NHLBI Small Biz Hangout: How Pharma Evaluates New Therapeutic Opportunities


-HI, EVERYONE. AND WELCOME TO TODAY’S
NHLBI SMALL BIZ HANGOUT TITLED “HOW PHARMA EVALUATES
NEW THERAPEUTIC OPPORTUNITIES.” OUR PRESENTER WILL BE
DR. CRAIG WEGNER OF ASTRAZENECA PHARMACEUTICALS, AND I’M GARY ROBINSON,
BUSINESS DEVELOPMENT ADVISOR AT THE NATIONAL HEART, LUNG,
AND BLOOD INSTITUTE. SO, TODAY’S PRESENTER IS
DR. CRAIG WEGNER. HE IS HEAD OF THE
BOSTON EMERGING INNOVATIONS UNIT WITHIN ASTRAZENECA’S
INNOVATIVE MEDICINES AND EARLY DEVELOPMENT
BIOTECH UNIT. CRAIG IS A PASSIONATE
TRANSLATIONAL SCIENTIST AND STRATEGIC LEADER
WITH MORE THAN 25 YEARS OF PHARMACEUTICAL RESEARCH
EXPERIENCE AT FIVE MAJOR PHARMA COMPANIES, AND HE’S PUBLISHED PEER-REVIEWED
ARTICLES, EDITED BOOKS, AND LEAD INITIATIVES IN TEAMS
SPANNING A RANGE OF DISEASE AREAS
AND DISCIPLINES. RELEVANT TO TODAY’S WEBINAR, CRAIG HAS HEADED INITIATIVES
AT BOTH PFIZER AND ASTRAZENECA RELATED TO ANALYZING AND AVOIDING PHARMACEUTICAL
PROJECT ATTRITION. AS THE EXECUTIVE DIRECTOR OF TRANSLATIONAL SCIENCE
AT ASTRAZENECA, CRAIG DIRECTS THE COMPANY’S DRUG
REPOSITIONING IDEATION TEAM. HE ALSO MANAGES AZ’S PARTNERSHIP
WITH THE NIH, NATIONAL CENTER FOR ADVANCING
TRANSLATIONAL SCIENCES, AKA NCATS. AND TAIWAN’S NATIONAL RESEARCH
PROGRAM FOR BIOPHARMACEUTICALS. HE ALSO HEADS ASTRAZENECA’S EXPANDING
OPEN INNOVATION PLATFORM, WHICH PARTNERS
INTERNAL ASTRAZENECA ASSETS AND KNOW-HOW WITH A DISEASE
INSIGHT AND EXPERTISE OF ACADEMIC PHYSICIAN
AND BASIC SCIENTISTS TO COLLABORATIVELY ADVANCE
PIONEERING RESEARCH IN THERAPIES TO THE BENEFIT OF PATIENTS. CRAIG RECEIVED HIS PhD
IN BIOMEDICAL ENGINEERING FROM THE UNIVERSITY
OF CALIFORNIA, DAVIS, AND OVER THE COURSE
OF HIS ACCOMPLISHED CAREER, HE’S MADE CRITICAL CONTRIBUTIONS
TO FIVE MARKETED DRUGS. IT’S A GREAT PLEASURE
TO HAVE CRAIG SPEAK TODAY ON HOW PHARMACEUTICAL COMPANIES
EVALUATE NEW THERAPEUTIC OPPORTUNITIES. AND AS I PASS THE BATON
OVER TO CRAIG, I WOULD JUST POINT OUT,
EVERYBODY SHOULD BE MUTED, BUT IN ANY EVENT,
PLEASE MUTE YOUR MICROPHONES, AND WE WILL BE TAKING QUESTIONS
THROUGH THE Q&A PANEL. -OKAY, THANKS, GARY,
FOR THE INTRODUCTION. THIS IS A TOPIC
THAT I AM PASSIONATE ABOUT. AS GARY SAID, I’VE BEEN INVOLVED WITH LOOKING
AT ATTRITION ANALYSIS WHILE I WAS AT PFIZER, AND AGAIN HERE
WHILE I WAS AT ASTRAZENECA. AND CONSEQUENTLY,
AS WE AND OTHER PHARMA LOOK — AND THAT WORK
HAS BEEN PUBLISHED, SO AS WE AND OTHER PHARMA LOOK AT NEW
THERAPEUTIC OPPORTUNITIES, WE KEEP A LOT OF THESE CONCEPTS
IN THE BACK OF OUR MIND. AND CONSEQUENTLY, IT’S GOOD FOR ANYONE
WHO’S ON THE OTHER SIDE TRYING TO FIND A PARTNER
IN A PHARMACEUTICAL COMPANY TO BE AWARE OF THOSE
SO YOU KNOW WHAT YOUR AUDIENCE WILL BE LOOKING FOR. SO, BY WAY OF INTRODUCTION,
DESPITE — WE ALL HAVE GREAT IDEAS, BUT IT’S BEEN SHOWN THAT 99%
OF THOSE INNOVATIVE IDEAS WILL ULTIMATELY FAIL. NOW, THOSE THAT ARE ON THE CALL
TODAY, I’M SURE THAT YOUR IDEAS
ARE BETTER THAN MOST OTHERS, SO IT MAY BE STILL 70%
OR MAYBE 80%, BUT IT’S STILL — THE VAST MAJORITY
OF THOSE IDEAS ARE GONNA FAIL. WHAT’S BEEN DISCOURAGING AS WE
IN THE PHARMACEUTICAL COMPANIES HAVE WENT BACK AND LOOKED
AT PROJECTS THAT FAIL VERSUS PROJECTS THAT SUCCEED
MANY TIMES. AND IN FACT,
IN ABOUT 50% OF THOSE CASES, WE COULD HAVE PREDICTED FAILURE PRIOR TO DOING
THE NEXT EXPENSIVE EXPERIMENT. SO, WHAT THAT HAS CAUSED
US TO DO IS TO RECOGNIZE THOSE
COMMON CAUSES OF ATTRITION, AND NOW USE THOSE
AS WE EVALUATE PROJECTS AND TRY TO BECOME UNBIASED
TO THOSE. AND AS I’LL SHARE TODAY,
I THINK IT’S IMPORTANT THAT YOU — AS YOU’RE VIEWING YOUR PROJECTS AND ULTIMATELY PREPARING
THEM FOR PRESENTATION TO EITHER INVESTORS
OR TO COMPANIES THAT YOU WOULD WANT TO PARTNER
WITH HAVE ATTENTION TO THESE. THEY WILL RESULT IN
BOTH THE SUCCESS IN THE PROJECT. THEY’LL RESULT
IN A TIMELY TRACTABILITY OR PROGRESSION OF THE PROJECT, AND THEY ARE GOING TO RELATE TO THE ATTRACTIVENESS
OF THE PROJECT TO INVESTORS. SO, THE REAL DRIVER
OF LOOKING BACK AT ATTRITION IS SHOWN ON THIS SLIDE. RELATIVE TO A SUCCESSFUL PERIOD
IN THE 1990s, SHOWN ON THE LEFT-HAND SIDE
OF THE SLIDE, THERE WAS AN EXTREME DROP IN THE NUMBER
OF APPROVED COMPOUNDS AS WE ENTERED IN THE MID-2000s. AND THIS WAS DESPITE AN INCREASE IN THE EXPENDITURE WITHIN
PHARMACEUTICAL COMPANIES R&Ds. SO, THIS LEVEL OF PRODUCTIVITY HAD DECREASED THE NUMBER
OF APPROVED DRUGS AT THE TIME YOU’RE INCREASING
YOUR EXPENSIVE R&D, OBVIOUSLY, IS UNSUSTAINABLE. AND WHEN WE WENT BACK
AND LOOKED AT, WELL, WHAT PHASE
WOULD COMPOUNDS ATTRIT AT, YOU CAN SEE THAT THERE WAS
AN INCREASE IN ATTRITION AT JUST ABOUT ALL THE STAGES. BUT THE ONES WITH THE MOST
PREDOMINANT SLOPES — EXCUSE ME — WERE DURING
PHASE TWO AND PHASE THREE, AND THESE ARE EXPENSIVE TIMES
IN DRUG DEVELOPMENT. SO, AT THE TIMES
WE WERE SPENDING THE MOST MONEY, WE’RE ALSO
GETTING THE HIGHEST ATTRITION. SO, THERE WERE SEPARATE
COMPANIES THAT WENT BACK AND LOOKED AT THIS ATTRITION, AND I’LL PRESENT TWO OF
THOSE TODAY THAT ARE PUBLISHED. THE FIRST WAS A TEAM
THAT I ACTUALLY LED AT PFIZER. WE LOOKED AT 44 PROGRAMS
THAT REACHED PHASE TWO AND A DECISION POINT
IN PHASE TWO IN THE PERIOD
BETWEEN 2005 AND 2009. AND WHAT WE FOUND
THAT WAS DISAPPOINTINGLY IN 43% OF THE CASES, WE WERE NOT SURE THAT THE
MECHANISM WAS ACTUALLY TESTED. NOW, IT’S ONE THING
