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FDA Breakthrough A’La CAR-T: Medness Focus on Novartis CTL019

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What’s the big news?

Novartis announced that the US Food and Drug Administration (FDA) has accepted the company’s Biologics License Application (BLA) filing and granted priority review for CTL019 (tisagenlecleucel-T), an investigational Chimeric Antigen Receptor T cell (CAR-T) therapy, in relapsed and refractory (r/r) pediatric and young adult patients with B-cell acute lymphoblastic leukemia (ALL). This is the first BLA submission by Novartis for a CAR-T. The priority review designation is expected to shorten the anticipated review time by the FDA.

What’s even bigger?

On April 18 (2017) CTL019 received the FDA granted breakthrough therapy designation for the treatment of adults with relapsed and refractory diffuse large B-cell lymphoma who failed two or more prior therapies. Read more

What is ALL?

Image reference

Acute Lymphoblastic Leukemia (ALL)

Each part of its name tells you something about the cancer itself:

    • Acute: Often fast-growing, requires early detection and treatment. Without treatment, bone marrow cells developmentally impaired, resulting in an unhealthy bone marrow filled with proliferating abnormal lymphocytes.
    • Lymphoblastic: Affects the lymphocytes of a patient’s white blood cells. Alternative term is lymphocytic.
    • Leukemia: Leukemia is a cancer of the blood cells.
  • Most common cancer in children, but it can also occur in adults of all ages (bimodal age distribution, with peaks at 3-7 years and 65 years of age).
  • Clinical presentation is nonspecific:
    1. fever;
    2. infection;
    3. bleeding;
    4. bone pain;
    5. lymphadenopathy;
    6. CNS involvement.
  • Disease classification based on evaluation of cells derived from a bone marrow or tissue biopsy. Clonal cells may be B cells (B-precursor lineage, 75%) or T cells. There are three main different ALL subtypes as follows:
    1. Pre (precursor) B cell ALL – most common in adults
    2. Mature B cell ALL – identified by particular genetic changes
    3. Pre (precursor) T cell ALL – more likely in young adults and more common in men
  • Management involves
    • remission induction with combination chemotherapy.
    • intrathecal chemotherapy is indicated for all patients to prevent CNS relapse.
    • Post-remission, patients undergo 1-3 years of maintenance therapy to eliminate residual disease.
    • Read more

 

What’s the history ?

  • CAR T-cell therapy, may appear to be overnight success, has a long experimental history.  Chemist and immunologist, Zelig Eshhar, developed the first CAR-T cells at the Weizmann Institute of Science in Israel in the late 1980s. In 1990, Eshhar took a year-long sabbatical, joined Steven Rosenberg at the National Institutes of Health, and prepared CARs that targeted human melanoma. “We designed CAR T cells to overcome a number of problems in getting T cells to attack cancer,” says Eshhar. The problems being a tumor’s ability to escape immune recognition by preventing the major histocompatibility complex molecules and the immunosuppressive tumor microenvironment.

  • CTL019 first developed by the University of Pennsylvania (Penn) by Carl June‘s group (link to original NEJM paper). Read more.
  • In 2012, Novartis and Penn created a global collaboration to advance research, develop and then commercialize CAR-T cell therapies, including CTL019, for the investigational treatment of cancers. Through the collaboration, Novartis holds the worldwide rights to CARs developed with Penn for all cancer indications. In March 2017, Novartis announced that the FDA accepted the company’s Biologics License Application filing and granted priority review for CTL019 in the treatment of r/r pediatric and young adult patients with B-cell ALL.

 

What is the science behind it?

https://youtu.be/Gzjzpysbveo

  • CAR-T therapies exploit the capability of a patient’s immune system to fight their disease, (sometimes referred to as “fifth pillar” of cancer treatment).
  • Therapy involves engineering patients’ own immune cells to recognize and attack their tumors (popularly known as Adoptive Cell Transfer).
  • Renier J. Brentjens, MD (Memorial Sloan Kettering Cancer Center) describes it like “giving patients a living drug.”

