DUBLIN – Alexion Pharmaceuticals Inc. is loading up on 'Scandi' technologies to broaden its clinical and research pipeline, striking deals with Solna, Sweden-based Affibody AB on clinical-stage "affibody" drug ABY-039, which targets the neonatal Fc receptor (FcRn), and with Copenhagen, Denmark-based Zealand Pharma A/S on an alliance to develop up to four peptide-based therapies for complement-mediated diseases.
Affibody and Zealand will each receive $25 million up front. Privately held Affibody also stands to earn up to $625 million in development and commercial milestones, as well as low double-digit royalties on product sales. Zealand is pocketing an equity investment of $15 million and could earn up to $115 million in development milestones and another $495 million in sales milestones for the first product, as well as additional, discounted milestones on the other three potential products. Alexion would also pay a $15 million option fee to take forward molecules against any of the three additional targets.
ABY-039, which is in development for immunoglobulin-G(IgG)-mediated autoimmune diseases, is currently undergoing a phase I trial in healthy volunteers. Affibody has touted its best-in-class potential, owing to its combination of small size – it has a molecular weight of 19 kilodaltons or about one-eighth that of an antibody – and its long half-life, which is achieved by the addition of Affibody's proprietary albumin-binding half-life extension technology, Albumod.
It is an addition to, not a replacement for, Boston-based Alexion's existing portfolio of FcRn-targeting drugs, which it gained through its acquisition last year of Syntimmune Inc. for $400 million up front plus up to $800 million in milestones. (See BioWorld, Sept. 27, 2018.)
The main asset it acquired through that transaction, SYNT-001 (now called ALXN-1830), a humanized monoclonal antibody that also targets FcRn, is slated to enter phase III trials in two indications, warm antibody hemolytic anemia (WAIHA) and generalized myasthenia gravis, before the end of this year. "We used to say it's a pipeline in a product. Now we say it's a pipeline in two products," Alexion CEO Ludwig Hantson said during Alexion's investor day presentation Wednesday. "We will be disclosing the Affibody indication later in the year," he added.
Affibodies are based on a post-antibody scaffold derived from an immunoglobulin-binding domain of Staphylococcus aureus protein A.
Although the presence of bacterial amino acid sequences should raise alarm bells in terms of immunogenicity, that has not been encountered with Affibody's lead drug, ABY-035, which is undergoing a phase II trial in psoriasis, Alexion R&D chief John Orloff said on the investor call. "That's a potential area of risk we're going to have to address in our SAD/MAD [single ascending-dose/multiple ascending-dose] studies," he said.
Alexion has plenty of company in the FcRn space, which has attracted several drug developers seeking to cut levels of pathological autoantibodies by targeting one of the body's key recycling mechanisms that help to maintain high circulating levels of antibody. Indeed, its plan to move ALXN-1830 into myasthenia gravis was inspired by the progress of a rival antibody, efgartigimod (ARGX-113), for which Argenx SE, of Breda, the Netherlands, established clinical proof of concept last year. A phase III trial of efgartigimod is now underway.
Alexion already has a commercial presence in myasthenia gravis. Its flagship product, the complement C5 inhibitor Soliris (eculizumab), gained FDA approval in 2017 for generalized myasthenia gravis, treating patients who produce antibodies directed at the acetylcholine receptor. It plans to move its long-acting successor, Ultomiris (ravulizumab-cwvz), into phase III development in the same indication this year. Ultimately, it aims to cover the entire patient spectrum, positioning ALXN-1830 for those with milder disease while offering Soliris and, later Ultomiris, for more severe cases.
Meanwhile, Alexion's deal with Zealand will further extend its complement-targeting efforts. The lead program entails complement C3, which is upstream from the C5 cleavage reaction that both Soliris and Ultomiris target.
The deal vindicates a decision by Zealand to diversify its peptide discovery research away from niche gastrointestinal and metabolic disease indications. "We've been working on the complement C3 opportunity for over two years," Zealand Pharma's chief medical and development officer and interim CEO, Adam Steensberg, told BioWorld. "We've managed to make something that has a very attractive half-life and is easy to administer."
It is formulated as a ready-to-use product, which patients can themselves inject at home.
The molecule is on course to enter the clinic in 2020. The lead indication has not yet been disclosed, but Alexion will make the call in any case. "There are several indications we could go for," Steensberg said. The partners have not disclosed the other three targets, either. "We see broad therapeutic application across multiple disease areas," Alexion's head of research Sharon Barr said on the investor call. Zealand has already shown its mettle in peptide drug development, having racked up a European approval in diabetes for Lyxumia/Adlyxin (lixisenatide), a GLP-1 agonist, as far back as 2013 and an FDA approval for the same product in 2016. "I think the technology has been proven. We've looked at it carefully for the targets we're interested in," Orloff said.
Shares in Zealand Pharma (COPENHAGEN:ZEAL) closed Wednesday at DKK113.20 (US$17.34), a gain of 6.2 percent on its previous close.