JAYPIRCA 50mg tablets medication leaflet

Jaypirca 50 mg film-coated tablets

Jaypirca 100 mg film-coated tablets

Jaypirca 50 mg film-coated tablets

Each film-coated tablet contains 50 mg of pirtobrutinib.

Each film-coated tablet contains 38 mg of lactose (as monohydrate).

Jaypirca 100 mg film-coated tablets

Each film-coated tablet contains 100 mg of pirtobrutinib.

Each film-coated tablet contains 77 mg of lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Jaypirca 50 mg film-coated tablets

Blue, 9 x 9 mm, arc-triangle shaped tablet debossed with “Lilly 50” on one side and “6902” on theother side.

Jaypirca 100 mg film-coated tablets

Blue, 10 mm, round tablet debossed with “Lilly 100” on one side and “7026” on the other side.

Jaypirca as monotherapy is indicated for the treatment of adult patients with relapsed or refractorymantle cell lymphoma (MCL) who have been previously treated with a Bruton’s tyrosine kinase(BTK) inhibitor.

Jaypirca as monotherapy is indicated for the treatment of adult patients with relapsed or refractorychronic lymphocytic leukaemia (CLL) who have been previously treated with a BTK inhibitor.

Jaypirca therapy should be initiated and supervised by physicians experienced in the use of anticancertherapies.

The recommended dose is 200 mg pirtobrutinib once daily (QD).

Jaypirca dosing should be interrupted until recovery to Grade 1 or baseline when the patientexperiences the following event:

* Grade 3 neutropenia with fever and/or infection

* Grade 4 neutropenia lasting ≥ 7 days

* Grade 3 thrombocytopenia with bleeding

* Grade 4 thrombocytopenia

* Grade 3 or 4 non-haematologic toxicity

Asymptomatic lymphocytosis is not regarded as an adverse reaction, and patients experiencing thisevent should continue taking Jaypirca.

In the clinical studies, adverse events in a limited number of patients were managed by dose reduction(see section 5.1).

Treatment should be continued until disease progression or unacceptable toxicity.

If more than 12 hours have passed after a patient has missed a dose, the patient should be instructed totake the next dose at its scheduled time; an additional dose should not be taken. If vomiting occurs, thepatient should not take an additional dose but continue with the next scheduled dose.

No dose adjustment is required based on age (see section 5.2).

No dose adjustment is required for patients with mild, moderate or severe renal impairment. There areno data in patients on dialysis (see section 5.2).

No dose adjustment is required for patients with mild, moderate, or severe hepatic impairment (seesection 5.2).

The safety and efficacy of Jaypirca in children and adolescents aged less than 18 years have not beenestablished. No data are available.

Jaypirca is for oral use.

The tablet should be swallowed whole with a glass of water to ensure consistent performance (patientsshould not chew, crush, or split tablets before swallowing) and can be taken with or without food.

Patients should take the dose at approximately the same time every day.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Serious infections, including fatal cases, have occurred in patients treated with Jaypirca. The mostfrequently reported Grade 3 or higher infections were pneumonia, COVID-19 pneumonia, COVID-19,and sepsis. Prophylactic antimicrobial therapy should be considered in patients who are at increasedrisk for opportunistic infections. Based on the grade of infection and whether it occurs withneutropenia, dose interruption may be required (see section 4.2).

Bleeding events, including fatal cases, have occurred in patients treated with Jaypirca, with andwithout thrombocytopenia. Major bleeding events of Grade 3 or higher, including gastrointestinalbleeding and intracranial haemorrhage have been observed. Patients should be monitored for signs andsymptoms of bleeding. Patients receiving anticoagulant or antiplatelet agents may be at increased riskof haemorrhage. The risks and benefits of anticoagulant or antiplatelet therapy should be consideredwhen co-administered with Jaypirca and consider additional monitoring for signs of bleeding. The useof Jaypirca has not been studied with warfarin or other vitamin K antagonists.

Dose interruption may be required for Grade 3 or 4 bleeding events (see section 4.2).

The benefit-risk of withholding Jaypirca for 3 to 5 days pre- and post-surgery should be considereddepending upon the type of surgery and risk of bleeding.

Cytopenias

Grade 3 or 4 cytopenias, including neutropenia, anaemia and thrombocytopenia occurred in patientstreated with Jaypirca. Complete blood counts should be monitored in patients during treatment asmedically indicated. Based on the grade of cytopenia, dose interruption may be required (seesection 4.2).

