OSNIG Discussion: Commercialization Issues: regulatory and workflow. Michael F Tweedle, PhD

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2 OSNIG Discussion: Commercialization Issues: regulatory and workflow Michael F Tweedle, PhD

3 Why should academics consider commercialization?

4 25 targets 30% novel Success Rate* COST Targeted therapeutic drugs in Molecular Medicine Attrition and Cost of targeted drugs Target Validation Hit Generation Lead optimization Biol. validation Preclinical Development 30% 90% 90% 75% 50% 4 y 8 y Some work (Gleevec) Difficult Validation P-I 70% P-II 50% P-III 70% NDA 90% 1 Rx in 12 >$1 BB * P. Ma; R. Zemmel, Nat. Drug Disc. 1, 571, 2002.

5 Costs of developing a diagnostic imaging agent A.D. Nunn, Invest. Radiol. 2006

6 Companies develop Molecular Imaging Agents with > $100,000,000 markets ~ 100,000 uses peak (5 y) Patient doses Cost per dose 1,000,000 $ ,000 $1,000 10,000 $10,000 20,000 doses of $50,000 = $1 BB 20,000 doses of VEGF-R $100 = $2 MM Pick an application worth $100 MM annually

7 Optical Surgical Navigation Applications Stage 1-II, USA Nos. $ Drug price* *@100% market penetration prostate Ex vivo agents << $ develop? < entry barrier 217,000 $ ,122 $735 40,000 $2,500 Head neck Cancer

8 Regulatory Considerations NIRF dyes are considered contrast agents The rules are fairly clear: Avoid shortcuts. The shortest cut is to follow the rules, and ask for advice.

9 Regulatory Considerations Preclinical and Phase I NIRF dyes are contrast agents No exploratory IND possible (dose is > 100 ug) Toxicity studies must be done in two species (rodent + non rodent). Acute and subacute x human dose Toxicity studies require almost GMP manufacture on close to the final formulation. Phase I agent must be GMP GMP final tested entity required (not the pieces, e.g. the dye itself) (not the dye, the final agent) Non immunogenicity, red cell damage, cardio-renal tox, reproductive, serum stability, clotting, PK? Not genotox Analytical tests for identity and purity Stability data appropriate to the Phase I study, monitored Sterility and pyrogenicity of the formulation Probably takes 5-10 g (@2000 Da) agent and 1 year

10 Regulatory Considerations Quantitation: science vs regulatory? Quantitation is required for Preclinical data. Solutions (blood/urine etc.) can be measured by fluorescence but in vivo quantitation of tissues requires extraction of the agent to solutions, or radiolabeling. Is fluorescence of solid tissues enough in rodent biodistributions? Surgeons will not know what to do with quantitative data Radiolabels that change the drug s structure are not tracers Argument for dual probe? True tracers have stringent preparative requirements. Clinical Ph-I only requires blood clearance and excretion, generally not requiring a radiolabel (cyanines appear to be excreted unchanged but each agent will require data)

11 Regulatory Considerations Quantitation Quantitation in clinical development/use needed? Opinions differ, but surgeons are not quantitating now. Analysis of excised tissues? Is pathology quantitative? No doubt artifacts will exist and competitors will try to ameliorate them Existing NIRF instruments were approved for use with ICG (for specific procedures). But if you alter the instrument, you have a combination filing (instrument + agent). Same for a new instrument. Approved Instrument + new NIRF in Surg Onc? Standardization of instruments? Unlikely? Are PET instruments standardized across manufacturers? The surgeon/pathologist are the existing standard system.

12 CMS reimbursement is the major issue for commercialization Insurers tend to follow CMS (+ CHIP) except for very high end insurance plans CMS Innovation Center established by ACA has the mission to improve health care while lowering costs. If 5 y survival of the target population is already %, what can be improved at lower cost? Example 1: + Breast cancer surgeons spend $300 MM annually in USA doing re-surgeries for positive margins + trauma, cosmesis, and time to Rx are better with 1 surgery -These will be considered improved outcomes (my opinion)

13 More difficult example 2: prostate cancer 200,000 localized case; ~40 gland resections save1 life Several promising targeted NIRF agents that should work (PMSA, GRPr, chloride channels, et al) But: Radiation ablation, full resection and watchful waiting all have ~100% 5 y survival So what is the reimbursement argument to improve heathcare and lower costs? QOL? CMS will be hard to convince? Caveat: in 5 years we should have 10 year survival data.

14 MRI/US Guided focal therapy in localized prostate cancer could become a competitive technology DCE MRI washin MRI + Trans rectal US + HiFU- or cryo-ablation will reach users before NIRF agents CK Kim, AJR 2008 VEGFR2-Targeted Microbubble in clinical trials (Bracco) Prof H Wijkstra (AMC, Amsterdam Pillai R, Fan H, Marinelli E et al..phospholipid Linked Peptide for Ultrasound Imaging of Angiogenesis Amino acids. The forum for amino acids, peptide and protein research, vol. 37, supplement 1, July 2009, 11 th International congress on Amino Acids Peptides and Proteins, Vienna, Austria, Aug 3 rd -7, Pochon, Tardy, Bettinger, von Wronski,Passantino, Schneider, Invest Radiol 2010.

15 Regulatory / CMS Considerations Clinical Diagnostic accuracy is the key criterion for FDA approval for marketing Biopsy / pathology is the current gold standard But commercial success requires reimbursement, and companies prefer to capture both in a trial. A danger is that the agent could be included within the procedure. Role for academics to remove risks early? Will some trials use QOL outcome endpoints? Long $ Do research funding agencies care about lowering healthcare costs?

16 Optical Surgical Navigation Issues Instruments: Five 510k cleared 800 nm instruments have ~1000s installed base. 510k are much faster than NDA. Engineering is faster than chemistry Agents will use only approved imagers What will become of 700 nm nm agent ideas. (e.g. nerves plus cancers)? How to develop?

17 Optical Surgical Navigation Issues Work Flow: when and who delivers the NIRF agent? Presurgical appointments necessary timing vs PK Longer circulation time than ICG Ab require days to localize, but even most peptides require some hours. All parenteral agents have adverse drug effects. Good news is the low dose: X ray agents >50 g; MRI agents > 10 g; NIRF ~ 5-50 mg (2000 Da peptide) How much for a 200,000 Da Antibody? Bad news is that even moderate ADR at home are not tolerated in diagnostic agents. Clinical trial design?

18 Dual Probes work flow issues Less expensive to develop a single entity? Complex clinical trials? Natural quantitation useful in development if not use Timing decay of nuclear tracer with post imaging surgery. Delicate balance of receptor sensitivity to doses

19 Acknowledgements Discussions Consultant Mike Olive (Olive Report, 2014) Biotech (Cellectar) Jaimie Weichert Corporate (Bracco) Giogio Vittadini, Milan Adrian Nunn, Princeton Francois Tranquart, Geneva