Therapeutic Potential of Dimethyl Fumarate to Treat Friedreich Ataxia: Francesco Saccà, MD, PhD

NeurologyLive. March 28, 2024. Fracesco Saccà, MD, PhD In an interview with NeurologyLive®, Saccà discussed the idea behind the study and the reasons to assess dimethyl fumarate. He spoke on the mechanism of action of the therapy, the research that led up to this point, and some of the intricacies about the study. He also spoke on the fact that omaveloxolone’s ability to improve patients’ condition without impacting frataxin has opened the door for other potential therapies to hopefully do the same.

Novel approach for evaluation of mitochondrial substrate utilization in fibroblasts from patients with Friedreich’s ataxia

Ahmadian N, Dallas S, Dedkova EN. Novel approach for evaluation of mitochondrial substrate utilization in fibroblasts from patients with Friedreich’s ataxia. Biophysical Journal. 8 de febrero de 2024;123(3):523a. doi:10.1016/j.bpj.2023.11.3162

We found that FA fibroblasts had decreased utilization of alpha-ketoglutaric, succinic, fumaric and malic acids. Utilization of alpha-keto-butyric acid was not changed, however, utilization of D, L-beta-hydroxybutyric acid was decreased in FA fibroblasts as compared to control cells. At the same time utilization of acetyl-L-carnitine and palmitoyl-D,L-carnitine was increased in FA fibroblasts. Utilization of L-glutamic acid, L-glutamine, L-ornithine, glycine/alanine and tryptamine was decreased in FA fibroblasts.     

Using synthetic genome readers/regulators to interrogate chromatin processes: A brief review

Philips SJ, Danda A, Ansari AZ. Using synthetic genome readers/regulators to interrogate chromatin processes: A brief review. Methods. 1 de mayo de 2024;225:20-7. doi:10.1016/j.ymeth.2024.03.001

 A major challenge for designing small molecule therapeutics aimed at targeting desired genomic loci is the minimization of widescale disruption of genomic functions. To address this challenge, we rationally design polyamide-based multi-functional molecules, i.e., Synthetic Genome Readers/Regulators (SynGRs), which, by design, target distinct sequences in the genome. Herein, we briefly review how SynGRs access chromatin-bound and chromatin-free genomic sites, then highlight the methods for the study of chromatin processes using SynGRs on positioned nucleosomes in vitro or disease-causing repressive genomic loci in vivo.

Unique combinations of ultrasound and electrophysiological findings distinguish Friedreich’s ataxia from other inherited ataxias

Pelosi L, Mulroy E, Leadbetter R, Rodrigues M, Roxburgh R. Unique combinations of ultrasound and electrophysiological findings distinguish Friedreich’s ataxia from other inherited ataxias. Clinical Neurophysiology. 1 de mayo de 2024;161:157-8. doi:10.1016/j.clinph.2024.02.035

Larimar Triumphs: Significant Strides Made on the Road to Treating Friedreich’s Ataxia

BALA CYNWYD, PA — Larimar Therapeutics, Inc. March 19, 2024 

 In their ongoing discussions with the FDA, Larimar is working on a potential use of frataxin as a novel surrogate endpoint. This may unlock the potential for accelerated approval. Moreover, the company is planning for a global double-blind placebo-controlled confirmatory study. The study is expected to be initiated before the potential BLA (Biologics License Application) is submitted. The targeted timeline for the submission is the second half of 2025.

Design Therapeutics, Inc. (NASDAQ:DSGN) Q4 2023 Earnings Call Transcript

Published on March 19 on Seeking Alpha. Transcripts.

We learned from the human studies that the duration of adequate levels of exposure of DT-216 was much shorter than expected. While we knew that the drug was short-lived in plasma. Human studies showed by muscle biopsy that it was also short-lived in tissue and that what you observe in plasma is predictive of what is observed in tissue. 

 The tissue levels from human muscle biopsies were approximately only eight to 10 nanomolar at day two, and the drug was almost gone with levels of one nanomolar by day seven. Well, despite that, there was a clear increase in frataxin expression observed in treated patients in a dose dependent fashion with one patient frataxin level, going to clinically normal carrier levels as shown in the right. However, the effect was transient because the drug exposure was transient, so we needed to develop a new drug product that could sustain this drug exposure. While the drug was generally well tolerated, there were injection site thrombophlebitis events observed, which limited the frequency and levels of dosing with the prior product candidate. Nonclinical studies showed that these reactions were attributable to the formulation excipients in the drug product. 

