARE REALLY THE
SYMPTOMS THAT ARE OFTEN THE MOST DISRUPTIVE TO CAREGIVERS AND LEAD TO PLACEMENT IN NURSING
HOME OR CARE FACILITIES. WE HAVE A NUMBER OF THOSE, SEVEN TOTAL.
AND THEY ARE BROKEN BY PHARMACOLOGIC AND NONPHARMACOLOGIC, MOST ARE PHARMACOLOGIC.
WHAT I'VE HIGHLIGHTED IS THAT THE FOCUS OF MOST OF THESE IS ON AGITATION AGGRESSION AS
WELL AS APATHY. THIS IS ONE OF THE SYMPTOMS THAT IS THE MOST
DISRUPTIVE TO CAREGIVERS, FAMILY AND ACTUALLY IN LONG TERM FACILITIES.
THE TRIAL I WANT TO HIGHLIGHT IS JUST GETTING READY TO START, IT'S BEING RUN THROUGH THE
ADCS, PHASE IIB MULTI CENTER 12 WEEK RANDOMIZED DOUBLE BLIND PLACEBO CONTROLLED TRIAL, 186
AD PARTICIPANTS LIVING IN LONG TERM CARE. PRAZACIN IS ANTI HYPERTENSIVE.
USING IN LONG TERM CARE RESIDENTS WITH A.D. PATIENTS WAS SUPERIOR TO PLACEBO FOR ALLEVIATING
DISRUPTIVE AGITATION. THIS IS JUST ABOUT GETTING READY TO LAUNCH,
THE START UP MEETING IS NEXT WEEK. THAT'S AN OVERVIEW OF THE CURRENT TRIALS IN
OUR PORTFOLIO. AND NOW I WANT TO TALK ABOUT OUR INFRASTRUCTURE,
THINGS WE'RE DOING TO ENHANCE CLINICAL TRIALS. I WANT TO START UP, RICHARD TALKED ABOUT THIS
EARLIER, A.D. CLINICAL TRIALS INFRASTRUCTURE, ALZHEIMER'S CLINICAL TRIALS CONSORTIUM, U24
RESOURCE MECHANISM JUST AWARDED IN DECEMBER. MULTIPLE P.I.s.
THE IDEA WAS TO ESTABLISH A CONSORTIUM THAT WOULD RUN TRIALS FOCUSED ON INTERVENTION THAT
COULD PREVENT DELAY OR TREAT SYMPTOMS, INCLUDING MULTIPLE CLINICAL TRIAL SITES WITH DEDICATED
SUPPORT AND MANAGEMENT INFRASTRUCTURE. SEPARATE FUNDING OPPORTUNITY ANNOUNCEMENT
WILL SOLICIT APPLICATIONS FOR CLINICAL TRIAL TO BE MANAGE AND SUPPORTED BY ACTC AND I WILL
SHOW THAT YOU IN A MINUTE. SO AGAIN THEY ARE CONDUCTING PHASE 1 TO PHASE
3 OF PROMISING PHARMACOLOGIC AND NONPHARMACOLOGIC INTERVENTION FOR COGNITIVE AND NEUROSYMPTOMS
FOR A.D. AND OTHER RELATED DEMENTIAS ACROSS DISEASE SPECTRUM, NOT JUST PREVENTION BUT
TREATMENT AS WELL. PROVIDING STATE OF THE ART CLINICAL TRIALS
INFRASTRUCTURE TO FACILITATE RAPID DEVELOPMENT OF PROTOCOLS, STANDARDIZING CONTRACTING, CENTRALIZED
IRB, LEADERSHIP, METHODS AND OUTCOMES, ANALYSES AND RECRUIT.
STRATEGIES, PARTICULARLY IN DIVERSE POPULATIONS WITH BROAD SHARES OF PROCEDURES AND METHODS.
SO THIS IS THE FOA THAT IS FOR THE TRIALS THAT WILL COME IN TO UTILIZE THE ACTC.
IMPORTANT THING HERE IS THIS WILL BE IMPLEMENTED THROUGH THE ACTC, COOPERATIVE VENTURE BETWEEN
THE APPLICANT AND NETWORK, THE LEADERSHIP WILL PROVIDE GUIDANCE TO POTENTIAL APPLICANTS.
WE ARE ENCOURAGING COLLECTION OF BLOOD AND OTHER BIOSAMPLES FOR FUTURE GENOMIC AND OTHER
OMIC ANALYSES LOOKING AT INTERROGATING TREATMENT RESPONSIVENESS AND INTERESTING PREDICTORS
OF PROGRESSION. THERE'S DATA SHARING THAT IS ATTACHED AWELL
AS DATA SHARING OF THE METHODS THAT WILL BE ACHIEVED THROUGH THE ACTC RESOURCES BUT THE
IMPORTANT THING, WE WANT THE CLINICAL TRIAL DATA AND BIOSAMPLES TO BE SHARED BY THE TIME
OF THE PRIMARY PUBLICATION AND RESULTS OR WITHIN NINE MONTHS OF DATABASE LOCK, WHICH
EVER COMES FIRST. SOMETIMES IT TAKES A LONG TIME FOR PEOPLE
TO GET PRIMARY PUBLICATIONS OUT. THAT IS NOT SOMETHING WE WANT TO SEE HAPPEN
HERE SO IF PEOPLE DON'T GET THEIR PRIMARY PUBLICATIONS THIS DATA IS GOING TO BE SHARED.
