A Single-arm, Dose-escalation Trial of Long-acting Recombinant Human IL-7 (NT-I7, Efineptakin Alfa) for Idiopathic CD4 Lymphopenia

Study Description:

Open-label trial of efineptakin alfa (NT-I7) to manage idiopathic CD4 lymphopenia (ICL). After baseline assessments, NT-I7 will be administered intramuscularly (IM) at the NIH Clinical Center (CC) once every 12 weeks for 3 total doses, with the final dose at week 24, in 3 cohorts of 10 participants each. The doses for each cohort are 240, 480, or 720 microgram/kg. Blood will be drawn at each dose visit, as well as 5 days before and 14 and 30 days after each dose visit. Blood laboratory evaluations will be performed at the NIH CC or by remote laboratory providers, with results shared with the NIH study team. Primary and secondary evaluations include assessment of adverse events (AEs) and T-cell counts. Questionnaires will be administered to assess patient health perceptions and quality of life. The final study visit will be at week 60.

Primary Objective:

Evaluate the safety (all AEs) of NT-I7 in patients with ICL.

Secondary Objective:

• Evaluate the immunologic effects of NT-I7 on peripheral CD4 T-cell counts in ICL patients.
• Evaluate the safety (study drug-related AEs) of NT-I7 in patients with ICL.

Exploratory Objectives:

• Evaluate the ability of NT-I7 to increase CD4 T-cell counts.
• Evaluate the clinical effects of NT-I7 administration in participants with treatment-refractory human papillomavirus (HPV)-related diseases.
• Evaluate the effect of NT-I7 on clinical sequelae, radiologic or laboratory findings associated with previous opportunistic infections.
• Evaluate effects of NT-I7 administration on presence/titer of clinical autoantibodies.
• Evaluate the immunogenicity of NT-I7.
• Evaluate the pharmacokinetics (PK) of NT-I7 and explore exposure-safety and exposure-efficacy relationships.

Primary Endpoint:

Number and severity of AEs observed after NT-I7 administration evaluated at week 60 (end-of-study visit).

Secondary Endpoints:

• Evaluation of the trajectory of absolute lymphocyte count (ALC), and CD4, CD8, B, and NK counts measured at all study visits up to week 60 (end-of-study visit).
• Evaluation of the trajectory of ALC and CD4, CD8, B, and NK counts measured at all study visits up to week 36 (interim analysis).
• Evaluation of the trajectory of ALC and CD4, CD8, B, and NK counts measured between week 36 (12 weeks after last dose of NT-I7) and week 60.
• Number and severity of AEs possibly, probably, or definitely related to NT-I7 administration evaluated at week 60 (end-of-study visit).

Exploratory Endpoints:

• Proportion of participants with CD4 T-cell counts >=300 cells/microliter with NT-I7 treatment evaluated at week 60 (end-of-study visit).
• Time (cumulative number of days or weeks) that participants with baseline CD4 T-cell counts <200 cells/microliter maintain CD4 T-cell counts >= 200 cells/microliter after initiating treatment with NT-I7.
• Changes in skin or mucosal manifestations of HPV diseases as evaluated by clinical photography, and dermatologic and histologic evaluation.
• Changes in the clinical, radiologic, or laboratory findings associated with previous history of opportunistic infections.
• Changes in presence and titer of clinical autoantibodies.
• Incidence of antidrug antibodies (ADA) to NT-I7 in the study population.
• Serum concentration of NT-I7 administered at specified timepoints for the maximum observed concentration (Cmax).

• INCLUSION CRITERIA:

Individuals must meet all of the following criteria to be eligible for study participation:

• Aged 18 to 75 years.
• Able to provide informed consent.
• Co-enrolled in NIH protocol 09-I-0102, Etiology, Pathogenesis, and Natural History of Idiopathic CD4+ Lymphocytopenia (EPIC) study (NCT0086726).
• Documented ICL, defined as CD4 T-cell count <300 cells/microliter in at least 2 different measurements at least 6 weeks apart, at any point in the past.
• Participants who can become pregnant or who can impregnate their partner must agree to remain abstinent or to use 2 highly effective methods of contraception, at least 1 of which must be a barrier method, when engaging in sexual activities that can result in pregnancy, beginning at the first pre-injection visit until the 30 days after the last injection. Acceptable methods of contraception include the following:

• Male or female condom.
• Diaphragm or cervical cap with a spermicide.
• Hormonal contraception.
• Intrauterine device.

Note: Contraception requirements do not apply to participants who are post-menopause (age >=45 years plus no menses for 12 consecutive months without an alternative medical cause).

Exclusion criteria

Individuals meeting any of the following criteria will be excluded from study participation:

• Current moderate or severe acute illness (eg, febrile illness, seizure, myocardial infarction, cerebrovascular accident, pulmonary embolism) that in the opinion of the study team would make the individual unsuitable for the study.
• Clinical or microbiologic evidence of active progressive cryptococcal central nervous system (CNS) disease or nontuberculous mycobacterial (NTM) infections within the last year. History of stable cryptococcal CNS disease or NTM diseases since more than 1 year can be enrolled but will need to have undetectable CSF cryptococcal antigen and initiate/maintain antifungal or antimycobacterial treatment, respectively.
• Pregnant or breastfeeding.
• HIV infection, chronic hepatitis B or C infection, and any other recognized congenital or acquired immunodeficiency (eg, SCID IL-2/JAK3/ADA, MAGT1, MHC1 deficiency, CVID, DOCK8).
• Serum creatinine >1.5 X ULN, platelets <50,000/microliter, hemoglobin <9 g/dL, AST/ALT>2.5 X ULN, total bilirubin >1.5 X ULN (except if due to Gilbert's syndrome), or immunoglobulin (Ig) G level <450 mg/L.
• Current (within 3 months of screening) use of systemic glucocorticosteroids or immunomodulants other than corticosteroid nasal spray or inhaler and topical steroids.
• Any established diagnosis of autoimmune disease requiring systemic treatment except for vitiligo or endocrine disease (including diabetes, thyroid disease, and adrenal disease) controlled by replacement therapy.
• Malignancy requiring systemic chemotherapy or immunotherapy within 2 months of screening.
• Receipt of any other investigational agents within 3 months of screening.
• Any condition that, in the opinion of the study team contraindicates participation in this study.

Participants will be selected in an equitable manner from the available pool of potentially eligible individuals, without regard to factors such as sex, gender, race, ethnicity, or socioeconomic status, except for age.