Merck’s Oral PCSK9 Macrocyclic Peptide Efficiacious in Ph. IIb, Roche’s RNA Splicing Modifier Continues to Work 4 Years into Ph. III for SMA, and 9 More Molecules in Motion

Merck’s oral PCSK9 inhibitor is a surprisingly bioavailable and orally effective macrocyclic peptide with picomolar activity. It recently demonstrated significant LDL cholesterol reduction in Ph. IIb, paving the way for it to enter Ph. III later this year. 

Roche’s oral, SMN2-directed RNA splicing modifier and first molecule of its kind to be FDA-approved in 2020 has demonstrated reclaimed motor-function even at 4 years into Ph. III for SMA. This report helps to validate the long-term efficacy of this treatment for the leading genetic cause of childhood mortality, spinal muscular atrophy. 

Read our summaries for all 11 molecules in motion from the news in March 2023, including clinical trial updates and FDA filings, below. 

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oral, once-daily T-type calcium channel blocker
mixed Ph. II results + planned Ph. III for essential tremor

Despite the failure of ulixacaltamide (PRAX-944, Z944) to meet its primary endpoint (mADS score) in Ph. II (NCT05021991), Praxis Precision Medicines is moving ahead with plans for a Ph. III trial for the treatment of neuronal excitation-inhibition imbalance or essential tremor (ET). The T-type calcium channel blocker did not show a statistically significant change from baseline to day 56 in the daily living activity (mADL) score at 60 or 100 mg QD (n = 132). However, meaningful amelioration in the daily functioning of patients was observed, with nominal statistically significant improvements for the secondary endpoints of 17% PGI-C and 16% CGI-S scores, as compared to placebo. The potential activity and good tolerability/safety profile convinced Praxis to move the compound into Ph. III studies later this year (Q3-4 2023).

The mechanism of ulixacaltamide involves blocking abnormal neuronal bursts in the Cerebello-Thalamo-Cortical (CTC) region within the brain. It is currently in development for the treatment of ET, but also as a non-dopaminergic treatment for Parkinson’s disease-related involuntary rhythmic shaking. Current treatments for ET include the beta blocker propranolol (FDA approved in 1967), which has limited efficacy and poor tolerability, making it contraindicated for comorbidities that affect a significant number of the ~7 million ET patients in the US alone.

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