Therapeutics

DNL151

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Overview

Name: DNL151
Synonyms: BIIB122
Therapy Type: Small Molecule (timeline)
Target Type: Inflammation (timeline), Other (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 2)
Company: Biogen, Denali Therapeutics Inc.

Background

DNL151 is an orally available, brain-penetrant inhibitor of the leucine-rich repeat kinase 2 (LRRK2). It started out as a backup to Denali’s lead LRRK2 inhibitor, DNL201; but it is now its lead candidate after development of DNL201 was stopped in 2020.

LRRK2, also known as Dardarin, is a large, multidomain protein containing serine and threonine kinase activity. Kinase-activating mutations in the LRRK2 gene are the most frequent cause of inherited PD (reviewed in Schneider and Alcalay, 2020). Other variants in the gene are associated with higher risk of sporadic PD, and there is some evidence for LRRK2 kinase activation in idiopathic PD (Di Maio et al., 2018). Increased LRRK2 kinase activity impairs vesicle trafficking and lysosome function, and promotes neuroinflammation, processes that contribute to PD pathology (see review by Taylor and Alessi, 2020; Shutinoski et al., 2019; Sep 2018 news).

Several companies are pursing LRRK2 inhibitors for treating PD; Denali was the first to begin clinical testing. Recently, cryoEM structures of wild-type and PD-linked mutants of LRRK2, with and without investigational inhibitors or it endogenous activator Rab29, were solved, supporting structure-based design of compounds targeting its kinase domain (Murillo et al., 2023, Zhu et al., 2023).

No preclinical data have been published on DNL151. However, reducing LRRK2 activity using other inhibitors or by genetic knockdown in rodent models of PD has been reported to reduce α-synuclein aggregation, neuroinflammation, and dopaminergic neuron loss (Daher et al., 2014; Daher et al., 2015, Ho et al., 2022; Ho et al., 2022). Inhibitors also promoted physiological tetramerization and synaptic localization of α-synuclein (Fonseca-Ornales et al., 2022; Brzozowski et al., 2021). In animal and cell models of Aβ42 toxicity, inhibiting LRRK2 attenuated neuroinflammation (Mutti et al., 2023; Filippini et al., 2023). 

Besides brain, LRRK2 is highly expressed in the lungs, kidneys, and spleen. Knockout or systemic inhibition of LRRK2 was found to change lung morphology in rats or macaque monkeys, possibly by affecting lysosomal function (Fuji et al., 2015). This raised safety concerns of systemic LRRK2 inhibition. Recent data confirmed that three different inhibitors caused an accumulation of large vacuoles in lung cells of treated monkeys; this response did not compromise lung function after two weeks of treatment, and the changes reversed after the drugs were stopped (Baptista et al., 2020). Other investigational LRRK2 inhibitors have been reported to cause lasting changes in lung tissue (Miller et al., 2023). LRRK2 knockout in rats caused changes in kidney function and morphology, which could be mitigated by diet (Ness et al., 2013; Gu et al., 2023). In people, mutations in one copy of the LRRK2 gene that lead to partial reductions in kinase activity do not impair lung, liver, or kidney, function, or appear to cause specific health problems (Whiffin et al., 2020).

For a review of patents on LRRK2 inhibitors, see Ding and Ren, 2020.

Findings

In December 2017, Denali began Phase 1 dosing of DNL151 (press release) with a 186-participant trial in the Netherlands. A January 2020 press release announced that DNL151 met biomarker and safety goals after evaluation in 153 healthy volunteers. The majority of participants had no or mild AEs at all doses tested. DNL151 dose-dependently reduced LRRK2 kinase activity by up to 80 percent, based on measuring phosphorylation of LRRK2 and its substrate pRab10 in blood. Urine levels of the lipid BMP, a marker of lysosome dysfunction, were reduced, as well. Based on these safety, target, and pathway engagement data, the trial was expanded to higher doses. It finished in February 2021. According to published results, DNL151 readily penetrated the brain, and showed evidence of LRRK2 inhibition in CSF (Jennings et al., 2023).

