DM-5689 (Gabapentin GR - Hot Flashes)

DM-5689 is an investigational formulation of gabapentin, an FDA-approved immediate release pharmaceutical for the treatment of partial epilepsy and management of postherpetic neuralgia (PHN). Recently published studies suggest the potential application of gabapentin for the treatment of menopausal hot flashes. Based on these findings, the company has secured exclusive rights to develop and commercialize DM-5689, an AcuForm™-enhanced formulation, for the treatment of menopausal hot flashes.

Hot flashes, also known as vasomotor symptoms, are sudden waves of heat that can start in the waist or chest and work their way to the neck and face and sometimes over the rest of the body. They are characterized by a sudden, temporary onset of body warmth, flushing and sweating. Depending on the intensity of the hot flash, some women may experience headaches, fatigue, dizziness, or heart palpitations. Each year approximately 32 million women in the United States experience menopausal hot flashes, of whom approximately 13 million seek treatment.

New Treatment Option Needed

Hormone replacement therapy (HRT) is currently the only FDA-approved single-agent therapy for the treatment of menopausal hot flashes. In 2003, prescriptions for HRT dropped dramatically following the National Institutes of Health’s decision to halt a large-scale clinical study of HRT due to preliminary results suggesting a correlation between HRT and an increase risk of breast cancer and cardiovascular disease.

DM-5689 – A Potential New Treatment Option

In the July 2006 issue of The Journal of Obstetrics and Gynecology, results were published from a small-scale clinical study that compared the efficacy of estrogen and immediate release gabapentin in the treatment of moderate to severe hot flashes. Data from the study, which was led by Sireesha Reddy, M.D., at the University of Rochester, suggest that gabapentin may be as effective as estrogen in reducing the frequency and severity of hot flashes.

DM-5689 could hold the potential to provide women suffering from menopausal hot flashes with a new treatment option that has more favorable safety profile than seen with HRT. Additionally, formulated with AcuForm™ drug delivery technology, DM-5689 could hold the potential to be efficacious and have fewer of the side effects commonly seen with immediate release formulations of gabapentin, including dizziness and daytime sleepiness.

Development Status

In June 2007, we randomized the first patient in a Phase 2 double-blind, placebo-controlled, multi-center trial evaluating DM-5689 for the treatment of women with moderate-to-severe menopausal hot flashes. The 124 patient study was fully enrolled in September 2007.

The study included 124 menopausal women (approximately 30 per group) with recurrent, moderate to severe hot flashes and was conducted at eight sites in the United States. The total study treatment duration after screening and baseline was 13 weeks. The primary objective of the study was to investigate the relationship between blood plasma concentrations of gabapentin observed in menopausal women after administration of DM-5689 and the frequency of hot flashes in those women. The plasma concentration data (pharmacokinetics) and the hot flash frequency and severity data (pharmacodynamics) will be used to construct a PK/PD dose response model designed to identify the dosing regimen to utilize in a Phase 3 program. The dose response model is expected to be presented to the FDA at an end of Phase 2 meeting in 2008.

In order to facilitate the generation of an optimal dose response model, patients in each of the three active treatment arms remained on a stable DM-5689 dose for five weeks at an initial dose, followed by five weeks on a stable, incrementally higher dose, as follows.

Efficacy. DM-5689 demonstrated a reduction in the mean frequency of moderate to severe hot flashes, and in the mean severity of hot flashes, in all active treatment groups, with statistical significance relative to placebo from baseline to the end of the study observed in the 1800mg and 2400mg treatment groups. The severity of hot flashes is based on a mean daily composite score, where the a moderate hot flash is assigned a score of “2” and a severe hot flash is assigned a score of “3”. The primary efficacy outcomes observed in the study are set forth in the table below.

Mean Daily Frequency (#)

 Mean Daily Severity Score

Safety. DM-5689 was generally well tolerated in the study, with one, two, one and three patients, respectively, withdrawing due to adverse events from the placebo, 1800mg, 2400mg and 3000mg groups. The most common side effects observed in the study were headache, somnolence, dizziness and nausea. The incidence of those side effects in each of the treatment groups is set forth in the table below.

Next Steps

Phase 3 Registration Program. In June 2008, we held an end-of-Phase 2 meeting with the FDA regarding our proposed Phase 3 registration program for DM-5689 in menopausal hot flashes, after which we finalized the design of the program. The Phase 3 registration program will include two randomized, double-blind, placebo-controlled studies of approximately 540 patients per study. In each study, patients will be randomized into three treatment arms: (i) placebo; (ii) 1200mg of DM-5689 dosed once daily; or (iii) a total dose of 1800mg of DM-5689 dosed 600mg in the morning and 1200mg in the evening. The treatment duration in one of the studies will be three months. The treatment duration in the other study will be six months, in order to assess safety and persistence of efficacy.

The primary efficacy endpoints in both studies will be reductions in the mean frequency of moderate to severe hot flashes, and the average severity of hot flashes, in both cases after four weeks and twelve weeks of stable treatment. Various secondary efficacy endpoints will be measured as well.