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

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)
    
    
• A strong and highly differentiated safety profile observed across 65 patients at all dose levels with no treatment-related SAEs or DLTs
  
  

SAN DIEGO, Oct. 23, 2023 (GLOBE NEWSWIRE) -- Ambrx Biopharma, Inc., or Ambrx, (NASDAQ:AMAM), today announced that in biomarker unselected patients ARX517 monotherapy demonstrated a strong antibody-drug conjugate (ADC) safety profile at all doses tested with promising early efficacy signals that included PSA50 declines, ctDNA reductions, and RECIST v1.1 tumor response. The ESMO clinical posters present updated safety, efficacy and PK data from Ambrx's on-going trial, APEX-01 (NCT04662580).   Posters were made available as part of the 2023 European Society for Medical Oncology (ESMO) Congress 2023 meeting, taking place in Madrid, Spain, October 20-24, 2023, and are summarized below.

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 2^nd 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 July 2021 and is the only on-going clinical trial in the United States targeting PSMA with an ADC. The two primary objectives of APEX-01 are to analyze the safety and tolerability of ARX517 and establish a recommended Phase 2 dose.

Dr. John Shen, a medical oncologist at UCLA and an investigator on APEX-01, stated that, "The PSA results are very encouraging especially in this heavily pre-treated patient population where eligible patients would have exhausted all available and appropriate treatment options prior to enrolling in this study."

Data Highlights

As of the data cutoff date (September 5, 2023), highlights from the safety and efficacy data are summarized below:

• 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

Regarding the recent data, Dr. Oliver Sartor, a medical oncologist and translational researcher with 33 years of professional experience and a special focus on prostate cancer, commented, "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 2^nd 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 (September 5, 2023), highlights from the PK data are below:

• 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
    
    

The full posters were made available online on the ESMO website and abstracts and posters are available on Ambrx's website via this link.

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 – 13:00 CEST.

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 T. Tagawa, M.D., M.S., FACP, FASCO

Date/Time: Sunday, October 22, 2023 from 12:00 – 13:00 CEST.

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 – 13:00 CEST.

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 – 13:00 CEST.

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 Ambrx proprietary potent microtubule inhibitor. ARX517 is designed to target the prostate-specific membrane antigen (PSMA). PSMA is highly expressed in metastatic castration-resistant prostate cancer (mCRPC) and has been validated as a therapeutic target.

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, Ambrx believes ARX517 can promote highly specific tumor cell killing with minimal off-target toxicity.

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

Ambrx is currently investigating ARX517 in the APEX-01 (NCT04662580) first-in-human Phase 1 / 2, multicenter, dose escalation and dose expansion clinical study to evaluate the safety, pharmacokinetics, and preliminary anti-tumor activity of ARX517 in adult subjects and is currently enrolling patients with advanced prostate cancer (mCRPC) whose tumors have progressed following at least two FDA approved treatments for prostate cancer, including at least one second-generation androgen receptor pathway inhibitor, and have met one of the following three criteria: PSA progression defined by a minimum of 2 rising PSA values or radiographic progression by RECIST v 1.1 or disease progression by the presence of new bone lesions.

About Ambrx Biopharma, Inc.

Ambrx is a clinical-stage biopharmaceutical company using an expanded genetic code technology platform to discover and develop next-generation antibody drug conjugates (ADCs) and other engineered therapies to modulate the immune system. Ambrx is advancing a focused portfolio of clinical and preclinical programs designed to optimize efficacy and safety in multiple cancer indications, including ARX517, its proprietary ADC targeting the prostate-specific membrane antigen (PSMA) and ARX788, its proprietary ADC targeting HER2. In addition, Ambrx has preclinical and clinical collaborations with multiple partners on drug candidates generated using Ambrx technology. Ambrx was spun out of The Scripps Research Institute in 2003 and has several other product candidates involving ADCs and other aspects of Ambrx's protein engineering technology. For more information, please visit www.ambrx.com. Ambrx routinely posts information that may be important to investors on its website.

Forward-Looking Statements

This press release includes certain "forward-looking statements" intended to qualify for the "safe harbor" from liability established by the Private Securities Litigation Reform Act of 1995, as amended. Forward-looking statements may be identified by the words "intend," "plan," and similar expressions. Forward-looking statements are based on Ambrx's current expectations and are subject to inherent uncertainties, risks and assumptions that are difficult to predict. Factors that could cause actual results to differ include, but are not limited to, those risks and uncertainties associated with: Ambrx's ability to execute on its strategy including with respect to the timing of its R&D efforts, initiation of clinical trials and other anticipated milestones; risks associated with development and marketing approval of novel therapeutics, including potential delays in clinical trials and regulatory submissions and the fact that future clinical trial results/data may not be consistent with interim, initial or preliminary results/data or results/data from prior preclinical studies or clinical trials; Ambrx's ability to fund operations as anticipated; and the additional risks and uncertainties set forth more fully under the caption "Risk Factors" in Ambrx's Current Report on Form 8-K filed with the SEC on October 12, 2023, and elsewhere in Ambrx's filings and reports with the SEC. Forward-looking statements contained in this press release are made as of this date, and Ambrx undertakes no duty to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as may be required under applicable law.

Contacts

INVESTORS

Mike Moyer

LifeSci Advisors

617-308-4306

[email protected]

MEDIA

Karissa Cross, Ph.D.

LifeSci Communications

615-651-4622

[email protected] 

Source: Ambrx Biopharma, Inc.