Drivers of managed entry agreements to reduce reimbursement challenges of orphan medicinal products: the development of a matrix

Callenbach, M.H.E., van den Berg, S., Hulsbosch, A. et al. Drivers of managed entry agreements to reduce reimbursement challenges of orphan medicinal products: the development of a matrix. Orphanet J Rare Dis 20, 540 (2025). doi:10.1186/s13023-025-04020-8 

"New orphan medicinal products (OMPs) are increasingly expensive and approved with limited clinical evidence". 

The matrix provides a systematic approach applied to mitigate clinical and cost-effectiveness uncertainties and/or reimbursement challenges specific to OMPs through advising MEAs. This study highlights the diversity in the drivers of MEAs to reduce risk and reimbursement challenges specific to OMPs and underscores the relevance of considering both established and innovative MEAs to address these.

Positron emission tomography reveals increased myocardial glucose uptake in a subset of Friedreich ataxia patients

Payne, R.M., O’Connell, T.M., Pride, P.M. et al. Positron emission tomography reveals increased myocardial glucose uptake in a subset of Friedreich ataxia patients. Sci Rep 15, 37247 (2025). https://doi.org/10.1038/s41598-025-21330-w 

 In this cohort of FRDA patients, a PET scan identified two metabolically distinct subclasses of FRDA cardiomyopathy. FRDA patients with severe LVH had greater FDG uptake relative to palmitate utilization than FRDA patients without severe LVH. FRDA patients with severe LVH have systolic and diastolic dysfunction, as well as ongoing cardiac damage as indicated by cTnI leak. These findings suggest that FRDA patients with significant LVH may be at increased risk of complications from surgery or major illness.

Development of an AAV-Based Gene Therapy for the Ocular Phenotype of Friedreich’s Ataxia

Tang H, Gupte S, Xu E, Calabro KR, Friend H, Crosson SM, Fajardo D,Kostamo Z, Zhang H, Peterson JJ, Lin F, Kozmik Z, Lutz CM, Boye SL, Boye SE, Development of an AAV-Based Gene Therapy for the Ocular Phenotype of Friedreich’s Ataxia, Molecular Therapy (2025), doi:10.1016/j.ymthe.2025.10.048.

Gene supplementation via intravitreal injection of a novel AAV2-based capsid carrying FXN partially preserved retinal structure and/or function in both models, establishing proof-of-concept for this therapeutic strategy.

Neuropsychiatric challenges of Friedreich ataxia in a patient residing in a long-term care facility

Wong J, Kwok J, Kim K. Neuropsychiatric challenges of Friedreich ataxia in a patient residing in a long-term care facility. Prim Care Companion CNS Disord 2025;27(5):25cr03965. doi:10.4088/PCC.25cr03965 

 The neuropsychiatric manifestations of FA are often under-recognized despite their significant impact on patient care and quality of life. This case underscores the necessity for comprehensive management strategies that address both the neurological and behavioral aspects of FA. This patient residing in a long-term care facility exhibited chronic depression and significant behavioral challenges including refusal of food, medications, and nursing care, alongside physical aggression. Despite initial treatment with citalopram, behavioral symptoms persisted while the neurovegetative signs of depression improved. As the escalation of the patient’s behavioral symptoms marked a critical turning point, divalproex ER was introduced and titrated to manage his mood instability. Subsequently, the patient’s mood and behavior symptoms noticeably improved without worsening motor dysfunction, highlighting the importance of personalized psychopharmacologic interventions.

