Lessons for clinical trial design in Friedreich's ataxia

Masha G Savelieff Eva L Feldman The Lancet Neurology; Published:March 23, 2021DOI:https://doi.org/10.1016/S1474-4422(21)00064-8 Friedreich's ataxia is a rare autosomal-recessive disease caused by mutations in the FXN gene, which encodes frataxin, a mitochondrial protein.  It is the most common inherited ataxia, which usually manifests as gait unsteadiness in adolescence, with slowly progressive trunk and limb ataxia, and eventual loss of independent movement.  Friedreich's ataxia often involves the heart and musculoskeletal system and raises diabetes risk, making it a multisystem disorder.

Rare-disease researchers face unique obstacles: Minoryx

29-Mar-2021 By Jenni Spinner A representative of the rare-disease specialist firm outlines the unique obstacles of orphan CNS disease research, and how professionals can overcome them.

Mapa epidemiológico transversal de las ataxias y paraparesias espásticas hereditarias en EspañaEpidemiology of ataxia and hereditary spastic paraplegia in Spain: a cross-sectional study

G. Ortega Suero, M.J. Abenza Abildúa, C. Serrano Munuera, I. Rouco Axpe, F.J. Arpa Gutiérrez, A.D. Adarmes Gómez, F.J. Rodríguez de Rivera, B. Quintans Castro, I. Posada Rodríguez, A. Vadillo Bermejo, Á. Domingo Santos, E. Blanco Vicente, I. Infante Ceberio, J. Pardo Fernández, E. Costa Arpín, C. Painous Martí, J.E. Muñoz, P. Mir Rivera, F. Montón Álvarez, L. Bataller Alberola, J. Gascón Bayarri, C. Casasnovas Pons, V. Vélez Santamaría, A. López Munain, G. Fernández García Eulate, J. Gazulla Abío, I. Sanz Gallego, L. Rojas Bartolomé, Ó. Ayo Martín, T. Segura Martín, C. González Mingot, M. Baraldés Rovira, R. Sivera Mascaró, E. Cubo Delgado, A. Echevarría Íñiguez, F. Vázquez Sánchez, M. Bártulos Iglesias, M.T. Casadevall Codina, E.M. Martínez Fernández, C. Labandeira Guerra, B. Alemany Perna, A. Carvajal Hernández, C. Fernández Moreno, M. Palacín Larroy, N. Caballol Pons, A. Ávila Rivera, F.J. Navacerrada Barrero, R. Lobato Rodríguez, M.J. Sobrido Gómez; Neurología, 2021, doi:10.1016/j.nrl.2021.01.006. 

 We conducted a cross-sectional, multicentre, retrospective, descriptive study of patients with ataxia and hereditary spastic paraplegia in Spain between March 2018 and December 2019. Mean (SD) age in our sample was 53.64 (20.51) years; 920 patients were men (50.8%) and 889 were women (49.2%). The genetic defect was unidentified in 920 patients (47.6%). A total of 1371 patients (70.9%) had ataxia and 562 (29.1%) had hereditary spastic paraplegia. Prevalence rates for ataxia and hereditary spastic paraplegia were estimated at 5.48 and 2.24 cases per 100 000 population, respectively. The most frequent type of dominant ataxia in our sample was SCA3, and the most frequent recessive ataxia was Friedreich ataxia. 

Pre-clinical left ventricular myocardial remodeling in patients with Friedreich's ataxia: A cardiac MRI study

Takazaki KAG, Quinaglia T, Venancio TD, Martinez ARM, Shah RV, Neilan TG, Jerosch-Herold M, Coelho-Filho OR, França MC Jr.; PLoS One. 2021 Mar 26;16(3):e0246633. doi: 10.1371/journal.pone.0246633. LV hypertrophy and concentric LV remodeling in FRDA are associated at the tissue level with an expansion of the ECV and an increase in cardiomyocyte size. The adverse tissue remodeling assessed by ECV and τic is associated with more severe cardiomyopathy classification, suggesting a role for these markers in tracking disease progression. 

