Round Up On Research Developments By Condition
Neuromuscular conditions can be difficult to diagnose and manage, so research is vital for families and for quality of life. In this issue, we include a round-up of some research developments that have taken place in recent months.
In this article:
Focus on myotonic dystrophy
Myotonic dystrophy (DM) is an inherited condition. It is abbreviated as DM as the Latin name for this condition is ‘dystrophia myotonica’. In DM, a defective gene causes progressive muscle weakness accompanied by myotonia, which is the delayed relaxation of muscles after contraction.
It is a multi-systemic condition, meaning that its effects are not limited to the voluntary muscle system, but can also affect tissues and organs throughout the body. Primarily the muscles of the face, neck, hands, forearms, and feet are affected. People can also experience respiratory, cardiac, gastrointestinal complications, and cognitive and behavioural concerns. DM is highly variable and can have a wide range of different effects on different individuals. DM can be classified into several types based upon the age of onset and the clinical symptoms experienced. DM affects both males and females. Age of onset is variable from birth through to old age.
Three main forms of DM have been identified so far:
• DM1, also known as Steinert’s disease
• DM2, also known as proximal myotonic myopathy (PROMM)
• Congenital myotonic dystrophy (CMyD).
DM1 is the most common of these forms. It was the largest group of genetic muscular dystrophies (28 per cent) in a prevalence study of adult neuromuscular conditions in the Republic of Ireland in 2014. No cases of DM2 were identified in this study. CMyD is much rarer and affects 1 in 100,000 people. Myotonic dystrophy has an effect called ‘anticipation’ which means that the condition can get progressively worse with each generation.
DM1 and DM2 are both caused by abnormally expanded stretches of DNA. The expansions occur in two different genes but appear to have similar effects on various cells, particularly the cells of the voluntary and involuntary muscles, including the heart and nervous system. In DM1 the abnormal DNA expansion is in the DMPK gene. The DNA building blocks cytosine, thymine, and guanine (abbreviated as CTG) are repeated many more times than average in this condition. In a healthy individual the number of ‘CTG repeats’ is approximately 35 but people with DM1 can have from 50 to 1,000 CTG repeats in most cells. The number of repeats may be even greater in certain types of cells, such as muscle cells.
The mutated DMPK gene produces an altered version of messenger RNA, which is a molecular blueprint of the gene that is normally used to guide the production of proteins. Researchers have found that the altered messenger RNA traps proteins to form clumps within the cell. The clumps interfere with the production of many other proteins. These changes prevent muscle cells and cells in other tissues from functioning properly, leading to muscle weakness and the other features of DM1.
Both DM1 and DM2 are inherited in an autosomal dominant pattern, meaning only one copy of the abnormal expansion is required, to cause symptoms of the condition. Therefore, if one parent has the condition, every child of that person has a 50 per cent chance of inheriting the gene flaw that causes it.
More information about myotonic dystrophy
· Consensus-based Care Recommendations for Adults with Myotonic Dystrophy Type 1, are available online here. You may wish to share them with your specialist or, if you or a family member have myotonic dystrophy, you may wish to become familiar with these.
· Myotonic Dystrophy Support Group (UK) have a range of leaflets available on different topics related to myotonic dystrophy. These can be viewed here. Please let us know if you’d like us to post you hard copies of any of them as we have some available in our office.
Myotonic Dystrophy Foundation (MDF) annual conference 2023
The Myotonic Dystrophy Foundation annual conference was held in Washington, DC in September. Click here to get the recordings of enlightening sessions, in-depth discussions and presentations on groundbreaking research, and here to explore the latest research findings and innovative projects showcased in research poster abstracts by young investigators and industry leaders. Poster abstracts offer a visual representation of the findings of a study.
AOC 1001
Avidity Biosciences, Inc. is a biopharmaceutical company committed to delivering a new class of RNA therapeutics called Antibody Oligonucleotide Conjugates (AOCs™). AOCs target the root cause of conditions previously untreatable with RNA therapeutics.
