NovoCodex Biopharmaceuticals Co., Ltd.

Almost a year to the day before Ambrx's ESMO presentation, the company laid off 15% of its staff and trimmed the pipeline down to ARX517 and a couple other early-stage assets. MADRID—When patients reached Ambrx Biopharma’s phase 1/2 clinical trial for prostate cancer, they were nearing the end of their treatment journey. It’s hard to read that some had gone through 13 rounds of treatment before they entered the study. CEO Daniel O’Connor and Chief Clinical Officer Sandra Aung don’t take that lightly. “They're last line patients, they have no other options and typically patients in that bucket go for clinical trials,” Aung said on the sidelines of the European Society for Medical Oncology Congress in Madrid. Ambrx wants to provide another option, but more importantly, a better option for these patients who are facing difficult decisions after a long fight with cancer. The company unveiled early-stage data from the APEX-01 study of the antibody-drug conjugate (ADC) ARX517 showing anti-cancer activity and few adverse events—none serious. For efficacy, Ambrx reported that more than half of the 23 patients had a 50% or more reduction in prostate specific antigen, which is elevated in prostate cancer. Seventeen out of 21, or 81% of evaluable patients, also had a steep reduction in circulating tumor DNA. In a smaller analysis of six patients, half who had prior prostate-specific membrane antigen (PSMA)-targeted radionuclide therapy, had more or equal to 50% reduction in prostate specific antigen. And out of four evaluable patients, half had a 30% or more reduction in target lesions. There were no treatment-related serious adverse events or dose limiting toxicities, a discontinuation rate of just 3.1% and fewer than 10% grade 3 treatment related adverse events—but no grade 4 or 5s. Aung said the safety data are particularly important for these late-stage patients: “We don’t want to make them sicker.” “I don't know if I've ever seen a late-stage cancer drug, after two years of clinical development, not having an [serious adverse event]. Not one,” O’Connor said in an interview. The grade 3 events were lymphocyte count decreases, platelet count decreases and one instance of left ventricular dysfunction, which Aung said was found in the course of the treatment and was not considered serious. “We don't want to diminish what a grade 3 is, but on a grand scheme of things for this late-line patient on this drug, [it’s] very tolerable. We would feel very comfortable calling it strong safety,” Aung said. While the data are from a small population, Ambrx is already forming a detailed strategy of next steps. Aung said that the safety profile resulted from the biotech’s careful testing and drug discovery process. “It's very rare to find this kind of safety profile. It is really born from technology, it's not luck,” she said. There’s still a lot to do in the clinic, including fully enrolling the study and conducting dose expansion, O’Connor said. With so few safety events, he thinks the dose can go higher to push efficacy even further. “Ultimately, if we see a data plateau and we see an impact over efficacy, we'll make a decision probably not to move forward to a higher level,” O’Connor said. “It's incumbent on us to continue to explore higher doses to see if there's more efficacy.” Ambrx also saw in the small dataset the possibility that the treatment will work regardless of a patient’s PSMA biomarker levels, which would mean ARX517 could have access to a wide patient population. The trial did not screen for PSMA, so the patients had a mix of high and low levels. “If we don't have to have a biomarker program, we do not want to have one,” O’Connor said. Aung said they are certainly going to collect that data, but the goal is not to pick one population over the other. “We want to be able to treat patients, not have to select them,” she added. “We're going to collect it and we're going to look at the data and make a decision on whether it's necessary or not.”   Ambrx's scorecard The ESMO presentation represents a major reset for Ambrx. Almost a year to the day, the biotech laid off 15% of its staff and trimmed the pipeline down to ARX517 and a couple other early-stage assets. The dramatic moves came after a breast cancer program fell apart. “Focus is really the key for us. And I think frankly, we’re really pleased with the progress the company has made this year,” said O’Connor, who took the helm in November 2022 after the layoffs. “There was a reduction that happened last fall. A year later, there's really kind of a complete change. A reset.” Aung is another fresh face, having taken on her role in February. Ambrx has also managed to raise some cash and extend its runway to 2026, all in a market O’Connor admits is challenging for the larger industry. The most recent offering in June closed with $75 million, which followed a $78 million raise in March. Even the breast cancer program, initially the cause of the company cutbacks, is returning. In March, Ambrx said that a phase 2 study in China conducted by partner NovoCodex Biopharmaceuticals showed that ARX788 demonstrated better progression-free survival than the control group. O’Connor moved to resurrect the drug. “It was shelved not because of efficacy, it was shelved because the company was concerned about cash burn a year ago, just before I was the CEO,” O’Connor said. Ambrx always believed there was a signal in the data. Now, he says Ambrx is conducting a small signal-finding study in a group of breast cancer patients who have no other options. The FDA had previously granted a fast-track tag for the treatment. “On each scorecard, we feel like we've really changed the trajectory of the company. And we are really pleased with the progress,” O’Connor said.

