Summary Basis of Decision for Olumiant

Clinical Pharmacology

The clinical pharmacology included reports on the human pharmacodynamic and pharmacokinetic studies. The clinical pharmacological data support the use of Olumiant for the recommended indication.

Olumiant contains the medicinal ingredient baricitinib which belongs to a group of medicines called Janus kinase (JAK) inhibitors. Baricitinib attaches to JAK enzymes (mainly JAK1 and JAK2) and can help reduce the swelling and tenderness in people with rheumatoid arthritis (RA).

The absolute bioavailability of baricitinib is approximately 80% and baricitinib shows an approximate dose proportionality between clinical doses of 2-20 mg once daily (QD). Baricitinib is moderately bound to plasma proteins (approximately 50%) and predominantly cleared renally and eliminated in the urine as parent drug (75%), while hepatic metabolism accounts for 6%. Comparison of pharmacokinetic data between healthy volunteers and rheumatoid arthritis (RA) patients at the baricitinib dose of 4 mg QD demonstrated that the maximum plasma concentration was approximately 1.46-fold higher, the area under the concentration-time curve for a dosing interval was approximately 2-fold higher, and the terminal elimination half-life was 1.25 times longer in RA patients at steady state compared to healthy volunteers. The apparent clearance was also approximately 50% reduced in RA patients compared to healthy volunteers.

Co-administration of baricitinib with probenecid (an organic anion transporter 3 inhibitor) increased the exposure of baricitinib two-fold. In RA patients, there is a risk of added immunosuppression when baricitinib is co-administered with potent immunosuppressant drugs (e.g., azathioprine, tacrolimus, and cyclosporine). Hence, Olumiant is not recommended for co-administration with organic anion transporter 3 inhibitors or potent immunosuppressants.

Renal function significantly alters baricitinib exposure. Based on the 2 mg QD dose being the only dose supported by a favourable benefit-risk profile, Olumiant is not recommended for use in patients with an estimated glomerular filtration rate of less than 60 mL/min/1.73 m² (moderate to severe renal impairment and end-stage renal disease). There is no available safe dose to permit dose adjustment in these patients. No dose adjustment of Olumiant is necessary in patients with mild renal impairment.

The use of Olumiant has not been studied in patients with severe hepatic impairment and is therefore not recommended. No dosage adjustment of Olumiant is necessary in patients with mild or moderate hepatic impairment.

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

Clinical Efficacy

The clinical efficacy of Olumiant (baricitinib) was assessed in four pivotal Phase III studies in patients ≥18 years with active rheumatoid arthritis (RA) diagnosed according to American College of Rheumatology (ACR) criteria. The New Drug Submission for Olumiant was filed with the intentions of getting authorization for the use of two strengths of Olumiant tablets, 2 mg and 4 mg. While all of four pivotal studies included the 4 mg once daily (QD) dose of baricitinib, only two of the four Phase III studies (Study RA-BUILD and Study RA-BEACON) assessed the efficacy of Olumiant 2 mg QD. The four Phase III studies ranged in duration from 24 weeks to 52 weeks. In addition to the two 24-week studies (Study RA-BUILD and Study RA-BEACON), there was a 52-week study (number of patients [n] = 1,305) with methotrexate inadequate responders (MTX-IR). This study compared baricitinib 4 mg QD as an add-on to methotrexate and ≤1 conventional disease-modifying anti-rheumatic drugs (cDMARDs) to adalimumab 40 mg once every 2 weeks (Q2W) and placebo. Also, there was a 48-month long-term extension study (n = 2,539) to assess long-term safety and tolerability of baricitinib in patients who had completed a previous baricitinib RA study and the secondary objective was to assess the maintenance of efficacy. Interim efficacy results for this study were also submitted. Upon completion of the clinical review, Health Canada recommended the dose of Olumiant 2 mg QD for the indication approved by Health Canada.

