SAFETY AND EFFICACY OF THE STEM CELL TRANSPLANTATION IN FRIEDREICH’S ATAXIA: A REPORT OF THREE CASES

Riza Azeri, Duygu Koyuncu Irmak, Eda Sun, Erdal Karaöz; Int J Physiother. Vol 8(1), 31-35, February (2021) doi:10.15621/ijphy/2021/v8i1/903 

Case Summary: Here, we report three FRDA cases treated with four consecutive allogeneic transplantations of umbilical cord-derived MSCs with 30 days interval, upon per patient regulatory approvals for advanced cellular therapy. Outcome Measures: The cases were followed up after the treatment in means of the therapeutic effect of the cellular treatment by attenuating the neurological findings and gene expression parameters. Conclusions: Closely followed promising safety and efficacy outcomes demonstrated that the MSC treatment for FRDA might positively affect the clinical results caused by the defect in this genetic-based disease.

An unusual combination of large Eustachian valve in a young patient with Friedreich's ataxia cardiomyopathy

Stylianos A. Karvounaris, Georgios S. Papaetis, Petros P. Mavrommatis; Cardiol J 2021;28(3):498-499. DOI: 10.5603/CJ.2021.0051 According to available research this is the first published description of a large Eustachian valve in a patient with FA-CM.

Gene therapy in PIDs, hemoglobin, ocular, neurodegenerative, and hemophilia B disorders

Odiba AS, Okoro NO, Durojaye OA, Wu Y., Open Life Sciences. 2021 ;16(1):431-441. DOI: 10.1515/biol-2021-0033.

Molecular biology and biotechnology tools remained important elements in gene therapy. Gene editing/modification (replacement, insertion, and deletion) largely characterizes this field of biological sciences. The idea of gene therapy was implemented clinically about three decades ago as an alternative to the limitations of pharmacotherapy. Approximately 3,000 known clinical trials are on record. Some limitations are associated with gene therapy; and hence, the need to improve on the current strategies. This has resulted in sophisticated tools using viral and nonviral vectors. Although most of the gene therapy studies are directed toward cancer worldwide, other areas of notable disease require the gene therapy approach; and these include primary immunodeficiency disorders (PIDs), hemoglobin, hemophilia B, ocular, and neurodegenerative disorders.

Mitochondrial and metabolic dysfunction in Friedreich ataxia: update on pathophysiological relevance and clinical interventions

David R. Lynch, Garrett Farmer; Mitochondrial and metabolic dysfunction in Friedreich ataxia: update on pathophysiological relevance and clinical interventions. Neuronal Signal 25 June 2021; 5 (2): NS20200093. doi: doi:10.1042/NS20200093

Friedreich ataxia (FRDA) is a recessive disorder resulting from relative deficiency of the mitochondrial protein frataxin. Frataxin functions in the process of iron–sulfur (Fe–S) cluster synthesis. In this review, we update some of the processes downstream of frataxin deficiency that may mediate the pathophysiology. Based on cellular models, in vivo models and observations of patients, ferroptosis may play a major role in the pathogenesis of FRDA along with depletion of antioxidant reserves and abnormalities of mitochondrial biogenesis. Ongoing clinical trials with ferroptosis inhibitors and nuclear factor erythroid 2-related factor 2 (Nrf2) activators are now targeting each of the processes. In addition, better understanding of the mitochondrial events in FRDA may allow the development of improved imaging methodology for assessing the disorder. Though not technologically feasible at present, metabolic imaging approaches may provide a direct methodology to understand the mitochondrial changes occurring in FRDA and provide a methodology to monitor upcoming trials of frataxin restoration.

The Oxford-Harrington Rare Disease Centre initiates first disease priority area: Friedreich’s Ataxia

27 May 2021, The Oxford-Harrington Rare Disease Centre is redoubling efforts to develop a therapeutics programme for Friedreich’s Ataxia.

