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U.S. FDA Approves Jaypirca™ (
pirtobrutinib
), the First and Only Non-Covalent (Reversible)
BTK Inhibitor
BTK
Inhibitor, for Adult Patients with
Relapsed or Refractory Mantle Cell Lymphoma
After at Least Two Lines of Systemic Therapy, Including a
BTK Inhibitor
BTK
Inhibitor
2023-01-27
·
BioSpace
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Jaypirca is the first
BTK inhibitor
BTK
inhibitor of any kind specifically approved for patients with
mantle cell lymphoma
previously treated with a covalent
BTK inhibitor
BTK
inhibitor In the BRUIN Phase 1/2 trial, covalent
BTK inhibitor
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
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
BTK
inhibitor. Jaypirca can reestablish
BTK
inhibition in
MCL
patients previously treated with a covalent
BTK inhibitor
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
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
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
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
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
BTK
inhibitor. Eighty-three percent (83%) of patients discontinued their last
BTK inhibitor
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: 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
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
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 curtailing its most devastating long-term effects, advancing the 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
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. Company Codes: NYSE:LLY
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机构
Eli Lilly & Co.
US Food & Drug Administration
The University of Texas at Austin
[+2]
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[+55]
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[+6]
药物
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