Meyd-873 Now

| Milestone | Timeline (est.) | Critical Success Factors | |-----------|----------------|---------------------------| | Phase IIa proof‑of‑concept (AML) | H2 2026 | Demonstrate ≥ 30 % CR rate in MYD‑high cohort; establish predictive biomarker (MYD1 IHC or RNA). | | Phase IIb combination (PDAC + anti‑PD‑1) | H1 2027 | Show additive TGI and improved overall survival; secure co‑development agreement with a checkpoint‑inhibitor partner. | | Regulatory IND‑enabling studies | 2026–2027 | GLP toxicology package, CMC scale‑up, and IND submission to FDA/EMA. | | Phase III pivotal (AML) | 2028‑2029 | Randomized, double‑blind, MEYD‑873 + azacitidine vs. azacitidine alone; target OS improvement of ≥ 4 months. | | Launch (US/EU) | 2030‑2031 | Market differentiation based on first‑in‑class MYD adaptor inhibition; companion diagnostic for MYD1 expression. |

Stay tuned as we move forward—MEYD‑873 could change the standard of care for KRAS‑driven solid tumors.

— Dr. Maya Patel, Head of Translational Oncology, NovaCure Therapeutics

| Parameter | Value | Interpretation | |-----------|-------|----------------| | IC₅₀ (off‑target Nav1.5) | > 10 µM | Negligible cardiac effects | | Plasma protein binding | 18 % | High free fraction for CNS delivery | | Cmax (IV, 5 mg kg⁻¹) | 2.3 µM | Well below toxicity threshold | | LD₅₀ (mouse, oral) | > 250 mg kg⁻¹ | Wide safety margin | | Neurotoxicity (in vitro) | No observable loss of viability at 10 µM for 48 h | Compatible with chronic use | MEYD-873

Repeated‑dose toxicology in rodents (28 days) showed only mild, reversible hepatic enzyme elevations that normalized after a two‑week washout. No histopathological lesions were observed in the brain, heart, or kidneys.

| Cellular read‑out | Effect of MEYD‑873 | |-------------------|--------------------| | NF‑κB luciferase reporter (TLR4 stimulation) | ↓ 85 % activity at 100 nM | | Cytokine release (IL‑6, TNF‑α) in macrophages | ↓ 70–90 % at 50–200 nM | | AML cell viability (MOLM‑13, THP‑1) | IC50 ≈ 30 nM; induces apoptosis (caspase‑3 activation) | | Synergy with PD‑1 blockade in murine B16‑F10 model | Tumor growth inhibition (TGI) = 78 % vs. 42 % for PD‑1 alone |

| Feature | Details | |---------|---------| | Core scaffold | 1,3‑benzothiazine fused to a 2‑pyridine ring | | Photocage | N‑alkyl‑aryl‑azobenzene moiety (cis–trans isomerization triggered at 720 nm) | | Side‑chain | A short PEG‑linked sulfonamide that confers aqueous solubility (≈15 mM) and limits off‑target binding | | Molecular weight | 452 Da | | Log P | 1.7 (balanced hydrophilicity/hydrophobicity for BBB penetration) | | Stability | Half‑life of 12 h in plasma; photostability > 95 % after 1 h of continuous NIR exposure | | Milestone | Timeline (est

The azobenzene photocage is the heart of MEYD‑873. In the dark (or under ambient visible light), the molecule adopts the cis conformation, sterically blocking the ligand‑binding pocket of Nav1.7. Upon NIR illumination, the azobenzene flips to the trans state, pulling the cage away and exposing the high‑affinity Nav1.7 agonist moiety. The process is fully reversible: a brief pulse of red light (∼630 nm) forces the azobenzene back to cis, instantly “turning off” the channel.

MEYD‑873 represents a paradigm shift in targeting the MYD signaling hub—a node that sits at the crossroads of oncogenic survival and pathological inflammation. Early data demonstrate:

If the upcoming Phase II trials confirm these signals, MEYD‑873 could become the first oral, adaptor‑targeted therapy on the market, offering clinicians a new lever to control both malignant growth and hyper‑inflammatory disease states. Stay tuned as we move forward— MEYD‑873 could

Stay tuned—the next few years will be decisive for MEYD‑873’s journey from the bench to the bedside.

| Cohort | Dose (mg) | Patients (n) | Safety | Pharmacodynamics (PD) | |--------|-----------|--------------|--------|----------------------| | Single‑Ascending Dose (SAD) | 10 → 200 | 30 | Mostly Grade 1–2 AEs (nausea, mild headache). No DLTs up to 200 mg. | Dose‑dependent reduction of peripheral IL‑6 (≈ 60 % at 150 mg). | | Multiple‑Ascending Dose (MAD) | 50 → 150 mg BID | 24 | One Grade 3 transient ALT elevation (resolved on hold). | Sustained NF‑κB inhibition (> 70 % baseline) in peripheral blood mononuclear cells (PBMCs). | | Expansion (AML pts) | 100 mg BID | 12 | Similar tolerability; no serious infections reported. | 2 CRs (complete remission), 4 PRs (partial remission); median time to response = 5 weeks. |

Key takeaway: Early human data confirm the pre‑clinical safety window and demonstrate biological activity (cytokine suppression, tumor responses) at tolerable doses.