Study RA-BUILD

Study RA-BUILD (n = 684) was a 24-week, Phase III randomized, double-blind, placebo-controlled, double-dummy, international, multicentre, outpatient study that compared the efficacy and safety of 2 mg (n = 229) and 4 mg (n = 227) QD doses of oral baricitinib to placebo (n = 228), in combination with cDMARDs, including methotrexate, for the treatment of moderate to severe RA. Patients had not been previously treated with a biologic disease-modifying anti-rheumatic drug (bDMARD). Inadequate responders could be rescued from Week 16; patients receiving placebo or baricitinib 2 mg were switched to baricitinib 4 mg treatment for the remaining weeks. The primary efficacy measure was a 20% improvement in ACR response criteria (ACR20) at Week 12.

Study RA-BUILD met its primary objective and all major secondary objectives at Week 12 for both baricitinib doses. The baricitinib groups demonstrated statistically significant improvements in numerous other accepted measures of RA disease activity and physical function. Study RA-BUILD was not powered to compare the baricitinib 4 mg vs. the baricitinib 2 mg dose, but the data showed a better numerical response for the 2 mg dose over the 4 mg dose for most efficacy endpoints. Specifically, compared to placebo, the ACR20 response rate at Week 12 (using nonresponder imputation) was numerically greater for baricitinib 2 mg over baricitinib 4 mg (65.9% vs. 61.7%, respectively), with a statistically significant improvement observed for both baricitinib groups (difference vs. placebo p≤0.001).

A similar trend was observed for many of the major secondary and other key efficacy endpoints, with a slightly greater improvement for baricitinib 2 mg compared to baricitinib 4 mg, including change from baseline to Week 12 in Health Assessment Questionnaire-Disability Index (HAQ-DI), Simplified Disease Activity Index (SDAI) ≤3.3 (remission) responder rate, duration of morning joint stiffness, the disease activity score for 28 joints (DAS28-ESR) <2.6, HAQ-DI improvement ≥0.22, HAQ-DI improvement ≥0.3, Clinical Disease Activity Index (CDAI) ≤2.8 (remission) response rate, and ACR/European League Against Rheumatism (ACR/EULAR) Boolean remission rate. Otherwise, results for baricitinib 2 mg were numerically similar compared to baricitinib 4 mg for some additional efficacy measures at Week 12, including severity of morning joint stiffness, the 50% improvement in ACR response criteria (ACR50), 70% improvement in ACR response criteria (ACR70), worst tiredness numerical rating scale (NRS), worst joint pain NRS, the 28 diarthrodial joint count for high sensitivity C-reactive protein (DAS28-hsCRP) <2.6, DAS28-ESR ≤3.2, and CDAI ≤10.0.

Radiographic structural joint damage was an exploratory endpoint in this study and was evaluated in 596 patients. Compared to placebo, a decrease in progression was observed from baseline to Week 24 for both baricitinib dose groups with a greater numerical response in the 4 mg group compared to the 2 mg group. Only this study provided radiographic response data for the baricitinib 2 mg dose, thus corroborative evidence from another study was not available.

Study RA-BEACON

Study RA-BEACON (n = 527) was a 24-week, Phase III, randomized, double-blind, placebo-controlled, double-dummy, international, multicentre, outpatient study comparing the efficacy and safety of 2 mg (n = 174) and 4 mg (n = 177) QD doses of oral baricitinib to placebo (n = 176), in combination with cDMARDs (with or without methotrexate [MTX]), for the treatment of moderate to severe RA during a 24-week treatment period. Study RA-BEACON was conducted in patients who had an inadequate response or intolerance to a biologic DMARD (bDMARD-IR), a patient population typically considered more difficult-to-treat because of long duration of disease and previous treatment failure on a bDMARD. Eligible patients had moderate to severe RA, had an inadequate response or intolerance to tumor necrosis factor inhibitors (TNF-α inhibitors), a bDMARD, and were on concomitant cDMARD therapy. Inadequate responders could be rescued beginning at Week 16; patients receiving placebo or baricitinib 2 mg were switched to baricitinib 4 mg treatment for the remaining 24 weeks.