Atrial fibrillation/ flutter

Atrial fibrillation and atrial flutter have been observed in patients treated with Jaypirca, particularly inpatients with a history of atrial fibrillation and/or multiple cardiovascular comorbidities. Signs andsymptoms of atrial fibrillation and atrial flutter should be monitored in patients; obtain anelectrocardiogram as medically indicated. Based on the grade of atrial fibrillation/atrial flutter, doseinterruption may be required (see section 4.2).

Second primary malignancies

Second primary malignancies have commonly occurred in patients treated with Jaypirca, with the mostfrequent types being non-melanoma skin cancers. Patients should be monitored for the appearance ofskin cancers and advise protection from sun exposure.

Tumour lysis syndrome (TLS) has been reported rarely with Jaypirca therapy. Patients at high risk of

TLS are those with high tumour burden prior to treatment. Patients should be assessed for possible riskof TLS and closely monitored as clinically indicated.

Contraception in women of childbearing potential and males

Based on findings in animals and the genotoxicity of pirtobrutinib (see section 5.3), pirtobrutinib cancause foetal harm when administered to a pregnant woman. Women of childbearing potential shoulduse an effective method of contraception during treatment and for 5 weeks after the last dose of

Jaypirca. Men are advised to use an effective method of contraception and not father a child duringtreatment and for 3 months after the last dose of Jaypirca (see section 4.6).

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency orglucose-galactose malabsorption should not take this medicinal product.

This medicinal product contains less than 1 mmol sodium (23 mg) per 200 mg daily dose, that is to sayessentially ‘sodium-free’.

Pirtobrutinib is primarily metabolised by CYP3A4, UGT1A8, and UGT1A9.

Effects of other medicinal products on the pharmacokinetics of pirtobrutinib

In a clinical study, itraconazole, a strong CYP3A4 inhibitor, increased the AUC of pirtobrutinib by48 % and did not change Cmax of pirtobrutinib. This increase in pirtobrutinib exposure is not clinicallymeaningful. Therefore, no dose adjustment of Jaypirca is necessary with CYP3A inhibitors.

In a clinical study, rifampin, a strong CYP3A inducer, decreased the AUC and Cmax of pirtobrutinib by71 % and 42 %, respectively. Though this decrease in pirtobrutinib exposure is not expected to beclinically meaningful, if possible avoid strong CYP3A inducers (e.g. rifampicin, carbamazepine,phenytoin).

Coadministration with medicinal products that are proton pump inhibitors

No clinically significant differences in pirtobrutinib pharmacokinetics were observed whenadministered concomitantly with omeprazole, a proton pump inhibitor.

Effects of pirtobrutinib on the pharmacokinetics of other medicinal products (increase in plasmaconcentration)

CYP2C8 substrates

Pirtobrutinib is a moderate inhibitor of CYP2C8. Pirtobrutinib increased the AUC and Cmax ofrepaglinide (a substrate of CYP2C8) by 130 % and 98 %, respectively. Therefore, since pirtobrutinibcan increase the plasma concentrations of CYP2C8 substrates, caution is advised whenco-administering with CYP2C8 substrates (e.g. repaglinide, dasabuvir, selexipag, rosiglitazone,pioglitazone, and montelukast).

Pirtobrutinib is a moderate inhibitor of BCRP. Pirtobrutinib increased the AUC and Cmax ofrosuvastatin (a BCRP substrate) by 140 % and 146 %, respectively. Therefore, since pirtobrutinib canincrease the plasma concentrations of BCRP substrates, caution is advised when co-administering

BCRP substrates (e.g. rosuvastatin). If co-administration with narrow therapeutic index BCRPsubstrates (e.g. high dose methotrexate, mitoxantrone) cannot be avoided, close clinical monitoringshould be considered.

Pirtobrutinib is a weak inhibitor of P-gp. Pirtobrutinib increased the AUC and Cmax of digoxin (a P-gpsubstrate) by 35 % and 55 %, respectively. Therefore, pirtobrutinib can increase the plasmaconcentrations of P-gp substrates. If co-administration with narrow therapeutic index P-gp substrates(e.g dabigatran etexilate and digoxin) cannot be avoided, close clinical monitoring should beconsidered.

