As many have feared, the FDA’s investigation into secondary T-cell cancers following treatment with existing CAR-T therapies is poised to lead to a class-wide black box warning.
For all six commercial CAR-T therapies, the FDA is requiring label updates to include T-cell malignancies in
the boxed warning section of each product’s label, according to the agency’s
separate notification letters dated Jan. 19 to Bristol Myers Squibb, Gilead
Sciences’ Kite Pharma, Johnson & Johnson and Novartis. A black box warning
is the most serious safety alert on a medication’s label.
The products involved are Bristol’s Abecma and Breyanzi, Kite’s
Yescarta and Tecartus, J&J’s Legend Biotech-partnered Carvykti and
Novartis’ Kymriah. The products are separately approved to treat multiple
myeloma, and large B-cell lymphoma, among other blood cancers.
Specifically, the U.S. agency wants the companies to include a
paragraph in those boxed warnings to say, “T-cell malignancies may occur
following treatment with BCMA- and CD19-directed genetically modified
autologous T-cell immunotherapies, including,” followed by the product’s name.
The same language is also required as part of the “secondary malignancies” item
in the less prominent “Warnings and Precautions” section of a drug’s label.
The required label update comes less than two months after the
FDA unveiled an investigation into secondary T-cell
malignancies among patients who received BCMA- or CD19-targeted CAR-Ts. The
agency at the time labelled the risk as “serious” based on cases it had received
from clinical trials and postmarketing surveillance. The FDA from the outset said
that it deemed the potential risk as applicable to all currently approved CAR-T
products. Based on those descriptions, industry watchers have speculated that a
classwide boxed warning would likely come next.
g FDA
investigates 'serious risk' of secondary cancer following CAR-T treatment
Now, the FDA has determined that the T-cell
malignancy safety signal “should be included in the labeling for all BCMA- and
CD19-directed genetically modified autologous T cell immunotherapies,” the
letters show.
That language suggests that even future CAR-T
contenders that fit the description will be subject to the same boxed
warning. Gracell’s BCMA/CD19 dual-targeting GC012F, which is the
centerpiece of AstraZeneca’s $1 billion
acquisition of the Chinese biotech, is one such product. Meanwhile,
the FDA’s distinction of “autologous” therapies offers a relief for
companies such as Allogene Therapeutics that are working on allogeneic, or
so-called "off-the-shelf," CAR-T therapies.
The companies now have the option to meet the
FDA’s demand and submit a supplement to offer the changes verbatim or file a
supplement with different wording. Alternatively, the companies may submit a
rebuttal statement detailing their disagreements. Whichever pathway they
choose, the companies must submit a response within 30 days or face potential
enforcement action, including monetary penalties and forced change of label.
As the FDA is asking for a classwide change,
J&J will “work with the agency to update the Carvykti prescribing
information,” a J&J spokesperson told Fierce Pharma. With more than 2,000
patients having been treated with Carvykti worldwide, J&J remains confident
in the favourable benefit-risk profile of Carvykti, the spokesperson added.
Separately, Novartis told Fierce Pharma that
it will update Kymriah’s label in accordance with guidance from the FDA. The
Swiss pharma pointed to 10,000 patients that have received Kymriah worldwide,
saying it has not found sufficient evidence to declare a causal relationship
between the CD19 therapy—which is the first FDA-approved CAR-T—and secondary
T-cell malignancies.
A Bristol Myers spokesperson said the company
is “evaluating next steps on the labels for Abecma and Breyanzi.” The company,
which got the CAR-T therapies from its acquisition of Celgene in 2019, also
said it hasn’t found a causal relationship between its products and T-cell
cancers.
Gilead is “reviewing FDA’s changes and will
determine appropriate next steps in the interest of patients and healthcare
providers,” a company spokesperson said. Gilead’s latest analysis of more
than 15,500 patients treated with Yescarta and more than 2,700 patients treated
with Tecartus didn’t establish a causal role in the development of T-cell
malignancies, the spokesperson said.
The fact that the FDA is allowing the products
to stay on the market mirrors the agency’s prior comment that their
benefit-risk profiles remain favorable in their existing indications.
In a commentary published in Nature Medicine a
few days ago, several cell therapy experts, including CAR-T pioneers Bruce
Levine, Ph.D., and Carl June, M.D., from Penn Medicine also suggested that treatment centers should continue to
use those commercial CAR-T products based on existing safety information. The
researchers noted that the “rate of T-cell malignancies observed is far lower
than that seen with some other treatments.”
But it’s unclear how the perceived risk of
secondary malignancies might affect the FDA’s calculation of benefit and risk
as those BCMA and CD19 CAR-T therapies move into earlier lines of therapy.
J&J and Legend’s application for Carvykti as a second-line multiple myeloma
therapy is currently under FDA review, and the agency will convene an
advisory committee meeting to discuss Bristol’s bid to move Abecma into the
third-line setting. Gilead is running the Zuma-23 trial that’s testing Yescarta
as first-line treatment in patients with high-risk large B-cell lymphoma.
