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Perifosine
Multiple cancers
Therapeutic area
Oncology
Target indication
Colorectal cancer, Kidney cancer and other types of cancer
Development stage
Phase 2
Description
Signal transduction pathways function by coordinated activation or inactivation of proteins within the cell membrane, cytoplasm or nucleus. Perifosine is an alkylphospholipid compound with structural similarity to phospholipids that are the main constituents of cellular membranes. Alkylphospholipids have been synthesized with the goal of modifying membrane-related signal transduction events. Perifosine is an orally active ingredient nearly completely bioavailable with antitumor capacities. Mode of action
 It was recently established that the cellular uptake of alkylphospholipid occurs via lipid microdomains of the plasma membrane called lipid rafts. These microdomains have been recognized as key mediators of alkylphospholipid-induced apoptosis. It is hypothesized that the formation of lipid rafts or other membrane microdomains is presumably disturbed by perifosine whereby Akt- and Raf-Mek-Erk-signalling is inhibited.
Perifosine would primarily interfere with membranes of proliferating cells. This means that tumor cells are found most sensitive to the action of perifosine, whereas normal cells display no or minimal toxicity.
As the SAPK/Jnk pathway has been implicated in mediating radiation induced apoptosis, perifosine causes an enhanced cytotoxic effect in terms of apoptotic cell death when combined with ionizing radiation. Since SAPK/Jnk also is a target of Sek1 which again is negatively regulated by Akt, perifosine induced inhibition of Akt leads to the activation of Sek1 and SAPK/Jnk. This additive effect opens the possibility to design and test more efficient anti-cancer treatment protocols. Trial results
A Phase 2 trial in advanced metastatic colon cancer and renal cell carcinoma conducted by our partner Keryx, showed that perifosine combined with capecitabine, more than doubled time to progression versus capecitabine plus placebo with a statistically significant p-value (0.0006). In addition, perifosine plus capecitabine more than doubled the Overall Response Rate and almost doubled the Clinical Benefit Rate versus capecitabine plus placebo. We conducted our own Phase 2 trial in non-small cell lung cancer, for which results were presented at the 2009 ASCO Meeting. A total of 177 patients were randomized and treated, of whom only 26 reached the milestone of one year post-treatment follow-up without disease relapse or progression, 14 of 95 patients (14.7%) in the perifosine and 12 of 82 patients (14.6%) in the placebo control group. No difference between treatment groups could be shown for local, loco-regional and overall disease control. Also the tumor response rate, as assessed after the end of the radiotherapy, was not different between the groups. In contrast to the lack of an observed local effect, patients in the perifosine group, particularly the subgroup of patients who entered the study without prior chemotherapy, showed a trend towards longer survival than patients of the placebo control group despite the short duration of treatment (5-week course of 150 mg perifosine daily). There were no safety signals that would lead to an amendment of the current safety data or risk benefit assessments of perifosine. The type and severity of side effects were in the expected range. In light of these neutral results and an unchanged safety profile, we can concentrate our efforts on the disease targets of both multiple myeloma and metastatic colon cancer where, unlike the non-small cell lung cancer study design, perifosine is dosed 50mg or 100mg daily until progression.
Development plan
Æterna Zentaris Program - Completed randomized, double-blind, placebo-controlled Phase 2 trial to assess the efficacy of daily oral perifosine when combined to radiotherapy in the treatment of patients with non-small cell lung cancer.
Keryx Program - Current Phase 3 trial in multiple myeloma with perifosine in combination with bortezomib (Velcade®) and dexamethasone, under SPA reached with the FDA. FDA also granted periosine Orphan Drug designation in September 2009 as well as Fast Track designation in December 2009
- Current Phase 3 trial in refractory advanced colorectal cancer with perifosine in combination with capecitabine (Xeloda®) vs. placebo and capecitabine (Xeloda®) under SPA reached with the FDA
- European Medicines Agency issued positive Scientific Advice for perifosine program in both multiple myeloma and colorectal cancer
- Phase 2 trials with Herceptin® and endocrine therapy for breast cancer
- Phase 2 trials all comers (monotherapy), sarcoma (monotherapy) and in combination with Gleevec®
- Monotherapy Phase 1/2 in NSCLC
- Phase 1 trials with Gemcitabine, Paclitaxel and Docetaxel (multiple cancers)
Partnership status
Perifosine rights have been licensed to Keryx BioPharmaceuticals for North America and to Handok for Korea. Æterna Zentaris holds the rest of the world right
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