Quantitative assessment of Friedreich Ataxia via self-drinking activity

Ragil Krishna, Pubudu N Pathirana, Malcolm Horne, Louise Corben, David Szmulewicz; IEEE J Biomed Health Inform. 2021 Mar 25;PP. doi: 10.1109/JBHI.2021.3069007.

In this study, we propose an ataxia measuring device, in the form of a pressure canister capable of sensing certain kinetic and kinematic parameters of interest to quantify the impairment levels of participants particularly when engaged in an activity that is closely associated with daily living. In particular, the functional task of simulated drinking was utilised to capture characteristic features of disability manifestation in terms of diagnosis (separation of individuals with FA and controls) and severity assessment of individuals diagnosed with the debilitating condition of FA. Time and frequency domain analysis of these biomarkers enabled the classification of individuals with FA and control subjects to reach an accuracy of 98\% and a correlation level reaching 96\% with the clinical scores. 

NAD+ Precursor Supplementation in Friedreich's Ataxia

ClinicalTrials.gov Identifier: NCT04817111. A Phase 2a Study of NAD+ Precursor Supplementation in Friedreich's Ataxia 

Sponsor: Metro International Biotech, LLC; Collaborator: Children's Hospital of Philadelphia

Detailed Description: The primary focus for this protocol is safety and tolerability. We will systematically assess for adverse events using a safety monitoring uniform report form. We will also use cardiac 31-Phosphorus-Magnetic Resonance Spectroscopy (MRS) to measure the Phosphocreatine(PCr)/Adenosine triphosphate (ATP)- γ ratio before and after treatment with MIB-626. In addition, if time permits we will use proton (1H)-MRS to measure skeletal muscle nicotinamide adenine dinucleotide (NAD+) before and after treatment.

A severe form of autosomal recessive spinocerebellar ataxia associated with novel PMPCA variants

Yoko Takahashi, Masaya Kubota, Rika Kosaki, Kenjiro Kosaki, Akira Ishiguro; Brain and Development, Volume 43, Issue 3, 2021, Pages 464-469, doi:10.1016/j.braindev.2020.11.008. 

Spinocerebellar ataxia, autosomal recessive 2 (SCAR2) [MIM:213200] is a rare autosomal recessive disease of spinocerebellar ataxia associated with degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR2 is characterized by onset of impaired motor development and ataxic gait in early childhood. Recently, several PMPCA gene variants have been reported in SCAR2 patients with mild and non-progressive symptoms. PMPCA codes frataxin, which is crucial for iron biosynthesis in cells. 

**Evidences showed that MPP ( Mitochondrial-processing peptidase subunit alpha) is an enzyme that in humans is encoded by the PMPCA gene, it's involved in the proteolytic maturation of Frataxin, a protein responsible for iron homeostasis. Accordingly, MPP deficiency was shown to be involved in Friedreich ataxia, an autossomic recessive neurodegenerative disorder.

Progression characteristics of the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS): a 4-year cohort study

Prof Kathrin Reetz, MD, Imis Dogan, PhD, Prof Ralf-Dieter Hilgers, PhD, Prof Paola Giunti, MD, Michael H Parkinson, MBBS, Caterina Mariotti, MD, Lorenzo Nanetti, MD, Prof Alexandra Durr, MD, Claire Ewenczyk, MD, Sylvia Boesch, MDWolfgang Nachbauer, MD, Thomas Klopstock, MD,, Claudia Stendel, MD, Francisco Javier Rodríguez de Rivera Garrido, MD, Christian Rummey, PhD, Prof Ludger Schöls, MD, Stefanie N Hayer, PhD Prof Thomas Klockgether, MD, Ilaria Giordano, MD, Claire Didszun, PhD, Myriam Rai, PhD, Prof Massimo Pandolfo, MD, Prof Jörg B Schulz on behalf of theEFACTS study group; The Lancet Neurology, Published:March 23, 2021 DOI:10.1016/S1474-4422(21)00027-2 

The European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) investigates the natural history of Friedreich's ataxia. We aimed to assess progression characteristics and to identify patient groups with differential progression rates based on longitudinal 4-year data to inform upcoming clinical trials in Friedreich's ataxia.

