A human trial assesses the impact of MND drug NuNerve

Amyotrophic lateral sclerosis (ALS) / motor neurone disease (MND) is a serious disease that affects the nervous system and causes a slow loss of muscle control. As the nerves that help control muscles die, people with ALS can experience very severe symptoms, and the disease often leads to an early death, usually within 2 to 4 years after it first diagnosed.

ALS/MND is rare, affecting about 4 people out of every 100,000 around the world, with most cases happening for no clear reason. Interestingly, about 10% of all ALS cases are inherited within families, also known as Familial ALS, while the majority arise in individuals without any known genetic link, which is known as Sporadic ALS. Sadly, there aren’t many treatments available; the focus is mostly on managing symptoms and helping with breathing, and the treatments that do exist don’t work very well.

The erythropoietin-producing hepatocellular carcinoma A4 (EphA4) receptor are highly expressed in the hippocampus, prefrontal cortex, and amygdala. This receptor has been found to play a significant role in ALS and is seen as a potential target for new treatments. This receptor is important for the development and function of the nervous system. However, when there is too much of it at the site of injury, it makes it harder for the motor neurons to heal and grow back.

Studies suggest that blocking EphA4 from binding to motor neurons can slow down ALS disease progression. To explore this, researchers combined EphA4 with part of an antibody. This “fusion”, called EphA4-FC, blocked the action of EphA4, potentially promoting nerve healing. However, EphA4-Fc may not last long in the body, meaning it might need to be given daily, which could be challenging for long-term treatment.

Why is the study important?

Researchers at the Queensland Brain Institute in Australia developed a new drug called NuNerve (NUN-004) to evaluate how well NUN-004 works and its safety in both healthy volunteers and people with ALS. This was the clinical study that proved successful for patients with ALS in terms of slowing disease progression and improving motor neuron function.

What did the authors do and how did they do it?

Researchers tested NUN-004, in two groups:

• Group1 (healthy volunteers), and
• Group2 (ALS patients both sporadic and familial).

The treatment was given weekly via injection into the veins. For the study, 20 healthy people (18-55 years old, which included males and females) received a single dose of the treatment, which was 30 milligrams per kilogram (mg/kg) of their body weight. On the other hand, eight patients with ALS (18-80 years old, also including males and females) received multiple doses at two levels: first at 15 mg/kg, and then at 30 mg/kg.

The ALS patients who did well continued receiving the NUN-004 treatment on a weekly basis for up to six months, as part of an extended study phase, named Phase 1b. Before participants received their first dose of the treatment and throughout the study, their safety was extensively monitored. This included physical check-ups, measuring vital signs like blood pressure, heart rate, breathing rate, and body temperature measured.

They also did a heart test called an electrocardiogram and looked at different biomarkers that could help understand the progression of ALS in patients. These included measuring levels of a protein called neurofilament light chain in both blood and cerebrospinal fluid. This protein is associated with nerve damage in various neurological conditions. They also measured a marker called urinary neurotrophin receptor p75, which is linked to the progression of ALS.

Researchers also monitored for any side effects too. On the day they received the treatment for the first time, they used 24-hour heart monitoring to assess safety. Additionally, for patients receiving multiple doses of NUN-004, their blood pressure was checked at home as needed, following recommendations from the Safety Monitoring Committee.

The researchers collected blood samples from healthy volunteers and ALS patients at various times, including pre-infusion (i.e., pre-injection), during infusion and 5 mins post-infusion. They also collected cerebrospinal fluid (CSF) from ALS patients during screening and at the end of the treatment cycle.

The main goal of the study was to see how safe the NUN-004 treatment was and how well it worked without causing any serious side-effects.

To check its effectiveness, the researchers looked at how well the ALS/MND patients performed daily activities, using the ALSFRS-R functionality scale (also known as Amyotrophic lateral Sclerosis Functional Rating Scale Revised Score), a questionnaire-based scale that measures and tracks changes in a person’s physical function over time, and includes measuring their lung capacity. The scale starts at 48 and goes down to zero, with the higher the score indicating better physical function.

The NUN-004 treatment was generally well tolerated by patients, meaning that there were no serious side effects or reasons for anyone to stop participating in the study. As the dose increased, the average peak levels of the drug also tended to increase in the blood. In healthy volunteers, the medication stayed in the body for about 112 hours after a single dose, while in ALS patients, it lasted about 74 hours. By day eight of treatment, patients reached a level of the medication where it remained stable. The stability of NUN-004 in patients showed that it stayed in the body for roughly 84 to 101 hours over multiple doses.

In the group that took 15 mg/kg of the drug during the multi-dose and extended access phases, there was a small amount of build-up of the drug. However, the group that took 30 mg/kg during the multi-dose phase and then 15 mg/kg during the extended access phase (Phase 1b) did not show any significant build-up.

When looking at the effects by gender, there were no noticeable differences and there were no detectable immune responses to the treatment. When researchers looked at the ALS functionality scale (ALSFRS-R), they found a small improvement in the first few weeks however, a slight decline was noted over the entire study. During the six-month treatment, patients who started with higher scores on their test saw an average drop of about 0.28 points, while those who started with lower scores experienced a bigger average drop of 0.41points. The main reason for the slight drop in patients’ scores could be the 50-day break without any treatments, which can lead to worsening symptoms. However, even though the average scores for those who received NUN-004 went down a little after that break, they did better than patients taking other ALS treatments such as sodium phenylbutyrate-taurursodiol (1.24/month decline) and edaravone (0.84/month decline) using the last observed data.

The breathing scores (Forced vital capacity) were essentially stable throughout the study, although a slight decline was observed at the end for three ALS patients out of the eight enrolled. Overall, the lung function matched the findings from the ALSFRS-R scale, indicating consistent results across different measures. The levels of certain biomarkers (a biological molecule that can predict the emergence of a disease) in blood, spinal fluid, and urine varied widely among ALS patients during the study, and no clear patterns were found, but these levels stayed stable throughout the treatment with NUN-004.

In general, patients had good things to say about the drug. They felt it helped them move better and improved their quality of life by keeping their disease symptoms under control. Many patients noticed they could do small tasks more easily, like gripping objects, moving their toes, using scissors, and untangling knots. They also experienced improvements in bigger movements, such as better balance, walking, stronger muscles, and feeling less tired.

What do the findings mean going forward for people with the disease?

There are only three drugs approved globally which may reduce the symptoms of ALS/MND, and partially improve quality of life, but there is no known treatment that reverses the disease.

The results of this first human study indicate that NUN-004 is safe, well-tolerated, and exposure is good in ALS patients, supporting its continued development as a long-term treatment for the disease.

This trial demonstrates the importance of fundamental research into the brain and nervous system and could also help in developing future treatments for conditions like stroke, spinal cord injuries, and sepsis.

This study can be found at
https://doi.org/10.1007/s40261-024-01410-x 

Paper title
Evaluation of NUN-004, a Novel Engineered Ephrin Antagonist, in Healthy Volunteers and Patients with Amyotrophic Lateral Sclerosis: A Phase I/Ib, Open-Label, Escalating Dose and Extended Access Study

Lead author
Mike Gerometta and Perry F. Bartlett

Publication details including date of publication
Clinical Drug Investigations, Springer Nature Link. 2nd December 2024