NKTT120 Reduces iNKT Cells without Dose Limiting Toxicity in Stable Adult Sickle Cell Patients in a Phase 1 Trial
Authors: Majerus Elaine M. , Ataga Kenneth I. , Vichinsky Elliott , Eaton Cheryl A. , Mazanet Rosemary , Nathan David G. , Field Joshua J. 
Published: October 2019

Abstract
An increased number of circulating activated iNKT cells have been reported in sickle cell disease patients, and in mouse studies, iNKT cells have been reported to have increased number and activation state in target organs. Depletion of iNKT cells in a mouse model of sickle cell disease decreases inflammation and prevents end-organ damage. NKTT 120 is a humanized monoclonal antibody directed against the iNKT cell invariant TCR that depletes these cells by antibody dependent cellular cytotoxicity. Preclinical studies show that NKTT120 has high affinity and specificity for iNKT cells. NKTT120 administration as a 10 minute IV infusion produces depletion and recovery of iNKT cells in a dose and time dependent manner. Our global hypothesis is that NKTT120 will deplete iNKT cells, reduce inflammation and prevent painful vaso-occlusive crises. In this phase 1 dose-escalation study, we have examined the safety of NKTT120 in adults with steady state SCD.
Objective: To determine the safety, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of NKTT120 in adults with steady state SCD. The optimal dose for a phase 2 study of NKTT120 will deplete iNKT for approximately 3 months allowing for periodic dosing.
Methods: Phase 1 study utilizing a 3+3 design to evaluate single doses escalating over a range of 5 doses from 0.001 mg/kg to 0.3 mg/kg thus far. The primary outcome measure is safety. Secondary outcomes include blood iNKT cell number depletion and recovery, pain, analgesic use, quality of life (QoL), and pulmonary function. During a screening run-in period and after dosing of NKTT120, subjects maintained a daily smartphone eDiary (eSCaPe) to report pain, respiratory symptoms and analgesic use. ASCQ-Me and PROMIS QoL questionnaires were administered at clinic visits. The screening run-in outcomes will be used as baseline comparison for values obtained post-dosing.
Results: At leastone month of follow-up data on iNKT cell numbers are available for the first eighteen patients dosed in the study. Three subjects were dosed at each dose level of 0.001, 0.003, 0.01, 0.03, and 0.1 and 0.3 mg/kg. Only iNKT cell counts were affected by NKTT120 dosing. No change in other hematologic parameters was observed. Eleven of 15 subjects in the first 5 cohorts had recovered iNKT cells by 28 days. Of the remaining 4 patients, 3 recovered iNKT cells by 56 days and the last recovered iNKT cells within 5 months. No patient has recovered iNKT cells in cohort 6 (0.3 mg/kg) within 28 days. Time to recovery of iNKT cells correlates with the starting circulating levels, with a longer recovery time for lower cell number. NKTT120 has been well tolerated with no dose limiting toxicities reported.
Conclusions: In steady state adults with SCD,NKTT120 administered up to a dose of 0.3 mg/kg specifically reduces iNKT cells without NKTT120 dose limiting toxicity. Patient cohorts at higher doses of NKTT120 are planned to further define the most effective dose and dose interval for iNKT cell depletion and recovery in the blood and target tissues. The final dose selection will support longer term studies on the reduction of iNKT cells in the suppression of the inflammatory stimuli that promote many of the pathophysiologic sequelae seen in SCD.

Disclosures
Vichinsky: ApoPharma: Research Funding; ARUP Research labs: Research Funding. Eaton:NKT Therapeutics: Employment. Mazanet:NKT Therapeutics: Employment.