In July 2019, a Phase 1b safety study began in 34 people with Parkinson’s disease. Participants with or without an LRRK2 mutation were randomized to a low, middle, or high dose of DNL151 or placebo, taken daily for 28 days. The primary outcome comprises adverse events and laboratory tests, vital signs, electrocardiogram, or neurological exam. Secondary outcomes include plasma pharmacokinetics, drug concentration in the CSF, and LRRK2 and Rab10 phosphorylation in blood. The trial finished in December 2020, after enrolling 36 participants in eight centers in the U.S. and Europe. In a January 2021 press release, Denali stated that the trial met target and pathway engagement goals.

In August 2020, Denali announced it would advance clinical development of DNL151 in collaboration with Biogen (press release).

In 2021, the companies completed additional Phase 1 studies of the absorption, metabolism, excretion, and bioavailability of radiolabeled DNL151 after single or multiple doses in healthy subjects. In 2022, another Phase 1 compared the pharmacokinetics, safety, and tolerability of single or multiple doses in 84 healthy Japanese, Chinese, and Caucasian people.

In May 2022, the companies began the Phase 2b LUMA trial in people with early stage Parkinson’s disease without a LRRK2 mutation. The 640 participants are receiving 225 mg BIIB122 once daily or matching placebo tablets, for 48 to 144 weeks. The primary outcome of time to worsening in the Movement Disorder Society-Unified Parkinson’s Disease Rating scale parts II and III assesses mainly motor symptoms and function. Secondary outcomes are adverse events, and change from baseline MDS-UPDRS, and time to worsening in daily activities. The trial is enrolling at 98 centers in North America, Asia, Europe, and Israel, and is expected to end in August 2025.

In September 2022, the LIGHTHOUSE Phase 3 study began recruiting a target number of 400 people with early stage Parkinson’s and specific LRRK2 mutations, for a similar course of treatment for up to 180 weeks, against the same primary and secondary outcome measures. This trial, at multiple sites in the U.S. and Europe, was slated for completion in January 2031. On June 5, 2023, Biogen announced a change in their development plan (press release). The company discontinued LIGHTHOUSE, reportedly due to its complexity and long time line. They amended the LUMA protocol to include patients with LRRK2 mutations, to get a quicker efficacy readout in patients without and without LRRK2 mutations. The seven patients who had enrolled in LIGHTHOUSE can join LUMA, whose end date remains August 2025.

For details on DNL151 trials, see clinicaltrials.gov.

