Aug. 6 at 12:49 PM
$GLUE Q2 + August corporate deck. Substantial new data.
MRT-8102 vs IL-6: NEK7 degradation blocks inflammasome assembly. Ziltivekimab neutralizes one cytokine at the bottom of the cascade.
Slide 38 is the cleanest separation in the deck. In human monocyte-derived macrophages, 8102 shuts down pyroptosis (SYTOX) and DAMP release (extracellular ATP) at low nM. Ziltivekimab and rilonacept are FLAT across the entire concentration range. Zero effect on either.
Antibodies don’t stop the cell rupturing and spilling IL-1α, IL-18, calprotectin and cholesterol crystals into the plaque. That debris is the necrotic core.
Slide 34: calprotectin feeds back to drive more NLRP3 assembly — a loop explicitly independent of IL-1/IL-6. No downstream antibody breaks it.
2/7
GFORCE-1 is fully enrolled AND fully dosed. Data 2H 2026.
Four arms: the original 40mg (n~27) + placebo (n~9) already complete, plus two ADDITIONAL dose levels at n~27 each. 28-day dosing. Population is obesity (waist ≥40”M/≥35”F or BMI ≥30) with CRP 3–15 mg/L.
Key detail most people missed: both added doses sit BELOW 40mg. They’re exploring down, not up — because Phase 1 showed max activity at the lowest dose tested.
Next disclosure includes UNBLINDED safety plus expanded biomarkers: NEK7, IL-6, IL-18, fibrinogen, SAA, body weight, other CV risk markers. CRP sampled pre-dose, D1, D7, D14, D21, D28, D35.
Purpose is to accelerate dose selection into GFORCE-2.
3/7
The Phase 1 base for context. 112 subjects. SAD 48, MAD 40, dosed 5–400mg.
• ~80–90% NEK7 degradation at EVERY dose level, incl. 5mg
• 78% hsCRP reduction in elevated-baseline subjects
• Part 3 (40mg, n=24, wk4): 85% sustained hsCRP reduction, 94% of subjects to <2 mg/L from 6.3 baseline
• 31% fibrinogen reduction — independent atherosclerotic risk factor
• 55% reduction in endogenous plasma IL-6, below the CV risk threshold
• ~80% inhibition of ex vivo IL-1β across 5–200mg
Safety: no SAEs, no TEAE above grade 2. TEAEs 29% on drug vs 32% on placebo. Headache 9% vs 9%.
3-month cyno tox: NOAEL at highest dose tested = ~200–300x therapeutic index.
CRP deepened wk1→wk4. No rebound.
4/7
NEW metabolic data (slide 41). Not previously disclosed.
Cynomolgus obesity model, 77 days:
• NEK7 MGD alone: −8.3% body weight
• Semaglutide alone: −17.0%
• COMBO: −23.4%
DEXA: preferential central abdominal fat loss, lean mass spared. That’s the profile incretins get criticized for missing.
Monkey, not human — be clear on that. But GFORCE-2 carries body weight, BMI, waist, liver fat and liver inflammation as exploratory endpoints. A metabolic/MASH read riding on a cardiology trial.
Also new: 100mg achieved pharmacologically active CSF concentrations. 75% CSF IL-6 reduction in 2 subjects with elevated baseline while plasma IL-6 stayed low = CNS-specific effect. Second-gen CNS-optimized NEK7 MGD, IND H2 2026.
5/7
Indication selection was ranked, not hand-waved. GLUE scored NLRP3 activity across 470 diseases / 513,390 patient profiles / 900+ RNA-seq datasets. HS, ASCVD and gout topped it.
HS (slide 60): IL-1β 14x and IL-18 4x elevated lesional vs perilesional. 8102 at 10nM cut IL-1β, IL-1α and IL-18 in ex vivo human HS explants, 3 donors. NLRP3:NLRP1 ratio rises with progression. GALAXY-1, ~160 pts, HiSCR75, H1 27.
Gout: 8102 beats selnoflast on caspase-1 potency by roughly a log. Rabbit MSU model cut joint swelling and MSKUS pathology. Thesis = dissolve tophi WITHOUT triggering flares. GEMINI-1, ~40 pts, CKD 3-4 allowed — precisely where SOC is contraindicated. Q4 26/Q1 27.
6/7
MRT-6160 is now free optionality — and there’s a near-dated cash event nobody is modeling.
GLUE’s external R&D on 6160 fell to
$16K in Q2, from
$1.5M. Novartis funds 100%.
Sjögren’s Ph2a/b (NCT07737743) — N=344, ESSDAI at wk24, explicitly designed to select a Phase 3 dose. Registry start 8/27/26.
Here’s the part: under the 2024 Novartis agreement, milestones begin ON Phase 2 initiation. That deal currently books ZERO revenue. Up to
$2.1B in milestones + 30% US P&L + ex-US royalties.
Ph1 was strong: >90% VAV1 degradation in T and B cells, >70 subjects, no SAEs, up to 99% inhibition of IL-2/IFN-γ/IL-17A.
Novartis guides to MULTIPLE Ph2 starts in 2026.
7/7
Oncology delivered too. MRT-2359 + AR inhibitor in AR-mutant mCRPC: 5/5 PSA responses (2 PSA90, 3 PSA50), 2 RECIST PRs, 3 SD = 100% DCR. Median 5 prior lines, 83% prior taxane, 57% prior Pluvicto. MODeFIRe-1 Ph2 activated, first patient Q3.
CCNE1 (MRT-55811) drove tumor regression in ovarian xenografts. IND 2027.
Balance sheet:
$626M, no debt, runway into 2029. ATM fully untouched. ~
$350M in collaboration payments over 3 years, potential >
$400M over the next 24 months across Novartis x2 and Roche.
Risks, plainly: the pyroptosis and metabolic legs are preclinical. On hsCRP alone the deck concedes parity with IL-6 antibodies. R&D spend is guided to rise.
NFD/DYOR