Avidity Biosciences, Inc. is investigating the safety, tolerability, efficacy, pharmacokinetics (how the body affects a specific substance after administration) and pharmacodynamics (the biochemical and physiologic effects of drugs on the body) of AOC 1001 in people with DM1.
In October the company presented early results from their Phase1/2 clinical trial called “MARINA” and MARINA open-label extension trial. The data demonstrated improvements in functional measures including hand grip, muscle strength and patient reported outcomes, increasing previously reported positive data showing improvements in myotonia, muscle strength and mobility. In addition, new long-term safety data of AOC 1001 continues to demonstrate favourable safety and tolerability with most adverse events reported as mild to moderate.
Avidity Biosciences, Inc. is now finalising the Phase 3 study design and global regulatory path for AOC 1001. The company is also advancing clinical programmes for Duchenne muscular dystrophy (DMD) and facioscapulohumeral muscular dystrophy (FSHD). You can read about the clinical programmes for FSHD (AOC 1020) and Duchenne muscular dystrophy (AOC 1044) below.
Facioscapulohumeral muscular dystrophy (FSHD)
AOC 1020
Avidity Biosciences, Inc. is a biopharmaceutical company committed to delivering a new class of RNA therapeutics called Antibody Oligonucleotide Conjugates (AOCs™). AOCs target the root cause of conditions previously untreatable with RNA therapeutics.
Avidity Biosciences, Inc is developing a drug called AOC 1020 for FSHD. It is currently in a Phase 1/2 clinical trial called FORTITUDE. The treatment is similar to AOC 1001 that they are developing as a therapy for myotonic dystrophy. Although this drug is aimed at a different gene, the ‘vehicle’ that delivers these genes to muscles is the same. Thus, if the myotonic dystrophy trial reveals any adverse side effects, these might also occur in people with FSHD. On the positive side, if AOC 1001 is improving symptoms for people with DM1, this suggests that the vehicle is effective in delivering therapeutic levels of RNA to muscles.
Therefore, Avidity’s announcement on their AOC 1001 drug is also encouraging for the FSHD community, with the hope that the AOC 1020 drug will similarly be found to be well-tolerated and effective at delivering its anti-DUX4 drug to the muscles. Data from a preliminary assessment in approximately half of the participants in the FORTITUDE trial is planned for the first half of 2024.
Duchenne muscular dystrophy
ELEVIDYS
In our last newsletter, we announced that the first gene therapy for Duchenne muscular dystrophy (DMD), called ELEVIDYS, was approved in United States (US) for children aged between four and five years, who can walk unassisted. (It is not suitable for children with a deletion in exon 8 and/or exon 9 in the DMD gene.)
This accelerated decision to allow people in the US to access the therapy sooner, means that ongoing monitoring and additional studies are required to confirm its benefits and whether access will be continued. This approach strikes a balance between addressing unmet medical needs and ensuring patient safety.
In October, results from a Phase 3 study called EMBARK Part 1 were announced. This trial analysed results from 125 boys aged four to seven years with DMD who can walk unassisted. Results showed that the study did not meet its primary endpoints of showing a positive change on the North Star Ambulatory Assessment. However, significant improvements were observed in time to rise from the floor and 10-metre walk test. The EMBARK study is ongoing and part 2 is expected to complete in late 2024.
Other studies are happening in the US to assess the treatment with older boys who can either walk unassisted or require mobility assistance. A trial planned to study this treatment in children under four years of age has not yet started.
Sarepta is the pharmaceutical company responsible for delivery of the treatment in US. MDI is in contact with Roche which is the company responsible for distribution of this drug outside the US. Roche plans to discuss EMBARK Part 1 results with the European Medicines Agency (EMA) to explore the path forward in Europe.
AGAMREE® (vamorolone)
In October, the European Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion in favour of the approval of AGAMREE® (vamorolone) for the treatment of people with DMD aged four years and older. The CHMP’s positive opinion shows signs of promise that this drug may be approved by the European Medicines Agency (EMA) for the treatment of this age group. A marketing authorisation decision is expected towards the end of December 2023 or January 2024. If approved by the EMA, the drug company, Santhera Pharmaceuticals, will need to submit an application to the HSE Corporate Pharmaceutical Unit (CPU) for evaluation of the drug treatment in the context of the Irish healthcare system.
