WELIREG 40mg film-coated tablets medication leaflet

WELIREG 40 mg film-coated tablets

Each film-coated tablet contains 40 mg of belzutifan.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Blue, oval tablet, approximately 13 x 8 mm, debossed with markings “177” on one side.

WELIREG is indicated as monotherapy for the treatment of adult patients with advanced clear cellrenal cell carcinoma that progressed following two or more lines of therapy that included a PD-(L)1inhibitor and at least two VEGF-targeted therapies.

von Hippel-Lindau (VHL) disease-associated tumours

WELIREG is indicated as monotherapy for the treatment of adult patients with von Hippel-Lindaudisease who require therapy for associated, localised renal cell carcinoma (RCC), central nervoussystem (CNS) haemangioblastomas, or pancreatic neuroendocrine tumours (pNET), and for whomlocalised procedures are unsuitable.

Therapy must be initiated and supervised by specialist physicians experienced in the treatment ofcancer.

The recommended dose of WELIREG is 120 mg belzutifan (three 40 mg tablets) administered oncedaily, at the same time every day.

Treatment should continue until disease progression or unacceptable toxicity occurs.

If a dose of WELIREG is missed, it can be taken as soon as possible on the same day. The regulardaily dose should be resumed the next day. Extra tablets should not be taken to make up for the misseddose.

If vomiting occurs any time after taking WELIREG, another dose should not be taken. The next doseshould be taken the next day.

Dose modifications for WELIREG for adverse reactions are summarised in Table 1.

Table 1: Recommended dose modifications

Adverse reactions Severity* Dose modification

Anaemia Grade 3 * Withhold until resolved(see section 4.4) (haemoglobin to ≤ Grade 2< 8 g/dL; * Resume at the same or< 4.9 mmol/L; reduced dose (reduce< 80 g/L; by 40 mg); considertransfusion discontinuingindicated) depending on theseverity and persistenceof anaemia

Grade 4 (life- * Withhold until resolvedthreatening to ≤ Grade 2consequences or * Resume at a reducedurgent dose (reduce by 40 mg)intervention or permanentlyindicated) discontinue uponrecurrence of Grade 4

Hypoxia Grade 3 * Option to continue or(see section 4.4) asymptomatic withhold until resolved(decreased oxygen to ≤ Grade 2saturation at rest * Resume at reduced dose(e.g., pulse (reduce by 40 mg) oroximeter < 88% or discontinue depending

Pa O2 ≤ 55 mm on the severity and

Hg)) persistence of hypoxia

Grade 3 * Withhold until resolvedsymptomatic to ≤ Grade 2(decreased oxygen * Resume at reduced dosesaturation at rest (reduce by 40 mg) or(e.g., pulse discontinue dependingoximeter < 88% or on the severity and

Pa O2 ≤ 55 mm persistence of hypoxia

Hg))

Grade 4 (life- * Permanentlythreatening airway discontinuecompromise;urgentinterventionneeded (e.g.,tracheotomy orintubation))

Other adverse Grade 3 * Withhold dosing untilreactions resolved to ≤ Grade 2(see section 4.8) * Consider resuming at areduced dose (reduceby 40 mg) dependingon the severity andpersistence

Adverse reactions Severity* Dose modification

* Permanentlydiscontinue uponrecurrence of Grade 3

Grade 4 * Permanentlydiscontinue

*Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0

No dose adjustment is recommended in elderly patients (see section 5.2).

No dose adjustment is recommended in patients with renal impairment including end-stage renaldisease (see section 5.2).

No dose adjustment is recommended in patients with mild (total bilirubin ≤ upper limit ofnormal (ULN) and aspartate aminotransferase (AST) > ULN or total bilirubin > 1 to 1.5 x ULN andany AST) or moderate (total bilirubin within range of > 1.5 x ULN and ≤ 3 x ULN and any AST or

Child-Pugh B) hepatic impairment. Belzutifan has not been studied in patients with severe hepaticimpairment (see section 5.2).

The safety and efficacy in children less than 18 years of age have not been established (seesection 5.1). No data are available.

WELIREG is for oral use.

The tablets should be swallowed whole and may be taken with or without food. Tablets should not besplit, crushed or chewed, as it is not known whether this impacts absorption of belzutifan.

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

* Pregnancy in patients with VHL disease-associated tumours (see section 4.6).

