Casting a wide clinical net has its drawbacks - cost, mainly - and its advantages, such as better chances of finding efficacy. But even the positive point isn't always entirely so, as Cytokinetics Inc. found out late last month, when its good/bad news regarding ispinesib, its kinesin spindle protein (KSP) inhibitor for cancer.

Final data proved encouraging from the second stage of partner GlaxoSmithKline plc's Phase II trial with the compound for breast cancer, reinforcing solid results from the first stage. But three separate Phase II studies sponsored by the National Cancer Institute in melanoma, hepatocellular cancer and hormone-resistant prostate cancer did not meet criteria needed to keep working in those indications.

"In this day and age, you aren't seeing companies doing as broad a clinical-trial program as we're doing," noted Robert Blum, Cytokinetics' president and CEO. The Phase II program involves nine studies - three by GSK and six by the NCI - across multiple tumor types, and activity has been found in three: breast, ovarian and non-small cell lung.

"How active is still to be determined," Blum conceded, "and how much do we spend to try to elucidate that is something that still requires critical thought." But he said the company is "optimistic and encouraged" by results so far.

"For a cancer drug candidate that has a mechanism of action that lends itself to something as broad as inhibiting cell division, it's prudent to think broadly," Blum told BioWorld Financial Watch, and called the most recently disclosed results "disappointing, but not altogether surprising."

Typical anti-mitotic drugs such as taxanes and vinca alkaloids target tubulin, and can disrupt cell functions beyond mitosis. With drugs like ispinesib, which goes after mitotic kinesins, Cytokinetics aims to stop cancer cell proliferation without dose-limiting toxicities that characterize the commonly used drugs.

London-based GSK designed its breast-cancer trial to test ispinesib in the second-line or third-line treatment of patients with locally advanced or metastatic disease, whose tumors 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 produced interim data last year. 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.

An independent radiology review confirmed the responses, seen in liver, lung and lymph node metastases. Duration of response, also 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 in the 50 safety-evaluable patients were neutropenia (21 patients), febrile neutropenia (four) and neutropenic sepsis (one).

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 ispinesib in that indication. The company has SB-921, a second KSP inhibitor, under development on its own. A Phase I study last year suggested stronger potency, but the pharmacokinetics look even more promising, with better distribution for efficacy against blood cancers such as Hodgkin's disease and non-Hodgkin's lymphoma. GSK intends to take a third compound into trials this year, GSK-295, an inhibitor of centrosome-associated protein E.

But there's plenty more to talk about than GSK and cancer, such as CK-1827452, the lead cardiovascular compound in Cytokinetics' potential $725 million deal with Amgen Inc.

Begun at the start of his year, the heart deal involves small-molecule drugs that activate cardiac muscle contractility. Cytokinetics got $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. CK-1827452, often known as CK-452, activates cardiac mycosin, which 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.

Cytokinetics plans to develop an intravenous and oral form, for acute and chronic patients respectively, and a Phase IIa trial with the IV version started about two months ago in U.K. patients with stable heart failure, testing the compound's safety and tolerability.

The trial will consist of at least five cohorts of eight patients with stable heart failure.

The first three cohorts will each undergo four treatment periods (three escalating doses of CK-452 and one placebo treatment), with those in the fourth and fifth cohorts getting a single dose.

In each cohort, patients will get a one-hour loading infusion to hit the target plasma concentration, followed by a slower infusion intended to maintain it. The maintenance infusions will last one hour in the first two cohorts and 23 hours in the last three, with data expected late this year or early next. Mark Monane, analyst with Needham & Co., wrote in a research report that results from the U.K. trial will set the stage for the next Phase II study, which will try IV CK452 against decompensated heart failure.

"We encourage investors to focus on [CK-452] as the primary value driver of the stock," Monane wrote, adding that the firm ended the first quarter with about $169 million in cash, enough to last into 2009, given a yearly burn rate of about $70 million.