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NEW YORK--( BUSINESS WIRE )--Pfizer Inc. (NYSE: PFE) today announced that the European Commission (EC) has approved TALZENNA ® (talazoparib), an oral poly ADP-ribose polymerase (PARP) inhibitor, in combination with XTANDI ® (enzalutamide), for the treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC) in whom chemotherapy is not clinically indicated. With this approval, TALZENNA is now the first and only PARP inhibitor licensed in the European Union for use with XTANDI for patients with mCRPC, with or without gene mutations. “ New treatment options are needed to increase the proportion of patients with metastatic castration-resistant prostate cancer who can benefit from current anticancer medicines that keep the disease under control for longer,” said Robert Jones, MBChB, PhD, Professor of Clinical Cancer Research, University of Glasgow. “ The European Commission’s approval of talazoparib in combination with enzalutamide offers a meaningful advancement for the treatment of patients with metastatic castration-resistant prostate cancer, the most advanced and aggressive stage of the disease.” “ After years of fighting prostate cancer, it can be devastating for a patient to learn that their cancer has stopped responding to testosterone-lowering treatments. At this stage of the disease, the prognosis is generally poor,” said Erik Briers, MS, PhD, Vice Chairman, Europa UOMO, a European advocacy movement for people with prostate cancer. “ Patients urgently need new treatment options and TALZENNA in combination with XTANDI can bring new hope to these patients.” This approval by the European Commission of TALZENNA in combination with XTANDI for the mCRPC indication is valid in all 27 EU member states plus Iceland, Liechtenstein, and Norway. The approval is based on data from the Phase 3 TALAPRO-2 trial, a multicenter, randomized, double-blind, placebo-controlled study, evaluating two mCRPC patient cohorts: Cohort 1 (all-comers [n=805]) and Cohort 2 (those with HRR gene mutations [HRRm; n=399]). The results from TALAPRO-2 Cohort 1, which were published in The Lancet , showed that treatment with TALZENNA plus XTANDI reduced the risk of disease progression or death by 37% versus placebo plus XTANDI (Hazard Ratio [HR]: 0.63; 95% Confidence Interval [CI], 0.51–0.78; P< 0.0001), meeting the study’s primary endpoint of improving radiographic progression-free survival (rPFS). At the time of the analysis, the median rPFS for those treated with TALZENNA plus XTANDI had not yet been reached versus 21.9 months for those treated with placebo plus XTANDI. Median rPFS is defined as the timepoint in which 50% of patients in each treatment arms have progressed. A trend in overall survival (OS), a key secondary endpoint, favoring TALZENNA plus XTANDI was also observed, though these data are immature. The safety of TALZENNA plus XTANDI in the TALAPRO-2 trial was generally consistent with the known safety profile of each medicine. “ Today’s approval of TALZENNA in combination with XTANDI represents an important advancement for men living with prostate cancer in Europe,” said Chris Boshoff, M.D., Ph.D., Chief Oncology Officer, Executive Vice President, Pfizer. “ The results from the pivotal TALAPRO-2 trial showed that this combination offers an effective treatment that addresses disease progression in patients with or without any specific gene mutation.” TALZENNA in combination with XTANDI was approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with HRR gene-mutated mCRPC in June 2023. Pfizer has also shared the TALAPRO-2 data with other regulatory agencies to support regulatory filings. About Metastatic Castration-Resistant Prostate Cancer Metastatic castration-resistant prostate cancer (mCRPC) is a cancer that has spread beyond the prostate gland and has progressed despite medical or surgical treatment to lower testosterone. There were ~1.4 million new cases of prostate cancer reported worldwide in 2020, of which ~470,000 new cases were in Europe. 1 Approximately 10%–20% of prostate cancer patients develop mCRPC within 5−7 years of diagnosis. 2 Between 1.2%–2.1% of all prostate cancer cases globally are mCRPC. 3 About TALAPRO-2 The Phase 3 TALAPRO-2 trial is a two-part, two-cohort, multicenter, randomized, double-blind, placebo-controlled study that enrolled 1,106 patients with mCRPC (with no systemic treatments initiated after documentation of mCRPC) at sites in the U.S., Canada, Europe, South America, and the Asia-Pacific region. The study included two patient cohorts: all-comers (n=805) and those with and without gene mutations (HRRm; n=399). Patients on androgen deprivation therapy (ADT) or who had bilateral orchiectomy in the trial were randomized to receive TALZENNA 0.5 mg/day plus XTANDI 160mg/day, or placebo plus XTANDI 160 mg/day. The primary endpoint of the trial is radiographic progression-free survival (rPFS), defined as the time from the date of randomization to first objective evidence of radiographic progression by blinded independent review, or death, whichever occurs first, in both Cohort 1 (all-comers) and Cohort 2 (those with HRRm). Secondary endpoints include overall survival (OS), objective response rate, duration of response, and PSA response. For more information on the TALAPRO-2 trial ( NCT03395197 ), go to www.clinicaltrials.gov . About TALZENNA ® (talazoparib) TALZENNA (talazoparib) is an oral inhibitor of poly ADP-ribose polymerase (PARP), which plays a role in DNA damage repair. Preclinical studies have demonstrated that TALZENNA blocks PARP enzyme activity and traps PARP at the site of DNA damage, leading to decreased cancer cell growth and cancer cell death. TALZENNA is approved in over 70 countries, including the U.S and the EU, as a once-daily monotherapy for the treatment of adult patients with deleterious or suspected deleterious germline breast cancer susceptibility gene (BRCA)-mutated (gBRCAm) human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer. In the U.S., TALZENNA is approved in combination with XTANDI ® (enzalutamide) for the treatment of adult patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC). In the EU, TALZENNA is now approved in combination with enzalutamide for the treatment of adult patients with mCRPC in whom chemotherapy is not clinically indicated. TALZENNA ® (talazoparib) Indication in the U.S. TALZENNA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for: Breast Cancer: As a single agent, for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) HER2-negative locally advanced or metastatic breast cancer. Select patients for therapy based on an FDA-approved companion diagnostic for TALZENNA. HRR Gene-mutated mCRPC: In combination with enzalutamide for the treatment of adult patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC). TALZENNA ® (talazoparib) Important Safety Information WARNINGS and