Drugs in R&D
Exisulind: Aptosyn, FGN 1, Prevatac, sulindac sulfone.
Exisulind [Aptosyn trade mark, FGN 1 trade mark, Prevatac trade mark, sulindac sulfone], the sulfone derivative of sulindac, is the lead compound in a series of selective apoptotic antineoplastic drugs (SAANDs) being developed by OSI Pharmaceuticals. The compounds were originally developed by Cell Pathways, which was acquired by, and integrated into, OSI Pharmaceuticals in June 2003. Exisulind inhibits the enzyme cyclic GMP phosphodiesterase (GMP-PDE), overexpressed in precancerous and cancerous colorectal cells, and induces apoptosis in such cells with minimal effects on normal cells. This apoptotic effect is independent of COX I or COX II inhibition, p53, Bcl-2, or cell-cycle arrest. Preclinical evidence suggests that exisulind also inhibits angiogenesis. Cell Pathways has formed sales and distribution agreements with three healthcare-related companies in the US for its future marketing and support campaign for exisulind. Innovex will hire and train sales representatives for Cell Pathways to launch and promote exisulind, Livingston Healthcare Services will be responsible for customer service, order and distribution administration, and Lash Group will be responsible for the development and implementation of reimbursement support services for exisulind. Cell Pathways has issued an exclusive licence for exisulind to Paladin Labs of Montreal, Canada. The agreement allows Paladin exclusive rights to commercialise the drug in Canada. In August 1999 Cell Pathways submitted an NDA application to the US FDA for exisulind (Aptosyn) for the treatment of familial adenomatous polyposis (FAP). However, in September 2000, the FDA announced that it had found deficiencies in the safety and efficacy data of Cell Pathways' NDA, and returned a non-approvable letter to the company. Cell Pathways then initiated another phase III study of the agent in combination with Aventis' docetaxel and comparing combination therapy with docetaxel alone. Exisulind has fast-track designation for FAP in the US. Phase I and II paediatric trials are also underway in the US. Cell Pathways announced in April 2000 that it had completed enrollment in an open-label phase II study in children with familial adenomatous polyposis (FAP). Patients will be evaluated to determine whether polyp numbers have been reduced after 1 year relative to baseline. In June 2000, Cell Pathways announced the results of a 1-year extension of a 1997-1999 phase III trial that showed that exisulind significantly reduced polyp formation in patients with FAP. Enrollment of 282 patients in a multicentre, placebo-controlled phase III trial for the treatment of sporadic colonic polyps was completed in the US in May 1999. In its 2003 Annual Report, Paladin Labs announced that it is conducting a phase III study of exisulind in patients with prostate cancer in Canada. Exisulind has completed a pivotal phase II/III trial for preventing the recurrence of prostate cancer in the US. Two phase II prostate cancer trials were initiated in June 1999. The first study assessed the efficacy of exisulind in 15 patients who had undergone prostatectomy, were receiving LHRH-agonist hormone therapy and had increasing PSA levels (study EX1001). The second trial was to enroll 20 hormone-refractory patients scheduled for radical prostatectomy within 2-8 weeks of diagnosis (study EX1004). This study compared the effect of exisulind + docetaxel on the rate of apoptosis and GMP-PDE expression in premalignant or malignant and normal prostate tissue. Cell Pathways and Rhône-Poulenc Rorer (now Aventis) agreed to collaborate on clinical trials of exisulind in combination with docetaxel in the treatment of various solid tumours. The first phase I/II trial (study 026) was to enroll previously untreated patients with non-small cell lung cancer (NSCLC). OSI Pharmaceuticals and Bristol-Myers Squibb are conducting a phase I/II trial (study EX 2002) of exisulind in combination with paclitaxel and carboplatin as first-line treatment for patients with NSCLC. Both companies will share costs and information gathered from the SCLC. Both companies will share costs and information gathered from the trial. A phase I/II trial (study EX 2006) of weekly paclitaxel and carboplatin combined with exisulind is also underway in patients with advanced NSCLC. Cell Pathways and Glaxo Wellcome are cooperating in supporting a clinical trial (study EX 2004) of exisulind in combination with vinorelbine as first-line treatment for elderly patients with advanced NSCLC. The study will be conducted at the University of Wisconsin, and the two companies will share the costs of the trial while maintaining the rights to their respective compounds. Cell Pathways and Eli Lilly have a phase I/II trial (study EX 2005) of exisulind in combination with gemcitabine underway in patients with NSCLC. This study will investigate the efficacy and tolerability of escalating doses of exisulind in combination with a standard gemcitabine regimen. The Cancer and Leukaemia Group B (CALGB) initiated a phase II study of exisulind in combination with etoposide and carboplatin in patients with small cell lung cancer in the US in September 2002. The Eastern Cooperative Oncology Group (ECOG) initiated a phase II study in NSCLC patients in September 2002 that will investigate the effects of exisulind in combination with gemcitabine and carboplatin. The objectives of the two studies are to determine the 12-month survival rate and response rates following treatment with the combination regimens. Patents covering the mechanism of action of exisulind have been allowed in Europe and Japan, and extend to the methods of identifying compounds that selectively stimulate apoptosis in precancerous and cancerous cells.