IF YOUR HYPOTHESIS IS WRONG, BUT IT’S ANOTHER THING IF YOU HAVE DELIVERED A COMPOUND
INTO PHASE TWO, AND YOU DON’T EVEN KNOW WHETHER YOU’VE TESTED
THAT PARTICULAR MECHANISM THAT THE COMPOUND HITS. THIS LED US TO — EXCUSE ME — DEVELOPING SOME PHARMACOKINETIC
AND PHARMACODYNAMIC OR PK AND PD PRINCIPLES TO PROVIDE A SOLUTION TO THIS. AND I’LL GO INTO MORE DETAILS AND GIVE YOU THE REFERENCE
TO THAT WORK, AS WELL, IN SUBSEQUENT SLIDES. THIS WAS FOLLOWED UP
BY A STUDY WITHIN ASTRAZENECA THAT OCCURRED ALMOST
IN THE SAME TIMEFRAME, A LITTLE BIT LATER
THAN THE PFIZER WORK AND ACCOMPLISHED ALL STAGES
OF DRUG DISCOVERY, WHERE THEY LOOKED AT 142 DRUGS
THAT WERE — THAT REACHED A DECISION
OF EITHER GOING FORWARD OR HALTING BETWEEN THE 2005
AND 2010 TIME PERIOD. AND THE REASON
THAT THEY DID THIS ANALYSIS WAS, AT THAT PERIOD OF TIME, THE SUCCESS WITHIN ASTRAZENECA WAS ABOUT ONE-THIRD
OF THE INDUSTRY MEDIAN. AND THE RESULT OF THEIR ANALYSIS
WAS THAT IN 75% OF THE TIME, THEY FOUND THAT THE PROJECT
HAD A REALLY BIG RISK. AND SO IF THEY HAD ELIMINATED
THOSE 75% OF THE PROJECTS AND FOCUSED THEIR INVESTMENT
ON THE 25% THAT DIDN’T HAVE THE BIG RISK, THEIR SUCCESS RATE ACTUALLY WOULD HAVE BEEN A LITTLE BIT
ABOVE THE INDUSTRY MEDIAN AS OPPOSED TO 70% BELOW. AND THIS LEAD THEM
WHAT THEY CALL THE FIVE R’s, OR THE RIGHT TARGET, THE RIGHT TISSUE, THE RIGHT SAFETY, THE RIGHT PATIENT, AND THE RIGHT COMMERCIAL. AND AGAIN,
I’LL GO INTO MORE DETAILS ON EACH OF THOSE
IN SUBSEQUENT SLIDES. AND FINALLY, JUST TO LET
YOU KNOW WHAT’S COMING, AT THE END OF THE PRESENTATION
TODAY, I’LL SORT OF TAKE AN ACCUMULATION OR A CONSOLATION OF THOSE TWO ATTRITION ANALYSIS TO COME UP WITH WHAT I THINK
ARE THE BUILDING BLOCKS THAT YOU SHOULD BE CONCERNED OF AS YOU PREPARE A PROJECT
FROM EARLY STAGE AND TO A STAGE WHERE
YOU’RE LOOKING FOR A PARTNER, EITHER AS AN INVESTOR OR AS A COMPANY
TO LICENSE THE OPPORTUNITY, TOO. SO, FIRST OF ALL,
THE PFIZER ANALYSIS RESULTED IN WHAT THEY CALL
THE THREE PILLARS OF SURVIVAL. AND BASICALLY, IT WAS THAT, IN ORDER TO KNOW THAT YOU’VE
TESTED YOUR MECHANISM IN YOUR CLINICAL STUDY,
IN THE PHASE TWO CLINICAL STUDY, YOU NEEDED EVIDENCE
IN THE TISSUE OF INTEREST OF FIRST THAT YOU HAD EXPOSURE
OF THE COMPOUND TO THAT TISSUE, THAT IT BOUND
TO YOUR MOLECULAR TARGET THAT YOU WERE TRYING
TO GET IT TO BIND TO. AND THAT FINALLY,
THAT IT PRODUCED A PHARMACODYNAMIC EFFECT. AND IF YOU
HAD THESE THREE PILLARS, THEN YOU WOULD — YOU HAD TWICE THE LIKELIHOOD OF GETTING A POSITIVE SIGNAL
IN YOUR PHASE TWO STUDY. MORE DETAILS ON THAT, THEY
WENT BACK OF THE 43 PROGRAMS THAT THEY ANALYZED
OR THAT WE ANALYZED, ACTUALLY. WE ALIGN THEM
INTO THIS 2×2 MATRIX WHERE WE HAD CONFIDENCE
IN EXPOSURE OR CONFIDENCE IN PHARMACOLOGY. SO, 12 OF THE PROGRAMS ACTUALLY ENDED UP
WHERE WE HAD LOW CONFIDENCE THAT WE WERE ACHIEVING
NECESSARY EXPOSURE FOR EFFICACY, AND WE HAD LOW CONFIDENCE,
MEANING NO EVIDENCE THAT WE WERE ACTUALLY
HITTING THE TARGET FROM A PHARMACOLOGY BIOMARKER. IN ALL 12 OF THOSE CASES, THE COMPOUND ULTIMATELY FAILED, AND WE FAILED
TO TEST THE MECHANISM. UP HERE IN THE UPPER
LEFT-HAND CORNER OF THIS MATRIX WHERE WE HAD CONFIDENCE
IN EXPOSURE AND BINDING TO TARGETS OF THE 12 PROJECTS
THAT GOT HERE, FIVE OF THEM WE WERE PRETTY CONFIDENT
THAT WE TESTED THE MECHANISM. AND TWO OF THOSE WERE SUCCESSES
IN THE PHASE TWO THAT THEY RESULTED
IN PHASE THREE STARTS. ON THE OTHER END
IN THE LOWER RIGHT WHERE WE HAD CONFIDENCE IN THE PHARMACOLOGIC EFFECT
OF THE SIX PROJECTS HERE, WE WERE CONFIDENT
THAT FIVE OF THEM WE HAD ACTUALLY
TESTED THE MECHANISM, ALTHOUGH NONE OF THEM
RESULTED IN PHASE THREE STARTS. SO, WE TESTED THE MECHANISM, BUT OUR ORIGINAL HYPOTHESIS
WAS PROBABLY WRONG. AND IN THE CASE
IN THE UPPER RIGHT, WHICH IS WHERE WE WANTED TO BE, IF YOU HAD ALL THREE PILLARS, THEN OF THE 14 PROJECTS
THAT ENDED UP HERE, ALL 14 WE WERE SURE
THAT WE TESTED THE MECHANISM, 12 OF THOSE ACHIEVED
PROOF OF CONCEPT IN PHASE TWO, AND 8 OF THOSE ADVANCED
INTO PHASE THREE. SO, IF WE JUST
LOOK AT CONFIDENCE IN EXPOSURE, MEANING THAT YOU KNOW
THAT YOU HAD ENOUGH COMPOUND THAT REACHED THE TARGET TISSUE, THEN IN 73% OF THE CASES, YOU WERE CONFIDENT THAT YOU
ACTUALLY TESTED THE MECHANISM. YOU TESTED YOUR HYPOTHESIS. AND IN ALMOST 40% OF THE CASES, IT SHOWS THOSE PROJECTS
ADVANCED INTO PHASE THREE. SO, YOUR HYPOTHESIS
WAS RIGHT IN 40% OF THE CASES, AND YOU COULD ADVANCE
THAT INTO PHASE THREE. ON THE OTHER HAND, IF YOU HAD CONFIDENCE
IN PHARMACOLOGY, THAT MEANING YOU HAD A BIOMARKER OF A PHARMACOLOGIC EFFECT
OF THAT PATHWAY WITHIN THAT MECHANISM,
NOW YOU ARE ALMOST ASSURED, 95% CONFIDENT THAT YOU
HAD TESTED THE MECHANISM, AND 40% OF THE TIME, AGAIN, YOU ADVANCED INTO PHASE THREE. NOW, JUST FOLLOWING THIS — AND THIS WORK WAS ALL PUBLISHED. WAIT, DID I FORGET
TO GIVE YOU THE PUBLICATION? IN DRUG DISCOVERY TODAY IN 2012. SO, JUST AFTER THAT, ASTRAZENECA DID AN ANALYSIS
OF THEIR DRUG PIPELINE, AND AGAIN, UNLIKE PFIZER WHICH HAD FOCUSED
SOLELY ON PHASE TWO DECISIONS, THEY FOCUSED ON DECISIONS ACROSS
THE WHOLE DISCOVERY PIPELINE FROM EARLY DISCOVERY
TO THOSE IN DEVELOPMENT AND LOOKED AT 142 PROJECTS. THAT’S ONE OF THE BENEFITS
OF BEING IN A BIG PHARMA IS, NOT ONLY DO
YOU HAVE A FEW SUCCESSES, BUT YOU HAVE A LOT OF FAILURES