PRECAUTIONS Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) , including cases with a fatal outcome, has been reported in patients who received TALZENNA. Overall, MDS/AML has been reported in 0.4% (3 out of 788) of solid tumor patients treated with TALZENNA as a single agent in clinical studies. In TALAPRO-2, MDS/AML occurred in 2 out of 511 (0.4%) patients treated with TALZENNA and enzalutamide and in 0 out of 517 (0%) patients treated with placebo and enzalutamide. The durations of TALZENNA treatment in these five patients prior to developing MDS/AML were 0.3, 1, 2, 3, and 5 years, respectively. Most of these patients had received previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy. Do not start TALZENNA until patients have adequately recovered from hematological toxicity caused by previous chemotherapy. Monitor blood counts monthly during treatment with TALZENNA. For prolonged hematological toxicities, interrupt TALZENNA and monitor blood counts weekly until recovery. If counts do not recover within 4 weeks, refer the patient to a hematologist for further investigations including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue TALZENNA. Myelosuppression consisting of anemia, neutropenia, and/or thrombocytopenia have been reported in patients treated with TALZENNA. In TALAPRO-2, Grade ≥3 anemia, neutropenia, and thrombocytopenia were reported, respectively, in 45%, 18%, and 8% of patients receiving TALZENNA and enzalutamide. Overall, 39% of patients (199/511) required a red blood cell transfusion, including 22% (111/511) who required multiple transfusions. Discontinuation due to anemia, neutropenia, and thrombocytopenia occurred, respectively, in 7%, 3%, and 0.4% of patients. Withhold TALZENNA until patients have adequately recovered from hematological toxicity caused by previous therapy. Monitor blood counts monthly during treatment with TALZENNA. If hematological toxicities do not resolve within 28 days, discontinue TALZENNA and refer the patient to a hematologist for further investigations including bone marrow analysis and blood sample for cytogenetics. Embryo-Fetal Toxicity TALZENNA can cause fetal harm when administered to pregnant women. Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment with TALZENNA and for 4 months after receiving the last dose. ADVERSE REACTIONS Serious adverse reactions reported in >2% of patients included anemia (9%) and fracture (3%). Fatal adverse reactions occurred in 1.5% of patients, including pneumonia, COVID infection, and sepsis (1 patient each). The most common adverse reactions (≥ 10%, all Grades), including laboratory abnormalities, for patients in the TALAPRO-2 study who received TALZENNA in combination with enzalutamide vs patients receiving placebo with enzalutamide were hemoglobin decreased (79% vs 34%), neutrophils decreased (60% vs 18%), lymphocytes decreased (58% vs 36%), fatigue (49% vs 40%), platelets decreased (45% vs 8%), calcium decreased (25% vs 11%), nausea (21% vs 17%), decreased appetite (20% vs 14%), sodium decreased (22% vs 20%), phosphate decreased (17% vs 13%), fractures (14% vs 10%), magnesium decreased (14% vs 12%), dizziness (13% vs 9%), bilirubin increased (11% vs 7%), potassium decreased (11% vs 7%), and dysgeusia (10% vs 4.5%). Clinically relevant adverse reactions in <10% of patients who received TALZENNA with enzalutamide included abdominal pain (9%), vomiting (9%), alopecia (7%), dyspepsia (4%), venous thromboembolism (3%) and stomatitis (2%). Based on animal studies, TALZENNA may impair fertility in males of reproductive potential. DRUG INTERACTIONS Coadministration with P-gp inhibitors The effect of coadministration of P-gp inhibitors on talazoparib exposure when TALZENNA is taken in combination with enzalutamide has not been studied. Monitor patients for increased adverse reactions and modify the dosage as recommended for adverse reactions when TALZENNA is coadministered with a P-gp inhibitor. Coadministration with BCRP inhibitors Monitor patients for increased adverse reactions and modify the dosage as recommended for adverse reactions when TALZENNA is coadministered with a BCRP inhibitor. Coadministration of TALZENNA with BCRP inhibitors may increase talazoparib exposure, which may increase the risk of adverse reactions. USE IN SPECIFIC POPULATIONS Renal Impairment The recommended dosage of TALZENNA for patients with moderate renal impairment (CLcr 30 - 59 mL/min) is 0.35 mg taken orally once daily in combination with enzalutamide. The recommended dosage of TALZENNA for patients with severe renal impairment (CLcr 15 - 29 mL/min) is 0.25 mg taken orally once daily in combination with enzalutamide. No dose adjustment is required for patients with mild renal impairment. TALZENNA has not been studied in patients requiring hemodialysis. Please see full U.S. Prescribing Information and Patient Information for TALZENNA ® (talazoparib) at www.TALZENNA.com . About XTANDI ® (enzalutamide) and Important Safety Information XTANDI ® (enzalutamide) is an androgen receptor signaling inhibitor. XTANDI is a standard of care and has received regulatory approvals in one or more countries around the world for use in men with metastatic castration-sensitive prostate cancer (mCSPC; also known as metastatic hormone-sensitive prostate cancer or mHSPC), metastatic castration-resistant prostate cancer (mCRPC), non-metastatic castration-resistant prostate cancer (nmCRPC) and nonmetastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence at high risk for metastasis (high-risk BCR). XTANDI is currently approved for one or more of these indications in more than 90 countries, including in the U.S., EU, and Japan. Over one million patients have been treated with XTANDI globally. 4 Warnings and Precautions Seizure occurred in 0.6% of patients receiving XTANDI in eight randomized clinical trials. In a study of patients with predisposing factors for seizure, 2.2% of XTANDI-treated patients experienced a seizure. It is unknown whether anti-epileptic medications will prevent seizures with XTANDI. Patients in the study had one or more of the following predisposing factors: use of medications that may lower the seizure threshold, history of traumatic brain or head injury, history of cerebrovascular accident or transient ischemic attack, and Alzheimer’s disease, meningioma, or leptomeningeal disease from prostate cancer, unexplained loss of consciousness within the last 12 months, history of seizure, presence of a space occupying lesion of the brain, history of arteriovenous malformation, or history of brain infection. Advise patients of the risk of developing a seizure while taking XTANDI and of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others. Permanently discontinue XTANDI in patients who develop a seizure during treatment. Posterior Reversible Encephalopathy Syndrome (PRES) There have been reports of PRES in patients receiving XTANDI. PRES is a neurological disorder that can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension. A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES. Hypersensitivity reactions, including edema of the face (0.5%), tongue (0.1%), or lip (0.1%) have been observed with XTANDI in eight randomized clinical trials. Pharyngeal edema has been reported in post-marketing cases. Advise patients who experience any symptoms of hypersensitivity to temporarily discontinue XTANDI and promptly seek medical care. Permanently discontinue XTANDI for serious hypersensitivity reactions. Ischemic Heart Disease In the combined data of five randomized, placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (3.5% vs 2%). Grade 3-4 ischemic events occurred in 1.8% of patients on XTANDI versus 1.1% on placebo. Ischemic events led to death in 0.4% of patients on XTANDI compared to 0.1% on placebo. