Synonyms: SAR 443060
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline)
Condition(s): Alzheimer's Disease, Amyotrophic Lateral Sclerosis
U.S. FDA Status: Alzheimer's Disease (Inactive), Amyotrophic Lateral Sclerosis (Inactive)
Company: Denali Therapeutics Inc., Sanofi
DNL747 is a brain-penetrant, small-molecule inhibitor of RIPK1, i.e., receptor-interacting serine/threonine-protein kinase 1. Originally developed in the laboratory of Junying Yuan at Harvard Medical School, the compound was licensed to Denali Therapeutics, which has partnered with Sanofi to develop it for the treatment of AD, ALS, and MS.
RIPK1 forms a signaling hub downstream of the TNF receptor pathway, which regulates inflammation. RIPK1 has been shown to initiate both necroptosis and apoptosis (Vandenabeele et al., 2010; Caccamo et al., 2017; Amin et al., 2018).
RIPK1 mediates disease-associated microglial activation and pro-inflammatory cytokine release in Alzheimer’s (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 necroptosis in multiple sclerosis (Ofengeim et al., 2015). This and other work have 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).
No preclinical studies on DNL747 are published in a peer-reviewed journal. Some efficacy data from human primary cells and 5xFAD and SOD1 mouse models, and safety results from toxicity studies in rats and cynomolgus monkeys, are publicly available as part of the company’s November 2017 filing with the Securities and Exchange Commission (pp 129-131 on sec.gov).
In March 2018, Denali started evaluating single and multiple doses of DNL747 in 56 healthy volunteers in the Netherlands. In November that year, the company announced that DNL747 was generally well-tolerated at doses that met goals for brain exposure and target engagement as measured by a blood-based biomarker of RIPK1 activity (see company press release).
In December 2018, Denali started a single-site, Phase 1 study of DNL747 in 16 people with ALS, also in the Netherlands. This crossover trial randomized participants to either DNL747 or placebo for 29 days and, after 14 days of washout, switched drug/placebo assignment in a second 29-day treatment period. Primary outcomes measured safety and tolerability, secondary outcomes measured pharmacokinetics and -dynamics by day 86.
In February 2019, a Phase 1 trial at three centers, in Florida and the Netherlands, began enrolling 16 people with an Alzheimer’s diagnosis supported by biomarker evidence of amyloid positivity. This trial uses the same 29-day crossover design and outcome measures, and is set to run until December 2019.
On June 9, 2020, the company announced it was pausing further clinical development of DNL747 in favor of its successor compound, DNL788. Both Phase 1 trials, for both AlS and AD, had shown DNL747 to have been safe and well-tolerated at the doses given. However, target receptor occupancy data indicated that higher doses would be needed to achieve therapeutic efficacy, and separate chronic toxicity studies in cynomolgus monkeys indicated potential safety risks of increasing dose (see press release).
For trials of this compounds, see clinicaltrials.gov
Last Updated: 10 Jun 2020
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Yuan J, Amin P, Ofengeim D. Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Nat Rev Neurosci. 2019 Jan;20(1):19-33. PubMed.
- Rubinsztein DC. RIPK1 promotes inflammation and β-amyloid accumulation in Alzheimer's disease. Proc Natl Acad Sci U S A. 2017 Oct 10;114(41):10813-10814. Epub 2017 Oct 2 PubMed.
- Politi K, Przedborski S. Axonal Degeneration: RIPK1 Multitasking in ALS. Curr Biol. 2016 Oct 24;26(20):R932-R934. PubMed.
- Yu H, Cleveland DW. Tuning Apoptosis and Neuroinflammation: TBK1 Restrains RIPK1. Cell. 2018 Sep 6;174(6):1339-1341. PubMed.
- Geng J, Ito Y, Shi L, Amin P, Chu J, Ouchida AT, Mookhtiar AK, Zhao H, Xu D, Shan B, Najafov A, Gao G, Akira S, Yuan J. Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis. Nat Commun. 2017 Aug 25;8(1):359. PubMed.
- Dondelinger Y, Delanghe T, Rojas-Rivera D, Priem D, Delvaeye T, Bruggeman I, Van Herreweghe F, Vandenabeele P, Bertrand MJ. MK2 phosphorylation of RIPK1 regulates TNF-mediated cell death. Nat Cell Biol. 2017 Oct;19(10):1237-1247. Epub 2017 Sep 18 PubMed.
- Fricker M, Vilalta A, Tolkovsky AM, Brown GC. Caspase inhibitors protect neurons by enabling selective necroptosis of inflamed microglia. J Biol Chem. 2013 Mar 29;288(13):9145-52. Epub 2013 Feb 5 PubMed.