Anaemia has been reported in patients receiving belzutifan in clinical studies (see section 4.8).

Patients should be monitored for anaemia before initiation of and periodically throughout treatmentwith belzutifan. For patients who develop Grade 3 anaemia, belzutifan should be withheld and patientsshould be treated according to standard medical practice, including erythropoiesis-stimulating agent(ESA) administration until resolved to ≤ Grade 2 (see the prescribing information for ESAs for moreinformation). For recurrent Grade 3 anaemia, belzutifan should be discontinued. For patients whodevelop Grade 4 anaemia, belzutifan should be withheld and permanently discontinued for recurrent

Grade 4 anaemia (see section 4.2).

Hypoxia

Hypoxia has been reported in patients receiving belzutifan in clinical studies (see section 4.8).

Patients should be monitored for oxygen saturation with pulse oximetry before initiation of andperiodically throughout treatment with belzutifan. For Grade 3 asymptomatic hypoxia, providingsupplemental oxygen and continuing or withholding treatment should be considered. If withheld,belzutifan should be resumed at a reduced dose. For patients who have Grade 3 symptomatic hypoxia,belzutifan should be withheld, hypoxia should be treated, and belzutifan should be resumed at areduced dose. If symptomatic hypoxia continues to recur, treatment should be discontinued. For

Grade 4 hypoxia, treatment should be permanently discontinued (see section 4.2).

Embryo-foetal toxicity: Women of childbearing potential

Belzutifan may cause embryo-foetal harm, including foetal loss, in humans (see sections 4.6 and 5.3).

The pregnancy status of women of childbearing potential should be verified prior to initiatingtreatment with belzutifan.

Women of childbearing potential have to use highly effective contraceptive methods during treatmentwith belzutifan and for at least 1 week after the last dose due to the potential risk to the foetus (seesections 4.5 and 4.6).

CNS haemorrhage in patients with VHL disease-associated CNS-haemangioblastomas (CNS-HB)

CNS haemorrhage, including with fatal outcome, has been observed in patients with VHL disease-associated CNS-HB. Physicians should be cautious of symptoms or signs of CNS haemorrhage inpatients with VHL disease-associated CNS-HB being treated with belzutifan.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially‘sodium-free’.

In vitro and pharmacogenomic studies indicate that belzutifan is metabolised by UGT2B17 and by

CYP2C19, and that belzutifan induces CYP3A4 in a concentration dependent manner.

Effects of belzutifan on other medicinal products

Coadministration of belzutifan with CYP3A4 substrates, including hormonal contraceptives, decreasesconcentrations of CYP3A4 substrates, which may reduce the efficacy of these substrates. Themagnitude of this decrease may be more pronounced in patients who are dual UGT2B17 and

CYP2C19 poor metabolisers (see section 5.2). Coadministration of belzutifan with sensitive CYP3A4substrates, for which minimal decrease in concentration may lead to therapeutic failures of thesubstrate should be avoided. If coadministration cannot be avoided, increase the sensitive CYP3A4substrate dose in accordance with its summary of product characteristics.

Coadministration of belzutifan with hormonal contraceptives may lead to contraceptive failure (seesections 4.4 and 4.6) or an increase in breakthrough bleeding. Patients using hormonal contraceptivesshould be advised to use an alternative non-hormonal contraceptive method or have their male partneruse a condom during treatment with belzutifan.

In a clinical study, repeat administration of belzutifan 120 mg daily resulted in a 40% reduction inmidazolam area under the curve (AUC), an effect consistent with a weak CYP3A4 inducer. Belzutifanmay exhibit moderate CYP3A4 induction in patients who have higher belzutifan plasma exposures(see section 5.2).

Based on in vitro data, MATE- 2K inhibition by belzutifan is expected at clinically relevant exposures,and inhibition of MATE1 cannot be excluded.

Belzutifan is a CYP2B6 and CYP2C8 inducer in vitro. In vivo investigations have not been performed.

Co-administration with belzutifan may result in a clinically relevant decrease in the plasmaconcentration of sensitive CYP2B6 and/or CYP2C8 substrates.

Effects of other medicinal products on belzutifan

Coadministration of belzutifan with inhibitors of UGT2B17 or CYP2C19 increases plasma exposuresof belzutifan, which may increase the incidence and severity of adverse reactions of belzutifan.

