Filanesib (ARRY–520) – KSP Program for Multiple Myeloma
ARRY-520 is a highly selective, targeted inhibitor of KSP, which is a novel mechanism of action in MM distinct from proteasome inhibitors and IMiDs currently approved for treatment of MM. ARRY-520 preferentially acts on MM and hematopoietic cells, versus terminally differentiated cells or epithelial cells, based on targeted tissue expression of KSP, and MCL-1 survival dependence. As predicted by its mechanism, only minimal non-hematologic adverse events, including peripheral neuropathy, gastrointestinal and dermatological toxicities, have been reported with ARRY-520 therapy at the recommended Phase 2 dose.
MM and other hematologic cancers frequently depend on MCL-1 as a key survival protein. In preclinical studies, ARRY-520 produced a rapid onset of apoptosis in tumor cells that depend on the MCL-1 survival protein, which supported further investigation of ARRY-520 in MM. In clinical studies, ARRY-520 has demonstrated durable, single-agent activity in patients with MM that is refractory to both Velcade® (bortezomib) and Revlimid® (lenalidomide), a population with significant unmet therapeutic needs. In addition, in clinical studies of ARRY-520 in combination with either Velcade or with Kyprolis® (carfilzomib), both combinations demonstrated initial signs of activity and both were well tolerated, with no unexpected hematologic toxicity and a manageable side effect profile. The results from these combination trials may support development opportunities in earlier lines of therapy.
Development milestones for ARRY-520 during fiscal 2013 included the following:
- completed enrollment in a Phase 2 trial in combination with dexamethasone in patients with MM refractory to Revlimid, Velcade and dexamethasone therapy;
- reached the prescribed or maximum single agent doses in our trial in combination with Velcade in patients with relapsed or refractory MM; and
- in collaboration with M.D. Anderson and Onyx Therapeutics, reached the prescribed or maximum single agent doses of ARRY-520 and Kyprolis in an investigator-sponsored Phase 1b dose escalation trial in patients with relapsed or refractory MM who are refractory or intolerant to Velcade therapy.
In addition, data from these and other ongoing trials were presented at conferences during fiscal 2013:
At the Congress of the European Hematology Association, or EHA, in June 2013, interim results were reported from the ongoing combination trial of ARRY-520 with Kyprolis in patients with relapsed or refractory MM who were refractory or intolerant to Velcade. The combination demonstrated early signs of activity with a disease control rate (complete response, partial response, minimal response or stable disease) of 82% and a clinical benefit rate (≥minimal response) of 53%, including one complete response. As of June 2013, more than half of the patients enrolled remain on study, with patients in the current cohort receiving full doses of both drugs.
Also at the EHA, data on a potential patient selection marker were presented from multiple studies of ARRY-520 as a single agent in patients with relapsed and refractory MM. To date, all responses have occurred in patients with low levels of alpha-1-acid glycoprotein, or AAG, a population which represents 75-80% of MM patients, and these patients had longer event-free survival (time to next treatment or death). In the single-agent Phase 2 clinical study of ARRY-520 in relapsed and refractory MM, patients with low AAG had a longer median overall survival (20.2 months versus 4.5 months), improved median event-free survival (5.3 months versus 2.4 months) and greater overall response rate (24% versus 0%) compared to patients with elevated AAG. The identification of this marker may enable more precise targeting of patient populations who will benefit from ARRY-520.
In April 2013, interim results from two ongoing ARRY-520 clinical trials in MM were reported at the International Myeloma Workshop, or IMW. In a Phase 2 trial in patients with relapsed or refractory MM, ARRY-520 demonstrated single-agent activity in heavily pretreated patients, with 19 months median overall survival and a 16% overall response rate. These results are comparable to those for recently approved products Kyprolis and Pomalyst® (pomalidomide) as single agents in similar patient populations. ARRY-520 was generally well tolerated, with the predominant adverse events being transient, non-cumulative and predominantly asymptomatic neutropenia and thrombocytopenia that were readily managed with growth factors and supportive care. Consistent with other reported ARRY-520 study results, there was a low incidence of non-hematologic adverse events with no treatment-related neuropathy observed. Further data on a potential patient selection marker was also presented. Also at IMW, interim results were reported from a clinical trial of ARRY-520 in combination with Velcade in patients with relapsed or refractory MM. Initial signs of activity, including responses and prolonged stable disease, were observed in this heavily pretreated population, the majority of whom were refractory to prior Velcade treatment. Additionally, the combination treatment was generally well tolerated, with neutropenia as the most common adverse event and limited non-hematologic grade 3 or 4 toxicity.
In December 2012, Phase 2 results with ARRY-520 plus low-dose dexamethasone were reported at the Annual Meeting of the American Society of Hematology, or ASH. In this Phase 2 trial in patients with triple-refractory (refractory to Revlimid, Velcade and dexamethasone) MM and a median number of 10 prior treatment regimens, ARRY-520 plus low-dose dexamethasone demonstrated a 22% overall response rate (≥ partial response), with manageable safety. The most common drug-related adverse events include myelosuppression. In a related abstract, it was observed that the overall response rate (â‰¥partial response) increased to 33% from 22% for the same group of ARRY-520-treated patients who were retrospectively selected with a low AAG level. The clinical benefit rate (≥minimal response) was 50% in the selected population.
Development Plan: During fiscal 2014, we plan to:
- report results from the Phase 2 study of ARRY-520 in combination with dexamethasone, interim results from the Phase 1b study of ARRY-520 in combination with Velcade and dexamethasone and interim results from the Phase 1b study of ARRY-520 in combination with Kyprolis;
- identify the maximum tolerated/recommended Phase 2 dose for both the Velcade and the Kyprolis combination Phase 1b studies and initiate additional studies to explore preliminary efficacy of these combinations in patients with relapsed/refractory MM; and
- pending positive results in any of the above trials, define a path to late-stage development for ARRY-520 in MM.