Minoryx recibe la aprobación de la Agencia Reguladora Española para iniciar el estudio de fase 2 en la ataxia de Friedreich

Mataró (Barcelona)-Charleroi (Bélgica), 27 de febrero de 2019. Minoryx Therapeutics, compañía biotecnológica especializada en el desarrollo de nuevos medicamentos para enfermedades huérfanas, anuncia hoy que la Agencia Española de Medicamentos y Productos Sanitarios (AEMPS) ha aprobado el lanzamiento de un ensayo clínico de fase II para el tratamiento de la ataxia de Friedreich (FRDA) con su fármaco candidato MIN-102.
El ensayo clínico, denominado FRAMES, iniciará el reclutamiento de pacientes en las próximas semanas en el Hospital Universitario La Paz (Madrid), bajo la dirección del Dr. Francisco Javier Rodríguez de Rivera. La compañía también trabaja en la apertura del ensayo en más centros en Bélgica, Alemania y Francia.
El ensayo será doble ciego y controlado con placebo, con el objetivo de evaluar la eficacia y seguridad del MIN-102 en los pacientes con ataxia de Friedreich. Participarán 36 pacientes mayores de 12 años.
MIN-102 es un novedoso agonista selectivo de PPAR gamma, biodisponible por vía oral, que ha mostrado un perfil superior en cuanto a penetración cerebral y seguridad. En modelos preclínicos de neurodegeneración el fármaco ha mostrado la capacidad de modular las vías que generan disfunción mitocondrial, estrés oxidativo, neuroinflamación, desmielinización y degeneración axonal. También se ha completado con éxito un estudio clínico de fase I que confirma que MIN-102 es bien tolerado y capaz de cruzar la barrera hematoencefálica a un nivel equivalente al de los estudios preclínicos. Actualmente, se encuentra en ensayo clínico de fase II/III para el tratamiento de la adrenomieloneuropatía (AMN) en Europa y Estados Unidos.

Como parte de la expansión de la compañía en nuevas indicaciones, se unen al consejo asesor científico dos líderes clave en neurología clínica: el Dr. Massimo Pandolfo, director del Laboratorio de Neurología Experimental en la Université Libre de Bruxelles que dirigió el equipo que identificó el gen de la ataxia de Friedreich en 1996, y la Dra. Fanny Mochel, líder de grupo en el Brain and Spine Institute (ICM) del hospital universitario Pitié-Salpêtrière en París y experta en resonancia magnética aplicada en neurología clínica.

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Minoryx Therapeutics lance une étude clinique de phase II dans l'ataxie de Friedreich avec l’autorisation de l'Agence Espagnole du Médicament

Mataró, Barcelone, Espagne et Charleroi, Belgique, le 27 février 2019 - Minoryx Therapeutics, une société spécialisée dans le développement de nouveaux médicaments contre des maladies orphelines, annonce aujourd'hui qu'elle a reçu l’autorisation de l'Agence espagnole du médicament et des dispositifs médicaux (AEMPS) pour lancer un essai clinique de phase II dans l'ataxie de Friedreich avec son principal candidat médicament, MIN-102. FRAMES, un essai clinique de phase II, va débuter dans les semaines à venir à l'hôpital La Paz (Madrid), et sera piloté par le Dr. Francisco Javier Rodríguez de Rivera. Minoryx prévoit également d’ouvrir des sites supplémentaires dans des institutions médicales en Belgique, en Allemagne et en France. L'essai, en double-aveugle avec contrôle placebo, doit permettre d'évaluer l'efficacité et l'innocuité de MIN-102 chez les patients souffrants d'ataxie de Friedreich. L’étude portera sur 36 patients âgés d’au moins 12 ans.
Le MIN-102 est un nouvel agoniste sélectif du PPAR gamma (récepteur activé par les proliférateurs des péroxisomes) avec une bonne biodisponibilité orale. Il a montré in vivo un profil de supériorité dans les maladies du système nerveux central (SNC) et une bonne efficacité. MIN-102 fait également l'objet d'un essai clinique de phase II/III pour le traitement de l'adrénomyéloneuropathie (AMN), le phénotype le plus courant de l'adrénoleucodystrophie liée à l’X (ALD).

Le Professeur Alexandra Durr, investigateur principal à l'Institut du Cerveau et de la Moëlle épinière (ICM) à l’hôpital de La Pitié-Salpêtrière à Paris sera la coordinatrice de la nouvelle étude.

