Jaypirca is the first BTK inhibitor of any
kind specifically approved for patients with mantle cell lymphoma
previously treated with a covalent BTK inhibitor
In the BRUIN Phase 1/2 trial, covalent
BTK inhibitor pre-treated patients with relapsed or refractory MCL
achieved an overall response rate of 50%, with 13% of patients
achieving a complete response
INDIANAPOLIS, Jan. 27,
2023 /PRNewswire/ -- Loxo@Lilly, the oncology unit of
Eli Lilly and Company (NYSE: LLY), today announced that the U.S.
Food and Drug Administration (FDA) approved Jaypirca™
(pirtobrutinib, 100 mg & 50 mg tablets) for the treatment of
adult patients with relapsed or refractory mantle cell lymphoma
(MCL) after at least two lines of systemic therapy, including a
Bruton's tyrosine kinase (BTK) inhibitor. Jaypirca was approved
under the FDA's Accelerated Approval pathway based on response rate
from the open-label, single-arm, international, Phase 1/2 study,
called the BRUIN trial.1 Continued approval for this
indication may be contingent upon verification and description of
clinical benefit in a confirmatory trial.
Jaypirca, a highly selective kinase inhibitor, utilizes a novel
binding mechanism and is the first and only FDA approved
non-covalent (reversible) BTK inhibitor. Jaypirca can reestablish
BTK inhibition in MCL patients previously treated with a covalent
BTK inhibitor (ibrutinib, acalabrutinib, or zanubrutinib) and
extend the benefit of targeting the BTK pathway.
"The approval of Jaypirca represents an important advance for
patients with relapsed or refractory MCL, who currently have
limited options and historically have had a poor prognosis
following discontinuation of treatment with a covalent BTK
inhibitor," said Michael Wang, M.D.,
Puddin Clarke Endowed Professor of Lymphoma and Myeloma at The
University of Texas MD Anderson Cancer
Center. "These data indicate that Jaypirca can provide efficacy in
patients previously treated with a covalent BTK inhibitor,
potentially extending the time patients may benefit from BTK
inhibition therapy. Jaypirca offers a new approach to targeting the
BTK pathway following treatment with a covalent BTK inhibitor and
has the potential to meaningfully impact the treatment paradigm for
relapsed and refractory MCL patients."
The labeling for Jaypirca contains warnings and precautions for
infections, hemorrhage, cytopenias, atrial fibrillation and
flutter, second primary malignancies, and embryo-fetal toxicity.
See Important Safety Information below and full Prescribing
Information for additional information, including dosing
modifications.
"We are pleased to bring a meaningful new therapeutic option to
patients with MCL that can reestablish the benefit of targeting the
BTK pathway after receiving multiple prior therapies, including a
covalent BTK inhibitor," said Jacob Van
Naarden, chief executive officer, Loxo@Lilly. "We are
grateful to the patients, investigators, and other members of the
clinical care teams for their contributions. Our team has been
committed to rapidly advancing the development of Jaypirca for
patients with MCL, and we look forward to building on this
milestone by continuing to bring forward important new treatments
for people with hematologic malignancies."
The FDA approval is based on data from a subset of patients in
the BRUIN Phase 1/2 trial. The assessment of efficacy was based on
120 patients with MCL treated with Jaypirca 200 mg once daily until
disease progression or unacceptable toxicity. Patients with active
central nervous system lymphoma or allogeneic hematopoietic stem
cell transplantation or CAR T-cell therapy within 60 days were
excluded. Patients had received a median of three prior lines of
therapy (range: 1 to 9), with 93% having two or more prior lines;
all patients received one or more prior lines of therapy containing
a covalent BTK inhibitor. Eighty-three percent (83%) of patients
discontinued their last BTK inhibitor due to refractory or
progressive disease. Efficacy was based on overall response rate
(ORR) and duration of response (DOR) as assessed by an independent
review committee (IRC) using 2014 Lugano criteria. Efficacy results
are summarized below:
Outcome
|
Jaypirca 200 mg once
daily (N=120)
|
Overall Response
Ratea,b
|
|
ORR, n
(95% CI, %)
|
60 (50 %)
41, 59
|
CR, n
|
15
(13 %)
|
PR, n
|
45
(38 %)
|
Time to
Response
Median (range),
months
|
1.8 (0.8,
4.2)
|
Duration of
Responsec
|
|
Number censored,
n
Median DOR, months (95%
CI)
DOR rate at 6 months, % (95%
CI)
|
36d
8.3 (5.7,
NE)
65.3 (49.8,
77.1)
|
|
CI, confidence
interval; CR, complete response; DOR, duration of response; PR,
partial response; NE, not estimable.