CYP2C19 substrates

Pirtobrutinib is a weak inhibitor of CYP2C19. Pirtobrutinib increased the AUC and Cmax ofomeprazole (a CYP2C19 substrate) by 56 % and 49 %, respectively. Therefore, pirtobrutinib canincrease the plasma concentrations of CYP2C19 substrates. If co-administration with narrowtherapeutic index CYP2C19 substrates (e.g. phenobarbital and mephenytoin) cannot be avoided, closeclinical monitoring should be considered.

Pirtobrutinib is a weak inhibitor of CYP3A. Pirtobrutinib increased the AUC and Cmax of orallyadministered midazolam (sensitive CYP3A substrate) by 70 % and 58 %, respectively. Pirtobrutinibdid not have a clinically meaningful effect on the exposure of intravenously administered midazolam.

Therefore, pirtobrutinib can increase the plasma concentrations of CYP3A substrates. Ifco-administration with narrow therapeutic index CYP3A substrates (e.g alfentanil, midazolam,tacrolimus) cannot be avoided, close clinical monitoring should be considered.

Based on findings in animals and the genotoxicity of pirtobrutinib (see section 5.3), pirtobrutinib cancause foetal harm when administered to a pregnant woman. Women of childbearing potential shoulduse an effective method of contraception during treatment and for 5 weeks after the last dose of

Jaypirca. Men are advised to use an effective method of contraception and not father a child duringtreatment and for 3 months after the last dose of Jayprica (see section 4.4).

There are no data from the use of Jaypirca in pregnant women. Studies in animals have shownreproductive toxicity (see section 5.3). Jaypirca should not be used during pregnancy.

It is unknown whether pirtobrutinib is excreted in human milk. A risk to the suckling child cannot beexcluded. Breast-feeding should be discontinued during treatment with Jaypirca and for one week afterthe last dose of Jaypirca.

There are no data on the effect of pirtobrutinib on human fertility.

Jaypirca has a minor influence on the ability to drive and use machines. Fatigue, dizziness, andasthenia have been reported in some patients during treatment with Jaypirca and should be consideredwhen assessing a patient’s ability to drive or operate machines.

The most common adverse reactions of any grade are: neutropenia (27.7 %), fatigue (26.2 %),diarrhoea (23.8 %), anaemia (20.7 %), rash (18.4 %) and contusion (17.8 %).

The most common severe (Grade ≥ 3) adverse reactions are: neutropenia (23.9 %), anaemia (11.2 %),thrombocytopenia (9.7 %), and pneumonia (9.0 %).

The frequency of treatment discontinuation due to adverse reactions is 4.2 % and the frequency ofdose reductions due to adverse reactions is 4.8 %.

The most common adverse reactions (reported in more than 2 patients) leading to dose reduction areneutropenia (2.5 %), rash (0.6 %), diarrhoea (0.4 %), fatigue (0.4 %) and thrombocytopenia (0.4 %).

The most common adverse reactions (reported in more than 2 patients) leading to dose discontinuationare neutropenia (1.0 %), anaemia (1.0 %), pneumonia (0.9 %), thrombocytopenia (0.7 %) and rash(0.4 %).

Serious adverse reactions associated with Jaypirca have occurred in 19.4 % of patients and the mostcommon serious adverse reactions (occurring in ≥1 % of patients) were pneumonia (8.0 %),neutropenia (3.2 %), anaemia (2.6 %), atrial fibrillation/atrial flutter (1.3 %) and urinary tract infection(1.0 %).

Fatal adverse reactions have been observed in 0.4 % of patients (3 patients) for pneumonia, in 0.3 % ofpatients (2 patients) for haemorrhage and in 0.1 % of patients (1 patient) for urinary tract infection.

Table 1 lists the adverse drug reactions (ADRs) associated with Jaypirca used as a monotherapy fromclinical study data. The ADRs are based on pooled data from 690 patients treated with Jaypircamonotherapy 200 mg QD starting dose with no dose escalation in a phase 1/2 clinical study, and frompatients treated with Jaypirca monotherapy 200 mg QD in a phase 3 study. Patients were treated for

MCL, chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) and other non-

Hodgkin lymphoma (NHL). Patients were exposed to Jaypirca for a median duration of 12 months.

ADRs are listed below by MedDRA body system organ class. Frequency groups are defined by thefollowing convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to< 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000), and not known (cannot be estimatedfrom the available data). Within each frequency grouping, ADRs are presented in order of decreasingseriousness.