Study RA-BEACON met its primary objective (ACR20 responder rate at Week 12, using non-responder imputation); however, only the first two of the major secondary objectives were met (change from baseline to Week 12 in HAQ-DI and DAS28-hsCRP) considering the sequential testing approach employed in this study. Ignoring the multiplicity rules, in Study RA-BEACON and in contrast to Study RA-BUILD, the data showed that a numerically greater response was achieved with the baricitinb 4 mg dose over the 2 mg dose for most efficacy endpoints. Specifically, results for the primary endpoint indicated a numerically greater response rate for baricitinib 4 mg vs. baricitinib 2 mg (55.4% vs. 48.9%, respectively), with a statistically significant improvement observed for both baricitinib groups (difference vs. placebo p≤0.001).

A similar trend was observed for the change from baseline to Week 12 in HAQ-DI, DAS28-hsCRP, ACR50, DAS28-hsCRP ≤3.2, DAS28-hsCRP <2.6, SDAI ≤11.0 and CDAI ≤10.0 responder rate, with a statistically significant response observed at Week 12 for both doses but with a greater magnitude of improvement with the 4 mg dose. For the major secondary endpoint of remission based on the SDAI ≤3.3 response rate, CDAI ≤2.8 response rate, and ACR/EULAR Boolean remission rate, a statistically significant difference versus placebo was not observed for either baricitinib dose at Week 12.

Joint structure was not assessed in Study RA-BEACON.

Overall Analysis of Efficacy

The original drug submission provided efficacy data from four Phase III studies for the treatment of moderate to severe RA.

The proposed dosing by the sponsor for Olumiant (baricitinib) was 4 mg QD, with a dose of 2 mg QD in patients with estimated glomerular filtration rate (eGFR) between 30 and 60 mL/min/1.73 m² and in patients taking organic anionic transporter 3 (OAT3) inhibitors with a strong inhibition potential, such as probenecid.

Compared to placebo, baricitinib was efficacious in both RA populations, cDMARD-IR and bDMARD-IR. Specifically, in Study RA-BUILD and Study RA-BEACON, baricitinib 2 mg and 4 mg doses resulted in statistically significant improvements on the primary objective of ACR20 compared to placebo. However, there was no consistent finding between these two studies to conclude greater efficacy with baricitinib 4 mg over the 2 mg dose.

The submitted clinical efficacy data for the baricitinib 2 mg QD dose was considered insufficient to clearly establish its relative role vs. the 4 mg QD dose in the context of the following:

• Baricitinib 2 mg was evaluated only in two of the four submitted Phase III controlled pivotal studies and these two studies were conducted in different patient populations. Study RA-BUILD was conducted in RA patients with an inadequate response or intolerance to cDMARDs and Study RA-BEACON was conducted in RA patients with an inadequate response or intolerance to bDMARDs.
• Neither Study RA-BUILD nor Study RA-BEACON were powered to compare the efficacy of the 4 mg dose with the 2 mg dose.
• The available efficacy data in pivotal studies Study RA-BUILD and Study RA-BEACON demonstrated inconsistent benefit for the baricitinib 4 mg dose over the 2 mg dose. None of these studies were designed to assess the potential incremental benefit in clinical response when escalating from an initial dose of baricitinib 2 mg to baricitinib 4 mg.
• Limited efficacy data were provided to support the recommendation of the baricitinib 2 mg dose in RA patients with an eGFR between 30-60 mL/min/1.73 m². In the two Phase III studies in which the 2 mg dose was systematically evaluated (Study RA-BUILD and Study RA-BEACON), patients with an eGFR <40 mL/min/1.73 m² were excluded and the number of patients with moderate renal impairment (eGFR <60 mL/min/1.73m²) in the baricitinib 2 mg group was very limited (<10% of the study population; n [%] = 30 [7.7]).

Based on the review of the four Phase III studies, three major concerns were identified. The first concern was based on uncertainty regarding the relative role for the 2 mg QD dose compared to the 4 mg QD dose of Olumiant in patients with moderate to severe RA, from both an efficacy and safety perspective. The two other concerns were dose-related safety issues including the potential for thromboembolic events. As a result, a Notice of Non-Compliance (NON) was issued.

