Novartis’ Fabhalta Gets FDA Approval for Rare Complement Blood Disorder

After receiving US Food and Drug Administration (FDA) approval for Fabhalta (iptacopan) last week for the treatment of the rare blood disorder paroxysmal nocturnal hemoglobinuria (PNH), Novartis presented trial data yesterday showing the drug’s promise in another indication.

Fabhalta, the highly anticipated factor B inhibitor touted to be a blockbuster by industry analysts, is the first FDA-approved oral monotherapy for PNH.

Less than a week after the approval, Novartis shared results from its APPEAR-C3G Phase III study of patients with C3 glomerulopathy (C3G) that showed iptacopan led to clinically meaningful reduction in proteinuria (protein in the urine) compared to placebo after six months of use.

Also yesterday, Novartis announced results from the extension period of one of its Fabhalta PNH trials, the pivotal Phase III APPLY-PNH trial. Results showed that continuous Fabhalta treatment for 48 weeks led to sustained hemoglobin-level increases to near-normal levels, reducing/avoiding the need for blood transfusion and reduced patient-reported fatigue in most patients.

PNH is caused by a mutation in the CFB gene that codes for complement factor B, a component of the alternative pathway of complement activation. Mutations in the gene result in the production of red blood cells that are prone to premature destruction (hemolysis). This can cause anemia, bone marrow failure and thrombosis among other symptoms. The disorder affects ten to 20 individuals per one million worldwide.

With its first FDA approval for Fabhalta locked down, Novartis has big plans for it in other complement dysregulated renal and hematological diseases. In addition to C3G, these include primary immunoglobulin A nephropathy (IgAN), also known as Berger’s disease, atypical hemolytic uremic syndrome (aHUS) and immune complex membranoproliferative glomerulonephritis (IC-MPGN).

Analysts at Jefferies predict iptacopan’s peak sales potential to be $3.6 billion.

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Fabhalta is a factor B inhibitor that regulates the destruction of red blood cells, developed for diseases like PNH that are driven by dysregulation of the immune complement system.

Novartis estimates that there are about 6,000 PNH patients in the US and one-third of them are treated with complement inhibitors — these include AstraZeneca’s blockbusters Soliris (eculizumab) and Ultomiris (ravulizumab-cwvz). Novartis hopes to replace these drugs and also increase treatment rates in the 70 percent of patients who aren’t already on therapy.

C3G is another ultra-rare disease caused by the overactivation of the complement pathway that results in protein buildup in the kidney. There are currently no treatments that address the root cause of C3G. Within ten years of diagnosis, approximately 50 percent of patients with C3G have kidney failure, and of transplant recipients, 55 percent experience disease recurrence. C3G is diagnosed in one to two people per million globally and presents mostly in children and young adults.

The FDA nod for Fabhalta in PNH was based on two Phase III trials involving PNH patients who had either previously received other PNH treatments such as C5 inhibitors or who had not. In the first study, treatment with Fabhalta led to sustained hemoglobin increases in 82 percent of participants compared to no increases in those who continued to receive C5 inhibitor treatment. In the other trial, about 78 percent of C5 inhibitor-naïve patients met this endpoint.

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Novartis said Fabhata will be available later this month for PNH treatment but has not shared details on its list price yet. The drug will have a boxed warning for increased risk of “life-threatening infections caused by encapsulated bacteria.” Given this, Fabhalta will be made available through a Risk Evaluation and Mitigation Strategy (REMS) program that requires vaccinations for encapsulated bacteria.

For C3G, in the APPEAR-C3G study, the trial met its primary endpoint with the safety profile measuring up to previous studies of iptacopan, Novartis said.

Given that C3G often affects younger people, Novartis is enrolling adolescent patients in a separate study.

Novartis said it will review the C3G results with regulators around the world to generate potential submissions in 2024. It said it will also be sharing detailed data from APPEAR-C3G at an upcoming meeting.

The company will also be putting in an application for iptacopan in IgAN for a potential fast-track approval in 2024. Data shared in October from the Phase III APPLAUSE-IgAN study showed that iptacopan met its pre-specified interim endpoint with significant proteinuria reductions.