Patients should be monitored for anaemia and hypoxia and the dose of belzutifan should be reduced asrecommended.

Effects of strong CYP2C19 inducers on belzutifan exposure have not yet been studied.

The pregnancy status of women of childbearing potential should be verified prior to initiatingtreatment with belzutifan.

Belzutifan may cause embryo-foetal harm, including foetal loss, when administered to a pregnantwoman (see sections 4.4 and 5.3). Women of childbearing potential should be informed of thepotential risk to a foetus.

Women of childbearing potential have to use highly effective contraception during treatment withbelzutifan and for at least 1 week after the last dose. Use of belzutifan may reduce the efficacy ofhormonal contraceptives. Patients using hormonal contraceptives should be advised to use analternative non-hormonal contraceptive method or have their male partner use a condom duringtreatment with belzutifan (see section 4.5).

There are no or limited amount of data from the use of belzutifan in pregnant women. Studies inanimals have shown reproductive toxicity (see section 5.3).

Belzutifan should not be used during pregnancy unless the clinical condition of the woman requirestreatment with belzutifan.

von Hippel-Lindau (VHL) disease-associated tumours

Belzutifan is contraindicated during pregnancy (see section 4.3). If pregnancy occurs during treatmentwith belzutifan, treatment should be discontinued.

There are no data on the presence of belzutifan or its metabolites in human milk, their effects on thebreast-fed child, or on milk production. Because of the potential for serious adverse reactions inbreast-fed children, advise women not to breast-feed during treatment with belzutifan and for 1 weekafter the last dose.

Based on findings in animals, belzutifan may impair fertility in males and females of reproductivepotential (see section 5.3). Patients should be advised of this potential risk. The reversibility of theeffect on fertility is unknown.

Belzutifan has minor influence on the ability to drive and use machines. Dizziness and fatigue mayoccur following administration of belzutifan (see section 4.8).

Patients should be advised not to drive and use machines, until they are reasonably certain belzutifantherapy does not affect them adversely.

The safety of belzutifan has been evaluated in 576 patients with advanced solid tumours and VHLdisease-associated localised tumours treated with 120 mg belzutifan once daily in clinical studies. Themedian duration of exposure to belzutifan was 9.2 months (range: 0.1 to 55.4 months).

The most common adverse reactions under treatment with belzutifan were anaemia (84.2%),fatigue (42.7%), nausea (24.1%), dyspnoea (21.4%), dizziness (17.9%) and hypoxia (16.3%).

The most common Grade 3 or 4 adverse reactions were anaemia (28.8%) and hypoxia (12.2%).

The most common serious adverse reactions were hypoxia (7.1%), anaemia (4.7%) anddyspnoea (1.2%).

The most common adverse reactions resulting in dose interruption of belzutifan were anaemia (7.1%),hypoxia (5.4%), fatigue (2.6%), nausea (2.4%), dyspnoea (1.7%) and dizziness (1.6%). The mostcommon adverse reactions resulting in dose reduction of belzutifan were hypoxia (6.3%),anaemia (3.8%) and fatigue (1.7%). The most common adverse reaction resulting in discontinuation ofbelzutifan was hypoxia (1.4%).

Adverse reactions reported in the pooled dataset for patients treated with belzutifan (n=576) orreported from post-marketing use are listed in Table 2. These reactions are presented by system organclass and by frequency. Frequencies are defined as: 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); and very rare (< 1/10 000).

Table 2: Adverse reactions in patients treated with belzutifan*

Adverse drug reaction All Grades Grade 3 - 4

Blood and lymphatic systemdisorders

Anaemia† Very common Very common

Dizziness Very common -

Respiratory, thoracic andmediastinal disorders

Dyspnoea Very common Common

Hypoxia Very common Very common

Haemorrhage‡# Very common Common

Nausea Very common Uncommon

General disorders andadministration site conditions

Fatigue Very common Common

Weight increased Common Common

*Adverse reaction frequencies presented in Table 2 may contain contributions from the underlying disease.†Anaemia includes anaemia and haemoglobin decreased.‡ Includes different bleeding events from different sites not listed individually.

Haemorrhage terms that occurred in 5 or more patients treated with belzutifan were: haematuria, haemoptysis, contusion andepistaxis (any grade); and haematuria (grades 3-4).#Includes CNS haemorrhage (a fatal case was observed) (see section 4.4).