AND FOR THE LATE STAGE PREVENTION TRIALS WE ACTUALLY WANT TO MAKE THE SCREEN OR PRE RANDOMIZATION
BASELINE DATA AVAILABLE, THAT WE'RE FOLLOWING WITHIN 12 MONTHS OF ENROLLMENT COMPLETION,
THE COALITION, CAP, I'LL SHOW YOU THAT IN JUST A MOMENT.
CAP IS REALLY A CONVENING HARMONIZING CONSENSUS BUILDING INITIATIVE TO HELP STAKEHOLDERS ADVANCE
A.D. PREVENTION RESEARCH WITH RIGOR, CARE AND MAXIMAL IMPACT.
FOUNDING MEMBERS WERE REPRESENTATIVE FROM LARGE TRIALS, DIAN, ALZHEIMER'S, FIDELITY
BIOSCIENCES. THE GOALS OF CAP ARE TO STANDARDIZE PROCEDURES
AND HARMONIZE DATA COLLECTION TO ALLOW FOR FUTURE COMPARISONS, SHARE DATA AND SAMPLES
WITH RESEARCH COMMUNITY WIDELY, ASSIST OTHER INVESTIGATORS AND ORGANIZATIONS IN PLANNING
OF PREVENTION TRIALS. IT WAS FOCUSED ON DRUG TRIALS, NONPHARMACOLOGICAL
PRECLINICAL A.D. TRIALS WOULD BENEFIT FROM CAP EFFORTS.
THIS SLIDE, THE HIGHLIGHTED ONES ARE THE TRIALS THAT STARTED OUT IN CAP THAT ARE ALL FUNDED
BY THE NIA, ALL PUBLIC/PRIVATE PARTNERSHIPS, FOUNDATION FUNDING AND INDUSTRY SPONSORSHIP
IN ADDITION TO NIA. AND I WANT TO HIGHLIGHT SOME OF OUR OTHER
CLINICAL TRIAL FUNDING MECHANISMS OUTSIDE THE ACTC.
YOU HEARD ABOUT THE ALZHEIMER'S DRUG DEVELOPMENT PROGRAM.
WHILE THIS IS PRECLINICAL, IT STARTS PRECLINICALLY, THERE IS A LATE STAGE ENTRY POINT FOR COMPOUNDS
WHICH ADVANCES DEVELOPMENT THROUGH IND, ENABLING TOXICOLOGY, ALL THE WAY INTO PHASE 1 CLINICAL
TESTING. WE HAVE AS I MENTIONED BEFORE THE PILOT CLINICAL
TRIAL, SPECTRUM OF ALZHEIMER'S DISEASE, AGE RELATED COGNITIVE DECLINE TO ENABLE CLINICAL
TESTING PHASE 1 AND 2 OF PROMISING PHARMACOLOGIC AND NONPHARMACOLOGIC INTERVENTIONS FOR COGNITIVE
AND NEUROPSYCHIATRIC SYMPTOMS, INDIVIDUALS WITH A.D. AND ADRD ACROSS THE SPECTRUM AS
WELL AS AGE RELATED COGNITIVE DECLINE. ADDITIONALLY, PHASE 1 AND PHASE 2 SAFETY,
IT ALSO LOOKS TO STIMULATE STUDIES TO ENHANCE TRIAL DESIGN AND METHODS.
WE HAVE ANOTHER THAT'S LOOKING AT THE LATER STAGE CLINICAL DEVELOPMENT, PHASE 3, THAT
ENABLES TESTING PROMISING PHARM AND NON PHARM FOR COGNITIVE SYMPTOMS, ACROSS THE STAGES
OF DISEASE, AND AGAIN AGE RELATED COGNITIVE DECLINE USING COMBINATION OF BIOMARKERS, FLUID,
IMAGING, COGNITIVE FUNCTIONAL MEASURES OF OUTCOME.
I ALSO WANT TO TOUCH THE ADVANCING RESEARCH ON ALZHEIMER'S DISEASE AND A.D. RELATED DEMENTIAS,
SMALL BUSINESS INNOVATIVE RESEARCH PROGRAM. WE'RE TRYING TO ALSO GET SMALL BUSINESSES
TO COME IN WITH TRIALS AND THIS IS THE MECHANISM THAT THEY CAN DO THAT.
AND THEN FINALLY I WANT TO WRAP UP BY TALKING ABOUT WHAT ARE WE DOING WITH RECRUITMENT.
WE HAVE TRIALS, HOW ARE WE GOING TO IMPROVE RECRUITMENT?
THAT'S A BOTTLENECK. THERE ARE A NUMBER OF EFFORTS I WANT TO TOUCH
ON THAT NIA IS INVOLVED WITH. FIRST A NATIONAL STRATEGY FOR RECRUITMENT
AND RESEARCH ACROSS THE BOARD. I SPOKE ABOUT THIS LAST YEAR AT THE NATIONAL
STRATEGY. SO IT'S TO ENGAGE BROAD SEGMENTS OF THE PUBLIC
AND ALZHEIMER'S RELATED DEMENTIA RESEARCH WITH A FOCUS ON UNDERREPRESENTED COMMUNITIES
TO SUCCESSFULLY AND MORE QUICKLY ENROLL AND RETAIN INDIVIDUALS IN THOSE STUDIES TO BETTER
UNDERSTAND, TREAT AND EVENTUALLY PREVENT THE DISORDER.
