Therapeutics

NB-4746

Overview

Name: NB-4746
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Amyotrophic Lateral Sclerosis
U.S. FDA Status: Amyotrophic Lateral Sclerosis (Phase 1)
Company: Nura Bio™ Inc.

Background

NB-4746 is an oral, brain-penetrant, small molecule inhibitor of the nicotinamide adenine dinucleotide (NAD) hydrolase SARM1. SARM1 activation is required for axon degeneration after nerve injury, and SARM1 inhibitors have the potential to prevent or slow neurodegenerative diseases that involve axon loss. Possible indications for NB-4746 include amyotrophic lateral sclerosis, multiple sclerosis, chemotherapy-induced peripheral neuropathy, traumatic brain injury, and stroke.

SARM1 was originally discovered as a suppressor of injury-induced axon death in Drosophila (Osterloh et al., 2012). It was shown to trigger an active process of axon degeneration by depleting the energy and NAD+ (Gerdts et al., 2015; Yang et al., 2015; Figley et al., 2021). Knockout of SARM1 improved nerve function after traumatic brain injury in mice (Henninger et al., 2016), but did not protect dopamine terminals in an α-synuclein overexpression model of Parkinson’s disease (Peters et al., 2021). SARM1 knockout accelerated progression in a mouse model of prion disease (Zhu et al., 2019).

Conflicting evidence exists for SARM1’s role in ALS. Variants in SARM1 affect a person’s risk of developing ALS (van Rheenen et al., 2016; Bloom et al., 2022). Expression was found to be downregulated in neurons, muscle and blood from ALS patients (Ma et al., 2024). In a C. elegans model of ALS, SARM1 was required for motor neuron degeneration (Vérièpe et al., 2015). However, in an SOD1 mutant mouse model of ALS , SARM1 knockout did not prevent loss of motor neurons (Peters et al., 2018), but did stem an increase in serum neurofilament light (Collins et al., 2022). Knockout protected axons in a model of TDP-43-linked motor neuron degeneration (White et al., 2019). Loss of SARM1 prevented acceleration of disease progression in these ALS mice after nerve injury (Dogan et al., 2025).

In AD mice, SARM1 knockout delayed disease progression and reduced pathology (Miao et al., 2024). Knockout also improved circadian rhythm disorder, decreased Aβ deposition, and rescued cognitive disorders in AD mice (Wang et al., 2023).

Nura Bio identified its proprietary SARM1 inhibitors by high-throughput screening and medicinal chemistry optimization. The inhibitors bind the SARM1 active site with low affinity, where they undergo conjugation to the enzyme reaction product to form a highly potent inhibitory adduct. The enzyme-adduct structure has been elucidated. In preclinical models, Nura Bio’s inhibitors reduced nerve fiber loss and plasma neurofilament light levels in models of nerve lesion or chemotherapy-induced toxicity (Bratkowski et al., 2022). Early versions of SARM1 inhibitors protected mice against chemotherapy-induced neuropathy (Bosanac et al., 2021), and in cell models of axotomy or toxin-induced nerve death (Hughes et al., 2021).

Findings

In August 2023, Nura Bio began Phase 1 with an ascending-dose safety trial in 66 healthy volunteers. Single doses of 50, 100, 175, 300, 450, and 600 mg, or 10 days of repeated dosing were compared to placebo. Besides safety, the trial measured plasma pharmacokinetics and CNS exposure, urinary excretion, and drug effects on CYP3A activity and urine cortisol. The trial ran in Australia and was completed in February 2024.

In September 2024, a second Phase 1 trial began, also in Australia, testing drug-drug interactions with the cytochrome p450 substrates caffeine and midazolam in healthy volunteers.