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue XTANDI for Grade 3-4 ischemic heart disease. Falls and Fractures occurred in patients receiving XTANDI. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents. In the combined data of five randomized, placebo-controlled clinical studies, falls occurred in 12% of patients treated with XTANDI compared to 6% of patients treated with placebo. Fractures occurred in 13% of patients treated with XTANDI and in 6% of patients treated with placebo. Embryo-Fetal Toxicity The safety and efficacy of XTANDI have not been established in females. XTANDI can cause fetal harm and loss of pregnancy when administered to a pregnant female. Advise males with female partners of reproductive potential to use effective contraception during treatment with XTANDI and for 3 months after the last dose of XTANDI. Adverse Reactions (ARs) In the data from the five randomized placebo-controlled trials, the most common ARs (≥ 10%) that occurred more frequently (≥ 2% over placebo) in XTANDI-treated patients were musculoskeletal pain, fatigue, hot flush, constipation, decreased appetite, diarrhea, hypertension, hemorrhage, fall, fracture, and headache. In the bicalutamide-controlled study, the most common ARs (≥ 10%) reported in XTANDI-treated patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, diarrhea, upper respiratory tract infection, and weight loss. In AFFIRM, the placebo-controlled study of metastatic CRPC (mCRPC) patients who previously received docetaxel, Grade 3 and higher ARs were reported among 47% of XTANDI-treated patients. Discontinuations due to ARs were reported for 16% of XTANDI-treated patients. In PREVAIL, the placebo-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to ARs were reported for 6% of XTANDI-treated patients. In TERRAIN, the bicalutamide-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 39% of XTANDI patients and 38% of bicalutamide patients. Discontinuations with an AR as the primary reason were reported for 8% of XTANDI patients and 6% of bicalutamide patients. In PROSPER, the placebo-controlled study of nonmetastatic CRPC (nmCRPC) patients, Grade 3 or higher ARs were reported in 31% of XTANDI patients and 23% of placebo patients. Discontinuations with an AR as the primary reason were reported for 9% of XTANDI patients and 6% of placebo patients. In ARCHES, the placebo-controlled study of metastatic CSPC (mCSPC) patients, Grade 3 or higher ARs were reported in 24% of XTANDI-treated patients. Permanent discontinuation due to ARs as the primary reason was reported in 5% of XTANDI patients and 4% of placebo patients. In EMBARK, the placebo-controlled study of nonmetastatic CSPC (nmCSPC) with high-risk biochemical recurrence (BCR) patients, Grade 3 or higher adverse reactions during the total duration of treatment were reported in 46% of patients treated with XTANDI plus leuprolide, 50% of patients receiving XTANDI as a single agent, and 43% of patients receiving placebo plus leuprolide. Permanent treatment discontinuation due to adverse reactions during the total duration of treatment as the primary reason was reported in 21% of patients treated with XTANDI plus leuprolide, 18% of patients receiving XTANDI as a single agent, and 10% of patients receiving placebo plus leuprolide. Lab Abnormalities: Lab abnormalities that occurred in ≥ 5% of patients, and more frequently (> 2%) in the XTANDI arm compared to placebo in the pooled, randomized, placebo-controlled studies are hemoglobin decrease, neutrophil count decreased, white blood cell decreased, hyperglycemia, hypermagnesemia, hyponatremia, hyperphosphatemia, and hypercalcemia. Hypertension: In the combined data from five randomized placebo-controlled clinical trials, hypertension was reported in 14.2% of XTANDI patients and 7.4% of placebo patients. Hypertension led to study discontinuation in < 1% of patients in each arm. Drug Interactions Effect of Other Drugs on XTANDI Avoid coadministration with strong CYP2C8 inhibitors. If coadministration cannot be avoided, reduce the dosage of XTANDI. Avoid coadministration with strong CYP3A4 inducers. If coadministration cannot be avoided, increase the dosage of XTANDI. Effect of XTANDI on Other Drugs Avoid coadministration with certain CYP3A4, CYP2C9, and CYP2C19 substrates for which minimal decrease in concentration may lead to therapeutic failure of the substrate. If coadministration cannot be avoided, increase the dosage of these substrates in accordance with their Prescribing Information. In cases where active metabolites are formed, there may be increased exposure to the active metabolites. Please see Full Prescribing Information for additional safety information. About Pfizer Oncology At Pfizer Oncology, we are at the forefront of a new era in cancer care. Our industry-leading portfolio and extensive pipeline includes game-changing mechanisms of action to attack cancer from multiple angles, including antibody-drug conjugates (ADCs), small molecules, bispecifics and other immunotherapies. We are focused on delivering transformative therapies in some of the world’s most common cancers, including breast cancer, genitourinary cancer and hematologic malignancies, as well as melanoma, gastrointestinal, gynecological and thoracic cancers, which includes lung cancer. Driven by science, we are committed to accelerating breakthroughs to extend and improve patients’ lives. About the Pfizer/Astellas Collaboration In October 2009, Medivation, Inc., which is now part of Pfizer (NYSE: PFE), and Astellas (TSE: 4503) entered into a global agreement to jointly develop and commercialize XTANDI ® (enzalutamide). The companies jointly commercialize XTANDI in the United States, and Astellas has responsibility for manufacturing and all additional regulatory filings globally, as well as commercializing XTANDI outside the United States. Disclosure Notice The information contained in this release is as of January 8, 2024. Pfizer assumes no obligation to update forward-looking statements contained in this release as the result of new information or