Sanford Burnham Prebys Medical Discovery Institute

Press Release – No. 2 / 2025 Steven R. Smith, MD, joins Zealand Pharma as Senior Global Medical Advisor in Obesity Copenhagen, Denmark, January 7, 2025 – Zealand Pharma A/S (Nasdaq Copenhagen: ZEAL) (CVR-no. 20045078), a biotechnology company focused on the discovery and development of innovative peptide-based medicines, today announced that Steven R. Smith, MD, has joined Zealand Pharma as Senior Global Medical Advisor – Obesity, as of January 1, 2025. Steven will report to David Kendall, Chief Medical Officer, and will support Zealand’s obesity research and clinical development programs. “We are very excited to welcome Steven to our team here at Zealand,” said David Kendall, Chief Medical Officer, Zealand Pharma. “As a recognized global leader in obesity and metabolism research, Steven will play a central role across the research and development organization as we advance our innovative peptide-based assets for the treatment of obesity and related health conditions.” Dr. Smith brings 30 years of clinical and translational research experience in obesity, diabetes, and metabolism with over 300 scientific publications. Prior to joining Zealand Pharma, Steven was Chief Scientific Officer at the AdventHealth Research Institute, where he developed and led the strategic research agenda across the organization. During his 15-year tenure at AdventHeath, he served as founding scientific director of the Translational Research Institute, with a focus on translating scientific discoveries into improved clinical care for the patient. Steven has held several academic positions, including adjunct professorships at Johns Hopkins University, the Pennington Biomedical Research Center, and the Sanford-Burnham Medical Research Institute. He is also a past President of The Obesity Society. Steven holds a medical degree from the University of Texas Health Science Center in San Antonio, Texas and postdoctoral experience from Baylor University Medical Center and the Ochsner Clinic. “It is a very exciting time in obesity research right now and Zealand Pharma has a strong pipeline of differentiated and innovative assets,” said Steven Smith, MD. “I am looking forward to working closely with my talented new colleagues and playing our part in addressing one of society’s biggest health care challenges.” About Zealand Pharma A/S Zealand Pharma A/S (Nasdaq: ZEAL) ("Zealand") is a biotechnology company focused on the discovery and development of peptide-based medicines. More than 10 drug candidates invented by Zealand have advanced into clinical development, of which two have reached the market and three candidates are in late-stage development. The company has development partnerships with a number of pharma companies as well as commercial partnerships for its marketed products. Zealand was founded in 1998 and is headquartered in Copenhagen, Denmark, with a presence in the U.S. For more information about Zealand’s business and activities, please visit www.zealandpharma.com. Contact: Adam Lange (Investors)Investor Relations OfficerEmail: alange@zealandpharma.com Neshat Ahmadi (Investors)Investor Relations ManagerEmail: neahmadi@zealandpharma.com Anna Krassowska, PhD (Media and Investors)Vice President, Investor Relations & Corporate CommunicationsEmail: akrassowska@zealandpharma.com

