Most Philadelphia chromosome-positive Chronic Myeloid Leukemia (CML) patients respond strongly to imatinib (Gleevec; below).  In a Phase 3 trial, 73.1% of patients on imatinib achieved complete cytogenetic response, versus 6.3% on interferon-alpha plus cytarabine, within 60 months of therapy (p<0.001).1 For the same patients, the rate of progression-free survival after 60 months was significantly better with imatinib than with the comparison treatment:  83.2% versus 64.1% (p<0.0001).1 But sadly, some patients don’t respond, or their leukemia becomes resistant, or they have intolerable side effects.  Crossover to dasatinib (FDA approval:  2006)2 or nilotinib (FDA approval:  2007)3 can help these people,4 if they are not among the 15% of imatinib-experienced patients with T315I mutation, which causes resistance to all three drugs.5 These patients were without a targeted treatment—until December 2012.6

gleevec

Ponatinib (Iclusig; below) came to market after a pivotal Phase 2 trial that year, and the FDA even bragged about approving it 3 months ahead of schedule on top of that.6 All of this was made possible by the FDA’s Accelerated Approval program,6 which has since 1992 allowed sponsors to bring desperately needed drugs to market sooner while recouping their R&D costs more quickly.7 Accelerated Approval was granted for ponatinib because 70% of patients with T315I mutation achieved a major cytogenetic response, and the patients were in such high need.  Because its long-term safety in a wider population and effect on survival weren’t yet established, ponatinib’s approval was contingent on results of ongoing patient surveillance.6

iclusig

Just 10 months after it was approved, ponatinib was taken off of the market.8 There was an upsetting amount of serious and fatal vascular problems, including heart attack and stroke, which was not previewed in Phase 1 and Phase 2 trials.  While 8% of Phase 2 patients did have a serious vascular problem,5 the problem wasn’t prevalent enough to stop approval.  But later follow-up on the Phase 1 and Phase 2 patients showed an alarming trend:  24% of Phase 2 patients had a serious vascular event (1.3 years median time on treatment), and 48% of Phase 1 patients had an event (2.7 years median time on treatment).5

After 3 months of marketing suspension, during which 370 patients sought a single patient New Drug Application to continue taking the effective drug, ponatinib came back.5 In response to the new information, the FDA “tightened” the label so that ponatinib was only indicated as a last-ditch targeted therapy for CML [or Philadelphia chromosome-positive Acute Lymphoblastic Leukemia (ALL)], or the first choice for CML and ALL patients with T315I mutation.3,9 The original label had allowed oncologists to prescribe ponatinib for patients who could benefit from nilotinib and dasatinib, drugs which don’t carry the same risk of serious vascular problems.3

Ponatinib remains a treatment option for CML and ALL patients with resistant disease, and it’s also the only Accelerated Approval drug ever taken off the market for safety reasons.10

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Please note that this is not medical advice.

References:

1. FDA label for imatinib.  http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021588s024lbl.pdf

2. FDA label for dasatinib.  https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021986s7s8lbl.pdf

3. FDA label for nilotinib.  https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/022068lbl.pdf

4. Dasatinib and nilotinib for imatinib-resistant or -intolerant chronic myeloid Leukaemia: A systematic review and economic evaluation. Health Technol. Assess. 2012, 16(22).

5. Oncologist. 2015, 20, 847–848.

6. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm332252.htm

7. https://www.fda.gov/Drugs/ResourcesForYou/HealthProfessionals/ucm313852.htm

8. (a) https://www.fda.gov/drugs/drugsafety/ucm373040.htm (b) https://www.cancer.gov/about-cancer/treatment/drugs/fda-ponatinibhydrochloride

9. FDA label for ponatinib.  http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/203469s022lbl.pdf

10. Oncologist. 2016, 21, 259–260.

Images:

Galloping pony (original source unknown; probably AllPosters.com):  http://diertjevandedag.classy.be/zoogdieren/onevenhoevigen/paardachtigen/paarden/welsh%20pony.htm

Time magazine cover:  http://content.time.com/time/covers/0,16641,20010528,00.html

Iclusig bottle:  http://phx.corporate-ir.net/phoenix.zhtml?c=118422&p=irol-newsArticle_pf&ID=1767523

Chemical structures:  Created by author using ChemDraw Professional

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