Cytokinetics, Incorporated announced that it has agreed with GlaxoSmithKline (GSK) to terminate their collaboration and license agreement, effective February 28, 2010. As a result, all rights for GSK-923295, an inhibitor of centromere-associated protein E (CENP-E), will revert to Cytokinetics effective February 28, 2010. GSK remains responsible for all activities and costs associated with completing and reporting on the ongoing phase I clinical trial of GSK-923295 in advanced, refractory solid tumour patients.
The decision to terminate the collaboration agreement with GSK reinforces Cytokinetics’ corporate commitment to focus its internal research and development to muscle function and related therapeutic applications. Previously, Cytokinetics had negotiated for the return of all rights to the kinesin spindle protein (KSP) inhibitors, SB-743921 and ispinesib (SB-715992), that had also been initially developed in collaboration with GSK. Each of these compounds has demonstrated favourable tolerability and clinical activity in one or more clinical trials. Cytokinetics is now seeking to license its portfolio of these three novel mechanism anti-mitotic drug candidates so that they can be advanced in further clinical trials.
“In our industry and especially in these challenging times, it is increasingly important to remain focused and execute on a core business strategy. At Cytokinetics, we believe our best opportunities are rooted in our multiple programs directed to the biology of muscle function. Today’s announcement, combined with our company’s previously disclosed decisions to discontinue oncology research and phase out related development activities and spending, is further evidence of our commitment to this strategy,” stated Robert I. Blum, Cytokinetics’ president and chief executive officer. “We appreciate the opportunity we have had to collaborate with GlaxoSmithKline over the last eight years and we look forward to the possibility of advancing these novel oncology drug candidates into next stages of clinical development with another partner.”
“Our collaboration with GlaxoSmithKline has been productive in validating the potential of mitotic kinesin inhibitors in both solid and hematologic malignancies,” stated Andrew A. Wolff, MD, FACC, Cytokinetics’ senior vice president of Clinical Research and Development and Chief Medical Officer. “We are encouraged by both the tolerability profiles and the clinical activity demonstrated by our three novel drug candidates in the treatment of a broad array of tumour types.”
In October 2008, GSK reported interim data from a Phase I dose-escalation and pharmacokinetic study of GSK-923295 in adult patients with solid tumors. The primary objective of this trial is to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety and pharmacokinetics of GSK-923295 in advanced, refractory solid tumours. In this clinical trial, the authors concluded that GSK-923295 was well-tolerated at doses evaluated to date, which ranged from 10-105 mg/m2. Of the adverse events observed, nausea and fatigue (all less than or equal to grade 2) were the most frequent non-haematological toxicities, and anaemia (all less than or equal to grade 2) was the most frequent hematological toxicity. In addition, no neurotoxicity was observed. The MTD had not been reached but one DLT was observed in the form of reversible aspartate aminotransferase (AST) elevation. Finally, the authors concluded that the plasma pharmacokinetics of GSK-923295 observed were dose-proportional and exhibited low intra-patient and modest inter-patient variability.
In December 2009, at the American Society of Hematology Annual Meeting, Cytokinetics reported data from the Phase I portion of a Phase I/II clinical trial of SB-743921 designed to evaluate the safety, tolerability, pharmacodynamics and pharmacokinetic profile of this novel inhibitor of KSP administered as a one-hour intravenous infusion on days 1 and 15 of a 28-day schedule, and to assess the potential efficacy and the MTD of SB-743921 administered on this schedule in patients with Hodgkin or non-Hodgkin lymphoma. The authors concluded that the MTD of SB-743921 given on this schedule with G-CSF support was 9 mg/m2. The main DLTs of SB-743921 on this schedule with G-CSF support were thrombocytopenia and neutropenia. The authors noted that a greater dose-density was achieved with SB-743921 given on a once every two week schedule without prophylactic G-CSF (i.e., 6 mg/m2 = 0.43 mg/m2/day) than a once every 21 days schedule without prophylactic G-CSF (i.e., 4 mg/m2 = 0.19 mg/m2/day). Dose-density with G-CSF on the once every two week schedule was equal to 0.64 mg/m2. Grade 3 or 4 toxicities other than myelosuppression were infrequent; in particular, there was no evidence of neuropathy or alopecia greater than Grade 1. An efficacy signal was observed at doses at or above 6 mg/m2 in Hodgkin lymphoma patients. Of the 55 patients evaluable for efficacy, four partial responses (three patients with Hodgkin lymphoma and one with indolent non-Hodgkin lymphoma) were observed. The duration of the response in the patients with a partial response was between 8 weeks and 28 weeks. Best response as a percentage reduction in the sum of the product of diameters for the dominant lesion ranged from 53% to 71%.
In June 2009, at the American Society of Clinical Oncology, Cytokinetics presented interim results from the Phase I portion of its Phase I/II clinical trial of ispinesib, an inhibitor of KSP. These data demonstrated that ispinesib was well-tolerated when administered as a 1-hour intravenous infusion on days 1 and 15 of a 28-day cycle, with the most frequent adverse event being neutropenia. At that time, it was announced that one Response Evaluation Criteria in Solid Tumors (RECIST)-confirmed partial response (PR) with duration of 6 months had been reported. Also, two additional patients had a reduction in tumour burden of 30% or more as their best response. Finally, 10 additional patients experienced stable disease without reaching PR criteria; four of these responses lasted 4 months or longer. The authors also noted that protocol-defined DLTs of Grade 3 ALT/AST increases with a questionable relationship to ispinesib were observed in two out of seven patients treated at the 14 mg/m2 dose level. The protocol has been amended to permit additional dose escalation beyond the 14 mg/m2 dose level.
Cytokinetics is a clinical-stage biopharmaceutical company focused on the discovery and development of small molecule therapeutics that modulate muscle function for the potential treatment of serious diseases and medical conditions.