THAT YOU CAN LEARN FROM. AND AGAIN, ASTRAZENECA DID THIS
BECAUSE THEIR SUCCESS RATE WAS ABOUT A THIRD
OF WHAT PEERS WERE. THEY PUBLISHED THIS WORK IN
NATURE REVIEWS ABOUT DISCOVERY. AND WHAT THEY FOUND
FROM LOOKING AT IT WAS THAT THERE WERE REALLY
FIVE KEY FRAMEWORKS THAT WERE IMPORTANT TO HAVE
KNOWLEDGE ABOUT TO ADVANCE A PROJECT
FORWARD. THE FIRST WAS,
IS IT THE RIGHT TARGET? IS THERE A STRONG LINK
BETWEEN THE TARGET AND THE DISEASE,
PARTICULARLY IN HUMANS? IS THERE EVIDENCE THAT IT’S
GOING TO BE DIFFERENTIATED? IS THERE EVIDENCE THAT THERE’S
AVAILABLE PREDICTIVE BIOMARKERS? AND I’LL SHOW YOU
SOME OF THAT EVIDENCE FOR WHY THAT IS IMPORTANT AS WE
GO FORWARD IN THIS PRESENTATION. THE SECOND THING THAT THEY SAID
WAS THE SAME THING AS PFIZER. IT’S IMPORTANT THAT YOU KNOW
THAT YOU’VE GOT THE RIGHT CONCENTRATION TO THE TISSUE. SO, DID YOU HAVE
ADEQUATE BIO AVAILABILITY AND TISSUE EXPOSURE
OF THE COMPOUND? DO YOU HAVE
SOME PHARMACODYNAMIC BIOMARKER THAT GIVES YOU EVIDENCE THAT YOU’VE NOT ONLY GOT
THE COMPOUND TO THE TARGET, BUT IT’S PRODUCED
A PHARMACOLOGIC EFFECT? AND HOPEFULLY A MAXIMAL
PHARMACOLOGIC EFFECT HITTING THAT TARGET. DO YOU UNDERSTAND
THE PK/PD RELATIONSHIP FROM PRE-CLINICAL MODELS TO BE ABLE TO TRANSLATE
THAT INTO THE CLINIC? DO YOU UNDERSTAND DRUG
INTERACTIONS SO THAT YOU KNOW THAT WHAT
CONCOMITANT MEDICINES TO AVOID, OR WHAT THE EFFECT
OF THEM WOULD BE. ASTRAZENECA ALSO FELT
IT IMPORTANT THAT YOU NEEDED
TO REALLY UNDERSTAND THE SAFETY BECAUSE A NUMBER
OF THEIR COMPOUNDS, THEY WERE LIMITED
ON THE EXPOSURE THAT THEY COULD GO
INTO IN THE CLINIC BECAUSE OF UNANTICIPATED
SAFETY FINDINGS. SO, BASED ON PRECLINICAL DATA, WAS THERE CLEAR KNOWLEDGE
OF THE DIFFERENTIATION AND MARGINS FOR SAFETY? WAS THERE AN UNDERSTANDING
OF THE SECONDARY PHARMACOLOGICAL RISK, I.E., THE OFF-TARGET
PHARMACOLOGICAL RISK? AND THEN ANY UNDERSTANDING
OF METABOLITES OR GENOTOX OR DRUG-DRUG INTERACTIONS,
AGAIN, WITH THE COMPOUND. AS WELL AS ANY ON-TARGET
SAFETY ISSUES THAT NEEDED TO BE DEALT WITH. NEXT, IT WAS IMPORTANT
NOT ONLY THAT YOU KNEW — THAT YOU HAD ALL THESE COVERED, BUT THAT YOU WENT INTO
THE RIGHT PATIENT POPULATION. AND THE RIGHT PATIENT POPULATION
MEANS NOT ONLY THE RIGHT INDICATION,
BUT WITHIN THE INDICATION, THE RIGHT PATIENT POPULATION
WITHIN THAT INDICATION. I’LL SHOW YOU SOME EXAMPLES
LATER IN THE SLIDE DECK OF WHERE WE, ASTRAZENECA,
GOT THAT WRONG, AND WHERE WE COULD HAVE
DONE THAT BETTER. AND THEN FINALLY, THAT WE, AT THE END OF THE DAY, WE’RE GONNA BE ABLE TO CREATE
A RETURN ON INVESTMENT. IN OTHER WORDS,
WE’RE GOING TO BE ABLE TO RECOUP OUR DEVELOPMENT COSTS BECAUSE OF THE COMMERCIAL VALUE
OF THE AGENT, THAT IT WAS GOING
TO BE DIFFERENTIATED RELATIVE TO THE THINGS
THAT WERE ALREADY ON THE MARKET OR ON THE PIPELINE. -HEY, CRAIG,
I JUST WANT TO BREAK IN HERE AND JUST REMIND PEOPLE TO, IF YOU HAVE ANY QUESTIONS,
PLEASE POST THEM ON THE BOTTOM
RIGHT HAND SIDE OF THE Q&A PANEL
OF THE WebEx SCREEN. THANK YOU. -GREAT, THANKS, GARY. SO, HERE’S A CASE STUDY OF HOW
TO PUT THE FIVE R’s INTO PLACE. AND I USE THIS ONE, EVEN THOUGH IT REALLY IS
OUTSIDE OF THE THERAPEUTIC AREA OF NHLBI, BUT I DO SO BECAUSE I THINK IT
GIVES SOME VERY GOOD PRINCIPLES THAT THEN CAN BE APPLIED
ACROSS OTHER CASE STUDIES THAT WILL COME LATER
IN THE SLIDE DECK ARE ACTUALLY
WITHIN THE NHLBI DISEASE AREAS. SO, THIS WAS A COMPOUND THAT WAS
A POSITIVE ALLOSTERIC MODULATOR OF MGLUR2 FOR THE TREATMENT
OF SCHIZOPHRENIA. AND THE HYPOTHESIS HERE IS
THAT THE FAILURE OR DECREASE IN CORTICAL
GLUTAMATE DRIVE RESULTS IN A DECREASE
IN SUBCORTICAL DOPAMINE FUNCTION AND CONSEQUENTLY PSYCHOSIS. AND AT THE TIME THIS PROJECT
WAS BEING BROUGHT FORWARD INTO CLINICAL STUDIES,
THERE WAS A LILLY COMPOUND THAT WAS A DUAL MGLUR2 AND 3
AGONIST THAT HAD SOME POSITIVE EFFECTS
IN A PHASE 2a STUDY. NOW, THAT LATER DIDN’T PAN OUT
IN PHASE 2b OR PHASE 3, BUT IT LEAD TO ASTRAZENECA
RUSHING THIS COMPOUND FORWARD. NOW, WHAT DO WE KNOW
ABOUT THIS COMPOUND? WELL, FIRST OF ALL,
AS I MENTIONED IT, SAY MGLUR POSITIVE ALLOSTERIC
MODULATOR, WHICH MEANS THAT IT FUNCTIONALLY
ENHANCES THE EFFECT OF GLUTAMATE ON THE MGLUR — GLUTAMATE RECEPTOR 2. IT WAS ACTIVE IN
SEVEN DIFFERENT PRECLINICAL ANTIPSYCHOTIC ACTIVITY MODELS,
AS WELL AS TWO ANXIETY MODELS. THE EFFECTIVE CONCENTRATION
IN THOSE PRECLINICAL MODELS RANGED FROM 2 NANOMOLAR
TO 1,000 NANOMOLARS. IT DID HAVE
SOME PRECLINICAL TOXICITY. IT CAUSED TESTICULAR TOX IN DOGS
AND SOME CATARACTS IN RATS, AND THIS CAPPED THE ALLOWABLE
EXPOSURE IN THE CLINIC. THE PHASE 2 WAS BASED — THE EXPOSURE TARGET
TO REACH IN THE PHASE 2a STUDY WAS BASED ON A COLLECTION OF WHAT WE FOUND
IN THE PRECLINICAL MODEL. SO, SOMEWHERE BETWEEN
THE 2 AND 1,000 NANOMOLAR, WE I THINK
PICKED CLOSER TO THE 2 THAN WE DID THE 1,000. AND THEN,
WE KNEW THAT THERE WAS — THAT DRUG ACTUALLY GOT
INTO THE CENTRAL NERVOUS SYSTEM, SO WE KNEW
THAT THERE WAS SOME EXPOSURE TO THE TARGET TISSUE
THAT WAS 50% OF THE PLASMA, WHICH IS PRETTY GOOD, BUT WE HAD NO PET LIGAND
OR ANY OTHER WAY OF ASSESSING THAT WE’D ACTUALLY
HIT THE TARGET IN THE CNS. THE OUTCOME OF THE PHASE 2a
STUDY IN SCHIZOPHRENIA WAS THAT IT WAS NEGATIVE. SO NOW,
IF WE LOOK AT THE 5R FRAMEWORK, WE CAN SAY, WELL, FIRST OF ALL, THERE’S A HUGE MARKET
FOR SCHIZOPHRENIA, AND THE EXISTING DRUGS
