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ZENECA’s SEROQUEL AND LILLY’s OLANZAPINE FOR SCHIZOPHRENIA SCHEDULED FOR NDA FILINGS IN 1995, PROZAC FOLLOW-ON DULOXETINE IS IN PHASE II/III CLINICALS

Executive Summary

Zeneca plans to file an NDA for Seroquel, its dibenzothiazepine product for schizophrenia, by the end of 1995, Zeneca CNS Pharmacology Principal Pharmacologist Jeffrey Goldstein, PhD, told a National Pharmaceutical Council press briefing Sept. 28 in New York City. Seroquel, developed in-house, is in Phase III "Currently, more than 500 patients have participated in clinical trials," Goldstein said. "We have an extensive Phase III clinical program which was started in mid-1993." These studies are looking at Seroquel (ICI 240,636) in the treatment of "the acute exacerbation of schizophrenia as well as in the prevention of psychotic relapse in schizophrenia outpatients," Goldstein said. Explaining Seroquel's mechanism of action, Goldstein said the dibenzothiazepine product has a high affinity for serotonin 5HT[2] receptors and a lower affinity for dopamine D[2] and dopamine D[1] receptors. The drug is active in classical tests for antipsychotic activity and is selective for the limbic system, he said. A multicenter, open-label, pilot trial of 105 hospitalized patients (73 males, 32 females) with acute psychotic symptomatology showed a "significant change in the Brief Psychiatric Rating Scale score," Goldstein told the briefing. In the study, patients were administered from 75 to 750 mg per day of Seroquel for 28 days; the dose was titrated to clinical response and tolerability. In the efficacy studies, mean reductions from baseline were significant from day seven onward for the BPRS total score, Clinical Global Impressions Severity of Illness score and the BPRS positive symptom item scores. Clinical response was observed in 36% of the patients. Laboratory tests for safety demonstrated no agranulocytosis in patients treated with Seroquel. Five patients developed reversible, asymptomatic SGPT liver enzyme levels greater than three times the upper limit of normal. Sandoz" antipsychotic drug, Clozatil (clozapine), is associated with agranulocytosis rates high enough to necessitate blood monitoring of patients. Six patients in the Seroquel open label pilot trial received treatment for extrapyramidal symptoms for a mean duration of 4.6 days. Goldstein said this showed "a low propensity for producing EPS." Lilly's anti-psychotic drug olanzapine is also scheduled for an NDA filing in 1995. Lilly Research Labs Psychopharmacology Executive Director Gary Toliefson, MD/PhD, described olanzapine as "structurally similar to clozapine in that it's a broad spectrum agent, but to date has been devoid of the hematological blood- related problems which are so commonly discussed with clozapins." Phase III trials involving more than 2,000 subjects are being conducted in 17 countries. Lilly has "completed all of our pivotal registration work with this compound and have now moved forward into a global Phase III study both in the U.S. and Europe and South Africa," Tollefson told the NPC briefing. The company is "approximately a third of the way through that trial." Blood monitoring of patients will be continued throughout the trials of olanzapine, which is being looked at in multiple formulations, Lilly said. Olanzapine's safety profile "appears to be quite favorable," Tollefson said. Lilly believes that the drug may "benefit some of the mood symptoms" of schizophrenia, a significant advance since "conventional antipsychotic drugs actually can cause post- psychotic depression," Tollefson noted. He cited possible "anxiolytic anti-anxiety activities as well" for olanzapine. Lilly has a Prozac follow-on in late stage clinical trials, Tollefson told the briefing. The anti-depressant duloxetine is in Phase II/III clinicals and is slated for a 1997 NDA filing. Lilly hopes duloxetine will improve on its currently marketed serotonin reuptake inhibitor Prozac (fluoxetine) by also inhibiting the uptake of nompinephrine. The development of duloxetine followed on that of tomoxetine, which was abandoned because it inhibited only norepinephrine uptake. In a six-week open label trial in Europe, 22 of 25 patients showed a response to duloxetine, according to the Hamilton Depression scale, and 15 of 25 had a remission. Toliefson noted that the HAM-D scores after two weeks were "what you would expect with any of the currently available antidepressants after six weeks," calling the remission results "profound." Tollefson noted that in "several hundred patients to date, we've had no serious adverse events noted...and very low discontinuation rates" in patients taking duloxetine. Lilly intends duloxetine to be taken orally once a day, to have an onset of action "ideally within the first week of treatment," and to help patients who cannot tolerate conventional antidepressants. The NPC press briefing on drugs in development to treat CNS disorders also included presentations from Hoffmann-La Roche on a now drug for Parkinson's disease, tolcapone (RO 40-7592), and from the Syntex/Synergen joint venture on its ciliary-derived nourotrophic factor for Lou Gehrig's disease and nerve growth factor for Alzheimer's. Roche's tolcapone inhibits catechol-O-methyltransferase (COMT), the enzyme which converts DOPA, the precursor of dopamine, into 3-OMD, Roche Preclinical CNS Research Director Jerry Sepinwall, PhD, told the briefing. The inhibition of COMT allows significantly higher levels of DOPA to enter the brain, Sepinwall said. Tolcapone is now in clinical trials. In March 1992, FDA requested more toxicology data before allowing Phase II trials to begin. Roche said then that it was preparing the necessary data and expected to be allowed to start Phase II trials by the end of 1992 ("The Pink Sheet" March 30, 1992, p. 9). An earlier Roche drug, Madopar (levadopa) has limited efficacy for Parkinson's because of "the induction of on-off effects... the end of the dose wearing off [and] dyskinesias," Sepinwall explained. Roche hopes that by inhibiting COMT, tolcapone will eliminate these "fluctuating responses." The Syntex/Synergen CNS joint venture has CNTF in Phase II/III pivotal clinical trials, with drug treatment beginning in August, Syntex Discovery Research VP and Director of Pharmacology Richard Eglen, PhD, said. CNTF will be used to treat amyotrophic lateral sclerosis (ALS). In March, Regeneron Chairman Leonard Schleifer announced the beginning of a pivotal Phase III trial of Regeneron's CNTF involving more than 700 patients at 30 clinical sites. He said the trial was slated for completion in mid-1994 ("The Pink Sheet" April 12, T&G-10). Enrollment for this trial is reportedly complete and the study is now taking place in 36 centers throughout the U.S. and Canada. A Phase II trial of more than 50 ALS patients did not show a statistically significant difference from the placebo at doses ranging from .5mcg/kg to 30 mcg/kg subcutaneous injections three times a week. The company decided to proceed with its Phase III trial based on the data for the patients who were given the highest dosage ("The Pink Sheet" Aug. 26, In Brief). In preclinical trials is the joint venture's neurotrophic growth factor (NGF) for Alzheimer's disease. Efficacy has been shown in animal models and the joint venture plans to file an IND in 1994, Eglen said. Because NGF is a large protein requiring special methods of delivery to the brain, "Syntex has formed a collaborative R&D agreement with Medtronic for...infusion pumps for proposed clinical trials," Eglen said.
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