Slide 1: A Phase 1, First-in-Human, Open-Label, Dose Escalation Study of MGD019
A Phase 1, First-in-Human, Open-Label, Dose Escalation Study of MGD019, an Investigational Bispecific PD-1 × CTLA-4 DART® Molecule in Patients with Advanced Solid Tumors Manish R. Sharma,1 Rachel E. Sanborn,2 Gregory M. Cote,3 Johanna Bendell,4 Sanjeev Kaul,5 Francine Chen,6 Alexey Berezhnoy,6 Paul
Slide 2: Presenter Disclosure Information
PRESENTER DISCLOSURE INFORMATION Manish R. Sharma, M.D. Research support (to the institution for clinical trials): • Alexo • Coordination • Incyte • Pfizer • Alpine Immune Sciences • Constellation • Ipsen • QED • Amgen • CytomX • Jounce Therapeutics • Regeneron • Apexian • Effector Therapeutics • KL
Slide 3: MGD019: Bispecific Molecule Engineered for Co-Blockade of PD-1 & CTLA-4
MGD019: Bispecific Molecule Engineered for Co-Blockade of PD-1 & CTLA-4 • PD-1 and CTLA-4 are checkpoint molecules with complementary mechanisms of action MGD019 • Dual blockade has yielded enhanced efficacy with approved agents, albeit with increased toxicity CTLA-4 CTLA-4 • MGD019, an investigatio
Slide 4: MGD019 is Well Tolerated in Non-human Primates
MGD019 is Well Tolerated in Non-human Primates GLP Toxicology Results Compare Favorably to Ipilimumab + Nivolumab Preclinical Profile PD-1 × CTLA-4 bispecific PD-1 mAb PD-1 + CTLA-4 two (MGD019) (Retifanlimab) mAb comboa Finding 10 mg/kg 40 mg/kg 100 mg/kg ≥100 mg/kg Adverse clinical signs – – – – +
Slide 5: MGD019 Phase 1 Trial Design
MGD019 Phase 1 Trial Design • Primary objectives: Dose Escalation in Previously Treated MGD019 Monotherapy – Safety, tolerability Advanced Solid Tumorsa Cohort Expansionb – DLTs, MTD, MAD – Alternate dose • Secondary objectives: – Pharmacokinetics – Immunogenicity – Preliminary activity • Explorator
Slide 6: Heavily Pre-treated Population Representing Diverse Tumor Types
Heavily Pre-treated Population Representing Diverse Tumor Types Baseline Demographics Dose Escalation Tumor Types Treated 0.03 – 10 mg/kg (n=43) prostate, 1 cholangio, 1 leiomyosarcoma, 1 eccrine, 1 Median age (range), years 62 (30, 85) breast, 1 endometrial, 1 Gender, n (%) anal, 1 pancreatic , 7 M
Slide 7: End of Treatment Disposition
End of Treatment Disposition Escalation Dose Levels 0.03 – 1.0 mg/kg 3.0 mg/kg 6.0 mg/kg 10.0 mg/kg Total Patients Treated, n 15 7 8 13 43 Response-Evaluable Patients, n (%) 12 (80) 7 (100) 3 (37.5) 8 (61.5) 30 (69.8) Median duration of therapy, weeks (min, max) 11.6 (1.3, 60.4) 14.1 (6.0, 34.9) 6.6
Slide 8: Pharmacokinetics and Receptor Occupancy
Pharmacokinetics and Receptor Occupancy Linear PK (1.0 – 10.0 mg/kg dose range) and Sustained Receptor Occupancy (≥ 1.0 mg/kg Q3W) First Dose PK Receptor (PD-1) Occupancy PD-1 Blockade 80 Day 1 (dose 1 pre) Day 8 "Open" PD-1, % of CD4 60 40 20 0 0.03 0.1 0.3 1 3 6 10 Dose Level (mg/kg) Estimated t1/
Slide 9: MGD019 Dose Escalation: Safety Summary
MGD019 Dose Escalation: Safety Summary • Generally well-tolerated at dose levels < 10 mg/kg • Despite no DLTs, intolerability at 10 mg/kg evident with increased incidence of Grade 3 irAEs, including: − Myocarditis (1) − Enterocolitis (1) − Hepatitis (1) − Bullous dermatitis (1) − Maculopapular rash
Slide 10: MGD019 Dose Escalation: Preliminary Activity
MGD019 Dose Escalation: Preliminary Activity Objective Responses (n=4): • Microsatellite stable CRC – cPR Best % Reduction of Target Lesions • Metastatic type AB thymoma – cPR RECIST Evaluable Population (n=30)a • Serous fallopian tube carcinomab – uPR • mCRPC – cCR • 10 patients with SD as best res
Slide 11: Patient Vignettes
Patient Vignettes Anti-tumor Activity in Tumors Conventionally Unresponsive to Checkpoint Inhibition 33-year-old female with CRC (3.0 mg/kg) 61-year-old male with mCRPC (3.0 mg/kg) • MSS disease, low TMB (5 mutations/mB), KRAS mutation • Post 6 prior lines of systemic therapy; disease limited to LNs
Slide 12: Pharmacodynamics of PD-1 and CTLA-4 Blockade
Pharmacodynamics of PD-1 and CTLA-4 Blockade T Tcell cellProliferation (Ki67) proliferation (Ki67) ICOS Upregulation by Dose Level and BoR 60 Day 1 Ki67 cells, % of CD8 50 Day 22 20 10 + 0 0.03 0.1 0.3 1 3 6 10 Day 1 10 Day 22 Ki67 cells, % of CD4 5 + 0 0.03 0.1 0.3 1 3 6 10 Dose level (mg/kg) Dose-
Slide 13: MGD019 (PD-1 × CTLA-4 DART Molecule): Conclusions
MGD019 (PD-1 × CTLA-4 DART Molecule): Conclusions Purpose-designed bispecific checkpoint inhibitor • Effects independent or coordinate blockade of PD-1 and CTLA-4 ― Enhanced CTLA-4 blockade on dual-expressing TILs vs. PD-1/CTLA-4 mAb combination ― Maintains uncompromised PD-1 blockade vs. anti-PD1 m