OHC will be building on the long history of important contributions to the FA field by Oxford researchers. As a first step in this new journey, with the support of EndFA, a philanthropic partner focused on FA, the OHC has recruited a new Research Facilitator in Friedreich’s Ataxia. Dr Geoffrey Denwood joined the OHC at the University of Oxford site in April 2021, and will dedicate his time and expertise into coordinating the activities of the OHC in FA. Dr Denwood will evaluate the current status of FA translational research and therapeutics development locally and globally, then work to fund and implement an OHC programme harnessing the best expertise and most promising therapeutic opportunities.

Iron-sulfur cluster deficiency can be sensed by IRP2 and regulates iron homeostasis and sensitivity to ferroptosis independent of IRP1 and FBXL5

ERDEM M. TERZI, VLADISLAV O. SVIDERSKIY, SAMANTHA W. ALVAREZ, GABRIELLE C. WHITEN, RICHARD POSSEMATO; Science Advances 26 May 2021: Vol. 7, no. 22, eabg4302, DOI: 10.1126/sciadv.abg4302 

Intracellular iron levels are strictly regulated to support homeostasis and avoid iron-mediated ROS production. Loss of iron-sulfur cluster (ISC) synthesis can increase iron loading and promote cell death by ferroptosis. Iron-responsive element-binding proteins IRP1 and IRP2 posttranscriptionally regulate iron homeostasis. IRP1 binding to target mRNAs is competitively regulated by ISC occupancy. However, IRP2 is principally thought to be regulated at the protein level via E3 ubiquitin ligase FBXL5–mediated degradation. Here, we show that ISC synthesis suppression can activate IRP2 and promote ferroptosis sensitivity via a previously unidentified mechanism. At tissue-level O2 concentrations, ISC deficiency enhances IRP2 binding to target mRNAs independent of IRP1, FBXL5, and changes in IRP2 protein level. Deletion of both IRP1 and IRP2 abolishes the iron-starvation response, preventing its activation by ISC synthesis inhibition. These findings will inform strategies to manipulate ferroptosis sensitivity and help illuminate the mechanism underlying ISC biosynthesis disorders, such as Friedreich’s ataxia.

Larimar Therapeutics Reports FDA Clinical Hold on CTI-1601 and Termination of Recently Announced Private Placement Financing

BALA CYNWYD, Pa., May 25, 2021 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (“Larimar”) (Nasdaq: LRMR), a clinical-stage biotechnology company focused on developing treatments for Friedreich’s ataxia (FA) and other complex rare diseases, today announced that the United States Food and Drug Administration (FDA) has placed a clinical hold on the CTI-1601 clinical program and that the company will not be closing a previously announced private placement financing. 

The clinical hold follows the previous notification by Larimar to the FDA of mortalities which occurred at the highest dose levels in an ongoing 180-day non-human primate (NHP) toxicology study, which is designed to support extended dosing of patients with CTI-1601. 

In the clinical hold letter, the FDA stated it needs a full study report from the ongoing NHP study and Larimar may not initiate additional clinical trials until the company has submitted the report and received notification from the agency that additional clinical trials may commence.

Generation of a Friedreich’s Ataxia patient-derived iPSC line USFi001-A

Mariana Burgos Angulo, Jiajia Yang, Mariana A. Argenziano, Alexander C. Bertalovitz, Maliheh Najari Beidokhti, Thomas V. McDonald; Stem Cell Research, Volume 54, 2021, 102399, doi:10.1016/j.scr.2021.102399. 

We generated an induced pluripotent stem cell (iPSC) line from an FA patient with a homozygous GAA expansion in intron 1 of the FXN gene. The IPSCs display pluripotent cell morphology, expression of pluripotency markers, normal karyotype, and the capability to differentiate into all three germ layers.

Larimar Therapeutics Announces $95 Million Private Placement Financing

BALA CYNWYD, Pa., May 21, 2021 (GLOBE NEWSWIRE) -- Larimar Therapeutics (“Larimar”) (Nasdaq: LRMR), a clinical-stage biotechnology company focused on developing treatments for Friedreich’s ataxia (FA) and other complex rare diseases, today announced that it has executed a securities purchase agreement to raise gross proceeds of approximately $95 million in a private placement financing of common stock.