ARE NOT VERY GOOD. SO, IT’S A HUGE
COMMERCIAL OPPORTUNITY, SO THIS ONE
WE WOULD SAY IS GREEN. BUT WHEN WE LOOKED AT SOME
OF THE OTHERS, WELL, WHAT ABOUT, IS THIS THE RIGHT TARGET
FOR SCHIZOPHRENIA? WELL, FIRST OF ALL, THE LILLY COMPOUND HAD BEEN
A DUAL AGONIST OF 2 AND 3. WE WERE GOING FORWARD
WITH THE 2. WAS THAT GOING TO BE EFFECTIVE? AND ULTIMATELY,
THERE WASN’T A LOT OF EVIDENCE THAT THAT WAS GOING
TO BE EFFECTIVE. SO, IN RETROSPECT, WE WOULD HAVE
GRADED RIGHT TARGET AS RED. THE SEVEN PRECLINICAL MODELS, AGAIN,
SHOWED A WIDE RANGE OF EFFICACY, AND THE TRANSLATION
OF THESE MODELS IS KNOWN TO BE NOT VERY GOOD. SO, THE OTHER THING IS, THAT SCHIZOPHRENIA IS A VERY
HETEROGENEOUS INDICATION, AND WE WENT INTO ALL COMERS
IN THE PHASE 2a STUDY, SO DID WE HAVE THE RIGHT PATIENT
WAS THE OTHER CONCERN THAT WE HAD. IN ADDITION,
WHAT ABOUT TISSUE EXPOSURE? WELL, WE KNEW
IT GOT INTO THE BRAIN, BUT WE DIDN’T KNOW
HOW MUCH WE REALLY NEEDED. SOME ANIMAL MODELS,
WE HAD EFFICACY AT 2 NANOMOLARS. OTHER, IT TOOK 1,000 NANOMOLAR. SO, WHAT’S THE RIGHT
CONCENTRATION HERE? WE WERE LIMITED
BY THE TESTICULAR TOXIN IN DOGS, SO WE COULD ONLY TEST UP
TO ABOUT 15 TO 20 NANOMOLAR IN THE CLINIC. WOULD WE HAVE GOTTEN EFFICACY
IF WE WENT HIGHER? AND THEN THE RIGHT SAFETY,
THE SAME THING BECAUSE WE WERE LIMITED
BY THE TESTICULAR TOXICITY. DID WE NEED ANOTHER COMPOUND? DID WE NEED A BETTER COMPOUND? AND ASTRAZENECA ACTUALLY WENT
BACK AND GOT A BETTER COMPOUND AND IS BRINGING
THAT INTO CLINICAL TRIALS NOW FOR OTHER INDICATIONS. SO, LET’S TALK
ABOUT A FEW OTHER CASE EXAMPLES THAT ARE MORE RELEVANT
TO THE THERAPEUTIC AREA THAT THOSE ON THIS CALL
ARE PROBABLY MOST INTERESTED IN. SO, THE FIRST PROGRAM IS THAT
OF 11 BETA HSD1 INHIBITOR. 11 BETA HSD1 PREVENTS
THE CONVERSION OF CORTISONE TO CORTISOL. THERE’S SOME PRECLINICAL
EVIDENCE THAT THIS WOULD BE EFFECTIVE
IN DIABETES AND OBESITY. HOWEVER,
WHEN WE WENT INTO THE CLINIC, WE FOUND THAT THE ACTIVITY
WAS QUITE WEAK. THIS WAS A SITUATION
WHERE I’M NOT SURE — WELL,
WE DIDN’T HAVE THE RIGHT TARGET. WE DIDN’T HAVE EVIDENCE
THAT IT WAS DIFFERENTIATED, OR THAT IT HAD
THE EFFICACY HORSEPOWER TO PRODUCE EFFICACY
THAT WAS GOING TO BE CLINICALLY MEANINGFUL
IN EITHER DIABETES OR OBESITY. THE SECOND MOLECULE
THAT I MENTIONED IS THE GLUCOKINASE ACTIVATOR. GLUCOKINASE ACTIVATION CATALYSES
THE CONVERSION OF GLUCOSE TO GLUCOSE 6-PHOSPHATE. SO, WHEN YOU ADMINISTER THIS
TO ANIMALS AND TO HUMANS, YOU GET A STRONG, ACUTE DECREASE
IN PLASMA GLUCOSE, SO EXACTLY WHAT YOU WANT
IN A DIABETIC PATIENT. BUT THIS EFFECT IS NOT
SUSTAINED. AGAIN, GOING BACK AND LOOKING
AT THIS IN PRECLINICAL MODELS, HAD WE DONE MODELS THAT WERE
MORE THAN TWO WEEKS IN DURATION, WE WOULD HAVE FOUND THAT
THIS EFFECT WAS NOT SUSTAINED. SO, AGAIN, WE DIDN’T HAVE THE RIGHT TARGET
HERE. THEN FINALLY, IN THE LUNG FIELD, WE TOOK A NEUTROPHIL
ELASTASE INHIBITOR INTO BRONCHIECTASIS CF AND COPD. AND WE SET THE DOSE BASED
ON SOME PRECLINICAL MODELS WHERE WE EXOGENOUSLY ADDED
NEUTROPHIL ELASTASE TOPICALLY INTRATRACHEALLY INTO THE LUNG. AND PERIPHERAL BLOOD INHIBITION
OF NEUTROPHIL ELASTASE ACTIVITY. WHAT WE FOUND WAS
THAT WE HAD SOME WEAK EFFICACY IN BRONCHIOLITIS, BUT WHEN WE WENT
INTO PHASE 2b STUDIES IN CF AND COPD, WHICH WERE
OUR PRIMARY INDICATIONS, THERE WAS NO EFFECT. AND WE REALLY HERE ARE UNSURE WHETHER WE HAVE THE RIGHT
EXPOSURE WITHIN THE TISSUE. NOW, EACH OF THESE ALSO
COULD HAVE BEEN A PROBLEM. DID WE HAVE THE RIGHT PATIENT? AND I MENTION THAT BECAUSE ONE
OF THE THINGS THAT MY GROUP IS INVOLVED
IN IS DRUG REPOSITIONING. AND EACH OF THESE COMPOUNDS ARE NOW BEING PURSUED
IN ANOTHER PATIENT POPULATION WHERE WE THINK THAT THEY
HAVE THE OPPORTUNITY TO SUCCEED, CORRECTING FOR THE RIGHT TARGET,
RIGHT INDICATION AND TISSUE EXPOSURE ISSUES
THAT OCCURRED IN THESE STUDIES. SO, THE IMPORTANT THING
FOR EACH OF YOU TO UNDERSTAND IS ACTUALLY THE CONSEQUENCE
THAT THIS ANALYSIS HAS LEAD TO. NOT ONLY WITHIN ASTRAZENECA, BUT THROUGHOUT
THE PHARMA INDUSTRY, AND THAT IS THE CONCEPT NOW, IF YOU LOOK AT
THE PHARMACEUTICAL DRUG FUNNEL FROM IDEA TO LAUNCH, YOU KNOW THAT IN THE PAST, AND IN PARTICULARLY,
IN THE LATE ’90s AND THROUGH THE FIRST DECADE
OF THIS CENTURY, SPENT A LOT OF TIME JUST
ENTERING AS MANY GOOD TARGETS AS WE COULD INTO THE PIPELINE TO HOPE
THAT ADDITIONAL COMPOUNDS WOULD COME OUT THE END. WHAT WE’VE FOUND NOW
IS THAT IT’S — WE CAN’T AFFORD TO DO THAT, AND THAT WHAT WE REALLY
NEED TO DO IS TO FOCUS ON THOSE PROJECTS THAT HAVE THE MOST GREEN
OF THE FIVE R’s. AND TO FOCUS OUR EFFORTS
ON THE OTHER PROJECTS OF EITHER MOVING THEM
INTO THIS AREA OR NOT DOING THEM AT ALL. SO, THE RESULT
IS THAT IF YOUR PROJECT DOESN’T SIT UP HERE WITH MOST
OF THOSE FIVE CRITERIA THAT I’VE MENTIONED BEING GREEN, YOU’RE NOT GONNA
GET THE ATTENTION OF BIG PHARMA GOING FORWARD. SO, LET ME JUST
REINFORCE SOME OF THIS WITH A FEW MORE CASE EXAMPLES AND SORT OF RUN THROUGH
HOW I NOW THINK OF ATTRITION AND HOW TO BUILD
A SUCCESSFUL PROJECT. AND I BUILT IT WITH BUILDING
BLOCKS AS SHOWN HERE, STARTING WITH CONFIDENCE THAT YOU’VE GOT THE RIGHT
COMPOUND AND THE RIGHT MOLECULE TO GET YOUR TARGETS, THAT YOU’RE ADMINISTERING IT
AT THE RIGHT DOSE TO COVER TARGETS
AND TO HAVE ACCEPTABLE SAFETY. THAT YOU HAVE THE RIGHT PATIENT
POPULATION IN TERMS OF THE INDICATION
