Zigakibart

Novartis has positioned Vanrafia as a “foundational therapy” in IgAN because it can address a broad population of patients with persistent proteinuria, the company’s U.S. president, Victor Bulto, told Fierce Pharma. When Novartis bought kidney disease biotech Chinook Therapeutics in 2023 for $3.2 billion upfront, the deal included a conditional payment tied to the timely FDA approval of atrasentan without a specific safety restriction.Now, investors in Chinook can claim an additional $2-per-share payout, or about $160 million in total, as the milestone has been met.The FDA has granted an accelerated approval for atrasentan to reduce elevated protein in the urine in adults with primary immunoglobulin A nephropathy (IgAN) at risk of rapid progression, Novartis said Wednesday.Bearing the commercial moniker Vanrafia, the selective endothelin A receptor antagonist (ERA) does not have to be used under an FDA-mandated safety-related program called REMS. A sans-REMS FDA approval for the drug in IgAN before the end of 2025 was needed to trigger a $2-per-share contingent value right (CVR) payment under Novartis’ merger agreement with Chinook.The special CVR arrangement highlights how important having a non-REMS label is for Novartis.The lack of a REMS requirement sets Vanrafia apart from Travere Therapeutics’ Filspari— which acts as both an ERA and an angiotensin receptor blocker (ARB)—for now. Filspari got its IgAN nod in 2023 and is only available through a REMS program mainly because of a potential risk of liver toxicity, which is also reflected as a boxed warning item on the drug’s label.However, a step ahead of Novartis, Travere last fall turned Filspari’s accelerated approval into a full go-ahead based on evidence that it can preserve kidney function. So far, Travere said the REMS program does not appear to pose a barrier for Filspari patients. The drug’s 2024 sales also suggested a good launch progress, with its $132 million beating analysts’ consensus estimates. However, as Leerink Partners analysts pointed out in a March note, “the question is, how many more patients are out there that might be a candidate with a looser REMS?”Both Novartis and Travere are trying to level the playing field against each other.For Travere, the biotech has submitted an application to the FDA to potentially reduce the REMS liver monitoring requirement from monthly testing to quarterly in the first year. The FDA has set a decision date of Aug. 28 this year.For Novartis, the company is collecting longer-term data for Vanrafia in the hopes of also showing a kidney function benefit to support a traditional approval.Novartis has positioned Vanrafia as a “foundational therapy” in IgAN because it can address a broad population of patients with persistent proteinuria, the company’s U.S. president, Victor Bulto, said during a recent interview with Fierce Pharma.In the phase 3 Align trial, Vanrafia led to a 36% reduction in proteinuria as measured by the urine protein-to-creatinine ratio (UPCR) compared with placebo after 36 weeks of treatment.  For Travere's Filspari, the result was a 35% reduction in UPCR at week 36 versus control, in its own IgAN trial called Protect.Because the two meds feature different mechanisms, their trials were designed differently. While Filspari was pitted directly against the ARB drug irbesartan, Vanrafia was tested against placebo in patients who were on maximally tolerated renin angiotensin system inhibitor, such as an ARB.As Filspari is a drug with dual mechanisms, it offers the convenience of a single drug, whereas Vanrafia is used on top of other agents. Novartis has argued that separate dosing allows doctors to adjust the dosage of each drug component, although Travere has contended that titration is more of an academic question than a real-world practice.Vanrafia is Novartis’ second IgAN drug to reach the market. Before that, the company’s complement inhibitor Fabhalta expanded into IgAN in August 2024. Another Chinook agent, the anti-APRIL antibody zigakibart, is also being developed for the rare kidney disease.With Fabhalta’s launch, Novartis is targeting patients with residual inflammation and activation of the complement pathway, Bulto said. This subgroup represents about 15% to 30% of at-risk patients with persistent proteinuria who are typically eligible for novel treatments.By comparison, Novartis believes Vanrafia can be used in all 45,000 U.S. IgAN patients potentially eligible for new therapies.“What we do fully expect is that this is going to be a combination market, given that heterogeneity [of disease manifestation], and that’s why we want to bring all the different tools that physicians may need to treat this disease,” Bulto said. In addition to IgAN, both Novartis and Travere are targeting other rare kidney diseases.Fabhalta a few days ago became the first FDA-approved agent for complement 3 glomerulopathy (C3G). Travere has recently filed Filspari for focal segmental glomeruloscelrosis (FSGS) despite missing the primary endpoint of a phase 3 trial.Novartis believes its commercial prowess and broad offerings may give it an edge.“By constructing the portfolio like this, like a multi-indication, multi-asset, it also creates compounding capabilities and expertise,” Bulto said.There are about 9,000 nephrologists in the U.S. who each treat about three IgAN patients and one C3G patient, so deploying a commercial force “for a single asset is a very difficult task,” the Novartis exec noted.“That’s why we just want to double down here in the space,” Bulto said. “I think that, in itself, will create a good competitive differentiation, which ultimately will help patients.”

