Competitor
| company / compound | description | status / clinical plan |
|---|---|---|
| HT-6184 (by Halia Therapeutics) |
a small molecule inhibitor of NEK7 and the NLRP3 pathway → target both NLRP3 priming and assembly, brain penetrant MCC950 specifically binds to both active and inactive NLRP3, → ↓ NLRP3 oligomerizaion We will go to AD along with pain, and oncology P1 | a single-center, randomized, placebo-controlled, SAD study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of HT-6184 in up to 32 healthy human participants. |
| Zydus (India) |
ZYIL-1 is a sulfonylurea, and was disclosed as "example 11" in this patent application: Zydus_LifeScience_WO2023_026222.pdf. And like selnoflast, it also contains a CAD structure. You can find profiling information from p.45 to 50, including Kpuu in mouse at 30 mg/kg po of around 0.1. SAD & MAD in HV: Parmar Hissaria CAPS IIa ZYL1_2023 STARTING p2 POC study in ALS |
-In phase I studies, ZYIL1 was found to be safe and well-tolerated in HV SAD (study 1) and MAD (study 2) Whole blood + LPS → ~90% ↓ IL-1b 70-90% ↓ IL-18 (Parmar 2022) -Zydus had demonstrated efficacy of ZYIL1 in CAPS (Cryopyrin Associated Periodic Syndrome) patients and was the first to establish the phase 2 proof-of-concept with an oral small molecule NLRP3 inhibitor in CAPS patients. The phase-2 data of ZYIL1 in CAPS has now been published in "Clinical Pharmacology in Drug Development". -STARTING p2 study in PD: The phase 2 study will evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics in patients with Parkinson's Disease. |
(Jewell, 2022 #2085)
| Therapeutic agent or class | Mechanism of action | Stage | References |
|---|---|---|---|
| MCC950 series and Inzomelid | Covalent NLRP3 inhibitor | Clinical | [12, 121] NCT04015076 |
| Belnacasan (VX-765) | Caspase-1 inhibitor | Clinical | [122] NCT01501383 |
| Fenamates | Inhibits ASC specks, caspase-1 activation, microglial activation | Preclinical | [119, 131] |
| Glibenclamide | NLRP3 inhibitor | Preclinical | [28] |
| BAY 11-7082 | Inhibits ATPase activity of NLRP3 | Preclinical | [132] |
| OTL1177 | Inhibits NLRP3-ASC and NLRP3-caspase-1 interactions | Preclinical | [120] |
| 3,4-methylenedioxy-β-nitrostyrene | Prevents NLRP3 ATPase activity | Preclinical | [116] |
| JC-171 | Prevents NLRP3 activation and IL1β release | Preclinical | [117] |
| BOT-4-ene | Impairs ATPase activity of NLRP3 | Preclinical | [114] |
| Parthenolide | Inhibits inflammasome priming through IκBα blockade and NFκB inhibition | Preclinical | [115] |
| Fc11a-2 | Decreases proinflammatory cytokine secretion | Preclinical | [118] |
| Genentech (GDC-2394) |
장래가능성으로서 coronary artery disease를 강조히는 걸 보니, brain penetrant 아닌가봄. P1 in HV. (Tang, 2023 #2372) two participants in the DDI stage experienced Grade 4 drug-induced liver injury (DILI), Exploratory ex vivo whole-blood stimulation (with a cocktail of LPS and ATP) assays showed rapid, reversible, and near-complete inhibition of the selected PD biomarkers, IL-1β and IL-18, across all tested doses. Methods (ELISA) and Results: main paper: (with model fit fig 3) and suppl1 |
| Japan tobacco |
- Non Brain penetrant compound: mta with takeda → experiment ongoing - Brain penetrant compound: finished GLP tox (dog rat, not cyno), (ahead of us) - Chemistry very close to ours |
| Olatec: Dapansutrile (=OLT1177) |
P2 IIT. PI: Caroline H. Williams-Gray Patients will be treated for up to 12 months allowing for the potential to measure a disease modifying effect on motor function and non-motor symptom "Anti-inflammatory Intervention with Dapansutrile (OLT1177®) for Parkinson's Disease Modification (DAPA-PD): A Randomised DB Placebo-Controlled Phase II Trial" is targeting to commence in mid-2024, subject to completion of all contractual agreements and regulatory authorizations. The trial will seek to enroll 36 participants with early PD. Treatment duration will be six m with placebo control, followed by an optional, six month open-label phase. This single center study will be conducted at the John van Geest Centre for Brain Repair, Department of Clinical Neurosciences at the University of Cambridge in the UK (Lonnemann, 2020 #2699) AD mouse model, ↓ IL-6, (. IL-6, which is induced by IL-1, sharply increases under pathological conditions and is significantly increased in the brains of AD patients (37) compared to the healthy adult brain (37, 50)) Note: gout trial (Klück, 2020 #2697) il-6, IL-1b, heart failure (Wohlford, 2021 #2698) |
| Monte Rosa: MRT-8102 |
