Bayer AG/Algeta ASA have halted early a Phase III trial evaluating their first-in-class targeted radioactive drug Alpharadin (radium 223-chloride) for the treatment of symptomatic bone metastases in advanced prostate cancer patients based on positive interim results.

Patients on the drug, a radium alpha pharmaceutical, showed a significant 2.8 month median survival benefit in an interim analysis, the companies announced June 6. The positive data could speed a regulatory filing for the drug, which the companies had hoped to file in the second half of 2012.

"Now clearly we will be doing everything we can with our partner Bayer to accelerate that," Algeta CEO Andrew Kay said in an interview. Nonetheless, he said the companies will need to discuss the results with FDA and European Medicines Agency before revising the timeline.

An independent data monitoring committee recommended halting the ALSYMPCA study so that patients on placebo can be offered treatment with Alpharadin. The double-blind study enrolled 922 patients with symptomatic castration-resistant hormone-refractory prostate cancer that had spread to the bone. Patients were randomized two to one to receive Alphradin plus standard of care compared to standard of care alone. The varying standard of care regimens included steroids, pain killers, ketoconazole, estrogen and bone strengthening agents like bisphosphonates.

Median overall survival - the primary endpoint - was 14 months for patients treated with Alpharadin versus 11.2 months for placebo. Secondary endpoints of the trial are time to occurrence of skeletal related events, changes and time to progression in prostate-specific antigen tests and alkaline phosphatase tests, and safety and impact on quality of life. The full data will be presented at a future medical meeting, the companies said.

A Novel Drug Targeted To Patients With End-Stage Disease

If approved, Alpharadin would join a growing field of novel prostate cancer medicines ('Prostate Cancer Market Snapshot: More Than Provenge,' 'The Pink Sheet,' Nov. 22, 2010). The drug is targeted to prostate cancer patients at the final stage of the disease when it has spread to the bones. It has flown under the radar compared to some higher-profile new launches in the prostate cancer space, like Dendreon Corp.'s cancer immunotherapy Provenge (sipuleucel-T) and Johnson & Johnson's Zytiga (abiraterone). But it is expected to be used later in the course of treatment than those drugs, drugs, which have also demonstrated a significant survival benefit in prostate cancer patients.

Alpharadin is also different from Amgen Inc.'s bone drug Xgeva (denosumab), which was shown to delay time to symptomatic bone metastases in a post hoc analysis of a Phase III trial in CRPC patients earlier this year (Also see "Amgen's Bone Drug Xgeva Delays Pain From Prostate Cancer Metastases" - Pink Sheet, 17 May, 2011.).

Xgeva, a bone-strengthening drug, was approved for prevention of skeletal related adverse events in patients with bone metastases from solid tumors last year, but the company is hoping to extend labeling to include the prevention of bone metastases. Nonetheless, Xgeva has not shown a benefit on overall survival. Alpharadin, in contrast, is a targeted tumor cell-killer that has a natural affinity for bone metastases. It travels directly to the bone metastases, where the alpha particles kill the cancer cells with minimal effect on surrounding normal cells.

"We believe that this is the mechanism of action that extends life and has delivered this survival benefit," Kay said.

"On all of these therapies, sadly, patients still progress and in the last year of their life, they develop symptoms of pain, and symptomatic bone metastases are diagnosed," Kay said. "That is the time for Alpharadin to be prescribed for a survival benefit." Chemotherapy is the current treatment for such patients. Nonetheless, some 50% of patients cannot tolerate chemotherapy or refuse treatment, according to Kay.

The primary competition would therefore be drugs like docetaxel (Sanofi-Aventis SA's Taxotere and generics) or Sanofi's newly-launched follow-on chemotherapy Jevtana (cabazitaxel). Both drugs have also shown a survival benefit in prostate cancer patients in Phase III clinical trials: 2.4 months for docetaxel in chemotherapy-naive patients, and 2.4 months for cabazitaxel in patients already treated with Taxotere.

Nonetheless, Alpharadin has had a benign side effect profile in clinical trials, with similar tolerability to placebo in Phase I and II clinical trials, with the exception of constipation. Thus, it could be positioned as a treatment of choice over chemotherapy. Tolerability in the Phase III study held up to earlier trials, the company noted, though no details were released.

Although generic versions of Taxotere became available for the first time earlier this year, Kay told investors on a same-day conference call that the pricing environment remains "very encouraging" in the prostate cancer space. "It is difficult to think we may have a price reimbursement lower than cabazitaxel," he said, noting the drug is priced at about $48,000 for treatment. Indeed, Jevtana has performed surprisingly well in its first months on the market, although it has significant toxicity. Jevtana generated €82 million in 2010, after launching in the U.S. in July.

Nearly 100,000 CRPC patients in the U.S. and top five European markets have bone metastases, a condition that affects 90% of CRPC patients, the company said.

A First Launch For Algeta

Alpharadin would be Oslo, Norway-based Algeta's first commercial product. The company partnered its lead asset with Bayer in September 2009, securing $61 million upfront, while retaining a 50% co-promote option and profit-share in the U.S. (Also see "Algeta Recruits Bayer To Deliver Prostate Cancer Drug Alpharadin To Market" - Pink Sheet, 3 September, 2009.). The company expects to receive another $160 million from Bayer between now and launch in filing- and launch-related milestones.

Algeta expects to exercise the co-promote option and establish a specialized oncology sales force and supporting commercial group in the U.S. Outside the U.S., Algeta stands to receive tiered double-digit royalties on sales of Alpharadin. The company, which had about $78 million in cash and equivalents available at the end of the first quarter, expects its current cash position and future milestones will be sufficient to build the commercial organization and fund the company through the launch and beyond.

Algeta is also responsible for manufacturing Alpharadin as well and expects to have a manufacturing facility completed and approved by the appropriate regulators in the first half of 2012.

Development plans for Alpharadin are continuing. Bayer and Algeta are already studying the drug in a Phase II trial in breast cancer patients with bone metastases and have also initiated a trial evaluating the safety of Alpharadin in combination with chemotherapy in prostate cancer patients.

-Jessica Merrill (j.merrill@elsevier.com)

Positive Data On Bayer/Algeta's Alpharadin Could Accelerate Filing Timeline

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