An Open Label Trial of Nemiralisib, an Inhaled PI3 Kinase Delta Inhibitor for the Treatment of Activated PI3 Kinase Delta Syndrome

Begg, Malcolm; Amour, Augustin; Jarvis, Emily; Tang, Teresa; Franco, Sara Santos; Want, Andrew; Beerahee, Misba; Fernando, Disala; Karkera, Yakshitha; Sander, Clare R.; Southworth, Thomas; Singh, Dave; Clark, Jonathan; Nejentsev, Sergey; okkenhaug, klaus; Condliffe, Alison M.; Chandra, Anita; Cahn, Anthony; Hall, Edward

doi:10.2139/ssrn.4206947

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“…A phase 2 trial of the inhaled agent nemiralisib was completed in 5 patients but further studies were not pursued ( NCT02593539 ). 35 A phase 3 trial of the oral inhibitor seletalisib was terminated; 36 published phase 1b and open label extension studies describe moderate efficacy and AEs that led to treatment discontinuation. 37 The reasons behind the differences in efficacy and tolerability between seletalisib and leniolisib are not immediately clear but may involve inhibitor structure and isoform selectivity.…”

Section: Discussionmentioning

confidence: 99%

A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome

Rao

Webster

Šedivá

et al. 2023

Blood

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Activated phosphoinositide 3-kinase delta syndrome (APDS) is an inborn error of immunity with clinical manifestations including infections, lymphoproliferation, autoimmunity, enteropathy, bronchiectasis, increased risk of lymphoma, and early mortality. Hyperactive PI3Kδ signaling causes APDS and is selectively targeted with leniolisib, an oral, small molecule inhibitor of PI3Kδ. Here, 31 patients with APDS aged ≥12 years were enrolled in a global, phase 3, triple-blinded trial and randomized 2:1 to receive 70-mg leniolisib or placebo twice daily for 12 weeks. Co-primary outcomes were differences from baseline in index lymph node size and in percentage of naïve B cells in peripheral blood, assessed as proxies for immune dysregulation and deficiency. Both primary outcomes were met: the difference in the adjusted mean change (95% CI) between leniolisib and placebo for lymph node size was -0.25 (-0.38, -0.12; P=0.0006; N=26) and for percentage of naïve B cells was 37.30 (24.06, 50.54; P=0.0002; N=13). Leniolisib reduced spleen volume compared to placebo (adjusted mean difference in 3-dimensional volume [cm3], -186; 95% CI, -297 to -76.2; P=0.0020) and improved key immune cell subsets. Fewer patients receiving leniolisib reported study treatment-related adverse events (mostly grades 1-2) compared to those receiving placebo (23.8% vs 30.0%). Overall, leniolisib was well tolerated and significant improvement over placebo was notable in the co-primary endpoints, reducing lymphadenopathy and increasing the percentage of naïve B cells, reflecting a favorable impact on the immune dysregulation and deficiency seen in patients with APDS. (Funded by DIR/NIAID, Novartis, and Pharming Group, NV; ClinicalTrials.gov identifier: NCT02435173.)

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Section: Discussionmentioning

confidence: 99%