PTC Therapeutics (PTCT) Q1 2025 Earnings Call

May 6, 2025. Vatiquinone (Friedreich's Ataxia): FDA review proceeding without AdCom; confirmatory evidence from long-term data compared to FA-COMS natural history registry showing a reported 50% slowing in disease progression over three years.

Omaveloxolone for treating Friedreich’s ataxia in people 16 years and over (terminated appraisal)

National Institute for Health and Care Excellence (NICE). 06 May 2025. 

NICE is unable to make a recommendation on omaveloxolone (Skyclarys) for treating Friedreich’s ataxia in people 16 years and over. This is because Biogen withdrew its evidence submission.

Anti-gene oligonucleotides targeting Friedreich’s ataxia expanded GAA•TTC repeats increase Frataxin expression

Negin Mozafari, Salomé Milagres, Tea Umek, Cristina S.J. Rocha, Claudia Marina Vargiu, Fiona Freyberger, Osama Saher, Marek Napierala, Jill S. Napierala, Pontus Blomberg, Per T. Jørgensen, Tanel Punga, C. I. Edvard Smith, Jesper Wengel, Rula Zain, Anti-gene oligonucleotides targeting Friedreich’s ataxia expanded GAA•TTC repeats increase Frataxin expression, Molecular Therapy Nucleic Acids, 2025, 102541, doi:10.1016/j.omtn.2025.102541. 

Friedreich’s ataxia is a progressive, autosomal recessive ataxia caused, in most cases, by homozygous expansion of GAA•TTC triplet-repeats in the first intron of the frataxin gene. GAA•TTC repeat expansion results in the formation of a non-B DNA intramolecular triplex as well as changes in the epigenetic landscape at the frataxin locus. Expansion of intronic GAA•TTC repeats is associated with reduced levels of frataxin mRNA and protein, resulting in disease development. In our previous study, we demonstrated that DNA-binding anti-gene oligonucleotides specifically targeting the GAA•TTC repeat expansion effectively disrupted the formation of intramolecular triplex structures. In this study, we extend these findings by showing that targeting repeat-expanded chromosomal DNA with anti-gene oligonucleotides leads to an increase in frataxin mRNA and protein levels in cells derived from Friedreich’s ataxia patients. We examined numerous anti-gene oligonucleotides and found that the design, length, and their locked nucleic acid composition have a high impact on the effectiveness of the treatment. Collectively, our results demonstrate the unique capability of specifically designed oligonucleotides targeting the GAA•TTC DNA repeats to upregulate frataxin gene expression.

Hepatic Manifestations Following Gene Therapy

Akash Roy, Shalini Bansal, Anand Kulkarni, K. Rajender Reddy, Hepatic Manifestations Following Gene Therapy, Gastro Hep Advances, 2025, 100681, ISSN 2772-5723, doi:10.1016/j.gastha.2025.100681.

 Abstract: Gene therapy (GT) involves the introduction of genetic materials, most commonly using viral vectors, to alter gene expression to ameliorate or cure disease symptoms and with minimal adverse events. While interest in GT has been on the increase, concerns have arisen about the potential for hepatotoxicity, which arises from diverse mechanisms. While viral vectors can produce dose-dependent hepatotoxicity secondary to integration, immune responses appear to be the primary driving mechanism. A mild increase in aminotransferases is the most common hepatic manifestation, occurring variably in 20-80%, while there has been rare progress to acute liver failure. The occurrence of hepatotoxicity is unpredictable and can vary depending on patient comorbidities, vector dose, vector type, and degree of immune activation. Pre-treatment screening for underlying chronic liver disease and exclusion of advanced fibrosis or cirrhosis using non-invasive tests is essential. Literature on liver biopsy pre and post-therapy is limited, but small studies show safety in the long term. Immunosuppression, most commonly using corticosteroids, is the first-line modality in management. Approaches vary between prophylactic and reactive strategies, and there remains an absence of consensus on the most appropriate strategies. First-line therapy for a variable duration and dose settles most cases of hepatoxicity. In selected difficult-to-treat cases, second-line agents (sirolimus, mycophenolate mofetil, calcineurin inhibitors) are required, while there is no current consensus on the ideal second-line strategy. Intense short-term and extended long-term hepatic monitoring is recommended. Variabilities in presentation and challenges in management strategies mandate a multidisciplinary collaboration with the active involvement of hepatologists/gastroenterologists to optimize liver health 

Rgenta Therapeutics Announces Presentation of Preclinical Data from Proprietary RSwitch Technology

WOBURN, Mass., April 30, 2025 /PRNewswire/ -- Rgenta Therapeutics, a clinical-stage biotechnology company pioneering the development of a new class of oral small molecules targeting RNA and RNA regulation for oncology and neurological disorders, announced today that preclinical data will be presented on its proprietary RSwitch technology, which enables the fine-tuning of transgene levels in gene and cell therapy applications, at the American Society of Gene And Cell Therapy (ASGCT) 28th Annual Meeting, which will be held from May 13 -17th, 2025, in New Orleans, LA. 

Title: RSwitch Enabled Gene Therapy to Fine Tune Frataxin Expression for the Treatment of Friedrich's Ataxia, Samuel A. Hasson, Jon Dempersmier, Mariam Elhawary, Diane Hamann, Ian McLachlan, Chris Yates, Travis Wager, and Simon Xi 

 RSwitch is a proprietary regulatable gene therapy system that enables oral, small molecule drug control of transgene levels in gene and cell therapy applications. RSwitch encodes a "dimmer" switch that makes the expression of transgene dependent on the administration of an oral small molecule drug that controls the system. Only when the drug is administered is the system activated. Furthermore, the level of gene expression is dependent on how much drug is administered. This precise gene control has the potential to enable fine control of the expression of a therapeutic protein.

Larimar Therapeutics Reports First Quarter 2025 Financial Results

BALA CYNWYD, Pa., April 30, 2025 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (Larimar) (Nasdaq: LRMR), a clinical-stage biotechnology company focused on developing treatments for complex rare diseases, today reported its first quarter 2025 operating and financial results.

Completed Dosing of Adolescents in Pharmacokinetic (PK) Run-In Study.

Potential for Accelerated Approval Pathway Based on Skin FXN Concentrations. 

Planned Upcoming Regulatory Discussions. 

50 mg OLE Data Expected in September 2025. 

Planned Transition to Lyophilized Form of Nomlabofusp. 

BLA Submission and Initiation of Global Phase 3 Study on Track

Gene circuits enable more precise control of gene therapy

Anne Trafton | MIT News Publication Date:April 28, 2025 

Very few gene therapy treatments have been approved by the FDA. One of the challenges to developing these treatments has been achieving control over how much the new gene is expressed in cells — too little and it won’t succeed, too much and it could cause serious side effects. 

To demonstrate this system, the researchers designed ComMAND circuits that could deliver the gene FXN, which is mutated in Friedreich’s ataxia — a disorder that affects the heart and nervous system. They also delivered the gene Fmr1, whose dysfunction causes fragile X syndrome. In tests in human cells, they showed that they could tune gene expression levels to about eight times the levels normally seen in healthy cells. 

Without ComMAND, gene expression was more than 50 times the normal level, which could pose safety risks. Further tests in animal models would be needed to determine the optimal levels, the researchers say.

Model-guided design of microRNA-based gene circuits supports precise dosage of transgenic cargoes into diverse primary cells

Model-guided design of microRNA-based gene circuits supports precise dosage of transgenic cargoes into diverse primary cells. Love, Kasey S. et al., Cell Systems, Volume 0, Issue 0, 101269 DOI: 10.1016/j.cels.2025.101269

In a therapeutic context, supraphysiological expression of transgenes can compromise engineered phenotypes and lead to toxicity. To ensure a narrow range of transgene expression, we developed a single-transcript, microRNA-based incoherent feedforward loop called compact microRNA-mediated attenuator of noise and dosage (ComMAND).

ComMAND effectively sets levels of the clinically relevant transgenes frataxin (FXN) and fragile X messenger ribonucleoprotein 1 (Fmr1) within a narrow window.

Progression of Friedreich Ataxia to Scoliosis and Cardiomyopathy: Utility of Real-World Data From Medical Claims (P12-5.032)

Progression of Friedreich Ataxia to Scoliosis and Cardiomyopathy: Utility of Real-World Data From Medical Claims (P12-5.032) April 8, 2025 issue 104 (7_Supplement_1) doi:10.1212/WNL.0000000000210504 

 Real-world data from medical claims can augment evidence from natural history studies in FA to allow for analyses of a broader range of commercially insured patients and explore patient characteristics, practice patterns, and outcomes not currently available.

Timing and Frequency of Onset Symptoms in Friedreich Ataxia Based on Real-world Medical Claims Data (P12-5.031)

Pravin Khemani, Shakti V. Nayar, Boyang Bian, Daniel Gomes, Sarah England, James McKay, Tony Wang, and Robin L. Avila​; Neurology® April 8, 2025 issue 104 (7_Supplement_1). doi:10.1212/WNL.0000000000210523

Real-world data from medical claims can augment evidence from prospectively designed natural history studies in helping to identify FA-related events at the time of disease onset and prior to FA diagnosis, allowing for additional insights on the early burden of disease.