Last Updated: 30 Jan 2024

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References

Therapeutics Citations

  1. DNL201

News Citations

  1. Does LRRK2 Sweep α-Synuclein from the Cell?

Paper Citations

  1. Jennings D, Huntwork-Rodriguez S, Vissers MF, Daryani VM, Diaz D, Goo MS, Chen JJ, Maciuca R, Fraser K, Mabrouk OS, van de Wetering de Rooij J, Heuberger JA, Groeneveld GJ, Borin MT, Cruz-Herranz A, Graham D, Scearce-Levie K, De Vicente J, Henry AG, Chin P, Ho C, Troyer MD. LRRK2 Inhibition by BIIB122 in Healthy Participants and Patients with Parkinson's Disease. Mov Disord. 2023 Mar;38(3):386-398. Epub 2023 Feb 18 PubMed.
  2. Schneider SA, Alcalay RN. Precision medicine in Parkinson's disease: emerging treatments for genetic Parkinson's disease. J Neurol. 2020 Mar;267(3):860-869. Epub 2020 Jan 23 PubMed.
  3. Di Maio R, Hoffman EK, Rocha EM, Keeney MT, Sanders LH, De Miranda BR, Zharikov A, Van Laar A, Stepan AF, Lanz TA, Kofler JK, Burton EA, Alessi DR, Hastings TG, Greenamyre JT. LRRK2 activation in idiopathic Parkinson's disease. Sci Transl Med. 2018 Jul 25;10(451) PubMed.
  4. Taylor M, Alessi DR. Advances in elucidating the function of leucine-rich repeat protein kinase-2 in normal cells and Parkinson's disease. Curr Opin Cell Biol. 2020 Apr;63:102-113. Epub 2020 Feb 7 PubMed.
  5. Shutinoski B, Hakimi M, Harmsen IE, Lunn M, Rocha J, Lengacher N, Zhou YY, Khan J, Nguyen A, Hake-Volling Q, El-Kodsi D, Li J, Alikashani A, Beauchamp C, Majithia J, Coombs K, Shimshek D, Marcogliese PC, Park DS, Rioux JD, Philpott DJ, Woulfe JM, Hayley S, Sad S, Tomlinson JJ, Brown EG, Schlossmacher MG. Lrrk2 alleles modulate inflammation during microbial infection of mice in a sex-dependent manner. Sci Transl Med. 2019 Sep 25;11(511) PubMed.
  6. Sanz Murillo M, Villagran Suarez A, Dederer V, Chatterjee D, Alegrio Louro J, Knapp S, Mathea S, Leschziner AE. Inhibition of Parkinson's disease-related LRRK2 by type I and type II kinase inhibitors: Activity and structures. Sci Adv. 2023 Dec;9(48):eadk6191. PubMed.
  7. Zhu H, Tonelli F, Turk M, Prescott A, Alessi DR, Sun J. Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2. Science. 2023 Dec 22;382(6677):1404-1411. Epub 2023 Dec 21 PubMed.
  8. Daher JP, Volpicelli-Daley LA, Blackburn JP, Moehle MS, West AB. Abrogation of α-synuclein-mediated dopaminergic neurodegeneration in LRRK2-deficient rats. Proc Natl Acad Sci U S A. 2014 Jun 24;111(25):9289-94. Epub 2014 Jun 9 PubMed.
  9. Daher JP, Abdelmotilib HA, Hu X, Volpicelli-Daley LA, Moehle MS, Fraser KB, Needle E, Chen Y, Steyn SJ, Galatsis P, Hirst WD, West AB. Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration. J Biol Chem. 2015 Aug 7;290(32):19433-44. Epub 2015 Jun 15 PubMed.
  10. Ho PW, Chang EE, Leung CT, Liu H, Malki Y, Pang SY, Choi ZY, Liang Y, Lai WS, Ruan Y, Leung KM, Yung S, Mak JC, Kung MH, Ramsden DB, Ho SL. Long-term inhibition of mutant LRRK2 hyper-kinase activity reduced mouse brain α-synuclein oligomers without adverse effects. NPJ Parkinsons Dis. 2022 Sep 10;8(1):115. PubMed.
  11. Ho DH, Nam D, Seo M, Park SW, Seol W, Son I. LRRK2 Inhibition Mitigates the Neuroinflammation Caused by TLR2-Specific α-Synuclein and Alleviates Neuroinflammation-Derived Dopaminergic Neuronal Loss. Cells. 2022 Mar 2;11(5) PubMed.
  12. Fonseca-Ornelas L, Stricker JM, Soriano-Cruz S, Weykopf B, Dettmer U, Muratore CR, Scherzer CR, Selkoe DJ. Parkinson-causing mutations in LRRK2 impair the physiological tetramerization of endogenous α-synuclein in human neurons. NPJ Parkinsons Dis. 2022 Sep 16;8(1):118. PubMed.