THAT YOU’RE GOING AFTER. BUT EVEN MORE THAN THAT, THEN YOU BUILD ON THAT AND LOOK
WITHIN THAT INDICATION INTO THE RIGHT SUBPOPULATION OF
PATIENTS WITHIN THAT INDICATION THAT ARE MOST LIKELY
TO RESPOND TO YOUR COMPOUND, RESPOND TO INHIBITION OR ACTIVATION
OF THAT PARTICULAR MECHANISM. THAT YOU’VE DONE
YOUR CLINICAL DESIGN TO NOT ONLY PROVE
YOUR HYPOTHESIS, BUT GAIN AS MUCH INFORMATION
ABOUT YOUR DRUG AND THAT INDICATION THAT
PATIENT POPULATION IS POSSIBLE. THAT YOU HAVE A CLEAR
REGULATORY PATH AND HAVE TALKED TO REGULATORS ON HOW TO MOVE THIS
THROUGH TO MARKET, AND IT’S PARTICULARLY IMPORTANT IF YOU’RE
IN NOVEL THERAPEUTIC AREAS, WHICH IS WHERE THE HIGHEST UNMET
MEDICAL NEED AND HIGHEST VALUE IS. AND THAT FINALLY, YOU UNDERSTAND
THE RETURN ON INVESTMENT. IN OTHER WORDS,
THAT IF SOMEONE INVESTS IN THIS MOLECULE
AT THE END OF THE DAY, THEY’LL BE ABLE TO RECOUP
THEIR INVESTMENT COSTS. SO, LET’S QUICKLY
WALK THROUGH EACH OF THESE. THERE’S A LOT OF INFORMATION
ON EACH OF THESE SLIDES, AND I’M JUST GONNA TOUCH
ON A LITTLE BIT OF IT SO THAT WE LEAVE SOME TIME
FOR Q&A. BUT AS GARY MENTIONED,
THESE SLIDES ARE AVAILABLE TO YOU
TO PERUSE AFTER THE WEBINAR, AND IF YOU HAVE ANY QUESTIONS, DON’T HESITATE TO REACH OUT
TO ME. SO, FIRST AND FUNDAMENTAL IS, YOU GOT TO HAVE THE RIGHT
COMPOUND OR THE RIGHT MOLECULE. THIS IS THE FOUNDATION. YOU GOT TO GET THIS RIGHT. THE FIRST FEATURE IS, YOU GOT
TO HAVE THE RIGHT POTENCY. IF YOU’RE TALKING ABOUT A SMALL,
MOLECULAR WEIGHT COMPOUND, IT NEEDS TO BE
IN THE NANOMOLAR RANGE, NOT IN THE MICROMOLAR RANGE. YOU’RE TALKING ABOUT
A MONOCLONAL ANTIBODY OR A BIOLOGIC, YOU NEED TO BE
IN THE PICOMOLAR RANGE, NOT THE NANOMOLAR RANGE. JUST SOME EXAMPLES OF THIS, ANTI-IL-18 ANTIBODY, NOT ONLY BY ASTRAZENECA, BUT BY PFIZER, ABBOTT. I THINK THERE WERE THREE OR FOUR
OTHER COMPANIES THAT CREATED ANTIBODIES TO
IL-18. NONE OF THESE WERE ABLE
TO BE EVEN BROUGHT SUCCESSFULLY INTO PHASE 2 STUDIES
BECAUSE THEY LACKED THE POTENCY. THEY WERE
IN THE NANOMOLAR RANGE, AND THEY DIDN’T COVER TARGETS
SUFFICIENTLY IN PHASE ONE TO GO FORWARD. ANTI-C5a ANTIBODY, GREAT TARGET
FOR ACUTE LUNG INJURY. UNFORTUNATELY,
THERE’S SO MUCH C5a THAT YOU CAN’T PRACTICALLY
ADMINISTER ENOUGH ANTIBODY TO COVER THIS TARGET. YOU HAVE TO KNOW THAT YOU’VE GOT
THE RIGHT SELECTIVITY AND THE RIGHT SAFETY PROFILE. SELECTIVITY AGAINST
OTHER TARGETS OF SIMILARITY TO MAKE SURE THAT YOU
AVOID THE KNOWN ADVERSE EFFECTS, BUT ALSO THAT YOU RUN A PANEL
OF RECEPTOR AND ENZYMES AND ION CHANNELS TO MAKE SURE THAT YOU HAVE
NO UNKNOWN SAFETY ISSUES. PK/PD, PROBABLY THE MOST
VALID USE OF ANIMAL MODELS. I’LL BE CRITICAL OF THEM IN TERMS
OF PICKING THE RIGHT TARGET, BUT IN TERMS
OF PICKING THE RIGHT EXPOSURE, BEING ABLE TO CONFIRM THAT YOU
CAN COVER THE TARGET IN ANIMALS, AND THAT THAT PRODUCES
A PHARMACODYNAMIC EFFECT. IDEALLY BY A BIOMARKER, BUT ALSO COULD BE
BY AN EFFICACY SIGNAL, A SYMPTOMATIC SIGNAL ALLOWS YOU
TO SET DOSE FOR GOING FORWARD. CONFIRMS YOUR ROUTE
OF ADMINISTRATION, CONFIRMS YOUR TISSUE GOAL. I OFTEN GET THIS PARTICULARLY
FOR RESPIRATORY DRUGS. WELL, IF IT’S NOT WELL-ABSORBED, OR IF WE’VE GOT
SOME SYSTEMIC TOX, LET’S JUST GIVE IT BY INHALATION. WELL,
THIS ISN’T AN EASY SOLUTION. FIRST OF ALL, IF YOU’RE GOING
TO DO A COMPOUND BY INHALATION, YOU ALMOST HAVE TO DESIGN IT
TO BE A COMPOUND BY INHALATION. ALL OF YOU
THAT ARE IN THE LUNG FIELD WERE TAUGHT EARLY ON
IN YOUR LUNG PHYSIOLOGY THAT THE SURFACE AREA
OF THE LUNG IS ABOUT THE SIZE
OF A TENNIS COURT. WELL, NOW YOU’RE GONNA
AEROSOLIZE A COMPOUND ONTO THAT TENNIS COURT THAT’S GOT A THIN FLUID LAYER
OVER IT. AND THAT COMPOUND
IS GOING TO HAVE TO DISPERSE OVER THAT THIN FLUID LAYER. IT’S GOT
TO BE SUBNANOMOLAR POTENCY IF IT’S GONNA HIT YOUR TARGET. ALSO, THE LUNG,
THINGS GO RIGHT THROUGH IT. SO, IF YOU’RE GONNA
KEEP IT ON THAT TARGET, IT’S EITHER GOT
TO BE NON-COMPETITIVELY BINDING, OR SLOW OFF-RATE
OF THAT MOLECULAR TARGET. AND THEN FINALLY,
IF YOU’RE GOING TO AVOID SYSTEMIC TOXICITY,
YOU WOULD WANT IT TO BE RAPIDLY METABOLIZED
OR ELIMINATED. AND THEN FINALLY, IT HAS TO BE
FORMULATABLE IN A DEVICE THAT YOU’RE GOING TO USE
TO ADMINISTER IT EITHER AS A DRY POWDER INHALATION,
OR AS A METER DOSE INHALER. SO, A DRUG OPTIMIZED
FOR ORAL DELIVERY THAT FAILS BECAUSE IT’S NOT VERY
GOOD IN TERMS OF ORAL ABSORPTION OR HAS SYSTEMIC SIDE EFFECTS. THE SOLUTION
ISN’T IMMEDIATELY, OH, WELL, JUST GIVE IT BY INHALATION. AND THEN FINALLY, YOU HAVE TO BE AWARE
THAT OTHER PEOPLE ARE ALSO WORKING
IN THE SAME AREA, SO HOW DO YOU STACK UP
RELATIVE TO YOUR COMPETITION? IF YOU’RE SELLING THIS
TO AN INVESTOR OR TO ANOTHER COMPANY, THEY WANT TO KNOW
THAT YOU’RE THE BEST. YOU’RE BETTER
THAN THE COMPETITION. AND SO YOU NEED TO GIVE THEM
SOME CONCRETE REASONS WHY AT LEAST YOU’RE AS GOOD
AS ANYBODY ELSE OUT THERE, IF NOT BEING THE BEST. AND THAT MEANS THAT YOU’VE ALSO
GOT INTELLECTUAL PROPERTY TO COVER THAT AGENT. -HEY, JUST WANT TO JUMP IN,
CRAIG, AND JUST REMIND PEOPLE
THAT THEY CAN SUBMIT QUESTIONS THROUGH THE Q&A BOX AT THE BOTTOM
OF THE WebEx SCREEN. THANK YOU. -OKAY, SO NOW THAT YOU GOT
A VERY GOOD MOLECULE, THE NEXT STEP IS,
YOU HAVE TO DECIDE ON ITS DOSE. AND AS I MENTIONED
IN THE PREVIOUS SLIDE, YOU NEED TO HAVE
REALLY STRONG PRECLINICAL DATA AROUND ITS PK/PD. AND A GREAT STORY AROUND THIS WAS THE LEUKOTRIENES
