Summary Basis of Decision for Rholistiq

As described above, the review of the clinical component of the New Drug Submission (NDS) for Rholistiq was completed by Health Canada as part of an international partnership with the United States Food and Drug Administration (FDA) as a Project Orbis Type A submission. Additionally, the review of the clinical component of the NDS for Rholistiq was conducted as per Method 3 described in the Draft Guidance Document: The Use of Foreign Reviews by Health Canada.

Clinical Pharmacology

Belumosudil, the medicinal ingredient in Rholistiq, is an inhibitor of Rho-associated, coiled-coil-containing protein kinase (ROCK) 2 and ROCK1. During an immune response, ROCK signaling is critical in the coordination and balancing of T cell-mediated immune responses, including cellular movement, T cell receptor (TCR) signaling and the acquisition of the appropriate T cell effector program.

Belmosudil inhibits ROCK2 and ROCK1 with half-maximal inhibitory concentrations (IC₅₀) of approximately 100 nM and 3 μM, respectively. In ex vivo or in vitro human T cell assays, belumosudil downregulated proinflammatory responses via modulation of CD4+ T cell activity and phosphorylation of the transcription factors signal transducer and activator of transcription (STAT) 3 and STAT5. Belumosudil also inhibited pro-fibrotic signaling in vitro. In vivo, Rholistiq demonstrated activity in animal models of chronic graft-versus-host disease (GVHD).

The pharmacokinetics of belumosudil was characterized in healthy subjects and in patients with chronic GVHD. Disease status was the most influential covariate, as clearance was 53% lower in patients with chronic GVHD than in healthy subjects. In patients with chronic GVHD, the mean (% coefficient of variation [CV]) apparent oral clearance was 9.8 L/h (46%) and the elimination half-life was 19 hours (39%).

The pharmacokinetics of belumosudil has not been studied in the pediatric population. Results from a population pharmacokinetic analysis in adult patients indicated that body weight ranging from 38.6 kg to 143.0 kg has no clinically meaningful effect on the pharmacokinetics of belumosudil. Based on allometric scaling, exposure as measured by the area under the concentration-time curve (AUC) was expected to be approximately 30% higher in adolescent patients than in adult patients. This difference in exposure is not considered clinically meaningful, as the safety and efficacy of belumosudil were similar over a range of 200 mg to 400 mg total daily dose in exposure-response analyses. The use of the same fixed dose of 200 mg once daily in adults and in adolescents 12 to 17 years of age is supported by the similar disease biology in both populations, the flat exposure-response relationship, and findings from the population pharmacokinetic analysis.

Rholistiq should be taken with food, as it has a significant effect on the rate and extent of belumosudil absorption. The coadministration of Rholistiq with proton pump inhibitors (PPIs) or strong cytochrome P450 (CYP) 3A inducers decreases belumosudil exposure. The coadministration of Rholistiq and strong CYP3A inducers should be avoided, and if this is not possible, the dose of Rholistiq should be increased to 200 mg twice daily. A dose adjustment to 200 mg twice daily is also recommended if Rholistiq is coadministered with PPIs.

The pharmacokinetics of belumosudil are not expected to be affected by mild to moderate renal or hepatic impairment. Belumosudil has not been studied in subjects with severe renal or hepatic impairment. The risks and potential benefits must be considered before initiating treatment with Rholistiq in these subjects.

A dedicated study to evaluate the effects of Rholistiq on the QT interval has not been conducted.

Overall, no issues were identified during the review of the clinical pharmacology studies that would preclude the approval of Rholistiq in the intended patient population. Key clinical pharmacology findings, relevant risks and uncertainties are adequately addressed in the Product Monograph.

For further details, please refer to the Rholistiq Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The results of the pivotal Phase II study, KD025-213, provided the main evidence of the clinical efficacy of Rholistiq. This study was conducted in 132 patients with chronic graft-versus-host disease (GVHD) who had failed two to five prior lines of systemic therapy. Patients were randomized in a 1:1 ratio to receive a 200 mg dose of belumosudil either once daily or twice daily, with 65 patients with active chronic GVHD treated on the belumosudil 200 mg once daily arm. Patients were treated in 28-day cycles until the occurrence of clinically significant progression of chronic GVHD requiring new systemic therapy, the recurrence of malignancy, or the occurrence of unacceptable toxicity. The median duration of treatment was 9.2 months.

The primary efficacy endpoint was the overall response rate (ORR), including complete response (CR) or partial response (PR), according to the 2014 National Institutes of Health (NIH) consensus criteria. Data collected through Cycle 7, Day 1 were included in the calculation of the ORR. Among patients in the once daily treatment arm, the ORR was 75% (95% confidence interval [CI]: 63, 85), with a PR rate of 69% and a CR rate of 6%. The responses to treatment were seen across all organ systems and were consistent across subgroups, including in patients who failed treatment with ibrutinib or ruxolitinib. The majority of responses were observed within 6 months of treatment initiation, with a median time to first response of 7.71 weeks (range: 3.7 to 24.1). The median duration of follow-up was 8.0 months (range: 0.6 to 15.4).