Last Updated: 07 Mar 2025

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References

Paper Citations

  1. Osterloh JM, Yang J, Rooney TM, Fox AN, Adalbert R, Powell EH, Sheehan AE, Avery MA, Hackett R, Logan MA, Macdonald JM, Ziegenfuss JS, Milde S, Hou YJ, Nathan C, Ding A, Brown RH, Conforti L, Coleman M, Tessier-Lavigne M, Züchner S, Freeman MR. dSarm/Sarm1 is required for activation of an injury-induced axon death pathway. Science. 2012 Jul 27;337(6093):481-4. PubMed.
  2. Gerdts J, Brace EJ, Sasaki Y, DiAntonio A, Milbrandt J. Neurobiology. SARM1 activation triggers axon degeneration locally via NAD⁺ destruction. Science. 2015 Apr 24;348(6233):453-7. Epub 2015 Apr 23 PubMed.
  3. Yang J, Wu Z, Renier N, Simon DJ, Uryu K, Park DS, Greer PA, Tournier C, Davis RJ, Tessier-Lavigne M. Pathological axonal death through a MAPK cascade that triggers a local energy deficit. Cell. 2015 Jan 15;160(1-2):161-76. PubMed.
  4. Figley MD, Gu W, Nanson JD, Shi Y, Sasaki Y, Cunnea K, Malde AK, Jia X, Luo Z, Saikot FK, Mosaiab T, Masic V, Holt S, Hartley-Tassell L, McGuinness HY, Manik MK, Bosanac T, Landsberg MJ, Kerry PS, Mobli M, Hughes RO, Milbrandt J, Kobe B, DiAntonio A, Ve T. SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration. Neuron. 2021 Apr 7;109(7):1118-1136.e11. Epub 2021 Mar 2 PubMed.
  5. Henninger N, Bouley J, Sikoglu EM, An J, Moore CM, King JA, Bowser R, Freeman MR, Brown RH Jr. Attenuated traumatic axonal injury and improved functional outcome after traumatic brain injury in mice lacking Sarm1. Brain. 2016 Apr;139(Pt 4):1094-105. Epub 2016 Feb 11 PubMed.
  6. Peters OM, Weiss A, Metterville J, Song L, Logan R, Smith GA, Schwarzschild MA, Mueller C, Brown RH, Freeman M. Genetic diversity of axon degenerative mechanisms in models of Parkinson's disease. Neurobiol Dis. 2021 Jul;155:105368. Epub 2021 Apr 20 PubMed.
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  8. Bloom AJ, Mao X, Strickland A, Sasaki Y, Milbrandt J, DiAntonio A. Constitutively active SARM1 variants that induce neuropathy are enriched in ALS patients. Mol Neurodegener. 2022 Jan 6;17(1):1. PubMed.
  9. Ma Y, Jia T, Qin F, He Y, Han F, Zhang C. Abnormal Brain Protein Abundance and Cross-tissue mRNA Expression in Amyotrophic Lateral Sclerosis. Mol Neurobiol. 2024 Jan;61(1):510-518. Epub 2023 Aug 28 PubMed.
  10. Vérièpe J, Fossouo L, Parker JA. Neurodegeneration in C. elegans models of ALS requires TIR-1/Sarm1 immune pathway activation in neurons. Nat Commun. 2015 Jun 10;6:7319. PubMed.
  11. Peters OM, Lewis EA, Osterloh JM, Weiss A, Salameh JS, Metterville J, Brown RH, Freeman MR. Loss of Sarm1 does not suppress motor neuron degeneration in the SOD1G93A mouse model of amyotrophic lateral sclerosis. Hum Mol Genet. 2018 Nov 1;27(21):3761-3771. PubMed.
  12. Collins JM, Atkinson RA, Matthews LM, Murray IC, Perry SE, King AE. Sarm1 knockout modifies biomarkers of neurodegeneration and spinal cord circuitry but not disease progression in the mSOD1G93A mouse model of ALS. Neurobiol Dis. 2022 Oct 1;172:105821. Epub 2022 Jul 18 PubMed.
  13. White MA, Lin Z, Kim E, Henstridge CM, Pena Altamira E, Hunt CK, Burchill E, Callaghan I, Loreto A, Brown-Wright H, Mead R, Simmons C, Cash D, Coleman MP, Sreedharan J. Sarm1 deletion suppresses TDP-43-linked motor neuron degeneration and cortical spine loss. Acta Neuropathol Commun. 2019 Oct 28;7(1):166. PubMed.
  14. Dogan EO, Simonini SR, Bouley J, Weiss A, Brown RH Jr, Henninger N. Genetic Ablation of Sarm1 Mitigates Disease Acceleration after Traumatic Brain Injury in the SOD1G93A Transgenic Mouse Model of Amyotrophic Lateral Sclerosis. Ann Neurol. 2025 Jan 10; Epub 2025 Jan 10 PubMed.
  15. Miao X, Wu Q, Du S, Xiang L, Zhou S, Zhu J, Chen Z, Wang H, Pan X, Fan Y, Zhang L, Qian J, Xing Y, Xie Y, Hu L, Xu H, Wang W, Wang Y, Huang Z. SARM1 Promotes Neurodegeneration and Memory Impairment in Mouse Models of Alzheimer's Disease. Aging Dis. 2023 May 25; PubMed.
  16. Wang Z, Zeng S, Jing Y, Mao W, Li H. Sarm1 Regulates Circadian Rhythm Disorder in Alzheimer's Disease in Mice. J Alzheimers Dis. 2023;92(2):713-722. PubMed.
  17. Bratkowski M, Burdett TC, Danao J, Wang X, Mathur P, Gu W, Beckstead JA, Talreja S, Yang YS, Danko G, Park JH, Walton M, Brown SP, Tegley CM, Joseph PR, Reynolds CH, Sambashivan S. Uncompetitive, adduct-forming SARM1 inhibitors are neuroprotective in preclinical models of nerve injury and disease. Neuron. 2022 Nov 16;110(22):3711-3726.e16. Epub 2022 Sep 9 PubMed.
  18. Bosanac T, Hughes RO, Engber T, Devraj R, Brearley A, Danker K, Young K, Kopatz J, Hermann M, Berthemy A, Boyce S, Bentley J, Krauss R. Pharmacological SARM1 inhibition protects axon structure and function in paclitaxel-induced peripheral neuropathy. Brain. 2021 Nov 29;144(10):3226-3238. PubMed.
  19. Hughes RO, Bosanac T, Mao X, Engber TM, DiAntonio A, Milbrandt J, Devraj R, Krauss R. Small Molecule SARM1 Inhibitors Recapitulate the SARM1-/- Phenotype and Allow Recovery of a Metastable Pool of Axons Fated to Degenerate. Cell Rep. 2021 Jan 5;34(1):108588. PubMed.

External Citations

  1. ascending-dose safety trial
  2. second Phase 1 trial
  3. Zhu et al., 2019

Further Reading

Papers

  1. Alexandris AS, Koliatsos VE. NAD+, Axonal Maintenance, and Neurological Disease. Antioxid Redox Signal. 2023 Sep 7; PubMed.
  2. Sambashivan S, Freeman MR. SARM1 signaling mechanisms in the injured nervous system. Curr Opin Neurobiol. 2021 Aug;69:247-255. Epub 2021 Jun 25 PubMed.
  3. Coleman MP, Höke A. Programmed axon degeneration: from mouse to mechanism to medicine. Nat Rev Neurosci. 2020 Apr;21(4):183-196. Epub 2020 Mar 9 PubMed.