La société annonce également l’arrivée de deux leaders d'opinion au sein de son conseil scientifique : le Dr. Massimo Pandolfo, directeur du Laboratoire de neurologie expérimentale de l'Université Libre de Bruxelles, et le Dr. Fanny Mochel, coordinatrice au sein de l'Institut du Cerveau et de la Moëlle épinière (ICM) à l’hôpital de La Pitié-Salpêtrière à Paris.



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Minoryx Therapeutics receives approval from Spanish Regulatory Agency to initiate phase 2 study in Friedreich’s Ataxia

Mataró, Barcelona, Spain and Charleroi, Belgium, February 27, 2019- Minoryx Therapeutics, a company specializing in the development of new drugs for orphan diseases, today announces that it has received approval from the Spanish Agency of Medicines and Medical Devices (AEMPS) to launch a phase 2 clinical trial in Friedreich’s Ataxia with its lead candidate, MIN-102 .

FRAMES trial expected to initiate patient recruitment in upcoming weeks in Spain, Belgium and other European countries.

Professor Alexandra Durr, principal investigator at the Brain and Spine Institute at La Pitié-Salpêtrière University Hospital (ICM) will be the co-ordinator of the new study

The phase 2 trial, FRAMES, is expected to start patient enrollment in the coming weeks in the Hospital La Paz (Madrid), lead by Dr. Francisco Javier Rodríguez de Rivera. The company is also working to open additional sites at medical institutions in Belgium, Germany and France. The upcoming trial is designed to be double-blind and placebo-controlled with the aim of assessing the efficacy and safety of MIN-102 in Friedreich’s Ataxia patients. It will enroll 36 patients aged 12 years or older.
MIN-102 is a novel, orally bioavailable and selective PPAR gamma agonist with a superior profile for central nervous system-related diseases and good in-vivo efficacy. MIN-102 is also in a phase 2/3 clinical trial for the treatment of adrenomyeloneuropathy (AMN), the most common phenotype of X-linked Adrenoleukodystrophy (X-ALD).

The company is also proud to announce the appointment of two key opinion leaders to its scientific advisory board, Dr. Massimo Pandolfo, director of the Laboratory of Experimental Neurology at the Université Libre de Bruxelles, and Dr. Fanny Mochel, group leader at the Brain and Spine Institute of La Pitié-Salpêtrière University Hospital in Paris (ICM).

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Guidelines on the diagnosis and management of the progressive ataxias

Rajith de Silva, Julie Greenfield, Arron Cook, Harriet Bonney, Julie Vallortigara, Barry Hunt and Paola Giunti, Orphanet Journal of Rare Diseases 201914:51 doi:10.1186/s13023-019-1013-9

These guidelines are aimed predominantly at HCPs in secondary care (such as general neurologists, clinical geneticists, physiotherapists, speech and language therapists, occupational therapists, etc.) who provide care for individuals with progressive ataxia and their families, and not ataxia specialists. It is a useful, practical tool to forward to HCPs at the time referrals are made for on-going care, for example in the community.

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The Role of Iron in Friedreich’s Ataxia: Insights From Studies in Human Tissues and Cellular and Animal Models

Llorens JV, Soriano S, Calap-Quintana P, Gonzalez-Cabo P and Moltó MD (2019). Front. Neurosci. 13:75. doi: 10.3389/fnins.2019.00075

we review the contribution of the cellular and animal models of FRDA and relevance of the studies using FRDA patient samples to gain knowledge about these issues. Mechanisms of mitochondrial iron overload are discussed considering the potential roles of frataxin in the major mitochondrial metabolic pathways that use iron. We also analyzed the effect of iron toxicity on neuronal degeneration in FRDA by reactive oxygen species (ROS)-dependent and ROS-independent mechanisms. Finally, therapeutic strategies based on the control of iron toxicity are considered.

The role of mitochondrial labile iron in Friedreich's ataxia skin fibroblasts sensitivity to ultraviolet A

Olivier Reelfs, Vincenzo Abbate, Agostino Cilibrizzi, Mark A. Pook, Robert C. Hider and Charareh Pourzan;DOI:10.1039/C8MT00257F

Our results reveal a link between FRDA as a disease of mitochondrial iron overload and sensitivity to UVA of skin fibroblasts. Our findings suggest that the high levels of mitochondrial LI in FRDA cells which contribute to high levels of mitochondrial ROS production after UVA irradiation are likely to play a crucial role in the marked sensitivity of these cells to UVA-induced oxidative damage. This study may have implications not only for FRDA but also for other diseases of mitochondrial iron overload, with the view to develop topical mitochondria-targeted iron chelators as skin photoprotective agents.