|
|
a.
|
PET-CT scans were
utilized in response assessments (in 41% of patients), with the
remainder being assessed by CT scans only.
|
|
b.
|
ORR using CT scan-based
assessments in all patients was 48% (95% CI: 38, 57), and CR rate
was 13%.
|
|
c.
|
Based on Kaplan-Meier
estimation. Estimated median follow-up was 7.3 months.
|
|
d.
|
Thirty-six (36) of 60
responders had not progressed or died prior to data
cutoff.
|
The pooled safety analysis of the full BRUIN study population
evaluated 583 patients with hematologic malignancies administered
Jaypirca 200 mg daily as a single agent. In this pooled safety
population, the most common adverse reactions (ARs) to Jaypirca
therapy, occurring in 20% of patients or more, were decreased
neutrophil count, decreased hemoglobin, decreased platelet count,
fatigue, musculoskeletal pain, decreased lymphocyte count,
bruising, and diarrhea.
The safety of Jaypirca was evaluated in 128 patients with MCL,
36% of whom were exposed for six months or longer and 10% of whom
were exposed for at least one year. ARs led to dosage reductions in
4.7%, treatment interruption in 32%, and permanent discontinuation
of Jaypirca in 9% of patients. ARs that resulted in permanent
discontinuation of Jaypirca in more than 1% of patients included
pneumonia. Serious ARs occurred in 38% of patients who received
Jaypirca. Serious ARs occurring in greater than or equal to 2% of
patients were pneumonia (14%), COVID-19 (4.7%), musculoskeletal
pain (3.9%), hemorrhage (2.3%), pleural effusion (2.3%), and sepsis
(2.3%).
"Until now, people living with MCL who can no longer be treated
with BTK inhibitors have had few alternatives," said Meghan
Gutierrez, chief executive officer, Lymphoma Research Foundation.
"The approval of Jaypirca brings a new treatment option and, along
with that, new hope for people with relapsed or refractory
MCL."
Jaypirca is expected to be available in the United States in the coming weeks.
The confirmatory Phase 3 trial (NCT04662255; BRUIN MCL-321) is
currently enrolling patients.
See Important Safety Information below and full Prescribing
Information for additional information.
Click here to view the mantle cell lymphoma infographic.
Click to view the Jaypirca product photos: 100 mg and 50 mg.
Click here to view the Jaypirca logo.
About the BRUIN Phase 1/2 Trial
The BRUIN Phase 1/2
clinical trial is the ongoing first-in-human, global, multi-center
evaluation of Jaypirca in patients with hematologic malignancies,
including mantle cell lymphoma (MCL).
The trial includes a Phase 1 dose-escalation phase, a Phase
1b combination arm, and a Phase 2
dose-expansion phase. The primary endpoint of the Phase 1 study is
maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D).
Secondary endpoints include safety, pharmacokinetics (PK), and
preliminary efficacy measured by overall response rate (ORR) for
monotherapy. The primary endpoint of the Phase 1b study is safety of the drug combinations. The
secondary endpoints are PK and preliminary efficacy measured by ORR
for the drug combinations. The primary endpoint for the Phase 2
study is ORR as determined by an independent review committee
(IRC). Secondary endpoints include ORR as determined by
investigator, best overall response (BOR), duration of response
(DOR), progression-free survival (PFS), overall survival (OS),
safety, and PK.
About Jaypirca™ (pirtobrutinib)
Jaypirca
(pirtobrutinib, formerly known as LOXO-305) (pronounced
jay-pihr-kaa) is a highly selective (300 times more selective for
BTK versus 98% of other kinases tested in preclinical studies),
non-covalent (reversible) inhibitor of the enzyme BTK.2
BTK is a validated molecular target found across numerous B-cell
leukemias and lymphomas including mantle cell
lymphoma.3,4 Jaypirca is a U.S. FDA-approved oral
prescription medicine, 100 mg or 50 mg tablets taken as a
once-daily 200 mg dose with or without food until disease
progression or unacceptable toxicity.
