DB-1310, an ADC comprised of a novel anti-HER3 antibody conjugated to a DNA topoisomerase I inhibitor, is highly effective for the treatment of HER3-positive solid tumors

Article

Author: Luo, Lan ; Hua, Haiqing ; Zhu, Zhongyuan ; Li, Bing ; Yao, Jun ; Zhang, Yu ; Qiu, Yang ; Li, Xi ; Qu, Chen

AbstractBackgroundHER3 (ErbB3), a member of the human epidermal growth factor receptor family, is frequently overexpressed in various cancers. Multiple HER3-targeting antibodies and antibody–drug conjugates (ADCs) were developed for the solid tumor treatment, however none of HER3-targeting agent has been approved for tumor therapy yet. We developed DB-1310, a HER3 ADC composed of a novel humanized anti-HER3 monoclonal antibody covalently linked to a proprietary DNA topoisomerase I inhibitor payload (P1021), and evaluate the efficacy and safety of DB-1310 in preclinical models.MethodsThe binding of DB-1310 to Her3 and other HER families were measured by ELISA and SPR. The competition of binding epitope for DB-1310 and patritumab was tested by FACS. The sensitivity of breast, lung, prostate and colon cancer cell lines to DB-1310 was evaluated by in vitro cell killing assay. In vivo growth inhibition study evaluated the sensitivity of DB-1310 to Her3 + breast, lung, colon and prostate cancer xenograft models. The safety profile was also measured in cynomolgus monkey.ResultsDB-1310 binds HER3 via a novel epitope with high affinity and internalization capacity. In vitro, DB-1310 exhibited cytotoxicity in numerous HER3 + breast, lung, prostate and colon cancer cell lines. In vivo studies in HER3 + HCC1569 breast cancer, NCI-H441 lung cancer and Colo205 colon cancer xenograft models showed DB-1310 to have dose-dependent tumoricidal activity. Tumor suppression was also observed in HER3 + non-small cell lung cancer (NSCLC) and prostate cancer patient-derived xenograft (PDX) models. Moreover, DB-1310 showed stronger tumor growth-inhibitory activity than patritumab deruxtecan (HER3-DXd), which is another HER3 ADC in clinical development at the same dose. The tumor-suppressive activity of DB-1310 synergized with that of EGFR tyrosine kinase inhibitor, osimertinib, and exerted efficacy also in osimertinib-resistant PDX model. The preclinical assessment of safety in cynomolgus monkeys further revealed DB-1310 to have a good safety profile with a highest non severely toxic dose (HNSTD) of 45 mg/kg.ConclusionsThese finding demonstrated that DB-1310 exerted potent antitumor activities against HER3 + tumors in in vitro and in vivo models, and showed acceptable safety profiles in nonclinical species. Therefore, DB-1310 may be effective for the clinical treatment of HER3 + solid tumors.

News (Medical) associated with HER3-ADC(Elevation Oncology)

17 Sep 2024

·endpts.com

Merck and Daiichi’s rejected HER3 ADC clears a Phase 3 in certain lung cancers

BARCELONA — Merck and Daiichi Sankyo have passed a Phase 3 with the lead antibody-drug conjugate from the megadeal they disclosed at last year’s European Society for Medical Oncology confab. The new topline result , which was released Tuesday morning with no hard data, came out as this year’s ESMO wrapped up, and a few months after the drug was rejected by the FDA over manufacturing concerns. The duo said its HER3 ADC, named patritumab deruxtecan, helped keep patients alive longer without disease progression in a study code-named HERTHENA-Lung02 . The companies said it was a statistically significant result compared to doublet chemotherapy, but they didn’t disclose how wide the margin was. The companies “plan to initiate regulatory discussions” based on the results announced Tuesday, a Merck spokesperson confirmed to Endpoints News . The trial included patients with locally advanced or metastatic EGFR-mutated non-small cell lung cancer who had previously tried an EGFR tyrosine kinase inhibitor. The companies had sought approval in the third-line setting based on a different trial, dubbed HERTHENA-Lung01, but the ADC was rejected this summer because of inspection findings at a third-party manufacturer. The companies said HERTHENA-Lung02 data on the secondary endpoint of overall survival were immature and that they’ll continue the study to further analyze that measure. Overall survival has become an increasingly important piece for the FDA. Merck and Daiichi said there were two deaths from interstitial lung disease, but that the majority of the ILD events were grades 1 and 2. The companies are working on two additional ADCs together and recently teamed up on a T cell engager that Merck got by way of its acquisition of Harpoon Therapeutics. Merck chief medical officer Eliav Barr told Endpoints News on the sidelines of ESMO this weekend that he hopes they can “ revolutionize ” small cell lung cancer with some of those therapies.

