Category: Leukodystrophy

The patient at the heart of research

Organised by ELA International, an innovative symposium on “CLINICAL RESEARCH and ETHICS OF CLINICAL STUDIES”  brought together experts and families to reflect on how to involve patients and their families in the various research studies that concern them, and on the impact of these trials on patients.

An innovative symposium

The objective of this symposium was to establish the ethical rules that will guide ELA International in its partnerships with both public and private laboratories.

ELA International and its President Guy Alba wanted to organise this symposium in order to bring together all patients to reflect on the ethics that are becoming urgent considering the increasing number of clinical trials for leukodystrophies.  This event is part of the continuity of the Family/Researchers meetings organised each year by ELA and underlines once again its desire to be more accessible to the international community of leukodystrophy patients.

The international symposium brought together around 100 people, experts and patients, and no less than 11 nationalities. Simultaneous interpretation into 5 languages (German, English, Spanish, French and Italian) allowed everyone to enjoy the discussions in the language they wanted.

Moderated by Professor Grégoire Moutel (Caen University Hospital), an expert in ethical issues, the symposium focused on two main themes:

• Increasing patient involvement in a research programme
• Ethics of partnerships: benefits for patients

The views of experts involved in clinical trials and the testimonies of families about their experiences as patients were illustrated from two trials, one of gene therapy in children and the other of drug treatment versus placebo in humans.

Clinical trials: information to patients

During the first session, an overview was given of the accessibility of clinical trials for patients through two examples: the gene therapy trial for metachromatic leukodystrophy conducted by the ORCHARD laboratory with Valeria Calbi(Saint Raphael Hospital, Milan, Italy), the chief investigator of the Milan site, and the drug trial in adrenomyeloneuropathy, conducted by the Minoryx laboratory with the chief investigator of the Boston site, Florian Eichler(Massachusetts General Hospital, Boston, USA).

The experts emphasised the importance of involving the patient in the trials, accompanying them through the different stages before they decided whether or not to be included in a trial and moving towards comprehensive family care.

Valeria Calbi described the complexity of implementing a trial and the vast amount of information that needs to be communicated to patients and the multitude of experts involved.  Experts know the disease well but do not necessarily have all the answers and should not lose sight of the objective of providing patients with the best possible information. Good coordination of all involved is essential.

Florian Eichler stressed the importance of patient feedback and is working on setting up questionnaires on the patient’s experience after a study, ” the patient must be an active contributor “. These insights are invaluable for the experts and will allow them to better adjust the processes and the approach to be taken to the tests.

The 10-minute presentations by the experts were accompanied by testimonies from families involved in the trials. They were able to recount their experiences, expressing how difficult it is for some of them to access information, and to deal with the cumbersome and lengthy administrative procedures in emergency situations that leave little room for reflection or questioning.

The discussion between the different speakers, moderated by Grégoire Moutel, highlighted the courage of the patients and the need to inform them about the constraints of the trial but also about the benefits it can represent: “Not everything can be communicated, but it is necessary to explain why, transparency is important,” said Grégoire Moutel.  He also emphasised the need to produce educational materials, which are just as accessible to the child/patient, and although written legal consent documents are essential, oral information is crucial and should be developed.

Finally, the discussion was opened up more widely to all participants. Questions on the conditions of access to trials, inclusion criteria, access to information, placebo-controlled trial or analysis of results, led to exchanges between experts and families.

On this occasion, Florian Eichler highlighted the complexity of the placebo-controlled trial, while specifying that the placebo element is a benefit for future patients, by making it possible to highlight the efficacy of a molecule and to reduce certain analysis biases. He insisted on the importance of speaking to the patient, which allows the experts to get closer to the facts and to feed their thinking. To develop further, he proposes that think tanks and observation groups be set up to encourage new links between the various research players.