The Role of Serum Levels of Neurofilament Light (NfL) Chain as a Biomarker in Friedreich Ataxia

Bernice Frempong, Robert B. Wilson, Kimberly Schadt and David R. Lynch; Front. Neurosci., 02 March 2021, doi:10.3389/fnins.2021.653241 

A deeper understanding of the mechanisms of NfL elevation in serum in FRDA is needed to make it a useful biomarker in FRDA.

The responsiveness of gait and balance outcomes to disease progression in Friedreich ataxia

Sarah C Milne, Seok Hun Kim, Anna Murphy, Jane Larkindale, Jennifer Farmer, Ritchie Malapira, Mary Danoudis, Jessica Shaw, Tyagi Ramakrishnan, Fatemeh Rasouli, Eppie M Yiu, Nellie Georgiou-Karistianis, Geneieve Tai, Zesiewicz Zesiewicz, Martin B Delatycki, Louise A Corben; doi: 10.1101/2021.03.18.434657 

The FARS USS and BBS are highly responsive and can detect change in a wide range of ambulant individuals with FRDA. However, therapeutic effects in children may be best measured by the DGI.

In vivo survival and differentiation of Friedreich ataxia iPSC-derived sensory neurons transplanted in the adult dorsal root ganglia

Viventi S, Frausin S, Howden SE, Lim SY, Finol-Urdaneta RK, McArthur JR, Abu-Bonsrah KD, Ng W, Ivanusic J, Thompson L, Dottori M.; Stem Cells Transl Med. 2021 Mar 18. doi: 10.1002/sctm.20-0334. Epub ahead of print. 

 Our data showed survival and differentiation of hESC and FRDA iPSC-derived progenitors in the DRG 2 and 8 weeks post-transplantation, respectively. Donor cells expressed neuronal markers, including sensory and glial markers, demonstrating differentiation to these lineages. These results are novel and a highly significant first step in showing the possibility of using stem cells as a cell replacement therapy to treat DRG neurodegeneration in FRDA as well as other peripheral neuropathies.

Research priorities for rare neurological diseases: a representative view of patient representatives and healthcare professionals from the European Reference Network for Rare Neurological Diseases

Annemarie E. M. Post, Thomas Klockgether, G. Bernhard Landwehrmeyer, Massimo Pandolfo, Astri Arnesen, Carola Reinhard & Holm Graessner. Orphanet J Rare Dis 16, 135 (2021). doi:10.1186/s13023-020-01641-z 

Patient involvement in research increases the impact of research and the likelihood of adoption in clinical practice. A first step is to know which research themes are important for patients. We distributed a survey on research priorities to ERN-RND members, both patient representatives and healthcare professionals, asking them to prioritize five research themes for rare neurological diseases on a scale ranging from 1 (most important) to 5 (least important). A follow-up e-mail interview was conducted with patient representatives and professionals to assess potential reasons for differences in opinions between these two groups.

Evaluation of the Effects of Calcitriol's in the Neurological Symptoms of Friedreich's Ataxia Patients (Calcitriol-FA)

ClinicalTrials.gov Identifier: NCT04801303. 

Recruitment Status : Not yet recruiting, First Posted : March 17, 2021, Last Update Posted : March 17, 2021 

 Description of the trial: to assess the effect of Calcitriol 0.25mcg/24h for a year in the neurological function of FA patients. Main objective of the trial: to evaluate the effects of Calcitriol in the neurological symptoms of patients with FA. The second objectives of the trial are: To evaluate the safety and the risk of hypercalcemia with the treatment with low dosis of Calcitriol (0.25mcg of Calcitriol every 24h) in patients with FA. To measure de change in the Frataxin's levels during the treatment with Calcitriol. To evaluate the effects of Calcitriol in the daily life activities and the life quality of the patients with FA. Sample size: The number of participants needed to compleat the trial is 20. 

