Cell Pathways has developed
exisulind (
Aptosyn), an oral apoptosis modulator and cGMP
phosphodiesterase inhibitor, for the potential treatment of several oncologic indications including precancerous
adenomatous polyposis coli (APC), also known as
familial adenomatous polyposis (FAP), precancerous sporadic
colonic polyps,
cervical dysplasia and the prevention of
tumor recurrence in prostate and
breast cancer. An NDA filing for the treatment of precancerous APC, for which the US FDA designated
exisulind a Fast Track product in July 1998, was initially expected in March 1999 [291313]. However, in January of the same year the company stated that it anticipated a delay in the NDA filing. The decision was based on unsatisfactory phase III data [308912], [313124]. In June 1999, the company completed analysis of the phase III trial data [328000] and the NDA was submitted in August 1999. An NDA was accepted for review by the FDA in October 1999 for the treatment of APC [328000], [338007], [344721], after data from three additional trials were submitted to the FDA in support of the NDA. At this time phase II/III trials were also ongoing for prostate and
breast cancer recurrence [287250], [326795]. Approval for the indication of FAP had been expected by the end of 2000 [365737] but in September 2000 the FDA completed its initial review and advised Cell Pathways that
exisulind will not be approved at this time. Cell Pathways has received a 'non-approvable' letter and intends to advise the FDA of its intent to amend the NDA and to request a meeting to address the deficiencies in the NDA [383249], [383560]. The first of the three additional trials submitted to the FDA in October 1999 was a 6-month, open-label trial involving 48 of the patients who completed a phase II/III study of
exisulind in early 1999. After 6 months of treatment with
exisulind, 25 patients who had previously been taking placebo experienced a 50% reduction in
polyp formation. The patients continuing treatment with
exisulind exhibited a further 50% reduction from their already reduced rate of
polyp formation [344991]. The second study was an extension study of 11 patients who participated in a 6-month, open-label, phase I/II, dose-ranging, safety and efficacy trial. As of October 1999, these patients were still on
therapy and had been receiving
exisulind for between 36 and 50 months. They had all experienced statistically significant reductions in
polyp formation rates [344991]. The third study was a double-blind, placebo-controlled safety study of 26 patients. All patients exhibited a trend of reduced new
polyp formation when compared to placebo.
Exisulind was generally well-tolerated by all patients during the course of the studies [344991]. In July 2000, Cell Pathways signed a marketing and distribution agreement for Canada with Paladin Labs, allowing Paladin exclusive rights to commercialize
exisulind within Canada [376072]. Also in July 2000, Cell Pathways announced that patents covering methods of identifying compounds that selectively stimulate apoptosis have been allowed in Europe and Japan. The patents describe the mechanism of action of Cell Pathways' SAANDs, including
exisulind, and use of that knowledge in screening for new drugs [374888]. In January 1999, the company received US-05858694 covering the mechanism of action of
exisulind [311504].