future events or developments. This release contains forward-looking information about Pfizer Oncology, TALZENNA and XTANDI, including their potential benefits, and an approval by the European Commission for TALZENNA in combination with XTANDI for the treatment of adult patients with metastatic castration-resistant prostate cancer in whom chemotherapy is not clinically indicated, that involves substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. Risks and uncertainties include, among other things, uncertainties regarding the commercial success of TALZENNA in combination with XTANDI; the uncertainties inherent in research and development, including the ability to meet anticipated clinical endpoints, commencement and/or completion dates for our clinical trials, regulatory submission dates, regulatory approval dates and/or launch dates, as well as the possibility of unfavorable new clinical data and further analyses of existing clinical data; whether TALAPRO-2 trial will meet the secondary endpoint for overall survival; the risk that clinical trial data are subject to differing interpretations and assessments by regulatory authorities; whether regulatory authorities will be satisfied with the design of and results from our clinical studies; whether and when applications for TALZENNA, XTANDI or a combination may be filed in any jurisdictions for any potential indications; whether and when any such applications for TALZENNA, XTANDI or a combination that may be pending or filed may be approved by regulatory authorities, which will depend on myriad factors, including making a determination as to whether the product’s benefits outweigh its known risks and determination of the product’s efficacy and, if approved, whether TALZENNA, XTANDI or a combination will be commercially successful; decisions by regulatory authorities impacting labeling, manufacturing processes, safety and/or other matters that could affect the availability or commercial potential of TALZENNA, XTANDI or a combination; uncertainties regarding the impact of COVID-19 on Pfizer’s business, operations and financial results; and competitive developments. A further description of risks and uncertainties can be found in Pfizer’s Annual Report on Form 10-K for the fiscal year ended December 31, 2022 and in its subsequent reports on Form 10-Q, including in the sections thereof captioned “Risk Factors” and “ Forward-Looking Information and Factors That May Affect Future Results”, as well as in its subsequent reports on Form 8-K, all of which are filed with the U.S. Securities and Exchange Commission and available at www.sec.gov and www.pfizer.com . Category: Prescription Medicines ________________________________ 1 World Health Organization Global Cancer Observatory. 27-Prostate-fact-sheet.pdf (iarc.fr) 2 Kirby M, et al. Int J Clin Pract. 2011;11:1180-1192. 3 Shore N, Oliver L, Shui I, Gayle A, Wong OY, Kim J, Payne S, Amin S, Ghate S. Systematic Literature Review of the Epidemiology of Advanced Prostate Cancer and Associated Homologous Recombination Repair Gene Alterations. J Urol. 2021 Apr;205(4):977-986. doi: 10.1097/JU.0000000000001570. Epub 2020 Dec 17. PMID: 33332152. 4 Data on file. Northbrook, IL: Astellas Inc.

INDIANAPOLIS, Dec. 11, 2023 /PRNewswire/ -- Eli Lilly and Company (NYSE: LLY) today announced updated clinical data from the international Phase 1/2 BRUIN trial of pirtobrutinib, a non-covalent (reversible) Bruton's tyrosine kinase (BTK) inhibitor, in adult patients with a range of B-cell malignancies. These data, which were presented in oral and poster presentations at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition, continue to support the role of pirtobrutinib in the treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) and mantle cell lymphoma (MCL). "With longer follow-up, we continue to observe efficacy and tolerability data that support the potential utility of pirtobrutinib in CLL and B-cell lymphomas in the post-covalent BTK inhibitor setting," said Matthew S. Davids, M.D., M.M.Sc., Dana-Farber Cancer Institute. "These data demonstrate the ability of pirtobrutinib to potentially lengthen the time patients may benefit from inhibiting BTK, a key target in these diseases. It is also encouraging to see the promising initial data for pirtobrutinib combined with venetoclax, which has the possibility to allow for a time-limited regimen for patients with CLL." "Following the two FDA accelerated approvals for pirtobrutinib in 2023, we are excited to present these data at ASH, further building the body of evidence for this medicine in CLL, SLL, MCL, and other B-cell malignancies," said David Hyman, M.D., chief medical officer, Lilly. "These data support the potential role that pirtobrutinib, the first and only FDA-approved non-covalent BTK inhibitor, can play in extending the time patients may benefit from BTK inhibition therapy and provide additional efficacy data in patients previously treated with a covalent BTK inhibitor. We look forward to expanding our understanding of the broader potential clinical utility of pirtobrutinib as we continue to progress our series of randomized Phase 3 studies in CLL, SLL, and MCL." The labeling for pirtobrutinib contains warnings and precautions for infections, hemorrhage, cytopenias, cardiac arrhythmias, second primary malignancies, and embryo-fetal toxicity. Data from the BRUIN Phase 1/2 Study The BRUIN Phase 1/2 clinical trial is evaluating pirtobrutinib in patients previously treated for MCL, CLL/SLL, or other non-Hodgkin lymphomas (NHL). The efficacy data presented at ASH for CLL/SLL and MCL are based on independent review committee (IRC) assessment. All presentations of safety and efficacy data from the BRUIN Phase 1/2 trial utilized a cutoff date of May 5, 2023. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma An oral presentation (Abstract #325) detailed updated, long-term follow-up data in patients with CLL/SLL. This data set consisted of 282 patients who had received a prior BTK inhibitor. Patients had received a median of four prior lines of therapy (range: 1-11). Efficacy results showed an overall response rate (ORR), including partial response with lymphocytosis (PR-L), of 81.6% (95% CI: 76.5, 85.9) for patients treated with pirtobrutinib. Response rates were consistent across all subgroups analyzed regardless of previous therapies, age, or mutation status. With a median follow-up of 27.5 months, median progression-free survival (PFS) was 19.4 months (95% CI: 16.6, 22.1). With a median follow-up of 29.3 months, median overall survival (OS) was not estimable. In patients treated with both a prior covalent BTK inhibitor and BCL-2 inhibitor (n=128, median of five prior lines of therapy, range: 1-11), pirtobrutinib demonstrated an ORR, including PR-L, of 79.7% (95% CI: 71.7, 86.3). With a median follow-up of 22.2 months, median PFS was 15.9 months (95% CI: 13.6, 17.5). With a median follow-up