PTC Therapeutics Announces Vatiquinone NDA Submission to FDA for the Treatment of Children and Adults Living with Friedreich Ataxia

WARREN, N.J., Dec. 19, 2024 /PRNewswire/ -- PTC Therapeutics, Inc. (NASDAQ: PTCT) announced today the submission of the vatiquinone New Drug Application (NDA) for the treatment of children and adults living with Friedreich ataxia (FA) to the U.S. Food and Drug Administration (FDA). 

The application is supported by data from a placebo-controlled study and two long-term studies that included pediatric and adult patients. 

Results from the three studies indicated significant, durable, and clinically meaningful evidence of slowing disease progression with vatiquinone.

Vatiquinone is known as a first-in-class selective inhibitor of 15-Lipoxygenase (15-LO), "an enzyme that is a key regulator of the energetic and oxidative stress pathways that are disrupted in Friedreich ataxia," according to PTC.

Larimar Therapeutics Announces Positive Initial Data from Ongoing Long-term Open Label Extension Study & Progress Across Nomlabofusp Program for Friedreich’s Ataxia

December 16, 2024. Source: Larimar Therapeutics BALA CYNWYD, Pa., Dec. 16, 2024 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (Larimar) (Nasdaq: LRMR), today announced positive initial data from the ongoing long-term OLE study evaluating daily subcutaneous injections of 25 mg of nomlabofusp self-administered or administered by a caregiver in participants with FA. 

The Company also provided a nomlabofusp development program update. 

We are pleased with the advancement of our OLE study that includes 14 patients dosed for up to 260 days. Importantly, 25 mg of nomlabofusp administered daily increased and maintained tissue FXN levels over time, with mean levels increasing from 15% of healthy volunteers at baseline to 30% in buccal cells and from 16% to 72% in skin cells at Day 90. At the time of data cut off for the OLE study, 14 adults with FA were included with up to 260 days (mean 99 days) of long-term daily treatment of 25 mg of nomlabofusp. Among these patients, more than 50% were non-ambulatory.

Larimar Therapeutics Reports Positive Initial Data from Nomlabofusp OLE Study for Friedreich’s Ataxia

Dec. 16, 2024. Larimar Therapeutics announced positive results from its ongoing open label extension study evaluating the daily subcutaneous administration of 25 mg nomlabofusp in participants with Friedreich’s ataxia. In a cohort of 14 patients, the treatment was generally well tolerated for up to 260 days, with tissue frataxin levels significantly increasing in both buccal and skin cells by Day 90. 

Plans for a global confirmatory study are set for mid-2025, with a Biologics License Application targeted for submission in the second half of 2025. Early trends towards improvement in clinical outcomes observed at Day 90, supporting the potential for nomlabofusp to benefit a broad spectrum of patients with Friedreich’s ataxia.

Serious adverse events occurred in two study participants during the OLE study, which, despite resolving quickly, may raise concerns about the safety profile of nomlabofusp.

Gradient of microstructural damage along the dentato- thalamo-cortical tract in Friedreich ataxia

Sirio Cocozza, Sara Bosticardo, Matteo Battocchio, Louise Corben, Martin Delatycki, Gary Egan, Nellie Georgiou-Karistianis, Serena Monti, Giuseppe Palma, Chiara Pane, Francesco Sacca, Simona Schiavi, Louisa Selvadurai, Mario Tranfa , Alessandro Daducci, Arturo Brunetti & Ian H. Harding. Gradient of microstructural damage along the dentato- thalamo-cortical tract in Friedreich ataxia. Annals of Clinical and Translational Neurology 2024; 11(7): 1691–1702. doi: 10.1002/acn3.52048

Our study further expands the current knowl- edge about brain involvement in FRDA, showing that microstructural abnormalities within the DTT are weighted to early segments of the tract (i.e., the superior cerebellar peduncle). These findings are consistent with the hypothesis of DTT undergoing anterograde degeneration arising from the dentate nuclei and progressing to the primary motor cortex.

