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Executive Summary

FIDIA's GM-1 GANGLIOSIDE ENHANCES SPINAL-CORD INJURY RECOVERY by improving muscle function in previously paralyzed muscle groups, according to a Phase II study of 37 patients at the University of Maryland Shock Trauma Center. The study conducted by Fred Geisler, MD/PhD, et al. and published in the June 27 New England Journal of Medicine, concluded that the results represented "a dramatic increase in neurologic function, with the majority of [the patients in the drug group] changing from paralyzed to ambulatory status." Patients in the prospective, randomized, placebo-controlled, double-blind study received either 100 mg/day I.V. of Fidia Pharmaceutical's GM-1 ganglioside (Sygen) or placebo for 18 to 32 doses, with the first dose taken within 72 hours of injury. Eighteen of the 34 patients that completed the study received the Fidia drug, with the rest receiving a placebo. Patients were followed for one year. The study measured patient neurological recovery via the Frankel scale and the ASIA motor score. The Frankel classification rates neurologic disability into five grades, with "A" signifying "no motor or sensory function clinically detectable below the level of the [spinal-cord] injury" and "E" representing "complete return of all motor and sensory function; abnormal reflexes may remain." Geigler, et al. noted that the "main limitation of the Frankel scale derives from its categorization of spinal-cord injury into five discrete groups, whereas in fact the injury and the recovery are a continuum." The study found that "the overall number of patients whose scores improved by two or more . . . grades was larger than historical data would have predicted (23.5%, or eight of 34 patients in this study compared with 4.4% in historical data)." Placebo patients more closely followed the historical pattern of improvement. In addition, the study found that seven of the eight patients who showed "considerable" neurologic improvement had received GM- 1. Among 28 patients who "had room to" improve by two or more Frankel grades, half (seven of 14) of the GM-1 group improved compared to one of 14 of the placebo group. Based on the ASIA motor score, which is the sum of scores for muscle strength measured in 20 motor groups, the GM-1 group had "a mean motor recovery of 36.9 points" from their entry into the study to the end of the one-year follow-up compared to a mean recovery of 21.6 points among placebo patients. The ASIA scale "does not indentify a unique anatomical site for the improvement," the study notes. The greater overall ASIA improvement in the GM-1 group was the result of improvements in score for these patients' muscle groups in their lower extremities, the study also notes: "the improvements in the scores for the upper extremities were similar in the two treatment groups." Twenty-three patients in the study had cervical injuries and 11 had thoracic injuries to the spinal cord. Specifically, 30.9% of the paralyzed muscle groups in the GM- 1-treated patients "(64 of 207) remained paralyzed, and 51.7% (107 of 207) recovered to regain useful-to-normal motor function." By comparison, among placebo patients, "65.5% (127 of 194) remained paralyzed, and 25.3% (49 of 194) regained useful-to-normal motor function." Commenting on the ASIA results, Geisler said: "The drug, GM-1 ganglioside, allowed paralyzed muscles to regain function instead of making weak, yet functioning, muscles stronger." In addition to the daily injections of GM-1, patients on admission also received 250 mg I.V. of the steroid methylprednisolone succinate followed by 125 mg I.V. every six hours for 72 hours. The authors note that "the results of the NASCIS [National Acute Spinal Cord Injury Study] II study (using much larger doses of methylprednisolone) were not known to us" until after the first draft of the NEJM paper was submitted. The NASCIS II trial results, published in the May 17, 1990 NEJM, showed that a bolus injection of 30 mg/kg of body weight over 15 minutes followed 45 minutes later by a maintenance dose of 5.4 mg/kg administered over the next 23 hours improves neurologic recovery in spinal-cord injury cases if initiated within eight hours of the injury. A third NASCIS study, including Upjohn's lazaroid compound tirilazad both alone and in combination with methylprednisolone, was scheduled to begin on July 1. GM-1 ganglioside is not included in that protocol. An editorial accompanying the study in the NEJM concludes that the GM-1 ganglioside treatment, "started well after the period of efficacy for methylprednisolone and used for three to four weeks, probably calls into play a different mechanism of action, which suggests the possibility of additive treatment for patients with acute spinal-cord injury." The author, Michael Walker, MD, National Institute of Neurological Disorders and Stroke, notes that the "potential cost-benefit ratios inherent in these trials [of GM-1 ganglioside and methylprednisolone] are highly favorable from both an individual and a social point of view. The cost of both drugs by modern-day standards is moderate. The toxicity and side effects are nil." Fidia is designing a larger scale, multicenter trial using GM- 1 in spinal-cord injuries. The Phase II and/or Phase III trial, which will study at least two dosage strengths, is expected to begin in September at six to eight U.S. centers and will enroll 200-400 patients. The study, is expected to last two-and-one-half years, will be monitored by an outside ethics committee, which could recommend cross-over treatment for placebo patients if GM-1 treatment results are warranted. Fidia is also planning to examine GM-1's mechanism of action, which appears to be different from that of methylprednisolone, as well as look into the possible drug interactions with the steroid. The company also plans to study GM-1's use in spinal-cord injury patients years after their injuries to see if any improvement is effected. The Walker Institute in San Francisco has filed an IND for that use. In addition, Fidia is studying GM-1 ganglioside in stroke and subarachnoid hemorrhage. Several Phase II multi-center trials for stroke are ongoing, including one in Europe and one at 12 centers in the U.S. The company expects to have results from the U.S. study in September.

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