We have now conducted new non GLP animal studies with DT-216P2, which lead us to believe that these issues have now been solved and we can progress to confirmatory GLP studies to get back into the clinic. Furthermore, this new drug product appears suitable for IV administration, compatible with injections or infusions, peripheral or central, and also appears suitable for a subcutaneous route of administration. As we showed in the beginning, the new drug product, DT-216P2 has a much more sustained exposure profile as seen in the single dose ID PK curve from non-human primates.

Stealth BioTherapeutics Presents Data of Novel Compound, SBT-589, in Friedreich's Ataxia Cardiac Models at the Wellcome Trust Mitochondrial Medicine Conference

NEEDHAM, Mass., March 19, 2024 /PRNewswire/ -- Stealth Biotherapeutics Inc. 

SBT-589 showed mitochondrial protection across models of Friedreich's ataxia. SBT-589 displayed cardioprotective effects in aggressive mouse model of FA cardiomyopathy. Ongoing studies are expected to build on these insights as SBT-589 progresses through developmental stage-gates. Stealth Biotherapeutics Inc. announced today the presentation of new SBT-589 data demonstrating cardioprotective effects across pre-clinical models of Friedreich's ataxia (FA). 

The data were presented at the Wellcome Trust Conference on Mitochondrial Medicine – Therapeutic Development, held March 18-20, 2024, in Cambridge, England. 

SBT-589 is a promising novel molecule that acts on mitochondrial pathways essential for cellular health and energy production that are impaired in FA cardiomyopathy. To evaluate the potential of SBT-589 in FA, a series of studies were conducted in FA patient-derived cells, isolated heart mitochondria, and an aggressive mouse model of FA cardiomyopathy. SBT-589 improved bioenergetics in FA patient-derived cells and mitochondria. In an FA mouse model with prominent cardiac hypertrophy and aggressive mortality, mice treated with once-daily SBT-589 displayed significantly reduced cardiac hypertrophy and a delay in the onset of mortality compared to vehicle-treated mice. The new findings presented today support continued development of SBT-589 as a potentially disease-modifying therapy to address the unmet need in cardiomyopathy associated with Friedreich's ataxia."

Design Therapeutics Outlines Progress Across GeneTAC™ Platform and Announces Fourth Quarter and Full Year 2023 Financial Results

CARLSBAD, Calif., March 19, 2024 (GLOBE NEWSWIRE) -- Design Therapeutics, Inc.. 

New Drug Product for Friedreich Ataxia (FA) DT-216P2 with Favorable Nonclinical Pharmacokinetic and Injection Site Safety Profile; Complete GLP Studies by Year-end 2024 to Start Patient Trials in 2025. 

Friedreich Ataxia (FA) Design has developed a new drug product, DT-216P2, for patients with FA that demonstrates an improved pharmacokinetic (PK) profile and a favorable injection site safety profile in nonclinical studies. When compared to the prior formulation, DT-216P2 demonstrated greater than 10-fold exposures that are more sustained over time. DT-216P2 also appears suitable for intravenous or subcutaneous routes of administration. 

 Design previously reported Phase 1 data using its prior formulation that showed increased levels of frataxin (FXN) mRNA in peripheral blood cells and skeletal muscle, confirming activity in patients with FA. Based on these findings, Design is advancing DT-216P2 for FA, with plans to complete GLP studies by year-end 2024 to start patient trials in 2025.

Accelerometer-based measures in Friedreich ataxia: a longitudinal study on real-life activity

Accelerometer-based measures in Friedreich ataxia: a longitudinal study on real-life activity. Front. Pharmacol., 19 March 2024, Sec. Neuropharmacology, Volume 15, 2024, doi:10.3389/fphar.2024.1342965   

Real-life activity monitoring is feasible and well tolerated by patients. Accelerometer-based measures can quantify disease progression in FRDA over 1 year, providing objective information about patient’s motor activities and supporting the usefulness of these data as complementary outcome measure in interventional trials.

P003: Clinical laboratory experience of frataxin quantification in blood for the diagnosis of Friedreich ataxia*

Iris Pantovich, Amy White, April Studinski, Weiyi Mu, Bonnie Kaas, Matthew Bower, Gisele Pino, Dawn Peck, Kyle Salsbery, Emily Lauer, Angela Pickart, Kandelaria Rumilla, Wei Shen, Zhiyv Niu, Patricia Hall, Matthew Schultz, Dimitar Gavrilov, Silvia Tortorelli, Dietrich Matern, Ralitza Gavrilova, Devin Oglesbee, P003: Clinical laboratory experience of frataxin quantification in blood for the diagnosis of Friedreich ataxia*, Genetics in Medicine Open, Volume 2, Supplement 1, 2024, 100880, ISSN 2949-7744, doi:10.1016/j.gimo.2024.100880. 