Table 1: ADRs of patients treated with Jaypirca monotherapya at 200 mg QD

System organ class ADR Frequency category (%) Grade ≥ 3c(MedDRA) (All grades) (%)

Infections and infestations Pneumonia Very common (13.8) 9.0

Upper respiratorytract infection Very common (10.1) 0.1

Urinary tractinfection Common (9.9) 1.4

Blood and lymphatic Neutropeniab Very common (27.7) 23.9system disorders Anaemiab Very common (20.7) 11.2

Thrombocytopeniab Very common (16.8) 9.7

Lymphocytosisb Common (6.4) 3.9

Nervous system disorders Headache Very common (12.6) 0.7

Cardiac disorders Atrialfibrillation/atrial Common (3.8) 1.7flutter

Vascular disorders Haemorrhageb Very common (20.3) 2.8

Epistaxis Common (5.2) 0

Haematuria Common (4.5) 0.1

Haematoma Common (1.7) 0.1

Conjunctivalhaemorrhage Common (1.7) 0.1

Bruisingb Very common (19.7) 0.3

Contusion Very common (17.8) 0.1

Petechiae Common (5.7) 0

Gastrointestinal disorders Diarrhoea Very common (23.8) 1.0

Nausea Very common (16.7) 0.4

Abdominal pain Very common (10.4) 1.0

Skin and subcutaneous Rashbtissue disorders Very common (18.4) 1.2

Musculoskeletal and Arthralgiaconnective tissue disorders Very common (14.6) 1.2

General disorders and Fatigue Very common (26.2) 1.9administration siteconditions Oedema peripheral Very common (11.6) 0.3a Frequencies are derived from Jaypirca exposure in patients with B-cell malignanciesb Includes multiple adverse reaction termsc Severity grade assignment based on National Cancer Institute Common Terminology Criteria for Adverse

Events (NCI CTCAE) version 5.0

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No maximum tolerated dose was reached in the phase 1 study in which patients received repeateddoses up to 300 mg once daily. In healthy volunteer studies, no dose related toxicity was observedwhen a maximum single dose of 900 mg was administered. Signs and symptoms of pirtobrutiniboverdose have not been established and there is no specific treatment for pirtobrutinib overdose.

For patients who experience overdose, closely monitor and provide appropriate supportive treatment.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EL05

Pirtobrutinib is a reversible, noncovalent inhibitor of BTK. BTK is a signalling protein of the B-cellantigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signalling results inactivation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.

Pirtobrutinib binds to wild type BTK as well as BTK harboring C481 mutations leading to inhibitionof BTK kinase activity.

The effect of a single 900 mg dose of pirtobrutinib on the corrected QT (QTc) interval was evaluatedin a study with placebo and positive controls in 30 healthy subjects. The selected dose is equivalent toapproximately 2 times higher than the concentrations achieved at steady state at the recommendeddosage of 200 mg once daily. Pirtobrutinib had no clinically meaningful effect on the change in QTcorrected for heart rate using Fridericia’s formula (QTcF) interval (i.e., > 10 ms) and there was norelationship between pirtobrutinib exposure and change in QTc interval.

Mantle Cell Lymphoma

The efficacy of Jaypirca was evaluated in adult patients with MCL in a phase 1/2 multicenter, openlabel, single arm clinical study: Study 18001 (BRUIN). The study included two parts: a phase 1 doseescalation, in which the dose range of monotherapy pirtobrutinib of 25 mg to 300 mg once daily wasinvestigated, and a phase 2 dose expansion. The primary objective of the phase 1 portion was todetermine the recommended phase 2 dose of pirtobrutinib, which was found to be 200 mg once daily,with a maximum tolerated dose not being established. The primary objective of the phase 2 part was toassess the anti-tumor activity of pirtobrutinib based on overall response rate as assessed by anindependent review committee. Patients received Jaypirca orally daily until disease progression orunacceptable toxicity.

