Ambrx Announces ARX517, a PSMA-Targeted ADC, Demonstrates a Promising 52% PSA50 (≥50% Reduction) and a Highly Differentiated Safety and PK Profile in Patients with mCRPC, who Progressed on Multiple FDA-Approved Treatments

• Multiple efficacy endpoints demonstrate consistent and promising anti-cancer activity at therapeutic doses of 2.0 – 2.88 mg/kg (Cohorts 6-8) in heavily pretreated patients (median of 4 and maximum of 13 prior lines of therapy):
  • 52% (12/23) of patients experienced a ≥50% PSA reduction
  • 81% (17/21) of patients experienced ≥50% circulating tumor DNA reduction
  • 50% (3/6) of patients with prior PSMA-targeted radionuclide therapy (TRT) experienced a ≥50% PSA reduction
  • 50% (2/4) experienced a >30% reduction in target lesion(s)
• A strong and highly differentiated safety profile observed across 65 patients at all dose levels with no treatment-related SAEs or DLTs

• Deep PSA reductions have been seen with increasing ARX517 dose. PSA reductions deepened as dose levels increased, demonstrating a dose dependent PSA reduction:
  • ≥50% PSA reduction observed in 25% (4/16) and 50% (7/14) of patients at 1.4 mg/kg (Cohort 4) and 2.0 mg/kg (Cohort 6), respectively
  • ≥90% PSA reduction observed in 6% (1/16) and 36% (5/14) of patients at 1.4 mg/kg (Cohort 4) and 2.0 mg/kg (Cohort 6), respectively
• Multiple coinciding efficacy endpoints demonstrate a consistent and promising anti-cancer activity at therapeutic doses of 2.0 – 2.88 mg/kg (Cohorts 6-8):
  • 52% (12/23) patients experienced a ≥50% PSA reduction
    • 7 of 14 patients at 2.0 mg/kg (Cohort 6)
    • 3 of 6 patients at 2.4 mg/kg (Cohort 7)
    • 2 of 3 patients at 2.88 mg/kg (Cohort 8)
  • 81% (17/21) patients experienced a ≥50% ctDNA reduction
  • 50% (2/4) experienced a >30% reduction in target lesion(s), one of which had a reduction in liver and lung lesions

"Patients with late stage mCRPC have few effective systemic therapy options. The data from the APEX-01 study show very promising PSA declines as well as ctDNA reductions, all pointing in the right direction, based on the safety and preliminary efficacy data presented in the poster. I believe this drug is worthy of further development.”

• ARX517 demonstrates a strong and differentiated safety profile in heavily pretreated late stage mCRPC patients:
  • No treatment-related SAEs or DLTs were observed
  • Low drug related discontinuation rate 3% (2/65)
  • Grade 3 TRAEs were reported in only 9.2% (6/65) patients across all cohorts, and only 13% (4/32) at doses 2.0-2.88 mg/kg
  • Three patients with lymphopenia, two patients with transient platelet count decrease, and one patient with asymptomatic left ventricular dysfunction that was not deemed serious
  • No Grade 4 or 5 treatment-related adverse events (TRAEs) were reported
  • Low frequency of Grade 1 or 2 TRAEs (≥10%), including dry mouth (24%), dry eye (22%) and fatigue (20%)
• Ongoing first-in-human Phase 1 trial enrolled 65 patients who exhausted approved life-extending treatments is representative of late line mCRPC patient population:
  • Median 4 with a maximum of 13 prior therapies
  • 100% received at least one 2nd generation ARPI (97% received either abiraterone or enzalutamide, 2% received either duralutamide or apalutamide), 48% of patients received both enzalutamide and abiraterone
  • 66% of patients received at least one prior taxane, 46% of patients received at least one prior immunotherapy and 17% of patients received at least one prior PSMA-targeted radionuclide therapy
• PSA reductions observed in patients who had prior PSMA-targeted radionuclide therapy (PSMA TRT):
  • 50% (3/6) of patients treated with a PSMA TRT experienced a ≥50% PSA reduction at therapeutic doses of 2.0 – 2.88 mg/kg (Cohorts 6-8)
• Deepening PSA response with dose escalation combined with not seeing SAEs and DLTs support continuing dose escalation to higher levels:
  • Cohort 8 (2.88 mg/kg) expansion underway
  • Cohort 9 (3.4 mg/kg) escalation underway

• Pharmacokinetics (PK) data demonstrates strong ADC stability:
  • Across all dose levels (0.32 to 2.4 mg/kg), PK data show virtually overlapping total antibody and ADC PK concentration time curves
• Full-loaded DAR2 ARX517 does not prematurely release its payload thus maximizing delivery of cytotoxic payload to PSMA-expressing cancer cells:
  • Low serum concentrations of free payload, with a molar ratio of payload to ADC was 0.06%
  • Free payload of ARX517 in serum reached a maximum concentration of <1nM, which is 100x below the concentration of the free payload used to kill normal cells in vitro
• Full-loaded DAR2 ARX517 is able to apply consistent pressure on PSMA-expressing cancer cells:
  • A long ADC terminal half-life of up to 10 days enables longer dosing intervals and ensures that ARX517 stays in circulation to enable consistent pressure on PSMA-expressing cancer cells