Pharma needs: Go No-Go Decisions in Therapeutic Drug Development
Diane Jorkasky, MD, FACP Independent Consultant (Retired from Pfizer Global Research & Development) February 8, 2009 Society of Nuclear Medicine
Why am I here?
nephrologist, clinical pharmacology early development x 23 years former chair, Yale / Pfizer Imaging Alliance in PET technology - 8 years
65 publications 10 major go / no go decisions several translational experiments state of the art PET imaging & analysis
Where are we?
Funding for Academia poor! Worst year in history for Pharma
Rising R&D Costs Declining productivity...... declining creativity? Uncertain pipelines big risks, exceptional failures Increasing regulatory conservatism Financial instability impacting all investment Conflict of interest impacts and yet.......
.....no more important time for academia and industry to work together to develop new therapeutic agents
Pharma needs: Go / No-Go decisions
1. Should we embark on this biological target? 2. Once you have a pharmacological agent, does the agent demonstrate its mechanism (POM) of action in humans?
a) Linkage to disease / outcome?
3. Once proof of mechanism is demonstrated, does the agent demonstrate proof of concept (POC) in the disease indication?
a) b) c) d) Linkage to disease indication's long term outcomes? Differentiation from other agents? Inherently better safety than other agents? How satisfied is the population with the disease?
Here is the rub:
We want great certainty of these decisions but at Walmart prices and today Unrealistic Inherently at the core of the problem
1. Should we embark on this biological target?
a) Evolving from a preclinical model in an isolated system to phase 0 research in humans b) Greater understanding of the target role in disease; how modulation of the target alters disease c) Which subpopulations might be best in which to eventually test the hypothesis, using imaging when indicated but coupled with other identifiers d) Best done in academia, not in Pharma
2. Does the agent demonstrate its mechanism of action in humans?
a) Necessary 1st step b) Ideally, mechanism of action should be in targeted organ, but may not be possible c) Ideally, conducted in small populations with exquisite sampling capability (biopsy) coupled with imaging analysis d) POM may be achieved but questions will still linger about impact on disease and disease progression
3. Does the agent demonstrate proof of concept in disease indication?
a) Far more difficult to acquire b) Proof of concept = enough data to warrant substantial investment, but what is proof? Still risk! c) How do data from small, contrived, focused subpopulations relate to large, unselected populations?
How do you extrapolate the data, if unknown?
Sounds easy? In reality, very hard and expensive
Example: Industry CNS drug development at a specific receptor
Need to plan years ahead of need to ensure availability of a validated, high performing ligand; mechanism may no longer be valid when needed Develop chemical matter which has physicochemical properties opposite of that needed for a drug = 2x cost Need tox, validation in 2 or 3 species How much occupancy do you want / need for proof of mechanism? Highly debated. Still the whole issue of proof of concept in disease
Example: Industry CNS drug development at a specific receptor, con't
In contrast without the ligand,
How do you know you are in the brain, let alone where? How do you measure drug's POM? How do you set dose, specifically if there is toxicity at low levels / or no toxicity despite high doses? What if the POC fails, do you test a backup or terminate that program? How do you know if you are not throwing away a good target?
Many companies are not making these investments in CNS PET imaging because of the perceived complexity Academia may spend too much time trying to achieve ligand nirvana for a single receptor (ex. D2) as opposed to being fit for purpose
Options to advance this field:
(not mutually exclusive)
1. Pharma companies to sell chemical matter to ligand companies to allow development 2. Develop joint industry / academic consortia to develop novel ligands to study CNS biology across many targets 3. All Pharma companies allow open access to academia for chemical matter for research driven projects. Is this well known in academia? Requests seem to be dropping.
We frankly need to do something to shake up the science if we are to progress novel therapeutics in CNS
Another alternative: Forgo target specific pharmacology and look for endogenous pathway markers which might be amenable to molecular imaging
1. 2. Immunomodulation: develop markers that are nonspecific to any single pharmacological target. Cardiovascular / metabolic disease what about markers that identify the various metabolic parameters of disease.
Question: because they are part of disease pathway, can these be leveraged more effectively into helping the go / no go decisions of industry in certain disease areas?
In oncology, develop molecular markers of genetic expression to allow specific targeting of drugs, personalized selection of therapy, and direct linkages to disease progression. Proposal: Allow open access for such novel agents.
Until these fundamental issues of molecular tools are solved, the science will not progress as rapidly as it needs to.
Needs of industry part II
Eliminate the "I" in imaging. Imaging as a noncompetitive sport in the US. Elimination of ego as a barrier to study conduct!
What is really needed from academia?
1. A group of highly functioning, cohesive, high resolution, molecular imaging centers that collaborate effectively around a translational problem and focus on that problem. Standardize the methodology and interpretation to one standard across the collaboration and do so quickly. Focus on the problem, not the gizmos. Become the POC sites for the drug, effectively integrating imaging, genetics, biopsy results, etc. Remain the imaging leaders for later phase studies, now widened to more centers who follow the algorithms designed.
If not done in the US, it will be done in other countries willing to take on that role: Korea, Manchester, Australia
Within companies, what is needed:
1. Internal education around imaging 2. The need for validation of the image relationship to traditional disease outcomes 3. The need for rapid computerized image measurement to reduce cost of studies 4. Strong emphasis on standardization within the protocol 5. Faster computation using GRIDS (available to most universities, but not used)
The field of imaging in drug development is slowly, too slowly progressing Greater collaboration among imagers, translational researchers, and industry is needed if the field is to be advanced
CDK-4,6 Inhibition: POM in MCL Cohort
Pre FDGPET Pre FLTPET
Pre Rb [pS807/811] Pre Ki67
Post Rb [pS807/811]
-78% -7% -44%
Leonard et al, American Society Hematology 2008 Annual Meeting, Abstract 264
CDK-4,6 Inhibition: Reduced Tumor Proliferation (after 1 Cycle)
Proliferative Response of Patients with FLT-PET (N=17) Proliferative PR 100% % Change Summed SUVmax 75% 50% 25% 0% -25% -50% -75% -100% Ranked Patients
Leonard et al, American Society Hematology (2008 Annual Meeting, Abstract 264) 26
Future state: Stratification. Differential response to Rx
Exon 11 Exon 17
1 week following sunitinib