Abstract| Volume 27, SUPPLEMENT 2, S207-S208, October 2017

Safety and efficacy findings in the first-in-human trial (FIH) of the oral splice modulator branaplam in type 1 spinal muscular atrophy (SMA): interim results

      LMI070X2201 is an open-label, multi-part, FIH study of oral branaplam (formerly LMI070) in infants with Type 1 spinal muscular atrophy with 2 SMN copies. The purpose of Part 1 of this study was to evaluate the safety, tolerability, PK, PD and efficacy after 13 weeks of treatment and to estimate the Maximum Tolerated Dose and optimal dosing regimen of enterally administered branaplam in patients with Type 1 SMA. Treatment extensions are allowed after the initial 13-week treatment period. Safety, PK, PD and efficacy outcomes were collected for an additional 13 months following completion of the initial treatment period. 14 patients enrolled in the trial. One patient failed screening. 13 patients were treated with branaplam. All continued into treatment extension period. Five patients have died during the course of the trial from disease progression as assessed by the investigators and the Data Monitoring Committee. 8 patients continue on branaplam for 16 -23 months, with patient ages ranging from 19 to 26 months. No MTD has been reached; the emerging safety profile of branaplam shows adverse events that are mostly mild, reversible and manageable. A preclinical study suggested a mechanistic understanding of the findings of axonal degeneration seen in a chronic dog toxicology study. Pharmacokinetic data show significant exposure with once weekly dosing. Improvements in CHOP INTEND, HINE and preservation of oral feeding and breathing without mechanical support were noted in some patients. Loss of motor function was noted in several patients following lowering the dose precipitated by preclinical toxicology findings in dogs. Partial recovery of motor functions has occurred in some patients following resumption to previous dose. Transition to oral administration has been successful. An interim analysis after a minimum of 14 months on treatment for safety, PD and efficacy is being conducted. Results in this ongoing open label FIH study support continued study of branaplam in SMA Type 1.
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