👉 The German HTAs on Yescarta and Kymriah (first CAR-T cell therapies in the EU) touch many HTA regulations. In this post on Yescarta you will learn about principles of orphan drug reassessment, reimbursement restriction for ATMPs, bundling of German HTAs, CAR-T cell therapies as appropriate comparators and price levels as well as rebate contracts of CAR-T cell therapies. 

Yescarta (active substance: axicabtagene ciloleucel) is a CAR-T cell therapy and currently authorized for three indications. The initial EU marketing authorization was in August 2018. Yescarta is indicated for treatment of patients with DLBCL and HGBL after first-line chemoimmunotherapy (authorized: October 2022), for treatment of patients with DLBCL and PMBCL after two or more lines of systemic therapy (authorized: August 2018), and for treatment of patients with FL after three or more lines of systemic therapy (authorized: June 2022). Authorization of the late stage DLBCL, PMBCL and FL was based on single arm trials. Remarkably, authorization of DLBCL and HGBL after first-line chemoimmunotherapy was based on the RCT ZUMA-7 comparing Yescarta to induction therapy followed by HDCT with autologous SCT. ZUMA-7 is one of the first comparative trials for CAR-T cell therapies.

Yescarta is available in Germany.

🏆German HTA rating:

To date Yescarta was assessed in 6️⃣ German HTAs.

1️⃣  Initially authorized indication: DLBCL after two or more lines of systemic therapy (HTA resolution: May 2019)

2️⃣  Initially authorized indication: PMBCL after two or more lines of systemic therapy (HTA resolution: May 2019)

3️⃣  Reassessment after limitation: DLBCL and PMBCL after two or more lines of systemic therapy (HTA resolution: November 2022)

The first three German HTA ratings resulted each in a hint for a non-quantifiable additional benefit since the scientific data did not allow quantification. As only non-randomized, non-controlled studies were submitted for HTA, the additional benefit was granted by law, because of the orphan drug status of Yescarta.

The first two resolutions were limited because treatment with Yescarta represented a novel therapeutic approach. The long-term effects could initially not be fully assessed, particularly with regard to a potential cure of the patients.

4️⃣  Reassessment after exceeding an annual revenue of € 30 million: DLBCL and PMBCL after two or more lines of systemic therapy (HTA resolution: December 2023)

If the sales of an orphan drug (like Yescarta) through the statutory health insurance exceed an amount of € 30 million in the last twelve calendar months, the additional benefit will be assessed vs. the appropriate comparator. Yescarta exceeded the € 30 million revenue limit in December 2022. In July 2023 a new assessment started without the orphan drug privilege. 👉 Of note, the German HTA body defined exclusively the other CAR-T cell therapies Kymriah and Breyanzi as appropriate comparators, giving credit to their relevance in the German health care context as well as to current guideline recommendations.

No direct comparative data of Yescarta vs. Kymriah or Breyanzi exists. Submitted retrospective uncontrolled data from French DESCAR-T registry, comparing Yescarta vs. Kymriah, was due to insufficient confounder adjustment unsuitable for the benefit assessment. Consequently, the resolution on German HTA from December 2023 resulted in no additional benefit for Yescarta.

5️⃣   New indication: DLBCL and HGBL after first-line chemoimmunotherapy (HTA resolution: December 2023)

German HTA was based on the RCT ZUMA-7 comparing Yescarta to induction therapy followed by HDCT with autologous SCT in patients eligible for high-dose therapy. The comparator of ZUMA-7 was the correct implementation of the appropriate comparator for one subpopulation. Yescarta showed significant advantages in event-free survival (EFS) and overall survival (OS). However, the effect is uncertain to the German HTA body as relevant protocol changes on endpoint read-out were made after start of the study. In conclusion, the advantage of Yescarta could not be quantified. The German HTA resulted in a hint for a non-quantifiable additional benefit in one subpopulation (patients eligible for high-dose therapy). For patients being ineligible for high-dose therapy no RCT was submitted and accordingly an additional benefit is not proven. 

6️⃣   New indication: FL after three or more lines of systemic therapy (HTA resolution: December 2023)

An additional benefit is not proven, as only a single-arm study and a retrospective study were submitted for HTA.

📚 Assessments 4, 5 and 6 were bundled and were assessed simultaneously by the German HTA body (bundling is possible if the beginning of the HTAs is no longer than 6 months apart; it must be applied for a bundling at the German HTA body). Simultaneous HTAs might be beneficial for the HTD, as results of these HTAs will be negotiated within a single price negotiation, allowing for more levers in the negotiation.

💵 Launch price: € 327,000. Yescarta is used as a one-time treatment. Reimbursement price: € 272,000 (so far two price reductions, joint price negotiations after bundled HTAs most likely not completed, yet). Current cumulated rebate: 17 %

📘 Special features of reimbursement:

Yescarta is reimbursed in Germany.

Health insurance companies have agreed with the HTD on a “pay for cure” contract. The contract is based on the outcome for patients in terms of survival. If the patient dies (due to the disease) within a defined period of time, the reimbursed price is partially refunded. Further details of the contract are not publicly available.

📜 The German HTA body has set up a binding guideline on minimum quality assurance requirements for gene and cell therapies, the so called “ATMP-Qualitätssicherungs-Richtlinie” (ATMP Quality Assurance Guideline). This guideline defines requirements for medical facilities and equipment as well as minimum case numbers. In the main part of the guideline e. g. general reporting obligations are described. The ATMP-specific requirements are annexed to the guideline. ATMP-specific annexes exist for CAR-T cell therapies in B-cell neoplasia (annex I), Zolgensma in spinal muscular atrophy (annex II), Ebvallo in EBV-positive post-transplant lymphomas (annex III) and gene therapies in hemophilia (annex IV). Annex V for Upstaza in AADC deficiency will most like come into effect in September 2024.

Annex I defines B-cell neoplasia by various ICD-10 codes, which include precursor B-lymphoblastic leukemias (like ALL), B-cell lymphomas (like DLBCL, FL, CLL and MCL) and multiple myeloma. For example, annex I presupposes extensive experience of a hospital in the treatment of the disease and in cell therapy: ≥ 150 treated patients with B-cell lymphomas and ≥ 120 treatments with allogeneic or autologous SCT or CAR-T cell therapies within the last three calendar years. In addition, the treatment centers must meet requirements to connect to the registry modules for CAR-T cell therapies for the DRST, PRST and EBMT registry. In particular, previous therapies, side effects, type and duration of response, follow-up therapies and overall survival must be documented in these registries.

❗ Yescarta is only reimbursed in hospitals, which meet all requirements of the ATMP Quality Assurance Guideline and the respective annex I. Consequently, the ATMP Quality Assurance Guideline restricts the reimbursement and practically the use of Yescarta to few very specialized treatment centers.

🔎 Yescarta exceeded an annual revenue of € 30 million, leading to reassessment of Yescarta without the orphan drug privilege and requiring evidence vs. the appropriate comparator. Often, direct comparative evidence for orphan drugs vs. the appropriate comparator does not exist. In the case of Yescarta generating such evidence is additionally challenging because the appropriate comparators are CAR-T cell therapies only. It is currently unclear how CAR-T cell therapies can be implemented as comparators in clinical trials. However, (high priced) CAR-T cell therapies as appropriate comparators are a good basis for reimbursement price negations.

Certain ATMPs are regulated by the ATMP Quality Assurance Guideline, which restricts the use and reimbursement of these ATMPs to few specialized treatment centers. The German HTA body might expand the current guideline to cover further ATMPs and/or indications, probably depending on future authorizations of ATMPs.