As many have feared, the
FDA’s investigation into secondary T-cell cancers following treatment with
existing CAR-T therapies is poised to lead to a class-wide black box warning.
For all six commercial CAR-T therapies, the FDA is requiring label updates to include T-cell malignancies in
the boxed warning section of each product’s label, according to the agency’s
separate notification letters dated Jan. 19 to Bristol Myers Squibb, Gilead
Sciences’ Kite Pharma, Johnson & Johnson and Novartis. A black box warning
is the most serious safety alert on a medication’s label.
The products involved are Bristol’s Abecma and Breyanzi, Kite’s
Yescarta and Tecartus, J&J’s Legend Biotech-partnered Carvykti and
Novartis’ Kymriah. The products are separately approved to treat multiple
myeloma, large B-cell lymphoma, among other blood cancers.
Specifically, the U.S. agency wants the companies to include a
paragraph in those boxed warnings to say, “T-cell malignancies may occur
following treatment with BCMA- and CD19-directed genetically modified
autologous T-cell immunotherapies, including,” followed by the product’s name.
The same language is also required as part of the “secondary malignancies” item
in the less prominent “Warnings and Precautions” section of a drug’s label.
The required label update comes less than two months after the
FDA unveiled an investigation into secondary T-cell
malignancies among patients who received BCMA- or CD19-targeted CAR-Ts. The
agency at the time labeled the risk as “serious” based on cases it had received
from clinical trials and postmarketing surveillance. The FDA from the outset said
that it deemed the potential risk as applicable to all currently approved CAR-T
products. Based on those descriptions, industry watchers have speculated that a
classwide boxed warning would likely come next.
g FDA
investigates 'serious risk' of secondary cancer following CAR-T treatment
Now, the FDA has determined that the T-cell
malignancy safety signal “should be included in the labeling for all BCMA- and
CD19-directed genetically modified autologous T cell immunotherapies,” the
letters show.
That language suggests that even future CAR-T
contenders that fit the description will be subject to the same boxed
warning. Gracell’s BCMA/CD19 dual-targeting GC012F, which is the
centrepiece of AstraZeneca’s $1 billion
acquisition of the Chinese biotech, is one such product. Meanwhile,
the FDA’s distinction of “autologous” therapies offers a relief for
companies such as Allogene Therapeutics that are working on allogeneic, or
so-called "off-the-shelf," CAR-T therapies.
The companies now have the option to meet the
FDA’s demand and submit a supplement to offer the changes verbatim or file a
supplement with different wording. Alternatively, the companies may submit a
rebuttal statement detailing their disagreements. Whichever pathway they
choose, the companies must submit a response within 30 days or face potential
enforcement action, including monetary penalties and forced change of label.
As the FDA is asking for a classwide change,
J&J will “work with the agency to update the Carvykti prescribing
information,” a J&J spokesperson told Fierce Pharma. With more than 2,000
patients having been treated with Carvykti worldwide, J&J remains confident
in the favourable benefit-risk profile of Carvykti, the spokesperson added.
Separately, Novartis told Fierce Pharma that
it will update Kymriah’s label in accordance with guidance from the FDA. The
Swiss pharma pointed to 10,000 patients that have received Kymriah worldwide,
saying it has not found sufficient evidence to declare a causal relationship
between the CD19 therapy—which is the first FDA-approved CAR-T—and secondary
T-cell malignancies.
A Bristol Myers spokesperson said the company
is “evaluating next steps on the labels for Abecma and Breyanzi.” The company,
which got the CAR-T therapies from its acquisition of Celgene in 2019, also
said it hasn’t found a causal relationship between its products and T-cell
cancers.
Gilead is “reviewing FDA’s changes and will
determine appropriate next steps in the interest of patients and healthcare
providers,” a company spokesperson said. Gilead’s latest analysis of more
than 15,500 patients treated with Yescarta and more than 2,700 patients treated
with Tecartus didn’t establish a causal role in the development of T-cell
malignancies, the spokesperson said.
The fact that the FDA is allowing the products
to stay on the market mirrors the agency’s prior comment that their
benefit-risk profiles remain favourable in their existing indications.
In a commentary published in Nature Medicine a
few days ago, several cell therapy experts, including CAR-T pioneers Bruce
Levine, PhD, and Carl June, M.D., from Penn Medicine also suggested that treatment centres should continue to
use those commercial CAR-T products based on existing safety information. The
researchers noted that the “rate of T-cell malignancies observed is far lower
than that seen with some other treatments.”
But it’s unclear how the perceived risk of
secondary malignancies might affect the FDA’s calculation of benefit and risk
as those BCMA and CD19 CAR-T therapies move into earlier lines of therapy.
J&J and Legend’s application for Carvykti as a second-line multiple myeloma
therapy is currently under FDA review, and the agency will convene an
advisory committee meeting to discuss Bristol’s bid to move Abecma into the
third-line setting. Gilead is running the Zuma-23 trial that’s testing Yescarta
as first-line treatment in patients with high-risk large B-cell lymphoma.
https://www.fiercepharma.com/pharma/fda-wants-classwide-boxed