Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants, ATC code: L04AA48.

Mechanism of action

Belumosudil is a potent and selective Rho-associated, coiled-coil containing protein kinase-2 (ROCK2) inhibitor that mediates signalling in immune cellular function and fibrotic pathways. In vivo, belumosudil has demonstrated activity in a variety of clinically relevant animal models of disease including chronic GVHD.

Pharmacodynamic effects

Cardiac Electrophysiology
At a dose of 5 times the recommended dose, belumosudil does not prolong the QT interval to any clinically relevant extent.

Clinical efficacy and safety

Two open-label Phase 2 studies (studies KD025-208 and KD025-213) were conducted in patients with chronic GVHD.

Study KD025-213
Study KD025-213 (N=131) was a randomized, open-label, multicentre study of belumosudil for treatment of patients with chronic GVHD. Patients were eligible for the study if they had received 2 to 5 prior lines of systemic therapy and required additional therapy. Patients received a stable dose of corticosteroids for two weeks prior to entry to the study. Patients were randomised 1:1 to receive belumosudil dosed orally at 200 mg once daily or 200 mg twice daily. Randomization was stratified according to prior cGVHD treatment with ibrutinib (yes/no) and severe cGVHD (yes/no).

Where patients were on a stable dose/schedule of standard of care therapies for chronic GVHD, concomitant use of these was permitted, including local and topical treatments and ECP. Transient increases in corticosteroid dosing (that did not exceed 1 mg/kg/day prednisone equivalent) were permitted for the treatment of cGVHD flare, but the dose must have been reduced back to the pre- randomization dose within 6 weeks. If the dose remained elevated for more than 6 weeks, this was considered a belumosudil treatment failure. More than 2 episodes of cGVHD flare that required increased corticosteroid therapy in the first 6 months of belumosudil treatment was also considered a belumosudil treatment failure. Initiation of one or more new systemic therapies for chronic GVHD indicated a new line of therapy and was classified as a treatment failure.

Of patients enrolled in the study, the median age was 55 years (range 21 to 77 years), 57% of patients were male and 85% were white. The majority (67%) of patients had severe cGVHD disease and 73% of patients were refractory to their last systemic therapy prior to enrolling in the study. The most common underlying malignancies leading to transplantation were acute myeloid leukaemia, acute lymphocytic leukaemia and myelodysplastic syndromes. The organs involved at baseline were skin (83%), joints/fascia (76%), eyes (74%), lung (36%), mouth (54%), oesophagus (24%), upper GI (17%), lower GI (10%) and liver (10%), and 51% of patients had 4 or more organs involved. The most common prior systemic therapy was corticosteroids (98%), followed by calcineurin inhibitors (tacrolimus 62% and sirolimus 47%), ECP (48%), ibrutinib (34%) and ruxolitinib (29%). The median prior lines of therapy was 3 (range 2-6).

The primary efficacy endpoint was the overall response rate (ORR), defined as the proportion of subjects who achieved a complete response or a partial response according to the 2014 NIH Consensus Development Project on Criteria for Clinical Trials in chronic GVHD. Responses were assessed by investigators. Secondary endpoints included duration of response, changes in symptom burden/bother using the Lee Symptom Scale Score (LSS) and time to next treatment.

Study KD025-213 met its primary objective. For the 200 mg once daily dose, the ORR (data cut-off: 19-Aug-2020) was 74% (62-84%); 6% of patients achieved a CR and 68% of patients achieved a PR.
Responses, including complete responses, were achieved across all organs involved (skin, eyes, joints/fascia, mouth, lung, oesophagus, upper GI, lower GI and liver). Duration of response (defined as the time from first ORR response to progression of disease in any organ measured in comparison to nadir, new systemic therapy, or death whichever comes first) was 8 weeks (95% CI 4-64 weeks).

Results for Study KD025-213 at the 200 mg once daily belumosudil dose are presented in Table 3.

Table 3:   Best overall response rate and other efficacy results in Study KD025-213 
Rezurock (N=131)
200 mg once daily
(N=65)
Overall response rate (%)                                                        73.8 95% CI (%)                                                                  (61.5, 84.0) Complete response (%)                                                             6.2 Partial response (%)                                                             67.7 
K-M duration of response, median, weeks (95% CI)                              8.1 (3.7, 64.3) Rezurock (N=131)
200 mg once daily
(N=65)
Time to response, median, weeks (range)                                       4.4 (3.7, 40.6) K-M time to next treatment, median, months (95% CI)                          NA (13.73, NA) ≥7 Point decrease in Lee Symptom Scale Score on consecutive                      28 (43) assessments, n (%)
Discontinued corticosteroid during Belumosudil treatment, n (%)                   12 (19) CI = Confidence interval; K-M = Kaplan Meier; NR = Not reached.

For the 200 mg twice daily dose, the ORR was 77.3% (95% CI 65.3%, 86.7%) and the DOR (defined as the time from first ORR response to progression of disease in any organ measured in comparison to nadir, new systemic therapy, or death whichever comes first) was 8 weeks (95% CI 2-81 weeks).

