Interview: A new age of ALS treatment?

NR Times reports on the much-anticipated trial of ALS treatment AMX0035, in an interview with Machelle Manuel, head of global medical affairs at its creator Amylyx.

Recently approved for treating ALS in the US, AMX0035 is now the subject of a major phase 3 clinical trial taking place across the US and Europe.

ALS is a relentlessly progressive and fatal neurodegenerative disorder that up until recent decades was thought to be impossible to treat. While the cause of the condition is still uncertain, a new wave of treatments is coming to the fore.

Caused by motor neuron death in the brain and spinal cord, the condition leads to deteriorating muscle function, the inability to move and speak, respiratory paralysis and eventually, death, with most patients passing away from the condition just two to three years after diagnosis.

The disease affects approximately 29,000 people in the US and more than 30,000 across Europe.

Treatments for ALS are few and far between.

There is currently no cure and no treatment that has yet been shown to reverse disease progression. In Europe, there is only one approved drug for slowing down progression of the condition, Riluzole, which received market approval in 1996.

In the US, riluzole is accompanied by several other FDA-approved drugs that seek to slow disease progression, including tofersen and edaravone.

Machelle Manuel

In October last year, a new drug named AMX00035 was added to the list of approved therapies and became the first to have shown a “statistically significant” benefit to function and survival in clinical trials.

It was developed by the Massachusetts-based pharmaceutical company Amylyx. Since receiving approval in the Autumn of last year, the therapy is now used by over 1500 patients across the US under the brand name RELYVRIO.

In Canada, it is marketed as ALBRIOZA and is used by several hundred patients.

Amylyx was founded by Josh Cohen and Justin Klee in 2013. The pair identified and combined two known compounds – sodium phenylbutyrate (PB) and tauroursodeoxycholic acid (TUDCA) – which target two separate mechanisms that are thought to cause neuron death.

Speaking to NR Times over Zoom, head of global medical affairs at Amylyx, Machelle Manuel, said: “The [co-founders] were really curious about why neurons die because at the heart of neurodegenerative diseases is either the nerve cells are not working well, or a lot of times it’s because the neurons have died because of neuronal death.

“What they set out to do was research what actually makes a neuron die and it turns out it is incredibly complex. There are many, many pathways.

“If you look across drug development for ALS, specifically, but also for other neurodegenerative diseases, you can see the breadth of the types of products that are being developed. And they’re all aimed at one or more of the pathways that can eventually lead to a neuron dying.”

The research stage that led to the development of AMX0035 focused on two key organelles within the neuron; the endoplasmic reticulum and the mitochondria.

These parts of the nerve cell are a common theme in neurodegenerative disease research.

Mitochondrial dysfunction can decrease the threshold for programmed cell death – or cellular suicide – which is one of the main contributors to cell death in patients with ALS.

Meanwhile, endoplasmic reticulum stress can lead to disruptions in protein folding. This is the process that takes proteins from their initial chain-like structure to a fully formed shape, allowing them to carry out their unique function in the body.

Scientists have theorised that a build-up of misfolded proteins contributes to the progression of numerous neurological conditions including ALS, Alzheimer’s, Parkinson’s and Huntington’s disease.

“Sodium phenylbutyrate has been shown in preclinical models and in some clinical data that it can help with endoplasmic reticulum stress and TUDCA can actually help mitigate mitochondrial dysfunction,” Manuel explained.

“The co-founders’ idea was, why don’t we combine these two together and address both of these stressors to the cell at the same time.”

A new approach to ALS clinical trials

Cohen and Klee tested the combination of compounds via lab models of neuronal death and discovered that their hypothesis was true.

Then, together with the ALS community and key industry players, Amylyx designed a clinical trial to test the new therapy in patients.

Over the last 30 years, more than 50 compounds have been tested for treating ALS but all have failed in the clinical stages, even those that showed positive results in phase 2 studies.