of 27.4 months, the median OS was not estimable. In BCL-2-naïve patients (n=154, median of three prior lines of therapy, range: 1-9), pirtobrutinib demonstrated an ORR, including PR-L, of 83.1% (95% CI: 76.2, 88.7). With a median follow-up of 27.6 months, median PFS was 23.0 months (95% CI: 19.6, 28.4). With a median follow-up of 31.6 months, the median OS was not estimable. In the CLL/SLL safety cohort (n=282), the most frequent treatment-emergent adverse events (TEAEs) were fatigue (36.9%), neutropenia (34.4%), diarrhea (28.4%), cough (27.3%), and contusion (26.2%). A second oral presentation (Abstract #326) detailed updated analyses of genomic evolution and resistance during pirtobrutinib therapy in patients with relapsed covalent BTK inhibitor pre-treated CLL who subsequently developed disease progression on pirtobrutinib monotherapy (n=88). These data showed that although many patients harbored BTK mutations (C481 and non-C481) prior to initiation of pirtobrutinib therapy, these baseline genomic features did not predict response to pirtobrutinib. Moreover, while many patients acquired mutations at progression (68%), fewer than half were in the BTK gene. A poster presentation (Abstract #3269) detailed updated data from the Phase 1b portion of the BRUIN trial, which investigated pirtobrutinib in combination with venetoclax with or without rituximab as a two-year fixed-duration therapy. This data set consisted of 25 patients, 17 of whom had received a prior BTK inhibitor. Patients were enrolled into sequential cohorts, first in the pirtobrutinib plus venetoclax (PV) cohort (n=15) and then the PV plus rituximab (PVR) cohort (n=10). Efficacy results showed an ORR of 96% (95% CI: 79.6, 99.9), with 40% complete responses (PV, n=7; PVR, n=3) and 56% partial responses (PV, n=7; PVR, n=7) across the two arms. Undetectable minimal residual disease (uMRD) was achieved by 87.5% of patients (PV, n=12; PVR, n=9) at some time during the trial. Across the two arms, the PFS rate at 24 months was 79.5% (95% CI: 52.0, 92.3). The primary endpoint was safety as assessed by TEAEs graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. The safety profiles were generally similar among both combination treatment groups, and no dose limiting toxicities were observed. In the PV cohort, the most frequent treatment-related AEs were neutropenia (46.7%), nausea (46.7%), fatigue (33.3%), diarrhea (26.7%), and decreased platelet count (26.7%). In the PVR cohort, the most frequent treatment-related AEs were neutropenia (70.0%), diarrhea (60.0%), nausea (40.0%), infusion-related reactions (40.0%), and chills (30.0%). There were no apparent drug interactions between pirtobrutinib and venetoclax. These efficacy and safety data support the ongoing BRUIN CLL-322 Phase 3 trial evaluating two years of pirtobrutinib plus venetoclax and rituximab versus two years of venetoclax plus rituximab in previously treated CLL/SLL. Mantle Cell Lymphoma An oral presentation (Abstract #981) detailed updated efficacy results, including in high-risk subgroups. This data set consisted of 152 patients who had received a prior covalent BTK inhibitor. Patients had received a median of three prior lines of therapy (range: 1-9). Efficacy results showed an ORR of 49.3% (95% CI: 41.1, 57.6), including 15.8% complete responses (n=24) and 33.6% partial responses (n=51) for patients treated with pirtobrutinib. At a median follow-up of 14.7 months, the median duration of response (DOR) was 21.6 months (95% CI: 9.2, 27.2). Median PFS and OS were 5.6 months (95% CI: 5.3, 9.2) and 23.5 months (95% CI: 17.1, not estimable), respectively. Response rates were consistent across subgroups regardless of prior treatment or high-risk molecular features. In the MCL safety cohort (n=166), the most frequent TEAEs were fatigue (31.9%), diarrhea (22.3%), and dyspnea (17.5%). Additionally, Lilly presented posters highlighting pirtobrutinib in relapsed or refractory follicular lymphoma (FL), relapsed or refractory marginal zone lymphoma (MZL), and Richter transformation (RT). Loxo@Lilly is studying pirtobrutinib in multiple Phase 3 studies. Details on the trials can be found by visiting clinicaltrials.gov. 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 pirtobrutinib in patients with hematologic malignancies, including chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and mantle cell lymphoma (MCL). The BRUIN trial includes one of the largest prospective cohorts of BTK inhibitor pre-treated CLL/SLL patients ever studied. 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 Pirtobrutinib Pirtobrutinib 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.1 BTK plays a key role in the B-cell antigen receptor signaling pathway, which is required for the development, activation, and survival of normal white blood cells, known as B-cells, and malignant B-cells. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas, including mantle cell lymphoma (MCL) and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).2,3 Pirtobrutinib was developed to reversibly bind BTK, deliver consistently high target coverage regardless of BTK turnover rate, and preserve activity in the presence of the C481 acquired resistance mutations. Pirtobrutinib was approved under the FDA's Accelerated Approval pathway as Jaypirca® (pirtobrutinib) on January 27, 2023, to treat adult patients with relapsed or refractory MCL after at least two lines of systemic therapy, including a BTK inhibitor, and on December 1, 2023, to treat adult patients with CLL/SLL who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. These indications are approved under accelerated approval based on response rate. Continued approval for these indications may be contingent upon verification and description of clinical benefit in a confirmatory trial. 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. Adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. These indications are approved under accelerated approval based on response rate. Continued approval for these indications 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, fungal) and opportunistic infections occurred in Jaypirca-treated patients. In a clinical trial, Grade ≥3 infections occurred in 24% of patients with hematologic malignancies, most commonly pneumonia (14%); fatal infections occurred in 4.4%. Sepsis (6%) and febrile neutropenia (4%) occurred. In patients with CLL/SLL, Grade ≥3 infections occurred (32%), with fatal infections occurring in 8%. Opportunistic infections included 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 3% of patients, including gastrointestinal hemorrhage; fatal hemorrhage occurred (0.3%). Bleeding of any grade, excluding bruising and petechiae, occurred in 17%. Major hemorrhage occurred in patients taking Jaypirca with (0.7%) and without (2.3%) 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: Jaypirca can cause cytopenias, including neutropenia, thrombocytopenia, and anemia. In a clinical trial, Grade 3 or 4 cytopenias, including decreased neutrophils (26%), decreased platelets (12%), and decreased hemoglobin (12%), developed in Jaypirca-treated patients. Grade 4 decreased neutrophils (14%) and Grade 4 decreased platelets (6%) developed. Monitor complete blood counts regularly during treatment. Based on severity, reduce dose, temporarily withhold, or permanently discontinue Jaypirca. Cardiac Arrhythmias: Cardiac arrhythmias occurred in patients who received Jaypirca. In a clinical trial of patients with hematologic malignancies, atrial fibrillation or flutter were reported in 3.2% of Jaypirca-treated patients, with Grade 3 or 4 atrial fibrillation or flutter in 1.5%. Other serious cardiac arrhythmias such as supraventricular tachycardia and cardiac arrest occurred (0.5%). 