Seletalisib for Activated PI3Kδ Syndromes: Open-Label Phase 1b and Extension Studies

Diaz, Nieves; Juárez, Maria; Cancrini, Caterina; Heeg, Maximilian; Soler‐Palacín, Pere; Payne, Andrew; Johnston, Geoffrey I.; Helmer, Eric; Cain, Dionne; Mann, Joanne; Yuill, Daisy; Conti, Francesca; Cesare, Silvia Di; Ehl, Stephan; García-Prat, Marina; Maccari, Maria Elena; Martin‐Nalda, Andrea; Martínez-Gallo, Mónica; Moshous, Despina; Santilli, Veronica; Semeraro, Michaela; Simonetti, Alessandra; Suarez, Félipe; Cavazzana, Marina; Kracker, Sven

doi:10.4049/jimmunol.2000326

Cited by 23 publications

(16 citation statements)

References 23 publications

(55 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 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

View full text Add to dashboard Cite

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.)

show abstract

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

View full text Add to dashboard Cite

show abstract

“…Third, it allowed the initiation of immunoglobulin substitution and azithromycin administration to prevent respiratory infections and bronchiectasis, which are a frequent complication of APDS (17). The diagnosis of APDS will also provide a future benefit for the patient as it will expand the therapeutic options when novel specific treatments for APDS (e.g., specific PI3K inhibitors such as leniolisib or seletalisib) become available (27,28).…”

Section: Discussionmentioning

confidence: 99%

Case Report: Intestinal Nodular Lymphoid Hyperplasia as First Manifestation of Activated PI3Kδ Syndrome Due to a Novel PIK3CD Variant

Antonio

Bresolin

Colavito³

et al. 2021

Front. Pediatr.

View full text Add to dashboard Cite

Nodular lymphoid hyperplasia (NLH) is a lymphoproliferative disease caused by non-clonal expansion of lymphoid cells in the gut mucosa. Little is known about the pathogenesis of NLH, which is often disregarded as an insignificant or para-physiologic phenomenon. We present the case of a girl with isolated diffuse NLH (extending from the stomach to the rectum) caused by activated PI3Kδ syndrome (APDS) due to the novel p.Glu525Gly variant in PIK3CD. The gain-of-function effect of the variant was confirmed by demonstration of over activation of the Akt/mTOR pathway in the patient's cells. APDS diagnosis led to treatment with sirolimus, which resulted in the complete remission of NLH and in the prevention of extra intestinal complications. In conclusion, we identify APDS as a novel cause of isolated NLH and suggest that patients with severe pan-enteric NLH should be screened for this disorder that may not be apparent on first-line immunological testing.

show abstract

“…Moreover, an open label phase 1b study on Seletalisib ( 60 ) demonstrated an acceptable safety profile and positive effects on several clinical features and disease activity in patients with APDS1 and APDS2.…”

Section: Targeted Therapiesmentioning

confidence: 99%

Targeted treatment of autoimmune cytopenias in primary immunodeficiencies

et al. 2022

Self Cite

View full text Add to dashboard Cite

Primary Immunodeficiencies (PID) are a group of rare congenital disorders of the immune system. Autoimmune cytopenia (AIC) represents the most common autoimmune manifestation in PID patients. Treatment of AIC in PID patients can be really challenging, since they are often chronic, relapsing and refractory to first line therapies, thus requiring a broad variety of alternative therapeutic options. Moreover, immunosuppression should be fine balanced considering the increased susceptibility to infections in these patients. Specific therapeutic guidelines for AIC in PID patients are lacking. Treatment choice should be guided by the underlying disease. The study of the pathogenic mechanisms involved in the genesis of AIC in PID and our growing ability to define the molecular underpinnings of immune dysregulation has paved the way for the development of novel targeted treatments. Ideally, targeted therapy is directed against an overexpressed or overactive gene product or substitutes a defective protein, restoring the impaired pathway. Actually, the molecular diagnosis or a specific drug is not always available. However, defining the category of PID or the immunological phenotype can help to choose a semi-targeted therapy directed towards the suspected pathogenic mechanism. In this review we overview all the therapeutic interventions available for AIC in PID patients, according to different immunologic targets. In particular, we focus on T and/or B cells targeting therapies. To support decision making in the future, prospective studies to define treatment response and predicting/stratifying biomarkers for patients with AIC and PID are needed.

show abstract

Seletalisib for Activated PI3Kδ Syndromes: Open-Label Phase 1b and Extension Studies

Cited by 23 publications

References 23 publications

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

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

Case Report: Intestinal Nodular Lymphoid Hyperplasia as First Manifestation of Activated PI3Kδ Syndrome Due to a Novel PIK3CD Variant

Targeted treatment of autoimmune cytopenias in primary immunodeficiencies

Contact Info

Product

Resources

About