About Mantle Cell Lymphoma
MCL is a rare blood cancer
and a form of non-Hodgkin lymphoma (NHL). Annually, about one in
200,000 people worldwide develop MCL.5
MCL arises in B lymphocytes, a type of white blood cell and part
of the immune system. MCL frequently begins in B cells located in
the mantle zone of the outer edge of lymph nodes. As the cancer
progresses, it can spread to bone marrow, the spleen, the liver, or
the digestive tract.5
INDICATIONS FOR JAYPIRCA
Jaypirca is a kinase inhibitor indicated for the treatment of
adult patients with relapsed or refractory mantle cell lymphoma
(MCL) after at least two lines of systemic therapy, including a BTK
inhibitor. This indication is approved under accelerated approval
based on response rate. Continued approval for this indication may
be contingent upon verification and description of clinical benefit
in a confirmatory trial.
IMPORTANT SAFETY INFORMATION FOR JAYPIRCA™
(pirtobrutinib)
Infections: Fatal and serious infections (including
bacterial, viral, or fungal) and opportunistic infections have
occurred in patients treated with Jaypirca. In the clinical trial,
Grade ≥3 infections occurred in 17% of 583 patients with
hematologic malignancies, most commonly pneumonia (9%); fatal
infections occurred in 4.1% of patients. Sepsis (4.5%) and febrile
neutropenia (2.9%) occurred. Opportunistic infections after
Jaypirca treatment included, but are not limited to,
Pneumocystis jirovecii pneumonia and fungal infection.
Consider prophylaxis, including vaccinations and antimicrobial
prophylaxis, in patients at increased risk for infection, including
opportunistic infections. Monitor patients for signs and symptoms,
evaluate promptly, and treat appropriately. Based on severity,
reduce dose, temporarily withhold, or permanently discontinue
Jaypirca.
Hemorrhage: Fatal and serious hemorrhage has occurred
with Jaypirca. Major hemorrhage (Grade ≥3 bleeding or any central
nervous system bleeding) occurred in 2.4% of 583 patients with
hematologic malignancies treated with Jaypirca, including
gastrointestinal hemorrhage; fatal hemorrhage occurred in 0.2% of
patients. Bleeding of any grade, excluding bruising and petechiae,
occurred in 14% of patients. Major hemorrhage occurred in patients
taking Jaypirca with (0.7%) and without (1.7%) antithrombotic
agents. Consider risks/benefits of co-administering antithrombotic
agents with Jaypirca. Monitor patients for signs of bleeding. Based
on severity, reduce dose, temporarily withhold, or permanently
discontinue Jaypirca. Consider benefit/risk of withholding Jaypirca
3-7 days pre- and post-surgery depending on type of surgery and
bleeding risk.
Cytopenias: Grade 3 or 4 cytopenias, including
neutropenia (24%), anemia (11%), and thrombocytopenia (11%), have
developed in patients with hematologic malignancies treated with
Jaypirca. In a clinical trial, Grade 4 neutropenia (13%) and Grade
4 thrombocytopenia (5%) developed. Monitor complete blood counts
regularly during treatment. Based on severity, reduce dose,
temporarily withhold, or permanently discontinue Jaypirca.
Atrial Fibrillation and Atrial Flutter: Atrial
fibrillation or flutter were reported in 2.7% of patients, with
Grade 3 or 4 atrial fibrillation or flutter reported in 1% of 583
patients with hematologic malignancies treated with Jaypirca.
Patients with cardiac risk factors such as hypertension or previous
arrhythmias may be at increased risk. Monitor for signs and
symptoms of arrhythmias (e.g., palpitations, dizziness, syncope,
dyspnea) and manage appropriately. Based on severity, reduce dose,
temporarily withhold, or permanently discontinue Jaypirca.
Second Primary Malignancies: Second primary malignancies,
including non-skin carcinomas, developed in 6% of 583 patients with
hematologic malignancies treated with Jaypirca monotherapy. The
most frequent malignancy was non-melanoma skin cancer (3.8%). Other
second primary malignancies included solid tumors (including
genitourinary and breast cancers) and melanoma. Advise patients to
use sun protection and monitor for development of second primary
malignancies.
