Target ALS Grantee NRG Therapeutics Advances NRG5051 into Phase I Clinical Trial
January 26, 2026
In ALS research, the hardest step is often the one between the discovery of a new therapeutic target and the development of a drug against that target. Promising biology does not automatically become a therapy. It takes years of validation, the right models, and the confidence to move forward when the stakes are high.
That is exactly where companies like NRG Therapeutics and organizations like Target ALS meet.
In January 2026, NRG Therapeutics announced a major milestone: the first participants were dosed in a first-in-human Phase 1 clinical trial of NRG5051, a novel therapy designed to stabilize mitochondrial function in neurodegenerative disease. The drug is being developed for Parkinson’s disease, with support from the Michael J. Fox Foundation, and for ALS. For ALS, this moment represents far more than a press release. It reflects nearly seven years of science, collaboration, and careful validation, including work supported through Target ALS’s In Vivo Target Validation award.
From Mechanism to Medicine: The role of mitochondria in ALS
It has long been known that in ALS, mitochondria in motor neurons become sick. Mitochondria are organelles that produce energy, they are the “power house” for the cell. For some time, it was assumed that mitochondria become sick once the cell is already in the process of dying.
Starting with a hard question: what if mitochondria are upstream of neuron death?
NRG Therapeutics was founded in 2018 by longtime neuroscience collaborators Neil Miller, PhD, and Richard Rutter, PhD, after decades in large pharma research. Their focus was not a fashionable target or a fast win. It was to address a long-standing, difficult biological question.
What if mitochondrial dysfunction is not just a downstream consequence of ALS, but an upstream driver of motor neuron degeneration?
Specifically, NRG focused on the mitochondrial permeability transition pore, or mPTP. When this pore opens abnormally, mitochondria lose their ability to produce energy efficiently and can trigger inflammatory and cell-death pathways. This mechanism has been studied for decades, but drugging it in the brain has been notoriously difficult due to a lack of understanding of what part of mitochondria we are trying to fix. Because they are so critical to normal cell function, fixing the ‘broken’ part of the mitochondria with specificity is important.
What changed was both the biology and the chemistry.
A series of academic discoveries showed that disease-associated proteins such as TDP-43 in ALS and alpha-synuclein in Parkinson’s directly stress mitochondria and activate the mPTP. In ALS models, mislocalized TDP-43 enters mitochondria, triggers pore opening, and causes mitochondrial DNA to leak into the cell, setting off innate immune activation. Inhibiting the pore opening is proposed to prevent DNA leakage, inflammation, and neurodegeneration. For NRG, this was the missing link. The mechanism was no longer theoretical. It was disease-relevant. Not only do they have a biological understanding of how to target mitochondria, they have novel treatments selectively targeting a component of the mPTP, differentiating their approach from earlier drugs with non-specific effects on mitochondria and the cell.
“We think we have something really quite exciting. We’ve validated this pathway and this mechanism in animal models, and we’ve shown a profound neuroprotective effect,” said Miller.
Why the right mouse model matters
Before any therapy can move toward people, it must show meaningful effects in living systems. That is where Target ALS’s in vivo target validation program played a critical role.
NRG tested NRG5051 in a TDP-43 NLS mouse model, but not the fastest or most aggressive version. Instead, they chose a slower-progressing model that unfolds over months rather than weeks. Through a no-strings-attached, in-kind grant, Target ALS enabled NRG to access this model at Biospective, a CRO with deep expertise in animal models and in vivo pharmacology. Importantly, NRG retained full ownership of their data and intellectual property, removing a common barrier that often slows or complicates therapeutic development.
That distinction matters.
In ultra-rapid ALS models, pathology overwhelms the system so quickly that even effective therapies may appear to fail. The slower-progressing model allowed NRG to ask more clinically relevant questions: does the drug reach the brain, engage its target, preserve neuronal health, and alter disease-relevant biology over time?
“The slower-progressing model is probably more reflective of what happens in human disease. It’s a more appropriate time course to assess the true therapeutic potential of an intervention,” Rutter said.
According to NRG’s team, this model provided the confidence they needed to move forward. It enabled them to observe neuroprotection and anti-inflammatory effects, along with reductions in plasma neurofilament light chain (NfL), a disease biomarker that is elevated in people with ALS and increasingly used to track disease activity and therapeutic response.
This is exactly why Target ALS invests in model diversity and rigor. Not all models answer the same questions. Choosing the right one can make the difference between a stalled program and a clinical candidate.
What gave them confidence to move into the clinic
Advancing a molecule into human trials requires multiple lines of evidence. For NRG5051, three were critical.
First, neuroprotection. In vivo data showed that inhibiting mPTP could protect neurons and reduce downstream inflammatory signaling linked to TDP-43 pathology.
Second, brain exposure. NRG5051 is orally bioavailable and crosses the blood–brain barrier, a major hurdle for CNS drugs.
Third, safety. Extensive preclinical toxicology studies demonstrated a therapeutic window wide enough to support human dosing.
Together, these data justified moving into Phase 1 testing in healthy volunteers, with plans to include ALS participants as early as next year.
The role of shared biofluids and biomarkers
One of the biggest challenges in early ALS trials is knowing whether a drug is doing what it is supposed to do in the human brain. Clinical outcomes take time. Biology must be measured sooner.
This is where Target ALS’s shared biofluids, deeply annotated patient cohorts, and open data resources become essential. Just as importantly, these resources are designed for rapid, low-friction access, allowing companies to move quickly while retaining full ownership of their data and intellectual property and without pressure to disclose confidential information.
NRG plans to prioritize biomarkers such as neurofilament light chain, a marker of neuronal injury already used in ALS clinical development, alongside mitochondrial and inflammatory readouts informed by their preclinical work. Being able to contextualize those biomarkers against well-characterized ALS datasets, without compromising data control, accelerates decision-making and reduces uncertainty at a stage where speed and clarity matter most.
As Richard Rutter put it, small companies cannot build this infrastructure alone. Shared resources, accessed securely and without strings attached, are what make translational science possible.
Fitting into a complex ALS pipeline
NRG’s approach does not compete with RNA-targeted therapies or immune modulators. It complements them.
ALS is not one disease with one cause. Especially in sporadic ALS, multiple pathways likely contribute to progression. Stabilizing mitochondrial function addresses a core vulnerability of motor neurons and may ultimately work best alongside other strategies.
Combination therapies are likely the future. But first, each mechanism must stand on its own.
NRG5051 is now on that path.
Why this matters for Target ALS’s mission
Target ALS exists to accelerate the pace at which fundamental discoveries become therapies. That means funding science early, supporting rigorous validation, and building shared resources that de-risk translation.
NRG Therapeutics’ journey shows what that acceleration looks like in practice.
From academic insight to animal validation. From mechanism to molecule. From preclinical data to first-in-human dosing.
This is how the gap closes.
And this is how Target ALS helps ensure that promising ideas do not stop at publications, but move forward toward people living with ALS.
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