Omaveloxolone for the Treatment of Friedreich’s Ataxia

Riley Kessler, Sonal Sharma, David R Lynch, Omaveloxolone for the Treatment of Friedreich’s Ataxia, Published Online: Aug 9th 2023 touchREVIEWS in Neurology. 2023;19(2):Online ahead of journal publication. 

 This review discusses the underlying cellular pathology and proposed mechanism of omaveloxolone in FRDA. The MOXIe study is presented in detail, including a discussion of the challenges faced in clinical trials in FRDA, and rare diseases more broadly. Finally, other therapies under investigation are reviewed briefly.

CRISPR/Cas9 Genome Editing for Tissue-Specific In Vivo Targeting: Nanomaterials and Translational Perspective

Sahel DK, Vora LK, Saraswat A, et al. CRISPR/Cas9 Genome Editing for Tissue-Specific In Vivo Targeting: Nanomaterials and Translational Perspective. Advanced Science (Weinheim, Baden-wurttemberg, Germany). 2023 Jul;10(19):e2207512. DOI: 10.1002/advs.202207512. PMID: 37166046; PMCID: PMC10323670. 

Despite DSBs, they have also been explored through epigenome editing and biosensor applications. However, its in vivo delivery is still a major challenge. Interestingly, ample nonviral nanocarriers have been developed and explored for the in vivo delivery of CRISPR components, but they are limited to some immune-prone organs of the body, such as the liver, lungs, or spleen. 

However, various pharmaceutical companies are showing interest in the CRISPR therapeutics area, and therefore, it will be interesting to watch the progress in this field. Since both ethical and social implications are associated with the usage of CRISPR, we need to move forward very responsibly.

Preparing for Disease-Modification Trials in Degenerative Cerebellar Ataxias: Which Endpoints to Choose?

Maas RPPWM. Preparing for Disease-Modification Trials in Degenerative Cerebellar Ataxias: Which Endpoints to Choose? Movement Disorders : Official Journal of the Movement Disorder Society. 2023 Jun;38(6):917-923. DOI: 10.1002/mds.29388. PMID: 37475615.

Brain MRI detects early-stage alterations and disease progression in Friedreich ataxia

Adanyeguh IM, Joers JM, Deelchand DK, et al. Brain MRI detects early-stage alterations and disease progression in Friedreich ataxia. Brain Communications. 2023 ;5(4):fcad196. DOI: 10.1093/braincomms/fcad196. PMID: 37483529. 

 We show that fixel-based analysis of diffusion MRI data is particularly sensitive to longitudinal change in the cerebellar peduncles, as well as motor and sensory white matter tracts. In combination with other morphometric measures, they may therefore provide sensitive imaging biomarkers of disease progression for clinical trials.

Recent advances in small molecules for improving mitochondrial disorders

Meng L, Wu G. Recent advances in small molecules for improving mitochondrial disorders. RSC Advances. 2023 Jul;13(30):20476-20485. DOI: 10.1039/d3ra03313a. PMID: 37435377; PMCID: PMC10331567. 

 This review focuses on the latest advances in developing bioactive compounds for treating mitochondrial disease, aiming to provide a broader perspective of fundamental studies that have been carried out to evaluate the effects of small molecules in regulating mitochondrial function. Novel-designed small molecules ameliorating mitochondrial functions are urgent for further research.

Patient-reported, health economic and psychosocial outcomes in patients with Friedreich ataxia (PROFA): protocol of an observational study using momentary data assessments via mobile health app

Buchholz M, Weber N, Borel S, et alPatient-reported, health economic and psychosocial outcomes in patients with Friedreich ataxia (PROFA): protocol of an observational study using momentary data assessments via mobile health appBMJ Open 2023;13:e075736. doi: 10.1136/bmjopen-2023-075736 

The symptoms affect the patients’ health-related quality of life (HRQoL) and psychosocial health. FA leads to an increasing need for care, associated with an economic burden. Little is known about the impact of FA on daily lives and HRQoL. To fill that gap, we will assess patient-reported, psychosocial and economic outcomes using momentary data assessment via a mobile health application (app).