Ages Eligible for Study: 16 Years to 65 Years (Child, Adult, Older Adult)

Duration: The duration of the trial is one year 

Locations: Spain, Hospital Santa Caterina/Parc Martí i Julià, Salt, Spain, 17190

The Complex Genetic Landscape of Hereditary Ataxias in Turkey and Implications in Clinical Practice

ural, A., Şimşir, G., Tekgül, Ş., Koçoğlu, C., Akçimen, F., Kartal, E., Şen, N.E., Lahut, S., Ömür, Ö., Saner, N., Gül, T., Bayraktar, E., Palvadeau, R., Tunca, C., Pirkevi Çetinkaya, C., Gündoğdu Eken, A., Şahbaz, I., Kovancılar Koç, M., Öztop Çakmak, Ö., Hanağası, H., Bilgiç, B., Eraksoy, M., Gündüz, A., Apaydın, H., Kızıltan, G., Özekmekçi, S., Siva, A., Altıntaş, A., Kaya Güleç, Z.E., Parman, Y., Oflazer, P., Deymeer, F., Durmuş, H., Şahin, E., Çakar, A., Tüfekçioğlu, Z., Tektürk, P., Çorbalı, M.O., Tireli, H., Akdal, G., Yiş, U., Hız, S., Şengün, İ., Bora, E., Serdaroğlu, G., Erer Özbek, S., Ağan, K., İnce Günal, D., Us, Ö., Kurt, S.G., Aksoy, D., Bora Tokçaer, A., Elmas, M., Gültekin, M., Kumandaş, S., Acer, H., Kaya Özçora, G.D., Yayla, V., Soysal, A., Genç, G., Güllüoğlu, H., Kotan, D., Özözen Ayas, Z., Şahin, H.A., Tan, E., Topçu, M., Topçuoğlu, E.S., Akbostancı, C., Koç, F., Ertan, S., Elibol, B. and Başak, A.N. (2021), Mov Disord. doi.:10.1002/mds.28518 

Mutations in known ataxia genes were identified in 30% of 1296 probands. Friedreich's ataxia was found to be the most common recessive ataxia in Turkey, followed by autosomal recessive spastic ataxia of Charlevoix–Saguenay. Spinocerebellar ataxia types 2 and 1 were the most common dominant ataxias. Whole‐exome sequencing was performed in 251 probands with an approximate diagnostic yield of 50%. Forty‐eight novel variants were found in a plethora of genes, suggesting a high heterogeneity. Variants of unknown significance were discussed in light of clinical data.

Early onset ataxia with Marfanoid features a new varient of Friedreich s ataxia

Khichar S.; IP Indian J Neurosci 2021;7(1):95-96, doi:10.18231/j.ijn.2021.015

A young male with ataxia since early childhood with Marfanoid features, normal intellect and no biochemical abnormality is reported. The syndrome has partial resemblance with previously described syndrome of arachnodactyle, cerebellar ataxia and other features, what has been named as "Bhaskar Syndrome". The documentation of such rare entities is worth for future research.

Design Therapeutics, Inc. (DSGN)

12/3/21. Design Therapeutics is a preclinical-stage biopharmaceutical company pioneering novel small-molecule therapeutic candidates, called gene targeted chimeras (GeneTACs), that are designed to be disease-modifying and target the underlying cause of inherited nucleotide repeat expansion diseases, of which there are more than 40 debilitating degenerative diseases. 

 In preclinical studies for our lead program, we have observed restoration of frataxin (FXN) levels in cells from Friedreich ataxia (FA) patients using our FA GeneTACs. 

 We plan to initiate clinical trials with our lead product candidate in FA patients to evaluate its safety, pharmacokinetics (PK) and effect on FXN levels by the first half of 2022, subject to receiving regulatory clearance to proceed into clinical trials.

