West Coast Editor
Cytokinetics Inc.'s mixed Phase II news regarding ispinesib, the kinesin spindle protein (KSP) inhibitor for cancer, put a dent in the share price and likely caused some investors to slide more of their chips onto CK-1827452, the lead cardiovascular compound in the potential $725 million deal with Amgen Inc.
"I'm recognizing that's the case - it's not new today," said Robert Blum, president and CEO of South San Francisco-based Cytokinetics.
While final data were encouraging from the second stage of partner GlaxoSmithKline plc's Phase II trial with ispinesib for breast cancer (backing up results from the first stage), three separate Phase II studies sponsored by the National Cancer Institute in melanoma, hepatocellular cancer and hormone-resistant prostate cancer fell short of criteria needed for continuing development.
The company's stock (NASDAQ:CYTK) closed Friday at $5.65, down 63 cents.
Nine studies - three by GSK and six by NCI - across multiple tumor types were included in the Phase II program. Blum called the latest NCI results "disappointing but not altogether surprising," and noted that activity so far has been found in three tumor types - breast, ovarian and non-small cell lung.
"How active is still to be determined," he said. "And how much do we spend to try to elucidate, that is something that still requires critical thought." Blum said he was "optimistic and encouraged" by progress so far, but understood how investors might view the "glass half full" in the cardiovascular program and half empty in oncology.
"We see value in pursuing both, albeit in a prudent way," he said.
London-based GSK designed its trial to test ispinesib in the second-line or third-line treatment of patients with locally advanced or metastatic breast cancer whose disease had recurred or progressed despite treatment with anthracyclines and taxanes. Patients got ispinesib as monotherapy at 18 mg/m2 as a one-hour intravenous infusion every 21 days.
The primary endpoint of the clinical trial was objective response as determined using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Using a conventional two-stage Green-Dahlberg design, which requires a level of proven efficacy before patients can move to the second stage, the study yielded interim data last year.
Now, in final data, GSK said the best overall responses observed with ispinesib were partial responses in four of 45 evaluable patients as measured by RECIST.
Responses were confirmed by independent radiology review and were seen in liver, lung and lymph node metastases. Duration of response, independently reviewed, ranged from 7.1 weeks to 30 weeks, and the median time to progression in the treated population was 5.9 weeks.
Adverse events were described as manageable, predictable and consistent with those seen in the Phase I trials. The most common grade 3/4 adverse events observed in the 50 patients evaluable for safety were neutropenia (21 patients), febrile neutropenia (four patients) and neutropenic sepsis (one patient).
Cytokinetics plans a Phase I/II trial in first-line advanced or metastatic breast cancer in the second half of this year, and data from that study will help the company decide what to do next with the compound in that indication.
Typical anti-mitotic drugs such as taxanes and vinca alkaloids target tubulin, and can disrupt cell functions beyond mitosis.
Cytokinetics hopes that, by taking aim at mitotic kinesins (which apparently have no role in cells other than mitosis), the firm can stop cancer cell proliferation without dose-limiting toxicities. The company has SB-921, a second KSP inhibitor, under development on its own. A Phase I study last year showed the compound might be more potent than ispinesib.
"It is slightly more potent, but that's probably not a key distinguishing fact," Blum said. Rather, the differing volume of distribution and pharmacokinetics could make SB-921 useful in such hematological cancers as Hodgkin's disease and non-Hodgkin's lymphoma. GSK will be taking a third compound into trials this year, GSK-295, an inhibitor of centrosome-associated protein E.
At the start of the year, Cytokinetics entered its heart deal with Thousand Oaks, Calif.-based Amgen. Targeting small-molecule drugs that activate cardiac muscle contractility, the arrangement brought Cytokinetics $42 million in an up-front license and technology access fee, as well $33 million in proceeds from the sale of about 3.5 million shares to Amgen at $9.47 each. (See BioWorld Today, Jan. 4, 2007.)
Leading that push is CK-1827452, often known as CK-452, which activates cardiac mycosin - a move that could help patients with congestive heart failure while avoiding "second-messenger" signaling that can bring about the negative side effects of inotropes used as therapy. The company plans to come up with an intravenous and oral form, for acute and chronic patients respectively.
A Phase IIa trial with the IV version started about two months ago in patients with stable heart failure.
Cytokinetics ended the first quarter of this year with about $169 million in cash.