In the same week that Kite Pharma announced positive data from a pivotal study of its lead CAR-T candidate, KTE-C19 (easier to remember- and to spell- than the non-proprietary designation axicabtagene ciloleucel) in patients with B-cell non-Hodgkin lymphoma (NHL) refractory to other treatments, a one-time leader in the CAR-T race, Juno Therapeutics, pulled the plug on its lead candidate, JCAR015.
CAR-T (chimeric antigen receptor – the “T” is for T cell) is a form of adoptive cell transfer therapy which involves collection of T-cells from the patient and genetically engineering them to express receptors specific for a protein expressed on the tumour surface. After expansion in the laboratory, the transformed cells are infused back into the patient to seek and destroy tumour cells.
CAR-T therapy first made headlines by achieving unprecedented remission rates in patients with acute lymphoblastic leukaemia (ALL), chronic lymphocytic leukaemia (CLL) and NHL where all available treatments had failed to slow disease progression. The other side of the coin was the accompanying high incidence of life-threatening adverse events arising from the massive release of cytokines (part and parcel of the anti-tumour response) and from immune-related neurotoxicity.
Juno’s JCAR015 was placed on clinical hold early in development following a death attributed to cytokine release syndrome and again twice in 2016 following five deaths from cerebral oedema during a Phase II study in ALL patients. The company initially speculated that the deaths might be related to changes in a pre-treatment regimen involving two chemotherapy drugs but the decision to halt further development suggests that JCAR015 itself is now thought be the culprit.
CAR-T candidates from Kite Pharma and Novartis have also resulted in high rates of cytokine release and neurotoxicity-related adverse events, but, so far, these have proved to be more manageable or of lesser severity than those occurring during the JCAR015 studies. No cerebral oedema occurred in the Kite Pharma pivotal study, with two treatment-related deaths probably arising from cytokine release.
Juno hope to stay in the game with an earlier stage CAR-T candidate, JCAR017, which showed a relatively low incidence of severe adverse events in a small study conducted in NHL patients, but the abandonment of JCAR015 puts Juno a long way behind Kite Pharma and Novartis, with both shooting for regulatory approval in 2017.
CAR-T treatment will probably never be a “safe” option, although adverse event management would be expected to improve with experience. If regulators can be convinced that the benefits of CAR-T therapy outweigh risk, safety is likely to be a secondary concern for individuals cursed with otherwise untreatable B-cell malignancies.
An arguably bigger challenge facing Kite Pharma, Novartis and other CAR-T contenders is whether individualised adoptive cell transfer therapies can be reliably scaled up and delivered at a cost that healthcare systems are able and willing to meet.
An arguably bigger challenge facing Kite Pharma, Novartis and other CAR-T contenders is whether individualised adoptive cell transfer therapies can be reliably scaled up and delivered at a cost that healthcare systems are able and willing to meet.
Kite Announces Positive Topline Primary Results of Axicabtagene Ciloleucel from First Pivotal CAR-T Trial in Patients with Aggressive Non-Hodgkin Lymphoma. Company press release online 28th February 2017. http://tinyurl.com/js7293j
Juno Therapeutics Reports Fourth Quarter and 2016 Financial Results. Company press release online 1st March 2017. http://tinyurl.com/hunp9uh
Added 4th October 2017:
Short piece on the human aspect of the path to CAR-T therapy approval.
Tragedy, Perseverance, and Chance — The Story of CAR-T Therapy. Lisa Rosenbaum, M.D.
N Engl J Med 2017; 377:1313-1315 October 5, 2017. http://tinyurl.com/y7txqno2
Free to read, may require registration.
Added 31st August 2017:
Novartis received FDA approval for Kymriah (tisagenlecleucel) for certain paediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL) on 30th August, making this this first US approval of any form of gene therapy. Novartis surprised industry watchers by pricing Kymriah at $475,000 per patient, towards the lower end of most estimates. The actual cost to healthcare systems will depend on horsetrading over outcome-based payment but it sets an interesting bar for CAR-T rivals that may not have the financial muscle to implement cost-efficient manufacturing and logistics.
