Reata Pharmaceuticals Announces Approval of Prior Approval Supplement for SKYCLARYS® (Omaveloxolone) and Commercial Availability of SKYCLARYS for Patients with Friedreich’s Ataxia

June 27, 2023. PLANO, Texas--(BUSINESS WIRE)-- Reata Pharmaceuticals, Inc. (Nasdaq: RETA) (“Reata,” the “Company,” “our,” “us,” or “we”), a global, biopharmaceutical company focused on developing and commercializing novel therapies for patients with severe diseases, announced that the United States Food and Drug Administration (FDA) has approved the Prior Approval Supplement (PAS) to update the drug substance specification for SKYCLARYS® (omaveloxolone), the first and only FDA approved drug for the treatment of Friedreich’s ataxia in adults and adolescents aged 16 years and older. With the approval of the PAS, SKYCLARYS is now available to patients with Friedreich’s ataxia in the United States.

Retinal hypoplasia and degeneration result in vision loss in Friedreich ataxia

Rodden, L.N., McIntyre, K., Keita, M., Wells, M., Park, C., Profeta, V., Waldman, A., Rummey, C., Balcer, L.J. and Lynch, D.R. (2023), Retinal hypoplasia and degeneration result in vision loss in Friedreich ataxia. Ann Clin Transl Neurol. doi:10.1002/acn3.51830 

 These data suggest that both hypoplasia and subsequent degeneration of the RNFL may be responsible for the optic nerve dysfunction in FRDA and support the development of a vision-directed treatment for selected patients early in the disease to prevent RNFL loss from reaching the critical threshold

Anodal Cerebellar Transcranial Direct Current Stimulation Reduces Motor and Cognitive Symptoms in Friedreich's Ataxia: A Randomized, Sham-Controlled Trial

Naeije, G., Rovai, A., Destrebecq, V., Trotta, N. and De Tiège, X. (2023), Anodal Cerebellar Transcranial Direct Current Stimulation Reduces Motor and Cognitive Symptoms in Friedreich's Ataxia: A Randomized, Sham-Controlled Trial. Mov Disord. doi:10.1002/mds.29453 

 One week of treatment with anodal ctDCS reduces motor and cognitive symptoms in individuals with FRDA, likely by restoring the neocortical inhibition normally exerted by cerebellar structures. This study provides class I evidence that ctDCS stimulation is effective and safe in FRDA

LEXEO Therapeutics Announces Completion of First Cohort and Dosing in Second Cohort in SUNRISE-FA, a Phase 1/2 Clinical Trial of LX2006 for the Treatment of Friedreich’s Ataxia Cardiomyopathy

NEW YORK, June 13, 2023 (GLOBE NEWSWIRE) -- LEXEO Therapeutics (LEXEO), a clinical-stage gene therapy company advancing adeno-associated virus (AAV)-based gene therapy candidates for genetically defined cardiovascular diseases and a genetically defined sub-group of Alzheimer’s disease, announced today the completion of the first dose cohort and the dosing of the first patient in the second dose cohort in SUNRISE-FA, a Phase 1/2 clinical trial of LX2006 in patients with Friedreich’s ataxia (FA) cardiomyopathy. In the first dose cohort, LX2006 has been well tolerated with no unexpected events or toxicities observed. Following the Data Safety Monitoring Board recommendation to proceed, investigators have initiated dosing in the second cohort.

A Retrospective Claims Analysis Characterizing Health Care Resource Use Among Patients with Friedreich Ataxia in the United States,

C. Qian, D. Lynch, L. Powell, A. Salvucci, G. Vasco, K.M Johnston, I. Tomazos, A Retrospective Claims Analysis Characterizing Health Care Resource Use Among Patients with Friedreich Ataxia in the United States, Value in Health, Volume 26, Issue 6, Supplement, 2023, Page S385, doi:10.1016/j.jval.2023.03.2157.

Patients with FA have significantly higher rates of HCRU, when compared to non-FA. This study demonstrates the multidisciplinary care required for this complex disease. Currently there are no disease modifying treatments for FA – these findings can help better estimate the impact of new interventions on the healthcare system.

The Clinical Burden of Friedreich Ataxia: A Retrospective Claims Analysis in the United States

L. Powell, D. Lynch, C. Qian, A. Salvucci, G. Vasco, K.M Johnston, I. Tomazos, The Clinical Burden of Friedreich Ataxia: A Retrospective Claims Analysis in the United States, Value in Health, Volume 26, Issue 6, Supplement, 2023, Page S379, doi:10.1016/j.jval.2023.03.2128. 

 Patients with FA in comparison to non-FA, experience significant clinical manifestations and comorbidities. This study provides real-world estimates of this disease burden, for commercially insured patients with FA in the US, underlying the unmet medical need in this population.