AGAMREE® (vamorolone) is a novel drug that works similarly to corticosteroids (anti-inflammatory medications used to help maintain muscle strength). AGAMREE® aims to retain the beneficial anti-inflammatory and muscle-strengthening aspects of corticosteroids, while decreasing some of the undesirable side effects (bone fragility, stunted growth, insulin resistance, mood changes, delay of puberty and others).
Translarna
Translarna is used to treat boys with DMD caused by a specific genetic defect (called a ‘nonsense mutation’) in the dystrophin gene. The European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) granted Translarna a ‘conditional marketing authorisation’ in 2014 because the medicine addressed a clear unmet medical need. It has been available in Ireland since 2019 for people diagnosed with the nonsense mutation Duchenne muscular dystrophy.
In September 2023, the CHMP recommended not to grant full marketing authorisation of Translarna for the treatment of the nonsense mutation Duchenne muscular dystrophy. PTC Therapeutics have requested a re-examination of the decision. This re-examination process is likely to last until January 2024, and the European Commission have 67 days to enforce the recommendation, that is, by the end March 2024. MDI is working collaboratively with clinicians in Ireland and other muscular dystrophy patient organisations from Europe to support people during this time. Click here to read our news release.
AOC 1044
Avidity Biosciences, Inc. is a biopharmaceutical company committed to delivering a new class of RNA therapeutics called Antibody Oligonucleotide Conjugates (AOCs™). AOCs target the root cause of conditions previously untreatable with RNA therapeutics.
Avidity Biosciences has reported positive findings from the Phase I/II EXPLORE44 clinical trial of AOC 1044 in healthy subjects to potentially treat Duchenne muscular dystrophy mutations amenable to exon 44 skipping (DMD44).
The next phase of the trial aims to enrol 40 healthy subjects and 24 people with DMD44 aged seven to 27 years. It will also analyse exon skipping and dystrophin protein levels in the participants. Recruitment is across three sites in the United States with estimated completion in March 2025.
Spinal muscular atrophy (SMA)
Reimbursement approval of Risdiplam (Evrysdi®)
On 1 September the HSE announced that Risdiplam (Evrysdi®) has been approved for reimbursement in Ireland. This makes Risdiplam the third SMA medicine available in Ireland, alongside Zolgensma and Spinraza. Developed by Roche Pharmaceuticals, Risdiplam is the only non-invasive SMA therapy, administered daily at home in liquid form by mouth or by feeding tube, making it more accessible and less invasive than other treatments.
Risdiplam has been approved by the European Medicines Agency (EMA) for all ages groups with SMA Type 1, Type 2, or Type 3 with four or fewer copies of the SMN2 gene. The HSE has approved access for people in Ireland who are aged between two months and under 18 years of age. As a result, there continue to be no treatment options for people in Ireland with SMA over 18 years of age. Zolgensma is a gene therapy used to treat children less than two years old with SMA, and Spinraza is also capped to people under 18 years of age in Ireland, even though it is available for adults in other European countries.
You can find out more about Risdiplam here.
Limb girdle muscular dystrophy (LGMD)
International LGMD conference 2023
The third International Limb Girdle Muscular Dystrophy conference took place in Washington DC in October. The focus was on establishing safe and effective treatments for all LGMDs. Recordings from this conference are now available on the Speak Foundation YouTube platform here.
Friedreich’s ataxia
SKYCLARYS® (omaveloxolone)
The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended marketing approval for SKYCLARYS® (omaveloxolone) for the treatment of Friedreich’s ataxia (FA) in people aged 16 years and older. If approved by the European Commission (EC), SKYCLARYS will be the first treatment approved within the European Union for this condition. The EC will review this recommendation with a final decision expected in the first quarter of 2024. You can read the news release here.