Yumanity Therapeutics announced the hold, which was in response to an investigational new drug application submitted to the FDA in December 2021.
The FDA has placed a partial clinical hold on multidose clinical trials of YTX-7739, a disease-modifying therapy for the treatment of Parkinson disease (PD), Yumanity Therapeutics recently announced. The hold was initiated in response to the company’s investigational new drug (IND) application, which was submitted in December 2021.1
The hold suspends initiation of multiple dose trials of the treatment in the US until questions from the FDA have been addressed, with Yumanity anticipating additional detail from the FDA in the next 30 days. YTX-7739 has previously been assessed in healthy patients, with results reported from 14- and 28-day multiple dosing studies, as well as in patients with PD in a 28-day multiple dose clinical study.
The treatment is designed to penetrate the blood-brain barrier (BBB), then inhibiting the activity of stearoyl-CoA desaturase (SCD), a novel target. By inhibiting SCD, YTX-7739 controls and upstream process in the α-synuclein pathological cascade, and in preclinical cellular and animal models, it has been shown to rescue or prevent toxicity, according to Yumanity.
In February 2021, the company provided updates for the lead clinical-stage therapeutic development for YTX-7739, namely the results of a single ascending dose (SAD) study, the completion of enrollment in a multiple ascending dose (MAD) study, as well as the initiation of a phase 1b study. Ultimately, the SAD study identified no safety concerns, and the treatment was considered well-tolerated. Most AEs were deemed mild or moderate in severity. In tandem with a favorable pharmacokinetic profile in the fed state, the half-life of the therapy supports the notion that low daily doses administered with food can sustain the targeted range of drug exposure.
Like the SAD study, the placebo-controlled, randomized, double-blind MAD study includes 2 cohorts of 8 healthy subjects each, randomized to treatment or placebo in a 6:2 ratio over the course of 14 to 28 days. Yumanity noted that it anticipates the reporting of the results of the MAD study by the end of Q1 2021, with detailed clinical data from the phase 1 studies in healthy volunteers with YTX-7739 planned to be presented at a future medical conference.2
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“YTX-7739 is a novel small molecule SCD inhibitor, which can be administered orally and was shown to be brain penetrant in preclinical models. We have completed the SAD study in healthy volunteers, which provides early evidence of the drug candidate’s safety and tolerability profile,” Brigitte Robertson, MD, chief medical officer of Yumanity Therapeutics at the time, said in a statement.2
In November 2021, positive topline results from the phase 1b trial were announced, along with plans to advance the program into phase 2. YTX-7739 demonstrated target engagement in patients with mild-to-moderate PD and was found to be generally well tolerated with favorable pharmacokinetic and pharmacodynamic profiles, which were consistent with previous studies. The investigational Parkinson disease agent further demonstrated a favorable safety profile with no serious adverse events reported.3
AEs were mild to moderate in severity, and those reported in the treatment group included increased PD symptoms (n = 2), lower back pain (n = 2), headache (n = 1), myalgia (n = 1), insomnia (n = 1), ligament sprain (n = 1), and vaccination complication (n = 1). In the placebo group, 1 patient reported moderate worsening of tremors and Parkinsonism, discontinuing the trial. Compared to placebo, procedural pain, myalgia, dry eye, hyperbilirubinemia, hypesthesia, lower back pain, and constipations comprised AEs occurred at a higher percentage in 2 or more patients administered YTX-7739, when compared with placebo. Orthostatic hypotension, headache, tremor, fatigue, and dizziness occurred at a higher percentage with placebo.
Following 28 days of treatment, the once-daily 20-mg dose showed a reduction in fatty acid desaturation index by approximate 20-40%. Additionally, the treatment was though to effectively cross the BBB, as shown by target engagement in the cerebrospinal fluid. No statistically significant differences were observed in clinical assessments, including the Unified Parkinson Disease Rating Scale 3 and the Montreal Cognitive Assessment, or most exploratory biomarkers.