Larimar intends to use the net proceeds from the private placement to support the clinical development of CTI-1601, for additional research and development and for working capital and general corporate purposes.

Larimar Therapeutics Receives European Medicines Agency Priority Medicines (PRIME) Designation for CTI-1601 in Friedreich’s Ataxia

BALA CYNWYD, Pa., May 20, 2021 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (“Larimar”) (Nasdaq: LRMR), a clinical-stage biotechnology company focused on developing treatments for Friedreich’s ataxia (FA) and other complex rare diseases, today announced that the European Medicines Agency (EMA) has granted Priority Medicines (PRIME) designation to CTI-1601 for the treatment of FA. CTI-1601 is a recombinant fusion protein intended to deliver human frataxin into the mitochondria of patients with FA who are unable to produce enough of this essential protein.

We look forward to CTI-1601’s continued clinical development and to the planned initiations of our Jive open label extension and pediatric multiple-ascending dose trials, which are expected in the second half of the year. 

In addition to PRIME designation, CTI-1601 has also been granted Rare Pediatric Disease designation, Fast Track designation and Orphan Drug designation by the U.S. Food and Drug Administration and Orphan Drug Designation by the European Commission.

Reata Announces that The FDA Has Asked The Company to Request a Pre-NDA Meeting for Omaveloxolone for the Treatment of Friedreich’s Ataxia

PLANO, Texas, May 19, 2021 (GLOBE NEWSWIRE) -- Reata Pharmaceuticals, Inc. (Nasdaq: RETA) (“Reata,” the “Company,” or “we”), a clinical-stage biopharmaceutical company, today announced that it received a communication from the Division of Neurology Products 1 (“Division”) of the U.S. Food and Drug Administration (“FDA”) stating that, after a preliminary review of briefing materials for an upcoming Type C meeting, a pre-NDA meeting is the most appropriate format for a discussion of the development program for omaveloxolone in Friedreich’s ataxia (“FA”). The Division suggested that the Company withdraw the current meeting request for a Type C meeting and instead request a pre-NDA meeting, which the Division will grant upon receipt. The Division asked the Company to focus the new briefing package on questions, issues, and needs applicable to a pre-NDA meeting. As requested by the FDA, the Company plans to withdraw the current request for a Type C meeting and submit a request for a pre-NDA meeting as soon as practicable. 

“We welcome the opportunity to have a pre-NDA meeting regarding our omaveloxolone development program for the treatment of patients with FA,” said Warren Huff, Reata’s President and Chief Executive Officer. “We look forward to working with the FDA on our goal of securing the regulatory review and approval necessary to make omaveloxolone available to patients with FA.”

Reverse phase protein array reveals correlation of retinoic acid metabolism with cardiomyopathy in Friedreich’s ataxia

Jill S. Napierala, Kimal Rajapakshe, Amanda Clark, Yu-Yun Chen, Shixia Huang, Clementina Mesaros, Peining Xu, Ian A. Blair, Lauren A. Hauser, Jennifer Farmer, David R. Lynch, Dean P. Edwards, Cristian Coarfa, Marek Napierala; Molecular & Cellular Proteomics, DOI:10.1016/j.mcpro.2021.100094 

 Among sixty-two fibroblast samples (44 FRDA and 18 controls) analyzed, 30 proteins/phosphoproteins were significantly changed in FRDA fibroblasts compared to control cells (p<0.05), mostly representing signaling molecules and metabolic enzymes. As expected, frataxin (FXN) was significantly downregulated in FRDA samples, thus serving as an internal control for assay integrity. Extensive bioinformatic analyses were conducted to correlate differentially expressed proteins with critical disease parameters (e.g. selected symptoms, age of onset, GAA sizes, FXN levels, FARS scores). Members of the integrin family of proteins specifically associated with hearing loss in FRDA. Also, RPPA data, combined with results of transcriptome profiling, uncovered defects in the retinoic acid (RA) metabolism pathway in FRDA samples. Moreover, expression of ALDH1A3 differed significantly between cardiomyopathy positive and negative FRDA cohorts, demonstrating that metabolites such as retinol, retinal or RA could become potential predictive biomarkers of cardiac presentation in FRDA.

