AstraZeneca's Alexion hopes to extend dominance in PNH as Big Pharma competitors close in

For years, Alexion has been the only name in the game for a blood disease called paroxysmal nocturnal hemoglobinuria (PNH). Now, a number of Big Pharmas want in, vying to show their candidates can go head-to-head with the AstraZeneca unit's market-leading therapies Ultomiris and Soliris.

The pharmas waiting in the wings include Roche, which is teeing up its antibody crovalimab for potential approval for PNH in China. Meanwhile, Apellis’ Empaveli won FDA approval in the indication last year, giving patients a subcutaneous alternative to AstraZeneca’s intravenous incumbents, while in October Novartis showed its oral candidate iptacopan was also capable of taking on Alexion’s market leaders.

The dominance in PNH is one of the reasons AstraZeneca’s acquisition of the rare-disease-focused Alexion looked like such a good move in 2020. The rare, acquired, life-threatening disease is characterized by destruction of red blood cells, blood clots and impaired bone marrow function. Soliris became the first FDA approved therapy for the condition in 2007, followed in 2018 by Ultomiris, which requires fewer intravenous infusions.

It's not hard to see why competitors have now come calling. Soliris raked in $2.92 billion for AstraZeneca in the first nine months of the year, while its sibling Ultomiris took in a respectable $1.37 billion. Between them, the two therapies account for the vast majority of the British-based drugmaker’s rare disease revenue.

“Alexion was the first company to harness targeting the complement system to try and bring complement therapies to patients with rare diseases,” said Anita Hill, M.D., Ph.D., Alexion’s global medical affairs lead for hematology and nephrology. “Maybe [Alexion] has set a pathway for others to explore that science.”

So with such a tantalizing prize at stake, what’s Alexion’s plan to retain the PNH crown? While not wanting to get drawn into direct comparisons with any competitors, Hill points to the so-called "factor D program" as the next focus of the unit’s efforts.

Most PNH treatments in the clinic, as well as Ultomiris and Soliris, inhibit the C5 protein in the terminal complement cascade, a part of the body's immune system. Alexion hopes that inhibiting an enzyme called factor D will help a specific group of PNH patients whose extravascular hemolysis (EVH) results in anemia, despite being on Ultomiris or Soliris. EVH occurs when a type of white blood cell normally found in the liver and spleen ingests antibody-coated red blood cells.

In essence, the aim of all PNH treatments is to induce so-called terminal complement inhibition. Uncontrolled complement activation can lead to the complications of PNH such as kidney damage, blood clots or EVH.

“Factor D is not an acute phase reactant, so it will not increase at the times of stresses such as infection or inflammation,” Hill told Fierce Biotech in an interview. “We believe therefore that factor D will be an easier target, potentially, to maintain that sustained complement inhibition that patients with PNH really need to avoid devastating complications.”

One of Alexion's two factor D candidates in the clinic is vemircopan. In an interim analysis of nine treatment-naïve patients in a phase 2 trial presented at the annual American Society of Hematology meeting last weekend, Alexion showed the therapy was able to both control intraventricular hemorrhage by reducing an enzyme called lactate dehydrogenase to almost normal levels, as well as prevent EVH.

“We demonstrated that there were no safety concerns and that we could improve the hemoglobin by more than two grams per deciliter,” Hill explains.

The data set up the drug to move into phase 3 trials, although Hill wouldn’t set out a specific timeline.

Alexion’s other factor D hopeful is danicopan. Unlike vemircopan, which Alexion intends as a monotherapy, danicopan is intended to be used as an add-on to its established players Ultomiris and Soliris. A phase 3 readout in September met the primary endpoint of changing hemoglobin levels from baseline at 12 weeks for PNH patients with EVH. The study also hit key secondary endpoints including patients not requiring a blood transfusion and a reduction in fatigue.

Following this late-stage success, Alexion told Fierce it intends to proceed with regulatory submissions for danicopan “in the coming months.”

By targeting a specific subset of patients whose anemia means they don’t enjoy the full benefits of approved treatments, Alexion has found new PNH challenges to address. Despite competitors queuing up to take their shot at the PNH top spot, Hill sounds confident that Alexion has more to contribute in this space and that the reign of Ultomiris and Soliris will continue.

“A primary goal for any [PNH] treatment has to be to achieve complete and sustained terminal complement inhibition,” Hill says. “We know that our C5 inhibitors can do that. That's why [they’ve] been the standard of care for nearly two decades in many countries and will remain the standard of care until we know whether that can be achieved from any of the treatments.”