@AICpMy worry is maintained. I can't come to a conclusion on the safety of the compound because I do not know what they did with the dose. If you evaluate the slide from the most recent Azer-cel presentation below, you'll notice that the inclusion of IL-2 decreases the frequency of ICANS. However, this does not reflect what is known for Azer-cel.
The 2022 ASH Azer-cel poster reviewed 44 patients. While maintaining standardised lymphodepletion, the dose levels (DL) used in this work are as follows:
DL1: 3 x 10^5 CAR T cells/kg
DL2: 1 x 10^6 CAR T cells/kg
DL3: 3 x 10^6 CAR T cells/kg
DL4: 500 x 10^6 CAR T cells/kg
https://precisionbiosciences.com/wp-content/uploads/2022/12/ASH-2022_poster_vF.pdfFigure 3 of the poster shows a significant increase (p < 0.01) in ICANS rates with the addition of IL-2 and not a decrease. This is not what has been observed from the P1 safety data, therefore, I suspect that they have reduced the dose of Azer-cel to make it safer.
Figure 1 from the poster quite clearly states a significant positive correlation (* = p <0.01) between the CAR T effective cell dose and
death. Another reason why you would want to decrease the dose, but decreasing the dose means reducing the efficacy. This may explain why the ORR and CR for Azer-cel recently was below what has been seen in previous studies. It seems like there is a fine line between giving enough to be effective or giving too much and risking being severely toxic.
Cema-cel (formerly ALLO-501A) achieved breakthrough therapy designation in June 2022 for the treatment of relapsed/refractory large B cell lymphoma. Allogene, the owner, completed their phase 1 clinical trial of Cema-cel recently, and the results are impressive.
https://allogene.com/pipeline/#scientific-publicationsThe median lines of therapy was 3. For those who had received the phase 2 dose, there were almost no grade 3 toxicities and no patients died as a result of allogeneic CAR T treatment. Moreover, there were no grade 3 cytokine release syndrome or ICANS.
For those who received the phase 2 dose, the ORR was 67% with 58% achieving CR, 42% maintaining CR at 6-months post infusion, and a median duration of response of 23.1 months. Using all 93 patients treated to date for Azer-cel, the average ORR is 57% with 45% achieving CR.
Allogene have already initiated a phase 2 registrational trial in large B cell lymphoma. The Boston Consulting group state that first-to-market drugs, particularly oncology, capture the largest market share. Followers need to establish themselves quickly (<2-years) if they are to challenge the first. If fast followers demonstrate a substantial benefit over the first-mover, then they can capture a large portion of the available market. Since Cema-cel demonstrates excellent efficacy and safety and that a phase 2 registrational trial has begun, even if Azer-cel is successful, IMU are going to struggle to capture adequate market share.
https://www.nature.com/articles/d41573-023-00048-2
I think you and others need to seriously consider your positions.
(20min delay)