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 9% of Jaypirca-treated patients. The most frequent malignancy was non-melanoma skin cancer (4.6%). 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: 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 fetal risk and females of reproductive potential to use effective contraception during treatment and for one week after last dose. Adverse Reactions (ARs) in Patients Who Received Jaypirca The most common (≥20%) ARs in the BRUIN pooled safety population of patients with hematologic malignancies (n=593) were decreased neutrophil count (46%), decreased hemoglobin (39%), fatigue (32%), decreased lymphocyte count (31%), musculoskeletal pain (30%), decreased platelet count (29%), diarrhea (24%), COVID-19 (22%), bruising (21%), cough (20%). Mantle Cell Lymphoma 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 Jaypirca dose occurred in 7% of patients, most commonly due to infections (4.7%), including COVID-19 (3.1% of all patients). Dose Modifications and Discontinuations: ARs led to dose 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 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). Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Serious ARs occurred in 56% of patients. Serious ARs occurring in ≥5% of patients were pneumonia (18%), COVID-19 (9%), sepsis (7%), and febrile neutropenia (7%). Fatal ARs within 28 days of last Jaypirca dose occurred in 11% of patients, most commonly due to infections (10%), including sepsis (5%) and COVID-19 (2.7%). Dose Modifications and Discontinuations: ARs led to dose reductions in 3.6%, treatment interruption in 42%, and permanent discontinuation of Jaypirca in 9% of patients. ARs resulting in dose reductions in >1% included neutropenia; treatment interruptions in >5% of patients included pneumonia, neutropenia, febrile neutropenia, and COVID-19; permanent discontinuation in >1% of patients included second primary malignancy, COVID-19, and sepsis. ARs (all Grades %; Grade 3-4 %) in ≥10% of Patients: fatigue (36; 2.7), bruising (36; -), cough (33; -), musculoskeletal pain (32; 0.9), COVID-19 (28; 7), pneumonia (27; 16), diarrhea (26; -), abdominal pain (25; 2.7), dyspnea (22; 2.7), hemorrhage (22; 2.7), edema (21; -), nausea (21; -), pyrexia (20; 2.7), headache (20; 0.9), arthritis/arthralgia (19; 1.8), rash (19; 0.9), peripheral neuropathy (16; 3.6), dizziness (15; -), fall (14; 0.9), constipation (14; -), insomnia (14; -), upper respiratory tract infections (13; 2.7), second primary malignancy (13; 2.7), renal insufficiency (12; 6), hypertension (12; 5), neurological changes (12; 2.7), mucositis (12; 0.9), decreased appetite (12; -), respiratory tract infection (11; 1.8), supraventricular tachycardia (10; 5). Select Laboratory Abnormalities (all Grades %; Grade 3 or 4 %) that Worsened from Baseline in ≥20% of Patients: neutrophil count decreased (63; 45), hemoglobin decreased (48; 19), calcium decreased (40; 2.8), platelet count decreased (30; 15), sodium decreased (30; -), lymphocyte count decreased (23; 8), ALT increased (23; 2.8), AST increased (23; 1.9), creatinine increased (23; -), lipase increased (21; 7), alkaline phosphatase increased (21; -). Grade 4 laboratory abnormalities in >5% of patients included neutrophils decreased (23). Drug Interactions Strong CYP3A Inhibitors: Concomitant use with Jaypirca increased pirtobrutinib systemic exposure, which may increase risk of Jaypirca ARs. Avoid use of strong CYP3A inhibitors with Jaypirca. If concomitant use is unavoidable, reduce Jaypirca dosage according to 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 Jaypirca dosage according to approved labeling. Sensitive CYP2C8, CYP2C19, CYP3A, P-gp, or 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: Due to 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 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, 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 increases pirtobrutinib exposure. Reduce Jaypirca dosage in patients with severe renal impairment according to approved labeling. PT HCP ISI COMBO DEC2023 Please see Prescribing Information and Patient Information for Jaypirca. 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 51 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 registered trademark owned by or licensed to Eli Lilly and Company, its subsidiaries, or affiliates. © Lilly USA, LLC 2023. ALL RIGHTS RESERVED. Lilly 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 pirtobrutinib as a treatment for adult patients with mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor, as a treatment for adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor, and a potential treatment for follicular lymphoma (FL), relapsed or refractory marginal zone lymphoma (MZL), and Richter transformation (RT) 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, or that pirtobrutinib will receive additional regulatory approvals. 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. 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 SOURCE Eli Lilly and Company