THERE'S NATIONAL EFFORTS LOOKING AT BROAD POLICIES AND ACTIVITIES.
CAPACITY BUILDING, THAT'S AIMED AT CHANGING THE WAY STUDY SITES DO BUSINESS.
AND ULTIMATELY CONNECTING AT THE LOCAL LEVEL BECAUSE REALLY AT THE END OF THE DAY ALL RECRUITMENT
IS LOCAL. TO IDENTIFY AND IMPLEMENT BEST PRACTICES TO
BUILD RELATIONSHIPS WITH COMMUNITIES TOWARD SHARED GOALS OF TREATING AND PREVENT A.D.
AND RELATED DEMENTIAS. THIS IS THE TIMELINE OF THE DEVELOPMENT OF
NATIONAL STRATEGY. I'VE BOLDED WHERE WE ARE NOW ESSENTIALLY BECAUSE
THAT'S THE TAKE HOME. WE'RE IN THE PUBLIC COMMENT PERIOD THAT WILL
BE ENDING IN MARCH. STRATEGY WILL THEN BE FINALIZED, IMPLEMENTATION
FOLLOW UP BEGINS HOPEFULLY JUNE JULY OF THIS YEAR.
IN ADDITION TO THE NATIONAL STRATEGY THERE'S OTHER EFFORTS GOING ON, GLOBAL ALZHEIMER'S
PLATFORM TRIAL READY COHORT, GAP TRACK PAD, THAT IS A GRANT, P.I.s ARE PAUL AND RISA AND
JEFF, SUPPORTED BY THE NIA AND GAP FOUNDATION. THE OVERARCHING GOAL HERE IS TO ACCELERATE
CURRENT AND FUTURE SECONDARY PREVENTION TRIAL ENROLLMENT.
IT'S GOING TO ESTABLISH A TRIAL READY BIOMARKER POSITIVE ABOUT 2000 INDIVIDUALS, MULTIPLE
SITES ACROSS NORTH AMERICA, TO FACILITATE RECRUITMENT INTO PRECLINICAL AND PRODROMAL
A.D. TRIALS. AND FINALLY I WANT TO WRAP UP WITH SOMETHING
THAT'S HOT OFF THE PRESSES BECAUSE WE JUST HAD COUNCIL LAST WEEK.
THERE'S AN UPCOMING FUNDING OPPORTUNITY ANNOUNCEMENT, THAT'S GOING TO BE ON EXAMINING FACTORS RELATED
TO RECRUITMENT AND RETENTION, AGING RESEARCH, FOCUS INVESTIGATORS ON DEVELOPMENT AND EVALUATION
OF INNOVATIVE PARTICIPANT RECRUITMENT AND STRATEGIES THAT SEEK TO ENHANCE DIVERSE ACTIVE
STUDY PARTICIPANTS, PROVIDING RESEARCH FUNDS FOR INVESTIGATORS TO STRENGTHEN OUTREACH AND
COMMUNITY ENGAGEMENT PRACTICES, DEVICE AND IMPROVE RECRUITMENT AND RETENTION STRATEGIES
AND DEMONSTRATE THAT SUCCESS EMPIRICALLY. AND THAT'S MY LAST SLIDE.
THANK YOU.
>> IT'S A GREAT PLEASURE, ON BEHALF OF ABBVIE, TO TALK ABOUT WHAT WE'RE DOING AND I'M GRATEFUL
TO BRAD FOR INVITING ME TO GIVER MY PERSPECTIVE. UNFORTUNATELY, THE SLIDES HAVE BEEN SOMEWHAT
DISTORTED. NEVER MIND, I'LL PUSH ON.
AT ABBVIE THERE ARE COMPELLING REASONS WE WANT TO STAY AND INTENSIFY OUR EFFORTS INTO
ALZHEIMER'S DISEASE. OF COURSE, EVERYTHING ABOVE THE SCIENTIFIC
COMPONENT IS THE UNMET MEDICAL NEED, WHICH IS VAST AND WE KNOW ABOUT THAT.
BUT ALSO WE THINK THAT THE SCIENCE SURROUNDING ALZHEIMER'S DISEASE, THE BIOMARKERS, THE INNOVATION
AND CLINICAL TRIALS AND ALSO REGULATORY ENVIRONMENT ARE ALL VERY SUPPORTIVE AND SO WE ARE INCREASING
OUR INVESTMENT CURRENTLY. THIS IS NEW BUILDING, NEW RESEARCH FACILITY,
WE OPENED IN CAMBRIDGE, MASSACHUSETTS, IT WILL HOUSE
50 LIFE SCIENTISTS AT CAPACITY. THESE ARE THE AREAS WE'RE WORKING ON, AND
THIS REFLECTS SOME OF THE INTERESTING GENETIC FINDINGS THAT WE HEARD ABOUT EARLIER FROM
OTHER SPEAKERS. BUT IT'S PART OF A GLOBAL EFFORT, WE HAVE
A LARGE NUMBER OF NEUROSCIENTISTS WORKING, AROUND 130 ADDITIONAL PEOPLE, 30 IN LAKE COUNTY
IN ILLINOIS, IN TOTAL IN EXCESS OF 200 SCIENTISTS DEVOTED TO NEURODEGENERATIVE DISEASE.