Exicure, Inc. Reports First Quarter 2021 Financial Results and Corporate Progress

CHICAGO & CAMBRIDGE, Mass.--(BUSINESS WIRE)--Exicure, Inc.® (NASDAQ: XCUR), a pioneer in gene regulatory and immunotherapeutic drugs utilizing spherical nucleic acid (SNA™) technology, today reported financial results for the quarter ended March 31, 2021 and provided an update on corporate progress.

Neurology – XCUR-FXN: The Company hosted a virtual R&D Day in January 2021 to discuss progress within its neurology pipeline, which included an overview of the Company’s XCUR-FXN path to clinical validation for the treatment of Friedreich’s Ataxia (FA). During the first quarter of 2021, the Company continued to advance preclinical and IND-enabling studies of XCUR-FXN in FA and disclosed encouraging preclinical mouse data, demonstrating significant upregulation of XCUR-FXN components in the brain and spinal cord. The Company believes these data support the potential for XCUR-FXN as a disease-modifying treatment for the disease. The Company is on track with prior guidance to submit an IND for XCUR-FXN in FA by year-end 2021 and expects to initiate a first-in-patient Phase 1b clinical trial of XCUR-FXN in FA in the first half of 2022.

Toxicity concerns send Larimar down

Evaluate Vantage. May 12, 2021. 

Slightly further behind is Larimar, which yesterday reported phase 1 results with its candidate CTI-1601. Although biomarker data looked promising, the group’s stock sank 36% yesterday on toxicity concerns in non-human primate studies. The company will need to iron out these issues if its asset is to progress. 

Source

We also have conducted several non-clinical toxicology studies, including 28 and 90-day studies in rats and non-human primates, and have an on-going 180- day non-human primate study. In the 90-day non-human primate study a mortality was observed, which was determined to be due to a bacterial meningitis infection and was unrelated to study drug. In addition, mortalities have been observed in the ongoing 180 day-non-human primate study at the highest dose levels. We have informed FDA of these findings and we are continuing to dose non-human primates in the study and are continuing to collect and evaluate data. While additional non-clinical information may be required before we initiate further clinical studies, based on all the information we have from the non-clinical program to date together with extensive input from toxicologists and other relevant experts, we currently expect to remain ontrack with our previously disclosed timeline of initiating both our open-label extension (the JIVE trial) and a pediatric MAD trial in Friedreich’s ataxia patients during the second half of 2021.

Larimar Therapeutics Reports Positive Topline Phase 1 Clinical Trial Data Showing Dose-Dependent Increases in Frataxin Levels in Patients with Friedreich’s Ataxia

BALA CYNWYD, Pa., May 11, 2021 (GLOBE NEWSWIRE) -- Larimar Therapeutics, Inc. (“Larimar”) (Nasdaq: LRMR), a clinical-stage biotechnology company focused on developing treatments for Friedreich’s ataxia (FA) and other complex rare diseases, today announced topline data from its Phase 1 multiple ascending dose (MAD) clinical trial (n=27) evaluating CTI-1601 as a treatment for FA.