Study 18001 enrolled and treated a total of 164 patients with a diagnosis of MCL and the primaryanalysis set (PAS) for the assessment of efficacy was based on the first 90 patients with MCL enrolledwho had no known central nervous system (CNS) involvement, were treated with a prior BTKinhibitor, had received one or more doses of Jaypirca and had at least 1 site of radiographicallyassessable disease. The median age was 70 years (range: 46 to 87 years), 80 % were male, 84.4 %were White, 67.8 % had a baseline Eastern Cooperative Oncology Group (ECOG) performance statusof 0 and 31.1 % had ECOG performance status of 1. Patients had a median number of 3 prior lines oftherapy (range: 1 to 8), with the reason for discontinuation from the most recent prior BTK inhibitortherapy being progression in 81.1 % of patients and intolerance in 13.3 % of patients. 95.6 % ofpatients received prior anti-CD20 therapy, 87.8 % chemotherapy, 18.9 % autologous stem celltransplantation, pct. 4.4 % allogenic stem cell transplantation, 15.6 % prior BCL2 inhibitor and 4.4 %received prior chimeric antigen receptor-modified T cells (CAR-T) therapy. 38.9 % patients hadextranodal involvement and 26.7 % had tumour bulk greater than or equal to 5 cm. The simplified

MCL International Prognostic Index (sMIPI) score was low in 22.2 %, intermediate in 55.6 % andhigh in 22.2 % of patients.

Of the 164 patients with MCL enrolled in Study 18001, 9 patients had a dose reduction, including6 responders that were able to remain on therapy and maintain a durable response following dosereductions to 150 mg QD (3), 100 mg QD (2), and 50 mg QD (1).

The efficacy of Jaypirca was based on a response as assessed using 2014 Lugano criteria for malignantlymphoma. Efficacy results for patients that received at least one prior BTK inhibitor and included inthe PAS are summarised in Table 2. For the 90 patients in the PAS, 79 received at least 1 dose of200 mg QD. Of these 79 patients, 77 started at 200 mg QD, 1 dose escalated from a lower dose and1 dose reduced from a higher dose. The median time on treatment was 5.24 months (range: 0.2 to39.6 months). Among the 51 responders, the median time to response was 1.84 months (range: 1.0 to7.5 months).

While subgroup analyses represent a limited number of patients, clinically meaningful efficacy resultswere observed across important subgroups, including patients that discontinued prior BTK inhibitortherapy due to intolerance or progression and irrespective of number and type of prior therapies.

Table 2: Summary of efficacy data in Study 18001 for MCL patients who received at least oneprior BTK inhibitor

Pirtobrutinib

N=90

Objective response rate (Complete response + partial response)

Rate - percent (95 % CI) 56.7 (45.8, 67.1)

CR - percent 18.9

PR - percent 37.8

Duration of response

Median - months (95 % CI) 17.61 (7.29, 27.24)

Abbreviations: CI = confidence interval, NE= not estimable, CR = complete response, PR = partialresponse.

Data cut-off date: 29 July 2022. The median follow-up time for duration of response was12.68 months.

Chronic Lymphocytic Leukaemia

The efficacy of Jaypirca in patients with BTK-inhibitor pretreated CLL was evaluated in arandomised, multicentre, international, open-label, actively-controlled trial (BRUIN CLL-321,

Study 20020). The trial enrolled 238 patients with CLL/SLL who were previously treated with a BTKinhibitor. Patients were randomised in a 1:1 ratio to receive either Jaypirca given orally once daily at adose of 200 mg until disease progression or unacceptable toxicity, or Investigator’s choice:

* Idelalisib plus a rituximab product (IR): Idelalisib 150 mg orally twice daily until diseaseprogression or unacceptable toxicity, in combination with 8 infusions of a rituximab product(375 mg/m2 intravenously on Day 1 of Cycle 1, followed by 500 mg/m2 every 2 weeks for4 doses and then every 4 weeks for 3 doses), with a 28-day cycle length.

* Bendamustine plus a rituximab product (BR): Bendamustine 70 mg/m2 intravenously (Day 1and 2 of each 28-day cycle), in combination with a rituximab product (375 mg/m2intravenously on Day 1 of Cycle 1, then 500 mg/m2 on Day 1 of subsequent cycles), for up to6 cycles.

Randomisation was stratified by 17p deletion status (yes/no) and receipt of prior venetoclax treatment(yes/no). Of the 238 patients total, 119 were assigned to Jaypirca monotherapy, 82 to IR and 37 to BR.