Phase 3ADCAcquisition

06 Aug 2024

·www.prnewswire.com

Elevation Oncology Reports Second Quarter 2024 Financial Results and Highlights Recent Business Achievements

-- Today announced promising initial data from Phase 1 clinical trial of EO-3021; 42.8% confirmed ORR observed in Claudin 18.2-enriched subset of gastric and GEJ cancer, with differentiated safety profile -- -- Advancing into dose expansion portion of Phase 1 trial; additional monotherapy data expected in 1H 2025 -- -- Secured clinical supply agreements to evaluate EO-3021 in combination with ramucirumab and dostarlimab with Lilly and GSK, respectively; expect to initiate dosing in combination portion of the Phase 1 trial by year-end 2024 -- -- On-track to nominate development candidate for HER3-ADC program in 2H 2024 -- -- Elevation Oncology to host conference call and webcast today at 8:30 a.m. ET -- BOSTON, Aug. 6, 2024 /PRNewswire/ -- Elevation Oncology, Inc. (Nasdaq: ELEV), an innovative oncology company focused on the discovery and development of selective cancer therapies to treat patients across a range of solid tumors with significant unmet medical needs, today announced financial results for the second quarter ended June 30, 2024, and highlighted recent business achievements. "Today, we announced promising initial data from our Phase 1 trial evaluating monotherapy EO-3021, which reinforce clinical proof-of-concept and support EO-3021's potential as a best-in-class Claudin 18.2 antibody drug conjugate. We are particularly excited to see encouraging anti-tumor activity in patients with Claudin 18.2-expressing gastric or GEJ cancer, as well as a differentiated safety profile, demonstrating the value of a targeted therapeutic approach and the benefit of EO-3021's site-specific conjugation," said Joseph Ferra, President and Chief Executive Officer of Elevation Oncology. "These results support our broad clinical development program for EO-3021 and strengthen our conviction that EO-3021 can provide meaningful benefit to patients living with gastric or GEJ cancer." Mr. Ferra continued, "Looking ahead, we remain on track to advance into monotherapy dose expansion and initiate the combination portion of our Phase 1 trial evaluating EO-3021 by year-end, report additional monotherapy data for EO-3021 in the first half of 2025, and nominate a development candidate from our HER3-ADC program in the second half of 2024. This year has been transformative for Elevation Oncology, marked by strong execution toward our goal of bringing important treatment options to patients with significant unmet medical needs, and we are eager to continue these efforts as we advance our pipeline of differentiated ADC therapies." Recent Business Achievements Earlier today, Elevation Oncology announced promising initial data from the dose escalation portion of the ongoing Phase 1 clinical trial of EO-3021 in patients with advanced, unresectable or metastatic solid tumors likely to express Claudin 18.2, including gastric, gastroesophageal junction (GEJ), pancreatic or esophageal cancers. As of the data cutoff date of June 10, 2024: EO-3021 was observed to be generally well-tolerated. No neutropenia or peripheral neuropathy/hypoesthesia, both known toxicities associated with monomethyl auristatin E (MMAE), were observed in the safety population of 32 patients treated with EO-3021. In seven patients with Claudin 18.2 in ≥20% of tumor cells at IHC 2+/3+, the objective response rate (ORR) was 42.8% (three confirmed partial responses, one of which was confirmed following the June 10, 2024, data cutoff) and the disease control rate (DCR) was 71.4%, including two patients with stable disease (SD). In eight patients with Claudin 18.2 in <20% of tumor cells at IHC 2+/3+, the ORR was 0% and the DCR was 50%, including four patients with SD. A press release with further details regarding these results is available in the News Releases section of Elevation Oncology's investor relations website at . In June 2024, Elevation Oncology announced plans to expand its ongoing Phase 1 clinical trial of EO-3021 to include two combination cohorts evaluating EO-3021 for the treatment of advanced gastric or GEJ cancer. Pursuant to clinical supply agreements with Lilly and Company and GSK, respectively, Elevation Oncology will evaluate EO-3021 in combination with ramucirumab, a VEGFR2 inhibitor, in the second-line setting and in combination with dostarlimab, a PD-1 inhibitor, in the front-line setting. Expected Upcoming Milestones EO-3021: Initiate dosing in combination portion of the ongoing Phase 1 clinical trial of EO-3021 by year-end 2024. Share additional data from the ongoing Phase 1 clinical trial of monotherapy EO-3021, including from the dose expansion cohort, in the first half of 2025. HER3-ADC: Nominate development candidate from HER3-ADC program in the second half of 2024. Second Quarter 2024 Financial Results As of June 30, 2024, Elevation Oncology had cash, cash equivalents and marketable securities totaling $110.8 million, compared to $83.1 million as of December 31, 2023. The increase in cash reflects net proceeds of $44.2 million, which Elevation Oncology raised through its at-the-market (ATM) facility in the first half of 2024, partially offset by cash used to fund operating activities. Research and development (R&D) expenses for the second quarter of 2024 were $6.6 million, compared to $6.0 million for the second quarter of 2023. The increase in R&D expenses in the second quarter of 2024 was primarily due to increased EO-3021 clinical trial expenses. General and administrative (G&A) expenses for the second quarter of 2024 were $4.4 million, compared to $3.8 million for the second quarter of 2023. The increase in G&A expenses in the second quarter of 2024 was primarily due to increased professional fees, including costs for accounting and legal services, and increased utilization of consultants. Net loss for the second quarter of 2024 was $10.5 million, compared to $10.1 million for the second quarter of 2023. Financial Outlook Elevation Oncology expects its existing cash, cash equivalents and marketable securities as of June 30, 2024 to be sufficient to fund its current operations into 2026. Conference Call Information Elevation Oncology will host a live conference call and webcast at 8:30 a.m. ET today to discuss the initial EO-3021 safety and efficacy data announced today. Participants may register for the conference call here. It is recommended that participants join the call ten minutes prior to the scheduled start. A webcast of the call will also be available on the Events page of Elevation Oncology's investor relations website at . The archived webcast will be available on the website approximately two hours after the conference call and will be available for 90 days following the call. About EO-3021 EO-3021 (also known as SYSA1801) is a differentiated, clinical-stage antibody drug conjugate (ADC) with best-in-class potential comprised of an immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that targets Claudin 18.2. EO-3021 is site-specifically conjugated to the monomethyl auristatin E (MMAE) payload via a cleavable linker with a drug-to-antibody ratio (DAR) of 2. Claudin 18.2 is a specific isoform of Claudin 18 that is normally expressed in gastric epithelial cells. During malignant transformation, the tight junctions may become disrupted, exposing Claudin 18.2 and allowing them to be accessible by Claudin 18.2 targeting agents. Elevation Oncology is evaluating EO-3021 in a Phase 1 study (NCT05980416) in patients with advanced, unresectable or metastatic solid tumors likely to express Claudin 18.2 including gastric, gastroesophageal junction, pancreatic or esophageal cancers. Elevation Oncology has the exclusive rights to develop and commercialize EO-3021 in all global territories outside Greater China. About Elevation Oncology, Inc. Elevation Oncology is an innovative oncology company focused on the discovery and development of selective cancer therapies to treat patients across a range of solid tumors with significant unmet medical needs. We are leveraging our antibody-drug conjugate (ADC) expertise to advance a novel pipeline, initially targeting two clinically validated targets in oncology, Claudin 18.2 and HER3. Our lead candidate, EO-3021, is a potential best-in-class ADC designed to target Claudin 18.2 and is currently being evaluated in a Phase 1 trial (NCT05980416) in patients with advanced, unresectable or metastatic solid tumors likely to express Claudin 18.2 including gastric, gastroesophageal junction, pancreatic or esophageal cancers. Additionally, we expect to nominate a development candidate for our second program, a HER3-targeting ADC for the treatment of patients with solid tumors that overexpress HER3, in 2024. For more information, visit . Forward-Looking Statements This press release contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, anticipated clinical and preclinical development activities, expected timing of announcements of clinical results, potential benefits of Elevation Oncology's product candidates, potential market opportunities for Elevation Oncology's product candidates, the ability of Elevation Oncology's product candidates to treat their targeted indications and Elevation Oncology's expectations about its cash runway. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. These forward-looking statements may be accompanied by such words as "aim," "anticipate," "believe," "could," "estimate," "expect," "forecast," "goal," "intend," "may," "might," "plan," "possible," "potential," "will," "would," and other words and terms of similar meaning. Although Elevation Oncology believes that the expectations reflected in such forward-looking statements are reasonable, Elevation Oncology cannot guarantee future events, results, actions, levels of activity, performance or achievements, and the timing and results of biotechnology development and potential regulatory approval are inherently uncertain. Forward-looking statements are subject to risks and uncertainties that may cause Elevation Oncology's actual activities or results to differ significantly from those expressed in any forward-looking statement, including risks and uncertainties related to Elevation Oncology's ability to advance its product candidates, the timing and results of preclinical studies and clinical trials, approvals and commercialization of product candidates, the receipt and timing of potential regulatory designations, Elevation Oncology's ability to fund development activities and achieve development goals, Elevation Oncology's ability to protect intellectual property, Elevation Oncology's ability to establish and maintain collaborations with third parties, and other risks and uncertainties described under the heading "Risk Factors" in documents Elevation Oncology files from time to time with the Securities and Exchange Commission. These forward-looking statements speak only as of the date of this press release, and Elevation Oncology undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date hereof. Elevation Oncology Investor and Media Contact Hannah Deresiewicz, 212-362-1200 EVP, Managing Director, Precision AQ [email protected] SOURCE Elevation Oncology

