Oxford BioMedica and AGI Therapeutics separately confirmed plans to continue development of candidates that did not fare as well as expected in Phase III trials.
The late-stage renal cancer TRIST study evaluating Oxford BioMedica’s (www.oxfordbiomedica.co.uk) cancer vaccine, TroVax, failed to meet its primary endpoint of improving overall survival, and further vaccinations were suspended in July last year. An analysis of interim data, however, now suggests the 5T4-targeting vaccine may have benefits in particular subsets of patients. The company also says that the FDA supports its goal of pushing on with development of the product in subsets of renal cancer patients and for other cancer indications.
AGI, meanwhile, gave up development of Rezular (AGI-003; arverapamil) against diarrhea-predominant IBS (IBS-D) in March following disappointing top-line results from the ARDIS1 trial. It now says that it aims to pursue development of the drug for other diarrhea-related indications and potentially for one indication in a completely different disease field. The company has also realigned its business strategy and is opening up its development programs to nongastrointestinal specialty areas of unmet need.
Oxford BioMedic’a TRIST study involved 733 patients with advanced or metastatic renal cancer who were classified as having a good or intermediate prognosis. Patients were randomized to receive either TroVax therapy or placebo in addition to standard of care with interleukin-2, interferon-alpha, or sunitinib. In July 2008, the trial’s independent DSM board recommended discontinuing any further vaccinations as the study was evidently not going to meet its predefined primary endpoint of improvement in overall survival.
The interim data, however, suggested that although TroVax therapy did not prolong survival significantly in the overall patient population, in those with a good prognostic profile who were also receiving interleukin-2, the addition of TroVax therapy reduced the risk of death by 46% compared with placebo.
Oxford BioMedica says that as well as the survival benefits associated with adding TroVax to IL-2 in this subset of renal cancer patients, the analysis also showed that the immune response to TroVax appeared significantly better in patients with normal baseline platelet levels than in those with abnormal baseline platelet levels. This magnitude of the 5T4 antibody response to TroVax then correlated with improved survival. Overall, for those patients with normal baseline levels of platelets and monocytes and with higher baseline hemoglobin levels, TroVax therapy showed a promising trend in overall survival, indicating a 27% reduction in the risk of death compared with placebo therapy.
In July of this year Oxford BioMedica confirmed receipt of final comments from the FDA, following the agency’s review of the Phase III TRIST study and the company’s proposed clinical development outline for TroVAx. The agency supported its proposal to pursue clinical development of TroVax in metastatic disease including colorectal, ovarian, hormone refractory prostate cancer, and triple-negative breast cancer prior to further trials in renal cancer. The agency also noted that in these indications, there tends to be less evidence of abnormal levels of platelets and other hematological parameters that could potentially impact adversely on the immune response to TroVax.
FDA also invited submissions of adaptive Phase II/III trial designs in metastatic colorectal cancer and said it would work with Oxford BioMedica and its collaborators to prepare suitable protocols for submission and review. Additionally, FDA said that it would consider further development of TroVax in adjuvant indications, particularly adjuvant colorectal cancer, pending further clinical data in the metastatic setting. The company confirmed that it is implementing a broad partnering initiative and is also progressing discussions with clinical trial networks and clinicians who may conduct independent studies of TroVax.
AGI has a pipeline of clinical-stage candidates that are either isomers or new drug delivery formulations of existing approved drugs. While lead product, Rezular, failed to meet its primary endpoint in the ARDIS1 Phase III trial in IBS-D, a review of study data confirmed that therapy with Rezular did result in statistically significant benefits in terms of GI motility and diarrhea symptoms as well as quality of life.
The company is therefore planning to continue development of the drug for other chronic diarrhea-associated indications potentially including orphan indications, which together could lead to peak sales of some $1 billion. AGI also hinted that it has identified a new orphan indication outside the area of gastrointestinal therapeutics, for which it believes Rezular may have unique benefits and a sales potential of some $500 million.
The company has in addition implemented a strategic sidestep that will spread its pipeline net wider in terms of therapeutic fields. It will also continue development of AGI-004 (transdermal mecamylamine for the treatment of chemotherapy-induced diarrhea), AGI-010 (a controlled-release omeprazole), AGI-022 (a targeted, controlled-release aminosalicylate), and AGI-006 (an upper-GI prokinetic agent). Development partners for these existing products may also be sought.