Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: antineoplastic agent, ATC code: L01XX74.

Mechanism of action
Belzutifan is an inhibitor of hypoxia-inducible factor 2 alpha (HIF-2α). HIF-2α is a transcription factor that plays a role in oxygen sensing by regulating genes that promote adaptation to hypoxia.
Under normal oxygen levels, HIF-2α is targeted for ubiquitin-proteasomal degradation by VHL protein. Lack of functional VHL protein results in stabilization and accumulation of HIF-2α. Upon stabilization, HIF-2α translocates into the nucleus and interacts with hypoxia-inducible factor 1 beta (HIF-1b) to form a transcriptional complex that regulates expression of downstream genes, including genes associated with cellular proliferation, angiogenesis, and tumour growth (including CCND1, VEGFA, SLC2A1 (GLUT1), IGFBP3, TGFa, AXL, CXCR4, IL6). Belzutifan binds to HIF-2α, and in conditions of hypoxia or impairment of VHL protein function, belzutifan blocks the HIF-2α-HIF-1b interaction, leading to reduced transcription and expression of HIF-2α target genes. In vivo, belzutifan demonstrated anti-tumour activity in mouse xenograft models of renal cell carcinoma.

Pharmacodynamic effects
The pharmacodynamic effects of belzutifan were evaluated in patients with VHL disease-associated RCC (Study-004) and in patients with non-VHL disease-associated advanced solid tumours (Study-001). Circulating plasma levels of EPO were monitored in patients as a pharmacodynamic marker of HIF-2α inhibition. Treatment with belzutifan resulted in reductions in EPO at all dose levels. Reductions in EPO were observed to be dose/exposure dependent and showed a plateauing effect on reduction at exposures achieved with doses above 120 mg once daily. In patients with VHL disease-associated RCC receiving 120 mg once daily of belzutifan, peak EPO suppression occurred at 2 weeks of treatment (mean percent decrease from baseline of approximately 60%). Mean EPO levels gradually returned to baseline values after 12 weeks of treatment.

Pharmacogenomics
Belzutifan is primarily metabolised by UGT2B17 and CYP2C19. The activity of these enzymes varies among individuals who carry different genetic variants, which may impact belzutifan concentrations.
Poor metabolisers are individuals who are considered to have no enzyme activity. 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 poor metabolisers.
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.
The impact of CYP2C19 and UGT2B17 poor metabolisers on belzutifan exposure was assessed in a population PK analysis. Based on the analysis, VHL disease-associated RCC patients who are UGT2B17, CYP2C19, or dual UGT2B17 and CYP2C19 poor metabolisers, are projected to have 1.5-, 1.6- or 2.3-fold the exposures (steady-state AUC0-24), respectively, compared to a typical reference patient (UGT2B17 intermediate metaboliser, CYP2C19 non-poor metaboliser) for the recommended dose. No dose adjustment is recommended based on exposure-response analyses for efficacy and safety and the risk-benefit profile.

Clinical efficacy
The efficacy of belzutifan was investigated in Study-004, an open-label Phase 2 clinical study in 61 patients with confirmed VHL disease, based on a VHL germline alteration, who had at least one measurable solid tumour (as defined by RECIST v1.1) localised to the kidney and who did not require immediate surgery. Enrolled patients had other VHL-associated tumours including CNS haemangioblastomas and pNET, identified by radiological appearance. The study excluded patients who had any evidence of metastatic disease, either RCC or other VHL disease-associated tumours.
Other exclusion criteria were immediate need for surgical intervention for tumour 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 systemic treatments for VHL disease-associated RCC. Patients were monitored for anaemia and hypoxia before initiation of belzutifan, and then every 2 weeks for the first month, monthly for the next 5 months, and then every 3 months thereafter throughout treatment.

The study population characteristics were: median age of 41 years [range 19-66 years], 3.3% age 65 or older; 52.5% male; 90.2% White; and 82.0% had an ECOG PS of 0 and 16.4% had an ECOG PS of 1. Seventy-seven percent of patients had prior RCC surgical procedures encompassing ablative procedures, partial nephrectomy, radical nephrectomy.
The median diameter of RCC target lesions per central independent review committee (IRC) was 2.2 cm (range 1-6.1). Median time from initial radiographic diagnosis of VHL-associated RCC tumours that led to enrolment on Study 004 to the time of treatment with WELIREG was 17.9 months (range 2.8-96.7).

Patients received belzutifan at a dose of 120 mg once daily. Patients were evaluated radiologically approximately 12 weeks after initiation of treatment and every 12 weeks thereafter. Treatment was continued until progression of disease or unacceptable toxicity. The effect of intermittent use and long treatment interruptions of belzutifan have not been evaluated.