FXN Change from Baseline in Buccal Cells Units: pg FXN / μg total protein Data presented as: n median (25th percentile, 75th percentile)
Dose Group	Day 4/7*						Day 13
Placebo (n=7)	-0.03		(-0.18, 0.97			)	0.35		(-0.02, 0.46	)
Cohort 1 Active (25 mg, n=6)	0.39		(0.01, 0.72			)	0.92		(0.48, 0.94	)
Cohort 2 Active (50 mg, n=6)	1.28		(1.09, 1.69			)	0.39		(0.35, 1.08	)
Cohort 3 Active (100 mg, n=7)	3.06		(1.70, 4.16			)	2.64		(1.93, 3.99	)
FXN Change from Baseline in Skin Biopsies# Units: pg FXN / μg total protein Data presented as: median (25th percentile, 75th percentile)
Dose Group	Day 4/7*						Day 13
Placebo (n=7)	N/A						0.92		(0.10, 1.17	)
Cohort 1 Active (25 mg, n=6)	N/A						0.87		(-0.07, 1.69	)
Cohort 2 Active (50 mg, n=6)	N/A						2.82		(1.93, 4.01	)
Cohort 3 Active (100 mg, n=7)	N/A						10.6		(7.20, 18.1	)
FXN Change from Baseline in Platelets Units: pg FXN / μg total protein Data presented as: median (25th percentile, 75th percentile)
Dose Group	Day 4/7*				Day 13
Placebo (n=7)	-0.38	(-1.23, 0.60		)	-0.65			(-1.71, 1.03		)
Cohort 1 Active (25 mg, n=6)	-0.15	(-2.18, 0.60		)	-0.53			(-1.01, 0.80		)
Cohort 2 Active (50 mg, n=6)	0.30	(-0.18, 0.75		)	-0.87			(-1.14, -0.70		)
Cohort 3 Active (100 mg, n=7)	2.54	(2.27, 2.70		)	3.55			(2.71, 4.93		)

Larimar Therapeutics Reports First Quarter 2021 Operating and Financial Results

BALA CYNWYD, Pa., May 10, 2021 (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 2021 operating and financial results. “Our Phase 1 program in Friedreich's ataxia (FA) made strong progress over the past few months and we will be announcing topline data from the program tomorrow,” said Carole Ben-Maimon, MD, President and Chief Executive Officer of Larimar. “In addition to safety and tolerability findings, the upcoming announcement will include pharmacodynamic data assessing frataxin levels in buccal cells, skin, and platelets. These data provide important insights that we expect will inform CTI-1601’s further development, as FA is caused by patients’ inability to produce sufficient amounts of frataxin and CTI-1601 is the only drug candidate that we are aware of in clinical development that is designed to address the root cause of the disease by delivering this crucial protein to patients.” 

Upcoming and Anticipated 2021 Milestones 

Announce topline data from placebo-controlled, Phase 1 program in FA patients on May 11, 2021 

Initiate Jive open-label extension clinical trial: expected in 2H 2021 

Initiate Multiple Ascending Dose (MAD) trial in patients under 18 years of age: expected in 2H 2021

Reata Pharmaceuticals, Inc. Announces First Quarter 2021 Financial Results and Provides an Update on Clinical Development Programs

May 06, 2021, Source: Reata Pharmaceuticals, Inc. 

Data from the registrational Part 2 portion of the MOXIe Phase 2 trial of omaveloxolone in patients with FA (“MOXIe Part 2") and the open-label extension study (the “MOXIe Extension”) were analyzed in additional exploratory analyses (the “Delayed-Start Analyses”), whereby parallel trajectories between the patients randomized to placebo (placebo-to-omaveloxolone group) and those randomized to omaveloxolone (omaveloxolone-to-omaveloxolone group) in the double-blind period from MOXIe Part 2 through 48 weeks in the MOXIe Extension could provide evidence of disease-modifying activity. A total of 73 out of 75 (97%) patients without pes cavus who completed MOXIe Part 2 enrolled in the MOXIe Extension. 

The FDA has granted us a Type C meeting, which is scheduled to occur in the second quarter of 2021, to discuss the Delayed-Start Analyses and the FA development program. We plan to initiate a second pivotal study in the fourth quarter of 2021, incorporating input from both the FDA and the European Medicines Agency into the protocol before we initiate enrollment.

Drp1-dependent peptide reverse mitochondrial fragmentation, a homeostatic response in Friedreich ataxia

Johnson J, Mercado-Ayón E, Clark E, Lynch D, Lin H.; Pharmacol Res Perspect. 2021 May;9(3):e00755. doi: 10.1002/prp2.755. PMID: 33951329.

