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Leidos Biomedical Research & National Center for Advancing Translational Sciences (NCATS)

Leidos Biomedical Research & National Center for Advancing Translational Sciences (NCATS). Bradley Gillespie 6 May2014 RACD. Who am I?. PharmD from the University of Illinois 7 years FDA: Clinical Pharmacology Reviewer 14 years Pharma / Biotech: Early Development

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Leidos Biomedical Research & National Center for Advancing Translational Sciences (NCATS)

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  1. Leidos Biomedical Research & National Center for Advancing Translational Sciences (NCATS)

    Bradley Gillespie 6 May2014 RACD
  2. Who am I? PharmD from the University of Illinois 7 years FDA: Clinical Pharmacology Reviewer 14 years Pharma/Biotech: Early Development 2 years PomWonderful: Built clinical development group, filed 2 IND 2-1/2 years at SAIC-F/Leidos: Director of Drug Development. Oversee virtual drug companies- TRND and BrIDGs
  3. What is NCATS? Complicated organization with many moving parts- geared towards overcoming barriers, driving partnerships and innovation in drug development One part: Division of Preclinical Innovation (DPI) Two pieces of DPI are my focus: Therapeutics for Rare and Neglected Disease (TRND) Bridging Interventional Development Gaps (BrIDGs)
  4. Approved drugs effective for new indications New drugs for untreatable diseases Drugs suitable for adoption for further development Predictive in vitro toxicology profiles Novel clinical trial designs Small molecule and siRNA research probes NCATS Division of Preclinical Innovation: An Integrated Pipeline Preclinical development candidate Clinical development candidate Project Entry Point Lead compound Unvalidated target Validated target Target assay Assay Dev Target Validation Probe/Lead Development Lead Optimization Preclinical Development Clinical Trials FDA approval Target I II III Probe Devel/NCGC RNAi Preclinical Development/TRND Assay , Chemistry Technologies RAID/BrIDGs Clinical FDA Collaboration DPI Systems Toxicology (Tox21) Repurposing Repurposing Paradigm/Technology Development Chemical genomics systems biology data Leads for therapeutic development Genome-wide RNAi systems biology data Deliverables More efficient/faster/cheaper translation and therapeutic development
  5. TRND/BrIDGs are Different $ Funding decision Funding announcement Apply Review TRND/BrIDGs Select Projects & Form Joint Project Teams with Collaborators Collaborators Receive In-KindResearch in Partnership with NIH Scientists Solicitation at Proposal CENTRAL Apply Review Typical NIH Mechanism

  6. TRND

  7. The Problem of Rare and Neglected Diseases >7,000 diseases affect humankind – but only a small fraction support commercial developmentof therapeutic agents Two types of neglected diseases: Low prevalence, i.e., “rare”(<200,000 prevalence in U.S.) There are ~7,000 rare (orphan) diseases Cumulative prevalence in U.S. ~ 25 – 30 million <250 have any pharmacotherapy available High prevalence but “neglected” Occur chiefly among impoverished and marginalized populations in developing nations (treatment costs prohibitive) Most are infectious

  8. Effective Therapies are Needed

  9. How Much Does Drug Development Cost? $1 Billion/per drug is the number that I have heard over the past several years Lilly Blog (2/12) states $1,300,000,000/per drug1 Unclear on how these were calculated, though I expect that it is actual costs for each approved therapeutic February 2012 Forbes article included development failures (Total R&D $/approvals)2: $4,000,000,000-11,000,000,000 (description of risk) 1http://lillypad.lilly.com/entry.php?id=1583 2http://www.forbes.com/sites/matthewherper/2012/02/10/the-truly-staggering-cost-of-inventing-new-drugs
  10. Cost of Rare and Neglected vs. Traditional Drug Development It may be argued that the path to approval is shorter Some say that the odds of approval are also higher than that of traditional drugs Unclear to me if any of this is true,regardless: The cost of Orphan Drug Development is extremely costly
  11. Drug Development: Risky Most candidates fail: Phase 2 failure rates are at an all time high3 In one review, only 18% succeeded in Phase 2, of the failures: 51% of these were due to insufficient efficacy 29% were due to strategic reasons 19% were due to safety concerns High Risk + Low Income = Muted Interest 3Nat Rev Drug Discov, 10;328-9
  12. How to pay? Orphans are becoming big business Established, revenue-generating companies are getting involved Survey Sample: NORD Corporate Council- About 44 Pharma Companies, ranging from 1 employee with no revenue to 126,000 employees with revenue of approximately $65,000,000,000 NORD conclusion: Activity present, but still, not nearly enough commercial interest in most indications
  13. What Can Be Done? Cannot increase the number of customers; and Difficult to control global economics; but Reduction of risk will shift the risk benefit analysis Risk, or lack of, is data-driven Optimize the lead Scale up the process Understand the ADME Characterize the toxicology Conduct a solid Phase 1 study, and obtain human safety and efficacy data IND
  14. Therapeutics for Rare and Neglected Diseases (TRND) Program Model: Collaboration between NIH intramural labs with preclinical drug development expertise and organizations with disease-area/target expertise Projects: May enter at various stages of development, but prior to IND Taken to stage needed to attract external organizations to adopt for clinical development (IND filing to Phase 2) Eligible Applicants: Academic, Non-Profit, Government Lab, Small Business, or Large Biotech / Pharma Ex-U.S. applicants accepted
  15. TRND Features: R&D Capabilities Drug project-specific activities New indications for clinical stage drugs and repurposing approved drugs Medicinal chemistry Rare disease bioassay development Efficacy, pharmacology, ADME, toxicology, PK/PD Compound scale-up, formulation Clinical and regulatory development strategy, natural history study assessments First in human clinical trials, and beyond, as needed (Almost) whatever it takes to de-risk agent and make it appealing for full partnering!
  16. TRND Application Sources Round 1 Round 2
  17. TRND Application Disease Areas All Top Scoring Skin All Other Infectious Disease Infectious Disease Addictive Cardiovasc. Renal Round 1 CNS Muscular Metabolic Blood CNS Cancer Cancer Skin Cardiovasc. Muscular All Other All Other Metabolic Metabolic Infectious Disease Infectious Disease Blood Blood Skin Round 2 Skin CNS Cardiovascular CNS Cardiovasc. Muscular Muscular Pulmonary Cancer Cancer Pulmonary
  18. TRND Portfolio a National Heart, Lung, and Blood Institute; b National Human Genome Research Institute; cEunice Kennedy Shriver National Institute of Child Health and Human Development; d National Institute of Neurological Disorders and Stroke; e National Institute of Allergy and Infectious Diseases
  19. TRND Highlights 15 projects through pilot phase & 2 public solicitations since 2009 Mix of small molecules and biologics 4 investigational drugs taken into humans CLL: IND filed, safe to proceed Aug 5th 2011 Phase 1 trial commenced September 2011 SCD: IND filed, safe to proceed Nov 10th 2011 Phase 1 trial commenced December 2011 Phase 2, patient trials in 2012 and 2013 ManNAc: IND filed, safe to proceed August 24, 2012 Phase I trial commenced October 2012 NPC: IND filed, safe to proceed December 23, 2012 Phase 1 trial commenced January 2013 Initiated two natural history studies Niemann-Pick type C Disease (NPC) Hereditary Inclusion Body Myopathy (HIBM)