THIS IS MY PERSONAL VIEW BASED ON QUITE A LONG CAREER IN THE PHARMACEUTICAL INDUSTRY.
ABBVIE IS MY FIFTH PHARMACEUTICAL COMPANY. WE NEED ACCESS TO ACADEMIC PARTNERS.
PEOPLE WHO ARE DOING FUNDAMENTAL SCIENTIFIC RESEARCH INTO DISEASE MECHANISMS.
WE NEED TO HAVE ACCESS TO CLINICIANS WHO REALLY KNOW THE DISEASE FROM THE PERSPECTIVE OF PATIENT
AND HAVE ACCESS TO KEY BIOMATERIALS TO HELP US DO OUR JOB AND MAKE SURE THAT WE TRANSLATE
FROM THE PATIENT BACK INTO DRUG DISCOVERY RATHER THAN THE OTHER WAY AROUND.
IN MY EXPERIENCE WE NEED FOUR CONDITIONS THAT ARE PREREQUISITES TO HAVE SUCCESS IN THIS
AREA, THEY DON'T GUARANTEE SUCCESS BUT THEY CERTAINTY INCREASE PROBABILITY.
WE NEED TO GO TO HIGHER REALLY TALENTED PEOPLE, TREAT THEM WELL.
PROVIDE THEM WITH RESOURCES THEY NEED TO DO THE JOB.
WE NEED TO SET A CLEAR MISSION AND NOT CHANGE THAT MISSION FOR THEM ON A REGULAR BASIS.
THEY NEED SOME CERTAINTY. AND WE NEED TO GIVE IT TIME.
SO TO USE A HORTICULTURAL ANALOGY, IF YOU PLANTS A TREE BUT DIG IT UP EVERY YEAR TO
CHECK THE ROOTS YOU'RE NOT GOING TO GROW IT EFFECTIVELY, THE SAME IS TRUE IN DRUG DISCOVERY.
IT TAKES TIME. AS IN THE ACADEMIC COMMUNITY WE NEED TO GENERATE
HIGH QUALITY RESEARCH, HIGH QUALITY SCIENCE, AND MAKE SURE THAT WE'RE DRIVEN BY THE DATA
RATHER THAN ANYTHING ELSE. SO THIS HAS BEEN TALKED ABOUT, I'LL GIVE A
FARMER'S PERSPECTIVE AND ALSO TALK ON AMPAD, WHERE DO THEY COME FROM.
GENETICS HAS CLEARLY INFORMED A.D. RESEARCH SIGNIFICANTLY, PREDOMINANTLY AMYLOID CASCADE
HYPOTHESIS. YOU CAN SEE THE THREE MUTATIONS WHICH INCREASE
PROBABILITY OF AMYLOID DEPOSITION AND TO GETTING A.D. TO 100%, THE ApoEG WHICH WE'VE KNOWN
FOR A QUARTER OF A CENTURY NOW TREND TO REALLY HIGHLIGHTED FOR THOSE WHO WEREN'T INFLAMATOLOSTS,
IMPORTANCE OF GENOME WIDE ASSOCIATION STUDIES, USEFUL INFORMATION.
AS I'LL SHOW YOU, CLINICAL DEVELOPMENT HAS BEEN DRIVEN FOR MANY YEARS BY A BETA.
WE HAVE TO BE CAUTIOUS IN HOW WE INTERPRET THIS INFORMATION, BECAUSE THESE GENES REALLY
TELL YOU ABOUT YOUR PREDISPOSITION FOR DISEASE ONSET.
THEY DO NOT NECESSARILY SAY WHETHER THESE GENES INFLUENCE DISEASE PROGRESSION.
AND IT COULD WELL BE THAT WHAT WE'RE LOOKING AT HERE IS THE INITIATION OF THE DISEASE BUT
NOT PROGRESS. BECAUSE SOMETHING RESULTS IN A BETA DEPOSITION
IT DOES NOT MEAN ATTACKING A BETA DEPOSITION PRODUCTION WHEN YOU GET THE DISEASE WILL BE
AN EFFECTIVE THERAPY, SOMETHING WE'RE COMING TO TERMS WITH.
I THINK THERE'S THE GAP BETWEEN ACADEMIA AND PHARMA IS CLOSING RAPIDLY, AND I'LL TALK MORE
ABOUT THIS, SOMETIMES DRUG TARGETS DO GET LOST IN TRANSLATION FROM THE ACADEMIC FIELD
TO THE PHARMACEUTICAL FIELD. AS A BROAD GENERALIZATION, WHAT WE THINK OF
IN PHARMA AS A GOOD DRUG TARGET THAT BE TRACED TO PATHWAYS WITH GENETIC EVIDENCE, NOT ALWAYS
THE CASE, PHARMACOLOGY THAT MAY TREAT A DISEASE MAY NOT BE THE SAME PATHWAYS THAT RESULT OR
CAUSE THE DISEASE. IT HAS TO HAVE A DRUGGABLE SITE FOR ACTIVITY,
SOMETHING WHERE WE UNDERSTAND THAT WE CAN MODULATE WITH A SMALL MOLECULE OR ANTIBODY
OR SOMETHING ELSE. AND THAT MODULATION HAS TO HAVE A POLARITY.