Anaemia (see section 4.4)

Anaemia occurred in 83% of patients with advanced RCC receiving belzutifan, 32% had Grade 3 and0.5% had Grade 4 anaemia. Median time to onset of anaemia was 29 days (range: 1 day to 27 months).

Of the patients with anaemia, 22% received transfusions only, 20% of patients received ESAs onlyand 14% received both transfusion and ESAs. The median number of ESA doses administered topatients was 6.5 (range: 1-87). Patients received an ESA based on haemoglobin levels and physiciandiscretion (see section 5.1).

Anaemia occurred in 90.2% of patients with VHL disease-associated tumours receiving belzutifan,11.5% of patients had Grade 3 anaemia. Median time to onset of all Grade anaemia events was30 days (range: 1 day to 8 months). Of the patients with anaemia, 1.8% received transfusions only,16.4% received ESAs only and 9.1% of patients received both transfusion and ESAs. The mediannumber of ESA doses administered to patients was 5 (range: 1- 35). Patients received an ESA basedon haemoglobin levels and physician discretion (see section 5.1).

The incidence of Grade 3 anaemia increased with higher belzutifan exposure in patients with baselinehaemoglobin levels < 12 g/dL (see section 4.4).

Hypoxia (see section 4.4)

Hypoxia occurred in 15% of patients with advanced RCC receiving belzutifan and 10% of patients had

Grade 3 hypoxia and 0.3% patients had Grade 4 hypoxia. Of the patients with hypoxia, 70% weretreated with oxygen therapy. Median time to onset of hypoxia was 31 days (range: 1 day to21 months).

Hypoxia (Grade 3) was reported in 1.6% of patients with VHL disease-associated tumours receivingbelzutifan. Time to onset of hypoxia was 56 days.

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.

There is no specific treatment for belzutifan overdose. In cases of suspected overdose, if necessary,withhold belzutifan and institute supportive care. The highest dose of belzutifan studied clinically was240 mg total daily dose (120 mg twice a day or 240 mg once a day). Grade 3 hypoxia occurred at120 mg twice a day and Grade 4 thrombocytopenia occurred at 240 mg once daily.

Pharmacotherapeutic group: Antineoplastic agent, other antineoplastic agents. ATC code: L01XX74

Belzutifan is an inhibitor of the transcription factor hypoxia-inducible factor 2 alpha (HIF-2α). Undernormal oxygen levels, HIF-2α is targeted for degradation by VHL protein. Impairment of VHL proteinfunction results in accumulation of HIF-2α. Consequently, HIF-2α translocates into the nucleus andregulates expression genes, associated with cellular proliferation, angiogenesis, and tumour growth.

Belzutifan binds to HIF-2α, and in conditions of hypoxia or impairment of VHL protein function,belzutifan blocks the HIF-2α-HIF-1β interaction, leading to reduced transcription and expression of

HIF-2α target genes.

Circulating plasma levels of erythropoietin (EPO) were monitored in patients as a pharmacodynamicmarker of HIF-2α inhibition. Reductions in EPO were observed to be dose/exposure dependent andshowed a plateauing effect on reduction at exposures achieved with doses above 120 mg once daily.

The maximum EPO suppression occurred following 2 weeks of consecutive dosing of belzutifan(mean percent decrease from baseline of approximately 60%). Mean EPO levels gradually returned tobaseline values after 12 weeks of treatment.

At the recommended dose (120 mg once daily) for belzutifan, there were no clinically relevant effectson the QTc interval.

Clinical study in adult patients with advanced renal cell carcinoma (RCC)

The efficacy of belzutifan was evaluated in LITESPARK-005, an open-label, randomised, active-controlled Phase 3 clinical study comparing belzutifan with everolimus in 746 patients withunresectable, locally advanced or metastatic clear cell RCC that has progressed following PD-1/L1checkpoint inhibitors and VEGF receptor targeted therapies either in sequence or in combination.

Patients could have received up to 3 prior treatment regimens and must have measurable disease per

RECIST v1.1. The study excluded patients with hypoxia, active CNS metastases and clinicallysignificant cardiac disease. Patients were randomised in a 1:1 ratio to receive 120 mg belzutifan or10 mg everolimus by oral administration once daily. Randomisation was stratified by International

Metastatic RCC Database Consortium (IMDC) risk categories (favourable versus intermediate versuspoor) and number of prior VEGF receptor targeted therapies (1 versus 2- 3).

