AZD-9550

Wegovy's new heart failure data could threaten AstraZeneca's Farxiga, but AZ's biopharma business chief Ruud Dobber said he's not concerned. GLP-1 agonists such as Novo Nordisk’s semaglutide and SGLT2 inhibitors like AstraZeneca’s Farxiga are already butting heads in the treatment of diabetes. But AstraZeneca’s biopharma business president, Ruud Dobber, said he’s not concerned about a potential clash between the two classes as they reach more patients. At the recent European Society for Cardiology (ESC) congress, Novo showed that Wegovy, or once-weekly semaglutide at the 2.4-mg dose, can significantly improve symptoms of heart failure in some patients. That could mean additional competition for AZ’s Farxiga because, as Dobber noted, the success of the AZ med is driven in large part by its use in heart failure. But Dobber said he doesn’t view GLP-1 drugs as a threat for the SGLT2 class—at least for now. Farxiga should be able to hold its own because it’s an oral drug, whereas Wegovy is administered via an injection, Dobber argued. Farxiga also bears an approval for treating chronic kidney disease in patients at risk of progression, while Wegovy has yet to show renal benefits. In heart failure, Farxiga boasts a broad label and can be prescribed regardless of a patient’s ejection fraction status or body weight. Novo’s new Wegovy win covered only obese patients with heart failure with preserved ejection fraction (HFpEF), although Novo noted that most people with HFpEF are overweight or obese. HFpEF makes up nearly half of all heart failure cases. Meanwhile, Wegovy’s STEP-HFpEF trial didn’t answer the key question of whether the Novo drug can reduce heart failure events or deaths. As the authors of a New England Journal of Medicine editorial accompanying the STEP-HFpEF data pointed out, those hard endpoints are crucial to determine the eventual roles of GLP-1 agonists and SGLT2 inhibitors in heart failure management. Those cardiovascular outcomes results typically take a large trial and a long time to obtain, Dobber noted. For its part, AZ’s Farxiga won its heart failure nod based on a phase 3 trial of 6,263 patients. Farxiga will go off patent around 2028. In a separate trial, Novo’s Wegovy cut the risk of a cardio death, heart attack or stroke by 20% compared with placebo and standard of care in overweight or obese patients with established cardiovascular disease. That trial enrolled 17,604 people and tested the Novo drug for up to five years in people 45 and older. Patients in that trial had cardiovascular disease, but not heart failure. Farxiga, known as Forxiga in Europe, had its own win to celebrate this past weekend. The ESC just updated its treatment guidelines to recommend SGLT2 inhibitors as first-line treatments for heart failure. The backing will “significantly simplify prescribing of SGLT2s for physicians,” Dobber said. But AZ’s drug faces competition from within its own class, most notably from Eli Lilly and Boehringer Ingelheim’s Jardiance, which is also approved for heart failure. Tuesday, both drugs appeared among the first 10 drugs up for Medicare price negotiations. Outside the SGLT2 class, Lilly has a GIP/GLP-1 dual agonist called Mounjaro. The drug is a rising star in diabetes and likely will be approved soon in obesity. Farxiga is currently the most used SGLT2 inhibitor in the world, but it lags Jardiance in the U.S. with about 30% to 35% market share stateside. And all the publicity around the GLP-1 class has created somewhat of a halo effect for Lilly. Publicity is nice, but physicians look for products that they’re comfortable with, Dobber said. “In the end of the day, it comes back to the belief of an individual physician, which product and which indication is most suitable to make the choice,” he said. AZ has been working on the GLP-1 pathway, too, including with its FDA-approved Bydureon. But the British pharma recently dropped twice-daily cotadutide to focus on its weekly GLP-1/glucagon candidate AZD9550, which is in early stages of development. Meanwhile, AZ its still focused on advancing Farxiga, and its strategy includes testing various combinations. AZ currently has three Farxiga combinations in phase 2 development, with readouts expected in late 2023 or early 2024, according to Dobber. One combo is testing the inclusion of baxdrostat, which AZ got from its $1.8 billion acquisition of CinCor Pharma earlier this year. Dobber called baxdrostat and Farxiga a “very attractive combination.” Baxdrostat, a selective aldosterone synthase inhibitor, has shown promise in lowering blood pressure, which is a risk factor for diabetes patients and nondiabetics with kidney disease, he noted. “Based on the data we’ve seen, we feel bullish and excited that that combination will help a lot of chronic kidney disease patients, irrespective whether they have diabetes or nondiabetes,” the AZ executive said.

AstraZeneca CEO Pascal Soriot AstraZeneca has dumped a rare disease drug candidate once considered worth $855 million after chalking up a pair of phase 2 flops, despite the prospect previously hitting the mark in a much larger phase 3 trial. The drugmaker disclosed the action alongside news of the jettisoning of a nonalcoholic steatohepatitis (NASH) therapy. Alexion paid $855 million to acquire Wilson Therapeutics and take control of its phase 3 asset WTX101, now known as ALXN1840, in 2018 as it sought to rebuild its pipeline after some M&A misadventure left it lacking a path to growth beyond Soliris. Evidence of the success of the plan emerged last year when AstraZeneca, having bought Alexion for $39 billion, revealed a phase 3 trial hit its primary endpoint. At the time, AstraZeneca said that “two ongoing mechanistic trials in Wilson disease are also underway” and that Alexion was “working closely with health authorities worldwide” and intended “to submit these data for review.” Ten months later, AstraZeneca has removed ALXN1840 from its clinical-phase pipeline. As recently as February, AstraZeneca was predicting (PDF) that it would file for approval in the second half of 2023. However, the Anglo-Swedish Big Pharma has since learned that two phase 2 trials missed their primary endpoints.  In a first-quarter earnings call with journalists, AstraZeneca Chief Financial Officer Aradhana Sarin described how the company had dropped (PDF) ALXN1840 “based off results of phase 2 mechanistic studies and discussions with regulatory authorities.” CEO Pascal Soriot expanded on the decision, explaining that the phase 2 studies had not been able “to show that copper was actually eliminated from the body.” “You may be facing a situation where copper is actually redistributed to all the organs, all the parts of the body,” the CEO said on the call. “We could have continued to invest and try to do more research, but we felt it was going to be a long shot, it was going to be taking too much time.” One phase 2 study enrolled nine patients and had a primary endpoint of mean daily copper balance. The other trial recruited 31 participants and had a primary endpoint of change from baseline at Week 48 in liver copper concentration. Neither study met its primary endpoint.  This morning's earnings update (PDF) also saw AstraZeneca clear the GLP-1/glucagon dual agonist cotadutide from its phase 2 pipeline. AstraZeneca took the candidate into a phase 2/3 NASH trial last year but recently revealed it stopped enrollment after recruiting 45 patients, well short of the targeted 1,860. Having dropped the daily cotadutide, AstraZeneca will focus on its weekly GLP-1/glucagon candidate AZD9550. “We have good clinical data [on cotadutide], but we decided to refocus on the weekly product,” Soriot told Fierce Biotech on the call. “A daily administration is not very convenient for patients, so we decided to focus our efforts on the follow-on compound, which is a weekly administration.”  Finally, the drugmaker discontinued a phase 1 trial of its anti-GDF15 candidate AZD8853 due to “strategic portfolio prioritization.” AstraZeneca moved the candidate into a phase 1/2 solid tumor trial last year in collaboration with ImaginAb, a biotech that it hooked up with in 2020.