Towards fair sharing

The second session, dealing with the ethical aspects of clinical trials, partnerships and patient outcomes, began with Dr Frederic Sedel speaking about the Biotin trial (MD1003), which was conducted by Medday Pharmaceuticals. The latter recalled ELA’s financial contribution to the trial and the framework of the contractual partnership between the two entities, highlighting the terms of the ” return on investment ” for ELA and its patient community. Thanks to the partnership agreement between the partners, this negative trial in adrenomyeloneuropathy gave rise to the full reimbursement of the sums paid by ELA, following the marketing of the molecule in certain European countries for use in multiple sclerosis. This example clearly shows the importance of the promotion of research and the place it must take in partnership contracts established at a very early stage of research. Guy Alba reminded the audience of the conditions of this type of partnership and ELA’s commitment to reinvest all the sums resulting from this research in the financing of new research projects.

Professor Marjo van der Knaap(Vu University Amsterdam, The Netherlands) presented the Guanabenz trial for CACH syndrome for which she is the Chief Investigator. She was able to highlight the involvement of the families involved at different stages of the study’s development. By mentioning the legal and administrative framework of this trial, she highlighted the difficulty of obtaining the many necessary authorisations from the various medical institutions involved and the obstacles encountered. The potential delay in the implementation of the trial is a real constraint to be considered.

Finally, Bruno Flesselles (Intellectual Property Advisor, Paris, France) gave an update on clinical studies in general, and more particularly on the role of ELA and the actions to be taken as well as the promotion of research results through partnerships.

To be a stakeholder in the development of research, ELA must be involved at a very early stage. To move in this direction, the association has already changed the way it approaches its call for tenders and will continue this work. In the supported clinical trials, ELA is a funder but can also assist in the recruitment and follow-up of patients, notably through its online clinical trial platform, Leuconnect, which brings together a community of patients who volunteer to participate in trials. Bruno Flesselles said that today, ELA should no longer be seen only as a funder but also as a real partner in research.

The outlook

Research involving leukodystrophy patients is on the increase and this reflection on ethics will help to define the framework of the partnerships set up between ELA and clinical research contributors to support tomorrow’s research and strengthen the medical and social support of families.

Guy Alba emphasised the importance of talking to the patient and providing information to families. He highlighted the crucial role of ELA as a partner in a sector that is still not very appealing to industry and highlighted the tools developed by ELA such as the Leuconnect platform to accelerate research into leukodystrophies. Finally, he concludes: “ELA is selflessly managed with a commitment to reinvest all of our partnership funds in leukodystrophy research

With this symposium, ELA is once again at the heart of current research issues and is fuelling the debate by giving families a voice to better understand their goals and experts to better understand their constraints and ambitions.

“This symposium strengthens the collaboration between physician-researchers, patients and families affected by leukodystrophy across the board and creates the strength that is essential for therapeutic progress.”

This event brought together the different points of view of families and researchers and enriched the reflection that could be achieved through workshops.
It has provided a real roadmap for the years to come.

Discover the entire ELA International 2021 Symposium

ELA International organized a virtual symposium on the topic Therapeutic innovation: what ethical rules and what access?

This event is a continuation of a first important event organized in last November on Clinical trials and Ethics.

It brought together medical experts, industrialists, health agencies and families to explore together the concepts of ethics, deontology and integrity and to discuss access to innovative treatments.

Simultaneously translated into five languages (English, French, German, Italian and Spanish), this symposium was once again opened to the families of ELA branches and the international community.

Discover the entire ELA International 2022 Symposium

The 2021 meeting took place in virtual on March 27-28

Families/Researchers virtual meeting: a huge success

Every year, ELA organizes a meeting in Paris which brings families and researchers together affected by leukodystrophies. This event could not take place in 2020 due to thethe global pandemic. The health context having made it impossible to organize the Families/Researchers meeting in person, ELA has had to adapt to allow this long-awaited meeting by families.

A first in ELA’s history

For the first time, ELA has organized a virtual family meeting, with the support of the CNSA (the French National Solidatity Fund for Autonomy), ORCHARD Therapeutics, and Autobahn Therapeutic. The meeting took place on the afternoon of 27 and 28 March, and welcomed the international community of patients affected by leukodystrophy. A simultaneous translation system in 5 languages (German, English, Spanish, French, Italian) allowed a large number of people to follow the presentations easily and live. It brought together some twenty different nationalities, testifying to the universality of the disease and the expectations of families around the world. Four workshops were held, 2 per half day, and covered all pathologies. About twenty researchers took part in the meeting, and gave an update of the progress of their work, and hopes of treatment. A time for discussion was allowed for the participants to ask their questions.

