Boehringer Shoots For Schizophrenia With PDE9 Inhibitor, Ends Alzheimer's R&D
Executive Summary
Boehringer's investigational drug, BI 409306, is the second big pharma PDE9 inhibitor to fail in Alzheimer's clinical trials; Eisai is still standing with a Phase I compound but the odds are not in its favor.
Boehringer Ingelheim GMBH has ended development of its investigational PDE9 inhibitor in Alzheimer's disease after it missed efficacy endpoints in Phase II trials. Eisai Co. Ltd. is the only developer still pursuing this mechanism of action in Alzheimer's.
Boehinger announced on Feb. 9 that BI 409306 failed to meet efficacy endpoints in Phase II clinical studies in Alzheimer's. Full data from these studies will be presented at the Alzheimer's Association International Conference (AAIC) in July this year. It's not the end of the road for the drug though: Boehringer will now focus on developing BI 409306 as a novel treatment for schizophrenia.
PDE9 Inhibitors In Development
Boehringer was not the only firm investigating a phosphodiesterase-9 (PDE9) inhibitor in Alzheimer's disease. Pfizer Inc. had been targeting this indication with its pipeline therapy PF-04447943 but suspended development of the drug in 2011 after Phase II.
Although generally safe and well-tolerated, PF-04447943 did not improve cognition in patients with mild to moderate Alzheimer's in a Phase II trial. Pfizer continues to assess to drug as a treatment for sickle cell anemia, where Phase I trials are ongoing.
With Boehringer ending development of BI 409306, Eisai is the only pharma firm with an active PDE9 inhibitor program in Alzheimer's. Eisai is expected to launch Phase II trials for its compound, E2027, in the coming months but analysts do not have high hopes for the drug. Datamonitor Healthcare analyst Sultan Khan noted that Alzheimer's treatment has seen little progression in recent years, and with the history of this drug class in the disease he expects E2027 to experience "a similar fate" to Pfizer and Boehringer's drug candidates.
New Class In Schizophrenia
BI 409306 was being explored in patients with cognitive impairment and those with memory dysfunction in schizophrenia and in Alzheimer’s disease; now Boehringer will shift all its resources for BI 409306 to the schizophrenia indication.
Datamonitor Healthcare analyst Stephanie Yip told Scrip that while BI 409306 is relatively early in development, the drug appears to be a novel prospect in schizophrenia. "As a phosphodiesterase inhibitor, BI 409306 distinctly belongs to a different drug class and this is welcomed as it potentially represents a much-needed new approach to treating schizophrenia patients."
The late-phase schizophrenia pipeline consists of atypical antipsychotics, which lack significant differentiation from treatments already available to patients. Also, the existing schizophrenia market is crowded with an abundance of atypical antipsychotics. "Critical unmet need persists for better treatment options for multiple facets of the disease," Yip said.
A Phase II placebo-controlled study to evaluate the efficacy, safety and tolerability of orally administered BI 409306 during a 28-week treatment period as adjunctive therapy to antipsychotic treatment for the prevention of relapse in patients with schizophrenia is currently recruiting participants. The trial, which launched in December 2017, is expected to enroll 387 participants. Also, a Phase II placebo-controlled study is ongoing to evaluate the efficacy, safety and tolerability of the drug during a 52-week treatment period as an early intervention in patients with attenuated psychosis syndrome. Estimated enrollment for this study is 300 patients and the trial launched in Sept. 2017.
Furthermore, Boehringer has completed enrollment for another Phase II study, which launched in 2016, that is testing BI 409306 during a 12-week treatment period in patients with schizophrenia on stable antipsychotic treatment.
"If this novel drug is successfully developed it has the potential to boast a broad label, facilitating it to target a wide pool of schizophrenia patients. However, more data is required to determine whether this drug class is amenable to the schizophrenia treatment algorithm," Yip said.
Boehringer's Next Alzheimer's Prospect
Boehringer is still active in Alzheimer's drug development despite its setback with BI 409306.
“We recognize the immense anticipation around any progress in brain research that brings us closer to finding solutions for the many millions of people living with dementia," Jan Poth, therapeutic area head, CNS and immunology, at Boehringer Ingelheim said in a statement. "However, this is what research is about: disappointments are a daily experience in science, but even these clinical trial results will add to the understanding of brain function and contribute to future progress in this area."
Boehringer plans to launch Phase II trials soon for another pipeline asset, BI 425809, a GlyT1 inhibitor. The company is testing this drug in a range of central nervous system indications which also include Alzheimer’s disease.
Khan noted that glutamate theories have yielded dividends in moderate to severe dementia with the approval of Allergan PLC's Namenda (memantine) 15 years ago, so Boehringer's BI 425809 is following a logical R&D route. "However, on the basis of BI 409306’s performance I’m more pessimistic on BI 425809’s outlook," he said. Khan did note that given its stage of development and novel mechanism of action, it is hard to fully assess the potential of BI 425809 in Alzheimer's without more data.