To The Moon

Recently, the sales figures for six global CAR-T therapies that have been marketed were announced. From a market perspective, five of the CAR-T therapies have continued to perform well, with sales revenue increasing year by year.

However, Kymriah, which is the first CAR-T therapy approved for marketing globally, has become the only CAR-T product with declining revenue.

In 2022, the world's first CAR-T therapy, Novartis' Kymriah, generated sales revenue of only $536 million, a 9% year-on-year decrease. However, Novartis stated that "the growth in sales revenue in emerging markets partially offset the decline in market sales revenue in the United States and Europe."

However, this seems to be a unilateral statement from Novartis to appease the market. Since Q2 2021, Kymriah's quarterly growth rate has shown negative growth. In comparison, Yescarta and Breyanzi, two other CAR-T therapies, continued to show quarter-on-quarter growth in 2022, with Yescarta still showing rapid growth. In comparison, Kymriah's decline has been evident for some time, and it seems that it will not be easy to reverse the situation in the future.

As the world's first CD19 CAR-T cell therapy, Kymriah currently has three indications approved by the FDA, including:

(1) Treatment of relapsed or refractory acute lymphoblastic leukemia (r/r ALL) in children and young adults (up to 25 years of age);

(2) Treatment of relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) in adult patients;

(3) Treatment of relapsed or refractory follicular lymphoma (r/r FL) in adult patients who have previously received two or more lines of systemic therapy.

Currently, three other CD19 CAR-T therapies, Yescarta (DLBCL & FL), Tecartus (FL & ALL) by Gilead, and Breyanzi (DLBCL) by BMS, have similar indications as Kymriah. In terms of efficacy, as the world's first CAR-T therapy, Kymriah's objective response rate (ORR) and complete response rate (CR) are significantly lower than other products, at only 52% and 40%, respectively.

In terms of safety, the incidence of grade 3 or higher cytokine release syndrome (CRS) for Kymriah is 22%, which is the worst among the four CAR-T products, but Kymriah maintains a good level of neurotoxicity.

From pricing perspective, Kymriah has no advantage. Currently, the treatment price of Kymriah is USD 475,000 per dose, while the prices of Yescarta and Tecartus are USD 373,000 per dose, and the price of Breyanzi is USD 410,300 per dose. The price difference of Kymriah compared to its competitor Yescarta is as high as USD 100,000, making it difficult for patients to have a choice.

It is worth noting that Kymriah is currently the only CAR-T therapy approved for use in children with acute lymphoblastic leukemia, but even with this advantage, it is still struggling due to various disadvantages.

A few months ago, the international giant GlaxoSmithKline (GSK) terminated its collaboration with three cell therapy companies, including Lyell Immunopharm, Adaptimmune, and Immatics, all of which started as early as 2019. Shortly thereafter, GSK formally announced the termination of its R&D investment in cell and gene therapy.

For GSK, the reason for giving up investment in cell therapy is not difficult to guess. The CAR-T race for blood tumors is too crowded, and the challenges of expanding into solid tumors are far more difficult than imagined. Moreover, CAR-T therapy requires a lot of human and material resources, and its production efficiency is relatively low. Currently, the production capacity still cannot fully meet clinical needs. This is also a hurdle that CAR-T is currently difficult to avoid.

In terms of indications, CD19 CAR-T also faces many new disruptors. On January 19th, Roche's new drug CD79b ADC was approved for use in combination with bendamustine and rituximab to treat r/r DLBCL. The combination therapy showed a best overall response rate of 56% and a median PFS of 5.5 months (95% CI, 4.3-12.8).

In addition to ADC, Roche's first CD20xCD3 bispecific antibody drug, Glofitamab, which is mainly used to treat relapsed or refractory mantle cell lymphoma (r/r) MCL, also received priority review from the FDA last month, with a PDUFA date set for July 1, 2023. In a previous phase 1/2 clinical trial, the overall response rate (ORR) and complete response rate (CR) of Glofitamab were 83.8% (31/37) and 73.0% (27/37), respectively.

Another CD20xCD3 bispecific antibody drug, Mosunetuzumab, is also actively progressing, mainly used to treat relapsed/refractory follicular lymphoma (r/r) FL. In a phase 2 clinical trial, the objective response rate (ORR) evaluated by IRC was 80% (95% CI, 70.3-87.7), and the CR rate was 60% (95% CI, 49.1-70.2).

In addition to these, there are several new drugs in the bispecific field, including Epcoritamab, Odronextamab, and IGM-2323, which already cover the indications of (r/r) DLBCL, (r/r) FL, and (r/r) MCL, which are currently the main indications approved for CD19 CAR-T. In the future, with better accessibility, more sufficient production capacity, and lower prices, these drugs will inevitably have a significant impact on the already marketed CAR-T market.