A Notice of Deficiency (NOD) was issued during the initial review of the submission, primarily due to concerns regarding the definition and measurement of the duration of response (DOR). The sponsor was asked to recalculate the DOR based on the NIH criteria (i.e., the loss of response relative to the best response rather than the baseline response from individual organ response). As the recalculated value for the median DOR was considerably lower, it was unclear whether the response was sufficiently durable. Health Canada issued a NOD requesting the new analyzed data regarding the recalculated primary DOR, as it was required to establish a full benefit-harm-uncertainty profile for Rholistiq. Alternatively, the sponsor was asked to provide an adequate rationale for the use of a different definition of the DOR to support the primary efficacy endpoint of ORR in the pivotal study.

To address the concerns, the DOR was measured in two different ways, as each provided clinically relevant information. Both measurements were included in the Product Monograph to more accurately reflect the clinical benefit gained by patients treated with Rholistiq. Due to the waxing and waning nature of chronic GVHD, measuring the DOR based on progression from individual organ response at nadir may underestimate treatment response. However, measuring the DOR based on a loss of response relative to baseline does not account for cases in which a patient’s condition worsens after achieving a response. When calculated from the time of first response to the time of progression in any organ, new systemic therapy for chronic GVHD, or death, the median DOR was 1.9 months (95% CI: 1.2, 2.9). When calculated from the time of first response to the time of deterioration from the best overall response, death, or new systemic therapy for chronic GVHD, the median DOR was 3.7 months (95% CI: 1.9, 8.3). In patients who achieved a response, no new systemic therapy initiation was required and no deaths occurred for at least 12 months afterwards in 62% of patients (95% CI: 46, 74).

The ORR results obtained through the pivotal study were supported by exploratory analyses from a Phase IIA supportive study of patient-reported symptoms in the validated Lee Symptom Scale (LSS) score. In the once daily treatment arm, 34 patients (52%) reported a 7-point reduction in symptoms from baseline, 7 patients (11%) were able to discontinue treatment with corticosteroids, and 37 patients (57%) were able to reduce their corticosteroid dose. Twenty-four patients in the once-daily treatment arm were taking calcineurin inhibitors (CNI) at baseline, of whom 7 patients (29.2%) were able to reduce their dose, and 2 patients (8.3%) were able to discontinue their dose. The results of the pivotal study were further supported by Study KD025-208, a Phase IIA dose escalation study in patients with steroid-dependent chronic GVHD who had failed one to three previous lines of treatment. Seventeen patients received 200 mg belumosudil once daily. Within 6 months, the ORR was 58.8% (95% CI: 32.9, 81.6).

There are recognized limitations of clinical study design for heterogeneous, waning and waxing diseases such as chronic GVHD. The significance of the ORR was substantial and reproducible across the two clinical studies and in patients who had previously failed several other treatments, which provided significant support for clinical effectiveness. Although the data were immature at the time of review, extended periods without new treatment were observed in many patients, even in those achieving only PRs. Additionally, a substantial portion of patients had achieved a clinically meaningful improvement in the LSS score. Through Cycle 7, Day 1, no CRs were observed in the supportive study (KD025-208) and a 6% CR rate was observed in the pivotal study (KD025-213). This was partially attributed to the advanced disease seen in the patient populations of the two studies. However, the CRs were observed across all organ systems and improvement was seen in severe manifestations of chronic GVHD. These results, combined with improvement in LSS scores and reductions in corticosteroid use, suggest that patients who achieved a PR experienced clinical benefit.

Despite the limitations, the collective evidence supports the efficacy of Rholistiq for use in patients with chronic GVHD. However, the evidence of efficacy in patients with only one prior line of systemic treatment was not sufficient. Rholistiq is therefore indicated for patients with chronic GVHD who have failed at least two prior lines of systemic therapy.

The approval of Rholistiq for pediatric patients 12 years of age and older is based on clinical efficacy results in adult patients, along with population pharmacokinetic analyses demonstrating that age and body weight did not have any clinically meaningful effects on the pharmacokinetics of Rholistiq.

Collectively, the results of the clinical studies provided substantial evidence of the efficacy of Rholistiq in patients 12 years of age and older with chronic GVHD, after the failure of at least two prior lines of systemic therapy. While the DOR is relatively brief, regardless of the measure of DOR used, a substantial number of patients did not require new treatment at 12 months. For a condition with limited available treatments, Rholistiq provides an effective option that may allow more time to achieve control of the disease until systemic treatment is no longer needed.

Indication

The number of patients in the clinical studies who had received only one previous line of systemic therapy was not sufficient to evaluate efficacy in this population. The indication was therefore amended to specify that Rholistiq is approved for chronic GVHD patients after the failure of at least two prior lines of systemic therapy. An additional statement was added to clarify that clinical efficacy was evaluated based on ORR and DOR in a single-arm study.

