Novartis rides IgAN trioka to 2 trial wins in rare kidney diseases
28 May 2024
Clinical ResultPhase 3Drug ApprovalAccelerated ApprovalPriority Review
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Source: FiercePharma
Novartis is developing three drugs against the kidney disease IgAN. In recent days, the company shared updates on two of them.
Novartis is eyeing an FDA filing for a second drug in immunoglobulin A nephropathy (IgAN), as the Swiss pharma goes all-in on the rare autoimmune kidney disease from three different angles.
Novartis plans to submit atrasentan to the FDA by the end of June for a potential accelerated approval in IgAN based on positive data from the phase 3 ALIGN trial. In the study, atrasentan led to a significant 36.1% relative reduction in proteinuria compared with placebo after 36 weeks of treatment, according to results presented at the European Renal Association Congress.
Atrasentan could be a potential competitor to Travere Therapeutics’ rival drug Filspari (sparsentan). But as analysts from William Blair and Leerink Partners suggested, the Novartis med does not seem to have the upper hand.
An IgAN showdown
Heading into atrasentan’s 36-week readout, investors were expecting to see at least a 40% placebo-adjusted urine protein reduction because of earlier readouts based on small patient populations and shorter treatment periods, Leerink analysts pointed out in a Monday note.
The Novartis drug pulled off a 38.1% reduction in proteinuria, as measured by urine protein to creatinine ratio (UPCR), versus 3.1% for placebo. Both groups also received standard supportive care.
By comparison, in the phase 3 PROTECT trial, Travere’s Filspari was associated with an average reduction in proteinuria of 49.8% after 36 weeks, compared with 15.1% for off-label irbesartan. This translates into a 41% relative reduction for Filspari.
The two drugs’ trials enrolled roughly similar populations, with some slight differences such as baseline UPCR that are not likely to significantly change the outcome or interpretation of results, William Blair analysts wrote in a Tuesday note. However, a notable difference in the percentage of Asian patients might be a confounding factor for a cross-trial comparison, the team added.
Despite the differences between the trials, atrasentan does not appear to be differentiated versus Filspari, Leerink’s analysts said. A recent Leerink survey suggested that doctors would split their use of Filspari and atrasentan equally.
Travere’s Filspari may have two advantages. First of all, Filspari already boasts an accelerated approval in IgAN since February 2023, and Travere has already filed for a full approval with a target decision date in September. That gives Filspari a roughly two-year head start against Novartis’ atrasentan, the William Blair team noted.
Secondly, Filspari could reduce the number of pills patients have to take, which is an important consideration for many with IgAN, Leerink analysts noted. Filspari is a dual endothelin angiotensin receptor antagonist, while atrasentan inhibits the endothelin A receptor alone. Filspari’s mechanism eliminates the need for an angiotensin receptor blocker such as irbesartan, which is part of the standard of care for IgAN.
However, having separate pills allows doctors to adjust the dose of each therapy for a patient, the Leerink team added. In the end, “choosing between the two will likely come down to a case-by-case decision, as well as which therapy is covered by payers/has an easier path to authorization,” the Leerink analysts said.
Filspari’s early launch has been progressing nicely, with about 2,000 patient start forms received by the end of March. The drug missed statistical significance on its confirmatory trial endpoint—change in estimated glomerular filtration rate (eGFR) slope, a measure of kidney function—in the PROTECT trial. But Travere believes the results observed in the study could convince the FDA and doctors of its benefits.
The confirmatory evidence flop leaves a window open for Novartis’ atrasentan to potentially differentiate itself with an eGFR win. Atrasentan’s ALIGN study remains ongoing and blinded toward its final eGFR analysis, which is expected in 2026. Plus, Filspari is still only penetrating a very small corner of the IgAN at this stage, and there remains significant room for a competitor, Willima Blair analysts aid.
IgAN troika
Atrasentan, which Novartis believes carries blockbuster potential, is one of the three drugs that the company is advancing in IgAN. Fabhalta, an oral factor B inhibitor, recently showed a 38.3% relative proteinuria reduction versus placebo in the phase 3 APPLAUSE-IgAN trial. The drug got its initial FDA approval in December for paroxysmal nocturnal hemoglobinuria (PNH), and Novartis has filed the IgAN indication with a decision now under priority review.
At the ERA Congress, Novartis also shared phase 3 results for Fabhalta in an ultra-rare kidney disease called C3 glomerulopathy. In the APPEAR-C3G study, patients who got Fabhalta achieved a 35.1% reduction in proteinuria compared with placebo after six months of treatment. Novartis plans to file for the indication based on that surrogate endpoint in the second half of this year. At this point, on the eGFR endpoint, Fabhalta showed a numerical improvement of 2.2mL/min/1.73m2.
The IgAN candidates target the kidney disease differently, and their ultimate positioning, including sequencing or combinations, will partly be defined by the data they generate, Shreeram Aradhye, M.D., said in a January interview with Fierce Pharma.
With Fabhalta, Novartis is targeting the alternative complement pathway. Overactivation of the pathway and deposition of the complement protein could cause kidney damage. So Fabhalta is intervening through that pathogenic mechanism of the injury, Aradhye explained.
Atrasentan, by targeting the endothelin receptor, inhibits excess proliferation and inflammatory signaling in mesangial cells, which are involved in IgAN.
The third agent, zigakibart, is a subcutaneous anti-APRIL antibody. Aradhye said the drug has the potential to be disease-modifying because it intervenes at an early stage when abnormal IgA is formed. Its phase 3 IgAN readout is expected in 2026, and Novartis also has blockbuster hopes for that drug.
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