ARIAAriad Pharmaceuticals, Inc. (NASDAQ:ARIA) announced the results of clinical and translational studies on Iclusig®(ponatinib), its approved BCR-ABL inhibitor, in heavily pretreated patients with resistant or intolerant chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). These data were featured in an oral and two poster presentations at the 57th Annual Meeting of the American Society of Hematology (ASH) taking place in San Diego.

“The data presented at ASH include the final report from the Phase 1 trial of ponatinib, with maximum follow-up of more than 7.5 years and median follow-up approaching five years that demonstrated ongoing cytogenetic and molecular responses. A separate study of CP-CML patients with the T315I mutation demonstrated a 72 percent probability of overall survival at 4.5 years among these patients who, prior to ponatinib, had no approved targeted treatment options and had a median survival of less than two years,” stated Timothy P. Clackson, Ph.D., president of research and development and chief scientific officer at ARIAD. “In addition, an oral presentation on studies in Ph+ ALL patients provides important new data on the molecular basis for Iclusig’s activity in these patients.”

Ponatinib in Chronic-Phase Chronic Myeloid Leukemia Patients: Final Report from a Phase 1 Trial (Poster, Abstract #92516)

The Phase 1 dose-escalation study of ponatinib (starting dose range: 2 to 60 mg once daily) enrolled 81 patients with resistant or refractory hematologic cancers, including 43 patients with chronic-phase CML (CP-CML). Sixty percent of CP-CML patients in this study had failed at least three prior tyrosine kinase inhibitors (TKIs), and 98 percent received at least two prior TKIs. Data presented at ASH focus on CP-CML patients and represent the longest follow-up of ponatinib patients to-date, through the termination of the study. Data are as of October 18, 2016 and include:

  • Median follow-up for CP-CML patients was approaching five years (55.4 months) with the maximum follow-up more than 7.5 years (91.3 months).
  • The median dose intensity was 26.4 mg/day.
  • Anti-leukemic activity was observed with ponatinib treatment:
    • Results showed that 72 percent of CP-CML patients had a major cytogenetic response (MCyR), 65 percent had a complete cytogenetic response (CCyR) and 56 percent had a major molecular response (MMR), a key secondary endpoint deeper than cytogenetic response.
    • Of note, 44 percent of CP-CML patients achieved MR4, 33 percent achieved MR4.5, and 26 percent achieved MR5; MR4, MR4.5 and MR5 are deeper levels of molecular response than MMR.
    • The median time to MCyR, CCyR and MMR was 2.8, 5.5 and 7.4 months, respectively.
    • By Kaplan-Meier analysis, among those who achieved response, median duration of MMR was 27.1 months. Median durations of MCyR, CCyR were not reached.
  • In 12 patients with the T315I mutation, MCyR was reported in 11 (92%) patients, CCyR in 10 (83%) patients and MMR in nine (75%) patients. In 15 patients with other mutations, MCyR was reported in 10 (67%) patients, CCyR in 10 (67%) patients and MMR in eight (53%) patients.
  • By Kaplan-Meier analysis, the probability of CP-CML patients maintaining MCyR at four years was estimated as 72 percent.
  • Ten of the 15 CP-CML patients (67%) who started ponatinib at a dose of 30 mg or less achieved MCyR, comparable to the overall response rate of 72 percent. The MCyR, CCyR and MMR rates in patients who received a starting dose of 30 mg/day or less were consistent with the corresponding response rates in the overall population.
  • The most common treatment-emergent adverse events (AEs) occurring in CP-CML patients were rash (65%), fatigue (63%), abdominal pain (58%), headache (58%), and arthralgia (53%). When analyzed by year, most adverse events occurred in the first year of treatment.
  • Forty-four percent (19/43) of CP-CML patients experienced any treatment-emergent arterial occlusive events (AOEs), of which 16 (37%) were serious adverse events (SAEs). Three venous thrombotic events (VTEs) and one serious venous thrombotic event were reported.

Long-Term Follow-up of the Efficacy and Safety of Ponatinib in Philadelphia Chromosome-Positive Leukemia Patients with the T315I Mutation (Poster, Abstract #93206)

The analysis describes the pooled efficacy and safety of ponatinib in patients with a T315I mutation detected at baseline from final report of the Phase 1 dose-escalation study and the four-year median follow-up of the Phase 2 PACE trial. The analysis includes 76 CP-CML patients with T315I from the Phase 1 trial (n=12) and the PACE trial (n=64). In this analysis, 26 (34%) patients remained on the study, as the Phase 1 study is no longer ongoing. Data presented on these patients are as of October 18, 2016 for the Phase 1 trial and August 3, 2015 for the PACE trial. Key data include:

