Lexeo Therapeutics' LX2006 Shows Promise in Treating Friedreich Ataxia Cardiomyopathy

August 9, 2024. By Andrew Cox, Pharm.D., MBA. Managed Healthcare Executive.

Although the initial results are promising, LX2006's ultimate success will depend on ongoing safety evaluations, long-term efficacy data, and the ability to navigate the regulatory landscape. Lexeo Therapeutics' interim clinical data for LX2006 represents a potentially transformative advancement in treating Friedreich Ataxia cardiomyopathy. While the early results are encouraging, ongoing clinical evaluations and regulatory engagements will be vital in determining the future of this promising gene therapy.

New and Emerging Drug and Gene Therapies for Friedreich Ataxia

Scott V, Delatycki MB, Tai G, Corben LA. New and Emerging Drug and Gene Therapies for Friedreich Ataxia. CNS Drugs. 2024 Aug 8. doi: 10.1007/s40263-024-01113-z. Epub ahead of print. PMID: 39115603. 

 This review provides a contemporary position of drug and gene therapies for FRDA currently in phase 1 clinical trials and beyond. Despite significant scientific advances in the specificity of both compounds and targets developed and investigated, challenges remain for the advancement of treatments in a limited recruitment population. Currently therapies focus on reducing oxidative stress and improving mitochondrial function, modulating frataxin controlled metabolic pathways and gene replacement and editing. Approval of omaveloxolone, the first treatment for individuals with FRDA aged 16 years and over, has created much excitement for both those living with FRDA and those that care for them.

Glial cell activation precedes neurodegeneration in the cerebellar cortex of the YG8–800 murine model of Friedreich ataxia

Andrés Vicente-Acosta, Saúl Herranz-Martín, María Ruth Pazos, Jorge Galán-Cruz, Mario Amores, Frida Loria, Javier Díaz-Nido, Glial cell activation precedes neurodegeneration in the cerebellar cortex of the YG8–800 murine model of Friedreich ataxia, Neurobiology of Disease, 2024, 106631, doi:10.1016/j.nbd.2024.106631.

Together, our results show that the YG8–800 mouse model exhibits a stronger phenotype than previous experimental murine models, reliably recapitulating some of the features observed in humans. Accordingly, this humanized model could represent a valuable tool for studying Friedreich ataxia molecular disease mechanisms and for preclinical evaluation of possible therapies.

Insulin sensitivity and insulin secretion in adults with Friedreich’s Ataxia: the role of skeletal muscle

Jaclyn Tamaroff, Sara Nguyen, Neil E Wilson, Darko Stefanovski, Rui Xiao, Theresa Scattergood, Christopher Capiola, Gayatri Maria Schur, Julia Dunn, Anna Dedio, Kristin Wade, Hardik Shah, Rohit Sharma, Vamsi K Mootha, Andrea Kelly, Kimberly Y Lin, David R Lynch, Ravinder Reddy, Michael R Rickels, Shana E McCormack, Insulin sensitivity and insulin secretion in adults with Friedreich’s Ataxia: the role of skeletal muscle, The Journal of Clinical Endocrinology & Metabolism, 2024;, dgae545, doi:10.1210/clinem/dgae545 

 Lower mitochondrial OXPHOS capacity, inactivity, and visceral adiposity contribute to lower insulin sensitivity in FRDA. Higher insulin secretion appears compensatory, and when inadequate, could herald DM. Further studies are needed to determine if muscle- or adipose-focused interventions could delay FRDA-related DM.

Larimar Therapeutics Reports Second Quarter 2024 Operating and Financial Results

BALA CYNWYD, Pa., Aug. 07, 2024 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (Larimar) “We made significant achievements in our nomlabofusp program this quarter that strongly position us for successful execution across important catalysts over the next 12 months. We were honored to be selected by the FDA to participate in the START pilot program which may be invaluable in helping us achieve our timeline for BLA submission targeted for the second half of 2025 to support accelerated approval. We are actively pursuing clinical sites in the U.S., Europe, U.K. Canada, and Australia in anticipation of initiating a global confirmatory study in mid-2025. We are excited to have recently joined the TRACK-FA Neuroimaging Consortium as an industry partner to support research to define disease-specific neuroimaging biomarkers for potential use in clinical trials.” said Carole Ben-Maimon, MD, President, and Chief Executive Officer of Larimar. “Our OLE study continues to progress with all seven sites now activated and interim data planned for the fourth quarter of this year. We plan to initiate a PK run-in study in adolescents with Friedreich’s ataxia (FA) by year-end, with option for study participants to transition to the OLE study after completing the run-in study. Expanding our clinical program into younger patients will allow us to evaluate the effect of nomlabofusp earlier in the disease process which may help further address the effect of the underlying frataxin deficiency in patients with FA.”

mTORC1 Signaling Inhibition Modulates Mitochondrial Function in Frataxin Deficiency

mTORC1 Signaling Inhibition Modulates Mitochondrial Function in Frataxin Deficiency, Madison Lehmer, Roberto Zoncu, bioRxiv 2024.08.06.606942; doi:10.1101/2024.08.06.606942

 We find that acute chemical modulation of mTORC1 signaling decreased mitochondrial oxygen consumption, increased mitochondrial membrane potential and reduced susceptibility to stress-induced mitophagy. In cellular models of Friedreich Ataxia (FA), where loss of the Frataxin (FXN) protein suppresses Fe-S cluster synthesis and mitochondrial respiration, the changes induced by mTORC1 inhibitors lead to improved cell survival. Proteomic-based profiling uncover compositional changes that could underlie mTORC1-dependent modulation of FXN-deficient mitochondria.

