Stealth Bio's Elamipretide Gets Orphan Drug Designation From FDA For Friedreich's Ataxia

BOSTON, March 28, 2022 /PRNewswire/ -- Stealth BioTherapeutics Corp (Nasdaq:MITO), a clinical-stage biotechnology company focused on the discovery, development, and commercialization of novel therapies for diseases involving mitochondrial dysfunction, announced today that the US Food and Drug Administration (FDA) Office of Orphan Products Development has granted Orphan Drug Designation to elamipretide for the treatment of patients with Friedreich's ataxia. 

ELVIS-FA , a phase 2a investigator-initiated trial evaluating elamipretide for the treatment of Friedreich's ataxia has been initiated at Children's Hospital of Philadelphia (CHOP) under the direction of Dr. David Lynch. The trial is evaluating two doses of elamipretide in patients with Friedreich's ataxia to assess safety, visual function, and cardiac function. 

ClinicalTrials.gov Identifier: NCT05168774. Phase 1, Phase 2. Drug: Elamipretide. Elamipretide is a tetra peptide with limited blood brain barrier penetration being developed for use in a variety of mitochondrial disorders, including FRDA, mitochondrial myopathy and Barth Syndrome.Other Names: MTP-131, SS-31

Cerebellar Pathology in an Inducible Mouse Model of Friedreich Ataxia

Mercado-Ayón E, Warren N, Halawani S, Rodden LN, Ngaba L, Dong YN, Chang JC, Fonck C, Mavilio F, Lynch DR and Lin H (2022). Front. Neurosci. 16:819569. doi: 10.3389/fnins.2022.819569 

Taken together, our findings show that frataxin knockdown leads to cerebellar degeneration in the FRDAkd mouse model, suggesting that frataxin helps maintain cerebellar structure and function.

The U.S. Food and Drug Administration granted orphan drug designation to elamipretide to treat Friedreich’s ataxia (FRDA).

 U.S. Food and Drug Administration, 03/22/2022

Generic Name:	elamipretide
Date Designated:	03/22/2022
Orphan Designation:	Treatment of Friedreich’s ataxia (FRDA)
Orphan Designation Status:	Designated
FDA Orphan Approval Status:	Not FDA Approved for Orphan Indication
Sponsor:	Stealth BioTherapeutics 275 Grove Street, Suite 3-107 Newton, Massachusetts 02466 United States The sponsor address listed is the last reported by the sponsor to OOPD.

Quantitative susceptibility mapping reveals alterations of dentate nuclei in common types of degenerative cerebellar ataxias

Deistung A, Jäschke D, Draganova R, Pfaffenrot V, Hulst T, Steiner KM, Thieme A, Giordano IA, Klockgether T, Tunc S, Münchau A, Minnerop M, Göricke SL, Reichenbach JR, Timmann D.; Brain Commun. 2022 Jan 13;4(1):fcab306. doi: 10.1093/braincomms/fcab306. PMID: 35291442; PMCID: PMC8914888. 

 Findings in FRDA were compared with findings in the most common forms of dominantly inherited ataxias [spinocerebellar ataxia types 1, 2, 3 and 6 (SCA1,2,3,6)] and a common form of non-hereditary degenerative ataxia [multiple system atrophy, cerebellar type (MSA-C)]. QSM revealed different patterns of abnormalities in the dentate nuclei. Abnormalities in susceptibility were most pronounced in SCA1, MSA-C and SCA6 patients. While susceptibility was significantly higher in SCA1 and MSA-C, it was significantly lower in SCA6 compared with healthy controls. Smaller changes in susceptibility were found in the dentate nuclei in FRDA and SCA2 and no change in SCA3 patients. Our data suggest that changes in iron concentration may contribute to the pathogenesis of a subset of cerebellar ataxias or at least be a result or indicator of the underlying pathology.

Study to Evaluate DT-216 in Adult Patients With Friedreich Ataxia

ClinicalTrials.gov Identifier: NCT05285540. First Posted : March 17, 2022 

The purpose of this study Phase 1 is to evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic effects of intravenous DT-216 in adult patients with Friedreich Ataxia. This single ascending dose study is randomized, double-blind, placebo-controlled.

