Therapeutics

DNL788

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Overview

Name: DNL788
Synonyms: SAR443820, oditrasertib
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline)
Condition(s): Amyotrophic Lateral Sclerosis
U.S. FDA Status: Amyotrophic Lateral Sclerosis (Discontinued)
Company: Denali Therapeutics Inc., Sanofi

Background

This small molecule is a brain-penetrant inhibitor of RIPK1, i.e., receptor-interacting serine/threonine-protein kinase 1. It comes in tablet form, to be taken by mouth. 

RIPK1 forms a signaling hub in the TNF receptor pathway, which regulates inflammation and cytokine release, necroptosis and apoptosis (Vandenabeele et al., 2010; Caccamo et al., 2017; Amin et al., 2018). In Alzheimer’s disease, RIPK1 mediates disease-associated microglial activation and pro-inflammatory cytokine release (Ofengeim et al., 2017). The kinase is located in the molecular pathogenic pathway of ALS/FTD caused by mutations in the endogenous RIPK1 suppressors optineurin and TBK1, and has been reported to regulate progranulin expression (Ito et al., 2016; Xu et al., 2018; Mason et al., 2017). RIPK1 has also been implicated in multiple sclerosis, and its inhibition in animal models decreases neuroinflammation and slows disease progression (Ofengeim et al., 2015; Zelic et al., 2021). These and other studies raised the profile of RIPK1 as a glial target to try to reduce neuroinflammation and cell death across several neurodegenerative diseases (Yuan et al., 2019).

In 2018, Denali partnered with Sanofi to develop RIPK inhibitors for the treatment of AD, ALS, and MS. DNL788 is a second-generation inhibitor, following DNL747, which Denali and Sanofi discontinued after Phase 1 because of concerns about long-term toxicity.

Findings

In 2021, Sanofi ran a Phase 1 trial that, according to the sponsors, showed robust target engagement at doses that met safety goals. Results were published after peer review (Hincelin-Mery et al., 2024). The drug showed good CNS penetration, reaching 0.8 to 1.3 times unbound plasma concentrations in CSF. RIPK1 inhibition in peripheral blood cells reached 90 percent after multiple dosing. The most common adverse events were dizziness and headache, with none leading to discontinuation of treatment.

The sponsors completed three additional Phase 1 trials between August 2021 and July 2022, testing safety and pharmacokinetics in healthy Chinese and Japanese adults, capsule versus tablet formulations, food effects, and drug interactions.

In October 2021, Denali announced that SAR443820/DNL788 had received U.S. FDA Fast-Track designation for ALS (company press release).

In May 2022, Sanofi began Phase 2 testing in people with ALS. In the HIMALAYA trial, 305 patients were randomized 2:1 to twice-daily SAR443820 or placebo for 24 weeks, followed by a long-term open-label extension out to two years. The primary outcome of the placebo-controlled phase is change from baseline in the ALSFRS-R total score. For the long-term extension, the primary outcome will be a combined assessment of function and survival. Secondaries include measures of muscle strength, breathing, and other functions, as well as changes in serum neurofilament light chain, safety, and pharmacokinetics. The trial is taking place at 63 sites in North America, Europe, China, and Japan. The placebo-controlled portion was planned to end in February 2024, with trial completion planned for January 2027. On February 14, 2024, Denali revealed in an SEC filing that HIMALAYA had failed to meet the primary endpoint of change in the ALSFRS-R. The companies terminated the study in March.

In December 2022, a Phase 2 began for relapsing-remitting multiple sclerosis. The study, in Europe, Canada, and China, enrolled 174 patients to twice-daily SAR443820 or placebo for 48 weeks, on a primary outcome of change in serum neurofilament light chain, with a long-term extension for an additional 48 weeks. On October 11, 2024, Denali reported that Sanofi had discontinued the study after it had not met its primary or key secondary endpoints (SEC filing).

For details on SAR443820/DNL788 trials, see clinicaltrials.gov.

