MND Australia

Research Directions | March 2024

Welcome to the MNDRA research update. In this report we will highlight outcomes and advances from the MND research world that have caught our attention over the last few weeks. 

Recent clinical trial developments

The US pharmaceutical company, Amylyx, recently released the news that their treatment, RELYVRIO, had failed its Phase 3 clinical trial. The Phase 3 clinical trial, called Phoenix, tested RELYVRIO (formerly known as AMX0035) in over 600 participants and looked at a number of measures including ALSFRS-R, survival and respiratory function over 48 weeks. Unfortunately, none of these measures have shown any difference between participants receiving the treatment or a placebo.  

Following on from promising Phase 2 results of the CENTAUR trial for this compound, there was a strong advocacy campaign from a number of community organisations to allow access to RELYVRIO, which likely contributed to the treatment being approved in the US and Canada in 2022. It is unusual for a treatment to be approved prior to a Phase 3 trial, and these recent results are not only disappointing, but also reinforce the importance of carefully considering approving treatments on Phase 2 data, even if that data looks positive. The company has announced it will now take 8 weeks to decide what its future steps will be. You can read more about this on the MND Australia news page.  

RELYVRIO is made up of sodium phenylbutyrate and taurursodiol (TUDCA). A Phase 3 trial for TUDCA alone was also recently completed. The results of this trial are expected in June. It will be very interesting to see if TUDCA has beneficial effects on its own vs the lack of effect we see in RELYVRIO, where TUDCA is combined with sodium phenylbutyrate. 

The second part of a Phase 1 clinical trial for the drug SPG302, developed by the US-based company Spinogenix, is due to begin soon in Australia. SPG302 has been developed to target the synapse in nerve cells. The synapse is the site of contact between two nerve cells or the nerve cell and muscle that enable communication via chemical signals and is key for the brain control of muscles for movement. One major aspect of MND is the loss of these synapses. The trial is the second part of a Phase 1 trial, which will test the drug in a small number of MND patients, but only for a very short period (4 weeks), to make sure the drug behaves in the same way in patients as it does in healthy volunteers (already completed) and to measure any changes in patients that may occur. There will also be an open-label extension (OLE) following on from the Phase 1b trial to enable those participants in the trial to keep receiving the drug for up to a year. 

The pharmaceutical company TEVA have resubmitted their application to have Edaravone listed on the Pharmaceutical Benefits Scheme (PBS). The public submission phase has now closed and the Pharmaceutical Benefits Advisory Committee (PBAC) are considering the application. We have been informed that a decision from the PBAC is due late April.  

The Europeans Medicines Agency (EMA) Committee for Human Medicines (CHMP) has recommended granting a marketing authorisation for Biogen’s Qalsody (tofersen) which targets people who have a mutation in the superoxide dismutase 1 (SOD1) gene. This is a major step in gaining full approval in Europe for Tofersen. It is hoped that once approval is finalised in Europe Biogen will seek approval in Australia. For now, the drug is available in Australia through Biogen’s compassionate access program and will remain so until the drug gains approval for listing on the PBS. 

Denali, a small biotechnology company, announced in February that their candidate drug, SAR443820/DNL788 had failed to show any significant effect on ALSFRS-R in their Phase 2 HIMILAYA trial. Denali have partnered with Sanofi to develop this drug which is a small molecule blocker of the RIPK1 protein that was hoped would reduce neuroinflammation and neuron cell death.

ALS Clinical Trial Navigator Platform
The US organisation, The ALS Therapy Development Institute (ALSTDI), have launched their ALS Trial Navigator Platform. This is a comprehensive resource for making informed decisions about ALS/MND clinical trials. It has specialised tools to better understand clinical trial options and have informed discussions with your care team. It has three main tools: a Trial Finder that can generate a curated list of ALS clinical trials based on your preferences and eligibility criteria, a Trial Map function to see where clinical trials are happening around the world and also a Trial Browser which allows you to view a comprehensive list of global ALS/MND clinical trials and filter for specific characteristics.

Other research outcomes 

Improving the measurement properties of the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R): deriving a valid measurement total for the calculation of change
A study published published from the UK has undertaken a complex statistical analysis of ALSFRS-R scores in over 1000 MND patients across the UK. By using several different types of analyses they have shown that a change in at least 5 points on the ALSFRS-R scale is required to show a true change in functional status. This agrees with another study from the US: Clinically meaningful change: evaluation of the Rasch-built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) and the ALSFRS-R. These finding should be considered carefully in interpreting data from clinical trials and are equally important in the design of new clinical trials.

RNA-binding properties orchestrate TDP-43 homeostasis through condensate formation in vivo
A group from Macquarie University led by Associate Professor Marco Morsch have published a very cool study where they have managed to live image the formation of TDP-43 clumps in living spinal motor neurons in a mouse. Formation of TDP-43 clumps is thought to play a major role in damaging neurons in MND. To be able to watch this process occur allows researchers to better understand how the process happens and identify how they can stop or slow it down