Pharming Group NV

This analysis evaluated literature on patients with activated phosphoinositide 3-kinase delta syndrome (APDS) to better understand the genetic etiologies and occurrence of mortality in this population.

A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses approach, including all articles published in English prior to March 13, 2023, in PubMed and Embase. Patients included in the study had reported either (1) APDS diagnosis or (2) ≥ 1 clinical sign consistent with APDS and a first-degree relative with genetically confirmed APDS. Reported age at last observation was also a required outcome. Publications not meeting these criteria were excluded. Data were summarized using descriptive statistics.

The search identified 108 publications describing 351 unique patients with 39 distinct disease-causing variants. Among these, 41 (12%) deaths were reported, with a mean age at last follow-up of 19.6 (range, 1-64) years. A cause of death was reported for 80% (33/41) of deaths; lymphoma (24%, 10/41) and infections (22%, 9/41) were the most common causes. Types of infections causing death were severe uncontrollable infections (n = 3), sepsis (n = 2), viral infection (varicella zoster pneumonitis [n = 1], cytomegalovirus and adenovirus [n = 1], and Epstein-Barr virus [n = 1]), and infection (n = 1). Mean age at death for lymphoma was 24.9 (range, 1-41) years, and all nine patients who died from infections died before the age of 15 years. The mean age at first APDS symptom was 2.0 (range, < 1-22) years, and mean age at APDS diagnosis was 13.4 (range, 0-56) years; the mean time between symptoms and diagnosis was 10.6 (range, 0-44) years. Limitations of the study were primarily related to the data source.

Patients with APDS suffer early mortality, largely from lymphoma and infection, with large time gaps between symptoms and diagnosis. These findings highlight the need for improved diagnostics, earlier genetic testing for APDS, increased awareness of familial testing, and targeted therapies.

Inequities in genetic testing have been documented in a range of diseases, and no-charge genetic testing programs have been proposed as a means to enhance access. However, no studies have examined disparities in genetic testing for inborn errors of immunity (IEI) and the impact of no-charge programs on testing equity.

To examine socioeconomic, geographic, and racial disparities in the uptake of genetic testing for IEI in the United States and the impact of a no-charge sponsored program on testing equity.

This was a retrospective cohort analysis of (1) a national claims database capturing individuals with IEI (n = 18,603), and (2) data from a clinical genetic testing laboratory capturing patients with IEI participating in a no-charge sponsored program (n = 6,681) and a non-sponsored program (n = 29,579) for IEI genetic testing.

Among patients with IEI captured in the claims database, those residing in areas of greater deprivation (odds ratio [OR] = 0.95; 95% CI, 0.92-0.98), rural areas (OR = 0.82; 95% CI, 0.71-0.96), and non-White neighborhoods (OR = 0.89, 95% CI 0.81-0.98) were less likely to undergo genetic testing. Participants in the sponsored IEI genetic testing program lived in areas of greater deprivation compared with the non-sponsored program (median, 46 vs 42; P < .001). However, historically excluded racial groups were underrepresented in both the sponsored and non-sponsored programs relative to disease burden.

We found significant disparities in genetic testing for IEI. Although eliminating the financial barriers to testing reduced socioeconomic disparities in genetic testing for IEI, racial disparities persisted. Further research is needed to address barriers to testing among underserved populations.

Leniolisib, an oral, targeted phosphoinositide 3-kinase delta (PI3Kδ) inhibitor, was well-tolerated and efficacious versus placebo in treating individuals with activated PI3Kδ syndrome (APDS), an ultra-rare inborn error of immunity (IEI), in a 12-week randomised controlled trial. However, longer-term comparative data versus standard of care are lacking. This externally controlled study compared the long-term effects of leniolisib on annual rate of respiratory tract infections and change in serum immunoglobulin M (IgM) levels versus current standard of care, using data from the leniolisib single-arm open-label extension study 2201E1 (NCT02859727) and the European Society for Immunodeficiencies (ESID) registry. The endpoints were chosen following feasibility assessment considering comparability and availability of data from both sources. Baseline characteristics between groups were balanced through inverse probability of treatment weighting. The leniolisib-treated group included 37 participants, with 62 and 49 participants in the control group for the respiratory tract infections and serum IgM analyses, respectively. Significant reductions in the annual rate of respiratory tract infections (rate ratio: 0.34; 95% confidence interval [CI]: 0.19, 0.59) and serum IgM levels (treatment effect: –1.09 g/L; 95% CI: –1.78, –0.39, P = 0.002) were observed in leniolisib-treated individuals versus standard of care. The results were consistent across all sensitivity analyses, regardless of censoring, baseline infection rate definition, missing data handling, or covariate selection. These novel data provide an extended comparison of leniolisib treatment versus standard of care, highlighting the potential for leniolisib to deliver long-term benefits by restoring immune system function and reducing infection rate, potentially reducing complications and treatment burden.