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VTX3232 was well-tolerated with no dose-limiting toxicities identified. All TEAE were graded mild or moderate. VTX3232 exhibited a dose-dependent and dose-linear PK profile. Repeat doses of 3 mg QD maintained steady-state IL-1β IC50 coverage in both plasma and CSF over 24 hours. Repeat doses of 40 mg QD exceeded steady-state IL-1β IC90 coverage in both plasma and CSF over 24 hours. Robust, dose-dependent pharmacodynamic effects were observed in a whole blood ex vivo IL-1β stimulation assay. Additionally, reductions in inflammatory biomarkers were observed in plasma and CSF samples.. We expect to initiate a Phase 2a trial of VTX3232 in patients with early PD during the second half of 2024. We also expect to initiate a Phase 2a trial of VTX3232 in subjects with obesity and certain additional risk factors for cardiovascular disease during the second half of 2024. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ventus | "brain penentrant" |
NLRP3 | Biomarkers of neuroinflammation upregulated in PD patients (slide)
P1 ONGOING Hv, sad, mad VENT-02 was well-tolerated, with no dose-limiting toxicities or SAEs reported and only mild or moderate treatment-related adverse events observed. The moderate adverse eventsincluded headache and nausea and were only observed at a dose multiple times higher than the intendedtherapeutic doses. VENT-02 demonstrated full target engagement through 100% inhibition of IL-1β in the blood in an ex vivo wholeblood challenge assay, signifi cant drug levels in the CSF for 24 hours, and reduction of inflammatorybiomarkers such as hsCRP. Based on the half-life and target coverage observed in the trial, VENT-02 hasdemonstrated the potential for once daily dosing. Ventus expects to initiate a Phase 1b trial of VENT-02 in patients with PD in the second half of 2024 and a Phase 2 trial in patients with treatment-refractory epilepsy in 2025. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Roche | RO7486967, RG-6418/ZD334/RG6418/Selnoflast/RO7486967 Kp,uu: 0.06~0.1 (Roche pipeline widget thumbnail) |
ISRCTN85338453 https://doi.org/10.1186/ISRCTN85338453 Phase 1b adaptive multicentre double-blind randomized placebo-controlled parallel design study Recruitment start date:15/07/2022 Recruitment end date:15/07/2023 , idiopathic PD 50 to 85 years (early PD), TSPO-PET will be used. Treatment Period of approximately 28 days Group 1 will receive RO7486967 given as two pills in the morning and two pills in the evening every day for about 4 weeks. Group 2 will receive a placebo given as two pills in the morning and two pills in the evening every day for about 4 week | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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There is nothing listed on clinicaltrials.gov for selnoflast (RO7486967) but on the Roche web page they list the PD study as "Not yet recruiting". The study number is BP43176 and its states that it will run in 3 countries (Netherlands, UK and USA). See https://forpatients.roche.com/en/trials/neurodegenerative-disorder/pd/a-phase-1b-adaptive--multi-center--randomized--double-blind--pl.html. On the NHS web page (https://www.hra.nhs.uk/planning-and-improving-research/application-summaries/research-summaries/bp43176-ro7486967-in-participants-with-parkinsons-disease/) it lists the date of the Rec opinion as March 9, 2022 and that it will run for 2 years. On the ISRCTN registry web page (https://www.isrctn.com/ISRCTN85338453) it is listed as recruiting. The start date is listed as 4/11/2021 and the end date is listed as 10/30/2023. [ex-vivo stimulation with LPS] and rapid inhibition of IL-1β release following the first oral administration Blood] C-Reactive Protein (CRP) levels decreased slightly upon treatment, with a mean (± SD) change from baseline at Day 7 of -1.8 (±3.65) mg/L compared to +0.51 (±1.43) mg/L in the placebo arm. However, this decrease was driven by one outlier and was not considered clinically significant. Plasma levels of IL-1β were below the limit of quantification. There were no significant changes in plasma IL-18 levels upon treatment. [Colon] However, there were no significant reductions in neutrophil numbers in either study arm (results not shown). Caspase-1 (pro- and active forms) did not show marked changes after 7 days' treatment with selnoflast (data not shown). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Nodthera |
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| las | Inflazome is also developing an NLRP3-targeted PET tracer, with funding from the MJF (press release). | Patent has PD data. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 950 ID-3 CP-73) |
Directly bonds to the NACHT domain and changes NLRP3 confirmation MCC950 reversibly binds to NLRP3 protein |
blocks NLRP3 activation at nanomolar concentration [64]. MCC950 directly bonds to the WALKER B region on the NACHT domain of NLRP3. The binding of MCC950 changes confirmation of NLRP3 to a "closed" state as detected by bioluminescence resonance energy transfer (BRET) method [21]. MCC950 directly interacts with the Walker B motif within the NLRP3 NACHT domain, thereby blocking ATP hydrolysis and inhibiting NLRP3 activation and inflammasome formation. MCC950 → ↓ NLRP3 oligomerization, The number of NLRP3 oligomer Closed (resting, ↑ BRET signal) vs open (activated): BRET assay (Tapia-Abellán, 2019 #1770) Monomer vs oligomer MCC950: resting NLRP3에도 좀 붙는 듯 ((Tapia-Abellán, 2019 #1770) (Coll, 2019 #1771) MCC950 binds non-covalently to NLRP3, proximal to the Walker B motif and blocks NLRP3 ATPase activity MCC950 specifically binds to both active and inactive NLRP3, | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
| Ventus row, embedded slide chart | four-panel scatter plot icons under “NLRP3 | Biomarkers of neuroinflammation upregulated in PD patients” | Slide is small inside the cell; only the title and the three bullet captions are legible. |
| Roche row, pipeline widget | colour-tagged stage labels | Stage chips read like “P1b study planned / completed / ongoing” but specific compound names beside chips are below legible threshold. |
| Nodthera Day 7 / Day 28 grid | %reduction from BL columns | Several percentage values (e.g. Day 28 NFL = 10.5) are at the edge of the cell; preserved as best-effort. |
| Nodthera narrative “ED50 of 2mg/kg, EC50 of 74 nM” | numeric values | Both values appear faint near the edge of the cell. |
| Halia row leftmost cell label | reads as “las” | The owner-name token at the start of the row is partly cut off; recorded as “las” (likely tail of “Halia”). |