For more information, refer to the Rholistiq Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The primary safety analysis was based on data from 83 patients from the pivotal Study KD025-213 and the supportive Study KD025-208. Both of these studies are described in the Clinical Efficacy section. All patients in the primary safety analysis received the recommended dose of 200 mg Rholistiq once daily. The median number of organs affected by chronic GVHD was 4.0 in the pivotal study and 3.5 in the supportive study. More than 50% of patients across both studies had 4 or more organs affected by GVHD. The safety database included data from 186 patients with chronic GVHD (132 patients in the pivotal study and 54 patients in the supportive study) who received Rholistiq through any of the dose regimens tested, including the 83 patients who received 200 mg once daily, as well as 82 patients who received 200 mg twice daily and 21 patients who received 400 mg once daily. All patients with chronic GVHD were taking a concomitant systemic corticosteroid at study initiation. The median duration of treatment was 9.2 months (range: 0.5 to 44.7 months).

Treatment-emergent adverse events (TEAEs) were observed in 99% of patients, including Grade 3-5 TEAEs observed in 55% of patients. Treatment-emergent adverse events resulted in drug interruption in 29% of patients, and in discontinuation in 25.3% of patients. Dose reductions due to TEAEs were uncommon, affecting 2.4% of patients receiving a 200 mg once daily dose of Rholistiq. Serious adverse events were observed in 37.3% of patients who received a 200 mg once daily dose. Overall, the most commonly reported serious adverse events for patients in the primary safety analysis and for all patients, respectively, were pneumonia (8.4%, 5.4%), dyspnea (1.2%, 3.8%), lung infection (1.2%, 3.2%), cellulitis (1.2%, 1.6%), acute kidney disease (2.4%, 1.6%), and sepsis (2.4%, 1.6%). A total of 7 patients (3.8%) with chronic GVHD experienced serious adverse events that were considered to be treatment-related.

The most common adverse reactions, reported in 10% of patients or higher, included infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, decreased phosphate, increased gamma-glutamyl transferase, increased alkaline phosphatase, decreased lymphocytes, hypertension, rash, and pruritus. A fatal adverse reaction related to belumosudil was reported in one patient with severe nausea, vomiting, diarrhea and multi-organ failure.

Based on the mechanism of action of belumosudil, anticipated adverse effects included impaired wound healing, infection and hyperbilirubinemia. In total, 116 patients (62.4%) reported at least one TEAE associated with infections. Respiratory infections were the most frequently reported, including upper respiratory tract infection (56 patients; 30.1%), pneumonia (17 patients; 9.1%) and influenza (11 patients; 5.9%).

Elevated levels of gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were observed in patients in the primary safety analysis group (receiving 200 mg once daily). The majority of cases were mild in severity (Grade 1) and resolved with few drug discontinuations, drug interruptions, or dose reductions. None of these events were found to be serious.

None of the 186 patients included in the overall safety database met the criteria for Hy’s law, defined as ALT or AST ≥3 × the upper limit of normal (ULN) and total bilirubin >2 × ULN. Monitoring of liver function is a standard clinical practice in hematopoietic stem cell transplant (HSCT) recipients, and it is also recommended that monthly liver function tests be performed for the duration of use of Rholistiq. The hepatic findings are confounded by the pathophysiology of chronic GVHD and concomitant medications used.

The most commonly reported gastrointestinal TEAEs included nausea (53 of 186 patients; 28.5%), diarrhea (75 of 186 patients; 30.6%), and vomiting (33 of 186 patients; 17.7%). The reported events were mainly of Grade 1 or 2 in severity. Events of diarrhea and vomiting each led to treatment interruption in 4 patients (2.2%) with nausea leading to treatment interruption in 3 patients (1.6%). These findings were likely confounded by the patients’ underlying chronic GVHD and concomitant medications.

Hematological adverse events, including anemia, neutropenia, leukopenia, and thrombocytopenia, were commonly reported among patients with chronic GVHD treated with Rholistiq. The incidences of hematological TEAEs were 14.5% in the 83 patients from the primary safety analysis group and 16.7% in all 186 patients in the safety database. The most frequently reported event was anemia (12% in the primary safety analysis group and 11.3% in all 186 patients).

Cases of prolongation of the corrected QT interval (QTc prolongation) were reported in the primary safety analysis group. However, there were no reported events of torsades de pointes, sudden death, ventricular tachycardia, ventricular fibrillation, ventricular flutter, or seizures. No dedicated studies have been conducted to evaluate the effects of Rholistiq on the QTc interval.

Overall, the reviewed safety data indicate that Rholistiq has an acceptable tolerability in patients with chronic GVHD, a serious and life-threatening disease. Treatment-related and treatment-emergent adverse events were common, which is expected in a complex population with a significant burden of disease and long-term immunosuppression. Most treatment-related adverse events were mild and reversible. Important safety signals for belumosudil include infection, gastrointestinal toxicity, hepatotoxicity and cytopenia.

For more information, refer to the Rholistiq Product Monograph, approved by Health Canada and available through the Drug Product Database.