Bringing patients and their families together to accelerate research

One of the major objectives of ELA International is to bring patients together at a global level, an indispensable condition for accelerating research. As President of ELA International, Guy Alba points out: “If we are not able to bring patients together when we start clinical trials, all of this is pointless. To test new treatments, it will take as many patients as possible to build cohorts and conduct these trials under good conditions. Only a structure like ELA International can do it for the benefit of all, because it is independent, because it is disinterested, because it has no conflict of interest, and because it represents all patients.”

With this new international meeting format, patients from all over the world are gathered around the researchers and receive the same information at the same time. On this occasion, Guy Alba  recalled the importance of Leuconnect, a clinical research support platform developed by ELA International that brings patients and their families together. He invited the largest number to register on https://www.leuconnect.com to be part of the Leuconnect community.

This innovative and large-scale format provided by ELA has satisfied all participants and has once again given the opportunity to  families to gather around the researchers.

The 2022 meeting took place in virtual on March 26-27

Families/Researchers Meeting 2022

After a successful first edition last year, ELA International held the Families/Researchers virtual meeting, a major event long awaited by families, again this year.

RICH AND DYNAMIC EXCHANGES AND A FORMAT THAT HAS FOUND ITS PLACE

The Families/Researchers meeting once again brought together families affected by leukodystrophies and researchers working on these diseases. This event gives families the opportunity to learn about the progress of research and the opportunity to exchange with researchers who have actively provided responses to questions. The discussion between the researchers themselves also created a dynamic and the information exchanged enhanced everyone’s knowledge. Four sessions were organised and covered a wide range of leukodystrophies and cross-cutting issues. Simultaneous translation into 5 languages made it possible to open up this meeting once again to international families wishing to attend. This year again, many women followed the researchers’ presentations live and exchanged views with them in the language of their choice. 16 nationalities were represented and 184 families participated in the event.

The support of our partners has helped us to organise this event in the best possible conditions in order to maintain the quality of the services provided, which have made this event a success.

A SCIENTIFIC PROGRAMME FOCUSED ON CLINICAL TRIALS

Under the aegis of ELA’s 30th anniversary, Guy Alba (President of ELA International) opened the meeting by outlining the path taken and the key stages of research that have punctuated the life of the association. He also expressed his indignation, on behalf of all ELA families, at the withdrawal of the laboratory Bluebird bio from Europe, even though it had just obtained the marketing authorisation for Skysona, a gene therapy treatment for cerebral adrenoleukodystrophy. This abrupt decision deprives the sick children concerned of vital treatment. Finally, he noted that after many years of research focused on identifying the genes involved and understanding the mechanisms of the disease, many clinical trials are now being conducted and offer hope.

The scientific programme covered topics common to several forms of leukodystrophies, such as neonatal screening, the importance of early diagnosis, patient management and the use of the Leuconnect platform for online studies. The new sequencing technologies presented by Isabelle Thiffault(Children’s Mercy Hospital, Kansas City, USA) show that the technological advances of recent years are accelerating the discovery of new genes. Today, the immense amount of data to be analysed is a new challenge for researchers in identifying the genes responsible for leukodystrophies.

The experts took turns presenting the ongoing trials in which they are involved and their initial results.

Prof. Dr. Wolfgang Koehler(Klinikum St.Georg, Leipzig, Germany), who is currently conducting a study on the quality of life of X-ALD women on the Leuconnect platform, expressed his satisfaction and enthusiasm for this tool, which, based on its success, has led the research team to extend the study to two new languages, Spanish and Italian. He invites X-ALD women who have not yet done so to apply for the study on leuconnect.com.
Although he too is outraged by the withdrawal of Bluebird Bio in Europe, Prof. Dr.  Jean-Hugues Dalle(transplant doctor at Robert Debré-Paris), presented the main results of cell and gene therapy in the treatment of cerebral ALD as “A treatment that works if administered very early”. The issue of improved diagnosis and early management of the disease is at the heart of the discussions.