STORY IN ASTHMA. A COMPANY BY THE NAME OF REVLON,
WHICH NO LONGER EXISTS, WAS THE FIRST TO GET A COMPOUND
TO THIS VERY HOT TARGET IN THE LATE 1980s, EARLY 1990s INTO THE CLINIC. AND THEY HAD A PRETTY GOOD
COMPOUND. THEY BROUGHT IT INTO PHASE 2. IT SHIFTED THE INHALED LTC4 DOSE
RESPONSE BY 3x, A HIGHER CONCENTRATION OF LTC4 TO PRODUCE
A BRONCHO CONSTRICTION THAT DECREASED IN FEV1. THEY WENT INTO ASTHMA STUDIES
AND FAILED. AT LEAST HALF
OF THE PHARMACEUTICAL INDUSTRY DROPPED THEIR LEUKOTRIENE
PROGRAMS BASED ON THIS REVLON FINDING
IN ADDITION TO REVLON. THEY’VE DROPPED AND SAID, YOU KNOW,
WE’VE TESTED THE MECHANISM. IT’S NOT ACTIVE IN ASTHMA. WE DON’T KNOW WHY, BUT IT ISN’T ACTIVE. AT THE SAME —
A FEW YEARS LATER, ACTUALLY A YEAR TO TWO YEARS
LATER BEHIND THEM WAS MERCK. WHO ACTUALLY MADE —
TOOK THE REVLON LEAD COMPOUND AND MADE IT A LITTLE BIT
MORE POTENT AND SLOWER OFF-RATE. AND THE MOST IMPORTANT THING IS
THAT THEY HAD PRECLINICAL PK/PD TO KNOW THAT A 3-FOLD SHIFT ISN’T GOING TO DO ANYTHING
IN ALLERGEN-INDUCED MODELS IN PRECLINICALLY, BUT A 30-FOLD SHIFT IS. SO, WHEN THEY WENT INTO
THE CLINIC, THEY TARGETED THE 30 FOLDS,
SELECTED A DOSE THAT WOULD PRODUCE
THIS 30-FOLD CHANGE IN THE CONCENTRATION OF LTC4 TO
PRODUCE A BRONCHO CONSTRICTION, AND THEY WERE EFFECTIVE
IN ASTHMA. THE COMPOUND WE KNOW
IS MONTELUKAST OR SINGULAIR, IT’S A $3 BILLION PRODUCT
RIGHT NOW FOR MERCK. IT IS CRITICALLY IMPORTANT
THAT YOU SELECT THE DOSE RIGHT, AND THAT YOU GET IT RIGHT, AND PRECLINICAL PK/PD
CAN HELP YOU DO THAT. TRANSLATIONAL BIOMARKERS,
EVEN BETTER BECAUSE NOW YOU KNOW THAT YOU’VE COVERED
THE TARGET IN HUMANS, AND OF COURSE, YOU NEED — SAFETY BIOMARKERS ARE HELPFUL,
AS WELL. SO, THIS IS A POINT
WHERE I’M GOING TO START MOVING A LITTLE BIT QUICKER AND CAPTURE
A FEW KEYS ON SOME OF THE SLIDES BECAUSE IF YOU
GET THESE TWO RIGHT, THE REST OF THE THINGS SORT
OF FALL INTO PLACE. YOU NEED TO PICK
THE RIGHT INDICATION, HUMAN PHARMACOLOGY, HUMAN GENETICS, HUMAN PATHWAY BIOMARKERS
AND OMICS ARE MUCH, MUCH MORE VALUABLE
THAN A VALIDATED ANIMAL MODEL. AND THAT’S WHY THE DOT,
DOT, DOT TO 99. HERE’S SOME DATA
FROM THE ASTRAZENECA PAPER THAT SHOWS
THAT IF YOU HAD HUMAN GENETICS, THAT 73% OF THE TIME, YOUR PROJECT ADVANCE
TO THE NEXT STAGE WAS SUCCESSFUL, STILL GOING ON. IF YOU DIDN’T HAVE
HUMAN GENETICS, ONLY 43% OF IT, GIVEN EVERYTHING ELSE
BEING SIMILAR. IF YOU HAD
A PHARMACODYNAMIC BIOMARKER, IT WAS EVEN BETTER,
82% OF THE TIME, IT WOULD ADVANCE VERSUS 29%. SELECTING THE RIGHT PATIENT — THERE’S LOTS OF TECHNIQUES NOW TO KNOW THAT NOT ALL ASTHMATICS, NOT ALL PATIENTS
WITH CONGESTIVE HEART FAILURE, NOT ALL DIABETICS ARE THE SAME. AND IN FACT, THIS WAS SOME WORK THAT WAS DONE
IN JOEL DUDLEY’S LAB. HE’S NOW IDENTIFIED
THREE DISTINCT POPULATIONS OF DIABETICS. AND AGAIN,
THE ASTRAZENECA WORK. IF YOU WERE ABLE
TO STRATIFY THE PATIENTS WITHIN AN INDICATION,
90% OF THE TIME, YOU WERE SUCCESSFUL. IF YOU WENT INTO ALL COMERS, 22% OF THE TIME
WERE YOU SUCCESSFUL. HERE’S ANOTHER EXAMPLE,
FIVE R’s. Th2 ANTAGONIST FOR ASTHMA. Th2 ANTAGONIST IS A RECEPTOR
FOR PGD2, RELEASE FROM MAST CELLS, ON ACTIVATED T LYMPHOCYTES
AND EOSINOPHILS. ASTRAZENECA WENT INTO A CLINICAL
STUDY IN PHASE 2a STUDY IN MODERATE TO MILD
ATOPIC ASTHMATICS. HAD VERY, VERY POSITIVE RESULTS
COMPLETELY INHIBITED THE POST — THE MORNING PEAK EXPIRATORY FLOW AFTER WITHDRAWAL OF INHALED CORTICOSTEROIDS
IN THIS RESULT AND ALSO A 75% REDUCTION
IN THE DECREASE IN FEV1 AFTER THE WITHDRAWAL
OF INHALED STEROIDS THAT THESE PATIENTS WERE ON. THEIR NEXT STUDY, HOWEVER, THEY SWITCHED AND WENT TO
MODERATE TO SEVERE ASTHMATICS. AND ADDED TREATMENT
AFTER A RUN-IN PERIOD, SO THESE ARE NOW ON TOP
OF INHALED CORTICOSTEROIDS. THE RESULT WAS THAT THEY ONLY
HAD MILD EFFICACY, BUT IN POST-HOC ANALYSIS FOUND THAT IT WAS EFFICACIOUS
IN ATOPIC PATIENTS AS OPPOSED
TO NON-ATOPIC PATIENTS. SO, THEY PHASED 2b, AND IT WAS A MASSIVE PHASE 2b
SIX-MONTH STUDY. NOW SWITCHED PATIENT POPULATIONS EVEN MORE AND WENT
TO MODERATE TO SEVERE. NOW ATOPIC PATIENTS,
BASED ON THE PHASE 2a RESULTS, BUT THESE WERE PATIENTS
THAT HAD ICS AND LABAs ON BOARD. NOW, SINCE ONE
OF THE MAIN THINGS THAT CORTICOSTEROIDS DO
IS DECREASE THE EOSINOPHILS AND DECREASE LYMPHOCYTES, AND THIS MECHANISM
IS SUPPOSED TO EXACTLY DO THAT. IF YOU ADD THE COMPOUND
ON TOP OF THOSE, IT’S JUST NOT THE RIGHT PATIENT
POPULATION. WHY WAS THIS DONE? BECAUSE ASTRAZENECA WANTED TO GO
FOR WHAT THE MEDICAL NEED WAS AND THE COMMERCIAL NEED WAS, SO
THEY HAD THE WRONG COMMERCIAL. IF THEY WANTED TO GO
INTO THAT PATIENT POPULATION, THEN THEY HAD THE WRONG TARGET. SO, YOU NEED TO GET — BACK TO THE PREVIOUS SLIDE — YOU NEED TO GET
THE RIGHT PATIENT POPULATION TO DO THE STUDY IN. QUICKLY, THEN, THE RIGHT DESIGN
IS CRITICAL, AS WELL. LEARNING AS MUCH AS YOU CAN
FROM THE CLINICAL STUDY. THE REGULATORY PATH, THAT YOU’RE ABLE TO MAP OUT
HOW YOU’RE GOING TO — THE LINE OF SIGHT
FROM WHERE YOU ARE NOW TO REGISTRATION IS IMPORTANT. AND FINALLY THAT,
AT THE END OF THE DAY, YOU’RE GOING TO BE ABLE
TO RECOUP THE DEVELOPMENT COST, THAT THERE’S A POSITIVE RETURN
ON INVESTMENT. IN SUMMARY, THE ATTRITION ANALYSIS THAT HAS BEEN DONE HAS LEAD
TO THIS ENHANCED RIGOR IN SELECTION OF THE PROGRAMS THAT PHARMACEUTICAL COMPANIES