Pattern of Cerebellar Atrophy in Friedreich’s Ataxia—Using the SUIT Template

Tobias Lindig, Benjamin Bender, Vinod J. Kumar, Till-Karsten Hauser, Wolfgang Grodd, Bettina Brendel, Jennifer Just, Matthis Synofzik, Uwe Klose, Klaus Scheffler, Ulrike Ernemann, Ludger Schöls; Cerebellum (2019). doi:10.1007/s12311-019-1008-z

Whole-brain voxel-based morphometry (VBM) studies revealed patterns of patchy atrophy within the cerebellum of Friedreich’s ataxia patients, missing clear clinico-anatomic correlations. Studies so far are lacking an appropriate registration to the infratentorial space. To circumvent these limitations, we applied a high-resolution atlas template of the human cerebellum and brainstem (SUIT template) to characterize regional cerebellar atrophy in Friedreich’s ataxia (FRDA) on 3-T MRI data. We used a spatially unbiased voxel-based morphometry approach together with T2-based manual segmentation, T2 histogram analysis, and atlas generation of the dentate nuclei in a representative cohort of 18 FRDA patients and matched healthy controls.

Phosphodiesterase Inhibitors Revert Axonal Dystrophy in Friedreich’s Ataxia Mouse Model

Belén Mollá, Diana C. Muñoz-Lasso, Pablo Calap, Angel Fernandez-Vilata, María de la Iglesia-Vaya, Federico V. Pallardó, Maria Dolores Moltó, Francesc Palau, Pilar Gonzalez-Cabo; Neurotherapeutics (2019). doi:10.1007/s13311-018-00706-z

Treatment of frataxin-deficient sensory neurons with phosphodiesterase (PDE) inhibitors was able to restore improper cytosolic Ca2+ levels and revert the axonal dystrophy found in DRG neurons of YG8R mice. In conclusion, the present study shows the effectiveness of PDE inhibitors against axonal degeneration of sensory neurons in YG8R mice. Our findings indicate that PDE inhibitors may become a future FRDA pharmacological treatment.

Fly screens for FA

Ellen P. Neff. Dis. Model Mech.11, dmm033811 (2018) doi:10.1038/s41684-018-0143-3

Friedreich’s ataxia (FA) is a degenerative disorder caused by mutations to the mitochondrial protein frataxin. Muscles, including those of the heart, waste over time, and cardiomyopathy is the leading cause of death. Researchers at Universite Paris Diderot previously described a frataxin-deficient Drosophila line that models FA cardiomyopathies. In their latest paper, they use their fly model to screen 1280 drugs that have been approved for use in humans.

Some drugs made things worse—five were toxic—but eleven improved cardiac function in the flies; most effective was the chemotherapy drug paclitaxel. Paclitaxel stabilizes microtubules; in the heart, these cytoskeletal fibers contribute to proper cardiac function. The drug can be toxic so the authors don’t recommend it for therapeutic use, but they suggest that its efficacy indicates a novel mechanism to investigate further.

Global Implications of Local Unfolding Phenomena, Probed by Cysteine Reactivity in Human Frataxin

Santiago E. Faraj, Martín E. Noguera, José María Delfino & Javier Santos; Scientific Reportsvolume 9, Article number: 1731 (2019) doi:10.1038/s41598-019-39429-2

Local events that affect specific regions of proteins are of utmost relevance for stability and function. The aim of this study is to quantitatively assess the importance of locally-focused dynamics by means of a simple chemical modification procedure. Taking human Frataxin as a working model, we investigated local fluctuations of the C-terminal region (the last 16 residues of the protein) by means of three L → C replacement mutants: L98C, L200C and L203C. The conformation and thermodynamic stability of each variant was assessed.