Modelling Protein Plasticity: The Example of Frataxin and Its Variants

Botticelli, S.; La Penna, G.; Nobili, G.; Rossi, G.; Stellato, F.; Morante, S.; Molecules 2022, 27, 1955. doi:10.3390/molecules27061955 

Frataxin (FXN) is a protein involved in storage and delivery of iron in the mitochondria. Single-point mutations in the FXN gene lead to reduced production of functional frataxin, with the consequent dyshomeostasis of iron. FXN variants are at the basis of neurological impairment (the Friedreich’s ataxia) and several types of cancer. By using altruistic metadynamics in conjunction with the maximal constrained entropy principle, we estimate the change of free energy in the protein unfolding of frataxin and of some of its pathological mutants. The sampled configurations highlight differences between the wild-type and mutated sequences in the stability of the folded state. In partial agreement with thermodynamic experiments, where most of the analyzed variants are characterized by lower thermal stability compared to wild type, the D104G variant is found with a stability comparable to the wild-type sequence and a lower water-accessible surface area. These observations, obtained with the new approach we propose in our work, point to a functional switch, affected by single-point mutations, of frataxin from iron storage to iron release. The method is suitable to investigate wide structural changes in proteins in general, after a proper tuning of the chosen collective variable used to perform the transition.

Control of arm movements in Friedreich's ataxia patients: role of sensory feedback

Zhang L, Straube A, Eggert T. ; Exp Brain Res. 2022 Mar 14. doi: 10.1007/s00221-022-06343-5. Epub ahead of print. PMID: 35286422. 

The model simulations revealed that the feedback delay, but not the feedback gain was affected in FA patients. They also showed that the descending control signal was scaled in time and amplitude and co-contraction was smaller in FA patients. Thus, our study explains how the motor deficits of FA patients result from pathological alterations of both top-down and feedback control.

Difficulties translating antisense-mediated activation of Frataxin expression from cell culture to mice

Audrius Kilikevicius, Jun Wang, Xiulong Shen, Frank Rigo, Thahza P. Prakash, Marek Napierala & David R. Corey (2022); RNA Biology, 19:1, 364-372, DOI: 10.1080/15476286.2022.2043650 

 In this study, we investigate the potential for oligonucleotides to increase frataxin expression in a mouse model for FA. After confirming successful in vivo delivery of oligonucleotides using a benchmark gapmer targeting the nuclear noncoding RNA Malat1, we tested anti-FXN oligonucleotides designed to function by various mechanisms. None of these strategies yielded enhanced expression of FXN in the model mice. Our inability to translate activation of FXN expression from cell culture to mice may be due to inadequate potency of our compounds or differences in the molecular mechanisms governing FXN gene repression and activation in FA model mice.

Bone Mineral Density and Current Bone Health Screening Practices in Friedreich’s Ataxia

Dunn J, Tamaroff J, DeDio A, Nguyen S, Wade K, Cilenti N, Weber DR, Lynch DR and McCormack SE (2022) Bone Mineral Density and Current Bone Health Screening Practices in Friedreich’s Ataxia. Front. Neurosci. 16:818750. doi: 10.3389/fnins.2022.818750 

 Low aBMD is prevalent in FRDA, but few of even the highest risk individuals are undergoing screening. Our findings highlight potential missed opportunities for the screening and treatment of low aBMD in FRDA.

Friedreich’s Ataxia Related Diabetes: Epidemiology and Management Practices

Jaclyn Tamaroff, Anna DeDio, Kristin Wade, McKenzie Wells, Courtney Park, Karla Leavens, Christian Rummey, Andrea Kelly, David R. Lynch, Shana E. McCormack; Diabetes Research and Clinical Practice, 2022, 109828, doi.org/10.1016/j.diabres.2022.109828. 

FRDA-related DM was reported by 8.7% of individuals. Age, severe disease, and FRDA cardiac complications were positively associated with DM risk. FRDA-related DM was generally well-controlled, as reflected by HbA1c, though diabetic ketoacidosis did occur. Insulin is the mainstay of treatment (64-74% overall); in adults, metformin use was common, and newer glucose-lowering agents were used rarely.

