Atrasentan

The proteinuria reductions shown by Travere Therapeutics' Filspari and Novartis' Fabhalta and atrasentan in their respective phase 3 trials were largely similar, despite differences in trial design. A year after missing on a trial endpoint, Travere Therapeutics can breathe a sigh a relief. The FDA has converted Filspari’s conditional nod in the kidney disease IgA nephropathy (IgAN) into a full approval.As part of the conversion Thursday, the FDA has removed a specific urine protein level requirement from Filspari’s label. Now, the only condition for treatment with Filspari is that patients be at risk of disease progression.The adjustment will allow Filspari to reach more patients who’re at lower risk of progression, Travere CEO Eric Dube, Ph.D., said in a recent interview. The company will be able to promote Filspari’s ability to preserve kidney function, and the full approval could give more doctors confidence to start using the drug, he added.During a drug launch, “those later adopters oftentimes look for things like guidelines, support or advocacy from their peers, or in this case, also full approval,” Dube said. “So we do expect that there’s going to be a broader set of nephrologists prescribing.”Filspari secured its accelerated approval in February 2023 based on phase 3 data showing it could significantly reduce proteinuria (protein in the urine) compared with irbesartan after 36 weeks of treatment. Proteinuria is a prominent measure of kidney function, with elevated levels being associated with serious kidney disease.The drug was the first non-immunosuppressive drug approved for IgAN, a rare autoimmune disease that causes damage to the kidney. Travere’s original plan was to use longer-term kidney function outcomes—as measured by the estimated glomerular filtration rate (eGFR)—to support a full approval. But in September, the company said the trial, coded PROTECT, had narrowly missed statistical significance on that endpoint.Still, pointing to a consistent treatment effect across various measurements and in patients with different base levels of proteinuria, Travere filed for full approval anyway after receiving positive feedback from the FDA.The full approval is now based on a modified analysis of 404 randomized patients. Unlike the original plan, this analysis counted patients who discontinued treatment early on. The previous analysis favored irbesartan because the comparator arm had a higher rate of early discontinuation mostly thanks to lack of treatment effect.As the new label shows, Filspari significantly reduced the rate of decline in kidney function from baseline to Week 110 compared to irbesartan. The average eGFR slope from baseline to Week 110 was -3.0 mL/min/1.73 m2/year for Filspari and -4.2 mL/min/1.73 m2/year for irbesartan, corresponding to a statistically significant effect of 1.2 mL/min/1.73 m2/year. Another element that previously gave Travere confidence came from a public comment made by the FDA’s deputy director of the cardiology and nephrology division, Aliza Thompson, M.D., at the American Society of Nephrology 2023 meeting, where the updated PROTECT data were presented. During a session on IgAN, Thompson said the FDA’s understanding of the eGFR slope endpoint is evolving and that the agency is looking to move away from the complex marker because clinicians don’t completely understand it, Travere’s chief medical officer, Jula Inrig, M.D., recalled in Fierce's joint interview with Dube.Increased competition Since Travere announced the eGFR readout, the FDA has handed out two IgAN approvals. The first full FDA approval for an IgAN drug, also converted from a previous accelerated approval, was given to Calliditas Therapeutics’ Tarpeyo in December 2023. That conversion was based on eGFR data spanning a two-year period, but with placebo as the comparator. Because Tarpeyo uses the traditional steroid approach with the active ingredient budesonide, it’s not considered a direct threat to Filspari, which is an endothelin type A (ETA) receptor and angiotensin receptor inhibitor.Then the FDA in August handed Novartis’ complement inhibitor Fabhalta an accelerated approval. The Swiss pharma’s selective ETA receptor inhibitor, atrasentan, is also under FDA review.The proteinuria reductions shown by Fabhalta, atrasentan and Filspari in their respective phase 3 trials were largely similar despite differences in trial designs and patient characteristics. Travere’s trial was a head-to-head between Filspari and the angiotensin II receptor blocker (ARB) irbesartan, while the Novartis trials are comparing its new drugs against placebo in patients who’re also on supportive care, including ARBs and ACE inhibitors.Filspari can be considered a combination in one tablet because of its dual mechanism of action, whereas atrasentan is an add-on to existing drugs.  Novartis has argued that atrasentan's add-on nature could enable a smooth transition and little disruption to a patient’s existing treatment routine. But to Travere’s Dube, adding a new pill may not be a winning formula from a psychological perspective.“For a patient that has to add on to an ACE or an ARB, they feel like they’re getting worse,” Dube said. Filspari, by replacing an existing med with better efficacy, could give patients a feeling of winning, which will influence doctors’ treatment decisions, he said.