BY THAT I MEAN WE NEED WHETHER WE WANT TO INCREASE THE ACTIVITY, DECREASE, OR MODULATE
THAT ACTIVITY IN SOME OTHER IN SOME OTHER WAY.
IF YOU JUST THINK BACK TO THE APOE4 EFFECT, WHICH IS VERY STRONG, WE HAVE NOT YET MANAGED
TO DRUG ApoE IN 25 YEARS, THAT'S NOT WITHOUT TRYING PRETTY HARD ACTUALLY.
THE TARGET HAS TO BE WITHOUT OBVIOUS SIDE EFFECTS OR TOXICITY LIABILITY, OTHERWISE WE
WON'T PROGRESS IT. HELPS IF IT HAS A FAVORABLE TISSUE DISTRIBUTION.
I DON'T MEAN IT'S PARENTHESES IN THE BRAIN IF THAT'S WHERE YOU WANT IT TO ACT BUT MORE
THAT IT ISN'T PRESENT IN THE LIVER AT ONE FOLD THE PREVALENCE YOU FIND IT IN THE BRAIN
BECAUSE THEN WE'RE PROBABLY GOING TO RUN INTO TOXICITY.
AND PREFERABLY IT'S NOT A MEMBER OF A GENE SUPER FAMILY WHERE SELECTIVITY IS GOING TO
BE VERY DIFFICULT AND FOR SOME TIME I USED TO LUMP JUST ABOUT EVERYTHING KINASE TARGET
INTO THAT CATEGORY, BUT I THINK WE'VE GOT BETTER NOW, BEING ABLE TO TARGET KINASE, MEMBERS
OF A LARGE FAMILY, MORE SELECTIVELY. AND JUST TO TOUCH ON AMPAD, AN EXCELLENT VEHICLE
TO BRING TOGETHER ACADEMIC AND PHARMA SCIENTISTS TO EDUCATE EACH OTHER, BIDIRECTIONAL, AND
I THINK WE NEED TO DO MORE OF THAT. THIS IS A BOILED DOWN COLLECTION OF INTERESTING
TARGETS THAT HAS COME OUT WITH THE AMPAD ANALYSIS, EACH ROW REPRESENTS A GENE OF INTEREST OR
PROTEIN OF INTEREST, WHICH I'VE ANONYMIZED FOR PURPOSE OF THIS PRESENTATION.
ACROSS THE TOP ON THE LEFT HAND SIDE ARE THE SIX ACADEMIC PARTNERS, HOW THEY RATED EACH
ONE OF THOSE TARGETS OF INTEREST, AND ON THE RIGHT IS HOW THE PHARMA PARTNERS ANONYMIZE
FOR THIS HAVE THOUGHT HOW DRUGGABLE OR TRACTABLE THEY ARE.
AND THIS IS WORK IN PROGRESS, SO IT'S NOT THE FINAL STAGE OF THIS PROCESS.
AND ALSO I'D LIKE TO THANK LILLY WHO WAS RESPONSIBLE FOR PUTTING THIS SPREADSHEET TOGETHER.
THERE'S HETEROGENEITY, IN WHAT THE ACADEMIC PARTNERS THOUGHT THESE GENES OR PROTEINS WERE
IN TERMS OF LEVEL OF INTEREST AS TARGET FOR ALZHEIMER'S DISEASE.
ON THE RIGHT YOU CAN SEE THERE'S SIGNIFICANT HETEROGENEITY WHETHER THE PHARMA PARTNERS
THOUGHT THEY WOULD BE ABLE TO PROGRESS A DRUG FOR EACH OF THOSE TARGETS.
THAT'S BY NO MEANS SURPRISING. I WOULD EXPECT MORE HETEROGENEITY IN TERMS
OF THE LEFT HAND SIDE LOOKING AT THE TARGETS BECAUSE ACTUALLY THAT IS THE A WHOLE LOT MORE
COMPLEX THAN DECIDING WHETHER OR NOT IT IS DRUGGABLE.
IF WE LOOK AT THIS PARTICULAR TARGET HERE, CAN YOU SEE THE PHARMA PARTNERS THOUGHT THIS
WAS A DRUGGABLE TARGET. THAT'S THE BEST THIS ANALYSIS SO FAR OR MOST
CONCORDANCE WE'VE HAD IN THIS ANALYSIS. IF WE LOOK AT THIS PARTICULAR TARGET, UNANIMITY
THAT THIS IS DRUGGABLE, ON THE LEFT HAND SIDE YOU CAN SEE THE ACADEMIC PARTNERS WERE NOT
HUGELY INTERESTED IN THIS TARGET. AT THE BOTTOM HERE, YOU CAN SEE THIS WAS THE
TARGET, THE ACADEMIC PARTNERS WERE MOST EXCITED ABOUT, AND THIS WAS A TARGET WHICH PHARMA
THOUGHT ESSENTIALLY WAS UNDRUGGABLE. AND THAT HAS ALREADY BEEN MENTIONED, THAT'S
VGQ, MENTIONED EARLIER. SO THIS REALLY THINK IS INCREDIBLY USEFUL
AND IT HIGHLIGHTS THE TECHNICAL CHALLENGE THAT WE ALL HAVE IN CHOOSING THE RIGHT TARGET
TO PROSECUTE. AND I THINK WHAT AMPAD IS BEING INCREDIBLY
USEFUL FOR AND WILL CONTINUE TO BE USEFUL FOR IS TO HAVE THIS DISCUSSION TO CONTINUE.
