ABSTRACT
Background. COVID19 associated moderate to severe acute respiratory distress syndrome (ARDS) is associated with high rates of morbidity and mortality. Immune dysfunction and hyper-inflammatory responses result in a vicious cycle of tissue inflammation and end organ damage. Based on the suggestion of early efficacy of adoptive therapy with allogeneic T regulatory cells in COVID19 ARDS (Gladstone et al., Ann Int Med 2020), Cellenkos ® initiated a randomized, placebo controlled, multi-center trial of multiple doses of CK0802 (allogeneic, off-the-shelf, cryopreserved, cord blood derived T regulatory cells) for treatment of moderate-to-severe COVID19-related ARDS patients. Study design. Multi-center, randomized, blinded, placebo controlled trial of CK0802 at two different doses (100 million cells and 300 million cells ) were compared to placebo. Each patient was randomized to receive the assigned product on days 0, 3 and 7 (Figure 1), without HLA matching. Enrollment was staggered for the first 6 active treatment patients with 7 days between each patient while monitoring for any safety signals. Subsequent patients were enrolled on a continuous basis. DSMB monitoring occurred after every cohort of 15 patients (5 controls;5 of each active treatment). Results are presented as median (with range) unless otherwise indicated. Primary Outcomes. The two co-primary outcomes were: • Dose Limiting Toxicity (DLT) = Regimen related grade 3, 4, or 5 toxicity within 48 hours of first infusion • S28 = [Alive and not intubated 28 days after the date of first infusion] = 28-day treatment success Secondary Outcomes. Secondary outcomes, recorded from first day of infusion up to 28 days later, included: i) time to extubation, ii) ventilator-free days;iii) organ failure-free days;iii) ICU free days;iv) PaO 2/FiO 2 between days 0 and 11;and v) 28-day all-cause mortality Covariates. Patient covariates recorded at enrollment included: i) age, ii) gender iii) on vasopressors;iii) on hemodialysis;iv) duration of intubation prior to enrollment. Study Conduct. The multicenter study (n=5 centers) was activated in October 2020 and enrollment completed in March 2021. Results. Forty-five patients were enrolled (60% male, median age 60 [range 21-85], 46.7% Caucasian race). At baseline 13% were on hemodialysis;62% on vasopressors;SOFA score=8 (6-13);PaO 2=85 mmHg (45-133);FiO 2=60% (40-100);PEEP=10 cmH 2O (5-18) with a median duration of intubation of 48 hrs (0-120) prior to enrollment. Patient were intubated a median of 72 [0-144] hours prior to infusion. Sixty percent of patients were alive and extubated at day 28. Median time to extubation from first infusion was 10.5 [2-46] days and median ventilator free days at day 28 was 12 [0-26]days. No treatment related SAEs were reported. Time to extubation from first infusion was 10.5 days (2-46) and at day 28 the ventilator free days were 12 (0-26). The estimated day 28 overall survival was 78.6% with the following breakdown according to the co-variates: i) age>60 yrs =77.5% vs. age<60yrs=79.9%;ii) female=85.7% vs male=73.7%;iii) on vasopressor=65.8% vs. 77.8%;iv) on hemodialysis=75% vs. 79%. Duration of intubation to enrollment had no impact on 28d survival. At baseline, 14 pts were positive for both HLA I and HLA II antibodies (Abs);3 pts positive for HLA I Ab only, and 9 positive for HLA II Ab only. In 20 paired samples collected on day 0 and day 28, HLA I Ab and HLA II Ab seroconversion was observed in 4 and 1 pt, respectively. Discussion This is the first clinical trial to examine safety and early efficacy of multiple doses of allogenic, off-the-shelf, cryopreserved, T regulatory cells for the treatment of COVID-19-related ARDS. Full data analysis of treatment groups (placebo;CK0802-100 million;CK0802-300 million) is ongoing and will be presented at the conference. Additional data to be presented will include: 3- and 6- month QOL, mental health, and cognitive index analyses, and paired Biomarker analysis. [Formula presented] Disclosures: Hari: Janssen: Honoraria, Membership on an ntity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau;GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau;Celgene-BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau;Millenium: Membership on an entity's Board of Directors or advisory committees, Research Funding;Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau;Adaptive Biotech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding, Speakers Bureau;Karyopharm: Consultancy;Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sadeghi: Cellenkos Inc.: Current Employment. Parmar: Cellenkos Inc.: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Mukherjee: Vor Biopharma: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: coinventor on issued and pending patent applications licensed to Vor Biopharma. S.M. has equity ownership and is on the Scientific Advisory Board of Vor Biopharma., Research Funding.
ABSTRACT
Background: Death from COVID-19 disproportionately affects men, with up to 80% of deaths in severe COVID-19cases being in men. There are a number of potential differences that might contribute to these sex differences.TMPRSS2 is a serine protease that primes the spike protein of SARS-CoV-2, a critical step in viral entry. TMPRSS2is most highly expressed in the prostate where it is under androgen control, upregulated by testosterone anddownregulated by antiandrogens. ACE2, the receptor used for entry into the host cell, is located on the Xchromosome and may also have levels that are altered by hormones, with estradiol downregulating its expression.Previous research on acute lung injury demonstrated that estradiol seems to have beneficial effects on repair of lunginjury. Therefore, our central hypothesis is that hormones may partially contribute to the gender disparity seen inCOVID-19 patients, with high levels of testosterone being harmful and high levels of estrogen being helpful.Bicalutamide is a nonsteroidal antiandrogen that inhibits the action of androgens and, via feedback on thehypothalamic-pituitary axis, upregulates estradiol. We are conducting a phase II clinical trial to determine ifbicalutamide improves the percentage of COVID+ patients with clinical improvement by 7 days. Methods: We will enroll 40 patients who are hospitalized for COVID-19 with minimal respiratory symptoms(respiratory rate <30 and < 6L oxygen by nasal canula). Patients with more severe symptoms or oxygenrequirements, who have taken hormones within the past month, or have pre-existing liver or cardiac disease will beexcluded. Patients will be randomized 1:1 (20 in each arm) to bicalutamide or standard of care and will be stratifiedby gender. The primary outcome is comparing the percentage of patients with clinical improvement at day 7, compared to historical controls based on the World Health Organization categorical scale of clinical improvement.Key secondary clinical endpoints include all-cause mortality at 28 and 60 days, need for mechanical ventilation orICU care, and safety of bicalutamide in this population. We will also determine the impact of bicalutamide therapy onviral infectivity by studying the reduction in viral load, hormone modulation and engagement of the endocrine axis, and immune response modulation promoting pro-repair immune function in patients with COVID-19. Clinical trialregistration number: NCT04374279.