Cardiomyopathy of Friedreich's Disease. Modern Methods of Diagnostic

Fomicheva E.I., Myasnikov R.P., Selivyorstov Y.A., Illarioshkin S.N., Dadali E.L., Drapkina O.M. ; Rational Pharmacotherapy in Cardiology. 2021;17(1):105-110. doi:10.20996/1819-6446-2021-01-05 

The basis of the clinical picture of Friedreich's disease is ataxia of a mixed (sensitive and cerebellar) nature. The steady and gradual progression of neurological symptoms significantly affects the quality of life of patients and is most often the leading reason for seeking medical attention. However, the prognosis is primarily due to the involvement of cardiac tissue in the pathological process. The main causes of death in patients with Friedreich's ataxia are severe heart failure and sudden cardiac death due to cardiomyopathy. The overwhelming majority of foreign and domestic publications on Friedreich's ataxia are devoted to the neurological manifestations of this disease, and little attention is paid to this problem in the cardiological scientific and practical society. The purpose of this review is to provide up-to-date information on modern methods of diagnosing myocardial damage at various stages of Friedreich's disease.

Coenzyme Q10 Analogues: Benefits and Challenges for Therapeutics

Suárez-Rivero JM, Pastor-Maldonado CJ, Povea-Cabello S, Álvarez-Córdoba M, Villalón-García I, Munuera-Cabeza M, Suárez-Carrillo A, Talaverón-Rey M, Sánchez-Alcázar JA.; Antioxidants. 2021; 10(2):236. doi:10.3390/antiox10020236

  Over the past few years, a wide variety of CoQ10 analogues with improved properties have been developed. These analogues conserve the antioxidant features of CoQ10 but present upgraded characteristics such as water solubility or enhanced mitochondrial accumulation. Moreover, recent studies have proven that some of these analogues might even outperform CoQ10 in the treatment of certain specific diseases. The aim of this review is to provide detailed information about these Coenzyme Q10 analogues, as well as their functionality and medical applications.

This synthetic quinone stands out for its efficacy as a treatment for Friedreich ataxia (FRDA). From 1990 and up to the present, several clinical trials have tested the impact of Idebenone supplementation on patients of FRDA. These studies have proven that the quinone ameliorates patients’ conditions through the improvement of neurological function (reduced general weakness, improvement in fine movement and speech, and decreased difficulty in swallowing) [49] and cardiac hypertrophy (reduction in interventricular septal wall thickness, left ventricular posterior wall thickness, or left ventricular mass index) [50,51]. Idebenone has been widely tested in clinical trials for several years. Its main relevance is in FRDA

Friedreich ataxia in a family from Mali, West Africa

heick Abdel Kader Cissé,Lassana Cissé,Hamidou O Bah,Oumar Samassékou,Assiatou Simaga,Abdoulaye Tamega,Salimata Diarra,Seybou Hassane Diallo,Thomas Coulibaly,Salimata Diallo,Abdoulaye Yalcouye,Alassane Baneye Maiga,Mohamed Kéita,Kenneth Fischbeck,Sekou Fantamady Traore,Cheick Guinto,Guida Landouré; West Africa. Authorea. February 24, 2021. DOI: 10.22541/au.161414432.28217723/v1 

Cissé, CAK, Cissé, L, Ba, HO, et al; from the H3Africa Consortium. Friedreich ataxia in a family from Mali, West Africa/Friedreich ataxia in a Malian family. Clin Case Rep. 2021; 9:e04065.  doi: 10.1002/ccr3.4065

 Friedreich ataxia is the most common inherited ataxia in the world, but yet to be reported in black African. We report the first genetically confirmed case in a West African family. Studying genetic diseases in populations with diverse backgrounds may give new insights into their pathophysiology for future therapeutic targets.

Crosstalk between nucleus and mitochondria in human disease: Mitochondrial iron and calcium homeostasis in Friedreich ataxia

Jordi Tamarit, Elena Britti, Fabien Delaspre, Marta Medina‐Carbonero, Arabela Sanz‐Alcázar, Elisa Cabiscol, Joaquim Ros; IUBMB Life. 2021; 1– 11. https://doi.org/10.1002/iub.2457

 Friedreich Ataxia is a neuro‐cardiodegenerative disease caused by the deficiency of frataxin, a mitochondrial protein. Many evidences indicate that frataxin deficiency causes an unbalance of iron homeostasis. Nevertheless, in the last decade many results also highlighted the importance of calcium unbalance in the deleterious downstream effects caused by frataxin deficiency. In this review, the role of these two metals has been gathered to give a whole view of how iron and calcium dyshomeostasys impacts on cellular functions and, as a result, which strategies can be followed to find an effective therapy for the disease.