This paper demonstrates that frataxin deficiency causes excessive mitochondrial fragmentation that is dependent upon Drp1 activity in Friedreich ataxia cellular models. Drp1 inhibition by the small peptide TAT-P110 reverses mitochondrial fragmentation but also decreases ATP levels in frataxin-knockdown fibroblasts and FRDA patient fibroblasts, suggesting that fragmentation may provide a homeostatic pathway for maintaining cellular ATP levels. The cardiolipin-stabilizing compound SS-31 similarly reverses fragmentation through a Drp1-dependent mechanism, but it does not affect ATP levels. The combination of TAT-P110 and SS-31 does not affect FRDA patient fibroblasts differently from SS-31 alone, suggesting that the two drugs act through the same pathway but differ in their ability to alter mitochondrial homeostasis. In approaching potential therapeutic strategies for FRDA, an important criterion for compounds that improve bioenergetics should be to do so without impairing the homeostatic response of mitochondrial fragmentation.

Scoliosis in Friedreich's ataxia: longitudinal characterization in a large heterogeneous cohort

Rummey C, Flynn JM, Corben LA, Delatycki MB, Wilmot G, Subramony SH, Bushara K, Duquette A, Gomez CM, Hoyle JC, Roxburgh R, Seeberger L, Yoon G, Mathews KD, Zesiewicz T, Perlman S, Lynch DR.; Ann Clin Transl Neurol. 2021 May 5. doi: 10.1002/acn3.51352. Epub ahead of print.

Well over 90% of early or typical FRDA patients (as determined by age of onset) developed intermediate to severe scoliosis, while patients with a later onset (>14 years) had no or much lower prevalence of scoliosis. Diagnosis of scoliosis occurs during the onset of ataxia and in rare cases even prior to that. Major progression follows throughout the growth phase and puberty, leading to the need for surgical intervention in more than 50% of individuals in the most severe subgroup. The youngest patients appear to delay surgery until the end of the growth period, leading to further progression before surgical intervention. Age of onset of FRDA before or after reaching 15 years sharply separated severe and relatively mild incidence and progression of scoliosis.

A multi-stakeholder multicriteria decision analysis for the reimbursement of orphan drugs (FinMHU-MCDA study)

Fernando de Andrés-Nogales, Encarnación Cruz, Miguel Ángel Calleja, Olga Delgado, Maria Queralt Gorgas, Jaime Espín, Jorge Mestre-Ferrándiz, Alba Ancochea, Rosabel Arce, Raquel Domínguez-Hernández, Miguel Ángel Casado on behalf of the FinMHU-MCDA Group; Orphanet J Rare Dis 16, 186 

(2021). doi:10.1186/s13023-021-01809-1 

To ensure adequate OMP access and reimbursement, it is necessary that decisions be arrived at through a process in which the preferences over the financing criteria are transparent and explicit, in which all types of agents involved in the field of rare diseases are incorporated, and in which practical tools that favor this process, such as MCDA, are applied. From a multi-stakeholder perspective, the financing of an orphan drug will be conditioned by its effect on the health-related quality of life, the degree of its therapeutic benefit, and the availability of other treatment options. The severity of the rare disease for which the OMP is indicated is also relevant, as is the extent to which the treatment can avoid the costs associated with this pathology.

Revisión Bibliográfica: Ataxia de Friedreich y sus manifestaciones cardiovasculares

Santiago Andrés Vintimilla Pesántez; Ocronos. Vol. IV. Nº 4–Abril 2021. Pág. Inicial: Vol. IV; nº4: 150. ORCID: https://orcid.org/ 0000-0003-1450-6128 

El objetivo de esta revisión bibliográfica es informar a la comunidad científica de la presencia de manifestaciones sistémicas, sobre todo cardiovasculares, en la Ataxia de Friedreich; ya que, esta enfermedad no solamente se caracteriza por la presencia de alteraciones neurológicas, sino de afecciones a diferentes aparatos y sistemas del cuerpo humano, como el corazón, debido a la alteración celular que la Ataxia de Friedreich provoca.