HOECHST-ROUSSEL’s SECOND GENERATION ALZHEIMER’s DRUG HP 749

HOECHST-ROUSSEL's SECOND GENERATION ALZHEIMER's DRUG HP 749 entered Phase I trials in mid-September, the company's Neurosciences Group Director Richard Allen, PhD, reported at an Oct. 10 "University Day" conference sponsored by parent firm Hoechst-Celanese in Warren, New Jersey. To date, patients in the study have received three doses of the agent without evidence of major toxicity. The company is planning a number of presentations on the drug at the annual meeting of the Society of Neuroscience in St. Louis, Missouri Oct. 28-Nov. 2. Hoechst-Roussel Pharmaceutical Inc. is calling the cholinergic/adrenergic compound a second generation Alzheimer's drug because it treats the major cause of the disease, acetylcholine deficiency, as well as other neurotransmitter deficiencies found in Alzheimer's patients. In preclinical trials, HP 749 was found to amplify the signals of cholinergic neurons and to increase the release of norepinephrine in the brain. HP 749 is Hoechst-Roussel's third Alzheimer's drug in clinicals after velnacrine maleate (Mentane) and suronacrine. Noting that Hoechst-Roussel currently has two other Alzheimer's drugs ready to enter the clinic and three more not far behind, Allen said: "We are in this for the long run [and] it is our objective to be the Alzheimer's company." Hoechst-Roussel's lead Alzheimer's compound, velnacrine, entered Phase III trials this summer and will be tested nationwide in 400 patients with early to middle-stage Alzheimer's disease. Those patients are receiving doses of 150-225 mg per day. Results of Phase II trials presented at the conference in 200 patients treated for 15 weeks with velnacrine showed that 40-50% of the patients experienced some response to the drug. Patients were dosed three times daily with either placebo or velnacrine for a total daily dose of 30 mg, 75 mg, 150 mg, or 225 mg. The major side effect of velnacrine treatment was liver toxicity. However, Allen maintained that in preclinical testing, overall "acute toxicity of velnacrine is anywhere from four to five times less than [Warner-Lambert's Cognex] tacrine [and that] velnacrine is clearly less toxic to liver cells than tacrine." Warner-Lambert filed an NDA for tacrine on June 4 ("The Pink Sheet" June 18, T&G-17). Allen noted that as with tacrine, "all patients do not respond [to velnacrine]." HP 749's increase of norepinepherine release, in addition to its colinergic enhancement, "is a key element in establishing that this compound should work in Alzheimer's patients beyond that subset of patients that velnacrine works in," Allen said. He added that the company feels "very certain [that HP 749] is going to be useful in patients with more advanced Alzheimer's." Allen also noted that velnacrine and HP 749 may act synergistically but that Hoechst-Roussel is currently testing them only as single agents. Hoechst-Roussel's third Alzheimer's compound, suronacrine, is currently in Phase II, but reportedly shows no clear efficacy advantage over the other Alzheimer's drugs in development.