The primary efficacy endpoint for the treatment of VHL disease-associated RCC was overall response rate (ORR) measured by radiology assessment using RECIST v1.1 as assessed by IRC. Secondary efficacy endpoints included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), time to response (TTR), and time to surgery (TTS).
Table 3 summarises the efficacy results for VHL disease-associated RCC tumours in Study-004 at a median follow-up time of 29.2 months (range 4.2-37.5). The median duration of exposure was 28.9 months (range 1.9-37.5).

Table 3: Efficacy results in VHL disease-associated RCC tumours in Study-004 
Endpoint                                             Belzutifan
120 mg daily n=61
Overall response rate
ORR* (95% CI)                                    59.0% (45.7, 71.4)
Complete response                                  3.3%
Partial response                                   55.7%
Stable disease                                     39.3%
Disease control rate†                                            98.4% Response duration‡
Median in weeks (range)                                      Not reached (36.1+, 119.9+)
% (n) with duration ≥ 18 months                              95.0% (19) Time to response
Median in weeks (range)                                    46.7 (11.6, 96.6) Time to surgery
Median in weeks (95% CI)                                      Not reached (NE, NE)
PFS‡
Median in weeks (95% CI)                               Median not estimated§ 24-month PFS rate                                            94.6%
* Response: Best objective response as confirmed complete response or partial response † Based on best response of stable disease or better
‡ Based on Kaplan-Meier estimates
§ Reliable median could not be estimated due to the number of progression events (n=7) and  a progression event that occurred at the latest timepoint when only 1 patient was at risk.
NE = Not estimable

During this period of treatment, two out of 61 (3.3%) patients required an RCC tumour reduction procedure. For comparison, in one retrospective natural history study of VHL patients with RCC, 28.7% of patients had their first tumour reduction procedure within 24 months of follow-up.

Objective response rates were in other VHL diseases associated tumours: 38% CNS haemangioblastomas (95% CI: 24.7, 52.8; 19 out of 50 patients), and 90% for pancreatic neuroendocrine tumours (95% CI: 68.3, 98.8; 18 out of 20 patients).

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

The pharmacokinetics of belzutifan are similar in healthy subjects and patients with solid tumours including advanced RCC. Based on a population-PK model analysis, the steady-state geometric mean (GCV%) for Cmax and AUC0-24hr for 120 mg once daily in patients with VHL disease-associated RCC are predicted to be 1.4 μg/mL (39.8%) and 16.7 µg•hr/mL (52.3%), respectively. Steady-state is reached after approximately 3 days of once daily dosing with belzutifan.

Absorption
Following single-dose oral administration of 120 mg of belzutifan, peak plasma concentrations (median Tmax) of belzutifan occurred at 1.5 hours post dose.

Effect of food
A high-fat, high-calorie meal delayed peak belzutifan concentration by approximately 2 hours, but had no effect on exposure (AUC). There was a modest decrease of Cmax by 35% following consumption of a high-fat, high-calorie meal, but this was not clinically meaningful. Therefore, belzutifan can be taken without regard to food.

Distribution
The mean steady-state apparent volume of distribution of belzutifan following an oral dose is 130 L.
Plasma protein binding of belzutifan is 45%. The blood-to-plasma concentration ratio of belzutifan is 0.88.

Elimination
The mean apparent clearance of belzutifan is 7.3 L/hr and the mean elimination half-life is 14 hrs.

Metabolism
Belzutifan is primarily metabolised by UGT2B17 and CYP2C19 and to a lesser extent by CYP3A4.
Both UGT2B17 and CYP2C19 display genetic polymorphisms (see section 5.1).
Linearity
The plasma Cmax and AUC increased in a dose-proportional manner following doses up to the recommended dose for belzutifan.

Special Populations

Renal impairment
No relevant increase in exposure (AUC) was observed for subjects with mild or moderate renal impairment. Renal impairment (as evaluated by eGFR) was not identified as a significant covariate in the population pharmacokinetic analysis. The pharmacokinetics of belzutifan have not been studied in patients with severe renal impairment (see sections 4.2 and 5.2).

Hepatic impairment
No relevant increase in exposure (AUC) was observed for subjects with mild hepatic impairment (using NCI index) based on population pharmacokinetic analysis. The pharmacokinetics of belzutifan have not been studied in patients with moderate or severe hepatic impairment (see sections 4.2 and 5.2).

Dual UGT2BI7 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 closely monitored (see sections 4.4, 4.8 and 5.1).

Effects of Age, Gender, Ethnicity, Race, and Body Weight
Based on a population pharmacokinetic analysis, age, gender, ethnicity, race, and body weight do not have a clinically meaningful effect on the pharmacokinetics of belzutifan. Potential differences in exposure across races are possible due to different frequencies of metabolising enzymes (see section 5.1).

Paediatric population
No studies with belzutifan have been performed in paediatric patients.