Adult-Onset Neuroepidemiology in Finland: Lessons to Learn and Work to Do

Sipilä, J.O.T. Adult-Onset Neuroepidemiology in Finland: Lessons to Learn and Work to Do. J. Clin. Med. 2023, 12, 3972. doi:10.3390/jcm12123972 

 Jokela type (SMAJ) and adult-onset dystonia. On the other hand, some disorders, such as Friedreich’s ataxia (FRDA) and Wilson’s disease (WD), are almost absent or completely absent in the population.

Jackson Laboratory receives $22.8 million grant for gene-editing based work

Published: Jun. 10, 2023​. BAR HARBOR, Maine (WABI) - Researchers aiming to develop and validate new gene-editing based therapeutic approaches have gotten a substantial financial investment.

The work being done revolves around four different neurological conditions including Spinal Muscular Atrophy, Friedreich’s Ataxia, Huntington’s Disease and Rett Syndrome.

Pharmacists are initiators in palliative care for patients with rare diseases

Dooms, M. Pharmacists are initiators in palliative care for patients with rare diseases. Orphanet J Rare Dis 18, 141 (2023). doi:10.1186/s13023-023-02765-8 

 A community pharmacist can play a key role in advocating timely access to palliative care. Medication reconciliation must alert them to start communicating with the patient and/or his relatives about refocusing treatment and care as part of palliative and terminal care. Pharmaceutical activities for these patients include dispensing of devices and medicinal products, compounding personalized medication and participating as a member of the Palliative Support Team. Most of the several thousands of rare diseases are caused by genetic defects and up to now have no cure and a late diagnosis.

Targeting Ion Channels and Purkinje Neuron Intrinsic Membrane Excitability as a Therapeutic Strategy for Cerebellar Ataxia

Huang H, Shakkottai VG. Targeting Ion Channels and Purkinje Neuron Intrinsic Membrane Excitability as a Therapeutic Strategy for Cerebellar Ataxia. Life. 2023; 13(6):1350. doi:10.3390/life13061350 

 In degenerative neurological disorders such as Parkinson’s disease, a convergence of widely varying insults results in a loss of dopaminergic neurons and, thus, the motor symptoms of the disease. Dopamine replacement therapy with agents such as levodopa is a mainstay of therapy. Cerebellar ataxias, a heterogeneous group of currently untreatable conditions, have not been identified to have a shared physiology that is a target of therapy. In this review, we propose that perturbations in cerebellar Purkinje neuron intrinsic membrane excitability, a result of ion channel dysregulation, is a common pathophysiologic mechanism that drives motor impairment and vulnerability to degeneration in cerebellar ataxias of widely differing genetic etiologies. We further propose that treatments aimed at restoring Purkinje neuron intrinsic membrane excitability have the potential to be a shared therapy in cerebellar ataxia akin to levodopa for Parkinson’s disease.

Randomized controlled trial data for successful new drug application for rare diseases in the United States

Kubota, Y., Narukawa, M. Randomized controlled trial data for successful new drug application for rare diseases in the United States. Orphanet J Rare Dis 18, 89 (2023). doi:10.1186/s13023-023-02702-9 

 This study focused on 233 drugs with orphan drug designations approved in the US between April 2001 and March 2021. Univariable and multivariable logistic regression analyses were conducted to investigate the association between the presence or absence of RCTs in the clinical data package for new drug applications.

Ataxia de Friedreich, revisión y actualización de la literatura con búsqueda sistemática de casos en Latinoamérica

Alfaro-Olivera M, Calle-Nuñez A, Uribe-León A, Aguirre-Quispe W, Sarapura-Castro E, Cornejo-Olivas M. Ataxia de Friedreich, revisión y actualización de la literatura con búsqueda sistemática de casos en Latinoamérica. Revista de Neuro-Psiquiatría [Internet]. 27abr.2023 [citado 7jun.2023];86(1):45-1. Available from: https://revistas.upch.edu.pe/index.php/RNP/article/view/4466 

 La prevalencia de AF en poblaciones caucásicas es estimada entre 2 y 5 casos por 100 000 habitantes. En Latinoamérica se han publicado 35 estudios que reúnen 1481 casos en 6 países.

XC-103 by Ixchel Pharma for Friedreich Ataxia: Likelihood of Approval

June 5, 2023. XC-103 is under clinical development by Ixchel Pharma and currently in Phase I for Friedreich Ataxia. According to GlobalData, Phase I drugs for Friedreich Ataxia does not have sufficient historical data to build an indication benchmark PTSR for Phase I. GlobalData uses proprietary data and analytics to create drugs-specific PTSR and LoA in the IXC-103 LoA Report.

Amplifying gene expression with RNA-targeted therapeutics

Khorkova O, Stahl J, Joji A, Volmar CH, Wahlestedt C. Amplifying gene expression with RNA-targeted therapeutics. Nature reviews. Drug Discovery. 2023 May. DOI: 10.1038/s41573-023-00704-7. PMID: 37253858; PMCID: PMC10227815. 

