branaplam (LMI070) / Novartis - LARVOL DELTA

Insights into the human pharmacokinetics and metabolism of branaplam, a splicing modulator of a survival motor neuron-2 and huntingtin pre-mRNAs, in infants and adults. (PubMed, Drug Metab Dispos) - "SIGNIFICANCE STATEMENT: This study provides a comprehensive overview of the metabolism of the tetramethyl piperidine moiety, contextualizing enzyme maturation by comparing metabolic fates in infants and adults. It also clearly explains human metabolism of branaplam and summarizes a rare Adenosine Triphosphate pathway observed in these studies."

Journal • PK/PD data • Genetic Disorders • Movement Disorders • Muscular Atrophy • Pediatrics • Rare Diseases • CYP3A4

An orthogonal TRAP enables intersectional genetic access to activated neurons in the mouse brain. (PubMed, bioRxiv) - "Here we describe an approach (X-TRAP) in which the activity-dependent expression of Flp recombinase is gated by branaplam, a small molecule that triggers splicing of the X-ON switch...We apply this strategy to map neural circuits that control food intake. This approach for intersectional, activity-dependent genetic labeling should enhance our ability to identify the neural correlates of behavior."

Journal • Preclinical

Oral splicing modulator branaplam in Huntington's disease: a phase 2 randomized controlled trial. (PubMed, Nat Med) - P2 | "Increased neurofilament light chain levels observed in most participants reversed after treatment discontinuation. ClinicalTrials.gov identifier: NCT05111249."

Journal • P2 data • CNS Disorders • Huntington's Disease • Movement Disorders • Pain • NEFL

Oral splicing modulator branaplam in Huntington’s disease: a phase 2 randomized controlled trial (Nature) - "Of the 21 participants in the initial cohort receiving branaplam 56 mg weekly, 18 (85.7%) showed at least one sign or symptom of peripheral neuropathy. This safety signal, along with dose-modeling results triggered the early termination of VIBRANT-HD. The primary outcome, a decrease in cerebrospinal fluid mutant HTT levels versus placebo, was summarized descriptively, making branaplam the first splicing modulator to lower mutant HTT levels in the cerebrospinal fluid of individuals with HD....The results of the initial NHP study, including cynomolgus monkeys (n = 12; all males) dosed with branaplam 0, 0.6, 3.0 or 6.0 mg kg−1 twice a week for a total of 6 weeks, demonstrated increased serum and CSF NfL levels at the end of treatment."

P2 data • Preclinical • Huntington's Disease

Chemically-inducible CRISPR/Cas9 circuits for ultra-high dynamic range gene perturbation. (PubMed, Nat Commun) - "As an alternative to Tet-mediated induction, we have created a Branaplam-regulated splice switch module for low-baseline and robust Cas9 activity control. Lastly, for circumstances where DNA damage needs to be avoided, we have constructed a dual-control, Tet-inducible CRISPRi module for tight and potent transcriptional silencing. This upgraded suite of inducible CRISPR systems has broad applications for numerous cell types and experimental conditions."

Journal

AI-driven platform voyager identifies a novel poison exon and splicing modulator to target specific degradation of STAT1 (ASH 2025) - "To discover potential PEs that regulate hematopoiesis, weemployed a pharmacogenomic screen in human HUDEP erythroid precursors to identify genessusceptible to alternative splicing induced degradation using branaplam (BRN)...SRE109 blocks IFN-ginduced transcriptomic and cytokine responses in models of benign erythropoiesis, MyeloproliferativeNeoplasms and Acute Myelogenous Leukemia.These data illustrate how this new AI-driven platform VoyageR has the potential to identify newmechanisms by which hematopoiesis is regulated and identification of compounds that modulate thesepathways. Here, we provide evidence for a novel therapeutic strategy and several candidate therapeuticagents to downregulate STAT1-driven processes through targeted splicing modulators to direct geneexpression."

Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Myeloproliferative Neoplasm • STAT1 • STAT3

An orthogonal TRAP for intersectional labeling of activated neurons in the mouse brain (Neuroscience 2025) - "Here we describe an orthogonal system (X-TRAP) in which the activity-dependent expression of Flp recombinase is gated by branaplam, a small molecule that triggers splicing of the X-ON switch...By combining the X-TRAP and TRAP2 alleles in the same mouse, it is possible to label cells with Cre and Flp recombination triggered by two different stimuli, and we apply this strategy to map neural circuits that control food intake. This approach for intersectional, activity-dependent labeling should enhance our ability to identify the neural correlates of behavior."