Patients were evaluated radiologically at Week 9 from the date of randomisation, then every 8 weeksthrough Week 49, and every 12 weeks thereafter.

Among the 746 patients in LITESPARK-005, 369 patients received two or more lines of therapy thatincluded a PD-(L)1 inhibitor and at least two VEGF-targeted therapies. The baseline characteristics ofthose patients were: median age 63 years (range: 33 to 82 years), 40 % age 65 or older; 11 % age 75 orolder; 79 % male; 78 % White; 12 % Asian; 1 % Black or African American; 42 % ECOGperformance status 0 and 56 % ECOG performance status 1. Prior lines of therapies: 17 % of patientshad 2 , 81 % had 3 and 2 % had 4 prior lines of therapies. Patient distribution by IMDC risk categorieswas 22 % favourable, 66 % intermediate, and 12 % poor.

The primary efficacy outcome measures were progression-free survival (PFS) measured by BICRusing RECIST v1.1, and overall survival (OS). Secondary efficacy outcome measures includedobjective response rate (ORR) and duration of response (DOR) by BICR using RECIST v1.1.

In the overall population, the study demonstrated statistically significant improvements of PFS(HR: 0.75 [95% CI 0.63, 0.90], p-Value 0.00077) and ORR (21.9% versus 3.5%, p-Value < 0.00001)for patients randomised to belzutifan compared with everolimus at a pre-specified interim analysis(median follow-up time of 13.5 months [range: 0.2 to 31.8 months]).

Table 3 summarises key efficacy measures in the subgroup of patients that received two or more linesof therapy that included a PD-(L)1 inhibitor and at least two VEGF-targeted therapies in

LITESPARK-005. The KM curves for PFS and OS are shown in Figures 1 and 2.

Table 3: Efficacy results (BICR assessment) in LITESPARK-005 for patients that received twoor more lines of therapy that included a PD-(L)1 inhibitor and at least two VEGF-targetedtherapies

Endpoint Belzutifan Everolimusn=187 n=182

PFS*

Number of events, n (%) 127 (67.9%) 130 (71.4%)

Median† PFS in months (95% 4.6 (3.5, 7.3) 5.4 (3.8, 6.5)

CI)

Hazard ratio‡ (95% CI) 0.73 (0.57, 0.94)

OS¶

Number of events, n (%) 128 (68.1%) 125 (68.7%)

Median† OS in months (95% 21.8 (17.4, 25.8) 18.1 (14.2, 23.9)

CI)

Hazard ratio‡ (95% CI) 0.94 (0.74, 1.21)

ORR* % (95% CI) 24.1% (18.1, 30.8) 3.3% (1.2, 7.0)

Complete response, n (%) 5 (2.7%) 0 (0%)

Partial response, n (%) 40 (21.4%) 6 (3.3%)

Response duration*

Median in months (range) NR (1.9+, 23.1+) 17.2 (3.8, 17.2)

* Based on first pre-specified interim analysis (median follow-up time of 13.5 months)† From product-limit (Kaplan-Meier) method for censored data‡ Based on Cox regression model¶ Based on final analysis (median follow-up time of 19.6 months)+ Denotes ongoing response

NR = Not reached

The median time to response (TTR) was 3.7 months (range: 1.7- 16.6) in the belzutifan arm and3.0 months (range: 1.8- 5.4) in the everolimus arm (median follow-up time of 13.5 months), in thesubgroup of patients that received two or more lines of therapy that included a PD-L(1) inhibitor andat least two VEGF-targeted therapies in LITESPARK-005.