iStock, Fotonen The pharma is seeking full approval for its anticoagulation reversal drug Andexxa, which the FDA granted accelerated approval in 2018 for patients who had been treated with apixaban or rivaroxaban. AstraZeneca had a tough day on Thursday, needing to allay clotting concerns associated with its anticoagulation reversal drug Andexxa (andexanet alfa) while also discontinuing a Phase II trial of its opioid use disorder therapy AZD4041. The FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee convened on Thursday to look at AstraZeneca’s supplemental Biologics License Application (sBLA) for Andexxa to convert its accelerated approval to full approval. The panel of external experts were not asked to vote on any specific matter. Instead, they discussed Andexxa’s safety signals and its overall benefit/risk profile. Andexxa is a recombinant coagulation factor, Xa, that won the FDA’s accelerated approval in 2018 to stop bleeding in patients who had been treated with the anticoagulants rivaroxaban or apixaban. To back its bid for full approval, AstraZeneca filed data from the Phase IV ANNEXA-I trial , a randomized, open-label and multicenter trial that enrolled patients with acute intracranial bleeding treated with oral FXa inhibitors. Results from ANNEXA-I showed that Andexxa could elicit significantly better hemostasis in patients than usual care, but the FDA’s internal reviewers, in a briefing document published ahead of the advisory committee meeting, raised several safety concerns. These included a twofold increase in the rate of thrombosis and thrombosis-related deaths in Andexxa-treated patients versus usual care. Panelists on Thursday had trouble taking the efficacy and safety findings from ANNEXA-I—which was conducted in a specific subset of patients needing coagulation support—and making recommendations for the much wider population of patients who have access to Andexxa. “We almost don’t have the data to evaluate the serious risks,” Taby Ahsan, committee chair and vice president of Cell and Gene Therapy Operations at the City of Hope, said during the committee’s discussion. The back-and-forth regarding Andexxa’s benefit/risk pro the study sample versus in the broader intended patient population reminded patient representative Joseph O’Brien, CEO of the National Scoliosis Foundation, of opioids. “When the indication of opioids was to eliminate pain, it was clear that it did that,” O’Brien said during the meeting, noting that the situation now is the same for Andexxa, which in ANNEXA-I showed strong overall clinical benefit in the specific set of patients that were treated. “But unfortunately, then we were left with two decades of side effects that have impacted patients more than anything else that we can find,” O’Brien continued, referring to opioids. Experts and regulators should be careful to avoid a similar outcome with Andexxa, he added: “Are we now exposing a very large population to the use of a drug that may in fact damage them or harm them? I think that’s a very legitimate question to ask.” Still, many physicians during the meeting highlighted the value of Andexxa in the clinical setting, particularly when faced with a bleeding patient. Evan Snyder, director of the Center for Stem Cells and Regenerative Medicine at the Sanford Burnham Prebys Medical Discovery Institute, said that “when you’re confronted with a patient who’s bleeding, as an intensivist I know the first thing you want to do is simply to just stop the bleeding. Later on, you can deal with the downstream consequences.” Also on Thursday, AstraZeneca announced that it has terminated a Phase II study for AZD4041, its investigational opioid use disorder medication, according to an update to the trial’s clinicaltrials.gov page . In a statement to Endpoints News , a company spokesperson said that the decision as driven by “a potential drug-drug interaction following a study to examine this risk.” These findings in turn “change the potential benefit-risk in this patient population and do not support further development of AZD4041 in opioid use disorder.”

Members of an FDA advisory committee were not asked to vote Thursday on AstraZeneca’s anticoagulant reversal drug Andexxa, but they did raise several safety and efficacy concerns. Last year, AstraZeneca began plans to shift Andexxa to a full approval from its accelerated approval after halting its confirmatory trial early due to positive efficacy. But the FDA explained in briefing documents and at the meeting that the confirmatory trial, known as ANNEXA-I, revealed “major safety findings,” including a “doubling of the rate of thromboses and thrombosis related deaths at Day 30 in the andexanet arm compared with” a standard of care clotting agent known as a prothrombin complex concentrate (PCC). While several hematologists on the adcomm explained how Andexxa does work at stopping serious bleeds, adcomm chair Taby Ahsan, VP of cell and gene therapy operations at City of Hope, said the committee generally indicated that there needs to be a better understanding of risks like thrombotic events. Committee members also questioned if the dose and the indicated population were understood well enough. While Andexxa demonstrated a statistically significant improvement in hemostasis in the confirmatory trial, the agency said that the “observed treatment difference between arms appears to be primarily driven by hematoma volume.” Panelist Rajiv Ratan, associate dean at Weill Cornell Medicine, said in the final discussion that “it doesn’t seem like the change in hematoma volume — especially because it was relatively large for patients who are untreated — is enough as a primary endpoint.” Others seemed to suggest that if the goal is the immediate reversal of the anti-coagulation drug, rather than long-term outcomes, then perhaps the drug should be converted to a full approval. “As a clinician this is a difficult decision,” said panelist Evan Snyder of Sanford Burnham Prebys Medical Discovery Institute. He stressed that other clinicians may want this drug in their toolbox, and potentially they would know that if a person is at high-risk for a thrombotic event they should not receive this drug. “We can be more nuanced with the indication,” Snyder said. Adcomm member Sanjay Ahuja of the Indiana Hemophilia and Thrombosis Center said that if a patient is bleeding on an anticoagulant, “the first thing you need to do is reverse that effect,” and Andexxa “does that. Looks like pretty well.” But thrombotic risk needs to be assessed before you place people at risk, panelist Thomas Ortel of Duke University Medical Center said. “There is no alternative here,” Ahuja said. “People use PCCs without any approval in that category and that actually complicates matters because a lot of physicians will use PCCs the way they want to use PCCs.”