Leniolisib

1 INDICATIONS AND USAGE JOENJA is indicated for the treatment of activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) in adult and pediatric patients 12 years of age and older. JOENJA is a kinase inhibitor indicated for the treatment of activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) in adult and pediatric patients 12 years of age and older. ( 1 )

12.1 Mechanism of Action Leniolisib inhibits PI3K-delta by blocking the active binding site of PI3K-delta. In cell-free isolated enzyme assays, leniolisib was selective for PI3K-delta over PI3K-alpha (28-fold), PI3K-beta (43-fold), and PI3K-gamma (257-fold), as well as the broader kinome. In cell-based assays, leniolisib reduced pAkt pathway activity and inhibited proliferation and activation of B and T cell subsets. Gain-of-function variants in the gene encoding the p110-delta catalytic subunit or loss of function variants in the gene encoding the p85-alpha regulatory subunit each cause hyperactivity of PI3K-delta. Leniolisib inhibits the signalling pathways that lead to increased production of PIP3, hyperactivity of the downstream mTOR/Akt pathway, and to the dysregulation of B and T cells.

2 DOSAGE AND ADMINISTRATION Verify pregnancy status in females of reproductive potential prior to initiating treatment. ( 2.1 , 5.1 ) Recommended dosage: 70 mg administered orally twice daily approximately 12 hours apart, with or without food, in adult and pediatric patients 12 years of age and older and weighing ≥ 45kg. ( 2.2 ) 2.1 Testing Prior to Treatment with JOENJA Verify pregnancy status in females of reproductive potential prior to initiating treatment with JOENJA [see Warnings and Precautions ( 5.1 ), and Use in Specific Populations ( 8.1 , 8.3 )] . 2.2 Recommended Dosage and Administration The recommended dosage of JOENJA in adult and pediatric patients 12 years of age and older weighing 45 kg or greater is 70 mg administered orally twice daily approximately 12 hours apart, with or without food. There is no recommended dosage for patients weighing less than 45 kg. Advise patients that if a dose is missed by more than 6 hours, wait and take the next dose at the usual time. Advise patients that if vomiting occurs within 1 hour after taking JOENJA, take JOENJA as soon as possible. If vomiting occurs more than 1 hour after dosing, wait and take the next dose at the usual time.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Risk of Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.3) ] Most common adverse reactions (incidence > 10%) were headache, sinusitis, and atopic dermatitis. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pharming Healthcare Inc. at 1-800-930-5221 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of JOENJA reflects exposure based on 38 adult and pediatric patients 12 years of age and older with activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) from the placebo-controlled portion of Study 2201 [see Clinical Studies ( 14 )] and additional open-label clinical safety data. Thirty-seven of 38 patients received JOENJA 70 mg orally twice daily for at least 25 weeks and 66% were exposed for 96 weeks or longer. Median duration of JOENJA treatment was approximately 2 years, and 4 patients had more than 5 years of JOENJA exposure. The data below are based on the 12-week, placebo-controlled portion of Study 2201 in which either JOENJA 70 mg (N=21) or placebo (N=10) was administered twice daily to patients with APDS. Demographics of the patients who participated in this study are summarized in Clinical Studies [see Clinical Studies ( 14 )] . Table 1 presents the number of patients and incidence, rounded to the nearest percent, of adverse reactions that occurred in 2 or more patients treated with JOENJA and for which the incidence in patients treated with JOENJA was greater than the incidence in patients treated with placebo. The most common adverse reactions (> 10%) were headache, sinusitis, and atopic dermatitis. Table 1 Adverse Reactions Reported by 2 or More JOENJA-Treated Patients and More Frequently than Placebo Adverse Reactions JOENJA N=21 n (%) Placebo N=10 n (%) 1 Dermatitis atopic: including dermatitis atopic and eczema 2 Tachycardia: including tachycardia and sinus tachycardia Headache 5 (24) 2 (20) Sinusitis 4 (19) 0 Dermatitis atopic 1 3 (14) 0 Tachycardia 2 2 (10) 0 Diarrhea 2 (10) 0 Fatigue 2 (10) 1 (10) Pyrexia 2 (10) 0 Back pain 2 (10) 0 Neck pain 2 (10) 0 Alopecia 2 (10) 0 Specific Adverse Reactions Laboratory Abnormalities Seven (33%) patients receiving JOENJA developed an absolute neutrophil count (ANC) between 500 and 1500 cells/microL. No patients developed an ANC < 500 cells/microL and there were no reports of infection associated with neutropenia. Weight Increase In the open-label clinical trial (n=37), five patients (14%) experienced weight gain. Some patients became overweight or obese. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of JOENJA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders : hypersensitivity (anaphylaxis)

5 WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity: JOENJA may cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.1 , 8.1 , 8.3 ) Vaccinations: Live, attenuated vaccinations may be less effective if administered during JOENJA treatment. ( 5.2 ) Risk of Hypersensitivty Reactions Including Anaphylaxis: Hypersensitivity reactions including anaphlyaxis have been reported in the postmarketing setting. If hypersensitivity reactions occur, discontinue JOENJA and institute appropriate therapy. ( 5.3 ) 5.1 Embryo-Fetal Toxicity Based on findings in animals, JOENJA may cause fetal harm when administered to a pregnant woman. Administration of leniolisib to rats and rabbits during the period of organogenesis caused embryo-fetal toxicity including malformations at exposures that were 2-6 times higher than the maximum recommended human dose (MRHD) in APDS patients based on AUC comparisons. Verify the pregnancy status of patients of reproductive potential prior to starting treatment. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use highly effective methods of contraception during treatment and for 1 week after the last dose [see Dosage and Administration ( 2.1 ), Use in Specific Populations ( 8.1 , 8.3 )] . 5.2 Vaccinations Live, attenuated vaccinations may be less effective if administered during JOENJA treatment. 5.3 Risk of Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reaction(s), including anaphylaxis, have been reported in postmarketing setting. If a clinically significant hypersensitivity reaction occurs, discontinue JOENJA and institute appropriate therapy [see Adverse Reactions (6.2) ].

4 CONTRAINDICATIONS None. None. ( 4 )

10 OVERDOSAGE If overdosage occurs, monitor the patient for any signs or symptoms of adverse reactions. Treatment of overdose with JOENJA consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient.