Ariad announces preliminary safety and efficacy data of ponatinib in patients with newly diagnosed cml from discontinued Phase 3 epic trial

ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced preliminary safety and efficacy data from the discontinued Phase 3 EPIC trial of Iclusig^® (ponatinib) vs. imatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML). These data are being featured this afternoon in a poster presentation and a poster discussion session at the 2014 American Society of Clinical Oncology (ASCO) annual meeting in Chicago, Illinois.

EPIC Trial Design

The EPIC trial (Evaluation of Ponatinib vs. Imatinib in CML) was a Phase 3, multicenter, international, two-arm, open-label trial of ponatinib (administered at a starting dose of 45 mg once daily) vs. imatinib (administered at a starting dose of 400 mg once daily) in patients with newly diagnosed chronic-phase CML.  Patients were randomized (1:1) to ponatinib or imatinib and stratified by Sokal risk score determined at time of diagnosis. 

On October 18, 2013, in consultation with the U.S. Food and Drug Administration (FDA), ARIAD terminated the EPIC trial due to the observation of the accumulation of arterial thrombotic events in the ponatinib clinical program.

From August 2012 to October 2013, 307 patients were randomized (58% of planned enrollment).  None of the prospectively defined endpoints could be analyzed due to the early termination of the trial.  However, the following endpoints were available for analysis: 

• <10% BCR-ABL transcript level by the international scale at 3 months
• Major Molecular Response (MMR), MR4, and MR4.5 rates at 3, 6, 9 and 12 months
• MMR, MR4, and MR4.5 rates at least 3, 6, 9 and 12 months
• MMR, MR4 and MR4.5 rates at any time (best response)
• Time to MMR, MR4 and MR4.5
• Complete Cytogenetic Response (CCyR) at any time and at 6 and 12 months
• Safety

Major Molecular Response (MMR) at 12 months was the primary end-point of the trial.  MMR is defined as a less than or equal to 0.1% ratio of BCR-ABL to ABL transcripts on the International Scale measured in peripheral blood.  MR4 and MR4.5 are 4 log and 4.5 log reductions in BCR transcript levels, respectively.

EPIC Trial Findings

Despite the fact the primary end-point could not be analyzed due to the early termination of the trial, analysis of key secondary end-points provides preliminary evidence of efficacy of ponatinib compared to imatinib in newly diagnosed patients with chronic-phase CML at the doses studied and at the time points reached. 

The median follow-up for both arms was 5 months at the time of termination of the trial, and the following observations were made:

• A higher proportion of evaluable ponatinib (94%, n=109) vs. imatinib (68%, n=114) patients achieved <10% BCR-ABL transcript level at 3 months (P<0.001).  This measure of efficacy has been shown in other trials to correlate with overall survival.
• While the primary end-point of the trial could not be assessed, the MMR rate at 12 months was higher for ponatinib patients (80% of n=10) than for imatinib patients (39% of n=13; P=0.074).
• MMR rates were higher for ponatinib vs. imatinib at 3, 6, and 9 months (P=0.001):
  – At 3 months, ponatinib MMR was 31% of n=109 vs. imatinib MMR of 3% of n=114
  – At 6 months, ponatinib MMR was 62% of n=69 vs. imatinib MMR of 22% of n=73
  – At 9 months, ponatinib MMR was 86% of n=22 vs. imatinib MMR of 33% of n=27
• MR4 and MR4.5 rates were higher for ponatinib vs. imatinib at all time points through 12 months (P<0.02).
• Median time to MMR was shorter for ponatinib (100 days) vs. imatinib (169 days).
• CCyR rates were higher for ponatinib (74% of n=54) vs. imatinib (53% of n=64) at any time (P=0.019).  CCyR for ponatinib at 6 months was 86% of n=36 vs. imatinib CCyR of 60% of n=50, P=0.012.

While no new safety signals were identified, there were more adverse events (AEs) in the ponatinib arm compared with imatinib:

• More ponatinib patients experienced vascular occlusive events (8%, n=12) vs. imatinib patients (2%, n=3).
• There was a higher incidence of treatment-emergent grade 3 or 4 AEs for ponatinib vs. imatinib.  The most common AEs were lipase increase (14%, n=22) vs. (2%, n=3), thrombocytopenia (12%, n=19) vs. (7%, n=10), rash (7%, n=10) vs. (1%, n=2). 
• There also was a higher incidence of serious AEs for ponatinib vs. imatinib.  The most common SAE was pancreatitis (3%, n=5) on the ponatinib arm; none reported with imatinib.
• More ponatinib patients vs. imatinib patients had dose reductions (36%, n= 55 vs.  7%, n=10) and discontinuations due to AEs (9%, n=14) vs. (1%, n=2).

The starting dose of ponatinib used in the EPIC trial was the same as the dose used in refractory CML patients.  Going forward, further evaluation in patients with newly diagnosed chronic-phase CML will require evaluation of lower doses of ponatinib.

“The data from the EPIC trial have helped inform a planned dose-ranging trial of ponatinib in patients with refractory CML and will help guide potential future studies in earlier lines of CML therapy, including in front-line patients,” stated Frank G. Haluska, M.D., Ph.D., senior vice president of clinical research and development and chief medical officer at ARIAD.  “Our continued goal is to optimize the benefit/risk of ponatinib in each of these patient populations.”

Investor and Analyst Briefing and Webcast

ARIAD will host an investor and analyst briefing from ASCO on Monday June 2, 2014. This breakfast meeting will feature Dr. Lyudmila Bazhenova from UC San Diego Moores Cancer Center to discuss the AP26113 clinical data being presented at ASCO, Dr. Michael J. Mauro from Memorial Sloan Kettering Cancer Center to discuss clinical data on ponatinib in CML, and Dr. Michael C. Heinrich from Oregon Health & Science University to discuss ponatinib clinical data in GIST.

The meeting will be webcast live along with slides and can be accessed by visiting the investor relations section of the Company’s website at http://investor.ariad.com.

Date:                  Monday, June 2, 2014

Time:                 7:30 a.m. to 8:30 a.m. (CT)

Location:           Hilton Chicago, Marquette Room

A replay of the investor event will be available on the ARIAD website approximately three hours after the presentation and will be archived on the site for four weeks.  To ensure a timely connection to the live webcast, participants should log onto the webcast at least 15 minutes prior to the scheduled start time.

About Iclusig^® (ponatinib) tablets

Iclusig is approved in the U.S., EU and Switzerland. Iclusig is a kinase inhibitor indicated in the U.S. for the:

• Treatment of adult patients with T315I-positive chronic myeloid leukemia (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).
• Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated.