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On July 2, 2024, Cartesian Therapeutics released four press releases in a single day, with "good news" continuing.Descartes-08 Phase 2b Trial for Generalized Myasthenia Gravis (gMG) Meets Primary Endpoint
Descartes-08 Treatment for Systemic Lupus Erythematosus (SLE) Phase 2 Trial Completes First Patient Dosing
CompanyCompleted a $130 millionPrivate Equity（PIPE）Financing
- Appointment of Kemal Malik to the Company's Board of Directors
Among them, Descartes-08 is Cartesian Therapeutics' first pipeline and also the world's first to enter the clinical stage.mRNA CAR-T Therapy,Under the spotlight.This time, not only did Descartes-08 succeed in its Phase 2b clinical trial, but it also further expanded its indications to include SLE. Influenced by this news, the company's stock price should have surged.But in fact, as of the close on July 2, Cartesian's stock price plummeted by 35%.
Cartesian Therapeutics, Inc. Stock Price (Source: Xueqiu)Why? Based on this scenario, two main reasons are considered:1. ConsiderCartesian was designed for hedgingThe short-term impact of PIPE (Private Equity In Public Equity) financing has led to the release of the aforementioned positive news.2. ConsiderationDescartes-08 ingMG'sPhase 2bThe actual results fell short of market expectations.According to the press release,In the modified intention-to-treat (mITT) population (n=26), the Descartes-08 treatment group had71%（10/14）subjects improved their MGC score by 5 points or more at the 3rd month of treatment, while only25% (3/12) (p=0.018), reaching a significant difference.In terms of safety, CartesianNo cases of cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome have been reported.The results were pretty good, even withLeerink Partners' analysts described the results as "a pivotal turning point in the CAR-T therapy field beyond oncology."”However, such success is questionable.Question 1: Replacement of Primary Endpoint
As early as May this year, Cartesian changed the primary clinical endpoint of the trial from the Myasthenia Gravis Activities of Daily Living Scale (MG-ADL) toMyasthenia Gravis Composite Scale（MG-C), the original MG-ADL was downgraded to a secondary endpoint.Note that the new drugs currently approved for gMG indications include Efgartigimod from Argenx/Zai Lab and Rozanolixizumab from UCB.All are based onMG-ADL as the trial endpoint.In previous studies,Cartesian Therapeutics usedMG-C、MG-ADL、MG-QoL-15r andQMG Four Scales for Evaluating Subjects. Among them, at 12 weeks of treatment, usingPatients on the MG-C scale showed the greatest improvement from baseline.
Average score change at Week 12 post-treatment (Image source: Cartesian Therapeutics' official website)AlthoughMG-C Scale forCartesianMore advantageous,But this does not mean that the replacement endpoint is bad; on the contrary, MG-C can more accurately measure the overall effect of the treatment.MG-C is a comprehensive scale that combines the commonly used MG-ADL, QMG, and MMT scales, and it is also relatively new (established in 2008, compared to 1999 for MG-ADL).
Preview of MG-C and MG-ADL Scales (Table Source: IgG Pioneer)In this clinical trial, the Descartes-08 treatment group showed significant improvement on the MG severity scale at the 3-month mark.Improvement（Average MG-ADL = -5.6;MGC = -8.3；QMG = -5.0；QoL-15r = -7.9）。And it is generally believed that a 3-point improvement in MG-C is clinically significant, while Cartesian adopts a stricter 5-point standard. (As for the data on 3-point improvement, Cartesian did not disclose it.)Concern 2: Limitations in the Analysis PopulationCartesian Therapeutics, Inc. in analyzing the data from this Phase 2b clinical trial,Excluding 9 subjects treated at community clinics, only 26 subjects enrolled at academic medical centers were retained.Which further led to the conclusion in the mITT population that "71% vs 25%"Experimental data.
Descartes-08 in the Phase 2b Clinical Trial Design for gMG (Image Source: Cartesian Therapeutics Official Website)However, Cartesian also announced the per-protocol population.）Analysis results of 31 subjects show that the response rates for the Descarte-08 group and the placebo group were69% and 33% (P=0.048), also showing a statistically significant difference.Concern 3: Imbalance in the Proportion of SubjectsIn the treatment group and the placebo group,The proportion of subjects with thymoma is not evenly distributed.42% of subjects in the placebo group had thymoma, but no one in the Descartes-08 group was affected.Meanwhile, the proportion of thymectomy in the placebo group was much higher than that in the treatment group, 21% vs 58% (n=3/7).
Distribution of Subjects in the Treatment Group and Placebo Group (Image Source: Cartesian Therapeutics Official Website)A randomized controlled trial (RCT) published in The New England Journal of Medicine indicated that thymectomy performed during the early stage of the disease in patients with myasthenia gravis (MG) without thymoma can reduce the time-weighted Quantitative Myasthenia Gravis Score (QMGS).That is, an unbalanced proportion of subjects is highly likely to affect the final scoring results.However, considering the small sample size of the trial, the impact is relatively limited, and we still need to wait for the phase III clinical data.In summary, although there are concerns about the use of Descarte-08 in gMG research, the impact on the actual results is not significant.The sharp drop in Cartesian's stock price is more attributable to the impact of PIPE financing. After all, if the issue were with clinical data, it would be difficult for the stock price to recover.The day after the press release was disclosed,That is, July 3,CartesianThe stock price rebounded to $17.62 per share, with an increase of 11.73%.
Last year, the FDA issued a black box warning for all CAR-T products on the U.S. market.Because traditional viral DNA transfection methods may cause random DNA insertion, leading to the development of T-cell tumors.And mRNA CAR-T, based on mRNA and does not integrate into the T-cell genome,Theoretically able to reduce DNA-related toxicity.In addition to being safer,Another significant challenge with traditional CAR-T therapy is that after the CAR-T cells are infused into the body and come into contact with the antigen, they undergo further expansion, which is uncontrollable. As a result, the efficacy also presents uncertainty.According toThe Cartesian official website states,Descarte-08 can be passed throughMultiple dosing,Help CAR-T cells expand better in patients. At the same time, this can also avoidClearing,ReducePatientSide effects caused by chemotherapy and the inconvenience of treatment.In the future,mWhether RNA CAR-T can be successfully used for autoimmune diseases, or even solid tumors, still requires more clinical data to prove. PharmaTimes will continue to follow up.
Cover image source: pixabay
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