Since 2011, our laboratory has offered a protein-based clinical assay to quantify frataxin concentrations in blood that is useful for low-cost, rapid FA screening and diagnosis. Here, we summarize our laboratory experience.

Larimar Therapeutics Reports Fourth Quarter and Full Year 2023 Operating and Financial Results and Provides Update on Nomlabofusp Development

BALA CYNWYD, Pa., March 14, 2024 (GLOBE NEWSWIRE). 

Positive top-line data from Phase 2 dose exploration study of nomlabofusp, which was generally well-tolerated, with dose-dependent increases in tissue frataxin levels observed 

Initiated discussions with the Food and Drug Administration (FDA) on the potential use of tissue frataxin levels as a novel surrogate endpoint to support a Biologics License Application (“BLA”) submission for accelerated approval targeted for 2H 2025 

In January 2024, initiated open label extension (OLE) study with 25 mg daily dosing of nomlabofusp, with first patient dosed in March 2024; interim data expected in Q4 2024

Standing Balance Conditions and Digital Sway Measures for Clinical Trials of Friedreich's Ataxia

Casey, H.L., Shah, V.V., Muzyka, D., McNames, J., El-Gohary, M., Sowalsky, K., Safarpour, D., Carlson-Kuhta, P., Schmahmann, J.D., Rosenthal, L.S., Perlman, S., Rummey, C., Horak, F.B. and Gomez, C.M. (2024), Standing Balance Conditions and Digital Sway Measures for Clinical Trials of Friedreich's Ataxia. Mov Disord. doi:10.1002/mds.29777

 Three of the six standing conditions had completion rates over 70%. Of these three conditions, natural stance and feet together with EO showed the greatest completion rates. All six of the sway measures' mean values were significantly different between FRDA and HC. Four of these six measures discriminated between groups with >0.9 AUC in all three conditions. The Friedreich Ataxia Rating Scale Upright Stability and Total scores correlated with sway measures with P-values

Larimar Therapeutics Announces the Dosing of the First Patient in Long-term Open Label Extension Study for Nomlabofusp in Patients with Friedreich’s Ataxia

BALA CYNWYD, Pa., March 11, 2024 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (“Larimar”) (Nasdaq: LRMR), a clinical-stage biotechnology company focused on developing treatments for complex rare diseases, today announced dosing of the first patient in an open label extension (OLE) study evaluating 25 mg daily subcutaneous injections of nomlabofusp in participants with Friedreich’s ataxia (FA). Nomlabofusp (CTI-1601) is a novel protein replacement therapy designed to address the root cause of Friedreich's ataxia (FA) by delivering frataxin to mitochondria.

Lexeo Therapeutics Reports Fourth Quarter and Full Year 2023 Financial Results and Operational Highlights

NEW YORK, March 11, 2024 (GLOBE NEWSWIRE). LX2006 for the Treatment of FA Cardiomyopathy: Announced preliminary frataxin protein expression data from the second dose cohort of SUNRISE-FA showing positive change in post-treatment frataxin levels three months following administration of LX2006. Lexeo expects to report additional interim data from the SUNRISE-FA Phase 1/2 clinical trial in mid-2024 with follow-up out to one year from the low-dose and multiple timepoints of follow-up expected from at least three patients treated at the mid-dose.

Generation and characterization of iPSC lines from Friedreich’s ataxia patient (FRDA) with GAA.TTC repeat expansion in the Frataxin (FXN) gene’s first intron (IGIBi016-A) and a non-FRDA healthy control individual (IGIBi017-A)

Istaq Ahmad, Asangla Kamai, Sana Zahra, Himanshi Kapoor, Achal Kumar Srivastava, Mohammed Faruq, Generation and characterization of iPSC lines from Friedreich’s ataxia patient (FRDA) with GAA.TTC repeat expansion in the Frataxin (FXN) gene’s first intron (IGIBi016-A) and a non-FRDA healthy control individual (IGIBi017-A), Stem Cell Research, 2024, 103382, doi:10.1016/j.scr.2024.103382.

Here, we developed iPSC lines from an FRDA patient (IGIBi016-A) and non-FRDA healthy control (IGIBi017-A). Both iPSC lines displayed typical iPSC morphology with pluripotency marker expression, regular karyotypes (46, XY; 46, XX), capacity to grow into three germ layers, and FRDA hallmark -GAA repeat expansion and decreased FXN mRNA. Through these iPSC lines, FRDA phenotypes may be replicated in the in vitro assays, by creating neuron subtypes, cardiomyocytes and 3D organoids, for molecular and cellular biomarkers and therapeutic applications.