Functional MRI Studies in Friedreich's Ataxia: A Systematic Review

Vavla M, Arrigoni F, Peruzzo D, Montanaro D, Frijia F, Pizzighello S, De Luca A, Della Libera E, Tessarotto F, Guerra P, Harding IH and Martinuzzi A (2022); Front. Neurol. 12:802496. doi: 10.3389/fneur.2021.802496 

fMRI designs included motor and cognitive task paradigms, and resting-state studies, with widespread changes in functionally activated areas and extensive variability in study methodologies. These studies highlight a mixed picture of both hypoactivation and hyperactivation in different cerebral and cerebellar brain regions depending on fMRI design and cohort characteristics. Functional changes often correlate with clinical variables. In aggregate, the findings provide support for cerebro-cerebellar loop damage and the compensatory mechanism hypothesis. Current literature indicates that fMRI is a valuable tool for gaining in vivo insights into FRDA pathology, but addressing that its limitations would be a key to improving the design, interpretation, and generalizability of studies in the future.

Cur@SF NPs alleviate Friedreich’s ataxia in a mouse model through synergistic iron chelation and antioxidation

Li Xu, Zichen Sun, Zhiyao Xing, Yutong Liu, Hongting Zhao, Zhongmin Tang, Yu Luo, Shuangying Hao & Kuanyu Li; J Nanobiotechnol 20, 118 (2022). doi;10.1186/s12951-022-01333-9 

 Cur@SF NPs exhibited a powerful effect in reducing the oxidative stress level and removing the accumulated iron in the myocardial tissue of FRDA mice. The behavioral and histological assays exhibited excellent therapeutic efficacy of Cur@SF NPs in improving neurological deficits and cardiomyopathy. Thus, we provide evidence for low-cost agent Cur@SF NPs by increasing their bioavailability, suggesting their potential in the treatment of FRDA disease.

Should Advanced Friedreich’s Ataxia Be a Contraindication for Heart Transplantation? A Case Report of a Successful Procedure in a 58-Year-Old Patient

Valero, M.J.; Muñoz-Blanco, J.L.; Sanchez, A.G.; Cuerpo, G.; Castrodeza, J.; Navas, P.; Sousa, I.; Villa, A.; Fernández-Avilés, F.; Martínez-Sellés; J. Cardiovasc. Dev. Dis. 2022, 9, 80. doi:10.3390/jcdd9030080

We conclude that HT is a safe option for end-stage heart disease in selected patients with FA. A multidisciplinary team should assess utility, justice, quality of life, and life expectancy. Patient involvement in the decision is essential.

The Cognitive Profile of Friedreich Ataxia: A Systemic Review and Meta-Analysis

Naeije g, Schul JB, Corben L.; Research Square; 2022. DOI: 10.21203/rs.3.rs-1010466/v1. 

Individuals with FRDA display significantly lower performances in many cognitive domains compared to control participants. The spectrum of the cognitive profile alterations in FRDA and its correlation with disease severity and cerebellar structural parameters suggest a cerebellar role in the pathophysiology of FRDA cognitive impairments. (Preprint)

Naeije G, Schulz JB, Corben LA. The cognitive profile of Friedreich ataxia: a systematic review and meta-analysis. BMC Neurol. 2022 Mar 17;22(1):97. doi: 10.1186/s12883-022-02615-3. PMID: 35300598.

Clinilabs is currently recruiting volunteers for DT-216 Clinical trial

March 8th, 2022

Gene therapy for Friedreich ataxia: Too much, too little, or just right?

R. Mark Payne, Molecular Therapy - Methods & Clinical Development, Volume 25, 2022, Pages 1-2, doi:10.1016/j.omtm.2022.02.008 

Defining minimal expression levels for normal cell function in different tissues, including brain, will be needed to develop effective therapies. These experiments are an important contribution to the field of FA, because they define toxicity of FXN overexpression and, more importantly, identify mechanisms underlying this toxicity.

1st Hellenic Friedreich's Ataxia Conference

7.3.2022; The Hellenic Friedreich's Ataxia Association plans to conduct on 6th May the 1st Hellenic Friedreich's Ataxia Conference, both, in person and virtual, with the kind and very strong support of US FARA.

