Innovative treatment for paroxysmal nocturnal hemoglobinuria (PNH)! Novartis' first complement factor B inhibitor iptacopan: phase 3 clinical efficacy is better than anti-C5 therapy!

October 24, 2022 /BioValleyBIOON/ -- Novartis today announced that the pivotal Phase 3 APPLY-PNH trial (NCT04558918) evaluating iptacopan (LNP023) for paroxysmal nocturnal hemoglobinuria (PNH) has met two primary endpoints
.
Patients enrolled in this trial remained anaemic
despite prior anti-C5 therapy.
The results of the trial showed that the oral monotherapy iptacopan (200 mg twice daily) was superior in efficacy to the anti-C5 therapies Soliris (eculizumab, eculizumab) and Ultomiris (ravulizumab, ravulizumab).

Detailed results will be presented at an upcoming medical meeting and as part of
the 2023 Global Regulatory Submission.
(Note: Soliris and Utomiiris are 2 complement C5 inhibitors for AstraZeneca, Utomiris is a long-acting version of Soliris, and 2 drugs are standard care therapies
for PNH.
) ）

PNH is a rare, life-threatening blood disorder characterized by complement-driven hemolysis, thrombosis, and impaired bone marrow function, leading to anemia, fatigue, and other debilitating symptoms that can seriously affect a patient's quality of life
.
Despite treatment with current anti-C5 standard care therapies, a large proportion of patients with PNH remain anaemic and dependent on blood
transfusions.

iptacopan is a first-in-class, oral, potent, selective, small molecule, reversible factor B inhibitor, a key serine protease
in the complement system replacement pathway.
iptacopan plays a role upstream of the C5 terminal pathway, preventing not only intravascular hemolysis of PNH, but also extravascular hemolysis
.
By targeting key parts responsible for PNH biology while offering oral monotherapy options, iptacopan has the potential to have a therapeutic advantage
over anti-C5 therapies.

Currently, iptacopan is being developed for the treatment of a number of kidney diseases with significant unmet needs involved in the complement system, including IgA nephropathy (IgAN), C3 glomerular disease (C3G), atypical hemolytic uremic syndrome (aHUS), and membranous nephropathy (MN)
in addition to PNH.

Dr.
Shreeram Aradhye, President and Chief Medical Officer of Novartis Global Drug Development, said: "These positive Phase 3 studies highlight the potential
of iptacopan to transform clinical practice for patients suffering from debilitating anemia as well as the lifelong transfusion burden of PNH.
We look forward to discussing the data with regulators to bring this first-of-its-kind alternative complement pathway inhibitor to the PNH patient population
as the first oral monotherapy.
" ”

Ipatapan chemical structure (Image source: medchemexpress.
com)

APPLY-PNH is a Phase 3, randomized, multinational, multicenter, active-controlled, open-label trial of adult PNH patients with residual anemia despite receiving a stable anti-C5 regimen in the last 6 months prior to randomization, designed to demonstrate the superiority of iptacopan monotherapy (200 mg orally twice daily) over anti-C5 therapy Soliris or Ultomiris
.

A primary endpoint of the trial was to assess the proportion of patients whose hemoglobin levels increased from baseline by ≥2 g/dL without the need for red blood cell (RBC) transfusions during 24 weeks of
treatment.
Another primary endpoint was to assess the proportion of patients who achieved sustained hemoglobin levels of ≥ 12 g/dL without RBC transfusion during 24 weeks of
treatment.
Secondary endpoints included percentage of patients without blood transfusion, mean change in haemoglobin levels, change in fatigue, mean change in absolute reticulocyte count, mean percentage change in lactate dehydrogenase (LDH) level, breakthrough hemolysis, and incidence of
major adverse vascular events.

The trial enrolled a total of 97 patients randomized to receive oral iptacopan monotherapy twice daily or intravenous anti-C5 therapy (continuing to receive the same regimen as before randomization
) in an 8:5 ratio.

Top line results showed that the trial met 2 primary endpoints: (1) the proportion of patients whose hemoglobin levels increased from baseline to ≥ 2 g/dL without RBC transfusion during 24 weeks of treatment, with a statistically significant and clinically significant increase
in the iptacopan treatment group compared to the anti-C5 therapy treatment group.
(2) The proportion of patients with sustained hemoglobin levels of ≥12g/dL achieved without RBC transfusion during 24 weeks of treatment, and there was also a statistically significant and clinically significant increase
in the iptacopan treatment group compared with the anti-C5 therapy treatment group.
In this trial, iptacopan was well tolerated and had a good safety profile, consistent with
previously reported data.

Complement activation cascade-PNH therapeutic modulation target (Image source: PMC6060635, click the picture for a larger image)

IPTACOPAN is the most advanced asset in Novartis' nephrology pipeline, targeting the complement replacement pathway, a key driver of
complement-driven kidney disease (CDRD).
Previously, iptacopan has been granted Orphan Drug Designation (ODD) for the treatment of PNH and C3G by the U.
S.
FDA and EU EMA, ODD for the treatment of IgAN, Breakthrough Drug Designation (BTD) for PNH by the FDA, and Priority Drug Designation (PRIME)
for the treatment of C3G by the EMA.

In addition to the Phase 3 APPLY-PNH trial mentioned above, iptacopan is currently being evaluated in the Phase 3 APPOINT-PNH trial (NCT04820530) for the treatment of PNH patients who have not previously received a complement inhibitor (complement inhibitor naive), which is expected to be published in the coming months
.

In addition, iptacopan is also being evaluated in multiple phase 3 clinical trials for the treatment of complement-mediated kidney disease (CMKD), C3 glomerular disease (C3G, APPEAR-C3G [NCT04817618]), IgA nephropathy (IgAN, APPLAUSE-IgAN [NCT05578834]), and atypical hemolytic uremic syndrome (aHUS, APPELHUS [NCT08989430]
。 IPTACOPAN is also being evaluated in multiple Phase 2 clinical trials for a number of other indications
.
(Bio Valley Bioon.
com)

Novartis investigational oral monotherapy iptacopan demonstrates clinically meaningful superiority over anti-C5 treatment in Phase III APPLY-PNH study