Embryo-Fetal Toxicity: Based on animal findings, Jaypirca
can cause fetal harm in pregnant women. Administration of
pirtobrutinib to pregnant rats during organogenesis caused
embryo-fetal toxicity, including embryo-fetal mortality and
malformations at maternal exposures (AUC) approximately 3-times the
recommended 200 mg/day dose. Advise pregnant women of potential
risk to a fetus and females of reproductive potential to use
effective contraception during treatment and for one week after
last dose.
Adverse Reactions (ARs) in Patients with Mantle Cell Lymphoma
Who Received Jaypirca
Serious ARs occurred in
38% of patients. Serious ARs occurring in ≥2% of patients were
pneumonia (14%), COVID-19 (4.7%), musculoskeletal pain (3.9%),
hemorrhage (2.3%), pleural effusion (2.3%), and sepsis (2.3%).
Fatal ARs within 28 days of last dose of Jaypirca occurred
in 7% of patients, most commonly due to infections (4.7%),
including COVID-19 (3.1%).
Dose Modifications and Discontinuations: ARs led to
dosage reductions in 4.7%, treatment interruption in 32%, and
permanent discontinuation of Jaypirca in 9% of patients. ARs
resulting in dosage modification in >5% of patients included
pneumonia and neutropenia. ARs resulting in permanent
discontinuation of Jaypirca in >1% of patients included
pneumonia.
ARs (all Grades %; Grade 3-4 %) in ≥10% of Patients:
fatigue (29; 1.6), musculoskeletal pain (27; 3.9), diarrhea (19;
-), edema (18; 0.8), dyspnea (17; 2.3), pneumonia (16; 14),
bruising (16; -), peripheral neuropathy (14; 0.8), cough (14; -),
rash (14; -), fever (13; -), constipation (13; -),
arthritis/arthralgia (12; 0.8), hemorrhage (11; 3.1), abdominal
pain (11; 0.8), nausea (11; -), upper respiratory tract infections
(10; 0.8), dizziness (10; -).
Select Laboratory Abnormalities (all Grades %; Grade 3
or 4 %) that Worsened from Baseline in ≥10% of
Patients: hemoglobin decreased (42; 9), platelet count
decreased (39; 14), neutrophil count decreased (36; 16), lymphocyte
count decreased (32; 15), creatinine increased (30;
1.6), calcium decreased (19; 1.6), AST increased (17; 1.6),
potassium decreased (13; 1.6), sodium decreased (13; -), lipase
increased (12; 4.4), alkaline phosphatase increased (11; -), ALT
increased (11; 1.6), potassium increased (11; 0.8). Grade 4
laboratory abnormalities in >5% of patients included neutrophils
decreased (10), platelets decreased (7), lymphocytes decreased
(6).
All grade ARs with higher frequencies in the total BRUIN
population of patients with hematologic malignancies (n=583) were
decreased neutrophil count (41%), bruising (20%), diarrhea
(20%).
Drug Interactions
Strong CYP3A Inhibitors:
Concomitant use with Jaypirca increased pirtobrutinib systemic
exposure, which may increase risk of Jaypirca adverse reactions.
Avoid use of strong CYP3A inhibitors during Jaypirca treatment. If
concomitant use is unavoidable, reduce Jaypirca dosage according to
the approved labeling.
Strong or Moderate CYP3A Inducers: Concomitant use with
Jaypirca decreased pirtobrutinib systemic exposure, which may
reduce Jaypirca efficacy. Avoid concomitant use of Jaypirca with
strong or moderate CYP3A inducers. If concomitant use with moderate
CYP3A inducers is unavoidable, increase the Jaypirca dosage
according to the approved labeling.
Sensitive CYP2C8, CYP2C19, CYP3A, P-gP, BCRP
Substrates: Concomitant use with Jaypirca increased their
plasma concentrations, which may increase risk of adverse reactions
related to these substrates for drugs that are sensitive to minimal
concentration changes. Follow recommendations for these sensitive
substrates in their approved labeling.
Use in Special Populations
Pregnancy and
Lactation: Inform pregnant women of potential for Jaypirca
to cause fetal harm. Verify pregnancy status in females of
reproductive potential prior to starting Jaypirca and advise use of
effective contraception during treatment and for one week after
last dose. Presence of pirtobrutinib in human milk and effects on
the breastfed child or on milk production is unknown. Advise women
not to breastfeed while taking Jaypirca and for one week after
last dose.