Regulatory Pathway Widening for Cardiac Gene Therapy Hopefuls

Published: Mar 11, 2024. www.biospace.com 

Lexeo Therapeutics is developing a gene therapy, LX2006, for Friedreich’s ataxia cardiomyopathy, for which the FDA has granted Rare Pediatric Disease designation and Orphan Drug designation. 

 In its Friedreich’s ataxia program, Lexeo is using both invasive and non-invasive biomarkers pretreatment and post-treatment to evaluate the one-time gene therapy’s efficacy. Townsend said he hopes the biomarker data will lead to an accelerated approval.

Vestibular Pathology as Early Finding of Friedreich's Ataxia in a 16 Years Old Woman

Fernández AG. Vestibular Pathology as Early Finding of Friedreich's Ataxia in a 16 Years Old Woman. Indian J Otolaryngol Head Neck Surg. 2024 Feb;76(1):1247-1250. doi: 10.1007/s12070-023-04249-4. Epub 2023 Oct 5. PMID: 38440644; PMCID: PMC10908728. 

 The development of vestibular pathology is common but not completely understood. A 16 years old woman with early vestibular defects in relation to a latter Friedreich's ataxia diagnosis is reported.

Frataxin Traps Low Abundance Quaternary Structure to Stimulate Human Fe-S Cluster Biosynthesis

1. Cory S, Lin C-W, Havens S, Patra S, Putnam C, Shirzadeh M, et al. Frataxin Traps Low Abundance Quaternary Structure to Stimulate Human Fe-S Cluster Biosynthesis. ChemRxiv. 2024; doi:10.26434/chemrxiv-2024-v0gw7 

 This content is a preprint and has not been peer-reviewed. The findings support architectural switching as a regulatory mechanism linked to FXN activation of the human Fe-S cluster biosynthetic complex and provide new opportunities for therapeutic interventions of the fatal neurodegenerative disease FRDA.

Characterization of Cardiac-Onset Initial Presentation in Friedreich Ataxia

Lynch, D.R., Subramony, S., Lin, K.Y. et al. Characterization of Cardiac-Onset Initial Presentation in Friedreich Ataxia. Pediatr Cardiol (2024). doi:10.1007/s00246-024-03429-5 

The present study shows that some FRDA patients present based on cardiac features, suggesting that earlier identification of FRDA might occur through enhancing awareness of FRDA among pediatric cardiologists who see such patients. This is important in the context of newly identified therapies for FRDA

Prime Medicine Reports Full Year 2023 Financial Results and Provides Business Updat

CAMBRIDGE, Mass., March 01, 2024 (GLOBE NEWSWIRE) -- Prime Medicine, Inc. (Nasdaq: PRME), a biotechnology company committed to delivering a new class of differentiated one-time curative genetic therapies, today reported financial results for the full year ended December 31, 2023 and provided a business update. 

-Continue to advance Friedreich’s Ataxia and advance one other program into lead optimization in 2024. --In large animal studies, establish adeno-associated virus (AAV) delivery platform and route of administration for neuromuscular programs in 2024.

After pair of failures, PTC finds a path through FDA jungle for Friedreich ataxia med

https://www.fiercebiotech.com. By Annalee Armstrong; Mar 1, 2024. In a fourth-quarter earnings update Thursday afternoon, PTC executives briefed investors on the results of a type C meeting with the FDA where they pled their case for using a subscale called upright stability to show efficacy using data already collected in the phase 3 MOVE-FA trial. 

PTC’s candidate for the disorder failed to move the needle on the modified Friedreich Ataxia Rating Scale (mFARS), which measures disease progression. The therapy had little impact on the lower and upper limbs, which led to the failure. Despite the primary endpoint miss, PTC saw a glimmer of efficacy in the data, pointing to the upright stability subscales. 

PTC is expecting to file the NDA for vatiquinone in late 2024. Klein said an open-label trial is currently ongoing, which will be used to support the package and could also provide confirmatory evidence if the FDA agrees to the accelerated review. For that type of approval, companies can get an advanced go-ahead to market a drug based on biomarker data but must later provide confirmatory evidence to show benefit.

PTC Therapeutics Provides Corporate Update and Reports Fourth Quarter and Full Year 2023 Financial Results

SOUTH PLAINFIELD, N.J., Feb. 29, 2024 /PRNewswire/ -- PTC Therapeutics, Inc. PTC had a Type C meeting with the FDA in the first quarter of 2024 to discuss the vatiquinone Friedreich ataxia program. Based on discussions with the FDA, PTC has a potential path to an NDA submission in late 2024 based on the placebo-controlled results of MOVE-FA, along with data from the ongoing open-label extension study.