The study of gene function and expression to accelerate diagnosis in Pelizaeus-Merzbacher disease (PMD) are successively advocated by Prof. Dr. David Rowitch(University of Cambridge, UK) and Dr.  Nicole Wolf (Amsterdam University Medical Center, Netherlands). They highlight the diversity and heterogeneity of these diseases, which makes them difficult to understand.

But new avenues of thought are developing, particularly with the use of stem cells (iPSC), which are revolutionising the field of research. These are dedifferentiated cells that have the ability to be reprogrammed. They represent new research tools that open up perspectives on new therapeutic strategies. In particular, they are used to reproduce the behaviour of the cells involved in the disease. Elly Hol, who is involved in a European research programme (EJP) on Alexander disease, with which ELA is associated, presents a study conducted on mini-brains developed in the laboratory from these cells. They are used to better understand disease mechanisms and test new treatments.

Guanabenz is a molecule that has been marketed for many years in the US and Europe for the treatment of hypertension in adults. An ongoing study led by Prof. Dr. Marjo van der Knaap(Amsterdam University Medical Center, Netherlands) measures the effectiveness of this molecule in CACH syndrome. The initial results are encouraging.

Finally, the treatment of metachromatic leukodystrophy (MLD) by gene therapy approved in Europe represents a real prospect for the treatment of this disease.

Other experts shared their initial results and encouraging information about new treatments to come. Although the scientific community still lacks knowledge about these diseases, these presentations demonstrated, in addition to the clear shift towards clinical trials, that technology continues to advance and research is accelerating.

The Scientific Council of ELA International expressed its support for the families affected by leukodystrophies and victims of the current war in Ukraine, a moving discourse with which ELA associates itself.
“The European Leukodystrophy Association international scientific advisory board wishes to express its concern and sympathy for people and families affected by leukodystrophy and the war in Ukraine. We understand the great difficulty of taking care of children with rare disease, especially without access to proper hospital care or medicines.
Our board members will endeavour to provide direct medical support to refugees as well as hospitals and healthcare providers in the region that can benefit from specialist medical advice on care of leukodystrophy patients.
This is a time of empathy and unity for all people and families affected by leukodystrophy”

30 YEARS OF RESEARCH

The 30 years of ELA and the advances made in the field of leukodystrophy research are in everyone’s mind. The researchers thanked the families who participate in the clinical studies. They were also full of praise and appreciation for the activities carried out by the association over the years and the investments they have been able to make.
Clinical trials continue to increase in number. ELA is continuing on this path towards the treatments of tomorrow.

The Families/Researchers meeting took place online on April 15^th and 16^th 2023 afternoon.

With a simultaneous translation in 5 languages (German, English, Spanish, French, Italian) this meeting was open to the international community of patients concerned by leukodystrophy and once again gives the opportunity to gather around researchers from around the world.

Discover the whole conference Families/Researchers

X-linked adrenoleukodystrophy (ALD) is the most common peroxisomal disease. The product of the affected gene is a peroxisomal membrane protein (ADLP), a member of the large family of ABC transporters (ATP-binding cassette, ATP binding cassette): ABCD1. The ABCD1 protein-deficient mouse model of X-ALD exhibits lateonset, progressive axonal degeneration resembling AMN in humans. We observe an early onset of oxidative stress accompanied by lesions, one year before the onset of the disease.

In these mice, treatment with a combination of antioxidants including α-tocopherol, N-acetyl-cysteine ​​and α-lipoic acid reverses oxidative damage, improves energy deficit as well as axonal degeneration and damage. Oxidative stress therefore appears to be underlying axonal degeneration in adrenoleukodystrophy; it is one of the hallmarks of the pathogenesis of X-ALD.

Our group has helped to demonstrate the glutathione imbalance present in the blood of patients with X-ALD, thus highlighting the importance of imbalance of forms of glutathione (its oxidised form versus its reduced form) as a characteristic and potential biomarker of this disease.