“Keep in mind, these are young patients that have decades of life ahead of them,” Dube said. “So the fewer medicines and the more effective medicines we can put them on, the better off they’re going to be.”Besides convenience for patients, a single pill also gives physicians assurance that patients are compliant. For a serious disease where the consequence is kidney failure, that reassurance is important, Dube said. “We know there’s a very robust literature within the chronic diseases, including chronic kidney disease and hypertension, where there is a factor of pill burden, where the more pills you’re on […] you do have a decrement in compliance and persistence,” Dube added.However, analysts at Leerink Partners previously pointed out that having separate pills allows doctors the flexibility to adjust the dose of each therapy. But Dube and Inrig argued that the ability to titrate medicine is a very academic concept that’s rarely adopted in real-world clinical practice. Monitoring for liver toxicity But in one disappointment for Travere, the FDA’s full approval has kept a liver monitoring requirement in Filspari’s boxed warning. Because of a potential risk of liver toxicity, Filspari patients are asked to be tested for liver functions monthly for the first year, and then every three months, during treatment. Novartis’ Fabhalta doesn’t have that warning.Inrig argued that educating doctors and patients upfront about safety will help ensure good uptake of Filspari. The FDA’s concern mostly stemmed from past cases with some endothelin receptor antagonists, while Filspari itself has not seen any cases of drug-induced liver injury.As for the tests themselves, Inrig noted the requirement shouldn’t be too burdensome because 90% of patients who are at moderate risk for progression are already seeing their nephrologists and getting lab tests done every three months.Travere is collecting more data on Filspari, including its real-world experience, to potentially ask the FDA to modify the requirement in the future, Dube said. So far, Filspari’s launch has been going well. The drug brought in $27.1 million in sales in the second quarter of the year, coming 37% above the prior quarter and ahead of analysts’ consensus of $24.7 million.Travere is exploring potential combinations for Filspari, including with SGLT-2 inhibitors, in IgAN. Dube argued that the drug’s ability to replace existing ACE and ARB drugs positions it well as a combination partner.Elsewhere, Travere hasn’t given up on Filspari in another kidney disease, focal segmental glomerulosclerosis (FSGS), after it had failed the primary endpoint in a phase 3 trial, which looked at the eGFR slope. A collaborative global project called PARASOL is examining the relationship between proteinuria and kidney failure in FSGS to potentially support the marker as a surrogate endpoint for regulatory approvals, Inrig noted. Once Travere gets a clearer understanding of that pathway likely this year, it plans to reengage with the FDA about a potential filing, Dube said. 

As well as the significant starter funds, Borealis is also stepping into the spotlight complete with $100 million in upfront and near-term cash from a licensing deal with Novartis. Novartis’ $3.2 billion deal for Chinook Therapeutics gave the Swiss Big Pharma such a taste for kidney disease-focused biotechs that it has partnered with VC firm Versant Ventures to create another company in a similar mold.Borealis Biosciences, which emerged from stealth today armed with $150 million in series A funds, has been created around a focus on “many key members of Chinook’s Vancouver-based research team,” according to Versant, which also founded Chinook.Borealis, which was jointly launched by Novartis and Versant, is working on next-generation RNA medicines for kidney disease, with the aim of harnessing recent industry breakthroughs like “an improved understanding of patient stratification, genetically defined targets, requirements for delivery of therapeutic payloads to specific kidney cell types, and RNA chemistry advancements,” according to an Aug. 22 release.As well as the significant starter funds, Borealis is also stepping into the spotlight complete with $100 million in upfront and near-term cash from a licensing deal with the Big Pharma that “complements Novartis’ priorities in renal medicine and xRNA technology platform innovation," according to the release. Under the deal, Borealis will be in line for up to $750 million in milestone payments should Novartis take up its option of acquiring two development-ready programs from the biotech and continuing their journey to regulators.“Novartis is committed to bringing forward new therapeutic options for patients with kidney diseases,” Fiona Marshall, President of Biomedical Research at Novartis, said in the release.“We believe Borealis will foster an ideal environment for an exceptional founding team to continue to pioneer renal science and drug discovery, and we are delighted to work with Versant on a partnership that exemplifies creative, collaborative dealmaking to enable the launch of this innovative biotech,” Marshall added.Borealis’ 25-person team will be based at a 23,000-square-foot operating site in Vancouver that was previously leased by Chinook. Versant said the biotech’s employees comprise “experienced drug hunters with extensive expertise in kidney disease, translational systems biology and data sciences, translational biology, chemistry, DMPK and pharmacology.” “Despite recent advances for patients with IgA nephropathy (IgAN), many other forms of highly prevalent kidney disease remain unaddressed,” Versant said in the release. “The understanding of patient subpopulations and distinct underlying pathologies has improved significantly in recent years, but some of the most validated, causal targets have not been amenable to traditional small molecule or biologic modalities.”It’s perhaps unsurprising that both Novartis and Versant want to repeat the success of Chinook. It only took a few months after the Big Pharma’s acquisition for Chinook’s oral endothelin A receptor antagonist atrasentan to demonstrate its value by significantly improving proteinuria in a phase 3 study in patients with IgA nephropathy (IgAN).Another IgAN asset from Chinook, called zigakibart, is also in phase 3 development at Novartis.Just a couple of weeks ago, Novartis' own iptacopan scored FDA approval in IgAN. That drug, marketed as Fabhalta, gained its original FDA nod in paroxysmal nocturnal hemoglobinuria late last year.