Study KD025-208

Study KD025-208 (N=54) was a dose-escalation, open-label, multicentre study of belumosudil for treatment of patients with chronic GVHD who had received 1 to 3 prior lines of systemic therapy and required additional therapy. Belumosudil was administered orally at 200 mg once daily (N=17), 200 mg twice daily (N=16), or 400 mg once daily (N=21).

Where patients were on a stable dose/schedule of standard of care therapies for chronic GVHD, concomitant use of these was permitted, including corticosteroids and calcineurin inhibitors. Initiation of one or more new systemic therapies for chronic GVHD indicated a new line of therapy and was classified as a treatment failure.

Of patients enrolled in the study, the median age was 52 years (range 20 to 75 years), 63% of patients were male and 87% were white. The majority (78%) of patients had severe cGVHD disease and 73% of patients were refractory to their last systemic therapy prior to enrolling in the study. The most common underlying malignancies leading to transplantation were acute myeloid leukaemia, acute lymphocytic leukaemia and myelodysplastic syndromes. The organs involved at baseline were eyes (78%), skin (74%), mouth (65%), joints/fascia (63%), lung (32%), upper GI (15%), oesophagus (11%), lower GI (7%), and liver (4%), and 50% of patients had 4 or more organs involved. The most common prior systemic therapy was corticosteroids (100%), followed by calcineurin inhibitors (tacrolimus 48% and sirolimus 44%), rituximab (30%), and ECP (28%). The median number of prior lines of therapy was 2.5 (range 1-4).

The primary efficacy endpoint was the overall response rate (ORR), defined as the proportion of subjects who achieved a complete response or a partial response according to the 2014 NIH Consensus Development Project on Criteria for Clinical Trials in chronic GVHD. Responses were assessed by investigators. Secondary endpoints included duration of response, failure free survival and time to next treatment.

Study KD025-208 met its primary objective. For the 200 mg once daily dose, the ORR was 64.7% (95% CI 38.3%, 85.8%). Responses (partial response) were achieved across all organs involved, there were no complete responses reported. Duration of response (defined as the time from first ORR response to progression of disease in any organ measured in comparison to nadir, new systemic therapy, or death whichever comes first) was 19 weeks (95% CI 7-128 weeks).

Safety and efficacy in older patients

Of the 186 patients with chronic GVHD in clinical studies of belumosudil, 25.8% were 65 years and older. No overall differences in safety or effectiveness of belumosudil were observed between these patients and younger patients.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Median Tmax of belumosudil across studies was approximately 3 hours. Following a single oral dose of belumosudil 200 mg, mean absorption (% coefficient of variation) was 64% (17%).

Effect of Food

In healthy subjects, the administration of a single 200 mg dose of belumosudil with a high-fat and high-calorie meal (800 to 1,000 calories with approximately 50% of total caloric content of the meal from fat) increased belumosudil Cmax to 2.2 times that following fasted administration and AUC to 2 times that following fasted administration. Median Tmax was delayed 0.5 hours.

The mean steady-state AUC (% coefficient of variation) observed in patients with chronic GVHD receiving 200 mg once daily administered with food was 22700 (48%) h•ng/mL; mean steady-state Cmax was 2390 (44%) ng/mL. With once daily administration, steady-state concentrations of belumosudil were achieved with an accumulation ratio of 1.4.

Distribution

Pharmacokinetics were described by a two compartmental model with a distribution half-life of 1.8 h.
Belumosudil volume of distribution of the central compartment (% coefficient of variation, CV) was 29.7 L (143%). In in vitro preparations, binding to human serum albumin was 99.9% and binding to human α1-acid glycoprotein was 98.6%.

Biotransformation

Based on in vitro assessment, CYP3A4 was the predominant CYP isoform responsible for the metabolism of belumosudil, although CYP2C8, CYP2D6 and UGT1A9 contributed to a lesser extent.

Elimination

Population PK modelling results in chronic GVHD patients showed that belumosudil elimination half- life (% coefficient of variation, CV) was 19.0 h (39%). Belumosudil clearance (% coefficient of variation, CV) was 9.83 L/h (46%).

The Human Mass Balance study results indicated that faecal excretion is the major route of excretion (85% of the dose). Of the dose recovered in faeces, 30% was parent belumosudil. Less than 5% of the dose was recovered in urine.

Linearity/non-linearity of dose

Exposure to belumosudil (Cmax and AUC) appears to be slightly greater than dose proportional over the 20 to 500 mg once daily dose range, but less than dose-proportional for doses above 500 mg in healthy subjects. In chronic GVHD subjects, the exposure increase between 200 and 400 mg is approximately proportional.

Special populations

No clinically relevant differences in belumosudil pharmacokinetics were observed with regard to age, race, sex, weight or renal impairment (mild or moderate; severe renal impairment has not been studied).

Hepatic impairment

In a hepatic impairment study, the exposure in subjects with mild (Child-Pugh class A) and moderate hepatic impairment (Child-Pugh class B) had exposure ≤1.51 times the exposure observed in normal subjects. Cmax was not changed significantly by mild and moderate hepatic impairment. The effect of severe hepatic impairment has not been evaluated.