Therapeutic: leniolisib for APDS

Published: 31-Mar-2022

APDS or activated phosphoinositide 3-kinase delta (PI3K∂) syndrome is an ultra-rare primary immunodeficiency disease

It’s caused by variants in one of two genes: PIK3CD and PIK3R1. Errors in either of these two genes lead to hyperactivity of the PI3K∂ pathway.

This results in immune cells failing to mature and function correctly, resulting in immunodeficiency and dysregulation. Patients with the condition experience severe and recurrent sinopulmonary infections as well as autoimmune responses, lymphoproliferation and enteropathy as a result of the disrupted signalling pathway.

There is no specific treatment, with therapy relying on immunoglobulin replacement therapy and antibiotics.

Diagnosis is difficult and the condition will typically not be identified for 7 years after the appearance of the first symptoms. The disease is progressive and the delay is likely to lead to greater cumulative effects, including permanent lung damage and lymphoma.

A potential treatment is being developed by Pharming Group, having been in-licensed from Novartis. Leniolisib is a small molecule inhibitor of the delta isoform of the 110 kDa catalytic subunit of class IA PI3K; as well as its immunomodulating properties, it has the potential to be antineoplastic.1

It inhibits the production of phosphatidylinositol 3,4,5-triphosphate (PIP3), which is a cellular messenger that regulates various cell functions, including proliferation, differentiation, cytokine production, angiogenesis, metabolism and survival.

PI3K∂ regulates cellular functions in the adaptive immune system as well as the innate immune system; as such, it has potential as a therapeutic target in a variety of immune diseases, including APDS.

After a successful study in healthy volunteers, a 12-week open label dose escalation trial was done in six patients with APDS.2,3 The drug gave a dose-dependent reduction in PI3K/AKT pathway activity, as assessed ex vivo, and improved immune dysregulation.

There was a normalisation of circulating transitional and naïve B cells, a reduction in PD-1+CD4+ and senescent CD57+CD4– cells. There were also decreases in elevated serum immunoglobulin M and inflammatory markers, including interferon-gamma, TNF, CXCL13 and CXCL10.

At the end of the 12 weeks, all patients had improved lymphoproliferation, with the sizes of lymph nodes and spleen volumes down by a mean 39% and 40%, respectively. It was well tolerated.

The company has also announced positive results from a Phase II/III trial via press release. In the blinded, randomised, placebo-controlled study, 31 patients were given 70 mg/day of the drug or a placebo for 12 weeks.

After this period, they could continue in an open label extension study to evaluate safety and efficacy in the longer-term. Both coprimary endpoints for a reduction in lymph node size and correction of immunodeficiency were met. It was generally well tolerated and there were fewer serious adverse events in the treatment group than with the placebo.


  1. K. Hoegenauer, et al., ACS Med. Chem. Lett. 8, 975 (2017).
  2. D. Pearson, et al., Xenobiotica 49, 953 (2019).
  3. V.K. Rao, et al., Blood 130, 2307 (2017).

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