The use of digital outcome measures in clinical trials in rare neurological diseases: a systematic literature review

Poleur, M., Markati, T. & Servais, L. The use of digital outcome measures in clinical trials in rare neurological diseases: a systematic literature review. Orphanet J Rare Dis 18, 224 (2023). doi:10.1186/s13023-023-02813-3 

 We found two studies of patients with FRDA that used inertial technology. Remote monitoring of several voice parameters, upper limb function through 14 parameters that can be grouped into parameters related to movement velocity, spectral frequency, and parameters related to deviation of the ideal trajectory, and 15 spatiotemporal gait parameters was feasible over 1 week. The sensitivity of an upper limb composite score, the AIM-S, obtained through sensors contained in a spoon designed to detect deterioration in upper limb function, was greater than other measures.

Biogen to Acquire Reata Pharmaceuticals

CAMBRIDGE, Mass. and PLANO, Texas, July 28, 2023 (GLOBE NEWSWIRE) -- Biogen Inc. (Nasdaq: BIIB) and Reata Pharmaceuticals, Inc. (Nasdaq: RETA) today announced the companies have entered into a definitive agreement under which Biogen has agreed to acquire Reata for $172.50 per share in cash, reflecting an enterprise value of approximately $7.3 billion. 

Reata has made significant advancements developing therapeutics that regulate cellular metabolism and inflammation in serious neurologic diseases. Reata’s FDA-approved SKYCLARYS® (omaveloxolone) is the first and only approved treatment for Friedreich’s ataxia (FA) in the United States, with a commercial launch underway, and European regulatory review ongoing. In addition, Reata is developing a portfolio of innovative products for a range of neurological diseases.

Larimar Therapeutics Receives FDA Clearance to Proceed to 50 mg Cohort in CTI-1601’s Phase 2 Friedreich's Ataxia Trial and to Initiate Open Label Extension Trial

BALA CYNWYD, Pa., July 25, 2023 (GLOBE NEWSWIRE). Larimar Therapeutics, Inc.. Today announced that the U.S. Food and Drug Administration (FDA) has cleared the Company’s four-week, placebo-controlled, Phase 2 dose exploration trial of CTI-1601 in patients with Friedreich's ataxia (FA) to proceed to a 50 mg cohort in which participants will be dosed daily for the first 14 days, and then every other day until day 28. In addition, Larimar’s open label extension (OLE) trial was also cleared for initiation by the FDA. Participants in the OLE will receive 25 mg of CTI-1601 daily. CTI-1601 is a novel protein replacement therapy designed to deliver frataxin to the mitochondria of patients with FA who have low levels of frataxin. 

Larimar received clearance to advance its Phase 2 trial to a 50 mg cohort and initiate its OLE trial following a review by the FDA of Larimar’s complete response to its partial clinical hold that included unblinded safety, pharmacokinetic (PK), and pharmacodynamic (PD) data from the Phase 2 trial’s completed 25 mg cohort. Data from the completed 25 mg cohort (n = 13) indicated that CTI-1601 was generally well tolerated and showed increases in frataxin (FXN) levels from baseline compared to placebo in all evaluated tissues (skin and buccal cells) at day 14 (the final day of daily dosing in the trial). Further dose escalation in the Phase 2 and OLE trials and the initiation of additional U.S. clinical trials evaluating CTI-1601 are contingent on FDA review of results from the Phase 2 trial’s 50 mg cohort in accordance with a partial clinical hold.

“Gaining clearance to advance to a 50 mg cohort in our Phase 2 trial and initiate the OLE trial are crucial steps in CTI-1601’s development as potentially the first therapy to increase frataxin levels in patients with FA,” said Carole Ben-Maimon, MD, President, and Chief Executive Officer of Larimar. “Given the inability of current treatments to address the frataxin deficiency underlying Friedreich's ataxia, we believe CTI-1601 has the potential to improve the treatment paradigm for this devastating disease. We now look forward to data from our Phase 2 trial’s 50 mg cohort in the first half of 2024, which will help us further characterize the safety and PK profiles of CTI-1601 and its ability to increase frataxin levels in a dose-dependent fashion as seen in our earlier Phase 1 studies.”

Leriglitazone

National Center for Biotechnology Information. PubChem Compound Summary for CID 4147757, Hydroxypioglitazone. https://pubchem.ncbi.nlm.nih.gov/compound/Hydroxypioglitazone. Accessed July 23, 2023.