More recently, a new drug, called EPI-743 (alphatocotrienol quinone), has been designed to reconstitute glutathione in reduced form (anti-oxidant form). The exact mechanism of action of EPI-743 has not yet been determined, but EPI-743 has been shown to be  potent in vitro protector of cells taken from patients with diseases of the mitochondrial respiratory chain, such as Friedreich’s ataxia, Leigh’s syndrome (SURF1) and Leber’s inherited optic neuropathy.

Six patients with Leber’s hereditary optic neuropathy are currently being treated with EPI-743 in open-label emergency treatment studies. Improvements in visual acuity, visual field and color vision have been observed.

Several pediatric patients with Leigh syndrome, Kearns-Sayre syndrome, POLG1 deficiency, MELAS syndrome and Friedreich’s ataxia are currently being treated with EPI-743 in open-label clinical studies. Clinical improvement associated with biomarkers was observed.

In a recently completed Phase 2A trial, EPI-743 was associated with signs of neurological improvement in 10 included children with Leigh syndrome.

Our goal is to determine the efficacy and safety of EPI-743 in an open study in 10 patients with X-linked adrenomyeloneuropathy (AMN).

The main objective of this study is to evaluate the effect of EPI-743 administered orally to subjects with AMN on the change in the association between clinical ALD score in adults ( AACS, Adult ALD Clinical Score) and the dependency rating scale (mRS-9Q) between baseline and the end of 48 weeks of treatment.

The secondary objectives of this study are evaluated from baseline to up to 48 weeks of treatment. They  are:

• to assess the safety of EPI-743 for 48 consecutive weeks;
• to assess the effect of EPI-743 on motor functions (6 minute walk test distance (6MWT), time required to travel 25 feet (T25FW);
• to assess the effect of EPI-743 on disease progression as assessed by the Clinical Overall Impression Improvement Scale (CGIIMP);
• to assess the effect of EPI-743 on the change in quality of life (SF-36 questionnaire);
• to assess the effect of EPI-743 on the evolution of the auditory evoked potential of the brainstem;
• to assess the effect of EPI-743 on changes in hormone levels;
• to explore the effect of EPI-743 on altering components of the glutathione cycle.

Frédéric Sedel – MedDay – 2015

Preliminary data has shown that the drug MD1003 can stop the progression of the disease in patients with primary or secondary progressive multiple sclerosis (MS) and improve their symptoms. Among the 23 patients with progressive MS treated for an average of 9.2 months with the drug MD1003, 21 patients (91.3% of them) improved. The positive effects of the drug MD1003 may be linked to an increase in energy production in demyelinated neurons and stimulation of myelin repair. Analysis of two clinical trials involving 250 patients with progressive MS is currently underway and should confirm the previous results.

Adrenomyeloneuropathy (AMN) and progressive MS have similarities including a secondary energy problem leading to progressive axonal degeneration. One patient with AMN was treated with the drug MD1003 for 5 months and showed clinical improvement comparable to the effects seen in progressive MS. The objectives of the trial are to assess the efficacy and safety of MD1003 in patients with AMN. Sixty patients from 4 different centers (two in France, one in Spain, and one in Germany) will initially be divided into 2 groups: a group of 20 patients will receive a placebo while the second group of 40 patients will receive the drug MD1003. The placebo study will last 12 months and will be followed by a 12-month extension phase where all patients will receive the drug. The primary end point will measure, before and after 12 months of treatment, the average change observed during the 2MWT walking test measuring the distance covered in 2 minutes. Secondary end points will include:

• the TW25FW walk test measuring walking time over a distance of approximately 8 meters,
• time to get up and walk (or timed chair test)
• the Euroqol ED-5D and MOS SF-36 quality of life questionnaires
• a Qualiveen urinary function questionnaire.

Exploratory analyzes will also be carried out in certain centers, such as MRIs, measurement of nerve conduction speed and assessment of muscle strength. The recruitment of all patients will be completed in mid-June 2015.

