Imatinib pre-clinical and clinical development

1. Imatinib pre-clinical and clinical development Stephen Oh, M.D, Ph.D. Markey Program October 30, 2014

2. Overview • Historical narrative of imatinib development • Paper discussion • Imatinib as a paradigm for other targeted therapies (e.g. JAK2 inhibitors)

3. Inhibiting the kinase activity of BCR/ABL “won’t work” because: • ATP binding pocket of ABL is well conserved among many TKs • Besides, inhibition of BCR/ABL will also inhibit c-ABL, giving unknown toxicity • What we need is drug to block cancer-specific pathways!

4. Goal: selective inhibitor of BCR-ABL • 518 protein kinases

5. Designing a BCR-ABL inhibitor • How do you screen or design a drug? • What preclinical tests do you want? • What animal studies do you want? • Who are the first patients to try drug? • What are endpoints? • What to compare to? • What is ultimate goal?

6. Discovery starts Year 8 (start Clinical) Year 15 ~$800 million

7. 1. Cancer cell physiology • 1960 = Nowell & Hungerford “Philadelphia” chromosome observed, short chr. 22 • 1973 = banding technique enables Rowley to identify Ph chr. = t(9;22) • 1982 = ABL involved on chr. 9, 1984 = BCR gene on chr. 22 • 1990 mouse models validate BCR-ABL is necessary and sufficient for CML development

8. 1985 1990

9. 2. Molecular target: Kinases • 1980 Ciba-Giegy (Novartis) shut down cancer research • 1983 re-opened under Alex Matter • Prior work on interferon convinced him that nature could produce compounds to kill cancer. • Interest in pursuing kinase inhibitors solidified in 1985Staurosporin inhibits PKC. PKC activity

10. Kinases at Ciba-Giegy (Novartis) • 1985 hired Nick Lydon to head kinase program under Matter. • 1988Staurosporin derivatives against PKC, but in search of a disease to target kinases. • PDGF-R identified as potential kinase with cancer and cardiology uses, so began search for inhibitor. • Lydon has connection with kinase group at DFCI in Boston.

11. Kinases at DFCI • Lydon meets Brian Druker in 1988 on visit to DFCI where he is post-doc fellow. • Druker convinced BCR-ABL could be targeted after seeing inhibition of EGFR results in Science 1988. • Approaches Lydon about BCR-ABL but CG is hesitant to pursue because small number of CML patients, agrees to include ABL in kinase screening panel. • 1990-1993 DFCI sever ties with CG in favor of Sandoz for kinase work. • Druker has no contact with Matter, Lydon.

12. 3. Lead identification/drug screening • 2 main Questions after identifying targets: • 1. What compounds to test in system? • 2. What is your screening system? • Empiric = NCI uses 60 cancer cell lines. Screens 10,000 chemicals/yr from library in proliferation assay, 500 drugs pass and 5 novel agents recently identified. • Rational synthesis = CG/Novartis approach.

13. 3. Lead identification/drug screening • 1990 chemist Jurg Zimmermann and biologist Elizabeth Buchdunger at CG. • Goal: Rational synthesis to design drug that binds ATP pocket in kinase domain (PDGF-R main target).

14. 3. Lead identification/drug screening • Rational synthesis = Staurosporin derivatives: 1988 inhibit PKC (s), 1990 EGF-R (s), Abl (non-selective) • Screen compounds using in vitro kinase phosphorylation assay against PKC, PKA, EGF-R, PDGF-R, Alb, Src, Lyn, Fgr. • Follow-up with in vitroantiproliferative assay using kinase-transformed cell lines. • 1990Zimmermann use PAP derivatives to screen for PKC inhibition. 1992 PDGF-R (ns- gets Abl also) = LEAD COMPOUND ID!

15. Phenylamino-pyrimidine (PAP) • Until PAP used hundreds of compounds screened but: lack Abl selectivity, poor “drug likeness” • PAP structure has good Drug likeness: absorb oral, nontoxic, not destroyed in liver, stable in stomach, not excreted too fast. Staurosporin PAP

16. 1985 1990 1992

17. 4. Lead (CGP57148) Optimization • August 26, 1992 first batch of drug. • Buchdunger using in vitro kinase assay in early 1993 inhibits Abl, and PDGF-R. • Spring 1993 CG started to contact physicians for CML interest – NO INTEREST.