  • Median follow-up for patients in this analysis was 40.3 months, with maximum follow-up of 91.4 months (7.6 years).
  • Among these CP-CML patients with T315I mutations, 50 percent had received treatment with two prior TKIs, and 26 percent had three or more prior TKIs. Overall, CP-CML patients with T315I at baseline in PACE were younger, less heavily treated, and had a shorter time since diagnosis, as compared with the non-T315I CP-CML population in PACE.
  • Responses continue to be observed in CP-CML patients with T315I patients treated with ponatinib at four years. In the combined analysis of these patients from both trials:
    • 75 percent (57/76) of T315I+ CP-CML patients achieved MCyR, 72 percent achieved CCyR, and 61 percent achieved MMR.
    • By Kaplan-Meier estimate, 83 percent of patients with response were estimated to maintain MCyR at four years, and 81 percent were estimated to maintain CCyR at four years. The median duration of response has not yet been reached.
  • The probability for overall survival in CP-CML patients with T315I in PACE at 4.5 years was 72 percent.
  • The most common treatment-emergent AEs in T315I+ CP-CML patients were rash (55%), dry skin (49%), headache (46%), abdominal pain (43%), fatigue (41%), and nausea (41%). The most common serious treatment-emergent AEs were pancreatitis (9%), myocardial infarction (8%) and coronary artery disease (7%). The safety profile of ponatinib in CP-CML patients with the T315I mutation was comparable to that observed among all CP-CML patients in the Phase 1 and PACE trials.
  • Thirty-three percent (25/76) of CP-CML patients with T315I experienced treatment-emergent AOEs, and seven percent experienced a VTE. Incidences of AOEs and VTEs in patients with the T315I mutation were similar to those observed in the overall patient population.

Analysis of the Sub-Clonal Origins of Compound Mutations in Patients with Refractory Ph+ Malignancies Treated with Ponatinib (Oral Presentation, Abstract #93238)

In order to analyze the sub-clonal origins of compound mutations, this study profiled potential compound mutational mechanisms using samples from CP-CML and Ph+ ALL patients in the PACE trial. Utilizing a multi-level sequencing strategy that combined Sanger Sequencing (SS), Next Generation Sequencing (NGS), and single molecule Duplex Sequencing (DS), which is more sensitive than NGS, this study utilized mutation burdens and patient specific clinical data to predict the extent of pre-existing mutations. Key data include:

  • In the PACE study, ponatinib induced high rates of major hematological response (MaHR) and MCyR in Ph+ ALL patients (41% and 47%), even though 91 percent of these patients had received at least two prior TKIs. For these patients, median progression-free survival (PFS) was three months for Ph+ ALL patients.
  • In TKI refractory patients treated with ponatinib, Ph+ ALL patients gained BCR-ABL compound mutants at end of treatment (EOT) more often than CP-CML patients.
    • At least 12/20 (60%) Ph+ ALL patients had compound mutations at EOT. In CP-CML patients 4/130 (3%) patients had these compound mutations at EOT.
  • Direct DS measurements and patient-specific clinical data predict that all resistance mutations in the kinase domain of BCR-ABL are likely to exist before the initiation of ponatinib treatment.
    • Refractory Ph+ ALL has a higher mutation burden, and a higher leukemia re-initiating fraction, which likely explains the clinical propensity in Ph+ ALL to relapse with on-target mutations as compared to CP-CML. This mutation burden is added to resistance mutations that were already acquired on prior TKI therapy.
    • Previous TKI failure selects for BCR-ABL mutations in Ph+ ALL and appears to limit the duration of response to ponatinib in Ph+ ALL through the development of compound mutations.
  • Coupled with estimates of leukemia initiating cell fractions, these data estimate the clinical propensity of Ph+ ALL to acquire on-target mutations. These findings provide a molecular hypothesis for the observation that Ph+ ALL patients treated with ponatinib in the front-line had estimated 80 percent overall survival (OS) at three years, as published in The Lancet Oncology1(Original Source)

Shares of Ariad Pharmaceuticals closed yesterday at $13.28, up $0.12 or 0.91%. ARIA has a 1-year high of $14.42 and a 1-year low of $4.37. The stock’s 50-day moving average is $11 and its 200-day moving average is $9.82.

On the ratings front, ARIA stock has been the subject of a number of recent research reports. In a report issued on November 30, JMP analyst Michael King reiterated a Hold rating on ARIA. Separately, on November 17, Leerink Swann’s Michael Schmidt reiterated a Buy rating on the stock .

According to TipRanks.com, which ranks over 7,500 financial analysts and bloggers to gauge the performance of their past recommendations, Michael King and Michael Schmidt have a yearly average loss of 0.8% and a return of 26.4% respectively. King has a success rate of 43% and is ranked #3048 out of 4256 analysts, while Schmidt has a success rate of 60% and is ranked #31.

Sentiment on the street is mostly bullish on ARIA stock. Out of 9 analysts who cover the stock, 5 suggest a Buy rating , 2 suggest a Sell and 2 recommend to Hold the stock. The 12-month average price target assigned to the stock is $12.50, which reflects a potential downside of -6% from last closing price.

ARIAD Pharmaceuticals, Inc. operates as an oncology company, which engages in the discovery, development, and commercialization of small-molecule drugs for the treatment of cancer. Its products include Iclusig and Caregivers.