In response to the NON, several post-hoc analyses from the studies previously reviewed in the original submission were provided. These analyses were not considered to provide rigorous evidence and were limited based on their exploratory nature. Moreover, they failed to show a consistently significant benefit of the 4 mg QD dose over the 2 mg QD dose across the studies. While there were some post-hoc analyses supporting that the 4 mg QD dose performed better than the 2 mg QD dose for most refractory patients, other analyses suggested that the 2 mg QD dose tended to be better than the 4 mg QD dose.

The comparative superior efficacy of baricitinib 4 mg QD to adalimumab was also presented in the response to the NON to support the 4 mg QD dosing regimen. However, comparison between baricitinib and adalimumab was done in only one study and not replicated in the clinical program nor was the 2 mg QD dose evaluated against adalimumab. Therefore, no conclusions could be drawn regarding the relative efficacy of the 2 mg QD baricitinib dose compared to adalimumab, and it is possible the 2 mg QD dose would have performed as well as the 4 mg QD baricitinib dose against this comparator.

The effect on structural joint damage was evaluated with more data for the 4 mg QD dose than for the 2 mg QD dose. Due to only one study (Study RA-BUILD) investigating this claim for the 2 mg QD dose, and the inherent study design limitations within this trial (considered an exploratory endpoint), no conclusions can be drawn regarding the effect of the 2 mg QD dose on progression of structural joint damage. The data submitted was also not adequate to conclude that the 4 mg QD dose was superior to the 2 mg QD dose for the prevention of structural damage.

An alternative dosing strategy was proposed to allow for approval of both the 2 and 4 mg QD doses. However, this dosing strategy was not supported by the overall clinical trial program and it was based on limited data from a select group of patients. It was argued that the 4 mg QD dose showed a more rapid onset of action than the 2 mg QD dose based on the evaluation of patient reported outcomes from daily diary assessments. However, these data are considered to be exploratory and did not support conclusions supporting rapidity of onset.

Interim data from the 48-month long-term extension study suggested that effectiveness of the 2 mg and 4 mg QD dose was generally sustained during 48 weeks of additional treatment.

Based on the additional data provided in the response to the NON, both the 2 and 4 mg QD doses of baricitinib demonstrated efficacy compared to placebo in RA patients. However, there was an absence of convincing efficacy evidence that the 4 mg QD dose provided meaningful added benefit over the 2 mg QD dose.

Overall, the clinical data supported a favourable benefit-risk profile for the 2 mg QD dose of Olumiant, in combination with methotrexate (MTX), for reducing the signs and symptoms of moderate to severe RA in adult patients who have responded inadequately to one or more disease-modifying anti-rheumatic drugs. Olumiant may be used as monotherapy in cases of intolerance to MTX.

Indication

The originally proposed indication in the New Drug Submission filed in March 2016 was as follows:

• Olumiant (baricitinib) is indicated for the treatment of moderate to severe rheumatoid arthritis (RA) in patients who are naïve to, have responded inadequately to, or who are intolerant to disease-modifying anti-rheumatic drugs (including conventional and biologic DMARDs).
• Olumiant may be used as monotherapy or in combination with conventional synthetic DMARDs including methotrexate (MTX).
• Olumiant has been shown to inhibit progression of structural joint damage as measured by X-ray, improve physical function and induce clinical remission.

The proposed indication, as presented in the response to the NON, was as follows:

• Olumiant (baricitinib) is indicated for the treatment of moderate to severe rheumatoid arthritis (RA) in patients who have responded inadequately to or who are intolerant to one or more disease-modifying anti-rheumatic drugs (including conventional and biologic DMARDs).
• Olumiant may be used as monotherapy or in combination with conventional synthetic DMARDs including methotrexate (MTX).
• Olumiant has been shown to inhibit progression of structural joint damage as measured by X-ray, improve physical function and induce clinical remission.