Phase 1Financial StatementADCLicense out/inClinical Result

28 Jun 2024

·www.fiercepharma.com

Fierce Pharma Asia—Daiichi, Merck's FDA rejection; Wegovy's expansion; Takeda CEO's hunt for China deals

The FDA's rejection of Daiichi and Merck's HER3 ADC, Wegovy's approval in China, and Takeda CEO's appetite for more deals with Chinese biotechs made our news this week. The FDA rejected Daiichi Sankyo and Merck's HER3 antibody-drug conjugate. Novo Nordisk's weight loss star Wegovy secured approval in China. After two large licensing deals, Takeda's CEO is open to more partnerships with Chinese biotechs. And more. 1. Daiichi's lung cancer ADC rejected by FDA in blow to first project under Merck partnership Daiichi Sankyo’s Merck-partnered HER3 antibody-drug conjugate, patritumab deruxtecan, was rejected by the FDA because of third-party manufacturing issues. The drug is one of three ADC programs featured as part of a $4 billion upfront deal between the two companies, and it would have been Merck’s first ADC launch. The partners are working with the contractor and the FDA to address the problems. 2. Novo Nordisk wins approval in China for GLP-1 obesity drug Wegovy China has approved Novo Nordisk’s Wegovy as a weight loss treatment for people with a body mass index of at least 30 or between 27 and 30 with one weight-related risk factor. However, the drug will be unlikely to get national reimbursement after China’s medical insurance authority in an April Q&A ruled out the inclusion of any anti-obesity drugs, along with seven other therapeutic categories, in the national insurance scheme. 3. Takeda keeps looking for China biotech partnerships, CEO says (Bloomberg) Since last year, Takeda has signed major deals with Chinese biotechs Hutchmed and Ascentage Pharma. Now, CEO Christophe Weber told Bloomberg the Japanese pharma “should remain very open of potential partnerships with Chinese biotech.” He also said that the draft BIOSECURE Act would have no impact on Takeda as the company’s manufacturing in China is for the Chinese market. 4. Takeda's anti-CD38 antibody on track for phase 3 after boosting platelet count in bleeding disorder Although Takeda has decided to wind down mezagitamab in myasthenia gravis and systemic lupus erythematosus, it’s still advancing the anti-CD38 antibody in primary immune thrombocytopenia. Latest data from 41 patients in a phase 2b trial showed that the drug improved platelet response compared with placebo across all three doses with what Takeda viewed as a favorable safety profile. 5. Sumitomo Pharma's new CEO weighs layoffs in Japan after sharp sales drop, US job cuts: report Sumitomo Pharma’s new CEO Toru Kimura, who just officially took the helm this week, is weighing a restructuring that could be implemented “as soon as this fiscal year,” he told Nikkei Asia. The reorg would follow a recent layoff round affecting 400 U.S. staffers. Recent revenue declines give the company “no choice but to take further measures, including offering early retirement,” he told the publication. 6. Despite J&J's Rybrevant full nod, FDA encourages Dizal to file rival lung cancer drug for accelerated approval The FDA has endorsed Dizal Pharma’s plan to file its China-approved sunvozertinib in the U.S. for an accelerated approval in previously treated EGFR exon 20 insertion-mutated non-small cell lung cancer, its CEO said. That’s despite the FDA’s recent full approval for Johnson & Johnson’s bispecific antibody Rybrevant in the same indication. The agency clearly sees the need for alternative or better therapies, Dizal’s CEO explained. 7. SK Bioscience begins 'globalization' push, paying $244M for majority stake in contract manufacturer IDT Biologika SK Bioscience has acquired a 60% stake in Germany’s IDT Biologika for 339 billion South Korean won ($244 million) as part of the company’s global expansion push. IDT ranks among the world’s top 10 firms in vaccine production. The transaction enables SK to expand its footprint geographically as well as in new treatment areas such as anti-cancer viruses and cell and gene therapy, SK said. Other News of Note: 8. FDA slams Dr. Reddy's plants in India with a pair of Form 483s 9. Haleon reels in $633M with sale of ex-US nicotine replacement unit to Dr. Reddy's 10. Fosun Pharma offers $690M to take biotech subsidiary Henlius private (Reuters) 11. GenScript's ProBio arm debuts new gene therapy production plant in NJ 12. Terns' ex-MASH drug cuts fat, not muscle or food intake, in GLP-1 combo in mice 13. Glenmark recalls 114 batches of low potassium drug in the US over potentially deadly hyperkalemia risk

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