The reasons for these failures are not just linked to the drugs themselves, but the way in which the trials were conducted.

The CENTAUR trial, which launched in 2017, sought to follow a different approach, trimming down the timescale of the study, adjusting the recruitment process and making the active treatment available to a larger number of participants compared to the placebo.

“The approach that was taken by this collaboration between industry and the community and the investigators was to really take a closer look at those trials and try to figure out is there a way to create a trial design that sets us up for success,” Manuel said.

The trial lasted around six months with two-thirds of the 137 subjects taking AMX0035 compared to the standard one to one ratio for placebo-controlled trials.

Given the rarity of the disease and high variability when it comes to progression, recruitment for ALS trials is a challenging step in the process.

While previous clinical trials accepted participants with a broad range of disease progression and level of function, the CENTAUR trial recruited a subset of patients with faster progression.

“[Previous studies] probably did not have enough time or enough people in the study to see if there was a slowing down in the loss of function,” Manuel said.

“ALS is a rare disease which makes it very hard to recruit for [trials]. The strategy that we used was to define a very fast-progressing population relative to the average so that if you look at them over a six-month period, you’re more likely to see a difference if AMX0035 is slowing that function loss down.”

The study proved a success and became the first ALS trial to show a “statistically significant” benefit in function and an observed benefit in survival in a longer-term post hoc analysis.

“ALS is a disease of loss of independence,” Manuel said.

“A loss of motor neurons which causes a loss of speech ability, loss of ability to climb stairs and it eventually affects breathing. So you measure a drug for its ability to slow that down.

“What the Centaur trial demonstrated was that RELYVRIO not only slowed down this loss of independence, but actually also resulted in survival in a post hoc analysis over the long term.

“It was really very exciting and set the stage for trial designs subsequently. Many trials are using some of the same techniques and it led to informing the [HEALEY] ALS Platform Trial.”

Off the back of the CENTAUR trial, AMX0035 received FDA approval for the treatment of adults with ALS last October, however, the road to approval was not straight forward.

Initially, a panel of external advisors to the FDA voted not to recommend the therapy for approval in March last year due to a lack of “substantially persuasive” data.

But after new analyses from the CENTAUR trial were submitted, a second meeting saw an unusual turnaround in which the panel voted 7 to 2 that the evidence was sufficient.

The new decision was in part due to the “substantial unmet medical need in ALS”.

“We were applying to the FDA with a single trial,” Manuel said. “And very often, regulatory authorities really like to see two trials; one initial trial and then a confirmatory trial.

“For us, we felt that these results were so compelling with the ability to show a 25 per cent slowing down in the loss of function and we had some initial data on the survival piece.

“When we went to the first advisory committee meeting, some of the data was still being analysed.

“We were able to provide additional analyses and that led to our second advisory committee meeting and then we were able to successfully demonstrate [clinical benefit] through the use of some natural history comparisons.

“It was really compelling that we could show that using AMX0035 actually provided a real survival benefit not only in our observation but also when compared to natural history.”

Next steps

Following the success of the phase 2 CENTAUR trial, Amylyx is now embarking on the next stage of research, working across more than 65 sites in Europe and the US.

In February, Amylyx completed enrollment of 664 ALS patients for a global 48-week phase 3 randomised, placebo-controlled clinical trial of AMX0035 called PHOENIX. Initial results are expected in mid-2024.

Elsewhere, AMX0035 is also being studied in a trial exploring its efficacy in treating Wolfram syndrome, a rare autosomal recessive degenerative disorder.

The condition is generally associated with child onset diabetes and affects the optic nerve, visual acuity and eventually leads to neurodegeneration.

As the condition affects similar signalling pathways to ALS, endoplasmic reticulum stress and mitochondrial dysfunction in particular, early clinical preclinical studies have shown promise for AMX0035 as a potential treatment.

The study is in its early stages but top-line data is expected by 2024.