Based on the review of submitted data, Health Canada revised the indication to:

• Olumiant (baricitinib), in combination with methotrexate (MTX), is indicated for reducing the signs and symptoms of moderate to severe rheumatoid arthritis (RA) in adult patients who have responded inadequately to one or more disease-modifying anti-rheumatic drugs (DMARDs).
• Olumiant may be used as monotherapy in cases of intolerance to MTX.

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

Clinical Safety

The New Drug Submission (NDS) for Olumiant provided safety data from a total of 3,464 patients with RA who were treated with Olumiant, representing 4,212 patient-years of exposure. Data from one Phase I study, three Phase II dose-ranging studies, and four pivotal Phase III studies and unblinded interim data from an ongoing Phase III long-term extension study were pooled in a variety of analysis sets to assess the safety of Olumiant in patients with moderate to severe rheumatoid arthritis. The pivotal Phase III studies were all multicentre, randomized, double-blind, double-dummy, placebo- and/or active-controlled and ranged in duration from 24 to 52 weeks. The mean age for the patients treated with baricitinib was 52.9 years (range 18-87 years). The majority of patients were <75 years of age (3,387 patients, 97.8%), with 77 patients (2.2%) ≥75 years. The majority of patients (79.0%) were female and White (66.3%). The mean time from symptom onset of RA was 8.6 years (range 0.04 to 56.42 years) and mean time from RA diagnosis was 7.6 years (range 0.02 to 56.42 years).

The NDS for Olumiant was filed with the intentions of getting authorization for the use of two strengths of Olumiant tablets, 2 mg and 4 mg. In the NDS, the proposed dose by the sponsor for the treatment of moderate to severe RA was Olumiant (baricitinib) 4 mg QD with a 2 mg QD dose proposed for some patients (including patients with an estimated glomerular filtration rate [eGFR] between 30 and 60 mL/min/1.73 m² and in patients taking OAT3 inhibitors with a strong inhibition potential, such as probenecid).

Safety issues were found to be dose-related up to Week 16 and/or Week 24 in the controlled Phase II/III pooled data sets, and over all treatment periods in extended analyses, with a greater incidence in the baricitinib 4 mg group vs. 2 mg group. The safety issues included treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and severe TEAEs; temporary or permanent discontinuations due to AEs; TEAE infections; serious infections; infections that led to permanent or temporary discontinuation of study drug and infections that required antimicrobial treatment, including herpes zoster; venous thromboembolism (VTE); increases in creatine phosphokinase (CPK), low-density lipoprotein (LDL) cholesterol, total cholesterol, triglycerides, aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin, creatinine, platelets, and lymphocyte counts. Dose-related decreases in eGFR, creatinine clearance, hemoglobin, neutrophil count, eosinophil count, basophil count, immunoglobulins, and glucose were also seen. Treatment-emergent high systolic and diastolic blood pressure (SBP and DBP) were also dose-dependent.

Nausea and herpes simplex were commonly reported at a frequency of ≥1% and more often with baricitinib 4 mg and/or baricitinib 2 mg vs. placebo. Additional notable adverse events or negative safety trends associated with baricitinib included vomiting, upper respiratory tract infections, potential opportunistic infections including pneumocystis pneumonia, tuberculosis, viral reactivation (Cytomegalovirus and Epstein-Barr virus), interstitial lung disease, decrease in natural killer cells, and decrease in serum immunoglobulins (IgA, IgG and IgM). The incidence of fatal SAEs, hospitalization due to SAEs, life-threatening SAEs, and AEs leading to study medication discontinuation was highest in the 75 to 84 years subgroup vs. the <65 years or 65 to 74 years subgroups.

There was an imbalance in the number of cases of venous thromboembolic/arterial thromboembolic (VTEs/ATEs) events with higher rates in baricitinib-exposed patients (with the majority taking ≥4 mg doses) vs. control-treated patients. The imbalance in cases of thromboembolism combined with an identified risk of elevated platelets/thrombocytosis seen with Olumiant but not for another JAK inhibitor already available in Canada for treatment of RA (Xeljanz [tofacitinib]), was identified as a major concern.