Jupiter Neurosciences, Inc. strategic partnership with Zina Biopharmaceutica

October 22, 2025. The company develops JNS101, which is in Phase II trial for the treatment of Friedreich's Ataxia, a rare inherited disease that causes damage to the nervous system, as well as mobility dysfunctions; and JNS108 that is in Phase II trial for treating mild cognitive impairment/early Alzheimer’s disease. It is also involved in the development of JNS102, which is in Phase II trial for the treatment of mucopolysaccharidosis type 1; and JNS107 that is in Phase II trial for treating mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes syndrome. In addition, the company develops JNS115, which is in Phase IIa trial for the treatment of Parkinson’s disease. It has a strategic partnership with Zina Biopharmaceuticals, LLC to advance Phase 2a clinical trial to evaluate the safety, tolerability, and pharmacokinetics of Resveratrol (JOTROLTM) in individuals with Parkinson’s disease; and with Aquanova AG to develop a series of consumer-focused nutritional products targeting longevity, aging, and healthspan. The company was formerly known as Jupiter Orphan Therapeutics, Inc. and changed its name to Jupiter Neurosciences, Inc. in August 2021. Jupiter Neurosciences, Inc. was incorporated in 2016 and is headquartered in Jupiter, Florida.

Exploring the pleiotropic effects of lncRNA in different repeat expansion disorders

Soumalya Das, Shubhi Khandelwal, Sakshi Shukla, Amit Kumar, Exploring the pleiotropic effects of lncRNA in different repeat expansion disorders, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2025, 168089, ISSN 0925-4439, doi:10.1016/j.bbadis.2025.168089.

A Probabilistic Deep Ensemble Framework for the Objective Assessment of Friedreich Ataxia

Maneesha Randeniya, Kanishka Ranaweera, Thang Ngo, et al. A Probabilistic Deep Ensemble Framework for the Objective Assessment of Friedreich Ataxia. TechRxiv. October 16, 2025. DOI: 10.36227/techrxiv.176062677.75204670/v1

There was strong agreement between the proposed ensemble and clinical mFARS scores, reflected in a Pearson correlation of 0.81, Spearman's correlation of 0.76, R² of 0.46, RMSE of 10.30, and MAE of 8.79 on the unseen test set. Uncertainty was systematically evaluated using Uncertainty Characteristics Curves (UCC), where the ensemble achieved an Area Under UCC (AUUCC) of 8.83.

Chapter 23 - Omaveloxolone: a nuclear factor erythroid 2-related factor 2 activator for Friedreich’s ataxia

Ziquan Zhao, Junjie Wang, Mengchen Lu, Qidong You, Zhengyu Jiang, Chapter 23 - Omaveloxolone: a nuclear factor erythroid 2-related factor 2 activator for Friedreich’s ataxia, Editor(s): Bin Yu, Peng Zhan, Drug Discovery Stories, Volume 2, Elsevier, 2026, Pages 331-344, ISBN 9780443338854, doi:10.1016/B978-0-443-33885-4.00038-X. 

 Nuclear factor erythroid 2-related factor 2 (NRF2) is an important cytoprotective transcription factor that affects the fate of the cell. Impairment of the NRF2 signaling pathway has been regarded as a major contributor to the pathophysiology of FRDA, and targeting NRF2 activation has become an attractive strategy for the treatment of FRDA.

Targeting rare splicing defects: Antisense oligonucleotides offer a therapeutic strategy in FRDA

Targeting rare splicing defects: Antisense oligonucleotides offer a therapeutic strategy in FRDA, Kerkhof, Laurie M.C. et al., Molecular Therapy Nucleic Acids, Volume 36, Issue 4, 102723 doi:10.1016/j.omtn.2025.102723

Using patient-derived cells, the authors demonstrated that antisense oligonucleotides (ASOs) targeting splicing regulatory elements effectively restore splicing deficits and increase frataxin expression. While encouraging in cell-based studies, this strategy is limited to a small subset of individuals with FRDA carrying these rare mutations and requires functional validation in disease-relevant tissues.

