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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
One example is the agent branaplam (Figure 5.100) which, as of July 2019, is in Phase I/II clinical trials for the treatment of children with Spinal Muscular Atrophy, branaplam is in a Phase II clinical trial SMA type 1. This molecule, based on a pyridazine building block, enhances the inclusion of exon 7, resulting in a full length and functional protein product. It represents the first example of splicing modulation using a sequence-selective small molecule and works by stabilizing the transient double-stranded RNA (dsRNA) structure formed between the SMN2 pre-mRNA and the U1 snRNP complex, a key component of the splicesome. It also increases the binding affinity of U1 snRNP to the 5’ splice site (5’ss) in a sequence-selective manner. Structure of branaplam (showing the keto-enol tautomers) which, as of July 2019, is in Phase I/II clinical trials for the treatment of children with spinal muscular atrophy (SMA).
Therapeutic interventions for spinal muscular atrophy: preclinical and early clinical development opportunities
Published in Expert Opinion on Investigational Drugs, 2021
Laurent Servais, Giovanni Baranello, Mariacristina Scoto, Aurore Daron, Maryam Oskoui
Branaplam (previously known as LMI070) is a pyridazine derivative that interacts with SMN2 pre-mRNA and enhances exon 7 inclusion. It increases the level of functional SMN protein [46]. Branaplam is currently being evaluated in a two-part phase 1b trial in infants with SMA1 (NCT02268552). A phase 2 trial is ongoing, intermediary results on 25 patients followed up for a mean duration of 7.6 months (0.03-11.83 months) have been presented, but not yet published [24,47]. Outside of the usual adverse events reported in a SMA1 population (pneumonia, constipation…) thrombocytosis was noticed in 9/25 patients, but this was manageable and did not lead to treatment arrest. No patient died or needed permanent ventilation, and 21/25 patients remained exclusively orally fed. These data must be interpreted in the context of a short follow-up. Regarding motor function, 15/25 patients who reached 218 days presented a mean CHOP intend increase of 14 points [47].
New treatments in spinal muscular atrophy: an overview of currently available data
Published in Expert Opinion on Pharmacotherapy, 2020
Sithara Ramdas, Laurent Servais
Branaplam (previously known as LMI070) is a pyridazine derivative that interacts with SMN2 pre-mRNA and enhances exon 7 inclusion to increase the level of functional SMN protein [57,58]. Like risdiplam, branaplam is given orally. Branaplam is currently being evaluated in SMA1 infants in an open-label, two-part, phase 1/2 study (NCT02268552). Data from part 1 are difficult to interpret because the clinical trial was halted temporarily due to safety concerns stemming from the results of studies in animals. Early results of part 2 have not been published, although safety and efficacy data have been presented [59]. In an analysis of eight patients, a median improvement of 4.5 points on the CHOP INTEND was observed after 86 days of treatment, and the drug had a good safety profile. The five patients treated over 127 days had a median improvement of 7.0 points.
Discovery of RNA-targeted small molecules through the merging of experimental and computational technologies
Published in Expert Opinion on Drug Discovery, 2023
Around the same time the PTC-Roche SMN2 splicing modifiers were identified, a team at Novartis also performed phenotypic screening to identify small molecules with the ability to reduce exon 7 exclusion [115]. An NSC34 motor neuron cell line expressing an SMN2 minigene reporter was employed to screen their compound library (~1,400,000 compounds). Two active compounds – branaplam (originally NVS-SM1) and NVS-SM2 – were found to have good efficacy, bioavailability, and distribution to the brain. Branaplam is currently in a Phase 1/2 clinical trial in infants with SMA (NCT02268552) [141]. Interestingly, branaplam also promotes the inclusion of a pseudoexon in huntingtin (HTT) transcripts, thereby downregulating HTT mRNAs and protein [142].