Figure 1: Kaplan-Meier curve for progression-free survival by treatment arm in

LITESPARK- 005 for patients that received two or more lines of therapy that included a

PD- (L)1 inhibitor and at least two VEGF-targeted therapies*

Treatment arm PFS Rate at 6 months PFS Rate at 12 months HR (95% CI)

Belzutifan 44% 33% 0.73 (0.57, 0.94)

Everolimus 43% 15%

Time in Months

Number at Risk

Belzutifan

* Median follow-up time of 13.5 months

Progression-Free Survival (%)

Figure 2: Kaplan-Meier curve for overall survival by treatment arm in LITESPARK-005 forpatients that received two or more lines of therapy that included a PD- (L)1 inhibitor and atleast two VEGF-targeted therapies*

Treatment arm OS Rate at 12 months OS Rate at 24 months HR (95% CI)

Belzutifan 67% 46% 0.94 (0.74, 1.21)

Everolimus 64% 43%

Time in Months

Number at Risk

Belzutifan

* Median follow-up time of 19.6 months

Clinical study in adult patients with von Hippel-Lindau (VHL) disease-associated tumours

The efficacy of belzutifan was investigated in LITESPARK-004, an open-label Phase 2 clinical studyin 61 patients with VHL disease who had at least one measurable solid tumour (as defined by RECISTv1.1) localised to the kidney and who did not require immediate surgery. Patients could also haveother VHL disease-associated tumours, such as CNS haemangioblastomas and pNET. Patientsreceived belzutifan at a dose of 120 mg once daily. Patients were evaluated radiologicallyapproximately 12 weeks after initiation of treatment and every 12 weeks thereafter. Treatment wascontinued until progression of disease or unacceptable toxicity. Patients were required to have an

ECOG PS of 0 or 1. The study excluded patients who had any evidence of metastatic disease, either

RCC or other VHL disease-associated tumours, an immediate need for surgical intervention fortumour treatment, any major surgical procedure completed within 4 weeks prior to study enrolment,any major cardiovascular event within 6 months prior to study drug administration, or prior systemictreatments for VHL disease-associated RCC.

Among the 61 patients enrolled in LITESPARK-004, the population characteristics were: median ageof 41 years, 3.3% age 65 or older; 52.5% male; 90.2% White; and 82.0% had an ECOG PS of 0 and16.4% had an ECOG PS of 1. Seventy-seven percent of patients had prior RCC surgical procedures.

Other VHL disease-associated tumours in patients included pancreatic lesions (100.0%) of which36.1% were pancreatic neuroendocrine tumours, CNS haemangioblastomas (82.0%), and retinalangiomas (19.7%).

Overall Survival (%)

The primary efficacy endpoint for the treatment of VHL disease-associated RCC was ORR measuredby radiology assessment using RECIST v1.1 as assessed by a central independent review committee(IRC). Additional efficacy endpoints included DOR and TTR. ORR and DOR in other VHL disease-associated tumours were assessed as secondary efficacy endpoints.

Table 4 summarises the efficacy results for VHL disease-associated RCC tumours in LITESPARK-004, based on an interim analysis with a median follow-up time of 49.7 months.

Table 4: Efficacy results in VHL disease-associated RCC tumours in LITESPARK-004

Endpoint Belzutifann=61

ORR* % (95% CI) 67.2% (54.0, 78.7)

Complete response 11.5%

Partial response 55.7%

Response duration†

Median in months (range) NR (8.6+, 44.4+)% with duration ≥ 12 months 100.0%

Time to response

Median in months (range) 11.1 (2.7, 41.2)

Efficacy data with a median follow-up of 49.7 months (cut-off date 3 Apr 2023)

* Response: Best objective response as confirmed complete response or partial response† Based on Kaplan-Meier estimates+ Denotes ongoing response

NR = Not reached

Efficacy endpoints for the treatment of other VHL disease-associated tumours included ORR and DOR,as assessed by IRC using RECIST v1.1. These results are shown in Table 5.

Table 5: Efficacy results for belzutifan for other VHL disease-associated tumours

Belzutifann=61

Endpoint Patients with Patients withevaluable CNS evaluable pancreatichaemangioblastomas neuroendocrinen=50 tumoursn=22

ORR* % (95% CI) 48% (33.7, 62.6) 90.9% (70.8, 98.9)

Complete response 8.0% 50.0%

Partial response 40.0% 40.9%

Response duration†

Median in months (range) NR NR(0.0+, 47.5+) (11.0+, 48.3+)% with duration ≥ 12 months 95.5% 100.0%

Efficacy data with a median follow-up of 49.7 months (cut-off date 3 Apr 2023)

* Response: Best objective response as confirmed complete response or partial response† Based on Kaplan-Meier estimates+ Denotes ongoing response

NR = Not reached

The European Medicines Agency has waived the obligation to submit the results of studies withbelzutifan in all subsets of the paediatric population in renal neoplasms and VHL disease (seesection 4.2 for information 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 Agencywill review new information on this medicinal product at least every year and this SmPC will beupdated as necessary.

