How HIV Inspired Drug Development for ALS
After watching AIDS-related dementia resolve with treatment, neuroinflammation became a disease agonistic target.
There are more than 100 different neurodegenerative diseases, each driven by distinct mechanisms. For years, scientists have gone after them one by one—what if targeting a shared weakness could provide a more universal solution?
A common vulnerability has been apparent for decades, and one approach targeting it is nearing Phase 3 evaluation.
Dr. Michael S. McGrath, emeritus professor of medicine at the University of California and chief executive officer of Neuvivo Inc., was working as a medical doctor in 1985, when the HIV epidemic began. McGrath observed the devastating consequences of acquired immunodeficiency syndrome (AIDS)-related dementia and, later, its apparent reversal with antiretroviral treatment.
“When we were able to treat AIDS with antiretrovirals, it went away,” McGrath recalled. “I thought, ‘This is going to be simple. I should just cure ALS [amyotrophic lateral sclerosis] now.’ I started working on ALS about 20 years ago. Of course, it was not simple.”
ALS is a progressive neurodegenerative disease; it affects the nerve cells in the brain and spinal cord. McGrath recognized that an imbalance in the innate immune system was driving inflammatory processes in ALS, which eventually led to the development of NP001.
Technology Networks sat down with McGrath to learn more about how NP001 targets ALS pathophysiology, what Phase 2 trials have revealed so far, and where the candidate is going next.
What role does immune dysfunction play in ALS?
Michael S. McGrath MD, PhD (MSM):
A tattoo is a colored oil droplet that they inject into your skin. It causes a little wound, and your immune system goes, “Ow! I've got a wound.” The innate immune system responds to the invasion, and a tissue macrophage engulfs the oil droplet. How long does that macrophage stay there? Not quite forever, but it lasts a very long time. Even when it’s gone, continued macrophage renewal seems to help the tattoo persist. Imagine if I provoked your innate immune system to turn against you. It's like your tattoo turning against you. Innate immunity protects you from the rest of the world.
We look at the possibility that it's this type of immunity that goes wrong in ALS and other neurodegenerative diseases. Imagine if the equivalent of a tattoo decided it was going to kill you in the brain or the nervous system. Inflammation happens in response, but the inflammation needs to balance out—you can't just have assault going on all the time.
IH:
MSM:
There are chemicals involved in balancing the innate immune system. NP001 gets converted into one of these chemicals.
ALS commonly starts in one spot—your head, arm, or foot—and then spreads. If you can start a therapy that puts the innate immune system back in balance before ALS spreads, I believe you can stop the disease.
Imagine that you've got a fire in your neighborhood. You are unlikely to go out of your house to see your next-door neighbor. If the fire was put out, you could go out and see your neighbor again. The house is the neuron in this analogy, and the fire is the abnormalities of the innate immune system in neurodegenerative disease. Once the fire is out, the innate immune system is back under control, the garbage workers return, the repair people return, and the body's mechanisms start working again. The expectation is that once you eliminate all underlying inflammation and fire, the growth factors will make things better.
Many rare diseases manifest later in life. I would argue that the innate immune system is what's keeping these things under control. How does a disease, like ALS, just decide to turn on you one day? I'm not saying that studying genes and how they relate to disease is a bad thing; I just think another approach could be taken.
IH:
MSM:
We have data from two Phase 2 trials: one completed in 2011 and one in 2017. Patients with slow-progressing ALS were included—this means ALS is in one spot and hasn't yet moved. The trials were six months long.
NP001 clinical trials and analyses
In the first Phase 2 trial, NP001 did not significantly slow ALS progression in the entire cohort. However, post hoc analysis indicated a promising response among patients with marked neuroinflammation.
The second trial investigated NP001 in ALS patients with evidence of elevated inflammation. Primary endpoints were not met, but post hoc analysis identified a subset of patients with a significantly slower decline across two endpoints.
In a 2024 analysis, ~98% of the patients who participated in those trials were identified, and long-term survival outcomes were calculated. Patients in the treatment group lived 4.8 months longer than controls.
In a 2025 paper, Goyal et al. found that patients with slowly progressive ALS who received NP001 lived one and a half years longer than the controls.
NP001 is administered as a 30-minute infusion on days 1, 2, and 3 each month. It essentially gives a big pulse of this chemical that forces the innate immune system back under control. In different individuals, it lasts for different periods of time. Can we rebalance it forever? I don't know. That's why you do these studies.
IH:
MSM:
The NP001 Phase 2 trials recruited people who have had symptoms for up to three years, which isn’t a typical window. Many ALS trials limit inclusion criteria to a year and a half from symptom onset. I would say that many patients have slowly progressive disease at the time they go see their doctor. Maybe they're dragging their foot or something like that. Essentially, it can take an average of two years after symptom onset for slowly progressive ALS patients to receive a diagnosis. By that time, they don't qualify for many trials.
Phase 3 trial plans for NP001
The phase 3 trial will be conducted over one year rather than six months. The FDA has agreed to the trial design, and the developers are arranging funding.
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