Ambrx ditched ARX788 as lead asset back in October and vowed to find a partner to continue development outside of China. Ambrx walked away from a breast cancer drug in October, citing the competitive pressure from AstraZeneca and Daiichi Sankyo’s blockbuster Enhertu. But new CEO Daniel O’Connor has spied an opportunity to get the drug back in the clinic. Last week, the company held an investor day trumpeting the new path for the med, which will see a small new phase 2 trial in third-line HER2-positive breast cancer, after patients have progressed on Enhertu. Today, Ambrx is touting an interim analysis from a phase 3 trial conducted by partner NovoCodex Biopharmaceuticals where ARX788 demonstrated better progression-free survival than the control group. O’Connor said this early data supports the resurrection of the HER2 antibody-drug conjugate. NovoCodex is testing ARX788 in the late-stage ACE-Breast-02 pivotal study in China, where the company holds the rights. The 441 patients in the trial have locally advanced or metastatic HER2-positive breast cancer and have previously received chemotherapy and Roche’s Herceptin. ARX788 met the pre-specified interim primary endpoint by achieving greater progression-free survival compared to the control group, which received Novartis’ Tykerb and a chemotherapy. Ambrx did not detail the numbers, but said the result was statistically significant.   Ambrx ditched ARX788 as the lead asset back in October and vowed to find a partner to continue development outside of China. The move came with a 15% workforce reduction, too. But now, the therapy is back. The company held an investor day last week where O’Connor said the data that has emerged is too good to leave the therapy behind. The CEO, who took the helm in November after the strategic review, detailed a new phase 2 trial of about 30 patients with breast cancer that has advanced on Enhertu, who have received no more than three prior lines of therapy. Enrollment is expected to take about 18 months. O’Connor said that a big milestone for Ambrx this year will be “first patient, first dose” in the new study. He expects to be able to pick things back up where they left off after the company paused development in October. The hope is to amend the original study protocol from the ACE-Breast-03 trial, which Ambrx was conducting, and utilize studies that were already open to speed things along. That will allow Ambrx to “jump right back into those sites,” O’Connor said. The protocol amendment will take about three months to clear through the FDA, the CEO noted. If the study shows a clinical signal of 20% to 30% objective response rate, ARX788 will be expanded into a registration-enabling trial. The cost of this new study will be about $20 million to $30 million but O’Connor said the spend is justified by the potential upside value creation for shareholders. Since ARX788 kills cancer cells in a different way than Enhertu, there’s an opportunity to capture the 25% of patients who progress while taking Enhertu within the first 12 months, the CEO explained. “For these reasons, we think 788 could be positioned to be among the first to deliver clinically meaningful results in the post-Enhertu patient population,” O’Connor said during the investor presentation. NovoCodex is also studying ARX788 in gastric cancer and other solid tumors and holds a fast-track designation for HER2-positive metastatic breast cancer and an orphan designation for gastric cancer. China’s regulators have also granted a breakthrough designation in breast cancer. The partnership with NovoCodex was signed with parent company Zhejiang Medicine in 2013.