Ignition of Small Molecule Inhibitors in Friedreich's Ataxia with Explainable Artificial Intelligence

Kübra Kirboğa, K., Küçüksille, E., & Kose, U. (2023). Ignition of Small Molecule Inhibitors in Friedreich's Ataxia with Explainable Artificial Intelligence. BRAIN. Broad Research In Artificial Intelligence And Neuroscience, 14(3), 287-313. Retrieved from https://brain.edusoft.ro/index.php/brain/article/view/1427

The results showed the importance of properties related to nitrogen-containing functional groups (SHAP value of PubchemFP656 is -0.29) and aromatic rings (SHAP value of PubchemFP12 is -0.16). As a result, we explained the effect of the molecular fingerprints on the models and the impact on possible drugs that can be developed for FA with artificial intelligence (XAI), which can be explained through SHAP (Shapley Additive Explanations) values. Model scripts and fingerprinting methods are also available at https://github.com/tissueandcells/XAI.

Altered calcium responses and antioxidant properties in Friedreich's ataxia-like cerebellar astrocytes

Marullo, Chiara & Croci, Laura & Giupponi, Iris & Rivoletti, Claudia & Zuffetti, Sofia & Bettegazzi, Barbara & Cremona, Ottavio & Giunti, Paola & Ambrosi, Alessandro & Casoni, Filippo & Consalez, Gian & Codazzi, Franca. (2024). Altered calcium responses and antioxidant properties in Friedreich's ataxia-like cerebellar astrocytes. Journal of cell science. 10.1242/jcs.263446.

Our findings shed light on cellular changes caused by FXN downregulation in cerebellar astrocytes, likely impairing their complex interaction with neurons. The potentially impaired ability to provide neuronal cells with glutathione or to release neuromodulators in a calcium-dependent manner could affect neuronal function, contributing to neurodegeneration.

Sexual dimorphism in a mouse model of Friedreich's ataxia with severe cardiomyopathy

Salinas L, Montgomery CB, Figueroa F, Thai PN, Chiamvimonvat N, Cortopassi G, Dedkova EN. Sexual dimorphism in a mouse model of Friedreich's ataxia with severe cardiomyopathy. Commun Biol. 2024 Oct 3;7(1):1250. doi: 10.1038/s42003-024-06962-4. PMID: 39363102; PMCID: PMC11449905. 

 The decrease in testosterone was related to decreased expression of proteins involved in cholesterol transfer into the mitochondria: StAR and TSPO on the outer mitochondrial membrane, and the cholesterol side-chain cleavage enzyme P450scc and ferredoxin on the inner mitochondrial membrane. Expression of excitation-contraction coupling proteins (L-type calcium channel, RyR2, SERCA2, phospholamban and CaMKIIδ) was decreased significantly more in Fxn-cKO males. This is the first study that extensively investigates the sexual dimorphism in FA mouse model with cardiac calcium signaling impairment.

Lack of Concentration-QTc Relationship and Cardiac Risk With Vatiquinone Therapeutic and Supratherapeutic Doses

Lee L, Flach S, Xue H, Arivelu L, Golden L, Kong R, Darpo B. Lack of Concentration-QTc Relationship and Cardiac Risk With Vatiquinone Therapeutic and Supratherapeutic Doses. Clin Pharmacol Drug Dev. 2024 Nov;13(11):1227-1238. doi: 10.1002/cpdd.1476. Epub 2024 Oct 17. PMID: 39415654. 

 No new safety signals were found, as safety data are consistent with the known safety profile of vatiquinone. These findings altogether demonstrated that there is a minimal cardiac risk for vatiquinone concentrations up to the supratherapeutic dose level.

Friedreich Ataxia

Bidichandani SI, Delatycki MB, Napierala M, Duquette A. Friedreich Ataxia. 1998 Dec 18 [updated 2024 Oct 31]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2024. PMID: 20301458. 

 Review (Last Update: October 31, 2024.)

Efficacy of Stabilometric Platform to Improve Standing Balance in Patients with Friedreich's Ataxia

ClinicalTrials.gov ID NCT06692296. Sponsor IRCCS Eugenio Medea. Last Update Posted 2024-11-21

The primary objective is to evaluate the potential effectiveness of an individualized intensive rehabilitation intervention using the "Prokin 252" stabilometric platform in the treatment of adolescent and adult patients with Friedreich's Ataxia. The secondary objective is to assess the retention of the rehabilitation treatment effects over time.