Analysis of a Modified Version of the Inventory of Non-Ataxia Signs Over 12 Years in Patients with Friedreich's Ataxia in the EFACTS Study

Lischewski, S.A., Dogan, I., Giunti, P., Parkinson, M.H., Mariotti, C., Durr, A., Ewenczyk, C., Boesch, S., Nachbauer, W., Klopstock, T., Stendel, C., de Rivera Garrido, F.J.R., Schöls, L., Fleszar, Z., Klockgether, T., Grobe-Einsler, M., Giordano, I., Rai, M., Pandolfo, M., Jacobi, H., Hilgers, R.-D., Schulz, J.B., Reetz, K. and the EFACTS Study Group (2025), Analysis of a Modified Version of the Inventory of Non-Ataxia Signs Over 12 Years in Patients with Friedreich's Ataxia in the EFACTS Study. Mov Disord. doi:10.1002/mds.70084

Participants were drawn from the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS). The modified INAS count (presence/absence, 0–16 scale) and modified INAS sum (severity-weighted, 0–84 scale) were evaluated using linear mixed-models and standardized response means (SRMs). Items rare (<5%) and uncharacteristic in Friedreich's ataxia were excluded (chorea, myoclonus, fasciculations, resting tremor, rigidity)

LEXEO Message to the Friedreich Ataxia Community

Message to the Friedreich Ataxia Community. October 7, 2025​.

This morning, we were pleased to share positive interim clinical data for LX2006, our investigational gene therapy, that includes both cardiac and neurological outcome measures. LX2006 (AAVrh10hFXN) is currently being studied in the Lexeo-sponsored SUNRISE-FA Phase 1/2 clinical trial and the Weill Cornell Medicine investigatorinitiated Phase 1A trial for the treatment of Friedreich ataxia cardiomyopathy.

Frataxin depletion leads to decreased soma size and activation of AMPK metabolic pathway in dorsal root ganglia sensory neurons

Frataxin depletion leads to decreased soma size and activation of AMPK metabolic pathway in dorsal root ganglia sensory neurons Olivier Griso, Deepika Mokkachamy Chellapandi, Amelie Weiss, Ioannis Manolaras, Helene Puccio. bioRxiv 2025.10.07.680891; doi:10.1101/2025.10.07.680891 

Our findings uncover AMPK-mTOR dysregulation as a key driver of neuronal growth impairment in FA. This robust neuronal model provides new insights into proprioceptive neuron vulnerability and offers a platform for therapeutic discovery.

Synthesis and Biological Profile of Omaveloxolone: The Cornerstone for Friedreich Ataxia Treatment

Cordaro, M.; Neri, G.; Ansari, S.A.M.K.; Buccheri, R.; Scala, A.; Piperno, A. Synthesis and Biological Profile of Omaveloxolone: The Cornerstone for Friedreich Ataxia Treatment. Int. J. Mol. Sci. 2025, 26, 9747. doi:10.3390/ijms26199747 

This review provides a comprehensive overview of the therapeutic potential of omaveloxone (OMA) for the treatment of Friedreich’s ataxia (FA), along with an analysis of the historical development and current status of the synthetic strategies for OMA production. OMA activates the nuclear factor-2-(erythroid-2)-related (Nrf2) pathway in vitro and in vivo, in both animal models and humans. The Nrf2 pathway plays a crucial role in the cellular response to oxidative stress. Furthermore, OMA has been shown to mitigate mitochondrial dysfunction, restore redox homeostasis and downregulate nuclear factor-κB (NF-κB), a key mediator of inflammatory responses. Through these mechanisms, OMA contributes to tissue protection and inflammation reduction in patients with FA. The review also highlights future perspective, focusing on the challenges associated with OMA reprofiling through innovative drug delivery approaches and its potential repurposing for diseases beyond FA.

Lexeo Therapeutics Stock Rallies On Discussions With FDA To Expedite Friedreich’s Ataxia Drug Approval Process

Published Oct 07, 2025. https://stocktwits.com 

The company stated that data from a planned pivotal study will be pooled with data from the ongoing Phase I/II studies of LX2006 to support an approval application to the U.S. Food and Drug Administration for the therapy. 

 Lexeo Therapeutics (LXEO) announced on Tuesday that the company is considering a smaller pivotal study for LX2006 in the treatment of Friedreich's ataxia (FA) cardiomyopathy, scheduled to begin in the first half of 2026, pending finalization of the study protocol. 