Preclinical • CNS Disorders

In vitro and in vivo comparison of three small molecule splicing modulators: Branaplam, PTC-518 and CHDI-113 (Neuroscience 2025) - "When orally dosed for 21 days BACHD mice, Branaplam showed the greatest peripheral tissue HTT lowering (compared to PTC-518 and CHDI-113) at doses resulting in 50% CNS mHTT lowering. The therapeutic Index (defined as the ratio of highest doses tolerated vs dose required to reach 50% mHTT lowering in CNS) was similar and very narrow (2-fold) for all three compounds"

Preclinical • CNS Disorders • Movement Disorders • FOXM1

Gene therapy CM-YAPon protects the mouse heart from myocardial infarction. (PubMed, Nat Cardiovasc Res) - "Here we develop an adeno-associated virus 9-based therapy, termed CM-YAPon, which enables transient expression of an active YAP variant (YAP5SA) in CMs after exposure to the small molecule LMI070...YAP5SA induction after MI rapidly improves cardiac function while pre-MI induction confers cardioprotection and reduces cell death across multiple cardiac cell types. These findings reveal the therapeutic potential of reversible gene activation for ischemic heart disease."

Journal • Preclinical • Cardiovascular • Coronary Artery Disease • Gene Therapies • Heart Failure • Myocardial Infarction

Towards a novel, regulatable pharmaco-genetic treatment for Anti-Neutrophil Cytoplasmic Antibody (ANCA)-vasculitis using AAV vector encoding DNaseI. (ESGCT 2024) - "A “molecular switch” (Xon, Montey et al, Nature, 2021) was integrated between the liver-specific promoter and the human DNaseI (hDNaseI) coding sequence to permit the induction of transgene expression via oral administration of a small molecule (Branaplam)...Differences across genders were reduced and activity levels enhanced by fusion of the vDNaseI with three modules of Carboxyl Terminal Peptide derived from human gonadotropin, which increases enzyme half-life, leading to ∼1200-fold and 630-fold higher enzyme activity in male and female mice, respectively. Further studies are in progress to determine the therapeutic efficacy of pharmacologically regulated DNaseI expression in the ANCA-vasculitis model."

ANCA Vasculitis • Gene Therapies • Glomerulonephritis • Infectious Disease • Lupus Nephritis • Nephrology • Renal Disease • Vasculitis

The U1 snRNP protein U1C and Helix H of U1 snRNA are critical for small molecule splicing modulator function. (PubMed, bioRxiv) - "Risdiplam and branaplam represent two classes of small-molecule splicing modulators that promote U1 snRNP recognition of weak non-canonical GA/GU-containing 5' splice sites (ss). Interestingly, a subset of cassette exons became responsive to compound only upon U1C knockdown, supporting a model in which U1C stabilizes specific conformations at the 5' ss/U1 snRNA interface in a context-dependent manner that can either facilitate or hinder compound binding. Surprisingly, risdiplam shows no effect on weak 5' ss recognition in vitro, suggesting additional cellular factors are required for its activity."

Journal

DIFFICULTIES OF EATING AND MASTICATING SOLID FOOD IN CHIDREN WITH SPINAL MUSCULAR ATROPHY – PRELIMINARY STUDY (ESPGHAN 2025) - "Methods We investigated 17 children with SMA (aged 7; 5 ± 2; 11), treated with various medications: nusinersen (n=13), risdiplam (n=4), branaplam (n=2), and onasemnogene (n=5)...Conclusions Difficulties with oral feeding still can affect patients with SMA, despite the treatment. Weakened tongue muscle strength can results in reduce effectiveness in eating solid foods."

