b'NIH Study Leads to First FDA ApprovalFor Rare Immunodeficiency SyndromeActivated phosphoinositide 3-kinase delta (PI3K) syndrome (APDS), is an extremely rare congenital immunodeficiency syndrome. Currently, the number of patients with the condition in the United States is thought to be fewer than 1,000, but that could change with increased genetic testing availability. For the first time, the FDA has approved a therapy which has added to the DoD formulary.By Annette BoyleBETHESDA, MDA phase III study led by a re- phase III trial, and others discovered the link between searcher at the National Institutes of Health (NIH)the mutations and APDS in 2013.1has resulted in the first approval of a drug for ac- Symptomsof APDSincludefrequentsinopulmo-tivatedphosphoinositide3-kinasedelta(PI3K)nary infections, lymphadenopathy, nodular lymphoid syndrome (APDS), a rare congenital immunodefi- hyperplasia, fatigue and chronic or recurrent infec-ciency syndrome. tions with cytomegalovirus (CMV), Epstein Barr virus Withitsapproval,theDoDsPharmacyand(EBV), herpes virus or varicella zoster with severely TherapeuticsCommitteehasaddedthedrug,leni- deficient nave and central memory T cells and excess olisib, to the uniform formulary for treatment of MHSsenescent effector T cells. APDS is also associated beneficiaries age 12 and older who weigh at least 45with gastrointestinal issues, and bronchiectasis. Up to kg and have diagnosed, symptomatic APDS. 25% of APDS patients develop lymphoma.Previouslycalledp110delta-activatingmutationTreatment for APDS previously focused on symp-causingsenescentTcells,lymphadenopathyandtom relief with prophylactic antibiotics and antivirals immunodeficiency(PASLI),APDSgenerallypres- tocontrolrecurrentinfections,anti-inflammatory ents as recurrent infections starting in childhood. Thedrugs to treat cytopenia and other autoimmune dis-diseaseiscausedbymutationsineitherthegeneseases, immunoglobulin replacement to reduce respira-PIK3CD (type 1) or PIK3R1 (type 2), which are typi- tory infections and hematopoietic stem-cell transplant callyinheritedinanautosomaldominantmanner,(HSCT) to treat lymphoma and life-threatening infec-with children having a 50% chance of inheriting thetions. Treatment with rapamycin, an mTOR inhibitor, variant. The gene also occasionally arises spontane- is used to decrease nonneoplastic lymphoproliferation.ously. Both types result in hyperactive PI3K signal- APDS is associated with a shortened lifespan, with ing and similar immunologic complications. the largest study of survival and mortality for APDS The condition is extremely rare and is thought toshowing conditional survival rate at age 20 of 87%, affect about 1 to 2 people per million worldwide.74% at age 30, and 68% at ages 40 and 50. Lymphoma In the United States, it is estimated that there areis the most-common cause of death, which had a mor-about 400 to 600 patients, although that number istality rate of 47.6%, followed by complications from expected to increase with the availability of geneticHSCT, which had a 15.6% overall mortality rate. 2testing for APDS.Researchers at the NIHs National Institute of AllergyRestores the Balanceand Infectious Diseases (NIAID) led by Carrie Lucas,Leniolisib is a potent, selective oral inhibitor that PhD, now of the Yale School of Medicine, as well astargets PI3K signaling and restores the balance be-V. Koneti Rao, MD, of the NIH NIAID, who led thetween immature and functional B and T cells. 70'