Background

BPN14770 is an allosteric inhibitor of phosphodiesterase 4D (PDE4D), a regulator of the intracellular second messenger cAMP in neurons. Inhibitors of PDE4D raise cAMP levels, which has been reported to support cognition and protect neurons. BPN14770 targets the same pathway as do acetyl cholinesterase inhibitors such as donepezil, but at a different point.

Allosteric PDE4D inhibitors reportedly are less likely to induce vomiting, a dose-limiting side effect of active-site PDE4D inhibitors (Burgin et al., 2010; Jan 2011 news).

In preclinical work, BPN14770 has been tested in a mouse line expressing a humanized PDE4D sequence. This was necessary because BPN14770 binds to a primate-specific, N-terminal region of PDE4D (Gurney et al., 2019). In these mice, BPN14770 enhanced brain cAMP, hippocampal long-term potentiation, and performance in a novel-object-recognition test. BPN14770 antagonized the amnestic effect of the anti-nausea drug scopolamine, whereby two weeks’ dosing boosted hippocampal phospho-CREB and BDNF, markers of memory consolidation. A subsequent study implicated cAMP-PKA-SIRT1-Akt -Bcl-2/Bax signaling in BPN14770's anti-scopolamine effect in these mice (Zhang et al., 2018; Wang et al, 2020). In the same mouse line, bilateral Aβ42 injection into the hippocampi induced memory deficits and synapse damage that was prevented by BPN14770. Two weeks’ dosing resulted in elevation of brain BDNF levels (Cui et al., 2019). 

The drug also improved behavioral readouts in a mouse model of Fragile X syndrome (Gurney et al., 2017).

Findings

In 2015 and 2016, Tetra ran two Phase 1 trials evaluating single and multiple oral doses of BPN14770 in 109 healthy adults, including elderly participants. Single doses up to 100 mg were well tolerated and produced linear pharmacokinetics. Higher doses caused transient nausea. In 45 aged volunteers taking 10, 20, or 40 mg twice daily for seven days, headaches were the most common side effect. The 40 mg group showed a decline in cognition. The combined 10 and 20 mg dose groups posted an improvement on the One Card Back working memory test compared to placebo, which appeared after first treatment and continued through the week of dosing (Dec 2016 press release; Dec 2017 conference news).

In January 2017, a Phase 1 trial began testing in 38 healthy volunteers whether a single dose of BPN14770 reverses cognitive impairment induced by scopolamine. The crossover design compared 10 and 50 mg dosing to 10 mg donepezil or placebo; each participant served as his or her own control. The trial ended in June 2017. No results have been presented. 

In April 2019, the company started PICASSO, a Phase 2 study in Alzheimer’s disease conducted at 60 sites in the U.S. The trial enrolled 255 participants with clinically diagnosed early AD who were on a stable dose of a cholinesterase inhibitor but not memantine. Proof of amyloid positivity was not required. They were randomized to 10 or 25 mg BPN14770 or placebo twice daily for three months. The primary outcome was change from baseline in the Repeatable Battery for the Assessment of Neurological Status-Delayed Memory Index; secondary outcomes were RBANS total score and other standard measures of memory, cognition, and function, including the ADCS-ADL, MMSE, CDR-SB, and CGI-I. The trial ended in February 2020.

In December 2018, Tetra started a collaboration with Shionogi Pharma to develop BPN14770 for AD, and in January 2020, Shionogi began evaluating single and multiple doses in 112 healthy adults and elderly in a Phase 1 study in Japan. Outcomes are safety and pharmacokinetics, including food effects and drug-drug interactions with midazolam and donepezil.

In May 2020, Shionogi bought Tetra Therapeutics, while also disclosing that PICASSO had missed its primary endpoint. There had been no significant change in the RBANS-D2MI with treatment; however, a subgroup analysis of patients in the 25 mg group with above-median CDR-SB scores at baseline indicated a signal for improvement on the CDR-SB. No safety issues were observed. The results warrant further development of BPN14770, according to Shionogi (see press release).

BPN14770 is also being tested with an orphan drug designation to treat Fragile X. Between July 2018 and July 2020, a Phase 2 trial at Rush University Medical Center compared 25 mg twice daily to placebo for 12 weeks in a crossover design in 30 men with the condition. The primary outcome was safety and tolerability; secondary measures included the computerized cognitive tests, and clinician and caregiver ratings of symptom severity and daily function. The trial met its primary outcome of safety and tolerability. All participants completed the study, with no adverse events attributed to drug. Participants were reported to have improved on secondary measures, including cognitive tests related to language, and caregiver ratings of language and daily function. The benefit was maintained up to 12 weeks after dosing stopped (Berry-Kravis et al., 2021).

The company is developing PET ligands to PDE4D. Two ligands were tested in primates. Specific binding was highest in prefrontal and temporal cortex and hippocampus, and was displaced by BPN14770. The radiolabeled ligand T1650 was tested in three people with depression but proved unstable (Wakabayashi et al., 2020); the ligand T2310 is being evaluated in a Phase 1 study that began in January 2020 at Weill Cornell College of Medicine, New York. 

For details on BPN14770 trials, see clinicaltrials.gov.