  13. Brzozowski CF, Hijaz BA, Singh V, Gcwensa NZ, Kelly K, Boyden ES, West AB, Sarkar D, Volpicelli-Daley LA. Inhibition of LRRK2 kinase activity promotes anterograde axonal transport and presynaptic targeting of α-synuclein. Acta Neuropathol Commun. 2021 Nov 8;9(1):180. PubMed.
  14. Mutti V, Carini G, Filippini A, Castrezzati S, Giugno L, Gennarelli M, Russo I. LRRK2 Kinase Inhibition Attenuates Neuroinflammation and Cytotoxicity in Animal Models of Alzheimer's and Parkinson's Disease-Related Neuroinflammation. Cells. 2023 Jul 6;12(13) PubMed.
  15. Filippini A, Salvi V, Dattilo V, Magri C, Castrezzati S, Veerhuis R, Bosisio D, Gennarelli M, Russo I. LRRK2 Kinase Inhibition Attenuates Astrocytic Activation in Response to Amyloid β1-42 Fibrils. Biomolecules. 2023 Feb 6;13(2) PubMed.
  16. Fuji RN, Flagella M, Baca M, Baptista MA, Brodbeck J, Chan BK, Fiske BK, Honigberg L, Jubb AM, Katavolos P, Lee DW, Lewin-Koh SC, Lin T, Liu X, Liu S, Lyssikatos JP, O'Mahony J, Reichelt M, Roose-Girma M, Sheng Z, Sherer T, Smith A, Solon M, Sweeney ZK, Tarrant J, Urkowitz A, Warming S, Yaylaoglu M, Zhang S, Zhu H, Estrada AA, Watts RJ. Effect of selective LRRK2 kinase inhibition on nonhuman primate lung. Sci Transl Med. 2015 Feb 4;7(273):273ra15. PubMed.
  17. Baptista MA, Merchant K, Barrett T, Bhargava S, Bryce DK, Ellis JM, Estrada AA, Fell MJ, Fiske BK, Fuji RN, Galatsis P, Henry AG, Hill S, Hirst W, Houle C, Kennedy ME, Liu X, Maddess ML, Markgraf C, Mei H, Meier WA, Needle E, Ploch S, Royer C, Rudolph K, Sharma AK, Stepan A, Steyn S, Trost C, Yin Z, Yu H, Wang X, Sherer TB. LRRK2 inhibitors induce reversible changes in nonhuman primate lungs without measurable pulmonary deficits. Sci Transl Med. 2020 Apr 22;12(540) PubMed.
  18. Miller GK, Kuruvilla S, Jacob B, LaFranco-Scheuch L, Bakthavatchalu V, Flor J, Flor K, Ziegler J, Reichard C, Manfre P, Firner S, McNutt T, Quay D, Bellum S, Doto G, Ciaccio PJ, Pearson K, Valentine J, Fuller P, Fell M, Tsuchiya T, Williamson T, Wollenberg G. Effects of LRRK2 Inhibitors in Nonhuman Primates. Toxicol Pathol. 2023 Jul;51(5):232-245. Epub 2023 Nov 2 PubMed.
  19. Ness D, Ren Z, Gardai S, Sharpnack D, Johnson VJ, Brennan RJ, Brigham EF, Olaharski AJ. Leucine-rich repeat kinase 2 (LRRK2)-deficient rats exhibit renal tubule injury and perturbations in metabolic and immunological homeostasis. PLoS One. 2013;8(6):e66164. Print 2013 PubMed.
  20. Gu YZ, Vlasakova K, Miller G, Gatto NT, Ciaccio PJ, Kuruvilla S, Besteman EG, Smith R, Reynolds SJ, Amin RP, Glaab WE, Wollenberg G, Lebron J, Sistare FD. Early-Onset albuminuria and Associated Renal Pathology in Leucine-Rich Repeat Kinase 2 Knockout Rats. Toxicol Pathol. 2023 Jan;51(1-2):15-26. Epub 2023 Apr 20 PubMed.
  21. Whiffin N, Armean IM, Kleinman A, Marshall JL, Minikel EV, Goodrich JK, Quaife NM, Cole JB, Wang Q, Karczewski KJ, Cummings BB, Francioli L, Laricchia K, Guan A, Alipanahi B, Morrison P, Baptista MA, Merchant KM, Genome Aggregation Database Production Team, Genome Aggregation Database Consortium, Ware JS, Havulinna AS, Iliadou B, Lee JJ, Nadkarni GN, Whiteman C, 23andMe Research Team, Daly M, Esko T, Hultman C, Loos RJ, Milani L, Palotie A, Pato C, Pato M, Saleheen D, Sullivan PF, Alföldi J, Cannon P, MacArthur DG. The effect of LRRK2 loss-of-function variants in humans. Nat Med. 2020 Jun;26(6):869-877. Epub 2020 May 27 PubMed.
  22. Ding X, Ren F. Leucine-rich repeat kinase 2 inhibitors: a patent review (2014-present). Expert Opin Ther Pat. 2020 Apr;30(4):275-286. Epub 2020 Feb 18 PubMed.

