Ponatinib – the third generation TKI
Ponatinib was designed to be BCR-ABL tyrosine kinase inhibitor with activity against
a wide range of mutations, including the T315I mutation, the one variant in which all
three marketed drugs fail. Ariad conducted a Phase I study of ponatinib in patients
with CML and other hematological malignancies (ALL, acute myeloid leukemia,
myelodysplastic syndromes, multiple myeloma and myelofibrosis) relapsed or
refractory to the standard of care. This dose escalation study examined 2, 4, 8, 15,
30, 45 and 60mg capsules and 45 and 60mg tablets. The demographics of the study
are listed in Table 12.Results for ponatinib Phase 1 study
The efficacy was reported for all the ponatinib doses examined in the CML
chronic and advanced phases at the 2010 ASH meeting (Table 13). Although it is
difficult to compare across trials, the efficacy observed for the chronic phase CML
patients (66% major cytogenetic response) as a 3rd or 4th line of therapy appears
better than Sprycel (45% major cytogenetic response) and Tasigna (35% major
cytogenetic response) results in patients that only received Gleevec (2nd line).
Major cytogenetic responses for ponatinib were comparable in the higher dose
range (30-60mg) relative to the overall pooled data, showing an average 64%
major cytogenetic response rate (Table 14). The numbers of patients treated are
small, but show ponatinib is highly active. Additionally, 9/9 of the patients that
had the T315I mutation recorded a major cytogenetic response, suggesting that
ponatinib is effective against the key mutation it was designed to overcome.
The overall ponatinib response rate in the advanced phase group (accelerated
and blast phases) is comparable with previous Sprycel and Tasigna results in the
advanced phases. Notably, ponatinib recorded no complete responses in the
advanced phase patients with the T315I mutation, and only 1 out of 5 patients
experienced a partial response. While patient numbers are even smaller in this
subset, experts do not expect any drug to be highly effective in the advanced
stages of disease because the cancer is very genetically unstable by that point.
Table 13: Results for ponatinib in chronic and advanced phases of CML
Chronic Phase CML Advanced Phases of CML
Overall T315I* Non-T315I Overall T315I* Non-T315I
N=38 N=9 N=29 N=17 N=5 N=12
Major cytogenetic response 66% 100% 55% 24% 20% 25%
Complete cytogenetic
response 53% 89% 41% 12% 0% 17%
Partial cytogenetic response 13% 11% 14% 12% 20% 8%
Complete hematologic
response 95% 100% 93% 35% 20% 42%
Source: 2010 ASH ponatinib presentation; *patients with T315I mutational status confirmed at entry
Adverse event profile acceptable
Ponatinib appears to be well tolerated and may prove to be differentiated relative
to the approved TKIs (Table 15). While it is difficult to draw a conclusion on small
patient numbers, we note the following:
?? Ponatinib is uniquely associated with pancreatitis, and the effect appears
dose related (Table 14). ARIA has noted the events were reversible and
managed by dose reductions. Expert feedback suggests the primary effect is
elevated lab metrics (amylase and lipase enzymes); in some cases there
was mild-to-moderate abdominal pains, and in one case, an imaging analysis
Table 12: Ponatinib Phase 1 study demographics
Cancer type N=74
CML (Chronic, Accelerated, Blast) 60 total (44, 7, 9)
Ph+ ALL 4
AML (FLT3 ITD) 6
Other (MM, MDS, MF) 4
Median age 56 years
Range 26-85 years
Female/Male 47%/53%
60 CML patients had previous TKI exposure
Resistant =2 TKIs 95%
Resistant =3 TKIs 65%
Prior approved therapies for enrolled patients
Drug Frequency
Gleevec 97%
Sprycel 90%
Tasigna 57%
Sprycel and Tasigna 52%
Source: 2010 ASH ponatinib presentation
Table 14: Response rates and pancreatitis by dose
Major cytogenetic
response Pancreatitis events
Dose* Rate Dose (N=81)**
Pancreatitis
events N (%)
30mg (N=5) 40% 2mg –30mg 3/31 (10%)
45mg (N=12) 83% 45mg 4/31 (13%)
60mg (N=11) 55% 60mg 4/19 (21%)
Average 64%
Source: 2010 ASH ponatinib presentation
W
Ariad Pharmaceuticals, Inc.
19 July 2011
11
revealed inflammation of the pancreas, although not a major concern to
clinicians at this point.
?? Ponatinib appears to have similar rates of rash and gastrointestinal adverse
events as Gleevec, although head to head data will be required to fully
assess these side effects.
?? To date there are no reports of pleural effusion as seen with Sprycel, or liver
abnormalities associated with Tasigna.
Based on the results from the Phase 1 study, Ariad has decided to move forward
with the 45mg dose in the ongoing Phase 2 PACE study.
Ongoing Phase 2 ponatinib PACE trial
In September 2010 ARIA started a pivotal Phase 2 study in resistant or intolerant
CML and Ph+ ALL called PACE (Ponatinib Ph+ ALL and CML Evaluation). The
study is expected to enroll over 400 patients with chronic phase, accelerated
phase and blast phase CML, as well as Philadelphia chromosome positive ALL.
PACE has six study arms as shown in Chart 1, evaluating T315I positive and
negative disease across chronic and blast/accelerated phase disease (Chart 1).
The study specifically requires patients to have failed a second-generation TKI
(Sprycel, Tasigna), although physicians note that most patients in the study will
have also failed Gleevec. Failure includes resistance or intolerability.
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