The first and only non-covalent (reversible) BTK inhibitor, Jaypirca has been shown to extend the benefit of BTK inhibition In the BRUIN Phase 1/2 trial, adult patients with CLL/SLL who have received at least two lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor, achieved an overall response rate of 72% INDIANAPOLIS, Dec. 1, 2023 /PRNewswire/ -- 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 chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have received at least two prior lines of therapy, including a Bruton's tyrosine kinase (BTK) inhibitor and a BCL-2 inhibitor. Jaypirca was approved under the FDA's Accelerated Approval pathway based on overall response rate (ORR) and duration of response (DOR) from the open-label, single-arm, multicohort, international, Phase 1/2 BRUIN trial.1 Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.1 Jaypirca, the first and only FDA-approved non-covalent (reversible) BTK inhibitor, is a highly selective kinase inhibitor that can extend the benefit of targeting the BTK pathway in CLL/SLL patients previously treated with a covalent BTK inhibitor (ibrutinib, acalabrutinib, or zanubrutinib) and a BCL-2 inhibitor.1,2 Jaypirca utilizes a novel binding mechanism and has the largest body of evidence of any targeted therapy in patients previously treated with a BTK inhibitor.1,2 "Once patients with CLL or SLL have progressed on covalent BTK inhibitor and BCL-2 inhibitor therapies, treatments are limited and outcomes can be poor, making the approval of Jaypirca a meaningful advance and much-needed new treatment option for these patients," said William G. Wierda, M.D., Ph.D., professor, medical director, and CLL section head for the Department of Leukemia at The University of Texas MD Anderson Cancer Center. "Jaypirca offers a new treatment option and different approach to targeting BTK, providing clinical benefit for a high proportion of patients with CLL or SLL in the BRUIN Phase 1/2 trial whose disease progressed following treatment with a covalent BTK inhibitor and with a BCL-2 inhibitor." The labeling for Jaypirca contains warnings and precautions for infections, hemorrhage, cytopenias, cardiac arrhythmias, second primary malignancies, and embryo-fetal toxicity. See Important Safety Information below and full Prescribing Information for additional information, including dosing modifications. "This FDA approval — the second for Jaypirca in 2023 — underscores the impactful clinical benefit of continuing to leverage the BTK pathway with Jaypirca for patients with CLL or SLL as seen in the BRUIN trial," said Jacob Van Naarden, chief executive officer, Loxo@Lilly. "These first two indications for Jaypirca represent the beginning of the eventual impact that we hope Jaypirca can have for patients, and we look forward to seeing the results of the comprehensive Phase 3 development program across CLL, SLL and MCL." "The treatment landscape for CLL has been dramatically improved by the introduction of covalent BTK inhibitors and BCL-2 inhibitors. However, most patients will unfortunately relapse eventually," said Brian Koffman, M.D., chief medical officer and executive vice president at the CLL Society. "Pirtobrutinib's approval gives patients a much-needed option and brings forward new possibilities as they continue their treatment journey." 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 108 patients with CLL/SLL treated with Jaypirca who were previously treated with at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. Jaypirca 200 mg was given once daily and was continued until disease progression or unacceptable toxicity. Patients with active central nervous system (CNS) involvement by lymphoma or allogeneic hematopoietic stem cell transplantation (HSCT) within 60 days were excluded. Patients in the efficacy-eligible population had received a median of five prior lines of therapy (range: 2 to 11). The most common prior BTK inhibitors received were ibrutinib (97%), acalabrutinib (9%), and zanubrutinib (0.9%). Seventy-seven percent (77%) of patients discontinued the last BTK inhibitor for refractory or progressive disease. Efficacy was established based on ORR and DOR, as assessed by an independent review committee (IRC) using 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria. Efficacy results are summarized below: The pooled safety analysis of the full BRUIN study population evaluated 593 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, including laboratory abnormalities, were decreased neutrophil count, decreased hemoglobin, fatigue, decreased lymphocyte count, musculoskeletal pain, decreased platelet count, diarrhea, COVID-19, bruising, and cough. The safety of Jaypirca was evaluated in the BRUIN trial in 110 patients with CLL/SLL, with 98% receiving at least two prior lines of systemic therapy, including a BTK inhibitor and a BCL-2 inhibitor. Sixty percent (60%) of these patients were exposed to Jaypirca for at least one year, and 14% were exposed for at least two years. ARs led to dose reductions in 3.6%, treatment interruption in 42%, and permanent discontinuation of Jaypirca in 9% of patients. ARs that resulted in permanent discontinuation of Jaypirca in more than 1% of patients included second primary malignancy, COVID-19, and sepsis. Serious ARs occurred in 56% of patients who received Jaypirca. Serious ARs occurring in greater than or equal to 5% of patients were pneumonia (18%), COVID-19 (9%), sepsis (7%), and febrile neutropenia (7%). Lilly is committed to delivering on the requirements of the FDA's Accelerated Approval pathway, including the completion of confirmatory studies supporting traditional approval as soon as possible. The Phase 3 randomized confirmatory trial intended to convert this approval to traditional approval is BRUIN CLL-321, which reached its target number of progression-free survival (PFS) events and met its primary endpoint. Topline results were shared with the FDA in November 2023, although these data have not yet been formally reviewed. BRUIN CLL-321 is a randomized Phase 3 trial comparing pirtobrutinib monotherapy versus the investigator's choice of either idelalisib in combination with rituximab or bendamustine in combination with rituximab in patients with CLL/SLL who have been treated with at least a BTK inhibitor. These data will be presented at an upcoming medical meeting. Jaypirca is not approved for use in the BRUIN CLL-321 population. This is the second FDA-approved indication for Jaypirca following the January 2023 Accelerated Approval 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. Loxo@Lilly is studying Jaypirca in CLL/SLL in multiple Phase 3 studies. Details on the trials can be found by visiting clinicaltrials.gov. See Important Safety Information below and full Prescribing Information for additional information. Click here to view the CLL 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 chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and 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 and chronic lymphocytic leukemia/small lymphocytic 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 Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma CLL and SLL are forms of slow-growing non-Hodgkin lymphoma that develop from white blood cells known as lymphocytes.5,6 CLL is one of the most common types of leukemia in adults.5 In the U.S., CLL accounts for about one-quarter of the new cases of leukemia and there are approximately 18,740 new cases of CLL diagnosed this year.5,7 SLL is identical to CLL from a pathologic and immunophenotypic standpoint, with the main difference between them being the location of the cancer cells.5 In CLL, the cancer cells are present in the blood, and in SLL, the cancer cells are found in the lymph nodes.