ERA-EDTA 2021 – Novartis’s iptacopan sets the bar in rare kidney disease

Novartis makes progress with its most valuable pipeline asset, but others also hope to make a mark in IgA nephropathy.

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It might come as a surprise that the oral complement inhibitor iptacopan is Novartis’s most valuable pipeline asset, according to the sellside. Yesterday the Swiss group filled in the blanks about the project’s mid-stage win in the rare kidney disease IgA nephropathy, where a high dose led to a 23% reduction in proteinuria.

Proteinuria is a surrogate endpoint, but one that many other groups are using. There are no approved therapies for IgAN, and the most advanced project here is Calliditas’s Nefecon, which is due an approval decision by September; another big milestone is coming in August, when pivotal data are expected with Travere Therapeutics’ lead project, sparsentan.

Various other assets are also in development, and Novartis is helping to set the bar for its rivals. Leerink had previously said a 20-30% reduction in proteinuria, measured via urine protein to creatinine ratio in a 24-hour urine collection, would be needed for a therapy to be competitive in IgAN – a stance it reiterated yesterday in light of the iptacopan phase II data.

Still, only the 200mg dose of iptacopan hit this goal; this is the regimen that Novartis has already taken forward into its phase 3 IgAN trial, Applause.

Source: Professor Jonathan Barratt & ERA-EDTA.

There was also a “trend towards stabilisation” of estimated glomerular filtration rate (eGFR), a harder endpoint, with all doses of iptacopan, versus a decline with placebo, attendees at the ERA-EDTA congress heard.

Iptacopan is an oral inhibitor of factor B, a component of the complement system. Other oral inhibitors of the alternative complement pathway, hitting factor D, are also in development; however, none appears to be in trials for IgAN.

Selected projects in mid to late-stage development for IgA nephropathy
Project Company Description Note
Filed
Nefecon Calliditas Therapeutics Oral formulation of the steroid budesonide Pdufa date Sep 15, 2021
Phase 3
Iptacopan/LNP023 Novartis Oral complement factor B inhibitor Positive ph2 data just reported, ph3 under way
Sparsentan Travere Therapeutics (previously known as Retrophin) Endothelin type A & angiotensin II type 1 inhibitor Pivotal Protect data due Aug 2021
Narsoplimab/OMS721 Omeros Anti-MASP2 antibody Artemis-IGAN recruiting
Phase 2
Bardoxolone methyl Reata Pharmaceuticals Nrf2 stimulant Reported data from Phoenix trial in 2019
IONIS-FB-LRX Ionis/Roche Complement factor B antisense Ph2 completed Jan 2021
Atacicept Vera Therapeutics Recombinant fusion protein binding to Blys and April Ph2b Origin recruiting; licensed from Merck KGaA
VIS649 Otsuka Anti-April antibody Ph2 recruiting
Cemdisiran Alnylam Pharmaceuticals Anti-complement C5 RNAi Ph2 recruiting
Source: Evaluate Pharma & clinicaltrials.gov.

Meanwhile, the most advanced IgAN project, Calliditas’s Nefecon, is a formulation of the steroid budesonide designed to target the small intestine, where the Swedish company says the disease originates. That project showed a placebo-adjusted 27% reduction in proteinuria in phase 3; there was also a statistically significant improvement in eGFR versus placebo.

Novartis will need to see more of the same in its pivotal study. The group has also already taken iptacopan into phase 3 in paroxysmal nocturnal haemoglobinuria, while a pivotal trial in C3 glomerulopathy, where the group also presented data today at ERA-EDTA, is due to start this year.

Iptacopan has a net present value of $4.1bn, according to Evaluate Omnium – ahead of Novartis's radiopharmaceutical 177Lu-PSMA-617, at $3.9bn.

Selected trials of iptacopan/LNP023
Indication Trial Data due
IgA nephropathy Ph3 Applause-IgAN recruiting Ph3 interim due 2023; ph2 data presented at ERA-EDTA 2021
C3 glomerulopathy Ph3 Appear-C3G not yet recruiting Completes Jul 2023; ph2 data presented at ERA-EDTA 2021
Paroxysmal nocturnal haemoglobinuria Ph3 Apply-PNH recruiting, vs Soliris/Ultomiris following Soliris/Ultomiris  Completes Jul 2022
Ph3 Appoint-PNH in complement inhibitor-naïve pts Completes Jan 2023
Atypical haemolytic uremic syndrome Ph3 Appelhus not yet recruiting, in complement inhibitor-naive pts Completes Oct 2024
Idiopathic membranous nephropathy Ph2 recruiting, vs Rituxan Completes Jul 2023
Source: Evaluate Pharma & clinicaltrials.gov.

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