Update on Novartis Gene Therapies Friedreich’s ataxia Program

Novartis Gene Therapies,  2022 . Novartis Gene Therapies had been developing a therapeutic approach for Friedreich’s ataxia. One candidate, OAV401, is an investigational AAV9-based gene therapy. The journey to bring new therapies from the lab to patients is complex and our team works with a sense of urgency, a need for flexibility and innovation, and an ability to accept challenges in a developing field of science. In this context, we have made the difficult decision to retire development of the OAV401 gene therapy program for Friedreich’s ataxia. However, we remain fully committed to innovative approaches, such as gene therapy, and are actively pursuing multiple pathways to harness this therapeutic platform. 

Unfortunately, the totality of the pre-clinical data for OAV401 does not support a path forward for this development candidate to human clinical trials. More specifically, data generated from a recent biodistribution study revealed that adequate gene expression was not achieved in the specific cells and tissues believed to be necessary for potential therapeutic benefit in patients with Friedreich’s ataxia. 

These data are complementary, not contradictory, to the research we have presented previously. The prior data demonstrated that OAV401 reached the brain. These more detailed findings, however, indicate that AAV9 does not distribute to the specific brain regions or cells that we believe would be necessary for therapeutic benefit in patients with Friedreich’s ataxia. 

We have made this data available to enhance the knowledge in the field of AAV9 gene therapy for neurologic conditions. The title of this paper is “Intrathecal sc-AAV9-CB-GFP: Systemic Distribution Predominates Following Single-Dose Administration in Cynomolgus Macaques,” and it is posted on bioRxiv https://www.biorxiv.org/content/10.1101/2021.11.28.470258v1 ahead of peer-reviewed publication, expected later in 2022. 

We recognize this update is especially disappointing to the Friedreich’s ataxia patient community. We highly value our collaboration with the community and recognize that this partnership has significantly advanced the scientific understanding of the potential impact gene therapy could have for patients and families and has contributed to the development of potential clinical programs. We will continue to partner with the Friedreich’s ataxia community as we explore therapeutic options for this and other diseases.

Establishing and boosting communication in the European Reference Network for Rare Neurological Diseases (ERN-RND): the impact of offering free educational webinars

Alicia Brunelle Praschberger, Annemarie E. M. Post, Sanja Hermanns & Holm Graessner; Orphanet J Rare Dis 17, 89 (2022). doi:10.1186/s13023-022-02209-9

Offering a tangible product—such as the webinars presented in this report—to a specific target group (healthcare professionals) supported our communication strategy by driving traffic to ERN-RND communication channels. It has also successfully tackled ERN-RND’s general aim: by enabling the flow of knowledge on rare neurological and movement disorders to the medical community in hospitals treating patients with these rare and complex conditions, patients ultimately benefit from improved and faster diagnosis, care, and treatment. We aim to set up similar strategies to effectively reach other or the same target groups. For healthcare professionals, organising eConsultations via the Clinical Patient Management System or disseminating standards of care such as diagnostic and therapeutic algorithms as well as clinical practice guidelines might offer potential. For the patient community, organising customised and multilingual webinars could also work.

Larimar Therapeutics Inc. (NASDAQ: LRMR) Announces That The FDA Has Retained the Clinical Hold on CTI-1601

BioPharma Journal, March 2, 2022. Larimar Therapeutics Inc. has announced that it has received feedback from the US FDA about the clinical hold in its CTI-1601 program. 

The FDA indicated that it is retaining its clinical hold for now and that more data is required to lift the hold. Larimar is delving deeper into previously completed studies to see if more research is necessary. The company also plans to work with the FDA to figure out the best way to deliver this data. As part of its efforts to satisfy the agency’s request, Larimar is reevaluating recommendations on scheduling the scheduled Jive open-label expansion and pediatric multiple-ascending dosage clinical trials.

Recent Advances in the Elucidation of Frataxin Biochemical Function Open Novel Perspectives for the Treatment of Friedreich’s Ataxia

Monfort B, Want K, Gervason S and D’Autréaux B.; Front. Neurosci. 16:838335. (2022) doi: 10.3389/fnins.2022.838335 

A picture is now emerging which points toward a unique function of FXN as an accelerator of a key step of sulfur transfer between two components of the Fe-S cluster biosynthetic complex. These findings should foster the development of new strategies for the treatment of FRDA. We will review here the latest discoveries on the biochemical function of frataxin and the implication for a potential therapeutic treatment of FRDA.