Design Therapeutics Provides Pipeline Updates and Reports First Quarter 2023 Financial Results

CARLSBAD, Calif., May 09, 2023 (GLOBE NEWSWIRE) -- Design Therapeutics, Inc. 

Initial Data from Ongoing Phase 1 MAD Trial of DT-216 for FA Expected in the Third Quarter of 2023: Design is evaluating its lead GeneTAC™ small molecule, DT-216, in an ongoing Phase 1 MAD clinical trial designed to evaluate the safety, tolerability, pharmacokinetic, biodistribution, and pharmacodynamic effects of three weekly doses of DT-216 in adults with FA. FA is a multisystem degenerative disease caused by a GAA nucleotide repeat expansion in the frataxin (FXN) gene that impairs transcription and reduces FXN mRNA. DT-216 is designed to specifically target the GAA repeat expansion mutation and restore FXN gene expression. An unanticipated vendor issue related to the study drug vial stopper caused a short delay in product supply, which has been resolved. Design now anticipates presenting initial results from the MAD trial in the third quarter of 2023. The company plans to initiate a Phase 2 trial in the second half of 2023.

Omaveloxolone: First Approval

Lee A. Omaveloxolone: First Approval. Drugs. 2023 May 8. doi: 10.1007/s40265-023-01874-9. Epub ahead of print. PMID: 37155124. 

Omaveloxolone (SKYCLARYS™) is an orally active, small molecule semi-synthetic triterpenoid drug that increases antioxidant activity, which is being developed by Reata Pharmaceuticals, Inc. for the treatment of Friedreich's ataxia. In patients with Friedreich's ataxia, the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway is suppressed, which is associated with oxidative stress, mitochondrial dysfunction and damage to cells, including central and peripheral neurones. The Nrf2 pathway may be activated by omaveloxolone as it blocks the ubiquitination and degradation of Nrf2. Omaveloxolone was approved in February 2023 in the USA for the treatment of Friedreich's ataxia. This article summarizes the milestones in the development of omaveloxolone leading to this first approval for the treatment of Friedreich's ataxia in adults and adolescents aged 16 years and older.

Omaveloxolone (SkyclarysTM) for patients with Friedreich’s ataxia

Sharadha Dayalan Naidu, Albena T. Dinkova-Kostova, Omaveloxolone (SkyclarysTM) for patients with Friedreich’s ataxia, Trends in Pharmacological Sciences, 2023, doi:10.1016/j.tips.2023.03.005.

Omaveloxolone is the first and only FDA-approved drug for patients with Friedreich’s ataxia. Omaveloxolone has received Orphan Drug, Fast Track, and Rare Pediatric Disease Designations from the FDA, and Orphan Drug Designation for the treatment of Friedreich’s ataxia from the European Commission. It is currently not approved outside of the USA.

A systematic overview of rare disease patient registries: challenges in design, quality management, and maintenance

Hageman, I.C., van Rooij, I.A., de Blaauw, I. et al. A systematic overview of rare disease patient registries: challenges in design, quality management, and maintenance. Orphanet J Rare Dis 18, 106 (2023). doi:10.1186/s13023-023-02719-0 

Rare disease patient registries are valuable for research and evaluation of clinical care, and an increasing number have emerged. However, registries need to be continuously evaluated for data quality and long-term sustainability to remain relevant for future use.

Ketolysis is required for the proper development and function of the somatosensory nervous system

Enders J, Jack J, Thomas S, Lynch P, Lasnier S, Cao X, Swanson MT, Ryals JM, Thyfault JP, Puchalska P, Crawford PA, Wright DE. Ketolysis is required for the proper development and function of the somatosensory nervous system. Exp Neurol. 2023 Apr 24:114428. doi: 10.1016/j.expneurol.2023.114428. Epub ahead of print. PMID: 37100111. 

We conclude that ketone metabolism is essential for the development of the somatosensory nervous system. These findings also suggest that decreased ketone oxidation in the somatosensory nervous system may explain the neurological symptoms of Friedreich's ataxia.

Natural History Studies Drive Data Sharing, Drug Approval

Heidt, A. (2023, May 1). Natural history studies drive data sharing, drug approval. Retrieved May 1, 2023, from BioSpace website: https://www.biospace.com/article/natural-history-studies-drive-data-sharing-drug-approval/ 

Two recent announcements—the world’s first treatment for Friedreich's ataxia (FA), whose approval was based in part on a natural history database, and a new data-sharing agreement between industry and nonprofit partners to investigate myopathy—underpin just how helpful these studies can be in establishing new collaborations to tackle rare diseases.

