AstraZeneca R&D chiefs talk roxadustat trial, Ultomiris threats and Imfinzi wingman treme's future

AstraZeneca’s R&D expense swelled 59% in 2021 to nearly $10 billion. The acquisition of Alexion contributed some, and a mid-stage cull related to the buyout of Ardea Biosciences also cost the company dearly. But the British pharma’s pipeline has a lot more going on as it counted 14 positive phase 3 readouts for the year.

Fierce Pharma just had a chance to catch up with AstraZeneca’s two R&D masterminds, biopharmaceuticals R&D head Mene Pangalos and oncology R&D chief Susan Galbraith, to talk about the company’s recent regulatory and drug development advances that interest us the most. They include AZ’s attitude toward another clinical trial for troubled anemia drug Evrenzo (roxadustat), emerging competition for Alexion’s blockbuster C5 franchise, and immunotherapy tremelimumab’s potential place in a competitive liver cancer market, among other topics.

Despite an increase in late-stage programs, AstraZeneca remains “very disciplined and having to make some really difficult choices” to make sure the R&D budget is growing at a sensible rate, Pangalos said during an interview Thursday.

Another Evrenzo trial?

One hard decision Pangalos needs to make soon is whether AZ will fund an additional clinical trial for FibroGen-partnered Evrenzo, which suffered an FDA rejection in anemia caused by chronic kidney disease in August no thanks to some cardiovascular safety signals. The FDA is asking for another trial to better understand the drug’s profile, but that could push out a filing for years.

Mene Pangalos
Mene Pangalos (AstraZeneca)

With rivals from the same oral HIF-PHI class by GlaxoSmithKline and a collaboration between Akebia Therapeutics and Otsuka nearing the market, industry watchers have questioned the economics of running another Evrenzo. Some industry watchers wonder whether AZ will withdraw from the U.S. partnership.

Pangalos struck a cautious tone for the moment.

“Is it feasible we could run another study to get an approval in the indications and get a good label and good profile? The answer is yes,” Pangalos said. “Do I think we’re going to do that yet? I’d say no because we haven’t got to a place where we’re comfortable either with the regulator or with FibroGen.”

AZ and FibroGen are still in discussions with the FDA and could reach a decision in the next few months, Pangalos said. If AZ were to do a new trial, the goal would be to target approvals for both the nondialysis- and dialysis-dependent populations, he said.

Farxiga's potential blockbuster expansion

One indication Pangalos has more confidence in lies with Farxiga’s potential blockbuster expansion in heart failure with preserved ejection fraction. In November, Farxiga’s SGLT2 archrival, Eli Lilly and Boehringer Ingelheim’s Jardiance, started an FDA priority review for that indication. Fraxiga’s own phase 3 trial in the indication, dubbed Deliver, is expected to read out in the first half of this year.

RELATED: ESC 2021: Eli Lilly, Boehringer's Jardiance racks up data for 2nd nod in crowded heart failure field

“Given the Lilly data, we have confidence that why shouldn’t we deliver a positive study—we’re studying very similar populations with similar endpoints,” Pangalos said. “I think it’s going to be another big opportunity and something that will get approval and be really important for the class.”

Farxiga and Jardiance have been going at each other for years in both Type 2 diabetes and heart disease.

C5 franchise threats

Meanwhile, AZ’s newly acquired C5 franchise—Soliris and its follow-on med Ultomiris—is facing new threats.

Apellis recently introduced C3 inhibitor Empaveli in paroxysmal nocturnal hemoglobinuria (PNH). Argenx just launched its FcRn inhibitor Vyvgart in generalized myasthenia gravis (gMG), and UCB is gunning for the same indication with late-stage FcRn candidate roznolixizumab and C5 inhibitor zilucoplan. Those advances come as AZ in December used a priority review voucher to speed up Ultomiris’ regulatory journey to gMG.

Pangalos pointed to Ultomiris’ ease of utilization in terms of infusion time and dosing frequency as being competitive. AZ has made Alexion a separate rare disease department, under management by former AZ chief financial officer Marc Dunoyer.

When it comes to convenience, AZ is expecting an FDA decision on a subcutaneous formulation of Ultomiris in its currently approved indications of PNH and atypical hemolytic uremic syndrome in the latter half of 2022. Argenx is close with topline phase 3 data for subcutaneous Vyvgart for gMG expected in the first quarter.

Competition in oncology

Outside of Pangalos’ purview, competition is also a key theme for Galbraith’s realm in oncology. One recent win from AZ’s oncology portfolio was Daiichi Sankyo-partnered Enhertu’s head-to-head victory against Roche’s Kadcyla in second-line HER2-positive breast cancer. In addition, armed with phase 3 data, both AZ’s Lynparza and Johnson & Johnson’s rival PARP inhibitor Zejula are aiming for combinations with J&J’s Zytiga in newly diagnosed metastatic castration-resistant prostate cancer.

RELATED: Fierce JPM Week: AstraZeneca cancer R&D head marks Imfinzi as 'core backbone' of oncology strategy with the right combo—including treme

Susan Galbraith
Susan Galbraith (AstraZeneca)

But the prospects for an immuno-oncology cocktail of Imfinzi and CTLA4 agent tremelimumab in previously untreated liver cancer are less certain. The combo cut the risk of death by 22% over Bayer’s Nexavar in the phase 3 Himalya trial in the disease setting. That was a smaller showing than the 41% reduction Roche posted for its own PD-L1 inhibitor Tecentriq’s combo with VEGF inhibitor Avastin.

For the liver cancer indication, AZ developed a novel regimen that involves priming the immune system with a single dose of treme to achieve long-lasting antitumor memory. AZ's Galbraith pointed to the long tail of the patient survival curve and as part of that, an “unprecedented” three-year survival rate, as an exciting result for the regimen.

For the Roche regimen, patients are required to undergo a check-up for enlarged veins known as esophageal varices before they can take Avastin. That procedure can cause delays in treatment initiation, Galbraith said. About a quarter to up to 40% or 50% of patients might be ineligible for the VEGF drug because of that restriction, she added, which leaves a large proportion of the market for Imfinzi and treme.

AZ now plans to file the Imfinzi-treme combo and Imfinzi monotherapy with the FDA in frontline liver cancer in the first half of the year. Filings for that combo and chemo as a first-line treatment for metastatic non-small cell lung cancer based on the phase 3 Posideon data have also been accepted by U.S. and EU regulators, with decisions expected in the second half of the year.