A new era in biomedicine
Kimraya: Meet the world's first T-cell CAR therapy
The US Food and Drug Administration (FDA) has granted Novartis a permit for Kymriah (tisagenlekleysel) – the world's first officially approved T-cell CAR therapy (CAR-T). The regulator issued a positive verdict ahead of the deadline set for the end of September.
Intravenous "Kimraya", previously held under the internal designation CTL019, is approved for use against B-cell acute lymphoblastic leukemia (ALL) from progenitor cells in children and adults (up to 25 years of age) whose disease is refractory to treatment or has recurred at least twice.
The appearance of "Kimraya", as a completely personalized therapy for the patient, proclaims the beginning of a new era in the field of biotechnology and the management of oncological diseases.
Current options for dealing with acute lymphoblastic leukemia are limited, despite the fact that the median overall survival is very modest, being within three to nine months. Acute lymphoblastic leukemia is diagnosed in a quarter of cancer cases in patients under the age of 15. The chances of survival within five years for those who have experienced multiple relapses or have not been able to reach remission are in the range of 10-30%.
The mechanism of action of "Kimraya"
The mechanism of action of tisagenlekleysel, developed jointly with the University of Pennsylvania, is as follows. Autologous T-cells of the patient, obtained from peripheral blood mononuclear cells through a standard leukapheresis procedure, are genetically reprogrammed by transfection with a lentiviral vector that causes the expression of chimeric antigenic receptors (CAR), which recognize and destroy CD19-positive cancer B-cells. Transfected T cells are cultured, purified and converted into a suspension, which is cryopreserved for safe delivery to the patient.
The CAR design consists of three components (scFv-41BB-cd3ζ): a single-stranded variable fragment of an anti-CD19 antibody binding to CD19; a 4-1BB costimulating domain (CD137) that enhances T-lymphocyte-mediated responses; an intracellular T-cell receptor CD3-zeta domain of the signal chain that induces activation of T-lymphocytes and antitumor activity. Image: Pharmacodia.
Clinical efficacy of "Kimraya"
Tisagenlekleysel is characterized by high targeting. This is confirmed by the results of the ELIANA phase II reference clinical trials, in which 68 patients received a single dose of tisagenlekleysel – an efficiency assessment was carried out for 63 people.
After three months, 83% of the participants went into complete remission (the number of blast cells in the bone marrow does not exceed 5%) or complete remission with partial restoration of the shaped blood elements (n=52/63; p<0.0001): 63% (n=40/63) and 19% (n=12/63) of patients, respectively. At the same time, minimal residual (residual) disease, as an oncohematological marker of a potential relapse, was not recorded in any of those who responded to treatment. The median duration of remission has not yet been reached.
Kimraya Security
Regarding the safety of the use of tisagenlekleysel, 49% of patients recorded cytokine release syndrome (CRS) level 3 or 4 – a known negative side reaction of CAR therapy associated with the activation of modified immunological cells. There were no deaths due to complications of treatment.
It is proposed to cope with the cytokine storm with the appointment of "Actemra" (Actemra, tocilizumab), an interleukin 6 blocker authored by "Roche" (Roche): the regulator has already made an appropriate appointment in the spectrum of indications of this drug.
The cost of treatment "Kimraya"
Taking into account both the peculiarities of drug pricing in the West and the innovative component of CAR therapy, coupled with its incredible effectiveness, the cost of tisagenlekleysel will simply be prohibitive. And so it turned out: Novartis wanted 475 thousand dollars for one infusion of Kimrair.
By the way, the Swiss pharmaceutical locomotive announced cooperation with the Centers for Medicare and Medicaid Services (CMS) – the federal health programs of the United States: payment for Kimraya treatment will be made only if the patient has responded to the drug by the end of the first month after injection.
The cost issue of such a unique medicine is closely related to the risks of its adoption in the community. So, for example, Bayogen asks for Spinraza (nusinersen), the first medicine against spinal muscular atrophy that appeared at the end of 2016, for 750 thousand dollars in the first year, and then for 375 thousand dollars annually. Despite the huge price tag, sales of antisense nusinersen are growing by leaps and bounds.
Nevertheless, in April, UniQure abandoned Glybera (Glybera, alipogen tiparvovek) against lipoprotein lipase deficiency (familial chylomicronemia, hyperlipoproteinemia type Ia). And in July, GlaxoSmithKline announced its desire to get rid of the orphan business, which includes Strimvelis against congenital adenosine deaminase deficiency. It should be understood that companies require 1.2 million and 665 thousand dollars, respectively, for the course of these gene therapy drugs.
Production of "Kimraya"
According to Novartis, which has seriously prepared for the launch of the new product on the market, the time required to launch the production cycle and release the finished tisagenlekleysel, individualized for each patient, will take 22 days.
The future of Kimraya
Novartis is going to apply this year to expand the prescriptions of tisagenlekleysel by connecting adult patients with recurrent and/or refractory diffuse B-large cell lymphoma (DLBCL) related to aggressive non-Hodgkin's lymphomas.
Interim results of JULIET phase II clinical trials demonstrated that in the third month after a single administration of tisagenlekleysel, a general response was recorded among 45% of patients (n=23/51): a complete response in 37% of participants (n=19) and a partial response in 8% (n=4). The complete response remained stable for three months after the data collection was stopped.
Competitors and CAR Therapy
The main confrontation in the CAR arena is currently being conducted between Novartis and Kite Pharma, which was recently bought by Gilead Sciences, which laid out approximately $ 11.9 billion in cash.
By the end of November, the FDA must decide on the application filed in March for the CAR-therapeutic axicabtagene ciloleucel, or KTE-C19, aimed at recurrent and/or refractory aggressive non-Hodgkin's lymphomas, such as DLBCL, transformed follicular lymphoma (TFL) and primary mediastinal B-large cell lymphoma (PMBCL).
Juno Therapeutics and Bluebird Bio have achieved some success, working separately, but each together with Celgene: the first boasts of the achievements of CAR therapy among patients with DLBCL, follicular lymphoma at stage 3B or mantle cell lymphoma (MCL), the second is pleased with the results of treatment of multiple myeloma.
A new strong player was the Chinese Nanjing Legend Biotech, which announced the amazing results of CAR therapy: five patients with recurrent and/or refractory multiple myeloma, who were monitored for over a year, continue to remain in the status of a strict complete response. And this is surprising, because the cells of the experimental LCAR-B38M persist in the body for only a few months. It is generally recognized that long-term remission requires the constant presence of CAR cells. So the patients are most likely completely cured.
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06.09.2017