Genetic Disorders • Infectious Disease • Movement Disorders • Muscular Atrophy • Pneumonia • Rare Diseases • Respiratory Diseases

RNA splicing modulator for Huntington's disease treatment induces peripheral neuropathy. (PubMed, iScience) - "These compounds hold promise for treating neurodegenerative disorders, including branaplam for lowering huntingtin levels in Huntington's disease...These findings illustrate the complex pharmacology of RNA splicing modulators with a small therapeutic window between lowering huntingtin levels and the clinically relevant off-target effect of neuropathy. Comprehensive toxicological screening in human stem cell models can complement pre-clinical testing before advancing RNA-targeting drugs to clinical trials."

Journal • CNS Disorders • Huntington's Disease • Movement Disorders • Pain • BBC3 • NEFL • TP53

Spinal Muscular Atrophy: Current Medications and Re-purposed Drugs. (PubMed, Cell Mol Neurobiol) - "This review explores the repurposed drugs that have shown some improvement in treating SMA, including branaplam, riluzole, olesoxime, harmine, and prednisolone. The current strategy for medication repurposing, however, lacks systematicity and frequently depends more on serendipitous discoveries than on organized approaches. To speed up the development of successful therapeutic interventions, it is apparent that a methodical approach targeting the molecular origins of SMA is strictly required."

Journal • Review • CNS Disorders • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases

VIBRANT-HD: A Dose Range Finding Study With Open-Label Extension to Evaluate the Safety of Oral LMI070/Branaplam in Early Manifest Huntington's Disease (clinicaltrials.gov) - P2 | N=26 | Terminated | Sponsor: Novartis Pharmaceuticals | Completed ➔ Terminated; The trial was halted prematurely due to signs and symptoms that suggested the possibility of peripheral neuropathy. All participants who received branaplam continued to undergo routine (safety) evaluations for up to a year following their final dose

Trial termination • Genetic Disorders • Huntington's Disease • Movement Disorders • NEFL

A sequential binding mechanism for 5' splice site recognition and modulation for the human U1 snRNP. (PubMed, Nat Commun) - "Drugs like risdiplam and branaplam change how human U1 snRNP recognizes particular 5' splice sites (5'SS) and promote U1 snRNP binding and splicing at these locations. Obligate orders of binding and unbinding explain how reversible branaplam interactions cause formation of long-lived U1 snRNP/5'SS complexes. Branaplam targets a ribonucleoprotein, not only an RNA duplex, and its action depends on fundamental properties of 5'SS recognition."

Journal

A compact, versatile drug-induced splicing switch system with minimal background expression. (PubMed, Cell Rep Methods) - "Here, we developed a compact drug-induced splicing system that maintains low background using a human ubiquitin C (hUBC) promoter and optimized drug (LMI070) binding sequences based on the Xon switch system...Furthermore, miniXon2G could be integrated into endogenous gene loci, resulting in precise, reversible regulation of target genes by both endogenous regulators and drugs. Overall, these findings highlight the performance of miniXon2G in controlling protein expression with great potential for general applicability to diverse biological scenarios requiring precise and delicate regulation."

Journal • Targeted Protein Degradation • UBC

Use of under-appreciated intramolecular sulfur-halogen interactions in the design of SMN2 splicing modulators (ACS-Fall 2024) - "Branaplam elevates levels of full-length SMN protein in vivo by modulating splicing of the related gene SMN2 to enhance exon-7 inclusion and increase levels of SMN...The resulting intramolecular chalcogen-bonding interaction is orthogonal to the more common “halogen bond” and with reversed polarity. Our optimization of a series of 2-halophenyl-1,3,4-thiadiazole SMN2 splicing modulators demonstrates that sulfur-halogen conformational constraints can provide an attractive alternative to intramolecular hydrogen-bonding and sulfur-oxygen interactions."

CNS Disorders • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases • SMA4 • SMN1

Engineered Branaplam Aptamers Exploit Structural Elements from Natural Riboswitches. (PubMed, ACS Chem Biol) - "A resulting variant retains the pseudoknot and two of the paired elements (P2 and P3) from the scaffold but lacks the enclosing paired element (P1) that is essential for the function of the natural Guanine-I riboswitch aptamer. A second combinatorial RNA pool based on the scaffold for TPP (thiamin pyrophosphate) riboswitches also yielded a candidate offering additional opportunities for branaplam aptamer development."