External Citations

  1. press release
  2. press release
  3. press release
  4. press release
  5. press release
  6. clinicaltrials.gov

Further Reading

Papers

  1. Ding X, Ren F. Leucine-rich repeat kinase 2 inhibitors: a patent review (2014-present). Expert Opin Ther Pat. 2020 Apr;30(4):275-286. Epub 2020 Feb 18 PubMed.
  2. Volpicelli-Daley LA, Abdelmotilib H, Liu Z, Stoyka L, Daher JP, Milnerwood AJ, Unni VK, Hirst WD, Yue Z, Zhao HT, Fraser K, Kennedy RE, West AB. G2019S-LRRK2 Expression Augments α-Synuclein Sequestration into Inclusions in Neurons. J Neurosci. 2016 Jul 13;36(28):7415-27. PubMed. Correction.
  3. Qin Q, Zhi LT, Li XT, Yue ZY, Li GZ, Zhang H. Effects of LRRK2 Inhibitors on Nigrostriatal Dopaminergic Neurotransmission. CNS Neurosci Ther. 2017 Feb;23(2):162-173. Epub 2016 Dec 9 PubMed.
  4. Jennings D, Huntwork-Rodriguez S, Henry AG, Sasaki JC, Meisner R, Diaz D, Solanoy H, Wang X, Negrou E, Bondar VV, Ghosh R, Maloney MT, Propson NE, Zhu Y, Maciuca RD, Harris L, Kay A, LeWitt P, King TA, Kern D, Ellenbogen A, Goodman I, Siderowf A, Aldred J, Omidvar O, Masoud ST, Davis SS, Arguello A, Estrada AA, de Vicente J, Sweeney ZK, Astarita G, Borin MT, Wong BK, Wong H, Nguyen H, Scearce-Levie K, Ho C, Troyer MD. Preclinical and clinical evaluation of the LRRK2 inhibitor DNL201 for Parkinson's disease. Sci Transl Med. 2022 Jun 8;14(648):eabj2658. PubMed.
  5. Lewis PA. A step forward for LRRK2 inhibitors in Parkinson's disease. Sci Transl Med. 2022 Jun 8;14(648):eabq7374. PubMed.
  6. Hu J, Zhang D, Tian K, Ren C, Li H, Lin C, Huang X, Liu J, Mao W, Zhang J. Small-molecule LRRK2 inhibitors for PD therapy: Current achievements and future perspectives. Eur J Med Chem. 2023 Aug 5;256:115475. Epub 2023 May 10 PubMed.
  7. Nazish I, Mamais A, Mallach A, Bettencourt C, Kaganovich A, Warner T, Hardy J, Lewis PA, Pocock J, Cookson MR, Bandopadhyay R. Differential LRRK2 Signalling and Gene Expression in WT-LRRK2 and G2019S-LRRK2 Mouse Microglia Treated with Zymosan and MLi2. Cells. 2023 Dec 26;13(1) PubMed.
  8. Bu M, Follett J, Deng I, Tatarnikov I, Wall S, Guenther D, Maczis M, Wimsatt G, Milnerwood A, Moehle MS, Khoshbouei H, Farrer MJ. Inhibition of LRRK2 kinase activity rescues deficits in striatal dopamine physiology in VPS35 p.D620N knock-in mice. NPJ Parkinsons Dis. 2023 Dec 18;9(1):167. PubMed.
  9. Pal P, Taylor M, Lam PY, Tonelli F, Hecht CA, Lis P, Nirujogi RS, Phung TK, Yeshaw WM, Jaimon E, Fasimoye R, Dickie EA, Wightman M, Macartney T, Pfeffer SR, Alessi DR. Parkinson's VPS35[D620N] mutation induces LRRK2-mediated lysosomal association of RILPL1 and TMEM55B. Sci Adv. 2023 Dec 15;9(50):eadj1205. Epub 2023 Dec 13 PubMed.
  10. Müller T. DNL151, DNL201, and BIIB094: experimental agents for the treatment of Parkinson's disease. Expert Opin Investig Drugs. 2023;32(9):787-792. Epub 2023 Oct 13 PubMed.
  11. Cao R, Chen C, Wen J, Zhao W, Zhang C, Sun L, Yuan L, Wu C, Shan L, Xi M, Sun H. Recent advances in targeting leucine-rich repeat kinase 2 as a potential strategy for the treatment of Parkinson's disease. Bioorg Chem. 2023 Dec;141:106906. Epub 2023 Oct 7 PubMed.
  12. Baidya AT, Deshwal S, Das B, Mathew AT, Devi B, Sandhir R, Kumar R. Catalyzing a Cure: Discovery and development of LRRK2 inhibitors for the treatment of Parkinson's disease. Bioorg Chem. 2024 Feb;143:106972. Epub 2023 Nov 15 PubMed.