After confirmed disease progression, patients randomised to IR or BR had the option to cross over to

Jaypirca monotherapy. Baseline characteristics were similar between treatment arms. Overall, themedian age was 67 years (range: 42 to 90 years), 70 % were male and 81 % were White. Baseline

ECOG performance status was 0 or 1 in 93% of patients and 44% of patients had Rai stage III or IVdisease. Among those patients with central testing available, 57 % (101 of 176 patients) had 17pdeletion and/or TP53 mutation, 86 % (164 of 190 patients) had unmutated IGHV, and 65 % (97 of149) had complex karyotype.

Patients received a median number of 3 prior lines of therapy (range: 1 to 13) with 57 % having atleast 3 prior therapies and 51 % having had prior BCL2-inhibitor therapy. The most common prior

BTK inhibitors received were ibrutinib (87 %), acalabrutinib (16 %), and zanubrutinib (7 %). 70 % ofpatients discontinued the most recent BTK inhibitor for refractory or progressive disease, 15 %discontinued for toxicity, and 15 % discontinued for other reasons.

Efficacy was based on progression-free survival (PFS) of pirtobrutinib monotherapy versusinvestigator’s choice arm as assessed by an Independent Review Committee (IRC). The study met itsprimary endpoint at the prespecified time of final analysis for IRC-assessed PFS (29 Aug 2023 cut-off). At an updated analysis (29 Aug 2024 cut-off) with a median follow-up of 19.4 months (range0.03 to 33.3 months) for pirtobrutinib and 17.7 months (range 0.03 to 27.9 months) for theinvestigator’s choice arm, improved IRC-assessed PFS was observed with pirtobrutinib compared tothe investigator’s choice arm, consistent with the primary analysis. Clinically meaningful efficacyresults in favour of pirtobrutinib were observed across important subgroups, including patients whodiscontinued prior BTK inhibitor therapy due to intolerance or progression and irrespective of numberand type of prior therapies. Efficacy results are presented in Table 3. The Kaplan-Meier curve for PFSis shown in Figure 1.

Table 3: Efficacy Results per IRC in Patients with CLL Previously Treated with a BTK

Inhibitor - ITT Population (Study 20020)

Pirtobrutinib 200 mg once Investigator’s Choice ofdaily Idelalisib plus Rituximab or(N = 119) Bendamustine plus Rituximab(N = 119)

Progression-free Survivala

Number of Events, n 74 (62 %) 79 (66 %)

Disease Progression 60 (50 %) 66 (55 %)

Death 14 (12 %) 13 (11 %)

Median PFS (95 % CI), 14.0 (11.2, 16.6) 8.7 (8.1, 10.4)months b

HR (95 % CI) c 0.54 (0.39, 0.75)

P-value d 0.0002

CI, confidence interval; HR, hazard ratio.

Data cut-off date 29 Aug 2024a Efficacy was assessed using the 2018 International Workshop for Chronic Lymphocytic Leukemia(iwCLL) guidelines.b Based on Kaplan-Meier estimation.c Based on stratified Cox proportional hazards model.d 2-sided nominal p-value based on stratified log-rank test.

Figure 1: Kaplan-Meier Curve of IRC-Assessed PFS in Patients with CLL Previously Treatedwith a BTK Inhibitor in Study 20020

With a median overall survival (OS) follow-up time of 20.4 months for pirtobrutinib and 19.2 monthsin investigator’s choice arm, 38 patients (32.0 %) in the pirtobrutinib arm and 32 patients (27.0 %) inthe investigator’s choice arm died. Median OS was 29.7 months (95 % CI: 27.1, NE) in thepirtobrutinib arm and not reached in the investigator’s choice arm. The HR was 1.090 (95% CI: 0.679,1.749; p = 0.7202). OS analysis may be confounded by the 50 out of 119 patients who crossed overfrom the investigator’s choice arm to pirtobrutinib.

The European Medicines Agency has waived the obligation to submit the results of studies with

Jaypirca in all subsets of the paediatric population in mature B-cell malignancies (see section 4.2 forinformation on paediatric use).

This medicinal product has been authorised under a so-called ‘conditional approval’ scheme. Thismeans that further evidence on this medicinal product is awaited.

The European Medicines Agency will review new information on this medicinal product at least everyyear and this SmPC will be updated as necessary.