A NON was recommended for the submission as the relative role for the 2 mg QD dose compared to the 4 mg QD dose of Olumiant in patients with moderate to severe RA was unclear both in terms of safety and efficacy. There was also insufficient data provided to support clinical efficacy, safety and exposure for the baricitinib 2 mg QD dose in patients with renal impairment, or as an alternative dose for some patients, as proposed in the Olumiant Product Monograph.

The response to the NON provided a safety update which included an integrated baricitinib database with an increase from 3,464 RA patients and 4,212 patient-years of exposure (PYE) from the initial submission to 3,492 RA patients and 7,860 PYE for the response to the NON. New data from 278 patients with RA (212.6 PYE) and 75 patients with atopic dermatitis were also provided.

The updated safety data showed a continued dose-response pattern, indicating higher exposure-adjusted incidence rates in the 4 mg QD dose vs. the 2 mg QD dose, for TEAEs, SAEs, discontinuations (temporary and permanent), severe TEAEs, TEAE infections, serious infections, infections that led to permanent or temporary discontinuation, infections requiring antimicrobial treatment, and laboratory parameters (including CPK >5 times the upper limit of normal [X ULN], LDL cholesterol increased ≥130 mg/dl, total cholesterol increased ≥500 mg/dL, creatinine >1.5 X ULN, low eGFR, thrombocytosis >600,000 cells/mm³, and low lymphocyte count). In addition, the majority of VTE and ATE cases occurred in patients taking the 4 mg QD dose of baricitinib, regardless of the original randomized treatment arm. Exposure adjusted incidence rates for VTEs were higher for baricitinib 4 mg QD compared to baricitinib 2 mg QD. Exposure adjusted incidence rates for ATEs were similar for bariticitinb 4 mg QD compared to baricitinib 2 mg QD. Based on the safety data in the NDS, including the data provided in the response to the NON, there was insufficient evidence to dismiss increased safety concerns with the higher strength dose (4 mg QD) relative to the lower dose (2 mg QD).

The case-level and integrated analyses provided with the response to the NON suggest that an overall increased risk of VTE cannot be excluded. In at least one integrated dataset, there also remains a suggestion of an imbalance of ATE cases that included major adverse cardiac events (MACE) in baricitinib versus placebo-treated patients in the placebo-controlled portions of the studies, although the total number of cases was small.

The potential risk of VTE and unknown risk of ATE and/or MACE can at this time be reasonably managed with appropriate product labelling, in addition to close follow-up in the post-market period in accordance with a risk management plan. Further post-marketing observational studies are planned to characterize ATE, MACE and other cardiovascular events over long term exposure with annual reports planned for at least one of the proposed post-market observational studies. The issue is also to be monitored further with an ongoing external Thrombosis Safety Advisory Committee and additional post-market pharmacovigilance activities.

While efficacy was supported for both the 2 mg and 4 mg doses for patients who had an inadequate response to one or more DMARDs, there was insufficient evidence provided in the response to the NON to support a gain in efficacy with the 4 mg dose, compared to the 2 mg dose. Approving 2 mg as the recommended dose of Olumiant, and limiting the indication to second-line use, provides a safe and effective treatment option for patients with moderate to severe RA. Safety risks with the 2 mg dose are considered manageable through risk mitigation strategies which sufficiently convey the risks and provide information and guidance for prescribers and patients.

Appropriate warnings and precautions are in place in the approved Olumiant Product Monograph to address the identified safety concerns. Warnings of serious infections, malignancies, and thrombosis have been included in a Serious Warnings and Precautions box in the Olumiant Product Monograph.

The Olumiant Product Monograph was revised to include new restrictions and provide information about safety concerns, including the addition of text on thrombosis. The indication recommended for approval reflects the pivotal data supporting the 2 mg dose while not permitting study populations (drug naïve) or claims (e.g. delay in structural joint damage) which are not supported by these data. Based on 2 mg being the only dose supported by a favourable benefit harm uncertainty profile, Olumiant is not recommended for use in patient populations requiring dose reduction based on increased exposure.

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