The pharmacokinetics of belzutifan are similar in healthy subjects and patients with solid tumoursincluding advanced RCC. Based on population PK analysis, the simulated geometric mean steady-state (CV%) Cmax is 1.5 mcg/mL (46%) and AUC0-24hr is 20.8 mcg*hr/mL (64%) in patients treatedwith 120 mg belzutifan. Steady state is reached after approximately 3 days.

Following single-dose oral administration of 120 mg of belzutifan, peak plasma concentrations(median Tmax) of belzutifan occurred at 1 to 2 hours post dose.

A high-fat, high-calorie meal delayed peak belzutifan concentration by approximately 2 hours but, hadno effect on exposure (AUC). There was a modest decrease of Cmax by 24% following consumption ofa high-fat, high-calorie meal, but this was not clinically meaningful. Therefore, belzutifan can be takenwithout regard to food.

Based on the population PK analysis, the mean (CV%) volume of distribution is 120 L (28.5%).

Plasma protein binding of belzutifan is 45%. The blood-to-plasma concentration ratio of belzutifanis 0.88.

Belzutifan is primarily metabolised by UGT2B17 and CYP2C19 and to lesser extent by CYP3A4.

Both UGT2B17 and CYP2C19 display genetic polymorphisms (see ‘Special populations - Dual

UGT2B17 and CYP2C19 Poor Metabolisers’).

In vitro assessment of drug interactions

Belzutifan is a substrate of UGT2B17, CYP2C19 and CYP3A4. Active transport is not an importantdeterminant of belzutifan disposition. Belzutifan is not an inhibitor of CYP enzymes, UGT enzymes,or transporters with the exception of MATE-2K, and potentially MATE1. Belzutifan does not induce

CYP1A2, however, belzutifan induces CYP2B6, CYP2C8 and CYP3A4 in a concentration dependentmanner (see section 4.5).

Based on the population PK analysis, the mean (CV%) clearance is 5.89 L/hr (60.6%) and the meanelimination half-life is approximately 14 hrs.

Following oral administration of radiolabelled belzutifan to healthy subjects, approximately 49.6% ofthe dose was excreted in urine and 51.7% in faeces (primarily as inactive metabolites). Approximately6% of the dose was recovered as parent drug in urine.

The plasma Cmax and AUC increased proportionally over a dose range of 40 mg to 120 mg.

Based on a population pharmacokinetic analysis of belzutifan in healthy subjects and patients withcancer, no clinically significant differences in the mean belzutifan exposure were observed betweensubjects with normal renal function and those with mild and moderate renal impairment (as evaluatedby estimated glomerular filtration rate (eGFR)). In a dedicated pharmacokinetic study, belzutifanexposure (AUC0-INF) decreased by 6% and increased by 14% in patients with end-stage renal diseasebefore and after haemodialysis, respectively (see section 4.2).

Based on a population pharmacokinetic analysis of belzutifan in healthy subjects and patients withcancer, no clinically significant differences in the mean belzutifan exposure were observed betweensubjects with normal liver function (total bilirubin and AST ≤ ULN), and those with mild hepaticimpairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin > 1 to 1.5 x ULN and any AST).

In a dedicated pharmacokinetic study, belzutifan exposure (AUC0-INF) increased by 52% in patientswith moderate hepatic impairment (Child-Pugh B). Patients with severe hepatic impairment have notbeen studied (see section 4.2).

Dual UGT2B17 and CYP2C19 Poor Metabolisers

Patients who are dual UGT2B17 and CYP2C19 poor metabolisers have higher belzutifan exposures,which may increase the incidence and severity of adverse reactions of belzutifan and should be closelymonitored (see sections 4.4 and 4.8).

Belzutifan is primarily metabolised by UGT2B17 and CYP2C19. The activity of these enzymes variesamong individuals who carry different genetic variants, which may impact belzutifan concentrations.

Poor metabolisers are individuals who are considered to have no enzyme activity. In patients who aredual UGT2B17 and CYP2C19 poor metabolisers, CYP3A4 may be a major elimination pathway.