Added 2nd April 2017:
And only two days behind the Novartis BLA filing, Kite Pharma announced the filing of a BLA for KTE-C19 (axicabtagene ciloleucel) as a treatment for patients with relapsed or refractory aggressive non-Hodgkin lymphoma who are ineligible for autologous stem cell transplant.Like the Novartis candidate, KTE-C19 is designated as a breakthrough therapy by the FDA although it has yet to secure priority review.
Kite Completes Submission of U.S. Biologics License Application (BLA) for Axicabtagene Ciloleucel as the First CAR-T Therapy for the Treatment of Patients With Aggressive Non-Hodgkin Lymphoma (NHL). Company press release online 31st March 2017. http://tinyurl.com/lse34jm
Added 30th March 2017:
On 29th March, Novartis announced that the FDA had accepted a Biologics License Application (BLA) filing and granted priority review for CTL019 (tisagenlecleucel-T) for use in children and young adults with relapsed and refractory (r/r) pediatric and young adult patients with B-cell ALL. Novartis plan to make additional filings in other indications before the of the year.
Company press release online 29th March 2017 http://tinyurl.com/mxgr5va
Added 10th March 2017:
Servier and Pfizer announced initiation of a US study of Cellectis's UCART19 candidate in B-ALL patients in the US (a UK study was was started mid-2016). Cellectis's approach differs from that of Juno, Kite and Novartis in that donor ("allogeneic") T cells are used. If successful, this "off-the-shelf" product could reduce some of the cost associated with CAR-T therapy.
Servier and Pfizer announce FDA clearance of IND application for UCART19 in Adult Relapsed/Refractory Acute Lymphoblastic Leukemia.
Company press release online 9th March 2017. http://tinyurl.com/jcdro2e
Added 4th October 2017:
Short piece on the human aspect of the path to CAR-T therapy approval.
Tragedy, Perseverance, and Chance — The Story of CAR-T Therapy. Lisa Rosenbaum, M.D.
N Engl J Med 2017; 377:1313-1315 October 5, 2017. http://tinyurl.com/y7txqno2
Free to read, may require registration.
Added 31st August 2017:
Novartis received FDA approval for Kymriah (tisagenlecleucel) for certain paediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL) on 30th August, making this this first US approval of any form of gene therapy. Novartis surprised industry watchers by pricing Kymriah at $475,000 per patient, towards the lower end of most estimates. The actual cost to healthcare systems will depend on horsetrading over outcome-based payment but it sets an interesting bar for CAR-T rivals that may not have the financial muscle to implement cost-efficient manufacturing and logistics.
Added 2nd April 2017:
And only two days behind the Novartis BLA filing, Kite Pharma announced the filing of a BLA for KTE-C19 (axicabtagene ciloleucel) as a treatment for patients with relapsed or refractory aggressive non-Hodgkin lymphoma who are ineligible for autologous stem cell transplant.Like the Novartis candidate, KTE-C19 is designated as a breakthrough therapy by the FDA although it has yet to secure priority review.
Kite Completes Submission of U.S. Biologics License Application (BLA) for Axicabtagene Ciloleucel as the First CAR-T Therapy for the Treatment of Patients With Aggressive Non-Hodgkin Lymphoma (NHL). Company press release online 31st March 2017. http://tinyurl.com/lse34jm
Added 30th March 2017:
On 29th March, Novartis announced that the FDA had accepted a Biologics License Application (BLA) filing and granted priority review for CTL019 (tisagenlecleucel-T) for use in children and young adults with relapsed and refractory (r/r) pediatric and young adult patients with B-cell ALL. Novartis plan to make additional filings in other indications before the of the year.
Company press release online 29th March 2017 http://tinyurl.com/mxgr5va
Added 10th March 2017:
Servier and Pfizer announced initiation of a US study of Cellectis's UCART19 candidate in B-ALL patients in the US (a UK study was was started mid-2016). Cellectis's approach differs from that of Juno, Kite and Novartis in that donor ("allogeneic") T cells are used. If successful, this "off-the-shelf" product could reduce some of the cost associated with CAR-T therapy.
Servier and Pfizer announce FDA clearance of IND application for UCART19 in Adult Relapsed/Refractory Acute Lymphoblastic Leukemia.
Company press release online 9th March 2017. http://tinyurl.com/jcdro2e
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