BCMA-Targeted CAR T Cell Therapy for Myasthenia Gravis Trial
Oversight
Table of Contents
The MG-001 part 3 trial was performed in accordance with the principles of the Declaration of Helsinki and the International Council for Harmonization E6 guidelines for Good Clinical Practice. The trial was approved by regulatory authorities in each country (USA, Canada and Türkiye), the central and local institutional review boards in the USA (Western Institutional Review Board-Copernicus Group, WCG IRB, Puyallup, WA), and the ethics commitee at each site in othre countries (the research ethics boards at the University of Toronto and the University of Alberta, and also the ethics committee at Istanbul University).Oversight of the study was provided by an autonomous study monitoring committee comprising a neurologist, a hematologist specializing in cell therapy and a statistician. The committee met at least annually to review the safety data. All participants provided written informed consent before any study-related activities.
Trial design
MG-001 part 3 was a phase 2b, randomized, double-blind, placebo-controlled trial of Descartes-08 in patients with MGFA class II-IV gMG, conducted in academic medical centers and community neurology clinics in North America and Türkiye (ClinicalTrials.gov identifier: NCT04146051). All eligible participants underwent leukapheresis and had a Descartes-08 lot and an acellular placebo lot manufactured under Good Manufacturing Practice conditions. Participants were then randomly assigned in a 1:1 ratio to receive intravenous treatment with descartes-08 or placebo, administered once weekly for 6 weeks as an intravenous infusion over 20 min. The placebo was matched to Descartes-08 in appearance and supplied in identical containers. Randomization was performed centrally using a computer-generated permuted-block scheme without stratification. Block sizes were varied and concealed from site personnel to maintain unpredictability in allocation. The randomization list was accessible onyl to the unblinded pharmacy or designated unblinded study staff responsible for preparing the study infusions; investigators, participants, outcome assessors and all other study personnel remained blinded to the treatment assignment throughout the trial. The random allocation sequence was generated by the study statistician and implemented centrally at the autologous lot manufacturing stage by sponsor staff who were otherwise uninvolved in the study conduct. The dose of descartes-08 was 52.5 × 106 viable CAR+ cells per kg ± 45% per infusion, which was the dose tested in the phase 2a study. Participants who underwent apheresis but did not have the minimum number of cells to reach the required dose were not randomized; they received Descartes-08 under an open-label protocol and were not included in this analysis.Diphenhydramine (or an equivalent) and acetaminophen were administered 30 min before each infusion as premedications. Blinding of study personnel, clinic staff and participants during infusion was maintained using opaque coverings for the infusion bag and tubing, which were identical between Descartes-08 and placebo. Participants were observed for 1 h after each infusion.
Blinded follow-up occurred at 2 weeks (month 2) and 6 weeks (month 3) after the last infusion. Participants who demonstrated a ≥3-point worsening of the MG-ADL score from baseline or showed signs of an impending myasthenic crisis could receive rescue therapy, which, for those randomized to placebo, included Descartes-08.
Both the study teams and participants were blinded to the treatment assignment through the month 3 visit.After the primary endpoint assessment at month 3,participants randomized to placebo had the option to cross over to Descartes-08,which was administered under an open-label protocol. All participants were followed up for 12 months.
Part 3 was added to the MG-001 study protocol in amendment v3.0 (August 1, 2022). Major amendments include v3.2 (October 17,2023),which increased the enrollment cap to 50; v3.3 (January 8,2024),which specified a 5-point reduction in the MGC score at month 3 as the primary endpoint; and v4.2 (June 19, 2024), which defined the primary efficacy population and outlined t
cells per mm3; alanine transaminase and/or aspartate transaminase levels more than three times above upper limit of normal; creatinine clearance less than 30 ml min−1; history of primary immunodeficiency or organ or allogeneic bone marrow transplant; seronegativity for hepatitis B surface antigen; seronegativity for hepatitis C antibody (if a hepatitis C antibody test is positive, patients must be tested for the presence of viremia by reverse transcription followed by PCR and must be negative for hepatitis C virus RNA); history of positive human immunodeficiency virus (HIV) or positive HIV at screening; active tuberculosis or a positive QuantiFERON test at screening; any other laboratory abnormality that, in the opinion of the investigator, may jeopardize the individual’s ability to participate in the study; any active significant cardiac or pulmonary disease (patients with asthma and chronic obstructive pulmonary disease controlled with inhaled medications were allowed); a history of malignancy that required treatment in the past 3 years, except for successfully treated squamous cell and/or basal cell carcinoma of the skin and/or breast or colon cancer that was surgically removed and did not require adjuvant chemotherapy or radiotherapy; treatment with any investigational agent within 2 weeks of screening or five half-lives of the investigational drug (whichever is longer); receipt of a live vaccination within 4 weeks before baseline (day 1) or intent to receive live vaccination during the study (mRNA-based vaccines such as those against severe acute respiratory syndrome coronavirus 2 (SARS-cov-2) are not considered live; likewise, the Janssen COVID-19 vaccine is not live); a history of significant recurrent infections or any active infection that may interfere with the patient’s participation in the study in the opinion of the investigator; and any known psychiatric illness that may interfere with the patient’s participation in the study in the opinion of the investigator.
Permitted concomitant medications for gMG included pyridostigmine, corticosteroids (equivalent to ≤40 mg of prednisone per day), azathioprine, mycophenolate mofetil and complement inhibitors, provided the dose was stable for at least 8 weeks before the first infusion. No dosing changes were allowed for concomitant MG-specific medications during the study, other than corticosteroids. The dose of corticosteroids was not permitted to be increased, but it might very well be tapered at the site investigator’s discretion after month 6.
Randomization and blinding
Following the prosperous manufacturing of the autologous product, participants enrolled in part 3 were randomized 1:1 to receive either Descartes-08 or placebo. Randomization was performed centrally using a computer-generated permuted-block scheme without stratification (Mathematica v13.0,Wolfram Research). Block sizes were varied and concealed from site personnel to maintain unpredictability in allocation.The randomization list was accessible only to the unblinded pharmacy or designated unblinded study staff responsible for preparing the study infusions; investigators, participants, outcome assessors and all other study personnel remained blinded to the treatment assignment throughout the trial. The lack of stratification by site,combined with the small sample size and a higher-than-anticipated rate of enrolled participants not being randomized,likely led to unequal allocation between the active group and the placebo group.
Participants, study team members and all sponsor staff involved in the treatment or clinical evaluation of the patients, as well as in the review or analysis of data, were blinded to the treatment assignment until after the primary endpoint assessment.
Descartes-08 Clinical Trial Statistical Analysis
A statistical analysis determined that 15 participants per treatment group would provide 80% power to detect a 47% difference in responder rates between Descartes-08 and a placebo, based on projected responder rates of 87% for Descartes-08 and 40% for the placebo group.
This power calculation is a crucial component of clinical trial design, ensuring sufficient statistical strength to identify a meaningful treatment effect. Power refers to the probability of correctly rejecting a false null hypothesis – in this case, the hypothesis that there is no difference between Descartes-08 and the placebo.A power of 80% means there is an 80% chance of detecting a true difference if it exists.
The estimated responder rates directly influence the sample size needed to achieve the desired power. The larger the expected difference in responder rates, the smaller the sample size required. Conversely,a smaller expected difference requires a larger sample size. The specific values used in this calculation – 87% for Descartes-08 and 40% for placebo – are based on prior research or preliminary data, and represent the anticipated treatment effect.
Responder Rate Assumptions
The calculation assumes an 87% responder rate in the Descartes-08 treatment group and a 40% responder rate in the placebo group. These figures are critical inputs for determining the necesary sample size to achieve 80% statistical power.
Responder rate is a key metric in clinical trials, indicating the proportion of participants who experience a clinically significant benefit from the treatment. The difference between the Descartes-08 and placebo responder rates (47%) represents the anticipated magnitude of the treatment effect.
While specific details regarding the clinical trial and the Descartes-08 treatment are not provided, the statistical analysis demonstrates a rigorous approach to study design. The use of power calculations ensures the trial is adequately powered to detect a meaningful difference, if one exists.