With the recent approval in the US of the first genetic therapy for MND, the next episode of the MNDRA State of Play webinar series will focus on the development of genetic therapies and considerations for genetic testing, titled Genetics in MND – therapies, testing and the future and presented by A/Prof Kelly Williams & Dr Ashley Crook. The webinar is scheduled for Tuesday, 20th June @ 7pm, register here. Recordings of previous webinars are available here.
The U.S. Food and Drug Administration (FDA) has granted conditional approval to Biogen’s tofersen, which has been renamed QALOSDY, for the treatment of those cases of MND associated with mutations in the SOD1 gene.
Mutations in the SOD1 gene are found in as many as 20% of people with familial ALS and in up to 2% of sporadic ALS cases. Such mutations result in a toxic form of the SOD1 protein that accumulates and forms clumps that damage nerve cells.
QALSODY is designed to lower SOD1 levels and preserve nerve cell function. By reducing the amount of SOD1 protein that is produced in cells, the therapy has the potential to slow disease progression and extend survival.
A conditional approval is in contrast to a full approval that would be based on primary outcome data such as an improvement in survival or ALSFRS-R. Further, this conditional approval means that Biogen will be required to continue to collect data on the effects of the treatment and report to the FDA any concerns around ongoing effectiveness.
We are currently waiting to hear the exact timeline for Biogen to apply for approval for QALSODY in Australia but we understand that the treatment will continue to be made available to eligible Australian patients through the Biogen extended access program (EAP) that is currently running, until a regulatory decision is made.
Microcals was an 18-month, randomised, double-blind, placebo-controlled clinical trial, investigating the use of low-dose Interleukin-2 (IL-2) in people living with MND.
Low-dose IL-2 can increase Regulatory T Cells (Tregs), an immune system cell that can control inflammation, and this was demonstrated in the MIROCALS trial.
Although IL2 treatment did not significantly improve outcomes for patients across the whole treatment group, a group of patients was identified that did respond to treatment. In this sub-group, there was slower disease progression resulting in a significant decrease in risk of death of over 40%, at 21 months.
Subsequent to these findings, in May 2023, ILTOO, a company that makes low-dose IL2, has signed a licence to analyse the MIROCALS data to further develop low-dose IL2 specifically as an MND treatment.
Dr Brian Dickie, Research Director at the UK Motor Neurone Disease Association said:
“ALS is a devastating and ultimately fatal disease, with very limited treatment options presently available. Novel therapeutics are desperately required, and this licence agreement will hopefully provide the springboard for rapid development of low dose IL-2 to address this urgent unmet medical need.”
Synapticure, a US-based organisation are commencing a study that focuses on pre-symptomatic individuals who carry a pathogenic or likely-pathogenic gene variant of MND. Participants in this study will be given the option to take Riluzole, the longest standing treatment for MND.
Although not available in Australia this is an important study as it is widely held that much of the initial damage in MND occurs well before diagnosis.
By targeting people more likely to develop MND i.e. carrying a MND genetic mutation, the potential benefits of preventative treatment can be investigated.
Unfortunately, following the good news of recent approvals and positive trial outcomes there has also been some bad news:
COURAGE-ALS was a Phase 3, multi-center, double-blind, randomized, placebo-controlled trial of a drug called reldesemtiv in approximately 555 patients with ALS. Reldesemtiv, produced by a company called Cytokinetics, is a drug that is designed to increase skeletal muscle contractility thereby improving muscle function.
COURAGE-ALS commenced in 2021, and included two planned unblinded interim analyses to check how the trial was progressing. Following the 2nd interim review in March 2023, it was recommended the trial be discontinued, as there was no evidence of effect in patients treated with reldesemtiv relative to placebo.
Cytokinetics plans to discontinue treatment with reldesemtiv in all patients including those in the open-label extension study, COURAGE-ALS OLE. Although a negative outcome, Cytokinetics should be commended for their strong study design incorporating these interim reviews which curtailed the unnecessary burden for participants in continuing on an ineffective treatment or placebo.
The MERIDIAN trial enrolled approximately 230 adults with sporadic MND to test pegcetacoplan (APL-2). Pegcetacoplan inhibits complement protein 3 (C3), a part of the body’s immune system involved in fending off infections, as well as removing dead cells and foreign material.
The trial has been completed and many patients were continuing in an open-label extension of the trial. However, they made the decision to discontinue the open-label period of the MERIDIAN study for MND following an unblinded review of the available data, which did not support continuation of treatment.
University of Queensland
Two publications from Dr Adam Walker and colleagues at the University of Queensland have shed further light on how a key protein, TDP-43, might contribute to MND.
“TDP-43 is a protein found in every cell of the body but is particularly important for the health of motor neurons, the brain cells that control voluntary muscle movement. We ran two research projects, looking at how TDP-43 proteins become dysfunctional in motor neurons,” Dr Walker said.
In the first study they used a mouse model with defective TDP-43 that allows them to look at the very early stages of disease development. They saw that a number of cell stress pathways are activated before any physical changes are seen providing useful insights into the cascade of changes that lead to MND.
In the second study they used a specially adapted version of TDP-43 that allows them to observe exactly how TDP-43 behaves in cells. They showed that mutant TDP-43 also causes non-mutated TDP-43 to become toxic to cells and identifies a mechanism by which MND symptoms can spread and worsen.
These projects were partially supported by funding from MNDRA.
Kelly Williams and Lyndal Henden at Macquarie University have shown that some patients with MND and frontotemporal dementia (MND/FTD) carry the same rare genetic defects that cause other neurodegenerative diseases.
These gene defects, known as short tandem repeat expansions, are the cause of more than 20 neurodegenerative diseases, including spinocerebellar ataxias and myotonic dystrophy. This Australian study has been the most comprehensive assessment of these gene defects in MND and FTD patients worldwide.
“This suggests shared risk factors among these diseases, shared mechanisms that cause nerves to die – and perhaps shared therapeutic strategies in the future. While the causes of sporadic MND and FTD remain unknown, this is an important step in a long-term effort to identify the risk factors for developing one of these diseases,” Kelly Williams said.
Researchers in Columbia have been studying an extended family whose members develop Alzheimer’s in their forties or earlier. Many of the approximately 6,000 family members carry a genetic variant called the paisa mutation that inevitably leads to early-onset dementia.
But the researchers identified a family member with a second genetic mutation – one that protected him from dementia until age 67. Even though the patient showed many of the same physical changes that are seen in patients who have already developed dementia, this patient was protected apart from mild cognitive impairment.
This discovery showed that a number of different pathways were connected in the development of dementia that were not known previously. Most research focuses on what causes disease, with few opportunities to find out how to protect against disease.
“The vast majority of research focuses on why some people have Alzheimer’s; very few are on conditions where a factor can go against this disease. This is one of those few cases that really opens the door for anti-Alzheimer’s research,” said Yadong Huang, a neurologist at the Gladstone Institutes in San Francisco, California.
If such a mutation could be found in MND it would be very exciting!