 

What was the outcome of the clinical trials?

  • The Children’s Hospital of Philadelphia (CHOP) study (link) showed disappearance of all signs of cancer (a complete response) in 27 of the 30 patients treated. 19 out of 27 are still in remission
  • The NIH Pediatric Oncology Branch study (link) 14 of 20 patients had a complete response with 10 of them receiving successful stem cell transplant and remain cancer free.
  • The Memorial Sloan Kettering Cancer center (MSKCC) clinical trial study (link) 14 of the 16 participants showed complete response and 7 eligible patients got stem cell transplant staying cancer-free.
  • The NCI-led study (link) showed “Of 15 patients, eight achieved complete remissions (CRs), four achieved partial remissions, one had stable lymphoma, and two were not evaluable for response”. This showed the “effectiveness of treating chemotherapy-refractory B-cell malignancies with anti-CD19 CAR T cells”.
  • Novartis clinical trial (ELIANA) evaluating efficacy and safety of CTL019 (with study enrollment having occurred across 25 centers in the US, EU, Canada, Australia and Japan) found that 82% (41 of 50) of infused patients achieved complete remission.
  • The second global CAR-T trial, JULIET, following the Novartis ELIANA study, led FDA to confer Breakthrough Therapy Designation for Treatment of Adult Patients withrelapsed and refractory (r/r) diffuse large B-cell lymphoma (DLBCL). The findings from JULIET are expected to be presented at an upcoming medical congress.

What are some of the doubts?

  • CAR-T, which induces an extreme immune response that attacks cancer cells, can create a cytokine storm leading to extreme side effects like high fever.
  • CAR-T might need the best – and presumably the most highly-paid – doctors and healthcare teams to ensure patients can manage the side effects.
  • The laboratory process of extracting immune system T-cells from each individual patient and altering the DNA to create chimeric antigen receptors will create additional costs (totaling upto $500,000-750,000 to treat one patient). Health providers might not be ready to foot the bill.
  • Initial failures from competitor Juno Therapeutics have created doubts on Novartis pulling out of the study. Novartis has previously backed out of large research programs like RNA interference.

What should the patients and their families know?

  • CTL019 is an investigational therapy- safety and efficacy profile not yet established.
  • Access to investigational therapies only available through carefully controlled and monitored clinical trials.
  • No guarantee that CTL019 will ever be commercially available anywhere in the world.

MedNess Quotient

After the announcement, Novartis shares were little changed but the shares of the company making CTL019 raw materials, Oxford BioMedica, rose by more than 4.5 percent. Alternatively, Kite Pharma, Novartis’ rival in CAR-T race, also submitted a rolling application for their chimeric antigen receptor T cell candidate. Rolling applications are allowed for promising new drugs. Kite’s application could be accepted early putting behind Novartis’. Therefore, the winner of the CAR-T race will set the price of the therapy and subsequently the stocks (Reuters and Nasdaq).

References and additional reading:

  1. https://www.novartis.com/news/media-releases/novartis-presents-results-first-global-registration-trial-ctl019-pediatric-and
  2. https://www.cancer.gov/about-cancer/treatment/research/car-t-cells
  3. https://www.drugs.com/history/ctl019.html
  4. https://www.novartis.com/news/media-releases/novartis-car-t-cell-therapy-ctl019-receives-fda-breakthrough-therapy-designation
  5. https://pharmaphorum.com/views-and-analysis/will-car-t-profitable-pharma/
  6. https://www.eurekalert.org/pub_releases/2015-09/uops-prr_1082515.php
  7. http://www.the-scientist.com/?articles.view/articleNo/42462/title/The-CAR-T-Cell-Race/
  8. http://www.healthline.com/health/acute-lymphocytic-leukemia-survival-rate-outlook#overview1
  9. http://www.azfamily.com/story/35026270/novartis-announces-first-car-t-cell-therapy-bla-for-pediatric-and-young-adult-patients-with-rr-b-cell-all-granted-fda-priority-review

Featured image source: Twitter

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