Some analysis of Lumateperone

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This is in an investment newsletter, but there’s still some good analysis.

Notes from a KOL call discussing the potential of Lumateperone in schizophrenia
(academic center psychiatrist in the Northeastern U.S., expertise in schizophrenia) organized by Slingshot Insights. The KOL considered Lumateperone to be so far the safest antipsychotic drug that he has seen so far when compared to the currently approved antipsychotic agents. He considered its slight somnolent property as good for dosing it at night (many schizophrenia patients have insomnia and sedative drugs like Seroquel are used commonly). He also pointed out certain issues in the failed second phase 3 study, for example, patients who did not tolerate risperidone due to side effects may have dropped out and not included in the analysis. He also agreed with higher than expected placebo effect in the study. He was convinced about the antipsychotic efficacy of lumateperone based on the maintenance of schizophrenia symptoms control when patients were switched from the standard of care antipsychotic agents. He also was excited about the lower side effect profile of lumateperone (since it is the only antipsychotic agent with D2 presynaptic partial agonist and postsynaptic antagonist properties). He also expressed excitement about the effects of Lumateperone in improving depressive symptoms (by serotonin reuptake inhibition), and negative symptoms of schizophrenia (due to only 40% postsynaptic dopamine blockade and pro-glutamatergic action) which could be another differentiator. He was not very optimistic about cariprazine (the only drug approved to treat negative symptoms of schizophrenia) due to its side effects like extrapyramidal symptoms and akathisia.

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Except it’s not.

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And on bipolar results

Higher than expected placebo response is a common problem in bipolar depression clinical trials. This paper also mentioned that high placebo response in BPD clinical trials is seen in patients with mild disease, bipolar II, mixed-episode, first-episode, rapid cycling, atypical, non-psychotic, substance abusers and medically ill. Other factors like female sex, older age, the use of concomitant medication like benzodiazepines, a high frequency of visits, a high number of treatment groups and sites, fixed-dose designs, and the concomitant use of psychotherapy also may increase placebo response. It’s possible that a difference in these characteristics between the two studies may have contributed to the different outcomes. Another explanation for the different results of the two trials could be a difference in the treatment approaches for BPD in the U.S. and outside the U.S. The management will announce more data from these trials, including subgroups analysis in the near future which may help to shed more light on the reasons for high placebo response in study 401.

In the conference call announcing the BPD data on July 8, the management expressed their excitement about the robust data in study 404, mentioned that drug’s pharmacology worked just as they expected and also mentioned that the study 404 results support developing Lumateperone to treat other depressive disorders like major depression. They also stated that about 50% of BPD trials fail even if the drug is efficacious. High placebo response in study 401 also could be due to more treatment arms (3 treatment arms vs two in study 404), which causes a bias, study 401 also had more severe depression at the baseline (measured by MADRS score) compared to study 404. Additional data like responder analysis from both studies and CGI endpoint data from study 401 will be released at a future medical meeting.

Moreover, there’s an unmet need for newer drugs to treat bipolar type 2 disorder since most drugs currently being used to treat bipolar type 2 (lithium, valproate, lamotrigine, seroquel, latuda, etc.) are in fact approved for bipolar type 1, and thus are used off-label and also are associated with side effects. Lumateperone was successful in study 404 in BPD type 2 subgroup as well, so it could be a new treatment option for these patients. The management plans to approach FDA with the results of both studies 404 and 401 to discuss further plans for lumateperone’s approval and will not wait for results of the phase 3 study 402 (lumateperone as an adjunct therapy to lithium or valproate in BPD, data in 2020). With industry veterans like Dr. Olchaskey as head of regulatory affairs (over 20 years of global regulatory affairs experience, including senior regulatory affairs positions at Allergan (NYSE:AGN)) and their past success in negotiating the NDA approval for lumateperone in schizophrenia indication (in a similar mixed results situation), I’m leaning toward a favorable outcome of BPD related discussions with FDA.

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I didn’t write that though. Whoever wrote the article probably misunderstood what the psychiatrist said about cariprazine.

Edit: it is written by a stock analyst, not a psychiatrist.

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