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Executive Summary

Hoffmann-La Roche's moclobemide second generation MAO-A inhibitor moclobemide (Aurorix) is an outlicense candidate in the U.S. market. The selective, reversible monoamine oxidase inhibitor (RO-11-1163) is approved in Sweden, Switzerland and Brazil and has been studied in an unpublished Phase II study in the U.S., according to Roche. The compound is one of a class of MAO-A inhibitors which have been developed over the past decade to correct the tight dietary (tyramine restrictions) requirements associated with the first generation MAO-A inhibitors. The Roche compound was cited at a recent conference on drugs in development in the U.S. as an example of an "exciting" area of antidepressant and anti-Parkinsonian research with MAO-A and MAO-B selective inhibitors. Roche's decision to stop pursuing the compound as an in-house project presumably reflects the change in commercial prospects in the antidepressant market in the wake of the Prozac launch and the intense interest in serotonin reuptake inhibitors. Lilly's success in the market diminishes the potential for second generation versions of previous therapies. Despite the rush of attention to 5HT inhibitors, Jay Amsterdam, of the Depression Research Unit of the Hospital of the University of Pennsylvania, expressed interest in the recent MAO research at a May 14 conference on the NDA pipeline. Amsterdam said that there may be a renewed place for MAO inhibitors in depression treatment, especially compounds without the diet restrictions, if they are used on the right subpopulation. He noted that the recently approved Somerset/Mylan product Eldepryl is a selective MAO-B inhibitor. Approved labeling for that product indicates that it is considered less of a risk to hypertensive side-effects from tyramine consumption because it does not bind to the MAO-A in the gut. Moclobemide appears interesting in clinical work, Amsterdam said, because of a relatively rapid onset of action and the possibility of fewer diet restrictions. The May 14 conference was sponsored in Washington, D.C. by F-D-C Reports and International Business Communications, Inc. Amsterdam noted that moclobemide is "almost a selective MAO-A inhibitor; there is about 30% MAO-B inhibition." A 1985 study conducted at the Karolinska Hospital in Stockholm found that moclobemide "did not inhibit monoamine oxidase B." Commenting on the reversibility of moclobemide and the newer MAO inhibitors, Amsterdam noted the compounds are of interest "because they bind very briefly to the enzyme; and therefore, if you stop the drug, the enzyme becomes readily available usually within 24 hours so you don't have to worry nearly as much about dietary restrictions or other restrictions." "Nobody has been quite sure what to use" the MAO inhibitors for, Amsterdam observed. "The initial thought about these drugs is that they did not work in patients who had endogenous depression, but they would work in patients who were having neurotic depression or reactive depression." The MAO inhibitors actually appear to be "very, very effective in endogenous depression, if you select the right type of endogenous depression," Amsterdam contended. A patient with a history of depression which "started when they were younger [and is] characterized not by a lot of agitation but by a lot of anergia, lack of energy, rather than insomnia, hypersomnia, [and] rather than anorexia and weight loss, carbohydrate craving and weight gain." Amsterdam described the patient type for MAO treatment as "what I would call a phenotypic variant of bi-polar or manic depressive illness and these people respond wonderfully to MAO inhibitors, usually very rapidly." Patients "with classic manic depression when they get into the depressed stage" may also be appropriate for MAO inhibitor treatment, Amsterdam suggested. Those patients "often don't do very well on tricyclic antidepressants. In fact, it can make them psycho; it can make them manic." The treatment of choice in that situation Amsterdam said, "probably,...would be an MAO inhibitor; but physicians are fearful of using these drugs." In a South American comparative trial versus imipramine and placebo on 490 patients, moclobemide "appeared to be as effective as imipramine in endogenous depression, and a little less effective than imipramine in neurotic/reactive depression." The trial, published in the British Journal of Psychiatry (1989), also found that moclobemide was more tolerable than imipramine. "Tolerability was judged to be good or very good in 85% of patients taking moclobemide, 74% of patients taking imipramine and 54% of those taking placebo," according to the South American study (Versiani et al). Amsterdam noted that MAO inhibitors show a rapid onset of action. "What was interesting [in a moclobemide study] was something that I have seen in patients clinically treating them with conventional MAO inhibitors and that is that there is a much more rapid onset in many patients in therapeutic response to MAO-inhibitors than there is to tricyclic antidepressants; that usually take four-to-six weeks until they begin to work," Amsterdam said. He noted that in one clinical study, the onset of action with imipramine was 12 days; the onset of action with meclobemide was seven days. "While that five days does not seem to be very profound," Amsterdam said, "if you have proven depression and you are suicidal and you are not sleeping, it can make a big, big difference." Amsterdam focused on the Roche compound, but also noted work on May & Baker's clorgyline and Delalande's cimoxatone.

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