The pharmacokinetics of pirtobrutinib were characterized in healthy subjects and in patients withcancer. Doses ranged from 25 mg to 300 mg once daily (0.125 to 1.5 times the recommended dosageof 200 mg once daily), up to single doses of 900 mg. Increases in plasma exposure wereapproximately dose proportional. Steady state was achieved within 5 days of once daily dosing, and incancer patients the mean [coefficient of variation (CV %)] accumulation ratio after administration of200 mg once daily was 1.63 (26.7 %) based on AUC. Three patient factors were attributed to changesin pirtobrutinib PK: body weight, serum albumin, and absolute eGFR. An increase in body weightfrom 70 kg to 120 kg is predicted to increase pirtobrutinib clearance by 24 %; a decrease in absoluteeGFR from 90 mL/min to 30 mL/min is predicted to reduce pirtobrutinib clearance by 16 %; and adecrease in serum albumin from 40 g/L to 30 g/L is predicted to increase pirtobrutinib clearance by21 %. These factors alone are unlikely to result in meaningful changes to pirtobrutinib PK and no doseadjustments are recommended.

The mean (CV %) steady-state AUC and Cmax were 92 600 h*ng/mL (39 %) and 6 500 ng/mL (25 %),respectively, at the recommended dosage of 200 mg once daily in cancer patients.

At the recommended dosage, pirtobrutinib achieves pharmacokinetic exposures that can exceed the

BTK IC96 at trough and thus deliver tonic BTK target inhibition throughout the once daily dosingperiod, regardless of the intrinsic rate of BTK turnover.

The absolute bioavailability of pirtobrutinib after a single oral 200 mg dose is 85.5 % in healthysubjects. The median time to reach peak plasma concentration (tmax) is approximately 2 hours in bothcancer patients and healthy subjects. There is no pH dependency for absorption.

A high-fat, high-calorie meal administered to healthy subjects decreased the Cmax of pirtobrutinib by23 % and delayed tmax by 1 hour. There was no effect on pirtobrutinib AUC. Pirtobrutinib can be takenwith or without food.

The mean apparent central volume of distribution of pirtobrutinib is 34.2 L in cancer patients. Theplasma protein binding is 96 % and was independent of concentration between 0.5 and 50 µM. Inplasma from healthy subjects and subjects with severe renal impairment the protein binding was 96 %.

Mean blood-to-plasma ratio is 0.79.

Hepatic metabolism is the main route of clearance for pirtobrutinib. Pirtobrutinib is metabolised toseveral inactive metabolites by CYP3A4, UGT1A8 and UGT1A9. There was no clinically meaningfulimpact of CYP3A modulation on pirtobrutinib exposures.

Pirtobrutinib inhibits CYP2C8, CYP2C9 and CYP3A4 in vitro and minimally inhibits CYP1A2,

CYP2B6, CYP2C19 or CYP2D6 at 60 µM. In vitro pirtobrutinib induces CYP3A4, CYP3A5,

CYP2C19, and CYP2B6.

Pirtobrutinib minimally inhibits UGT1A1 in vitro with an IC50 = 18 µM.

Co-administration with transport substrates/inhibitors

In vitro studies indicated that pirtobrutinib is a substrate of P-gp and BCRP.

Pirtobrutinib is an in vitro inhibitor of P-gp and BCRP. Pirtobrutinib affected the PK of digoxin, a P-gp substrate, and rosuvastatin, a BCRP substrate, in clinical studies (see section 4.5).

The mean apparent clearance of pirtobrutinib is 2.05 L/h with an effective half-life of approximately19.9 hours. Following a single radiolabeled dose of pirtobrutinib 200 mg to healthy subjects, 37 % ofthe dose was recovered in faeces (18 % unchanged) and 57 % in urine (10 % unchanged).

Age, gender, race and body weight

Based on a population pharmacokinetic analysis in patients with cancer, age (range 22-95 years), race,gender, and body weight (range 35.7-152 kg) had no clinically meaningful effect on the exposure ofpirtobrutinib.

In a population PK analysis of cancer patients, patients with mild (eGFR 60 to < 90 ml/min) ormoderate renal impairment (eGFR 30 to < 60 ml/min), pirtobrutinib clearance was 16 % to 27 % lowercompared to clearance in patients with normal renal function, resulting in expected exposure of

AUC = 94 100 ng*h/mL and Cmax = 6 680 ng/mL in patients with mild renal impairment (16-19 %higher compared to patients with normal renal function) and AUC = 108 000 ng*h/mL and

Cmax = 7 360 ng/mL in patients with moderate renal impairment (28 to 36 % higher compared topatients with normal renal function).