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare and still incurable genetic leukodystrophy characterised by a slowly progressive course leading to motor and cognitive deficits as well as epilepsy. The clinical condition of patients is often worsened after trauma or certain infections. Patient care requires intensive parental, educational and social support.

About 80% of people with MLC carry mutations in the MLC1 gene encoding a protein whose function is not yet fully understood; a minority of patients (around 15%) have mutations in the Hepacam / Glialcam gene which encodes a cell adhesion molecule.

These two proteins are very strongly expressed in a population of brain cells called astrocytes. Astrocytes are essential for homeostasis and brain function, including maintaining water and ion balance. Studies by our research group and others suggest that MLC1 may regulate the exchange of ions and water. We recently began to study the role of MLC1 in the intracellular processes controlling the response of astrocytes to stress conditions (osmotic, inflammatory and oxidative stress). The results obtained will provide us with fundamental knowledge to study how mutations in MLC1 alter the functionality of astrocytes and lead to brain damage.

For this, we obtained inducible pluripotent stem cells from skin fibroblasts of people suffering from MLC and we are currently in the process of differentiating them into astrocytes carrying pathological mutations of MLC. This model should allow us to gain new insights into molecules and pathways that may become pharmacological targets to restore astrocyte function(s) and ultimately correct neurological deficits, which would pave the way for the development of treatments that can cure MLC or improve the quality of life of people with it.

Florian Eichler, M.D., Christine Duncan, M.D., Patricia L. Musolino, M.D., Ph.D., Paul J. Orchard, M.D., Satiro De Oliveira, M.D., Adrian J. Thrasher, M.D., Myriam Armant, Ph.D., Colleen Dansereau, M.S.N., R.N., Troy C. Lund, M.D., Weston P. Miller, M.D., Gerald V. Raymond, M.D., Raman Sankar, M.D., Ami J. Shah, M.D., Caroline Sevin, M.D., Ph.D., H. Bobby Gaspar, M.D., Paul Gissen, M.D., Hernan Amartino, M.D., Drago Bratkovic, M.D., Nicholas J.C. Smith, M.D., Asif M. Paker, M.D., Esther Shamir, M.P.H., Tara O’Meara, B.S., David Davidson, M.D., Patrick Aubourg, M.D., et David A. Williams, M.D.– 2017

Wolfgang Köhler, Marc Engelen, Florian Eichler, Robin Lachmann, Ali Fatemi , Jacinda Sampson, Ettore Salsano, Josep Gamez, Maria Judit Molnar, Sílvia Pascual, Maria Rovira, Anna Vilà, Guillem Pina, Itziar Martín-Ugarte, Adriana Mantilla, Pilar Pizcueta, Laura Rodríguez-Pascau, Estefania Traver, Anna Vilalta, María Pascual, Marc Martinell, Uwe Meya, Fanny Mochel, and the ADVANCE Study Group – 2023

A clinical trial carried out in several countries has just been completed. Although it has not shown a favorable effect on adrenomyeloneuropathy, it provides interesting information for the treatment of cerebral adrenoleukodystrophy. Indeed, no patient who received the drug developed brain damage during the trial, unlike the men in the placebo group.

Most adults with the adrenoleukodystrophy gene develop adrenomyeloneuropathy, a chronic myelopathy which usually begins before the age of 30. Adrenomyeloneuropathy is characterized by severe and continuous axonal damage in the central and peripheral nervous system, and in particular causes stiffness when walking and balance disorders.

Cerebral adrenoleukodystrophy (cALD) is an aggressive inflammation of the brain. It affects 30 to 40% of boys aged 4 to 8 born with an ABCD1 gene mutation. Men with adrenomyeloneuropathy also develop cerebral adrenoleukodystrophy for more than half of them.