Last Updated: 18 Oct 2024

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References

Therapeutics Citations

  1. DNL747

Paper Citations

  1. Hincelin-Mery A, Nicolas X, Cantalloube C, Pomponio R, Lewanczyk P, Benamor M, Ofengeim D, Krupka E, Hsiao-Nakamoto J, Eastenson A, Atassi N. Safety, pharmacokinetics, and target engagement of a brain penetrant RIPK1 inhibitor, SAR443820 (DNL788), in healthy adult participants. Clin Transl Sci. 2024 Jan;17(1):e13690. Epub 2023 Dec 11 PubMed.
  2. Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol. 2010 Oct;11(10):700-14. Epub 2010 Sep 8 PubMed.
  3. Caccamo A, Branca C, Piras IS, Ferreira E, Huentelman MJ, Liang WS, Readhead B, Dudley JT, Spangenberg EE, Green KN, Belfiore R, Winslow W, Oddo S. Necroptosis activation in Alzheimer's disease. Nat Neurosci. 2017 Sep;20(9):1236-1246. Epub 2017 Jul 24 PubMed.
  4. Amin P, Florez M, Najafov A, Pan H, Geng J, Ofengeim D, Dziedzic SA, Wang H, Barrett VJ, Ito Y, LaVoie MJ, Yuan J. Regulation of a distinct activated RIPK1 intermediate bridging complex I and complex II in TNFα-mediated apoptosis. Proc Natl Acad Sci U S A. 2018 Jun 26;115(26):E5944-E5953. Epub 2018 Jun 11 PubMed.
  5. Ofengeim D, Mazzitelli S, Ito Y, DeWitt JP, Mifflin L, Zou C, Das S, Adiconis X, Chen H, Zhu H, Kelliher MA, Levin JZ, Yuan J. RIPK1 mediates a disease-associated microglial response in Alzheimer's disease. Proc Natl Acad Sci U S A. 2017 Oct 10;114(41):E8788-E8797. Epub 2017 Sep 13 PubMed.
  6. Ito Y, Ofengeim D, Najafov A, Das S, Saberi S, Li Y, Hitomi J, Zhu H, Chen H, Mayo L, Geng J, Amin P, DeWitt JP, Mookhtiar AK, Florez M, Ouchida AT, Fan JB, Pasparakis M, Kelliher MA, Ravits J, Yuan J. RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS. Science. 2016 Aug 5;353(6299):603-8. PubMed.
  7. Xu D, Jin T, Zhu H, Chen H, Ofengeim D, Zou C, Mifflin L, Pan L, Amin P, Li W, Shan B, Naito MG, Meng H, Li Y, Pan H, Aron L, Adiconis X, Levin JZ, Yankner BA, Yuan J. TBK1 Suppresses RIPK1-Driven Apoptosis and Inflammation during Development and in Aging. Cell. 2018 Sep 6;174(6):1477-1491.e19. Epub 2018 Aug 23 PubMed.
  8. Mason AR, Elia LP, Finkbeiner S. The Receptor-interacting Serine/Threonine Protein Kinase 1 (RIPK1) Regulates Progranulin Levels. J Biol Chem. 2017 Feb 24;292(8):3262-3272. Epub 2017 Jan 9 PubMed.
  9. Ofengeim D, Ito Y, Najafov A, Zhang Y, Shan B, DeWitt JP, Ye J, Zhang X, Chang A, Vakifahmetoglu-Norberg H, Geng J, Py B, Zhou W, Amin P, Berlink Lima J, Qi C, Yu Q, Trapp B, Yuan J. Activation of necroptosis in multiple sclerosis. Cell Rep. 2015 Mar 24;10(11):1836-49. PubMed.
  10. Zelic M, Pontarelli F, Woodworth L, Zhu C, Mahan A, Ren Y, LaMorte M, Gruber R, Keane A, Loring P, Guo L, Xia TH, Zhang B, Orning P, Lien E, Degterev A, Hammond T, Ofengeim D. RIPK1 activation mediates neuroinflammation and disease progression in multiple sclerosis. Cell Rep. 2021 May 11;35(6):109112. PubMed.
  11. Yuan J, Amin P, Ofengeim D. Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Nat Rev Neurosci. 2019 Jan;20(1):19-33. PubMed.

External Citations

  1. press release
  2. SEC filing
  3. SEC filing
  4. clinicaltrials.gov

Further Reading