Mapa epidemiológico transversal de las ataxias y paraparesias espásticas hereditarias en España

G. Ortega Suero, M.J. Abenza Abildúa, C. Serrano Munuera, I. Rouco Axpe, F.J. Arpa Gutiérrez, A.D. Adarmes Gómez, F.J. Rodríguez de Rivera, B. Quintans Castro, I. Posada Rodríguez, A. Vadillo Bermejo, Á. Domingo Santos, E. Blanco Vicente, I. Infante Ceberio, J. Pardo Fernández, E. Costa Arpín, C. Painous Martí, J.E. Muñoz, P. Mir Rivera, F. Montón Álvarez, L. Bataller Alberola, J. Gascón Bayarri, C. Casasnovas Pons, V. Vélez Santamaría, A. López de Munain, G. Fernández-Eulate, J. Gazulla Abío, I. Sanz Gallego, L. Rojas Bartolomé, Ó. Ayo Martín, T. Segura Martín, C. González Mingot, M. Baraldés Rovira, R. Sivera Mascaró, E. Cubo Delgado, A. Echavarría Íñiguez, F. Vázquez Sánchez, M. Bártulos Iglesias, M.T. Casadevall Codina, E.M. Martínez Fernández, C. Labandeira Guerra, B. Alemany Perna, A. Carvajal Hernández, C. Fernández Moreno, M. Palacín Larroy, N. Caballol Pons, A. Ávila Rivera, F.J. Navacerrada Barrero, R. Lobato Rodríguez, M.J. Sobrido Gómez, Mapa epidemiológico transversal de las ataxias y paraparesias espásticas hereditarias en España (Epidemiology of ataxia and hereditary spastic paraplegia in Spain: a cross-sectional study), Neurología (English Edition), 2023, doi.org/:10.1016/j.nrleng.2023.04.003. 

 In our sample, the estimated prevalence of ataxia and hereditary spastic paraplegia was 7.73 cases per 100 000 population. This rate is similar to those reported for other countries. Genetic diagnosis was not available in 47.6% of cases. Despite these limitations, our study provides useful data for estimating the necessary healthcare resources for these patients, raising awareness of these diseases, determining the most frequent causal mutations for local screening programmes, and promoting the development of clinical trials.

Short-read genome sequencing allows ‘en route’ diagnosis of patients with atypical Friedreich ataxia

Fleszar, Z., Dufke, C., Sturm, M. et al. Short-read genome sequencing allows ‘en route’ diagnosis of patients with atypical Friedreich ataxia. J Neurol (2023). doi:10.1007/s00415-023-11745-8 

We here showcase how the introduction of short-read genome sequencing (SR-GS) allows to overcome these biases in the work-up of complex ataxias, as it allows to detect even intronic STRs (i) “en route”, i.e. with detection not requiring any primary direct gene analysis; and (ii) in a phenotype-independent fashion”, i.e. also for those atypical phenotypic presentations where the corresponding gene and mutational mechanism had not been part of the prior differential clinical diagnosis.

Communicating Health Literacy on Prescription Medications on Social Media: In-depth Interviews With “Patient Influencers”

Willis E, Friedel K, Heisten M, Pickett M, Bhowmick A; Communicating Health Literacy on Prescription Medications on Social Media: In-depth Interviews With “Patient Influencers”, J Med Internet Res 2023;25:e41867, URL: https://www.jmir.org/2023/1/e41867, DOI: 10.2196/41867 

This study aimed to explore how patient influencers communicate health literacy on pharmaceutical medications on social media to their communities of followers.

Adenosine Improves Mitochondrial Function and Biogenesis in Friedreich’s Ataxia Fibroblasts Following L-Buthionine Sulfoximine-Induced Oxidative Stress

Lew, S.Y.; Mohd Hisam, N.S.; Phang, M.W.L.; Syed Abdul Rahman, S.N.; Poh, R.Y.Y.; Lim, S.H.; Kamaruzzaman, M.A.; Chau, S.C.; Tsui, K.C.; Lim, L.W.; Wong, K.H. Adenosine Improves Mitochondrial Function and Biogenesis in Friedreich’s Ataxia Fibroblasts Following L-Buthionine Sulfoximine-Induced Oxidative Stress. Biology 2023, 12, 559. doi:10.3390/biology12040559 

 Our study demonstrated that adenosine targeted mitochondrial defects in FRDA, contributing to improved mitochondrial function and biogenesis, leading to cellular iron homeostasis. Therefore, we suggest a possible therapeutic role for adenosine in FRDA.