20240311] molecular glue degrader (MGD)-based medicines, today announced a novel development candidate, MRT-8102, a potent, highly selective and orally bioavailable NIMA related kinase 7 (NEK7)-directed MGD. Announces Initiation of IND Enabling Studies. "In preclinical non-human primate studies, MRT-8102 has demonstrated potent and selective degradation of NEK7, reducing downstream IL-1β. We believe MRT-8102 has the potential to be developed in multiple inflammatory diseases, including gout, pericarditis and other cardiovascular diseases. We are also evaluating opportunities for the program in CNS disorders such as Parkinson's disease as well as in obesity and other metabolic disorders in light of the ability of our NEK7-directed MGDs to penetrate BBB. IND-enabling studies are underway, and we plan to file our first IND for the program in the first quarter of 2025. |
Havrda
Clinical
4years ago
| control | PD | P value | |
|---|---|---|---|
| 'all samples' (=w/o outliers) |
145 Outlier: 0 NLRP3 Detection: 67 (46%) Ave: 15.46 |
177, NLRP3 Detection: 63 (35%), Ave: 14.5 | 오히려 PD군이 더 적음. 0.07 |
| 'with outliers' 더 많은 수 |
145 # of outlier: 0 Ave: 15.46 NLRP3 detection: |
182 (outlier 5 포함), NLRP3 detection: ? Ave: 114 (outliers 도 포함했으니 값이 큼) GSDMD detection: 31/83 (37%) (PD w NLRP3 detected group 에선 22/43 (51%) PD w/o NLRP3 detected group 에선 9/40 (22.5%): OR 3.6 |
Below is only Dartmouth cohort
| N | UPDRS | P= | GSDMD (ng/mL) | P= | IL-18 (pg/mL) | P= | SYN (pg/mL) | CRP (ng/mL) | P= | ||
|---|---|---|---|---|---|---|---|---|---|---|---|
| PD w NLRP3 detected | 43 | 28.0±14.9 | P=0.39 | 163.0 (461.5) | P=0.03 | 10,678 (13,732) | P=0.26 | 29,592 (17379) | 16 | 4,273 (7,087) | P=0.20 |
| PD patients w/o NLRP3 detected | 40 | 25.0±14.0 | 5.2 (12.4) | 15,135 (17,645) | 38,228 (30,361) | 2,503 (2,612) | |||||
| Control w NLRP3 detected | 22 | 23.1 (61.2) | 17,022 | 35,372 | 2,548 | ||||||
| control w/o NLRP3 detected | 24 | 12.9 (19.5) | 18,266 | 39,157 | 4,952 |
- He measured plasma NLRP3 in 182 PD patients. It would be useful to see the clinical severity data (ie MDS-UPDRS and/or H&Y score, if available) and we can explore the impact of NLRP3 level in clinical severity.
- (Anderson 2021) A single antibody pair was found capable of detecting recombinant NLRP3 protein: capture, Cryo 2 (AG-20B-0014-C100, Adipogen, San Diego, CA), detection, D4D8T (15101, Cell Signaling Technologies, Danvers, MA).
- o Because, based on the available data, Cusabio ELISA that Sebastian’s working on appears to have a better potential, the best option is to wait for the Cusabio experiments, and use the MSD assay as a mitigation plan if we are not happy with the performance
Link to CNS – PNS: CSF 달라
- A natural Hx study-type of analysis would be useful with his patient (and control) cohort.
- o If he can provide us with the plasma samples of the cohort and we do measure with our assays for NLRP3, ASC, Casp-1, IL-1/18, it would be useful.
- o To measure CSF markers (NLRP3, ASC, Casp-1, IL-1/18) and microglial imaging (TSPO or P2X7 PET) in the cohort 🔲 these would address the question whether blood NLRP3 markers correlate with those in the CNS. → 일단 Havrda 에게 추진하도록 부탁? CPHS (Committee for the Protection of Human Subjects) protocol?
Subpopulation strategy
| Disease impact | Clinical severity correlation? | Group difference between PD and HC in the brain | Statistically different group difference | Nice to have | |
|---|---|---|---|---|---|
| TV | |||||
| BM | Does plasma NLRP3 overactivation predict that of brain? | 5-8 postmortem PD brain and matched plasma Microglial PET (Preferred over CSF) CSF NLRP3 increase (Not very useful) | |||
| Pharmacological validation | Dartmouth college, Harvard Biomarker Study (https://www.bwhparkinsoncenter.org/biobank/) 99,100 | ||||
LINK between NLRP3, AS, CASP, IL-1
Preclinical
Figure 1. Validation of the Nlrp3L351P/Tmem119CRE mice.
A-C. Nlrp3L351P mice harboring Tmem119CRE were bred with mice harboring the functionally null homozygous Nlrp3L351P allele. D. Representative genotyping with PCR-based detection of the Tmem119CRE allele. E. mRNA was extracted from the mesencephalon of otherwise Nlrp3L351P mice treated with Tamoxifen for 7 days to induce the expression of Tmem119CRE, removing the stop codon, and activating the Nlrp3L351P allele (see A-C). Data demonstrate complete loss of Nlrp3 expression in the Tmem119CRE and Tmem119CRE/Nlrp3L351P backgrounds (lanes 1 and 2). Data demonstrate tight tamoxifen (Tx) inducibility in the Tmem119CRE/Nlrp3L351P backgrounds (lanes 3 and 4). H.
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| Genentech / GDC-2394 | coronary artery disease를 강조히는 | Korean particle 강조히는 may be 강조하는; preserved verbatim. |
| Preclinical Figure 1 H. | trailing H. letter | Figure caption ends mid-sentence at H.. |