Interim analysis of the ACE-Breast-02 study being conducted by Ambrx’s partner, NovoCodex Biopharmaceuticals, was completed by the Independent Data Monitoring Committee (IDMC) The pivotal Phase 3 ACE-Breast-02 study met its pre-specified interim primary efficacy endpoint with statistical significance, demonstrating a greater progression free survival benefit compared to the control SAN DIEGO--(BUSINESS WIRE)-- Ambrx Biopharma Inc., or Ambrx, (NYSE: AMAM) announced today that it has been informed by its partner, NovoCodex Biopharmaceuticals, Inc. (NovoCodex), that an interim analysis for ACE-Breast-02, a randomized Phase 3 breast cancer clinical trial investigating Ambrx’s ARX788, an anti-HER2 antibody drug conjugate (ADC), has met its pre-specified interim primary efficacy endpoint with statistical significance, demonstrating a greater progression free survival (PFS) benefit compared to the active control. ACE-Breast-02 is a randomized, controlled pivotal Phase 3 clinical trial of humanized anti-HER2 monoclonal antibody-AS269 conjugate (ARX788) in the treatment of HER2 positive patients with locally advanced or metastatic breast cancers in China. The trial enrolled 441 HER2 positive breast cancer patients who have been previously treated with taxane and trastuzumab. Eligible subjects were randomly assigned in a 1:1 ratio to receive ARX788 or the control drugs, lapatinib combined with capecitabine. The primary endpoint was PFS based on Blinded Independent Review Committee (BIRC) assessment. An interim analysis was conducted by an Independent Data Monitoring Committee (IDMC) when two thirds (2/3) of the PFS events occurred. After reviewing the interim results, the IDMC informed NovoCodex that the ACE-Breast-02 study met its pre-specified interim primary efficacy endpoint with statistical significance, demonstrating a greater PFS benefit compared to the control. Based on the results from the interim analysis, NovoCodex plans to submit a communication application to seek marketing approval in China pending discussion with National Medical Products Administration (NMPA). Daniel O’Connor, Chief Executive Officer of Ambrx commented: “We congratulate our partner, NovoCodex, on this positive Phase 3 study. The positive results from this large Phase 3 study provide further support for our rationale to develop ARX788 globally in HER2 positive breast cancer patients.” ARX788 is an anti-HER2 ADC currently being studied broadly in breast cancer, gastric/GEJ cancer and other solid tumor clinical trials with our partner NovoCodex. The United States Food and Drug Administration (FDA) has granted Fast Track Designation for ARX788 in HER2 positive metastatic breast cancer and Orphan Drug Designation for ARX788 in gastric cancer. The NMPA has granted Breakthrough Therapy Designations for ARX788 in breast cancer. In June 2013, Ambrx entered into a collaboration with Zhejiang Medicine Co., Ltd., which was transferred to it subsidiary NovoCodex, to develop and commercialize ARX788, Ambrx’s most advanced internally developed site-specific ADC targeting HER2-positive breast cancer. Under the agreement, NovoCodex licensed commercial rights for ARX788 in China while Ambrx retained commercial rights outside of China and is entitled to receive royalties on sales of ARX788 in China. About Ambrx Biopharma Inc. Ambrx is a clinical stage biopharmaceutical company using an expanded genetic code technology platform to discover and develop Engineered Precision Biologics. These include 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 the prostate-specific membrane antigen (PSMA) and ARX788, its proprietary ADC targeting HER2. In addition, Ambrx has preclinical and clinical collaborations with multiple partners for drug candidates generated using Ambrx technology. Ambrx 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 . 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, and include, without limitation, express or implied statements regarding Ambrx’s beliefs and expectations regarding the potential benefits of ARX788, clinical development and strategic plans for ARX788 and the timing of trial updates, the potential for ARX788 to obtain marketing approval, and data updates and milestones related to ARX788. 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: the continuing impact of the COVID-19 pandemic and other public health-related risks and events on Ambrx’s business, operations, strategy, goals and anticipated milestones; 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 Annual Report on Form 20-F filed with the SEC on April 26, 2022, 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.