Rare disease clinical trials in the European Union: navigating regulatory and clinical challenges

Mishra, S., Venkatesh, M. Rare disease clinical trials in the European Union: navigating regulatory and clinical challenges. Orphanet J Rare Dis 19, 285 (2024). doi:10.1186/s13023-024-03146-5

Collaboration among academic institutions, pharmaceutical companies (both small and major), patient groups, and health authorities is crucial in overcoming obstacles related to clinical trials and providing assistance and creative ideas. The ultimate objective of granting rare disease patients timely and affordable access to medications with a positive balance between benefits and risks is to be met.

GLP-1R mediates idebenone-reduced blood glucose in mice

Xin Zhao, Qingxuan Zeng, Siting Yu, Xiaochan Zhu, Bin Hu, Lijiao Deng, Yi Zhang, Yunfeng Liu,, GLP-1R mediates idebenone-reduced blood glucose in mice, Biomedicine & Pharmacotherapy, Volume 178, 2024, 117202, ISSN 0753-3322, doi:10.1016/j.biopha.2024.117202. 

( GLP-1 receptor agonists (GLP-1RAs) are an innovative class of drugs with significant therapeutic value for type 2 diabetes mellitus (T2DM). The GLP-1RAs currently available on the market are biologic macromolecular peptide agents that are expensive to treat and not easy to take orally. Therefore, the development of small molecule GLP-1RAs is becoming one of the most sought-after research targets for hypoglycemic drugs. In this study, we sought to find a potential oral small molecule GLP-1RA and to evaluate its effect on insulin secretion in rat pancreatic β cells and on blood glucose in mice. We downloaded the mRNA expression profiles of GSE102194 and GSE37936 from the Gene Expression Omnibus database. Subsequently, the small molecule compound idebenone was screened through the connectivity map database. The results of molecular docking, biolayer interferometry, and cellular thermal shift assay indicated that idebenone could bind potently with GLP-1R. Furthermore, ibebenone elevated intracellular cAMP levels. The radioimmunoassay data showed that idebenone enhanced glucose-stimulated insulin secretion via agonism of GLP-1R. Moreover, the results of oral glucose tolerance tests in C57BL/6, Glp-1r-/-, and hGlp-1r mice demonstrated that the glucose-lowering effects of idebenone were mediated by GLP-1R and that there were no species differences in the agonistic effect of idebenone on GLP-1R. In summary, idebenone reduces blood glucose in mice by promoting insulin release through agonism of GLP-1R, suggesting that idebenone is probably a potential GLP-1RA, which is expected to provide a new therapeutic strategy for the prevention and treatment of metabolic diseases such as T2DM.

Microfluidic formulation of diazoxide-loaded solid lipid nanoparticles as a Novel approach for Friedreich's ataxia treatment

Ilaria Arduino, Antonella Santoro, Silvia De Santis, Rosa Maria Iacobazzi, Angela Assunta Lopedota, Eleonora Paradies, Giuseppe Merla, Sara Anjomani Virmouni, Luigi Palmieri, Carlo Marya Thomas Marobbio, Nunzio Denora, Microfluidic formulation of diazoxide-loaded solid lipid nanoparticles as a Novel approach for Friedreich's ataxia treatment, Journal of Drug Delivery Science and Technology, Volume 97, 2024, 105837, ISSN 1773-2247, doi:10.1016/j.jddst.2024.105837. 

 This study aimed to create solid lipid nanoparticles (SLNs) loaded with DZX by microfluidic technique to improve blood-brain barrier (BBB) penetration and reduce side effects. Employing an in vitro BBB model, SLN-DZX demonstrated enhanced permeability compared to plain DZX. Cell viability assays carried out on FRDA fibroblast cells indicated enhanced viability with 1 μM SLN-DZX. Cellular uptake studies confirmed SLN internalization in FRDA fibroblasts, and subsequent treatment with SLN-DZX significantly reduced both total and mitochondrial ROS levels compared to control and empty SLN-treated cells. These findings suggest SLN-DZX as a potential therapeutic approach for FRDA, mitigating oxidative stress with improved BBB penetration and reduced toxicity.

Phase 2 Trial of Dimethyl Fumarate for Friedrich Ataxia

NeurologyLive. July 17, 2024. Updates in Therapeutic Development: Clinical Trial Readouts to Watch in the Second Half of 2024 

According to a recent interview with Francesco Saccà, MD, PhD, an associate professor of neurology at the University of Naples, the phase 2 study assessing the use of dimethyl fumarate (DMF), an approved product for relapsing multiple sclerosis and psoriasis in Europe, in patients with Friedreich ataxia (FA), potentially anticipates some data, at least the primary and many of the secondary endpoints, by September or October of this year. Saccà also noted that potentially by the end of the year, investigators will close the entire analysis. 

The study, which two sequential 12-week phases, assesses whether DMF can increase the expression of the FXN gene and frataxin protein and ameliorate in-vivo detectable measures of mitochondrial dysfunction in FA. FA, which is typically associated with several developmental features, is caused by a genetic deficiency of frataxin, a small, nuclear-encoded mitochondrial protein. Frataxin deficiency leads to impairment of iron-sulphur cluster synthesis, and consequently ATP production abnormalities.