BECAUSE CHOOSING THE RIGHT TARGET IS CRITICAL. WHAT I'VE GOT HERE, THE PYRAMID AT THE TOP
IS DRUG DISCOVERY PROCESS, GENERALLY MORE STARTS AT THE BOTTOM OF THAT PYRAMID, GETS
TO THE TOP, ON THE LEFT HAND SIDE YOU CAN SEE THE YEARS, WHETHER YOU ARE FROM HAVING
AN EFFECTIVE TREATMENT, ON THE RIGHT HAND SITE YOU CAN SEE PROBABILITY OF PATIENT BENEFIT
OF ANY PARTICULAR DRUG DISCOVERY PROJECT COMING OUT OF EACH OF THOSE PHASES, BASED ON ALL
THERAPIES, TAKEN FROM THE NATURE OF DRUG DISCOVERY. WE'VE HEARD THE SUCCESS RATE IN ALZHEIMER'S
DISEASE IS MUCH, MUCH, MUCH LOWER THAN THIS. BUT THIS GIVES I THINK GENERIC VIEW OF HOW
SUCCESSFUL PHARMA IS. AND THE SUCCESS RATE OF COURSE IS A PRODUCT
OF EACH OF THOSE WHICH I CAN ASSURE YOU IS A VERY LOW NUMBER INDEED.
NOW, IN PHASE 2 THAT'S CALLED THE VALLEY OF DEATH BECAUSE PROBABILITY OF COMING OUT OF
THERE IS LOW BUT IF YOU LOOK AT THE TARGET DISCOVERY TARGET VALIDATION BUCKET THAT IS
NOT DISSIMILAR. SO THIS REALLY EMPHASIZES NEED FOR TO US DO
A MUCH BETTER JOB OF SELECTING TARGETS. AND THE SIZE OF THAT PYRAMID AT THE TOP IS
VERY MUCH A FEATURE OF WHAT UNDERLIES IT WHICH IS THE BASIC SCIENCE THAT GOES ON AROUND THE
WORLD IN ACADEMIC LABS AND AMOUNT OF FUNDING THAT THAT RECEIVES.
AND I THINK IF WE CAN HAVE SOMETHING OR MORE ACTIVITY LIKE AMP AD THAT STIMULATES DISCUSSION
BETWEEN ACADEMIA AND PHARMA OF BASIC SCIENCE, THE BETTER OUR ABILITY WILL BE TO CHOOSE HIGHER
QUALITY TARGETS, AND THEN POSSIBLY WE WOULD BE ABLE TO INCREASE THE SUCCESS RATE GOING
THROUGH CLINICAL DEVELOPMENT ULTIMATELY. SO THE SIZE OF THAT BOX AT THE BOTTOM I THINK
IS IMPORTANT. THIS IS TAKEN FROM THE NIH WEBSITE WHERE MONEY
CURRENTLY IS GOING, SOME CATEGORIES I'VE CHOSEN SOME BIG ONES THERE.
YOU CAN SEE CURRENTLY ONCOLOGY PROBABLY QUITE RIGHTLY OCCUPIES A HUGE CHUNK OF FUNDING,
ON THE LEFT HAND SIDE THE FIRST COLUMN THERE IS ALZHEIMER'S DISEASE AND RELATED DEMENTIAS.
AND I THINK IT'S NO SURPRISE THAT WHEN YOU LOOK AT THE NUMBER OF DRUG APPROVALS WE HAD
LAST YEAR ONCOLOGY IS THE GREATEST AT 26%. SO THERE'S A RELATIONSHIP BETWEEN BASIC FUNDING
AND THE NUMBER OF DRUGS THAT GET APPROVED. I DON'T THINK IT'S A DIRECT RELATIONSHIP,
BUT CLEARLY IF WE INCREASE FUNDING I THINK WE INCREASE PROBABILITY THAT WE WILL BE ABLE
TO GET SUCCESSFUL DRUGS TO MARKET. WE'VE HEARD ABOUT IN VIVO MODELS, I OFTEN
READ THE REASON THERE'S BEEN A LOT OF FAILURE IN ALZHEIMER'S DISEASE IS BECAUSE THE IN VIVO
MODELS ARE NOT FIT FOR PURPOSE. THEY LEAD US ASTRAY.
IS THAT TRUE? I'D LIKE TO QUOTE A COUPLE PEOPLE, ONE A BRIT,
ANOTHER AN AMERICAN, TO TRY AND PUT MY PART TO FORGE THAT SPECIAL RELATIONSHIP WE'RE HOLD
EXISTS. THIS IS GEORGE BOX, BRITISH STATISTICS, ALL
MODELS ARE WRONG, SOME MODELS ARE USEFUL. THAT'S VERY TRUE.
AND THIS IS H L MENCKEN, TO EVERY COMPLEX PROBLEM THERE IS AN ART THAT'S CLEAR, SIMPLE
AND WRONG. I DON'T THINK THE ANSWER TO THE FAILURE IS
HAVING BETTER MODELS. HAVING ADDITIONAL MODELS IS USEFUL BUT WON'T
BE A SOLUTION. DO WE NEED MORE IN VIVO?