This Review highlights emerging RNA-targeted therapeutics for gene activation, focusing on opportunities and challenges for translation to the clinic.

Anaesthetic management of thyroid storm in a patient with Friederich’s ataxia. A case report

M. Sneyers Closa, A. Pérez Requena, S. Sánchez García, J. Sistac Ballarín, Anaesthetic management of thyroid storm in a patient with Friederich’s ataxia. A case report, Revista Española de Anestesiología y Reanimación (English Edition), 2023, doi:10.1016/j.redare.2023.06.002.

 A 26-year-old patient with Friederich's ataxia with hypertrophic obstructive cardiomyopathy undergoing total thyroidectomy due to persistent amiodarone-induced thyrotoxicosis (despite high doses of antithyroid drugs and corticosteroids), presented an intraoperative episode suggestive of thyroid storm. Thyroid storm is an endocrine emergency that is associated with high morbidity and mortality. Early diagnosis and treatment, which is of vital importance to improve survival, includes symptomatic treatment, treatment of cardiovascular, neurological, and/or hepatic manifestations and thyrotoxicosis, measures to suppress or avoid triggering stimuli, and definitive treatment. 

 Paciente de 26 años afecto de ataxia de Friederich con una miocardiopatía hipertrófica obstructiva sometido a una tiroidectomía total por tirotoxicosis secundaria a amiodarona persistente (a pesar de elevadas dosis de antitiroideos y corticoides) que intraoperatoriamente presentó un episodio sugestivo de tormenta tiroidea. La tormenta tiroidea es una emergencia endocrinológica que asocia una elevada morbimortalidad. Para mejorar la supervivencia es de vital importancia un diagnóstico y tratamiento precoz que incluya: un tratamiento sintomático; el tratamiento de las manifestaciones cardiovasculares, neurológicas y/o hepáticas y de la tirotoxicosis; y así como suprimir o evitar estímulos desencadenantes y practicar un tratamiento definitivo.

Continuous, but not intermittent, regimens of hypoxia prevent and reverse ataxia in a murine model of Friedreich’s ataxia

Tslil Ast, Hong Wang, Eizo Marutani, Fumiaki Nagashima, Rajeev Malhotra, Fumito Ichinose, Vamsi K Mootha, Continuous, but not intermittent, regimens of hypoxia prevent and reverse ataxia in a murine model of Friedreich’s ataxia, Human Molecular Genetics, 2023;, ddad091, doi:10.1093/hmg/ddad091 

 The detrimental effect of this regimen is likely due to transient tissue hyperoxia that results when daily exposure to 21% O2 combines with chronic polycythemia, as we could blunt this toxicity by pharmacologically inhibiting polycythemia. Second, we report that more mild regimens of chronic hypoxia (17% O2) confer a modest benefit by delaying the onset of ataxia. Third, excitingly, we show that initiating chronic, continuous 11% O2 breathing once advanced neurological disease has already started can rapidly reverse ataxia. Our studies showcase both the promise and limitations of candidate hypoxia-inspired regimens for FA and underscore the need for additional pre-clinical optimization before future translation into humans.

SEXUAL DIMORPHISM AND CARDIAC ARRHYTHMIAS IN A MOUSE MODEL OF FRIEDREICH'S ATAXIA: WHAT DO WE KNOW?

Francisco Figueroa, Lili Salinas, Claire Montgomery, Phung N. Thai, Nipavan Chiamvimonvat, Gino Cortopassi, Elena Dedkova, PO-01-126 SEXUAL DIMORPHISM AND CARDIAC ARRHYTHMIAS IN A MOUSE MODEL OF FRIEDREICH'S ATAXIA: WHAT DO WE KNOW?, Heart Rhythm, Volume 20, Issue 5, Supplement, 2023, Page S141, doi.:10.1016/j.hrthm.2023.03.489. 

Our study revealed sexual dimorphism and significant impairment in electrical and contractile function in FXN cKO males compared to females. A detailed characterization of impaired electrical signals in FA hearts will build a platform for drug testing to treat lethal cardiomyopathy in FA.

THE CALCIUM HANDLING MACHINERY IS REMODELED IN FRIEDREICH’S ATAXIA

Bojjibabu Chidipi, Roman Czornobil, Elizabeth Remily-Wood, David R. Lynch, Sami F. Noujaim, PO-01-124 THE CALCIUM HANDLING MACHINERY IS REMODELED IN FRIEDREICH’S ATAXIA, Heart Rhythm, Volume 20, Issue 5, Supplement, 2023, Page S140, doi:10.1016/j.hrthm.2023.03.487. 

The development of left ventricular contractile dysfunction in FA is associated with reduced expression of calcium handling proteins, abnormal calcium cycling, and mitochondrial dysfunction.