The patient’s view on rare disease trial design – a qualitative study

C. M. W. Gaasterland, M. C. Jansen – van der Weide, M. J. du Prie – Olthof, M. Donk, M. M. Kaatee, R. Kaczmarek, C. Lavery, K. Leeson-Beevers, N. O’Neill, O. Timmis, V. van Nederveen, E. Vroom and J. H. van der Lee; Orphanet Journal of Rare Diseases 2019 14:31 doi:10.1186/s13023-019-1002-z

linical trials in rare diseases are more challenging than trials in frequent diseases. Small numbers of eligible trial participants, often complicated by heterogeneity among rare disease patients, hamper the design and conduct of a ‘classical’ Randomized Controlled Trial. Therefore, novel designs are developed by statisticians. However, it is important to be aware of possible design aspects that may jeopardize the feasibility of trial conduct. If the burden of participation is considered out of proportion by patients or parents, recruitment may fail or participants may drop out before trial completion. In order to maximize the chance of success of trials in small populations, it is important to know which aspects of trial design are considered important by patients.

Structural and functional characterization of a frataxin from a thermophilic organism

Rasheed, M. , Jamshidiha, M. , Puglisi, R. , Yan, R. , Cota, E. and Pastore, A. (2019), FEBS J, 286: 495-506. doi:10.1111/febs.14750

Frataxins form an interesting family of iron‐binding proteins with an almost unique fold and are highly conserved from bacteria to primates. They have a pivotal role in iron–sulfur cluster biogenesis as regulators of the rates of cluster formation, as it is testified by the fact that frataxin absence is incompatible with life and reduced levels of the protein lead to the recessive neurodegenerative disease Friedreich's ataxia. Despite its importance, the structure of frataxin has been solved only from relatively few species. Here, we discuss the X‐ray structure of frataxin from the thermophilic fungus Chaetomium thermophilum, and the characterization of its interactions and dynamics in solution. We show that this eukaryotic frataxin has an unusual variation in the classical frataxin fold: the last helix is shorter than in other frataxins which results in a less symmetrical and compact structure. The stability of this protein is comparable to that of human frataxin, currently the most stable among the frataxin orthologues. We also characterized the iron‐binding mode of Ct frataxin and demonstrated that it binds it through a semiconserved negatively charged ridge on the first helix and beta‐strand. Moreover, this frataxin is also able to bind the bacterial ortholog of the desulfurase, which is central in iron–sulfur cluster synthesis, and act as its inhibitor.

Cardiomiòcits de rata com a model d'Atàxia de Friedreich: alteracions cel·lulars i aproximacions terapèutiques

Purroy Lledós, Rosa. Universitat de Lleida. Departament de Ciències Mèdiques Bàsiques, (03-12-2018) Tesis, Director/a: Tamarit Sumalla, Jordi; Ros Salvador, Joaquim

Friedreich Ataxia is an inherited neurodegenerative disease with cardiac alterations and without any effective therapy. It is caused by a decrease of the mitochondrial protein frataxin. Nowadays, the exact function of this protein is still under discussion but it is related to iron homeostasis and oxidative stress. To study the frataxin deficiency consequences we have used a cardiac model based on primary cultures of neonatal rat cardiomyocytess. In this work it has been detected that frataxin deficiency causes i) mitochondrial permeability transition pore (MPTP) alterations, ii) mitochondrial calcium exporter NCLX decrease and iii) activation of calcineurin/NFAT cytosolic pathway that induces hypertrophy. Moreover, oxidative stress has been also studied detecting alterations of the glutathione levels and the redox state of PDH and KGDH mitochondrial complexes. Finally, the use of compounds to revert this phenotype, such as antioxidants or MPTP inhibitors, opens a new therapeutic strategy.

L’Atàxia de Friedreich és una malaltia neurodegenerativa hereditària amb afectació cardíaca per la qual no existeix cap teràpia efectiva. És causada per una disminució de la proteïna mitocondrial frataxina. Actualment, la funció precisa d’aquesta proteïna està en discussió però s’associa amb l’homeòstasi del ferro i l’estrès oxidatiu. Per a estudiar les conseqüències de la manca de frataxina s’ha utilitzat un model cardíac basat en cultius primaris de cardiomiòcits de rates nounades. En aquest treball s’ha detectat que el dèficit de frataxina provoca i) alteració del porus de transició de permeabilitat mitocondrial (MPTP), ii) disminució dels nivells de NCLX, exportador de calci mitocondrial i iii) activació de la via citosòlica calcineurina/NFAT, inductora de la hipertròfia. També s’ha estudiat l’estrès oxidatiu detectant alteracions en els nivells de glutatió i en l’estat redox dels complexos mitocondrials PDH i KGDH. Finalment, la utilització de compostos per revertir aquest fenotip, com antioxidants o inhibidors del MPTP, obren una nova estratègia terapèutica.(CAT)