Geriatric Use: In the pooled safety population of
patients with hematologic malignancies, 392 (67%) were ≥65 years of
age. Patients aged ≥65 years experienced higher rates of Grade ≥3
ARs and serious ARs compared to patients <65 years of age.
Renal Impairment: Severe renal impairment (eGFR 15-29
mL/min) increases pirtobrutinib exposure. Reduce Jaypirca dosage in
patients with severe renal impairment according to the approved
labeling. No dosage adjustment is recommended in patients with mild
or moderate renal impairment.
Please see Prescribing Information and
Patient Information for Jaypirca.
PT HCP ISI MCL APP
About Lilly
Lilly unites caring with discovery to
create medicines that make life better for people around the world.
We've been pioneering life-changing discoveries for nearly 150
years, and today our medicines help more than 47 million people
across the globe. Harnessing the power of biotechnology, chemistry
and genetic medicine, our scientists are urgently advancing new
discoveries to solve some of the world's most significant health
challenges, redefining diabetes care, treating obesity and
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fight against Alzheimer's disease, providing solutions to some of
the most debilitating immune system disorders, and transforming the
most difficult-to-treat cancers into manageable diseases. With each
step toward a healthier world, we're motivated by one thing: making
life better for millions more people. That includes delivering
innovative clinical trials that reflect the diversity of our world
and working to ensure our medicines are accessible and affordable.
To learn more, visit Lilly.com and Lilly.com/newsroom or
follow us on Facebook, Instagram and LinkedIn. P-LLY
Jaypirca™ is a trademark owned by or licensed to Eli Lilly and
Company, its subsidiaries, or affiliates.
PP-PT-US-0260 01/2023
© Lilly USA, LLC 2023. ALL
RIGHTS RESERVED.
Cautionary Statement Regarding Forward-Looking
Statements
This press release contains forward-looking statements (as that
term is defined in the Private Securities Litigation Reform Act of
1995) about Jaypirca™ as a treatment for people with
mantle cell lymphoma previously treated with a BTK inhibitor and as
a potential treatment for patients with chronic lymphocytic
leukemia (CLL), small lymphocytic lymphoma (SLL), or other
non-Hodgkin's lymphomas (NHL) and other conditions and reflects
Lilly's current beliefs and expectations. However, as with any
pharmaceutical product, there are substantial risks and
uncertainties in the process of drug research, development, and
commercialization. Among other things, there is no guarantee that
planned or ongoing studies will be completed as planned, that
future study results will be consistent with study results to date,
that Jaypirca will receive additional regulatory approvals, or that
Jaypirca will be commercially successful. For further discussion of
these and other risks and uncertainties that could cause actual
results to differ from Lilly's expectations, see Lilly's Form 10-K
and Form 10-Q filings with the United States Securities and
Exchange Commission. Except as required by law, Lilly undertakes no
duty to update forward-looking statements to reflect events after
the date of this release.
- Jaypirca. Prescribing information. Lilly USA, LLC.
- Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed
or refractory B-cell malignancies (BRUIN): a phase 1/2 study.
Lancet. 2021;397(10277):892-901.
doi:10.1016/S0140-6736(21)00224-5
- Hanel W, Epperla N. Emerging therapies in mantle cell lymphoma.
J Hematol Oncol. 2020;13(1):79. Published 2020 Jun 17.
doi:10.1186/s13045-020-00914-1
- Gu D, Tang H, Wu J, Li J, Miao Y. Targeting Bruton tyrosine
kinase using non-covalent inhibitors in B cell malignancies. J
Hematol Oncol. 2021;14(1):40. Published 2021 Mar 6. doi:10.1186/s13045-021-01049-7
- National Organization for Rare Disorders. Mantle cell lymphoma.
Accessed 26 October 2022.
https://rarediseases.org/rare-diseases/mantle-cell-lymphoma/
Refer
to:
|
Kyle Owens;
Owens_Kyle@lilly.com; (332) 259-3932 – media
|
|
Joe Fletcher;
jfletcher@lilly.com; (317) 296-2884 – investors
|
|
|
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