WOULD IT BE USEFUL TO HAVE A MODEL OF ALZHEIMER'S DISEASE?
SURE WOULD, YES. IS THAT REALISTIC OBJECTIVE?
I DON'T THINK IT IS. DIFFERENCE BETWEEN MAN AND HOUSE IS TOO GREAT.
DO WE NEED ADDITIONAL IN VIVO SYSTEMS, YES. IS THAT REALISTIC, I THINK IT IS.
THESE ARE SOME AREAS I WOULD HIGHLIGHT BEING PARTICULARLY INTERESTED WE'RE NOT GOOD AT
MODELING CURRENTLY. AND I THINK IT'S WORTH STATING THAT THERE'S
A BIG DIFFERENCE BETWEEN HAVING A BAD MODEL AND USING A MODEL BADLY.
AND I THINK WE'VE BEEN GUILTY MORE OF THE LATTER THAN THE FORMER.
THIS IS THE MOST IMPORTANT USE, PROOF OF PHARMACOLOGY THAT THE AGENT YOU WANT TO TAKE INTO MAN DOES
WHAT YOU THINK IT'S GOING TO DO. BIOMARKER, PHARMACODYNAMIC MARKER DISCOVERY,
SO CAN WE FIND THINGS THAT HAPPEN IN THE IN VIVO MODELS THAT WE CAN THEN MEASURE IN HUMANS
THAT GIVE US A SENSE WHETHER WE'RE HITTING THE TARGET APPROPRIATELY, HAVING APPROPRIATE
DOWNSTREAM EFFECTS, THIS IS CRITICALLY IMPORTANT, SAFETY VERSUS EFFICACY.
I PUT EFFICACY IN QUOTES THERE BECAUSE REAL EFFICACY CAN BE ONLY DEMONSTRATED IN HUMANS
WITH DISEASE, IT CAN'T BE DEMONSTRATED IN RODENTS.
PROJECTING DOSES TO MAN, YOU'VE GOT THE AGENT, DEMONSTRATED EFFICACY, HOW MUCH DO YOU THINK
YOU'RE GOING TO HAVE TO ADMINISTER TO PEOPLE? TARGET VALIDATION AGAIN THAT ONLY REALLY OCCURS
IN HUMANS, IN QUOTES, HYPOTHESIS TESTING. AND PHARMA, SOMETIMES BUT RARELY USED TO UNDERSTAND
DISEASE PROCESSES DE NOVO. THE REASON FOR THAT IS THESE MODELS HAVE SOMETHING
CALLED CONSTRUCT VALIDITY. IN OTHER WORDS, HOW DO THEY REALLY RELATE
TO THE HUMAN DISEASE? AND I THINK WE HAVE TO BE EXTREMELY CAUTIOUS
AT DISCOVERING SOMETHING NOVEL IN AN IN VIVO MODEL, AND PROJECTING THAT FORWARD TO THE
CLINICAL DISEASE. AND IN GENERAL, MY PREFERENCE IS TO WORK IN
THE OPPOSITE DIRECTION. LET'S TALK ABOUT CLINICAL DEVELOPMENT.
WHY HAVE THERE BEEN FAILURES IN CLINICAL DEVELOPMENT? CLEARLY BEING IN PHARMA THIS IS SOMETHING
I STUDY QUITE INTENSIVELY. THERE IS NO SINGLE REASON WHY THERE HAS BEEN
A LOT OF FAILURE. IN SOME CASES IF YOU LOOK VERY CAREFUL AT
THE PRE CLINICAL DATA, YOU COULD PROBABLY PREDICT CHANCE OF SUCCESS WERE GOING TO BE
VANISHINGLY SMALL. IN SOME CASES FOR SURE WE'VE GOT SOME VERY
GOOD AGENTS, BUT THEY JUST HAVE NOT BEEN TESTED AT THE RIGHT TIME, IN THE DISEASE PROCESS,
AND WE NEED TO GO MUCH, MUCH EARLIER AND I THINK WHAT WE'RE STRUGGLING WITH AS A FIELD
TO KNOW ESPECIALLY WITH RESPECT TO AMYLOID OR A BETA MECHANISMS HOW EARLY THAT NEEDS
TO BE. THE OTHER REASON, THIS MIGHT SEEM AN ASININE
COMMENTS, THERE'S BEEN NO SUCCESS, WHAT I MEAN, IF WE HAD SOMETHING THAT WORKED EVEN
MODESTLY, IT WOULD TELL US SO MUCH ABOUT THE DISEASE PROCESS.
IT WOULD TELL US WHAT CLINICAL INSTRUMENT WORKS, WHAT PATIENT POPULATION WE CAN SELECT,
GIVES US A MECHANISM AT LAST WHICH WORKS WE CAN BUILD TO FIND RELATED MECHANISMS.
IF YOU LOOK BACK AT OTHER FIELDS, CAN YOU SEE I THINK THAT HAS ALSO BEEN TRUE.