ARE GOING TO INVEST IN. AND SO, EACH OF US
NEED TO REALIZE THAT AS WE’RE BRINGING FORWARD
PROJECTS TO VENTURE CAPITAL INVESTORS
OR TO PHARMACEUTICAL COMPANIES. IF OUR PROJECTS
ARE NOT IN THIS GREEN AREA AND MOSTLY GREENS,
THEN WE NEED TO FIGURE OUT HOW TO MOVE THEM
INTO THAT GREEN AREA OR SELECT ANOTHER TARGET
THAT IS THERE. THE RESULT OF THIS ANALYSIS IS,
THAT THERE’S BEEN A REVERSAL IN THE NUMBER OF DRUGS
THAT WERE APPROVED. REMEMBER,
I SHOWED YOU AT THE BEGINNING, THE DECREASE IN APPROVAL RATE
AND THE INCREASE IN COSTS. COSTS NOW WITHIN
THE PHARMACEUTICAL COMPANY HAVE LEVELED OUT
BECAUSE BUDGETS JUST WON’T — INCOME WON’T ALLOW THE R&D COSTS
TO INCREASE ANYMORE. BUT YOU CAN SEE
THAT THE APPROVAL RATE HAS STARTED TO INCREASE. SO, IF YOU’LL FOLLOW THESE
CONFIDENCE BUILDING BLOCKS, YOU’RE GONNA
CREATE A SWELL OF ENTHUSIASM, A VOLCANO OF HEAT AND SMOKE
AROUND YOUR PROJECTS THAT’S GOING TO LEAD
TO A LOT OF INVESTORS AND A LOT OF OTHER COLLABORATORS
AND PHARMACEUTICAL COMPANIES BEING INTERESTED
IN YOUR PROJECT. AND I THANK YOU
FOR YOUR ATTENTION AND OPEN IT UP TO A Q&A. -THANKS, CRAIG, THAT WAS GREAT. SO, MOST OF THE QUESTIONS WERE, HOW DO I GET A COPY
OF THE SLIDES? BECAUSE A NUMBER OF PEOPLE
I GUESS JOINED A BIT LATE. I WANT TO REMIND EVERYONE THAT WHEN THE WEBINAR
IS COMPLETED, THERE WILL BE A FEEDBACK FORM THAT WILL POP UP
IN A SEPARATE BROWSER WINDOW. IF YOU COMPLETE THAT FORM
AND ENTER YOUR E-MAIL ADDRESS, I WILL BE HAPPY TO SEND YOU
A COPY OF THE SLIDES. SO, WITH THAT OUT OF THE WAY, LET ME JUMP
INTO SOME OF THE QUESTIONS THAT WE’VE GOTTEN. YOU’VE KIND OF ANSWERED THIS
IN THE CASE OF THE REPURPOSING OF — I FORGET EXACTLY
WHICH COMPOUND IT WAS. SO, THE QUESTION WAS, IF YOU PICKED THE WRONG PATIENTS
IN THE FIRST ATTEMPT, DOES IT KILL THE DRUG
DEVELOPMENT PROCESS? AND THE SECOND QUESTION, IS
THERE A DIFFERENCE IN THE ANSWER DEPENDING ON WHETHER THE DRUG
IS FOR A BIG PHARMA COMPANY VERSUS A SMALL PHARMA COMPANY? SO, I COULD HELP
WITH THE SECOND QUESTION, BUT MAYBE WITH THE FIRST ONE. IF YOU PICK THE WRONG PATIENTS
THE FIRST TIME AROUND, WHAT EFFECT
DOES THAT HAVE ON THE PROCESS? -IT ACTUALLY HAS A HUGE EFFECT. YOU’D HOPE THAT YOU’D LEARN
FROM THAT AND WOULD GO BACK AND GET A SECOND CHANCE, BUT I CAN TELL YOU,
THERE’S VERY LITTLE PATIENCE AT LEAST WITHIN
BIG PHARMACEUTICAL COMPANIES FOR SECOND CHANCES. WE’VE GOT OTHER PROGRAMS THAT HAVEN’T HAD
THEIR FIRST CHANCE THAT EXECUTIVES
WOULD RATHER INVEST IN. SO, YOU’RE MUCH BETTER OFF
GETTING IT RIGHT THE FIRST TIME. HAVING SAID THAT, THAT IS WHY,
WHEN YOU DO THIS STUDY, YOU WANT TO GATHER
AS MUCH INFORMATION AS IS REASONABLY FEASIBLE BECAUSE THAT ADDITIONAL
INFORMATION MIGHT OPEN UP A CLUE TO A BETTER INDICATION
OR A BETTER SUBSET OF PATIENTS OR EVEN A BETTER INDICATION
TO GO AFTER. AND EVEN IF IT ISN’T THE COMPANY THAT THE COMPOUND
STARTED OUT WITH, OFTENTIMES, A GROUP OF THE PROJECT TEAM WILL GET SO EXCITED
ABOUT THAT LEARNING THAT THEY’LL SPIN IT OUT AND TAKE THAT ADDITIONAL
EDUCATION FORWARD, AND THAT’S HAPPENING
MORE AND MORE TODAY. NO WITH THE ANSWER, BUT IT’S A QUALIFIED NO. -YES,
SO I THINK WITH SMALL COMPANIES, I THINK THERE ARE A LOT OF — YOU KNOW,
THEY CAN’T ALWAYS AFFORD TO RUN THROUGH THE SAME SORT
OF RIGOROUS ANALYSIS. AND SO THEY OFTEN WILL MAKE BETS
ON COMPOUNDS THAT MAY FALL SHORT IN A FEW AREAS, HOPING THEY COULD TWEAK
THE PHARMACOKINETICS OR THE BIOAVAILABILITY
THROUGH A FORMULATION. BUT I THINK SMALLER COMPANIES
WOULD PROBABLY BE MORE INCLINED TO TAKE RISKS ON MOLECULES THAT DON’T FIT
THE RIGHT PROFILE. WOULD YOU TEND TO AGREE
WITH THAT? -I WOULD ABSOLUTELY
AGREE WITH THAT, AND IN FACT, THERE’S EVEN ONE
LARGE PHARMACEUTICAL COMPANY, NOVARTIS,
THAT HAS THE STRATEGY THAT IT’S VERY DIFFICULT
TO PICK THE RIGHT INDICATION, LET ALONE THE RIGHT PATIENT
POPULATION IN YOUR FIRST STUDY. SO, THEY WILL DO THREE TO FIVE
SMALL CLINICAL STUDIES IN SEPARATE PATIENT POPULATIONS
OR SEPARATE INDICATIONS, AND THEN USE THAT DATA
TO ADVANCE FORWARD. THAT’S UNUSUAL
WITHIN THE INDUSTRY, BUT THEY’VE SHOWN SOME CLEAR
SUCCESS WITH THAT STRATEGY. -OKAY, ANOTHER QUESTION IS, ARE SOME OF THE QUESTIONS
RELATING TO THE FIVE R’s BETTER ASKED
AT SPECIFIC DEVELOPMENT STAGES? FOR EXAMPLE, DURING PRECLINICAL
DEVELOPMENT VERSUS PHASE ONE, AND SHOULD YOU KEEP
MOVING FORWARD IF YOU DON’T KNOW THE ANSWERS TO EACH OF THE FIVE
R’s AT EACH OF THE STAGES? -I THINK
IT’S A CUMULATIVE PROGRESSION ON EACH OF THE FIVE R’s
AS THE PROJECT PROGRESSES, BUT THE ANSWER IS, THAT YOU SHOULD HAVE AN IDEA
ABOUT EACH OF THEM FROM ALL THE WAY
THROUGH THE PROCESS, FROM THE VERY BEGINNING
TO THE VERY END. AND CONTINUING
TO TEST YOUR HYPOTHESES AND TRY TO STRENGTHEN YOUR R’s
AS YOU GO THROUGH. -OKAY. THERE WAS ANOTHER QUESTION
ON AN ASTRAZENECA DRUG. COULD YOU COMMENT
ON THE HISTORY OF XIMELAGATRAN AND HOW DID THE COMPANY FAIL
TO DETECT THE LIVER TOXICITY PRIOR TO HUMAN TRIALS? DO YOU KNOW ABOUT THAT? -I’M NOT COMPETENT AND ABLE TO
ANSWER THAT QUESTION, NO, SORRY. -OKAY. THERE WAS A QUESTION
ABOUT HOW PHARMA COMPANIES VIEW BIOLOGIC TREATMENTS
FOR RARE DISEASES IN TERMS OF, SAY, THEIR INTEREST
IN DEVELOPING THEM. AND A RELATED QUESTION
ON WHAT SIZE OF A MARKET WILL JUSTIFY A RETURN
ON INVESTMENT. I GUESS IT’S A QUESTION
OF HOW BIG OF AN INDICATION REALLY DOES IT NEED TO BE FOR
