HOECHST-ROUSSEL's VELNACRINE NDA FILING SET FOR LATE 1992; DUPONT MOVES AHEAD WITH COGNITION ENHANCER; FDA CIRCULATING ALZHEIMER's GUIDELINES

Hoechst-Roussel is planning a late 1992 NDA filing for its first Alzheimer's drug, velnacrine maleate (Mentane), Hoechst- Roussel Pharmaceutical Clinical Neuroscience Director Michael Murphy, MD, said at an April 30 National Pharmaceutical Council press briefing on treatments for Alzheimer's disease. Velnacrine, a cholinesterase inhibitor, has been tested in over 1,000 patients in 70 centers nationwide, Murphy reported, and is currently in Phase III studies. "Our target for submission to the FDA is December 1992 for an NDA," he said. In Phase II, velnacrine demonstrated some efficacy in patients; however, Murphy noted that "the magnitude of the effect is clinically uncertain." Like Warner-Lambert's Cognex (tacrine), there is an effect in about 40% of the patients and "maybe 15% have a clinically important change." Also like tacrine, the major side effect of velnacrine is hepatotoxicity. Hoechst's Phase III trials will address whether velnacrine has a persistent effect over time, Murphy noted. Persistence of effect was an issue raised at the March 15 FDA Peripheral & CNS Drugs Advisory Committee meeting that examined Cognex ("The Pink Sheet" March 25, p. 4). Hoechst is also testing a simple way to determine which patients will benefit most from velnacrine therapy: patients who show a large drop in blood pressure when their systolic/diastolic measures are taken are less likely to respond to velnacrine. Non-objective measures also are being studied for inclusion in the velnacrine data packet. Hoechst will collect data on quality of life as measured by the amount of time Alzheimer's patients spend in nursing homes and under medical care. Improvements in the quality of life for Alzheimer's patient caregivers also will be examined. Many on the panel assembled by NPC, including Hoechst's Murphy, agreed that cholinomimetic therapies such as tacrine (Warner-Lambert's Cognex) and velnacrine are simply "transitional" agents that may have minimal effects in select patients and do not affect the pathology of Alzheimer's. "We need to buy time while we in industry and the academic community make some of the breakthroughs in understanding the etiology of the disease process," Dupont Merck Central Nervous System Disease Research Director Errol de Souza, PhD, commented. "Clearly now all we have is symptomatic treatment. What we are doing is attempting to keep the patient in the home a little longer before they move to the nursing home." In spite of the difficulty in showing significant patient improvements with the lead drugs, FDA appears to be pushing for clinically meaningful effects in Alzheimer's drug development. The agency is reportedly circulating a draft of guidelines for the development of Alzheimer's drugs that emphasizes global improvement of the patient in addition to improvements in the performance-based Alzheimer's Disease Assessment Scale (ADAS). The guidelines reportedly also require clinical trials to follow 300 patients or more for at least six months. Among those companies working on Alzheimer's therapies, Dupont Merck appears to be the most advanced in the development of a second generation product. Such drugs as the company's DUP 996 not only enhance the activity of acetylcholine in the brain but also act on other neurotransmitter systems. DUP 996 is nearing the end of Phase II trials, de Souza reported. "The drug has a good range of efficacious doses [and] a good safety range in animals as well as in humans." DUP 996, "both in rodents and in primates, as well as humans, shows an [electroencephalogram] profile of vigilance," de Souza noted. While DUP 996 may be the first second-generation Alzheimer's therapy to reach Phase III, Hoechst-Roussel is planning an accelerated development for its cholinergic/adrenergic enhancer HP 749 that could obviate Phase III trials. HP 749 "will be the first drug that [Hoechst has] a priori decided to accelerate the development process by designing a clinical program [that answers] some clinical questions very early," Murphy told the group. By addressing the question in Phase II of whether HP 749 is modifying the course of disease progression, Murphy said, the company may "be able to leapfrog over Phase III, skip Phase III, and hopefully present the collective data to the FDA for consideration." Phase I trials with HP 749 began in September of last year ("The Pink Sheet" Oct. 15, T&G-7). In addition to its enhancement of acetylcholine, norepinephrine and serotonin activity, HP 749 "has been discovered to potentiate the effect of nerve growth factor on neurite outgrowth and cell viability," Murphy said, suggesting that the drug could retard neuron degeneration in Alzheimer's patients. Hoechst is planning large Phase II trials of long duration, beginning in the fourth quarter. Patients will be treated for six to nine months. Hoffmann-La Roche's Alzheimer's program was discussed by the company's Neurobiology and Obesity Research Director Jerry Sepinwall, PhD. The company is testing its monoamine oxidase inhibitor (MAO) moclobemide in cognition enhancement. The antidepressant, currently marketed in Europe, blocks the metabolism of norepinephrine. In early European studies, moclobemide "produced a very significant reversal of the scopolamine-induced impairment [and] seemed to have a beneficial effect on the cognitive deficits over and above any antidepressant effect it has," Sepinwall said. Roche appears to be planning to move directly into Phase II trials with the data it has on hand. "We think we are in good shape here to now move ahead to do a formal double-blind trial in Alzheimer's patients with this drug," Seppinwall said. Roche also is looking at benzodiazepine receptor agonists. Sarmazenil in Phase I trials has shown "mild signs of increased vigilance and activation" in healthy human volunteers. However, Sepinwall noted that "sarmazenil itself might not end up being the actual drug that we develop" for Alzheimer's. Warner-Lambert currently is trying to gain approval of its cholinesterase inhibitor tacrine (Cognex) following mixed results before FDA's Peripheral & CNS Drugs Advisory Committee ("The Pink Sheet" March 25, p. 4). The company has suggested that it will take a second advisory committee review to get the drug approved. FDA Commissioner Kessler recently made encouraging remarks regarding the Cognex review in a prerecorded broadcast of the PBS television magazine "Technopolitics." According to a news release by Washington, D.C. station WETA, Kessler suggested that "patients who suffer from Alzheimer's disease deserve to get drugs that work as soon as possible." FDA is "still analyzing whether [tacrine] works, what its safety is, and also what the right mechanism is," Kessler added. The program will air on May 7 at 11 p.m. on Channel 26 in the Washington, D.C. area (on different stations in other cities). In addition to tacrine, the company recently enter Phase I trials with its muscarinic agonist CI 979. In animal studies, CI 979 reversed cholinergic deficits and increased cortical arousal. Parke-Davis Cognition Neuroscience Section Director Robert Davis, PhD, said at the meeting that the company has developed a selective muscarinic agonist that acts on the cortex and hippocampus while having "limited [undesirable] effects on the gastrointestinal tract, the heart and other peripheral organs."