A Phase 2 Multi–Dose Pharmacokinetic Study of MSI–1256F (Squalamine Lactate) for the Treatment of Subfoveal Choroidal Neovascularization Associated With Age–Related Macular Degeneration (AMD)

Abstract

Abstract: : Purpose: To characterize the pharmacokinetic (PK) profile and the safety/tolerability of squalamine lactate at three different doses. Methods: Men and women more than 50 years of age with a diagnosis of subfoveal choroidal neovascularization (CNV) associated with AMD (angiographic predominantly classic, minimally classic or active occult subtypes) were treated. Squalamine was infused (0.25 mg/mL concentration, 4.0 mL/min infusion rate), once a week, for 4 weeks followed by additional examinations at Month 2 and 4. PK samples were obtained at various time–points during week 1 through week 5. Patients were assigned to one of the following three parallel treatment groups (40 mg over 40 min; 20 mg over 20 min; 10 mg over 10 min) at three centers in the USA. All patients, regardless of treatment group, were withdrawn from the study if their visual acuity (VA) deteriorated ≥ 3 lines on the ETDRS chart. Both eyes were studied during the trial. Results: The mean squalamine plasma concentration for the 10 mg dose at the end of 10 min. infusion was approximately 3µg/mL and declined to below 0.1µg/mL 6–8 hours post dose. Squalamine (10 mg dose) was detectable (more than 0.01 µg/mL) at 24 hours post dose in 2 of 6 subjects. Elimination was biphasic and the disposition of squalmine did not change with repeated weekly dosing. There were no serious adverse events related to study drug reported. A small number of patients reported injection site pain, but no patients withdrew due to adverse events. Mean change from baseline VA (57.7 letters) for study eyes in patients on the 40 mg dose (n=6) was +3.8, +5.8, and +0.3 EDTRS letters at week 3 (after 2^nd dose), end of therapy (EOT) (one week after 4^th dose), and at 2 months, respectively. Mean change from baseline VA (27.3 letters) for patients with a second affected eye (n=6) was +6.7, +8.8, and +4.0 EDTRS letters at week 3, EOT, and at 2 months, respectively. Conclusions: Preliminary PK data suggest a rapid clearance of squalamine from blood with a biphasic plasma concentration–time profile that is unaffected by repeated dosing. Brief systemic exposure is associated with an excellent safety profile for squalamine lactate in AMD patients. Systemic squalamine lactate may represent a convenient potential treatment option for patients with one or both eyes affected with all subtypes of "wet" AMD.

Keywords: age-related macular degeneration • visual acuity • choroid: neovascularization