YOU GUYS TO HAVE AN INTEREST? -SO, IT VARIES ON THE COMPANY. MOST OF YOUR BIG PHARMA, YOUR TOP TIER COMPANIES
WILL REQUIRE SOME PEAK YEAR SALES
CERTAINLY NORTH OF $250 MILLION AND SOMETIMES NORTH
OF $400 MILLION. BUT THERE’S NICHE
BIOTECH COMPANIES THAT ARE VERY ENTHUSIASTIC ABOUT $50 MILLION
TO $150 MILLION MARKETS. NOW, THAT’S TOTAL SALES. YOU KNOW, OF COURSE, IT DEPENDS
ON THE DEVELOPMENT COSTS, AND WHETHER
THAT’S ULTIMATELY GOING TO BE A GOOD RETURN ON INVESTMENT. BUT FOR RARE DISEASES, USUALLY THE STUDIES ARE SMALL,
AND NOT AS LONG, AND THE SAFETY PACKAGES
THAT ARE REQUIRED FOR REGISTRATION WITH THE FDA
ARE NOT AS LARGE, SO THE COSTS OF DEVELOPMENT
ARE SMALLER, AS WELL. IT REALLY DEPENDS
ON THE COMPANY. THIS IS WHERE KNOWING
YOUR CUSTOMER BECOMES IMPORTANT. -ANOTHER QUESTION IS, IS THE USE
OF IMAGING STUDIES TO SEGMENT PATIENTS
FOR TREATMENT AND FOLLOWING EARLY RESPONSES
ACCEPTABLE TO PHARMA IN GENERAL? OR, I GUESS, I’M PARSING THIS. OR IS IT UNDESIRABLE BECAUSE
OF A RESTRICTION ON LABELING OR POTENTIALLY EXPENSIVE
GATEWAY? -YEAH,
THAT’S AN EXCELLENT QUESTION. CERTAINLY FOR PHASE 2 STUDIES,
WE USE IT ALL THE TIME. IT’S VERY ACCEPTABLE. WE WOULD HOPE TO BE ABLE
TO CONVERT THAT TO SOME SORT OF DIAGNOSTIC HIT SO THAT IT WOULD BE UNIVERSALLY
AVAILABLE AND INEXPENSIVE IF YOU’VE GOT THE COMPOUND
TO MARKET. BUT THE MOST IMPORTANT THING IS IDENTIFYING
THE PATIENT POPULATION WHERE YOU HAVE CLEAR EFFICACY
EARLY ON IN YOUR DEVELOPMENT. AND USUALLY, YOU CAN SOLVE
THOSE OTHER PROBLEMS AS YOU GO FORWARD. AS A DIAGNOSTIC,
TO PUT A PATIENT INTO A — ONCE YOU HAVE A MARKETED DRUG,
THEN IT BECOMES RESTRICTIVE. -YEAH. LET’S SEE. QUESTION ABOUT,
HOW DO THE BUILDING BLOCKS, I GUESS THE VARIOUS KIND
OF STEPS THAT YOU PRESENTED APPLY TO
REPURPOSING OF EXISTING DRUGS, ESPECIALLY IF THE REPURPOSING IS BEING DONE BY A BUSINESS
OR LAB OTHER THAN THE ONE THAT ORIGINALLY
DEVELOPED THE DRUG. -SO, I THINK
THAT THEY’RE CRUCIAL IN THAT IF YOU ARE TRYING
TO REPURPOSE A POOR COMPOUND OR IT’S THE WRONG DOSE, YOU’RE GOING TO RUN INTO
THE SAME ATTRITION ISSUES THAT THE PRIMARY PROJECT
RAN INTO. BUT IF YOU HAVE
THAT VERY SOLID FOUNDATION, THEN THEY OFFER YOU A CLEAR ADVANTAGE. FOR EXAMPLE, THERE’S MANY — WHEN WE ENTERED INTO
OUR RELATIONSHIP WITH THE NCATS, NCATS AND FRANCIS COLLINS FELT YOU MUST HAVE HUNDREDS OF DRUGS
SITTING ON YOUR SHELF. WELL, IT’S TRUE WE HAVE HUNDREDS
OF DRUGS SITTING ON OUR SHELF, BUT AFTER GOING THROUGH
PHASE 2 STUDIES, WE KNOW ONLY ABOUT 20 OF ‘EM
THAT COVER TARGETS, HAVE A GOOD SAFETY INDEX, AND ARE CONSEQUENTLY SUITABLE TO
TESTING IN THE NEW INDICATION. -SO, ANOTHER QUESTION IS,
SO A LOT OF THIS — WHAT YOU’RE DESCRIBING IS SORT
OF AN ANALYSIS OF A DRUG — A POST-HOC ANALYSIS OF DRUGS THAT YOU WOULD APPLY
IN A PRE-HOC APPROACH. BUT IT LEAVES OPEN THE QUESTION OF HOW TO DECIDE ON
WHAT AN APPROPRIATE TARGET IS. WHAT AN ULTIMATELY GOOD TARGET
IS, AND WHAT IS YOUR THINKING OR WHAT IS THE PREVALENT
THINKING ABOUT THE BEST WAY OF IDENTIFYING
GOOD DISEASE TARGETS? -HUMAN FUNCTIONAL GENOMICS
OR HUMAN FUNCTIONAL OMICS, MEANING THAT YOU HAVE HUMAN DATA THAT SHOWS THAT THAT PATHWAY
IS PERTURBED AND DISEASED, AND THAT IDEALLY THROUGH GENETIC
EXPERIMENTS OF GENETIC NATURE, OR THROUGH OTHER
PHARMACEUTICAL AGENTS, YOU HAVE SOME EVIDENCE
THAT BLOCKING THAT PATHWAY WILL ULTIMATELY LEAD TO
A POSITIVE EFFECT. ABSENT THAT, SIMPLY THAT
THAT PATHWAY IS ALTERED, EITHER POSITIVELY OR NEGATIVELY
IN THE DISEASE IN HUMANS. -OKAY, AND THE FINAL QUESTION. OFTEN YOU MAY GET POSITIVE
FINDINGS IN PRE-CLINICAL STUDIES AS YOU NOTED FOR AZD8529. WHAT COULD HAVE BEEN DONE
DIFFERENTLY TO BETTER ASSESS THE TARGET? -WELL, CERTAINLY MAKING SURE
THAT YOU UNDERSTOOD WHAT CONCENTRATION
IN THE PRE-CLINICAL MODELS IS REQUIRED TO PRODUCE
A PHARMACODYNAMIC EFFECT THAT YOU’RE LOOKING
FOR THAT’S RELEVANT TO HUMANS AND THEN ACHIEVING
THAT IN THE CLINIC. THE TRANSLATION OF ANIMAL MODELS
OF THE DISEASE TO THE HUMAN DISEASE SITUATION
ARE JUST SO POOR THAT SOMETIMES YOU JUST HAVE TO
GO FORWARD AND TEST YOUR HYPOTHESIS
IN HUMANS. BUT IF YOU’RE GOING TO THAT,
YOU HAVE TO MAKE SURE THAT YOU’RE GONNA TEST
YOUR HYPOTHESIS. IN OTHER WORDS, YOU HAVE
A COMPOUND THAT’S GONNA HIT YOUR MECHANISM
AND THAT AT THE END OF THE DAY, IF IT DOESN’T WORK,
YOU CAN WALK AWAY FROM THAT AND MOVE ON
TO ANOTHER INDICATION OR ANOTHER COMPOUND,
ANOTHER MECHANISM. -OKAY. THANKS. SO, ANOTHER NOTE
ON THE FEEDBACK FORM TO BE ABLE TO GET SOME SLIDES. I WANT TO REMIND EVERYBODY THAT
THE NHLBI SMALL-BUSINESS PROGRAM HAS A VARIETY
OF RESOURCES AND OPPORTUNITIES WE WANT YOU TO KNOW ABOUT. AND YOU CAN REACH OUT TO US
IN A VARIETY OF WAYS DESCRIBED HERE. AND A FINAL DISCLAIMER, THAT THESE ARE ORGANIZED BY THE NATIONAL HEART, LUNG,
AND BLOOD INSTITUTE AND ARE DIRECTED FOR FOLKS
WHO ARE APPLYING FOR OR RECEIVED FUNDING
THROUGH THE NHLBI. IF YOU’RE DEVELOPING PRODUCTS
OUTSIDE OF OUR MISSION SPACE, YOU CAN REACH OUT
TO PROGRAM OFFICERS IN THE APPROPRIATE INSTITUTE. AND YOU CAN FIND
THOSE INDIVIDUALS ON THE CENTRAL SBIR WEBSITE
FOR THE NIH. CRAIG,
I WANT TO THANK YOU VERY MUCH FOR A REALLY GREAT PRESENTATION. VERY INFORMATIVE. AND THANK YOU TO EVERYBODY
FOR LISTENING AND ATTENDING. AND I HOPE YOU TUNE IN
TO A FUTURE HANG OUT. TAKE CARE. BYE.