SO RATHER THAN DWELLING ON FAILURE WHAT WOULD INCREASE OUR CHANCES AT SUCCESS WHICH I THINK
IS IMPORTANT. OF COURSE, THE RIGHT THERAPEUTIC TARGET AND
RIGHT DRUG AT THE RIGHT TIME. MY PERSONAL OPINION HERE IS UNDERSTANDING
GENETIC ARCHITECTURE, SOMETHING BRAD SAID ABOUT THE TWINS, ALSO THE ENVIRONMENT, INFLUENCES
RATE OF DISEASE PROGRESSION, NOT JUST PREDISPOSITION TO DISEASE ONSET.
I THINK THAT WOULD GIVE US A LOT OF INTERESTING TARGETS.
APPROPRIATE USE OF IN VIVO MODELS, I THINK THEY HAVE SOMETIMES BEEN INAPPROPRIATELY USED
AND THEY HAVE NOT TRANSLATED TO MAN. IT'S NOT BEEN THE FAULT OF THE MODELS.
IT'S BEEN INAPPROPRIATE USE. IT WOULD BE FANTASTIC THAT WE HAD BLOOD BIOMARKERS
THAT REVEAL DISEASE STATE AND STATUS. SO DOES THIS PERSON HAVE THE DISEASE AND HOW
FAR ADVANCED IS THAT DISEASE? THAT WOULD BE SO, SO USEFUL FOR RAPID PATIENT
SCREENING AND RECRUITMENT. BIOMARKERS THAT MEASURE NEURONAL AND SYNAPTIC
LOSS WHICH ULTIMATELY IS WHERE NEURODEGENERATIVE DISEASE ENDS UP, I THINK WE'RE GETTING THERE
BUT COULD ACCELERATE. TRIAL READY.
THERE'S BEEN A TENDENCY FOR PHARMACEUTICAL COMPANIES TO SKIP PHASE 2 AND GO TO PHASE
3. WE NEED TO ROLL BACK.
IF YOU DO THAT, IF YOU SKIP PHASE 2 AND SUCCEED THAT'S ENLIGHTENED DRUG DISCOVERY AND DEVELOPMENT.
IF YOU FAIL, THEN PEOPLE SAY, YOU KNOW, YOU'VE MADE A BIG MISTAKE.
THIS IS NOT MY SPHERE OF EXPERTISE, CLINICAL INSTRUMENTS, BUT I'M SURE WE COULD DO WITH
BETTER CLINICAL INSTRUMENTS ALTHOUGH I THINK THIS IS A COMBINATION OF THE CLINICAL INSTRUMENT
AND ALSO THE DRUG SO IF WE HAD A REALLY, REALLY EFFECTIVE THERAPEUTIC, THAT DELAYED OR OFFSET
DISEASE PROGRESSION I DON'T THINK WE'D HAVE DIFFICULTY PICKING IT UP.
THIS IS THE CLINICAL PIPELINE, COLOR CODED FOR SIMPLICITY.
AND IN PURPLE AND DARK BLUE, ALL OF THOSE ARE TARGETING THE PURPLE TARGETING BASE, AN
ENZYME, AND IN DARK BLUE THOSE ARE ANTI A BETA OR ANTI AMYLOID ANTIBODIES.
THIS HAS FAILED. YOU CAN SEE IN THAT BUCKET THERE'S NOT MUCH
TARGET DIVERSITY. I WOULD LOVE TO SEE ONE OF THOSE SUCCEED.
I REALLY WOULD. I THINK THOSE THAT ARE GOING AS EARLY AS POSSIBLE
HAVE THE GREATEST CHANCE OF SUCCESS. (INDISCERNIBLE) ALSO GENERATED INTRIGUING
AND INTERESTING PHASE 1B DATA BUT I HAVE TO SAY ALSO THAT I WOULD NOT BE SHOCKED IF THEY
ALL FAILED BECAUSE WE'VE KNOWN FOR SOME TIME THAT AMYLOID ACTUALLY DOES NOT CORRELATE PARTICULARLY
WELL WITH COGNITIVE IMPAIR. THOUGH CLEARLY IS NECESSARY WITH TAU PATHOLOGY
FOR DIAGNOSIS OF ALZHEIMER'S DISEASE. GREEN IS THERAPEUTICS COMING THROUGH FOR TAU.
SO JUST TO WRAP UP, THERE HAVE BEEN A NUMBER OF HIGHLY SUCCESSFUL PUBLIC/PRIVATE CONSORTIA
ESTABLISHED, AND ADVANCED OUR UNDERSTANDING OF A.D. SIGNIFICANTLY, AND I HOPE AMP AD WILL
BE THAT VALUABLE. SUSTAINING IS A WONDERFUL EXAMPLE WILL INCREASE
PROBABILITY THAT WE SHALL SUCCEED. I MEAN EVERYONE, BECAUSE THE CURRENT DEGREE
OF COLLABORATION AND SENSE OF SHARED MISSION IS ABSOLUTELY UNPRECEDENTED IN MY EXPERIENCE,
NOT ONLY BETWEEN THE ACADEMIC COMMUNITY AND PHARMA BUT ACTUALLY WITHIN THE PHARMACEUTICAL
INDUSTRY, AS WELL. NOW, I WORK FOR ABBVIE, I REALLY WANT ABBVIE
TO COME FORWARD WITH A SUCCESSFUL DISEASE MODIFYING THERAPEUTIC.
I WOULD BE DELIGHTED IF A COMPETITOR WOULD DO THAT AS WELL.
THANK YOU VERY MUCH.
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