18. 1985 1990 1992 1994-5 1994-5

19. 5. Drug candidate selection/production • August 1993Druker leaving DFCI for OHSU (no longer committed to Sandoz) contacts Lydon at CG for update on inhibitors. • Druker is convinced Abl inhibitors will work. Gets 4 drugs from CG to test on BCR-ABL using protein, cell and animal experiments. • Feb. 1994 presents results to CG = 90% inhibition of BCR-ABL in vitro and picks CGP57148 as best drug to pursue for CML.

20. Nature Medicine, 1996

24. Fig. 4 In vivo antitumor activity of CGP 57148

25. Fig. 5 Colony-forming assays

26. 1985 Typical 8yr 1990 1992 1994-95 1994-95 1995-97

27. Animal safety/toxicology • 1995 rodent studies no problems with IP delivery. • March 1996 Ciba-Geigy and Sandoz merge to become Novartis and new management take over. • 1996 dog study problem. Clots develop at IV catheter site entrance. • Phase I planning slowed at Novartis. • Nov. 1996 rats develop liver toxicity and all human/animal trial planning stopped. • 1997 Druker convinces Novartis to continue with STI571 and drug is made orally bioavailable. • Rats and dogs absorb oral formulation. • Monkeys only got liver toxicity at “hi” doses. • Decided to proceed to human studies with same formulation, despite rat/dog toxicity.

28. 1985 1990 1992 1994-95 1994-95 1995-97 Year 8 (start Clinical) 1998-2000 (Imatinib = 3yrs.) 1999-2001 2000 Apply 2/27/01- approved 5/10/01 Year 15

29. Cancer clinical trials - Phase I • Phase I = What is the tolerable dose of new drug for phase II studies? • Typically not tumor specific, 10-30 patients • Patients with advanced disease, resistant to standard therapy, and good organ function • Dose escalation, looking for acute toxicity. • 3-6 patients at each dose • DLT = 33%, Rx. 3 more patients at same dose. STOP if toxicity, go up if not • DLT > 33%, STOP • Use highest dose with DLT < 33% for phase II

33. At 300 mg or higher, 53/54 (98%) with CHR

34. STI571 – Phase I • Novartis now has to mass produce for anticipated demand – this has never happened for a drug so early. • Plans to scale production from 50 kg in 9/99 to 23 tons in 2001.

35. Cancer clinical trials - Phase II/III • Phase II = Does drug have activity against specific tumor? • Tumor specific study. • Pick patients that are active (good performance status) and minimal prior chemotherapy. • Phase III = Compare efficacy of new drug to standard of care in order to help physicians make treatment decisions. • Randomized, broad eligibility better, multi-institutional – applicable to “community” doctors. • Endpoints usually survival or symptom control.

36. 532 chronic phase IFN failures • 400 mg imatinib daily • Complete hematologic response: 95% • Major cytogenetic response: 60% • Median 18 month f/u, 89% still in chronic phase, 95% alive • 2% d/c due to adverse events, no treatment-related deaths

37. FDA approval May 2001 based on Phase II data

38. 1106 patients randomized • Complete hematologic response: 95% vs 56% • Major cytogenetic response: 85% vs 22% • Complete cytogenetic response: 74% vs 9%

42. Drug discovery cost analysis 6 yrs DiMasi et al, J Health Econ. 2003 Mar;22(2):151-85. Discovery to phase I = 4.3 years Phase I to FDA approval = 7.5 years 12 year process Imatinib = 10 years

43. Drug discovery cost analysis DiMasi et al, J Health Econ. 2003 Mar;22(2):151-85. Methods in this analysis have been criticized – other estimates range widely: $55 million to $2 billion!

44. Imatinib costs • Interferon about $1,700-3,300/month • Initial cost ~ $2,200/mo • Price has more than tripled since initial approval ~$100k/yr • Revenue for imatinib in 2012 ~$4.7 billion

45. Generic Gleevec • Initial patent application filed in 1993 • Did not claim any specific salts or mention imatinibmesylate • Patent application filed in 1998 specifically mentioned beta crystalline form of imatinibmesylate • After lengthy delay, application in India rejected in 2006 – ruling that imatinibmesylate was already known prior to development of Gleevec • Appealed to Indian supreme court – rejected April 2013 • Gleevec to go off patent in US July 2015 • Generic Gleevecto become available in US Feb 2016

46. Generic Gleevec

47. Imatinib as a paradigm for targeted therapies in hematologic malignancies

48. BCR-ABL negative MPNs

49. Activation of JAK-STAT signaling in MPNs

50. JAK2 V617F