Journal • Genetic Disorders • Huntington's Disease • Movement Disorders • Muscular Atrophy • Rare Diseases

miXon, a System for Tunable Control of miRNA Expression by Drug-Induced Splicing (ASGCT 2024) - "Previously, we developed Xon, a drug-induced splicing switch that controls translation initiation in response to the small molecule LMI070 (Monteys et al...This disparity between miRNA processing and knockdown could indicate an upper threshold for miRNA silencing by transfection and supports future efforts to optimize strand biasing and scaffold design for robust silencing. Overall, miXon displays significant promise as a novel system for drug-inducible control over miRNA expression."

Splice modulators target PMS1 to reduce somatic expansion of the Huntington's disease-associated CAG repeat. (PubMed, Nat Commun) - "We find that branaplam and risdiplam, small molecule splice modulators that lower huntingtin by promoting HTT pseudoexon inclusion, also decrease expansion of an unstable HTT exon 1 CAG repeat in an engineered cell model. Homozygous but not heterozygous inactivation of PMS1 also reduces CAG repeat expansion, supporting PMS1 as a genetic modifier of HD and a potential target for therapeutic intervention. Although splice modulation provides one strategy, genome-wide transcriptomics also emphasize consideration of cell-type specific effects and polymorphic variation at both target and off-target sites."

Journal • CNS Disorders • Huntington's Disease • Movement Disorders • PMS1

Understanding Pharmacy Costs and the Changing Treatment Landscape in Huntington's Disease (HD) in the US: A Systematic Literature Review (SLR) and Database Review for Disease-Modifying Therapies (DMT) in Development (ISPOR 2024) - "Motor symptoms incur the greatest annual drug cost, with high median costs per patient (2019) for tetrabenazine ($24,996), deutetrabenazine ($69,972), and valbenazine ($76,908). Ten clinical trials are investigating potential future DMTs: two-antisense oligonucleotides (n=5; Tominersen [RO7234292, ISIS 443139], WVE-003), two-RNA-targeting small molecules (n=2; PTC518, Branaplam), monoclonal antibodies (n=2; ANX005, VX15/2503), and gene therapy (n=1; rAAV5-miHTT). Pharmacy costs for symptomatic treatment are substantial in HD, with these costs increasing as HD progresses and symptom severity increases. This significant burden illustrates the importance of developing new DMTs that can prevent or slow disease progression for patients with HD."

Review • CNS Disorders • Depression • Gene Therapies • Huntington's Disease • Mood Disorders • Movement Disorders • Psychiatry

The diversity of splicing modifiers acting on A-1 bulged 5'-splice sites reveals rules for rational drug design. (PubMed, Nucleic Acids Res) - "Despite notable differences in their scaffolds, risdiplam, SMN-CX, SMN-CY and branaplam contact the RNA epitope similarly to SMN-C5, suggesting that the 5'-splice site bulge repair mechanism can be generalised. These findings not only deepen our understanding of the chemical diversity of splicing modifiers that target A-1 bulged 5'-splice sites, but also identify common pharmacophores required for modulating 5'-splice site selection with small molecules."

Journal

Specificity, synergy, and mechanisms of splice-modifying drugs. (PubMed, Nat Commun) - "Using massively parallel splicing assays, RNA-seq experiments, and precision dose-response curves, we obtain quantitative models for two small-molecule drugs, risdiplam and branaplam, developed for treating spinal muscular atrophy. The results also show that anomalous single-drug cooperativity, as well as multi-drug synergy, are widespread among small-molecule drugs and antisense-oligonucleotide drugs that promote exon inclusion. Our quantitative models thus clarify the mechanisms of existing treatments and provide a basis for the rational development of new therapies."

Journal • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases

Synergistic Effect of an Antisense Oligonucleotide and Small Molecule on Splicing Correction of the Spinal Muscular Atrophy Gene. (PubMed, Neurosci Insights) - "Here we test the effects of a combination treatment of a splice-correcting antisense oligonucleotide (ASO) Anti-N1 with the small compounds risdiplam and branaplam...For individual genes targeted by the 3 compounds, we observe little to no additive effects of combination treatment. Overall, we conclude that the combination treatment of a splice-correcting ASO with small compounds represents a promising strategy for achieving a high level of SMN expression while minimizing the risk of off-target effects."

Journal • Gene Therapies • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases