Papillon Therapeutics Receives Rare Pediatric Disease Designation from the U.S. Food and Drug Administration for PPL-001 for the Treatment of Friedreich's Ataxia

October 15, 2024. SAN DIEGO--Papillon Therapeutics Inc., today announced that the U.S. Food and Drug Administration (FDA) has granted Rare Pediatric Disease designation to Papillon’s PPL-001, an experimental treatment for Friedreich's ataxia. 

PPL-001 has previously received Orphan Drug designation. PPL-001 is an experimental gene-corrected CD34+ hematopoietic stem and progenitor cell (HSPC) therapy. This therapeutic’s novel approach utilizes targeted excision to correct the GAA repeat expansion in Intron 1 of the FXN gene.

PTC Therapeutics Announces Positive Results from Long-Term Treatment Studies and Updates on Regulatory Progress for Vatiquinone Friedreich Ataxia Program

WARREN, N.J., Oct. 8, 2024 /PRNewswire/ -- PTC Therapeutics, Inc. provided today several positive updates on the vatiquinone Friedreich ataxia (FA) program. The pre-specified endpoint for two different FA long-term extension studies was met, with highly statistically significant evidence of durable treatment benefit on disease progression. In addition, PTC recently aligned with FDA on key aspects of the planned NDA submission for vatiquinone.

Analysis of the MOVE-FA long-term extension study demonstrated that 144 weeks of vatiquinone treatment resulted in a 3.7-point benefit (p<0.0001, N=70) on the modified Friedreich Ataxia Rating Scale (mFARS) relative to a matched natural history cohort from the FACOMS (Friedreich Ataxia Clinical Outcome Measures) disease registry. This treatment difference on the primary endpoint represents a clinically meaningful 50% slowing in disease progression over 3 years. These results confirm that the slowing of disease progression recorded in the 72-week placebo-controlled MOVE-FA trial are maintained over 144 weeks of treatment. In addition, vatiquinone continued to be safe and well tolerated without any treatment-related serious adverse events reported.In addition, PTC analyzed long-term open-label data from an earlier study of vatiquinone in adults with FA. Following 24-months of treatment with vatiquinone, subjects had a 4.8-point benefit on the mFARS relative to a matched natural history population (p<0.0001, N=41).

The SIRT-1/Nrf2/HO-1 Axis: Guardians of Neuronal Health in Neurological Disorders

Pranshul Sethi, Sidharth Mehan, Zuber Khan, Pankaj Kumar Maurya, Nitish Kumar, Aakash Kumar, Aarti Tiwari, Tarun Sharma, Ghanshyam Das Gupta, Acharan S Narula, Reni Kalfin, The SIRT-1/Nrf2/HO-1 Axis: Guardians of Neuronal Health in Neurological Disorders, Behavioural Brain Research, 2024, 115280, ISSN 0166-4328, doi:10.1016/j.bbr.2024.115280. 

SIRT1 (Sirtuin 1) is a NAD+-dependent deacetylase that functions through nucleoplasmic transfer and is present in nearly all mammalian tissues. SIRT1 is believed to deacetylate its protein substrates, resulting in neuroprotective actions, including reduced oxidative stress and inflammation, increased autophagy, increased nerve growth factors, and preserved neuronal integrity in aging or neurological disease. Nrf2 is a transcription factor that regulates the genes responsible for oxidative stress response and substance detoxification. The activation of Nrf2 guards cells against oxidative damage, inflammation, and carcinogenic stimuli. Several neurological abnormalities and inflammatory disorders have been associated with variations in Nrf2 activation caused by either pharmacological or genetic factors. Recent evidence indicates that Nrf2 is at the center of a complex cellular regulatory network, establishing it as a transcription factor with genuine pleiotropy. HO-1 is most likely a component of a defense mechanism in cells under stress, as it provides negative feedback for cell activation and mediator synthesis. This mediator is upregulated by Nrf2, nitric oxide (NO), and other factors in various inflammatory states. HO-1 or its metabolites, such as CO, may mitigate inflammation by modulating signal transduction pathways. Neurological diseases may be effectively treated by modulating the activity of HO-1. Multiple studies have demonstrated that SIRT1 and Nrf2 share an important connection. SIRT1 enhances Nrf2, activates HO-1, protects against oxidative injury, and decreases neuronal death. This has been associated with numerous neurodegenerative and neuropsychiatric disorders. Therefore, activating the SIRT1/Nrf2/HO-1 pathway may help treat various neurological disorders. This review focuses on the current understanding of the SIRT1 and Nrf2/HO-1 neuroprotective processes and the potential therapeutic applications of their target activators in neurodegenerative and neuropsychiatric disorders.

Understanding the mechanisms of food effect on omaveloxolone pharmacokinetics through physiologically based biopharmaceutics modeling

Pepin XJH, Hynes SM, Zahir H, Walker D, Semmens LQ, Suarez-Sharp S. Understanding the mechanisms of food effect on omaveloxolone pharmacokinetics through physiologically based biopharmaceutics modeling. CPT Pharmacometrics Syst Pharmacol. 2024 Sep 2. doi: 10.1002/psp4.13221. Epub ahead of print. PMID: 39219492. 

Mechanistically, in vivo omaveloxolone absorption was solubility and dissolution rate limited. However, in the fed state, higher bile salt solubilization led to more rapid dissolution with predominant absorption in the upper gastrointestinal tract, resulting in increased susceptibility to first-pass gut extraction; this accounts for the lack of correlation between Cmax and AUC for omaveloxolone.

ASSAIGS CLÍNICS I REVISIÓ FARMACOLÒGICA DE L’ATÀXIA DE FRIEDREICH

Treball Final de Grau Grau de Farmàcia ASSAIGS CLÍNICS I REVISIÓ FARMACOLÒGICA.NÚRIA BAIGES BEGUER. Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona Barcelona, Juny 2024 

 Aquest treball fa una anàlisi dels assaigs clínics actius en l’actualitat, relacionant-los amb les dianes terapèutiques definides pels mecanismes d’acció dels diferents fàrmacs. En el treball s’analitzen tretze fàrmacs, incloent-hi el fàrmac recentment aprovat, i es fa una breu referència a la recerca preclínica que encara no ha estat provada en persones, fixant-me especialment en aquelles recerques en teràpies avançades, ja que són prometedores per les malalties d’origen genètic.

This paper analyses the clinical trials currently active, relating them to the therapeutic targets defined by the mechanisms of action of the different drugs. Thirteen drugs are analysed, including the recently approved drug, and a brief reference is made to preclinical research that has not yet been tested in humans, focusing especially on research into advanced therapies, as these are promising for diseases of genetic origin. 

Case Report of Friedreich's Ataxia and ALG1-Related Biochemical Abnormalities in a Patient With Progressive Spastic Paraplegia

Quinlan, A., Rodan, L., Barkoudah, E., Tam, A., Saffari, A., Shammas, I., Ranatunga, W., Morava-Kozicz, E., Oglesbee, D., Berry, G., Ebrahimi-Fakhari, D. and Srivastava, S. (2024), Case Report of Friedreich's Ataxia and ALG1-Related Biochemical Abnormalities in a Patient With Progressive Spastic Paraplegia. Am J Med Genet e63890. doi:10.1002/ajmg.a.63890 

 Our findings underscore the importance of considering FRDA as a differential diagnosis in cases of complex HSP and demonstrate the utility of unbiased genome sequencing approaches that include detection of trinucleotide repeat expansions for progressive motor disorders.

VIDEOFLUOROSCOPIC SWALLOWING STUDY FINDINGS AND RESPIRATORY FUNCTION TESTING IN PATIENTS WITH FRIEDREICH ATAXIA

VIDEOFLUOROSCOPIC SWALLOWING STUDY FINDINGS AND RESPIRATORY FUNCTION TESTING IN PATIENTS WITH FRIEDREICH ATAXIA. LEON ASTUDILLO, CARMEN E et al.. CHEST, Volume 166, Issue 4, A6528 - A6529 doi:10.1016/j.chest.2024.07.118

 Dysphagia was present in 2 subjects based on PAS score, and in 3 subjects based on DIGEST scores. Although EAT-10 was abnormal in 4 out of 5 subjects, the results did not correspond to objective findings on VFSS. Similarly, VFSS results did not correspond with other clinical metrics including pulmonary function testing, EAT-10 or IOPI. Four subjects received interventions or dietary modifications based on VFSS results. Our study is limited by the small sample. 

CLINICAL IMPLICATIONS: Dysphagia can be seen in FRDA regardless of respiratory or functional testing results. VFSS or fiberoptic endoscopic evaluation of swallowing (FEES) can be considered as an objective tool for evaluation of swallowing in this population. Further research is needed to identify risk factors, correlation with other clinical metrics and outcomes.

Early Genetic Testing Avoids Treatment Delays for Patients with Friedreich Ataxia

EMJ. 2024;9[3]:14-23. doi:10.33590/emj/RSCJ7037 

This industry-sponsored symposium took place during the European Association of Neurology (EAN) Congress held in Helsinki, Finland, 29 June−2 July, 2024.

At the 2024 European Association of Neurology (EAN) Congress, one satellite symposium discussed the recognition, diagnosis, and treatment of Friedreich ataxia (FA), the most common hereditary ataxia. This condition is characterised by progressive neurodegeneration, multisystem complications, loss of ambulation, and reductions in the ability to carry out activities of daily living (ADL). For many, there is also a premature death. FA is caused by guanine-adenine-adenine triplet (GAA) repeat expansions in the gene FXN. This codes for the protein frataxin, loss of which is associated with impaired mitochondrial function, increased sensitivity to oxidative stress and reactive oxygen species levels, increased inflammation, and cell death.

Papillon Therapeutics Receives Orphan Drug Designation from the U.S. Food and Drug Administration for PPL-001 for the Treatment of Friedreich's Ataxia

SAN DIEGO--(BUSINESS WIRE)--Sep 17, 2024-- Papillon Therapeutics Inc., today announced that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to Papillon’s PPL-001, an experimental treatment for Friedreich's ataxia. 

PPL-001 is an experimental gene-corrected CD34+ hematopoietic stem and progenitor cell (HSPC) therapy. This therapeutic’s novel approach utilizes targeted excision to correct the GAA repeat expansion in Intron 1 of the FXN gene.

Mitotech Presents Promising Results in Friedreich's Ataxia

LONDON, Sept. 17, 2024 /PRNewswire-PRWeb/ -- Mitotech Ltd, a mitochondria-focused clinical-stage biotechnology company, presented new data for its mitochondria-targeted ferroptosis inhibitor in Friedreich's Ataxia (FA) model at the 149th annual meeting of the American Neurological Association. The conference took place on September 14-17, 2024, in Orlando, FL. 

Those new data demonstrated high level of efficacy of the company's lead compound SkQ1 – a mitochondria-targeted ferroptosis inhibitor – against ferroptosis and oxidative stress at strikingly low doses.The Friedreich's Ataxia-specific model has not only demonstrated SkQ1's great potential as a monotherapy for FA, but also highlighted its MoA as complementary to that of the currently available therapy – omaveloxolone. The latter aspect of our latest dataset opens the door for studying SkQ1 in a combination treatment in the clinic,"