Abstract SY19-04: Design and development of ponatinib, a pan-BCR-ABL inhibitor for CML.
Authors: Clackson Tim 
Published: August 2014

Abstract
The fusion protein product of the Philadelphia chromosome (Ph), BCR-ABL, is a constitutively active tyrosine kinase that gives rise to chronic myeloid leukemia (CML) and a subset of acute lymphoblastic leukemia (Ph+ ALL). Tyrosine kinase inhibitors (TKIs) targeting BCR-ABL are the standard treatment for patients with newly diagnosed disease. TKI resistance, often mediated by mutations in the ABL kinase domain, is the major reason Ph+ patients experience failure of therapy, and the gatekeeper mutation T315I is uniformly refractory to first and second generation TKIs. Because mutations, including gatekeeper mutations, are a common theme in resistance to kinase-targeted therapies, CML has become a paradigm for understanding and overcoming such resistance. A key question is whether drug design can advance to the point that all mutation-based resistance can be overcome, and perhaps even prevented.
Design of PonatinibPonatinib was designed using a computational structure-based approach to incorporate two key design elements. First, the molecule has an optimal fit to the ABL binding site with distributed binding energy, with the aim of withstanding the loss of binding energy caused by any single mutation. Second, the molecule incorporates a unique, carbon-carbon triple bond linker with a narrow, linear profile that allows binding to the T315I gatekeeper mutant (1). This design allows ponatinib to retain potency against all tested forms of BCR-ABL, including the native (unmutated) kinase, the T315I mutant, and all other tested clinically relevant resistance mutants. In an accelerated mutagenesis screen that is predictive of clinical resistance to other TKIs, a concentration of 40 nM of ponatinib was able to completely suppress resistance. This indicated that, at this concentration, ponatinib has the profile of a pan-BCR-ABL inhibitor (2).
Ponatinib also has potent activity against other kinases implicated in both hematologic and solid tumor malignancies, including FMS-like tyrosine kinase-3 (FLT3), which is over-activated in a subset of acute myeloid leukemia (AML) patients, fibroblast growth factor receptors (FGFRs), KIT, and platelet-derived growth factor receptor (PDGFR) and retains activity against gatekeeper-mutated variants of those kinases(3).
Initial Clinical DevelopmentPonatinib was first evaluated clinically in a phase 1, multicenter, open-label, single-arm, dose escalation study in patients with all phases of chronic myeloid leukemia (CML), Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL), and other refractory hematologic malignancies. Dose limiting toxicities were increased amylase/lipase and pancreatitis, which were generally manageable with dose modification. The study found that at ponatinib doses ≥30 mg, the trough plasma ponatinib concentration exceeded the 40 nM target for pan-BCR-ABL inhibition. Clinically significant response rates in patients without and with BCR-ABL mutations, including the T315I mutation, were observed in chronic phase CML (CP-CML) and advanced Ph+ disease. Responses in CP-CML were durable, with 84% of patients with a major cytogenetic response estimated to remain in response at 2 years (median follow-up 30 months). Based on the dose-limiting toxicity data, safety, pharmacokinetic, pharmacodynamic, and anti-leukemic activity data, ponatinib 45 mg once daily was the recommended dose selected for phase 2 testing (4, 5).
The PACE Pivotal TrialPACE (Ponatinib Ph+ ALL and CML Evaluation) is a pivotal, phase 2, multicenter, open-label, single-arm study in patients with CML and Ph+ ALL resistant or intolerant to prior dasatinib or nilotinib therapy or with the T315I mutation confirmed at entry. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 months for CP-CML and major hematologic response (MaHR) at any time within 6 months for advanced Ph+ leukemia. Among the 449 enrolled patients, the median time from diagnosis to ponatinib was 6 (0.3-28) years, and the median number of prior TKIs was 3, with 53% exposed to imatinib, dasatinib, and nilotinib. The reported best prior response to most recent dasatinib or nilotinib was 26% major cytogenetic response or better in CP-CML, and 23% major hematologic response or better in advanced Ph+ leukemia.
After a median follow-up of 15 months, consistent with the findings in the phase 1 study, ponatinib demonstrated substantial anti-leukemic activity in these heavily pretreated patients, regardless of BCR-ABL mutation status at baseline (6). Responses in CP-CML were rapid, deep, and durable. The median time to major cytogenetic response was 3 months, with major cytogenetic response achieved by 56% of CP-CML patients. Major molecular response was achieved by 34% of CP-CML patients, and by 56% of CP-CML patients with the T315I mutation. Ninety-one percent of CP-CML patients with major cytogenetic response were estimated to remain in response at 12 months. In addition, clinically significant responses were observed in patients with advanced Ph+ disease. At the time of analysis, 49% of patients remained on therapy (63% CP-CML). The most frequent reasons for discontinuation were progression (19%) and adverse events (12%). Ponatinib was generally well tolerated. The most common non-hematologic treatment-emergent adverse events were rash (in 38% of patients), abdominal pain (38%), headache (35%), dry skin (35%), and constipation (34%), with the majority being grades 1 or 2 in severity. The most common hematologic treatment-emergent adverse events were thrombocytopenia (42%), neutropenia (24%), and anemia (20%), which were primarily grades 3 or 4 in severity.
Initial Approval and Future Development. Based on the results of these clinical trials, ponatinib (Iclusig) received FDA approval in December 2012 for the treatment of patients with CML and Ph+ ALL that are resistant or intolerant to prior TKI therapy. Ponatinib is currently being evaluated in newly diagnosed CP-CML patients in a phase 3 randomized, international clinical trial (EPIC, Evaluation of Ponatinib vs. Imatinib in CML). This trial will offer the opportunity to evaluate the ability of a pan-BCR-ABL inhibitor to suppress emergence of BCR-ABL resistance mutations.
In summary, ponatinib was designed for high-affinity, optimized binding to the active site of BCR-ABL, with an emphasis on potency and the ability to overcome mutation-based resistance. The preclinical and clinical trial data suggest that the structure-based approach to the design of ponatinib may have broad applicability in rationally designing TKIs to overcome mutation-based, and especially gatekeeper mutation-driven, resistance.
Citation Format: Tim Clackson. Design and development of ponatinib, a pan-BCR-ABL inhibitor for CML. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY19-04. doi:10.1158/1538-7445.AM2013-SY19-04