Dutch clinical stage biopharmaceutical company Byondis has entered into a license, collaboration and supply agreement with Medac, a privately owned pharmaceutical company based in Germany.
Byondis and medac will partner to commercialize Byondis’ lead program, [vic-] duocarmazine (SYD985), an anti-HER2 antibody-drug conjugate (ADC) which is pending approval by the US Food and Drug Administration, the European Medicines Agency (EMA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), as well as other regulatory authorities around the world.
HER-2 targeting ADCs
The human epidermal growth factor receptor 2 (HER2) has been fertile ground for ADC drug hunters, spearheaded by the earlier approval of trastuzumab-emtansine (T-DM1; Kadcyla®; Genentech/Roche) and trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca).
Interestingly, both of these ADCs incorporate trastuzumab (Herceptin®; Genentech/Roche) as the monoclonal antibody, and the influence of this targeting agent does not stop there, with [vic-]trastuzumab duocarmazine (SYD985) containing trastuzumab in Phase III, as well as other trastuzumab-ADC Phase I candidates and several engineered variants in different phases of clinical development. This is supplemented by the Chineses developed HER2-targeting ADC disitamab vedotin (爱地希®/Aidixi®; Remegen; Previously known as RC48) and the Indian approved trastuzumab-emtansine biosimilar (ZRC-3256; Ujvira®; Zydus) with several others following this route in different countries.
Trastuzumab-emtansine, the first HER2-targering ADC, was approved for the treatment of HER2 (human epidermal growth factor receptor 2)-positive breast cancer. The drug consists of trastuzumab covalently linked to the cytotoxic maytansinoid DM1 via a non-cleavable linker. Despite its efficacy, primary or acquired resistance frequently develops, particularly in advanced stages of the disease. Second generation ADCs targeting HER2 are meant to supersede T-DM1 by using a cleavable linker and a more potent payload with a different mechanism of action.
Trastuzumab deruxtecan, a HER2-directed antibody and DNA topoisomerase I inhibitor conjugate was developed for the treatment of HER2-expressing solid tumors, including breast cancer, gastric cancer, colorectal cancer and non-small cell lung cancer. Based primarily on the results of the phase 2 DESTINY-Breast01 trial, trastuzumab deruxtecan was initially approved by the FDA under accelerated approval for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. 
[Vic-]trastuzumab duocarmazine targets a range of HER2-expressing cancers including metastatic breast and endometrial (uterine) tumors. And While earlier generation ADCs improved targeting and cell killing, they were generally unstable in the bloodstream, leading to premature release of the cytotoxic payload, impacting healthy tissue and narrowing the therapeutic window. In contrast, [vic-] trastuzumab duocarmazine is highly stable in circulation and carries an intricate, inactivated and potent cytotoxic drug that rapidly self-destructs if prematurely released, limiting damage to healthy tissue and improving the therapeutic window.
The differentiated linker-drug (valine-citrulline-seco-DUocarmycin-hydroxyBenzamide-Azaindole or vc-seco-DUBA), owes its potent antitumor activity to a synthetic duocarmycin-based cytotoxin. Duocarmycins, were first isolated from Streptomyces bacteria in the 1970s and bind to the minor groove of DNA and alkylate the adenine residues at the N3 position, disrupting the nucleic acid architecture, which eventually leads to tumor cell death.
The first member of the duocarmycin family to be evaluated in vivo was CC-1065. Similar to calicheamicins, the members of duocarmycin family of naturally occurring antitumor antibiotics are potent, and despite showing moderate antitumor activity, they cannot be used clinically on their own because of delayed toxicity, in this case hepatotoxicity. In efforts to improve the therapeutic index of duocarmycin-based therapeutics, several ADCs were developed including MDX-1203 / BMS-936561 (Bristol-Myers Squibb), a fully human monoclonal antibody-drug conjugate targeting CD70 cell-surface protein. This experimental agent was first analyzed in patients with advanced clear cell carcinoma and B-cell non–Hodgkin lymphoma. However, the clinical trial was stopped during Phase I despite being tolerated at doses up to 8 milligrams per kilogram (mpk). 
In developing [vic-]trastuzumab duocarmazine, scientists at Byondis developed a novel linker drug. The distinctive design of the selectively cleavable linker connecting the antibody to the duocarmycin drug leads to high stability in circulation and induces efficient release of the cytotoxin in the tumor. Uptake of the activated payload by neighboring tumor cells with lower HER2 expression improves the efficacy potential, the so-called bystander effect.
Data from the pivotal Phase 3 TULIP® study (SYD985.002) in HER2-positive unresectable locally advanced or metastatic breast cancer demonstrated a statistically significant progression-free survival (PFS) results compared to physician’s choice (PC) treatment. The ongoing TULIP study continues to study overall survival and a Marketing Authorization Application (MAA) for this initial clinical indication will soon be submitted to the EMA. The ADC is also in a Phase II multiregional clinical trial to evaluate its safety and efficacy in patients with HER2-expressing recurrent, advanced or metastatic endometrial cancer (SYD985.003).
Europe and the United Kingdom
Under the terms of the agreement, Medac receives an exclusive license to commercialize trastuzumab duocarmazine in the European Union, the United Kingdom and non-EU countries in Europe. Byondis will receive an undisclosed upfront payment and sales royalties and will also be eligible for payments upon achievement of certain development and sales milestones.
“This collaboration with medac on trastuzumab duocarmazine is a crucial step in ensuring that the therapy, once approved, is available to patients, who desperately need other treatment options,” noted Jacques Lemmens, Ph.D., Founder and Chairman of Byondis.
“Like Byondis, Medac is committed to developing novel therapies, especially in areas of unmet medical need. We believe in the potential of Byondis and SYD985 and look forward to bringing this next generation ADC to patients who need it,” said Jörg Hans, Managing Director and Chief Executive Officer of Medac.
“We are pleased to have found in Medac a true partner who shares our passion for innovation and making a difference in the lives of patients,” added Marco Timmers, Ph.D. Beyondis Chief Executive Officer.
SYD985 vs. Physician’s Choice in Participants With HER2-positive Locally Advanced or Metastatic Breast Cancer (TULIP) – NCT03262935
SYD985 in Patients With HER2-expressing Recurrent, Advanced or Metastatic Endometrial Carcinoma – NCT04205630
A Study of DS-8201a in Metastatic Breast Cancer Previously Treated With Trastuzumab Emtansine (T-DM1) – NCT03248492
Study of MDX-1203 in Subjects With Advanced/Recurrent Clear Cell Renal Cell Carcinoma (ccRCC) or Relapsed/Refractory B-Cell Non-Hodgkin’s Lymphoma (B-NHL) – NCT00944905
Highlights of prescribing information
Trastuzumab (Herceptin®; Genentech/Roche) (Prescribing Information)
Trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche)(Prescription information)
Trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca) (Prescribing Information)
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