Safety and efficacy of leriglitazone for preventing disease progression in men with adrenomyeloneuropathy (ADVANCE): a randomised, double-blind, multi-centre, placebo-controlled phase 2–3 trial

Wolfgang Köhler, Marc Engelen, Florian Eichler, Robin Lachmann, Ali Fatemi, Jacinda Sampson, Ettore Salsano, Josep Gamez, Maria Judit Molnar, Sílvia Pascual, Maria Rovira, Anna Vilà, Guillem Pina, Itziar Martín-Ugarte, Adriana Mantilla, Pilar Pizcueta, Laura Rodríguez-Pascau, Estefania Traver, Anna Vilalta, María Pascual, Marc Martinell, Uwe Meya, Fanny Mochel, and the ADVANCE Study Group

Background

Adult patients with adrenoleukodystrophy have a poor prognosis owing to development of adrenomyeloneuropathy. Additionally, a large proportion of patients with adrenomyeloneuropathy develop life threatening progressive cerebral adrenoleukodystrophy. Leriglitazone is a novel selective peroxisome proliferator activated receptor gamma agonist that regulates expression of key genes that contribute to neuroinflammatory and neurodegenerative processes implicated in adrenoleukodystrophy disease progression. We aimed to assess the effect of leriglitazone on clinical, imaging, and biochemical markers of disease progression in adults with adrenomyeloneuropathy.

Methods

ADVANCE was a 96-week, randomised, double-blind, placebo-controlled, phase 2–3 trial done at ten hospitals in France, Germany, Hungary, Italy, the Netherlands, Spain, the UK, and the USA. Ambulatory men aged 18–65 years with adrenomyeloneuropathy without gadolinium enhancing lesions suggestive of progressive cerebral adrenoleukodystrophy were randomly assigned (2:1 without stratification) to receive daily oral suspensions of leriglitazone (150 mg starting dose; between baseline and week 12, doses were increased or decreased to achieve plasma concentrations of 200 μg·h/mL [SD 20%]) or placebo by means of an interactive response system and a computer-generated sequence. Investigators and patients were masked to group assignment. The primary efficacy endpoint was change from baseline in the Six-Minute Walk Test distance at week 96, analysed in the full-analysis set by means of a mixed model for repeated measures with restricted maximum likelihood and baseline value as a covariate. Adverse events were also assessed in the full-analysis set. This study was registered with ClinicalTrials.gov, NCT03231878; the primary study is complete; patients had the option to continue treatment in an open-label extension, which is ongoing.

Findings

Between Dec 8, 2017, and Oct 16, 2018, of 136 patients screened, 116 were randomly assigned; 62 [81%] of 77 patients receiving leriglitazone and 34 [87%] of 39 receiving placebo completed treatment. There was no between group difference in the primary endpoint (mean [SD] change from baseline leriglitazone: −27·7 [41·4] m; placebo: −30·3 [60·5] m; least-squares mean difference −1·2 m; 95% CI −22·6 to 20·2; p=0·91). The most common treatment emergent adverse events in both the leriglitazone and placebo groups were weight gain (54 [70%] of 77 vs nine [23%] of 39 patients, respectively) and peripheral oedema (49 [64%] of 77 vs seven [18%] of 39). There were no deaths. Serious treatment-emergent adverse events occurred in 14 (18%) of 77 patients receiving leriglitazone and ten (26%) of 39 patients receiving placebo. The most common serious treatment emergent adverse event, clinically progressive cerebral adrenoleukodystrophy, occurred in six [5%] of 116 patients, all of whom were in the placebo group.

Interpretation

The primary endpoint was not met, but leriglitazone was generally well tolerated and rates of adverse events were in line with the expected safety profile for this drug class. The finding that cerebral adrenoleukodystrophy, a life-threatening event for patients with adrenomyeloneuropathy, occurred only in patients in the placebo group supports further investigation of whether leriglitazone might slow the progression of cerebral adrenoleukodystrophy.

Funding: Minoryx Therapeutics

Reference : Köhler, W., Engelen, M., Eichler, F., Lachmann, R., Fatemi, A., Sampson, J., Salsano, E., Gamez, J., Molnar, M.J., Pascual, S., et al. (2023). Safety and efficacy of leriglitazone for preventing disease progression in men with adrenomyeloneuropathy (ADVANCE): a randomised, double-blind, multi-centre, placebo-controlled phase 2-3 trial. Lancet Neurol. 22, 127–136