EVIZON (Squalamine) for wet macular degeneration

Background:

EVIZON (Squalamine) is an aminosterol originally purified from the tissue of the dogfish shark. It is a potent inhibitor of growth factor-mediated endothelial cell proliferation and migration . Its antiangiogenic activity does not appear to be mediated by altering production of VEGF or by blocking the VEGF receptor. Instead, directly interrupts and reverses multiple facets of the angiogenic process. Working within activated endothelial cells, EVIZON inhibits integrin expression, and reverses cytoskeletal formation, thereby resulting in endothelial cell inactivation and apoptosis. Experimental evidence indicates that squalamine inhibits the sodium-proton exchange pump, thereby affecting endothelial cell volume, pH, growth, and motility. Squalamine may alter cellular responses to growth stimuli that increase intracellular. EVIZON is administered systemically (intravenous injection). Genaera corporation is developing EVIZON.

EVIZON Clinical Trials

Phase I/II

Results were reported at ARVO 2004. Patients who met eligibility criteria received weekly intravenous infusions of squalamine lactate either at the doses of 25 and 50 mg/m2 at various durations of infusion (180, 90, 45 minutes) for 4 weeks. 40 patients were enrolled. 17 (43%) were male and 23 (57%) female. Ages ranged from 51-92 years. Ten patients (26%) had three lines or greater improvement in visual acuity, and 29 (74%) maintained their initial VA or had less than 3 lines of VA loss at the 4 month visit. The greatest improvement in VA was 8 lines, from 20/125 to 20/20. There were no significant adverse events reported.

Phase II

Trial-209 began in 2005. It is the largest of Genaera's three Phase II studies. It will evaluate the safety and efficacy of EVIZON in all subtypes of wet AMD over a two-year period and is designed to run concurrently with Phase III trials. This Phase II study will evaluate two dose levels of EVIZON (20 mg or 40 mg) given once weekly for four weeks, followed by maintenance doses once every four weeks until week 48. At the end of 48 weeks of therapy, each patient will be followed for a further 12 months. Analyses from the 209 Trial will be used to coordinate our Phase III activities including determining the final sample size.

Trial-208 is a Phase II trial designed to evaluate the effects of three different doses of EVIZON (10 mg, 20 mg or 40 mg) with initial concomitant Visudyne® (QLT Inc., Vancouver, Canada) treatment in 45 patients with AMD. Specifically, this study will evaluate the safety and effects of systemically administered EVIZON before and after photodynamic therapy with Visudyne. The multi-center, randomized, controlled, double-masked study also includes monthly EVIZON maintenance therapy through six months, along with an additional twelve months follow-up for each patient. Enrollment in this trial is closed.

Preliminary results of Trial-208 were reported at ARVO 2005. In the primary treatment groups (N=29) received intravenous infusions of 10, 20 or 40 mg of EVIZON in weeks 1, 2, 4 and 5 of the trial and were treated with PDT in week 3. Seventeen control subjects were treated with PDT at week 3 but received vehicle-only infusions instead of EVIZON. Monthly EVIZON or control infusions will continue through week 25, with optional PDT at weeks 15 and 27 if deemed medically necessary. One year of additional follow up will be provided to all subjects after week 25.

EVIZON with concomitant PDT was well tolerated in all subjects, with no drug-related serious adverse events reported to date by subjects involved in the study. The most common adverse events involved infusion site reactions. These events were generally mild and were distributed evenly across the EVIZON treatment groups. There were no drug-related ocular adverse events reported for subjects involved in this trial. Study eyes in subjects receiving EVIZON with concomitant PDT treatment in Trial 208 (N=28) had a mean gain of 1.5 EDTRS letters (range +16 to -17) in visual acuity at week 3 (prior to PDT) compared to baseline. Similarly, at week 3 the study eyes for subjects in the PDT control group (N=17) gained an average of 1.5 EDTRS letters (range +11 to -11). At week 9, study eyes of subjects in the EVIZON treatment groups (N=24) gained an average of 1.3 ETDRS letters (range +11 to -10), while study eyes among subjects in the PDT control group (N=15) lost an average of 0.9 EDTRS letters (range +15 to -19). Thirty-seven of the 46 subjects (80%) were diagnosed as having wet AMD in both eyes. At week 9, subjects with a fellow affected eye in the EVIZON treatment groups (N=20) on average lost 1.9 letters (range +11 to -17) compared to baseline visual acuity, while fellow affected eyes in the PDT control group experienced an average loss of 4.0 ETDRS letters (range +7 to -31). In clinical trials evaluating therapies for wet AMD, gain or loss of less than 15 letters (three lines) for an individual patient on the ETDRS chart constitutes stable vision, while gain or loss equal to or greater than 15 letters constitutes a significant improvement or loss of vision, respectively.

Trial-207 is a Phase II pharmacokinetic and safety trial that will evaluate 18 patients with AMD at three different doses of EVIZON (10 mg, 20 mg or 40 mg) over four months. In this multi-center, open-label, parallel group study, EVIZON is administered intravenously at three doses, once weekly for four weeks, and followed out to month 4 with no retreatment. Depending on their response, patients may continue to receive EVIZON as needed for up to one additional year in a separate study (MSI-1256F-211). Enrollment in this trial is closed.