👉 HTA on Zalmoxis demonstrates several major assessment principles of the German HTA body.

Zalmoxis (active substance: nalotimagene carmaleucel) was approved as an adjunctive treatment in haploidentical HSCT of adult patients with high-risk hematological malignancies in June 2016. Zalmoxis is a somatic cell therapy product. The pivotal study TK007 was a single-arm, uncontrolled phase 1/2 study. In this trial 30 patients with various malignant hematologic diseases were treated with Zalmoxis. In addition, the EMA requested a matched-pair analysis. This analysis compared the efficacy of Zalmoxis in patients from study TK007 and from the ongoing RCT TK008 to a historical control cohort from the EBMT registry.

As the marketing authorization for Zalmoxis was withdrawn in October 2019, it is no longer available in Germany.

🏆German HTA rating:

The German HTA rating in July 2018 resulted in a hint for a non-quantifiable additional benefit since the scientific data did not allow quantification. The additional benefit was only granted by law, because of the orphan drug status of Zalmoxis. The German HTA body commented the submitted evidence in the following way:

✅ The endpoint GvHD (acute and chronic) can be used for HTA, even though it is a composite endpoint partly based on laboratory parameters  

❌ HTA based on study TK007 was not possible due to the single-arm, uncontrolled design

❌The comparative matched-pair analysis is invalid, as adverse events were not analyzed, the analysis was insufficiently documented, and relevant matching factors were missing

❌Uncertainties arise from the small number of only 30 patients in a heterogeneous patient population with very different malignant hematological diseases

❌The study results are outdated, as the study was conducted from August 2002 to November 2013 and the clinical practice has further improved until time point of HTA

The HTA resolution on Zalmoxis was limited to April 2021, because the RCT TK008 was still ongoing and might have been potentially relevant for the assessment of the additional benefit of Zalmoxis.

💵 Launch price: € 163,900 per infusion bag with a concentration of 5 – 20 × 10⁶ cells/mL. Zalmoxis was approved for up to four infusions. Reimbursement price: 130,000. Rebate: 21 %.

📘 Special features of reimbursement:

The ATMP Zalmoxis was reimbursed, e. g. in all the bone marrow transplant centers operating in Germany, before market authorization was withdrawn.

💡 Insights for German HTA: The endpoint GvHD is considered patient relevant; indications with heterogeneous patient populations require trials with sufficient patient numbers; timewise, trial data should be collected within the current state of clinical practice; it is challenging to prepare data with an external control for submission; in case an RCT is still ongoing, the resolution on HTA might be limited, which requires a resubmission and an additional price negotiation.