  20. TRND: Sickle Cell Disease (SCD)

    AesRx, LLC Aes-103 5-hydroxymethyl-2-furfural (5-HMF)
  21. SCD Rare and Neglected Primary market: US: 75,000 (Orphan Drug) EU: 40,000 Secondary market: Middle East: 100,000 India: 1,000,000 Tertiary market: Sub-Saharan Africa: 12,000,000 Nigeria: 2% births = 100,000 annually Total: > 13,000,000
  22. Aes-103 (5-hydroxymethyl-2-furfural) Discovered at Virginia Commonwealth University (patents) AesRx: exclusive world-wide licensee Small molecule: 126 Da Increases the affinity of HbS for oxygen Orally bioavailable Safe in animal studieswhen given in large doses NIH SCDRL (NIH Sickle Cell Disease Reference Laboratory): screened 700 compounds, Aes-103 is one of the most potent anti-sickling compounds AesRx hoped to commence Phase 1 clinical trials by 2010, but lacked funding to conduct pre-clinical or clinical studies
  23. Initial Development Plan Beginning status: pre-IND API (active pharmaceutical ingredient) available via a RAID (now BrIDGs) grant 3-year plan IND enabling pre-clinical First in Human Trial Proof of Concept in patients End of Phase 2 meeting But, no money and no partners
  24. First TRND Partnership IND-enabling pre-clinical Pharmacology, ADME, toxicology GMP API synthesis Formulation Regulatory Affairs Clinical Trials FIH Two phase 2 trials AesRx actively seeking a full development partner
  25. Bridging Interventional Development Gaps (BrIDGs) Program Model: In-kind, government contract-based services provided to overcome obstacles in later-stage preclinical development Projects: May address any disease or disorder, regardless of prevalence or incidence May require only one or two key development steps Eligible Applicants: Academic, Non-Profit, or SBIR EligibleSmall Business Ex-U.S. applicants accepted, but businesses must satisfy SBIR criteria
  26. Bridging Interventional Development Gaps (BrIDGs) Program NIH-wide contract-access program that assists public or private entities with steps needed to transition from identified clinical candidate to IND ● Supported by the NIH Common Fund ● Provides access to contract services for: ● Production/bulk supply ● GMP manufacturing ● Formulation ● Pharmacokinetic testing ● Animal toxicology ● Manufacture of clinical trial supplies ● Product development planning and advice in IND preparation Involvement terminates at time of IND Filing
  27. BrIDGs Portfolio 180 applications submitted between 2005 – 2011 34 approved projects since 2006 27 different diseases 10 rare or neglected disease projects 11 NIH ICs have co-funded projects 18 completed projects have contributed to 12 INDs 8 projects are in the clinic 3 are in Phase II testing 5 agents were licensed during / after BrIDGs involvement
  28. BrIDGs Portfolio

  29. BrIDGs: PF614

    Abuse Resistant Opioid Prodrug Program
  30. Description of the Problem Prescription opioid abuse and addiction are major burdens to patients and society, resulting in significant costs, illnesses, and deaths. The intertwined issues of i) the widespread and increasing abuse of prescription opioids; and ii) reluctance of prescribers to write prescriptions for opioid analgesics: Has resulted in the under-treatment of patients with moderate-to severe pain.
  31. PF614: novel delivery technology PF614 is an oxycodone-derived molecular delivery system Designed to resist both oral and non-oral modes of abuse unaffected by simple physical manipulations (e.g. extraction and/or chewing of the dose form provided to patients manufactured in a pro-drug, inactive form that becomes effective only when ingested and exposed to trypsin Inactive in blood, and does not cross the BBB
  32. PF614 BrIDGS Support Synthesis of drug material for preclinical and phase 1 clinical studies; Packaging of clinical trial supply; stability studies on drug substance and drug supply Toxicology, genotoxicity and safety pharmacology studies ADME studies Everything needed to file an IND
  33. Which Program Is A Fit?
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