Shionogi is mulling over the fate of its fragile X syndrome (FXS) therapy, zatolmilast, after the drug failed to meet its primary endpoints in a duo of Phase IIb/III trials – potentially devaluing the company’s $500m takeover of the drug’s creator, Tetra Therapeutics, six years ago.
Shionogi broke this news to the FXS community through a letter later published by the FRAXA Research Foundation, which noted that zatolmilast failed to meet respective endpoints in both the adult-focused EXPERIENCE-301 (NCT05358886) and adolescent-centred EXPERIENCE-204 (NCT05163808) studies. Both trials used National Institutes of Health Toolbox Cognitive Battery cognition crystallized composite score (NIH-TCB CCC) as a primary endpoint, with measurements being taken after 13 weeks.
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Despite the double primary endpoint miss, Shionogi did note that it identified an efficacy signal through a secondary endpoint in the adult study, with patients reportedly experiencing significant improvements in language, communication and daily function, as per the FXS numerical rating scale (NRS). However, the company does not consider this outcome “conclusive”, given the trial’s primary endpoint miss. In a statement, The FRAXA Research Foundation noted that this efficacy signal alone is unlikely to win zatolmilast regulatory approval.
Shionogi reported that FXS patients generally tolerated the drug well and that operators did not observe any new safety signals in relation to treatment.
FXS is a genetic disorder caused by a mutation in the FMR1 gene, which encodes a protein linked to brain development. The disease can impact patients in different ways due to its heterogeneity, but many with the condition present with intellectual disabilities, and sensory issues are common.
Determining next steps
While the FRAXA Research Foundation views this Phase III outcome as a “considerable setback” for the zatolmilast programme, Shionogi is forging ahead with its open-label extension study (NCT05367960) on the drug, which will evaluate patients already enrolled onto the trial who have chosen to continue receiving treatment.
The Japanese pharma company will also run further exploratory analyses on the EXPERIENCE-301 and EXPERIENCE-204 results, which will help determine the zatolmilast programme’s future in FXS.
The drug, otherwise known as BPN14770, is a selective phosphodiesterase-4D (PDE4D) inhibitor. Tetra originally designed the drug to boost neuronal connectivity and synaptic plasticity by diminishing the breakdown of cyclic adenosine monophosphate (cAMP),a key secondary messenger molecule and cell growth driver.
The results of the EXPERIENCE programme represent another failure in the drug development arena for FXS. Regulators are yet to approve a medication specifically indicated for FXS. Currently, treatment options centre around symptom management through non-drug interventions like occupational, speech or physical therapy, or off-label use of symptom-managing medications such as antidepressants and antipsychotics.
Recently within the FXS space, Harmony’s cannabidiol formulation, ZYN002, failed a Phase III trial. Spinogenix’s SPG601, however, became the first drug to rescue well-established resting EEG abnormalities – suggesting a normalisation of brain function – in a Phase IIa study.
Zatolmilast’s latest data could also potentially devalue Shionogi’s merger with Tetra Therapeutics in 2020, as zatolmilast was the centrepiece of the deal at the time. However, if the drug does not make it to market in FXS, it could still hold commercial potential, as Shionogi is currently conducting trials with the asset in Alzheimer’s disease and a rare neurodevelopmental disorder called Jordan Syndrome.
