Will Vertex’s “pipeline-in-a-product” pay off?
That’s the bet behind the company’s $4.9 billion acquisition of Alpine Immune Sciences and its mid-stage IgA nephropathy drug, which is designed to inhibit two key cytokines.
The companies announced the deal last week, touting povetacicept’s potential in IgA nephropathy (IgAN) and hinting at its broader ambitions to treat autoimmune conditions.
Jeff Leiden“Pove holds the promise of a pipeline-in-a-product for a number of B cell-driven serious diseases,” Vertex chair Jeff Leiden said during an April 10 investor call. “This reminds me very much of the potential we saw in Humira in the early days of biologics for the treatment of autoimmune diseases.”
Given the lack of disease-modifying treatments for IgAN, povetacicept and other drugs in its class may address a significant unmet need if they reach the market. Jefferies analyst Michael Yee said the drug could achieve $3 billion in peak IgAN sales in the US.
But some experts interviewed by Endpoints News said povetacicept is not necessarily one-size-fits-all. Systemic lupus erythematosus (SLE) may be a trickier indication due to a competitive clinical pipeline and market spanning a range of drug classes. But lupus nephritis could offer a better opportunity due to safety concerns with the standard of care.
Despite the validity of povetacicept’s mechanism in B cell-driven autoimmune diseases, success in each indication depends on competition, treatment dynamics and the degree of unmet need.
“Given Vertex’s existing programs in renal diseases and hematology, we have strong expertise in these fields and believe have the opportunity to further accelerate development of povetacicept,” a company spokesperson wrote in an email.
SLE vs. lupus nephritis
Povetacicept is a dual inhibitor of a proliferation-inducing ligand (APRIL) and B cell activating factor (BAFF). These cytokines are overexpressed in IgAN, triggering overactivity of the immune system and a buildup of immunoglobulin A proteins in the kidney’s glomeruli.
“Most IgaN patients end up on the kidney transplant registry, permanent dialysis or pass away,” William Blair analyst Myles Minter said, adding the “largely untapped market” was in need of new treatment options.
The APRIL/BAFF pathway is “likely to be important in many antibody-mediated kidney diseases,” said Jonathan Barratt, professor of renal medicine at the University of Leicester. One example is lupus nephritis, where povetacicept is in early development as part of a Phase 1b/2a basket trial of glomerular diseases.
Abdallah GearaIn lupus nephritis, clinicians are looking for safer alternatives to rituximab, which has a high risk of infection, said Abdallah Geara, clinical director of the glomerular disease program at Penn Medicine. He added that APRIL/BAFF inhibitors have the most potential in lupus nephritis and IgAN.
Povetacicept is also in Phase 2 development for SLE. Stifel analyst Alex Thompson said that “BAFF inhibition alone works” in the disease, but “the question of whether or not [additional] APRIL [inhibition] will help is still an open one.”
In 2011, GSK’s BAFF inhibitor Benlysta won FDA approval for certain SLE patients. The indication is much more competitive than IgAN, Minter said. SLE patients also tend to have waxing and waning periods with their treatment, he added, which means less consistent sales of any SLE therapies.
Povetacicept is also in a Phase 1b basket study in autoimmune cytopenias.
“Targeting the maturation of B cells towards plasma cells, which are actually the ones that produce autoantibodies, does give you a lot of optionality for de-risking a broad set of autoimmune diseases,” Thompson said.
The race for better IgAN therapies
IgAN is an orphan disease that affects around 60,000 people in the US. While a few new therapies have been approved in recent years, there is still room for more efficacious drugs.
Calliditas Therapeutics’ delayed release steroid Tarpeyo was the first IgAN drug to get an FDA thumbs-up. It won accelerated approval in 2021, and was later converted to a full approval. Travere Therapeutics’ Filspari won an IgAN accelerated approval in 2023, though it came with a risk evaluation and mitigation strategy.
Neither drug, however, addresses estimated glomerular filtration rate (eGFR). “You’re not getting stabilization of eGFR [with these drugs] so [patients] are still progressing towards the stage of needing a kidney transplant,” Minter said. “You’re just delaying that progression.”
APRIL/BAFF inhibitors like povetacicept, on the other hand, have the potential to stop disease progression.
In a Phase 2 trial, once-monthly povetacicept achieved a 64.1% reduction from baseline in urine protein to creatinine (UPCR) ratio at 36 weeks, per an Alpine release.
Marshall FordyceThe FDA has a threshold of 30% UPCR reduction relative to placebo at around 39 weeks for accelerated approval in IgAN, Vera Therapeutics CEO Marshall Fordyce said. Vera has an APRIL/BAFF inhibitor, dubbed atacicept, that’s in late-stage trials for IgAN and lupus nephritis.
In the Phase 2b ORIGIN trial, once-weekly atacicept attained a 48% reduction in UPCR at 72 weeks, per a Vera release. The drug is now in the Phase 3 ORIGIN 3 trial with patient enrollment set to complete in the second half of the year.
With the caveat of cross-trial comparison, Stifel’s Thompson said “Alpine’s data at this point looks nominally better” than Vera’s. Plus, povetacicept offers a less frequent dosing regimen. Nonetheless, atacicept is further along in clinical development, and that could make it an “attractive asset” for potential deals, according to William Blair’s Minter.
Fordyce said Vera is in “ongoing conversations” for atacicept business development opportunities, but declined to comment on specifics.