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. Adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. These indications are approved under accelerated approval based on response rate. Continued approval for these indications 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, fungal) and opportunistic infections occurred in Jaypirca-treated patients. In a clinical trial, Grade ≥3 infections occurred in 24% of patients with hematologic malignancies, most commonly pneumonia (14%); fatal infections occurred in 4.4%. Sepsis (6%) and febrile neutropenia (4%) occurred. In patients with CLL/SLL, Grade ≥3 infections occurred (32%), with fatal infections occurring in 8%. Opportunistic infections included 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 3% of patients, including gastrointestinal hemorrhage; fatal hemorrhage occurred (0.3%). Bleeding of any grade, excluding bruising and petechiae, occurred in 17%. Major hemorrhage occurred in patients taking Jaypirca with (0.7%) and without (2.3%) 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: Jaypirca can cause cytopenias, including neutropenia, thrombocytopenia, and anemia. In a clinical trial, Grade 3 or 4 cytopenias, including decreased neutrophils (26%), decreased platelets (12%), and decreased hemoglobin (12%), developed in Jaypirca-treated patients. Grade 4 decreased neutrophils (14%) and Grade 4 decreased platelets (6%) developed. Monitor complete blood counts regularly during treatment. Based on severity, reduce dose, temporarily withhold, or permanently discontinue Jaypirca. Cardiac Arrhythmias: Cardiac arrhythmias occurred in patients who received Jaypirca. In a clinical trial of patients with hematologic malignancies, atrial fibrillation or flutter were reported in 3.2% of Jaypirca-treated patients, with Grade 3 or 4 atrial fibrillation or flutter in 1.5%. Other serious cardiac arrhythmias such as supraventricular tachycardia and cardiac arrest occurred (0.5%). 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 9% of Jaypirca-treated patients. The most frequent malignancy was non-melanoma skin cancer (4.6%). 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: 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 fetal risk and females of reproductive potential to use effective contraception during treatment and for one week after last dose. Adverse Reactions (ARs) in Patients Who Received Jaypirca The most common (≥20%) ARs in the BRUIN pooled safety population of patients with hematologic malignancies (n=593) were decreased neutrophil count (46%), decreased hemoglobin (39%), fatigue (32%), decreased lymphocyte count (31%), musculoskeletal pain (30%), decreased platelet count (29%), diarrhea (24%), COVID-19 (22%), bruising (21%), cough (20%). Mantle Cell Lymphoma 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 Jaypirca dose occurred in 7% of patients, most commonly due to infections (4.7%), including COVID-19 (3.1% of all patients). Dose Modifications and Discontinuations: ARs led to dose 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 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). Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Serious ARs occurred in 56% of patients. Serious ARs occurring in ≥5% of patients were pneumonia (18%), COVID-19 (9%), sepsis (7%), and febrile neutropenia (7%). Fatal ARs within 28 days of last Jaypirca dose occurred in 11% of patients, most commonly due to infections (10%), including sepsis (5%) and COVID-19 (2.7%). Dose Modifications and Discontinuations: ARs led to dose reductions in 3.6%, treatment interruption in 42%, and permanent discontinuation of Jaypirca in 9% of patients. ARs resulting in dose reductions in >1% included neutropenia; treatment interruptions in >5% of patients included pneumonia, neutropenia, febrile neutropenia, and COVID-19; permanent discontinuation in >1% of patients included second primary malignancy, COVID-19, and sepsis. ARs (all Grades %; Grade 3-4 %) in ≥10% of Patients: fatigue (36; 2.7), bruising (36; -), cough (33; -), musculoskeletal pain (32; 0.9), COVID-19 (28; 7), pneumonia (27; 16), diarrhea (26; -), abdominal pain (25; 2.7), dyspnea (22; 2.7), hemorrhage (22; 2.7), edema (21; -), nausea (21; -), pyrexia (20; 2.7), headache (20; 0.9), arthritis/arthralgia (19; 1.8), rash (19; 0.9), peripheral neuropathy (16; 3.6), dizziness (15; -), fall (14; 0.9), constipation (14; -), insomnia (14; -), upper respiratory tract infections (13; 2.7), second primary malignancy (13; 2.7), renal insufficiency (12; 6), hypertension (12; 5), neurological changes (12; 2.7), mucositis (12; 0.9), decreased appetite (12; -), respiratory tract infection (11; 1.8), supraventricular tachycardia (10; 5). Select Laboratory Abnormalities (all Grades %; Grade 3 or 4 %) that Worsened from Baseline in ≥20% of Patients: neutrophil count decreased (63; 45), hemoglobin decreased (48; 19), calcium decreased (40; 2.8), platelet count decreased (30; 15), sodium decreased (30; -), lymphocyte count decreased (23; 8), ALT increased (23; 2.8), AST increased (23; 1.9), creatinine increased (23; -), lipase increased (21; 7), alkaline phosphatase increased (21; -). Grade 4 laboratory abnormalities in >5% of patients included neutrophils decreased (23). Drug Interactions Strong CYP3A Inhibitors: Concomitant use with Jaypirca increased pirtobrutinib systemic exposure, which may increase risk of Jaypirca ARs. Avoid use of strong CYP3A inhibitors with Jaypirca. If concomitant use is unavoidable, reduce Jaypirca dosage according to 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 Jaypirca dosage according to approved labeling. Sensitive CYP2C8, CYP2C19, CYP3A, P-gp, or 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: Due to 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 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, 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 increases pirtobrutinib exposure. Reduce Jaypirca dosage in patients with severe renal impairment according to approved labeling. PT HCP ISI COMBO DEC2023 Please see Prescribing Information and Patient Information for Jaypirca. 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 51 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 registered trademark owned by or licensed to Eli Lilly and Company, its subsidiaries, or affiliates. PP-PT-US-0760 12/2023 © Lilly USA, LLC 2023. ALL RIGHTS RESERVED. Lilly 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 adult patients with mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor, and as a treatment for adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor 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 Mukkamalla SKR, Taneja A, Malipeddi D, et al. Chronic Lymphocytic Leukemia. [Updated 2023 Feb 18]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: The Leukemia and Lymphoma Society. NHL Subtypes. Access here: . Accessed on October 25, 2023. NIH National Cancer Institute. Cancer Stat Facts: Leukemia – Chronic Lymphocytic Leukemia (CLL). Access here: . Accessed on October 3, 2023. SOURCE Eli Lilly and Company