Preclinical autoimmune disease biotech Design Therapeutics files for a $100 million IPO

March 5, 2021, Design Therapeutics is a preclinical-stage biopharmaceutical company pioneering novel small-molecule therapeutic candidates, called gene targeted chimeras (GeneTACs), that are designed to be disease-modifying and target the underlying cause of inherited nucleotide repeat expansion diseases. The GeneTACs are designed to selectively bind to genetic repeat sequences, modulate gene expression either by restoring or blocking transcription, and restore cellular health. As a platform, the company believes that GeneTACs have broad applicability across monogenic nucleotide repeat expansion diseases. Design plans to initiate clinical trials with its lead product candidate in Friedreich ataxia patients to evaluate its safety, pharmacokinetics, and effect on frataxin levels by the first half of 2022, subject to receiving regulatory clearance to proceed into clinical trials.

Ectopic Burden via Holter Monitors in Friedreich Ataxia.

Erika Mejia,Abigail Lynch,Patrick Hearle,Oluwatimilehin Okunowo,Heather Griffis,Maully Shah,David Lynch,Kimberly Y Lin; Physician's Weekly; Mar 4, 2021

Using a natural history study of patients with Friedreich ataxia at a single center, we analyzed portable heart rhythm monitors (Holters). Ectopic burden was defined as the proportion of atrial or ventricular ectopic beats over total beats.
Of 456 patients, 131 had Holters. Sixty-eight (52.0%) were male, median age of symptom onset was 8.0 years (5.0 to 13.0, n = 111), median age at time of Holter was 17.3 years (interquartile range [IQR] 12.9 to 22.8, n = 129), and median duration of illness was 8.7 years (IQR 5.3 to 11.6, n = 110). Median GAA length on the shorter FXN allele was 706.0 (IQR 550.0 to 840.0, n = 112). Eight (7.8%, n = 103) had diminished cardiac function, and 74 (74.0%, n = 100) had ventricular hypertrophy. Ninety patients (83.0%) had atrial ectopy (supraventricular ectopy [SVE]): 85 (78.0%) with rare SVE (>0% to 5%) and five (5.0%) with frequent SVE (>10%). Twenty-five (19.0%) had supraventricular runs, and one (0.8%) had atrial fibrillation/flutter. Forty-five (41.0%) had ventricular ectopy (VE): 43 (39.0%) with rare VE (0% to 5%) and two (2.0%) with moderate VE (5% to 10%). Compared with patients with none and rare SVE, patients with frequent SVE had longer disease duration (18.3 versus 4.6 versus 9.0 years, P = 0.0005).
Patients with longer disease duration had higher rates of SVE. Heart rhythm monitoring may be considered for risk stratification; however, longitudinal analysis is needed.

Larimar Therapeutics Reports Fourth Quarter and Full Year 2020 Operating and Financial Results

BioSpace.com, Published: Mar 04, 2021​. 

 

Reported preliminary Phase 1 findings from a Single Ascending Dose (SAD) trial that suggest single subcutaneous injections of CTI-1601 were well tolerated at doses up to 100 mg in Friedreich'sataxia (FA) patients Placebo-controlled Phase 1 trials in FA patients remain on track for topline data in Q2 2021

LEXEO Therapeutics Announces License Agreement and Consolidation of Comprehensive Pre-clinical Data Package to Support Cardiac Friedreich's Ataxia Gene Therapy Program (LX2006)

Published: Mar 01, 2021 NEW YORK, March 01, 2021 (GLOBE NEWSWIRE) -- LEXEO Therapeutics, a clinical-stage gene therapy company, today announced it has licensed worldwide intellectual property rights and pre-clinical data from Adverum Biotechnologies to its Friedreich's ataxia gene therapy program. With exclusive rights to data from seven pre-clinical studies now combined, LEXEO will advance LX2006 through final IND-enabling studies and into a planned Phase 1 clinical trial in 2021.