Iclusig was approved for patients with refractory Philadelphia-positive leukemia in December of last year by the FDA and July of this year by the EMA.
Frank G. Haluska, M.D., Ph.D., Chief Medical Officer and Senior Vice President, Clinical R&D covered the following points:
- continued analysis of follow-up data from particularly the PACE trial
- actions Ariad Pharmaceuticals and the FDA are taking in the response
- decision to place a hold on enrollment in ongoing clinical trials of ponatinib
- the FDA's enactment of a partial clinical hold
- discussions concerning the private labeling and associated events
At the time the PACE data were analyzed and submitted for regulatory review and approval some cardiovascular, cerebrovascular, and peripheral vascular events had begun to be observed. The approval of Iclusig was a consequence of a positive risk evaluation by the agency as well as by the EMA taking into account these events.
Ariad has analyzed the PACE data continually since their initial submission. Patients have continued to benefit from Iclusig therapy. Responses of patients in chronic-phase continue to prove to be durable and over 90% of responding patients remain in response. Yet with increasing exposure and longer follow-up the arterial thrombotic events have continued to be observed.
Iclusig provides benefit to many patients who have failed prior TKI therapy and the company is dedicated to studying and understanding the optimal way to utilize the drug therapeutically. Ariad anticipates that the clinical hold that the FDA has enacted will be temporary and will allow the company to institute modification to initial doses and to doses for patients already undergoing therapy.
The company does not have data supportive efficacy in situations of dose reduction and this data will support its evolving dosing recommendations. Ariad plans to resume new patient enrollment as soon as it is feasible with FDA guidance.
As part of the long-term follow-up of the pivotal PACE trial, now with the median follow-up of approximately 24 months, serious arterial thrombosis occurred in 11.8% of Iclusig treated patients. Specific events rates were cardiovascular events 6.2%, cerebrovascular events 4.0% and peripheral vascular events 3.6% with some patients having more than one type of events. This compares to initial serious arterial thrombotic incidents of 8.0% after 11 months of follow-up reflected in the current U.S. prescribing information for Iclusig.
At approximately 24 months, serious venous occlusion occurred in 2.9% of Iclusig treated patients compared to 2.3% in the current U.S. prescribing information for Iclusig. The incidence rate of these updated events were normalized, the duration of treatment exposure has not increased, being approximately 10.0 events per 100 patient years in initial analysis and 9.6 events per 100 patient years in the current analysis. Non-serious and serious arterial and venous events combined occurred in approximately 20% of Iclusig treated patients.
Patients who are currently receiving Iclusig in clinical trials will continue on therapy. Reductions in Iclusig dose from 45 milligram daily will be implemented on a trial-by-trial basis for patients whose Iclusig treatment is ongoing. The dose of Iclusig in patients who are currently enrolled in the EPIC trial will be reduced to 30 milligrams daily unless they have achieved a major molecular response or reach one in the future in which case the dose will be further reduced to 15 milligrams daily. The data monitoring committee of the EPIC trial has endorsed these changes.
The eligibility criteria for all Iclusig clinical trials will be modified to exclude patients who have experienced prior arterial thrombosis resulting in a heart attack or a stroke. The PACE trial demonstrates continued efficacy after dose reduction of 270 chronic-phase patients in the pivotal study, 190 or 70% of patients were dose reduced to either 30 milligrams or 15 milligrams daily.
Of 110 of those patients, 58% patients who initially achieved a major cytogenetic response, over 90% of these patients maintained this response after a median follow-up with 19 months despite dose reduction and of 35 patients who achieved the major cytogenetic response and subsequently reduced to 15 milligrams all but two patients maintained the response.
Harvey J. Berger, M.D., Chairman and Chief Executive Officer said ‘At this time the U.S. prescribing information for Iclusig remains unchanged. Iclusig continues to be available in the U.S. to patients with resistance or intolerant CML and Philadelphia-chromosome positive ALL in the commercial setting at the approved once-daily dose of 45 milligrams. We've been in consultation with the FDA and other health authorities regarding potential changes in Iclusig product labeling to reflect the updated information’.