Approximately 15% of Caucasians, 11% of Latinos, 6% of African Americans, 38% of South Asians,and 70% of East Asians are UGT2B17 poor metabolisers. Approximately 2% of Caucasians, 1% of

Latinos, 5% of African Americans, 8% of South Asians, and 13% of East Asians are CYP2C19 poormetabolisers. Approximately 0.3% of Caucasians, 0.1% of Latinos, 0.3% of African Americans, 3% of

South Asians, and 9% of East Asians are dual UGT2B17 and CYP2C19 poor metabolisers. Expectedfrequencies in the Japanese population for the UGT2B17, CYP2C19, and dual UGT2B17 and

CYP2C19 poor metabolisers are approximately 77%, 19%, and 15%, respectively. Expectedfrequencies in the United States population for the UGT2B17, CYP2C19, and dual UGT2B17 and

CYP2C19 poor metabolisers are approximately 16%, 3%, and 0.5%, respectively based on thereported proportion of the US population represented by major racial/ethnic groups.

The impact of CYP2C19 and UGT2B17 poor metabolisers on belzutifan exposure was assessed in apopulation PK analysis. Based on the population PK model, patients who are CYP2C19, UGT2B17, ordual UGT2B17 and CYP2C19 poor metabolisers, are projected to have 1.3-, 2.7- or 3.3 -fold theexposures (steady-state AUC0-24hr), respectively, compared to a typical reference patient (UGT2B17extensive metaboliser, CYP2C19 extensive/intermediate metaboliser) for the recommended dose. Nodose adjustment is recommended based on exposure-response analyses for efficacy and safety and therisk-benefit profile.

Effects of age, gender, ethnicity, race, and body weight

Based on a population pharmacokinetic analysis, age (range: 19 to 90 years), gender, ethnicity, race,and body weight (range: 42.1 to 166 kg) do not have a clinically meaningful effect on thepharmacokinetics of belzutifan. Potential differences in exposure across races are possible due todifferent frequencies of metabolising enzymes (see ‘Special populations - Dual UGT2B17 and

CYP2C19 Poor Metabolisers’).

Repeat-dose oral toxicity studies in rats and dogs for up to 3 months duration revealed anaemia at alldoses including at exposure levels lower than the human exposure levels. Although the anaemia wasreversible, this is relevant to humans.

A 26-week transgenic rasH2 mouse carcinogenicity study has been conducted with belzutifan at dosesup to 600 mg/kg/day, corresponding to exposures up to 28-fold the human exposure at the approveddose. No belzutifan-related neoplastic findings were observed at any dose level and no carcinogenicrisk was identified in the study.

Belzutifan was not genotoxic in in vitro bacterial mutagenesis and micronucleus assays, and an in vivorat micronucleus assay at 1.7-fold human exposure.

Fertility studies with belzutifan have not been conducted. In the 3-month repeat-dose toxicity study inrats, irreversible testicular atrophy/degeneration and oligospermia was observed at exposures lowerthan the human exposure at the recommended dose of 120 mg daily. No testicular toxicity wasobserved in dogs up to an exposure similar to the human exposure. There were no findings in femalereproductive organs in either rat or dog 3-month toxicity studies, but HIF-2α has a functional role inthe uterus during embryo implantation and establishment of pregnancy in mice. HIF-2α inhibition byexposure to belzutifan has the potential to interfere with embryo implantation, leading to impairmentof female fertility.

In a rat embryo-foetal development study, administration of belzutifan during organogenesis causedembryo-foetal lethality up to 100%, reduced foetal body weight, and foetal skeletal abnormalities atexposures similar to or below the human exposure at the recommended dose of 120 mg daily.

Hypromellose acetate succinate

Cellulose microcrystalline (E460)

Mannitol (E421)

Croscarmellose sodium (E468)

Silica, colloidal anhydrous (E551)

Magnesium stearate (E470b)

Polyvinyl alcohol (E1203)

Titanium dioxide (E171)

Macrogol (E1521)

Talc (E553b)

Indigo carmine aluminium lake (E132)

Not applicable.

4 years

This medicinal product does not require any special storage conditions.

Aluminium/aluminium blisters.

Pack containing 30 film-coated tablets.

Multipack containing 90 (3 packs of 30) 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.

Merck Sharp & Dohme B.V.

Waarderweg 392031 BN Haarlem

The Netherlands

EU/1/24/1893/001

EU/1/24/1893/002

Date of first authorisation:

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

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