Newly published data from the Phase 1 portion of the on-going
Phase 1 / 2 APEX-01 trial provide the following key points:
- 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)
- 52% (12/23) of patients experienced a ≥50% PSA reduction
- A strong and highly differentiated safety profile observed across 65 patients at all dose levels with no treatment-related SAEs or DLTs
APEX-01 is a Phase 1 / 2, first-in-human, open label dose escalation and dose expansion trial enrolling patients with metastatic castration-resistant prostate cancer (mCRPC). To be eligible for APEX-01, patients with mCRPC had to satisfy certain criteria, including receiving at least two prior FDA-approved therapies for metastatic disease, with at least one being a 2nd generation androgen receptor pathway inhibitor (ARPI), and who have met at least one of the following three criteria: PSA progression defined by a minimum of two rising PSA values, radiographic progression by RECIST v1.1, and/or disease progression by the presence of new bone lesions.
APEX-01 opened for enrollment in
Dr.
Data Highlights
As of the data cutoff date (
- 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
- 52% (12/23) patients experienced a ≥50% PSA reduction
Regarding the recent data, Dr.
- 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
As of the data cutoff date (
- 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
- 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
The full posters were made available online on the ESMO website and abstracts and posters are available on Ambrx’s website via thislink.
Details of the poster presentations are as follows:
Session Title: Prostate Cancer Poster Session
Title: ARX517, an Anti-Prostate-Specific Membrane Antigen (PSMA) Antibody-Drug Conjugate (ADC), Demonstrating Promising Safety and Efficacy in Heavily Pre-Treated Patients With Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Presenting Author: John Shen, M.D.
Date/Time: Sunday, October 22, 2023 from 12:00 –
Session Title: Prostate Cancer Poster Session
Title: ARX517, a Next Generation Anti-PSMA Antibody Drug Conjugate (ADC) Demonstrates Stability, Dose-Dependent Exposure, and Long Half-Life
Presenting Author: Scott
Date/Time: Sunday, October 22, 2023 from 12:00 –
Session Title: Basic Science Poster Session
Title: ARX517, a Next-Generation Anti-PSMA Antibody Drug Conjugate for the Treatment of Metastatic Castration-Resistant Prostate Cancer, Demonstrates Anti-tumor Activity in Enzalutamide-Resistant and Enzalutamide-Sensitive Models and a Clear Therapeutic Index in a Non-human Primate Model
Presenting Author: Shawn Zhang, Ph.D.,
Date/Time: Sunday, October 22, 2023 from 12:00 –
Session Title: Basic Science Poster Session
Title: Preclinical characterization of ARX305, a next-generation anti-CD70 antibody drug conjugate for the treatment of CD70-expressing cancers
Presenting Author: David Mills, Ph.D.,
Date/Time: Sunday, October 22, 2023 from 12:00 –
Ambrx APEX-01 ARX517 Webcast Information
Click here to login and view the webcast replay of Ambrx’s KOL Event discussing the ARX517 data presented at ESMO 2023 showcasing presentations from PK and prostate cancer experts.
About ARX517
ARX517 is an investigational antibody-drug conjugate composed of a humanized anti-PSMA mAb linked to AS269, an
In preclinical studies, the cancer cell killing payload of ARX517, pAF-AS269, is highly cytotoxic when delivered by a mAb into cancer cells. ARX517’s site-specific linkage, stable conjugation chemistry, and non-cleavable linker result in an ADC with a homogenous drug-antibody-ratio, mAb-like biophysical properties, and exceptional stability. Therefore,
ARX517 has the potential to be a first- and best-in-class anti-PSMA ADC addressing the high unmet medical need in mCRPC.
About APEX-01
About
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