One of Novartis’ most important clinical catalysts of the year came Thursday, with the accelerated approval in the US of its rare kidney disease drug. Atrasentan, which is now named Vanrafia, is a once-daily pill that may be used to treat protein accumulation in patients with primary IgA nephropathy (IgAN). Specifically, the drug may be used in patients at risk of rapid disease progression, which is generally defined using the urine protein-to-creatinine ratio, according to a release . The drug can be added on top of supportive care, such as the widely used renin-angiotensin system inhibitors, with or without the kidney disease meds known as SGLT2 inhibitors. Novartis has not yet disclosed the list price for Vanrafia. IgAN is a chronic disease that occurs when abnormal antibodies build up in the kidney’s tiny filters, which can damage the organ. Some people who have IgAN eventually require dialysis or a transplant. Importantly, the FDA did not require a risk evaluation mitigation strategy (REMS) program for Vanrafia. But patients must have their liver enzyme levels tested before and during treatment “when clinically indicated,” according to Novartis, as some similar drugs have been linked with increases in aminotransferases, hepatotoxicity and liver failure. The company also warned that Vanrafia may cause serious birth defects. Unlike Travere Therapeutics’ Filspari, which won full approval last year for the disease, Vanrafia is not subject to a drug safety program, or REMS. Filspari is only available via a REMS because of risk of liver toxicity and birth defects. Vanrafia, a selective endothelin A receptor antagonist, was approved on the strength of the ALIGN trial. In that study, it demonstrated a significant 36.1% cut in proteinuria, compared with placebo, after 36 weeks of treatment. Reduction in protein in the urine is a surrogate biomarker for improvement in IgAN, though, and may not translate into actual clinical benefit. And so the ALIGN trial is continuing, with the aim of showing a decline in patients’ estimated glomerular filtration rate (eGFR), a measure of kidney function. Those data could come next year, and the Swiss pharma hopes they will support full FDA approval. But if no benefit on kidney function is seen, the drug could be withdrawn. Two other IgAN drugs — Calliditas Therapeutics’ Tarpeyo and Travere’s Filspari — also gained accelerated approval based on proteinuria reductions. However, when it came to their confirmatory eGFR readouts, Tarpeyo managed a hit and converted to full approval, but Filspari did not — despite posting a stronger effect on proteinuria. As far as Novartis is concerned, that is a problem for the future. Its focus now is on ramping up sales. Novartis obtained Vanrafia via its $3.2 billion acquisition of Chinook Therapeutics in 2023, and the pill will have to do well commercially to help justify that deal. Novartis US President Victor Bultó told Endpoints News ahead of the FDA decision that the company expects atrasentan to reach blockbuster status worldwide. He said that Novartis expects about a population of about 45,000 in the US to be eligible to receive the drug. The company has another Chinook-originated IgAN asset in zigakibart. A subcutaneous anti-APRIL antibody, zigakibart is currently in Phase 3 trials, with results expected in 2026. Novartis has yet another IgAN drug, Fabhalta, which was developed in-house and got US accelerated approval last August . Its pivotal study is continuing, and kidney function data could come late this year. In an interview, Bultó explained that the three treatments tackle the heterogeneous disease in different ways. “For many patients, the damage to the kidney has already happened, so you will need to manage the damage with drugs like atrasentan, drugs like iptacopan [Fabhalta]. What we will do with zigakibart hopefully — the anti-APRILs — is try to work upstream so that damage is minimized and we can treat as soon as possible,” said Bultó. “When we talk with nephrologists, they fully anticipate this to be a combination market, given the heterogeneity of the patients, and today, about 60% of them are already multiple therapies trying to slow down that proteinuria and that progression.” Editor’s note: This article was updated to include further comments from Novartis.