BioWorld International Correspondent
LONDON - British Biotech's marimastat has failed in two Phase III trials in small-cell lung cancer, ending the vision of an oral treatment for solid tumors on which the company was founded.
Adding to the misery, the company also announced it is dropping BB-3644, its second-generation matrix metalloproteinase inhibitor (MMPI). BB-3644 was optimized to avoid the dose-limiting side effects of marimastat, but in fact it caused the same musculoskeletal pain in cancer patients in the Phase Ib trial.
Marimastat, along with other MMPIs, was licensed to Schering-Plough Corp. in September 1999, in a deal worth up to US$60 million, including $8 million up front. Tanabe Seiyaku Co. Ltd. has the Japanese rights.
CEO Elliot Goldstein told BioWorld International he is reviewing the contractual arrangements with Schering-Plough, and will resolve the discussion by the end of March.
"We got $8 million up front, and in terms of the other $50 million, that was based on filings and approvals so we won't get any of that. However, we expect to retain a research deal with Schering for MMPIs in cancer generally, though it probably won't be very active."
This failure in small-cell lung cancer is a huge blow, because despite marimastat failing in pancreatic, ovarian and gastric cancer and glioblastoma, British Biotech thought it would get a positive result in this indication. Marimastat works by stopping tumors from spreading, and the company believed it failed in the other trials because the patients all had advanced cancer. Schering Plough shared this view.
There was optimism about the lung cancer studies because they had more patients (360 in one, 540 in the other) and included subsets of patients with less extensive disease. Although the previous trials were negative, there was evidence of efficacy in patients with less advanced disease, including a positive result in a subset of gastric cancer patients.
However, the musculoskeletal pain, a side effect of marimastat, makes it unsuitable for long-term administration in early stage patients, which is why the news on BB-3644 adds to the discouragement. From the animal studies, British Biotech, based in Oxford, England, believed it had optimized BB-3644 to get around this dose-limiting problem. Although well tolerated at 20 mg twice a day, at 30 mg twice a day it caused the same pain, giving it no advantage over marimastat.
Goldstein said there were no implications of the failure of marimastat and BB-3644 in cancer for its deal with Serono SA to develop MMPIs for the treatment of inflammatory diseases. Serono paid British Biotech $5 million up front when the deal was signed at the end of 2000. "If BB-3644 has a future, it is in a noncancer setting," he said.
Three further Phase III trials of marimastat (out of eleven in total) in non-small-cell lung cancer, pancreatic cancer and breast cancer are still in progress. Interim analyses will be carried out to see if there are any benefits for patients, and whether the trials should continue.
The extensive program of Phase III trials of marimastat was put in place four years ago, under the previous management. The program was rationalized two years ago, but it was not possible to change the protocols or add more patients.
The string of Phase III failures particularly exposes the use of levels of cancer antigens as the endpoint in Phase II studies. Not only is the measure not approved for regulatory purposes, but as the history of marimastat illustrates, there is no cause-and-effect relationship.
In the past 18 months British Biotech has put together 10 collaborations to broaden its portfolio, and has also diversified its metalloenzyme inhibitors expertise into antibiotics.
Goldstein, who was celebrating his 50th birthday Tuesday as he performed the last rites on marimastat, said, "Today is a significant milestone both personally and professionally. While marimastat was going forward to the conclusion we saw today, we have been building the business for the future."