In a clinical pharmacology study of otherwise healthy volunteers, apparent clearance was 35 % lowerin four participants with severe renal impairment (eGFR 15 to < 30 ml/min) compared toeight participants with normal renal function (eGFR ≥ 90 ml/min), resulting in exposures of

AUC0-inf = 115 000 ng*h/mL and Cmax = 2 980 ng/mL (62 % higher and 7 % lower, respectively,compared to normal renal function).

Patients with end-stage renal disease receiving dialysis were not studied (see section 4.2).

There were no clinically significant differences in the PK of pirtobrutinib for any degree of hepaticimpairment (by Child-Pugh A, B, and C or any total bilirubin and any AST). In a dedicated hepaticimpairment study mean AUC and Cmax of pirtobrutinib were similar between subjects with mildhepatic impairment (Child-Pugh A) and subjects with normal hepatic function. In subjects withmoderate hepatic impairment (Child-Pugh B) the AUC was 15 % lower compared to normal hepaticfunction and the Cmax was similar. In subjects with severe hepatic impairment (Child-Pugh C) the

AUC of pirtobrutinib was 21 % lower and mean Cmax was 24 % lower compared to subjects withnormal hepatic function. The fraction unbound (fu) for pirtobrutinib in subjects generally increased asthe severity of hepatic impairment increased. Therefore, after correcting pirtobrutinib PK exposureparameters with fu, there was no clinically significant difference observed in the unbound pirtobrutinib

PK exposure parameters (AUCu and Cmax,u) between subjects with any degree of hepatic impairmentand normal hepatic function.

No pharmacokinetic studies were performed with pirtobrutinib in patients under 18 years of age.

In the repeat-dose studies decreased T-cell dependent antibody response in rats (at 0.69-fold humanexposure at the recommended dose of 200 mg based on AUC) and minimal to mild corneal lesions indogs (at 0.42-fold human exposure) were observed. Mild to moderate vascular necrosis andvascular/perivascular inflammation in large pulmonary blood vessels were observed only in rats.

These effects occurred at clinically relevant exposure levels.

Pirtobrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay. Pirtobrutinib was aneugenicin two in vitro micronucleus assays using human peripheral blood lymphocytes. Pirtobrutinib had noeffect in an in vivo rat bone marrow micronucleus assay at doses up to 2 000 mg/kg (single dose),which is approximately 11-fold higher exposure (considering unbound Cmax value in female animals)than human exposure at 200 mg.

Carcinogenicity studies have not been conducted with pirtobrutinib.

Embryotoxicity/ Teratogenicity

In animal reproduction studies, administration of pirtobrutinib to pregnant rats during organogenesisresulted in decreased foetal weight, embryo-foetal mortality, and foetal malformations at maternalexposures 3.0-fold human exposure at the recommended dose of 200 mg based on AUC.

Reproduction toxicity

No fertility studies have been conducted with pirtobrutinib. In repeat-dose toxicity studies of up to3 months duration, pirtobrutinib had no effect on male reproductive organs at 0.69-fold and 0.42-foldhuman exposure in rats and dogs, respectively, at the recommended dose of 200 mg based on AUC.

Pirtobrutinib had no effect on female reproductive organs at 4.0-fold and 0.42-fold human exposure inrats and dogs, respectively.

Hypromellose acetate succinate

Cellulose, microcrystalline

Lactose monohydrate

Croscarmellose sodium

Magnesium stearate

Silica, colloidal hydrated

Hypromellose

Titanium dioxide

Triacetin

Indigo carmine (E132)

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Jaypirca 50 mg film-coated tablets

Polyvinylchloride/polychlorotrifluoroethylene blisters sealed with an aluminium foil in packs of 28, 30or 84 film-coated tablets.

Jaypirca 100 mg film-coated tablets

Polyvinylchloride/polychlorotrifluoroethylene blisters sealed with an aluminium foil in packs of 28,30, 56, 60, 84 or 168 film-coated tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Eli Lilly Nederland B.V.

Papendorpseweg 833528 BJ Utrecht

The Netherlands

EU/1/23/1738/001

EU/1/23/1738/002

EU/1/23/1738/003

EU/1/23/1738/004

EU/1/23/1738/005

EU/1/23/1738/006

EU/1/23/1738/007

EU/1/23/1738/008

EU/1/23/1738/009

Date of first authorisation: 30 October 2023

Date of latest renewal: 16 August 2024

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.