 The data from the planned pivotal study will be pooled with data from the ongoing Phase I/II studies of LX2006 to support an approval application to the U.S. Food and Drug Administration for the therapy, the company stated after discussions with the agency.

Lexeo says FDA open to speedier approval of rare disease gene therapy

Published Oct. 7, 2025. https://www.biopharmadive.com/ 

The agency will consider a submission that includes pooled data from ongoing studies, a decision analysts viewed as a notable, additional sign of regulatory flexibility for gene therapies.

According to the company, the agency has “indicated openness” to an accelerated approval filing for its treatment — a gene therapy called LX2006 for the neurodegenerative condition Friedreich’s ataxia — that’s based on pooled data from ongoing studies as well as results from a planned pivotal trial.

A25-86 Omaveloxolone (Friedreich’s ataxia) – Benefit assessment according to §35a Social Code Book V

Commission awarded on 01.07.2025 by the Federal Joint Committee (G-BA). Last updated 01.10.2025. 

Result of dossier assessment: Added benefit not proven.

Delphi study to elicit expert consensus around decision-making in the treatment of Friedreich ataxia

Delphi study to elicit expert consensus around decision-making in the treatment of Friedreich ataxia. Front. Neurol.Sec. Movement Disorders Volume 16 - 2025 | doi: 10.3389/fneur.2025.1669059

Consensus was reached on a portion of questions regarding FA diagnosis and assessment, perhaps due to the rarity of disease and panelists' varying FA experience. To improve and standardize management of FA, it is important to establish best practices and educate potential FA treaters as new therapies emerge.

357PLong-term vatiquinone treatment slows Friedreich’s ataxia disease progression relative to FACOMS natural history

357PLong-term vatiquinone treatment slows Friedreich’s ataxia disease progression relative to FACOMS natural history. Vagabov, A. et al. Neuromuscular Disorders, Volume 53, 106087 DOI:10.1016/j.nmd.2025.106087 

 The results of the extension studies provide further evidence of the potential benefit of vatiquinone for the treatment of FA. The pre-specified endpoints for two different long-term extension studies were met, with highly statistically significant evidence of durable treatment benefit in slowing disease progression in paediatric and adult patients.

234PLong-term use of omaveloxolone in patients with Friedreich ataxia: up to 5 years of natural history propensity score matching from the MOXIe OLE

234PLong-term use of omaveloxolone in patients with Friedreich ataxia: up to 5 years of natural history propensity score matching from the MOXIe OLE. Nachbauer, W. et al.. Neuromuscular Disorders, Volume 53, 106043 doi:10.1016/j.nmd.2025.106043 

 Continued analysis of the MOXIe OLE data informs on long-term efficacy and safety of omaveloxolone in patients with FA and provides relevant insights regarding disease progression in patients treated with omaveloxolone relative to the natural pattern of FA progression in the FACOMS cohort.

Friedreich Ataxia and Related Diabetes: Therapeutic Approach Targeting Mitochondrial Dysfunction

Pichakacheri Sureshkumar, Sidharth S Kumar, Johny Cheriyan, Asif Masood, Friedreich Ataxia and Related Diabetes: Therapeutic Approach Targeting Mitochondrial Dysfunction, JCEM Case Reports, Volume 3, Issue 11, November 2025, luaf215, doi:10.1210/jcemcr/luaf215 

 This case report discusses a 32-year-old woman with Friedreich ataxia (FA) and suboptimally managed diabetes mellitus (DM), focusing on a treatment strategy aimed at improving mitochondrial function for better glycemic control and symptom management. Her regimen included insulin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, neurotropic vitamins, and mitochondriotropic agents and antioxidants, specifically L-carnitine, coenzyme Q10 (CoQ10), and vitamin E. Imeglimin, a mitochondriotropic antihyperglycemic agent, was also part of her regimen.

