Evaluation of the efficacy, safety and tolerability of orally administered BI 409306, a novel phosphodiesterase type 9 inhibitor, in two randomised controlled phase II studies in patients with prodromal and mild Alzheimer's disease

Abstract

Background: There are currently no approved treatments for the prodromal stage of Alzheimer's disease (AD). Approved symptomatic treatments for mild-to-moderate AD include acetylcholinesterase inhibitors and memantine, but more efficacious treatments are needed. BI 409306 is a potent and selective phosphodiesterase 9 inhibitor assessed for the symptomatic treatment of AD. Efficacy and safety of BI 409306 was analysed in two phase II proof-of-concept clinical trials in cognitive impairment associated with prodromal AD (study 1) and mild AD (study 2).

Methods: Two multicentre, double-blind, parallel-group, randomised controlled phase II studies were conducted (North America/Europe). Following study run-in, eligible subjects were randomised to one of four oral doses of BI 409306 (10-50 mg daily) or placebo (1:1:1:1:2 ratio) for 12 weeks. The primary efficacy endpoint was the change from baseline in Neuropsychological Test Battery (NTB) total z-score after 12 weeks' treatment. Secondary efficacy assessments included change from baseline in Clinical Dementia Rating scale-Sum of Boxes (CDR-SB), Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-Cog11) and Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-ADL; mild cognitive impairment [MCI] version for prodromal patients) after 12 weeks' treatment. Safety and tolerability assessments included adverse event reporting and vital sign monitoring. Change from baseline in NTB total z-score (primary endpoint) and CDR-SB were analysed using the restricted maximum likelihood-based mixed-effects model with repeated measurement. An analysis of covariance model was used to assess other secondary endpoints.

Results: Four hundred fifty-seven patients were randomised (study 1 for prodromal AD, N = 128; study 2 for mild AD, N = 329); 427 (93.4%) completed. A prespecified pooled analysis of the primary endpoint revealed no significant changes in NTB total composite z-score at week 12 in the BI 409306 treatment groups compared with placebo, with similar findings observed in the individual studies. The analysis of all secondary endpoints, including pooled analysis of CDR-SB and ADAS-Cog11, ADCS-MCI-ADL (study 1), ADCS-ADL (study 2), also gave no indication of a treatment benefit for BI 409306, compared with placebo. BI 409306 was well tolerated.

Conclusions: Overall, the data do not demonstrate efficacy of BI 409306 in improving cognition in patients with prodromal and mild AD. BI 409306 is well tolerated.

Trial registration: ClinicalTrials.gov, NCT02240693 and NCT02337907 . Registered 15 September 2014 and 09 January 2015, respectively.

Keywords: Alzheimer’s disease; Neuropsychological test battery; Phosphodiesterase type 9 inhibitor; Prodromal stage; Safety; Treatment efficacy.

Conflict of interest statement

Ethics approval and consent to participate

Both studies were approved by their respective institutional review board/independent ethics committee and the competent authorities as per national and international regulations (Study 1: Medizinische Ethikkommission II der Medizinischen Fakultät Mannhein, Germany; Study 2: CPP Ile -de-France X, Hôpital Robert Ballanger, France), and conducted in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Guideline for Good Clinical Practice and local legislation, as per the principles of the Declaration of Helsinki [16, 17].

Consent for publication

Not applicable.

Competing interests

LF has previously received grants from Novartis, Piramal, Merz Pharma GmbH and Janssen-Cilag GmbH and has also received personal fees from AstraZeneca, Avraham Pharma, Axon Neuroscience, Baxter, Biogen, Boehringer Ingelheim, Eisai, Eli Lilly & Co, GE Healthcare, Janssen-Cilag, Lundbeck A/S, Merck Sharp and Dohme, Novartis, Nutricia, Pfizer, Pharnext, PharmatrophiX, Piramal, Schering-Plough and Takeda. CT and MR are employees of Boehringer Ingelheim International GmbH. GW is an employee of Boehringer Ingelheim Canada Ltd. MG is an employee of Boehringer Ingelheim Pharmaceuticals Inc. BD has participated in advisory boards for Axovant, Biogen, Boehringer Ingelheim International and Lilly and has previously received grants from Merck, Pfizer and Roche.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1

Putative mode of action of phosphodiesterase type 9 inhibition by BI 409306. Ca2+, calcium; cGMP, cyclic guanosine monophosphate; GTP, guanosine triphosphate; LTP, long-term potentiation; NMDA-R, N-methyl-D-aspartate receptor; NO, nitric oxide; NOS, nitric oxide synthase; PDE9, phosphodiesterase type 9; sGC, soluble guanylate cyclase. Figure adapted from Moschetti et al. [7]

Fig. 2

Study design for prodromal and mild Alzheimer’s disease studies. All n numbers represent the planned values. BID, twice daily, QD, once daily; R, randomisation

Fig. 3

Disposition of patients. BID twice daily, QD once daily

Fig. 4

Change from baseline in mean Neuropsychological Test Battery total composite z-score by visit for individual BI 409306 doses and placebo (pooled analysis). BID, twice daily; QD, once daily; SD, standard deviation