357P Long-term vatiquinone treatment slows Friedreich’s ataxia disease progression relative to FACOMS natural history

A. Vagabov, J. Cherry, A. Duqette, M. França, S. Perlman, A. Durr, E. Bertini, K. Mathews, L. Schöls, A. Fournier, M. Delatycki, S. Subramony, R. Roxburgh, M. Rance, O. Zhang, L. Golden, J. Gruenert, C. Werner, D. Lynch, T. Zesiewicz, 357PLong-term vatiquinone treatment slows Friedreich’s ataxia disease progression relative to FACOMS natural history, Neuromuscular Disorders, Volume 53, Supplement, 2025, 106087, ISSN 0960-8966, doi:10.1016/j.nmd.2025.106087. 

 Vatiquinone (EPI-743) is an investigational, oral, first-in-class 15-lipoxygenase inhibitor being developed for the treatment of patients with Friedreich’s ataxia (FA). Here, we report long-term results of vatiquinone treatment in patients with FA from the MOVE-FA extension study (36 months) and Study EPI-2010-006 (24 months), compared with matched natural history cohorts from FACOMS (Friedreich Ataxia Clinical Outcome Measures). MOVE-FA (NCT04577352) was a global phase 3 study of vatiquinone in patients with FA aged ≥ 7 years (N = 143; mean age: 18.7 years); participants who completed MOVE-FA were eligible to rollover into the long-term extension (NCT05515536). EPI-2010-006 (NCT01728064) was a phase 2 study of vatiquinone in adult patients with FA ≥ 18 years (N = 63; mean age: 28.9 years). The pre-specified primary endpoint for these analyses was the modified Friedreich’s Ataxia Rating Scale (mFARS). After 36 months in the MOVE-FA long-term extension study, participants in the vatiquinone treatment group demonstrated a 3.75-point increase in mFARS. The matched FACOMS cohort progressed by 7.48 points over the same period. Vatiquinone treatment resulted in a 3.7-point benefit (p < 0.0001, n = 70) in mFARS relative to FACOMS, representing a clinically meaningful 50% slowing of disease progression over 3 years. Following 24-months of treatment with vatiquinone in EPI-2010-006, participants demonstrated a 0.92-point decrease in mFARS while participants in the matched FACOMS cohort progressed by 3.89 points. This resulted in a 4.8-point treatment benefit (p < 0.0001, n = 41), consistent with a 2-year delay in progression. The results of the extension studies provide further evidence of the potential benefit of vatiquinone for the treatment of FA. The pre-specified endpoints for two different long-term extension studies were met, with highly statistically significant evidence of durable treatment benefit in slowing disease progression in paediatric and adult patients.

Emerging therapies for Friedreich Ataxia and the prospect of future combination treatments

Lees, J. G., Li, L., & Lim, S. Y. (2025). Emerging therapies for Friedreich Ataxia and the prospect of future combination treatments. Future Rare Diseases, 5(1). doi:10.1080/23995270.2025.2563497

Although no single therapy has yet delivered a cure, the growing understanding of FRDA’s underlying mechanisms, coupled with an expanding therapeutic arsenal and more refined clinical measures, offers genuine hope that transformative, life-changing treatments are within reach. Realizing this promise will depend on continued collaboration among patients, clinicians, researchers, industry, and regulatory stakeholders to ensure that scientific advances translate into tangible, meaningful benefits for the FRDA community.

Larimar Therapeutics Announces Positive Data from Ongoing Long-term Open Label Study and Updates to Nomlabofusp Program for Friedreich’s Ataxia

BALA CYNWYD, Pa., Sept. 29, 2025 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (Larimar) (Nasdaq: LRMR), a clinical-stage biotechnology company focused on developing treatments for complex rare diseases, today announced positive 25 mg and 50 mg data from the ongoing long-term open label (OL) study evaluating daily subcutaneous injections of nomlabofusp self-administered or administered by a caregiver in participants with Friedreich’s ataxia (FA), a rare, progressive, and systemic disease with neurologic deterioration. The Company also provided a nomlabofusp development program update.