Summary Basis of Decision for Tavneos

Clinical Pharmacology

Avacopan, the medicinal ingredient in Tavneos, is a complement 5a (C5a) receptor antagonist that selectively blocks the effect of C5a through the C5a receptor 1 (C5aR1, also known as CD88), including blocking neutrophil chemoattraction and activation. Avacopan competitively inhibits the interaction between C5aR1 and C5a.

The clinical pharmacology of avacopan was evaluated in healthy subjects, in subjects with hepatic impairment, and in subjects with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis. The impact of renal impairment on the pharmacokinetics of avacopan was studied using the data from subjects with ANCA-associated vasculitis, because most of these subjects had renal impairment. Additionally, a population pharmacokinetic model was developed to describe the pharmacokinetics of avacopan and its major metabolite, M1, as well as to assess the effect of extrinsic and intrinsic factors on exposure.

The clinical pharmacodynamic program of avacopan aimed to demonstrate inhibition of C5a-C5aR1 signalling. Two endpoints were measured in blood samples taken from avacopan-treated healthy volunteers: CD11b expression in neutrophils and neutrophil chemotaxis. Avacopan treatment was expected to decrease the expression of CD11b in neutrophils and inhibit neutrophil chemotaxis. Ex vivo C5a-induced CD11b upregulation on neutrophils was reduced in a dose-dependent fashion by avacopan following a single 30 mg dose; however, in the group receiving 30 mg avacopan twice daily, the overall expression levels of CD11b were higher than in the single-dose groups, and the trend of CD11b inhibition was less pronounced. Although the chemotaxis of neutrophils was inhibited in some participants, it was not considered a reliable metric to measure C5a-C5aR1 inhibition. This study provided only preliminary data in support of the proposed mechanism of action for avacopan. Given the study limitations (i.e., the lack of validation, statistical analysis, and appropriate data processing), relevant sections of the Tavneos Product Monograph were revised to reflect the factual pharmacodynamic data.

Avacopan was not observed to have any pharmacodynamic effect on the QTc interval, QRS duration, PR interval, or heart rate in healthy volunteers who received avacopan at a dose of 30 mg twice daily (i.e., the therapeutic dose) for 7 days, followed by 100 mg twice daily (i.e., 3.3 times the therapeutic dose) for an additional 7 days.

The pharmacokinetics of avacopan and its metabolite M1 was described across Phase I, II, and III studies, as well as in the population pharmacokinetic model. In healthy volunteers, the pharmacokinetic profile of avacopan was approximately dose linear, with a dose-proportional increase in systemic exposure in the dose range of 10 mg to 30 mg and a slightly more than dose-proportional increase in the dose range of 30 mg to 100 mg. The population pharmacokinetic model reasonably described the pharmacokinetics of avacopan and its metabolite M1 in patients with ANCA-associated vasculitis. Therefore, major pharmacokinetic parameters in patients with ANCA-associated vasculitis were estimated using this model.

Avacopan is rapidly absorbed following oral administration, with maximum plasma concentration (C_max) achieved within 2.5 hours. Absorption after oral administration of 100 mg of avacopan was at least 93.3%. After reaching the C_max, plasma avacopan concentrations declined in a multiphasic manner. The predominant component observed in plasma samples was avacopan itself, accounting for approximately 18% of the total plasma radioactivity, followed by M1, accounting for 11.9% of the total plasma radioactivity. After oral administration, the primary elimination pathway for avacopan is hepatic metabolism by cytochrome P450 (CYP) 3A4-mediated oxidation, followed by biliary excretion of the metabolites into feces.

Population pharmacokinetic analysis found that the exposures of avacopan and metabolite M1 were influenced by age; however, the impacts were not significant enough to warrant dose adjustment. The analysis further found that the exposures of avacopan and metabolite M1 were not significantly impacted by race or gender in subjects with ANCA-associated vasculitis.

The effect of hepatic impairment on avacopan exposure was evaluated in a dedicated study and in the population pharmacokinetic model. Overall, no dose adjustment is recommended for patients with mild or moderate hepatic impairment. Avacopan has not been studied in patients with cirrhosis or severe hepatic impairment (Child-Pugh Class C); therefore, it is not recommended for use in these patient populations.

A specific study in patients with renal impairment was not conducted, as over 85% of patients with ANCA-associated vasculitis in the Phase II and III studies had mild to severe renal impairment. The population pharmacokinetic model estimated that patients with ANCA-associated vasculitis with renal impairment had, on average, 21% to 42% higher exposure levels of avacopan compared to patients with normal renal function. An ethnobridging study involving healthy Japanese and Caucasian subjects showed no remarkable differences in plasma pharmacokinetic profiles of avacopan or its metabolite M1 following single- or multiple-dose administration of avacopan.

Avacopan is a substrate of CYP3A4. In a dedicated drug-drug interaction study, co-administration of avacopan and midazolam, a CYP3A4 substrate, resulted in an increase of approximately 81% and 55% of the area under the concentration-time curve (AUC) from time zero extrapolated to infinity (AUC_0-∞) and C_max of midazolam, respectively. Co-administration with celecoxib, a CYP2C9 substrate, resulted in an increase of approximately 15% and 64% of the AUC_0-∞ and C_max of celecoxib, respectively. Accordingly, the Tavneos Product Monograph includes recommendations for dose reduction of sensitive CYP3A4 substrates with narrow therapeutic windows.

Co-administration of avacopan and itraconazole, a strong CYP3A4 inhibitor, resulted in an increase in the AUC to the end of the dosing period (AUC_0-tau) and the C_max of avacopan by approximately 119% and 87%, respectively, whereas the AUC_0-tau and C_max of M1 increased slightly, by approximately 19% and 3%, respectively. Therefore, the Tavneos Product Monograph recommends reducing the dose of Tavneos (to 30 mg once daily) for patients taking strong CYP3A4 inhibitors.

Co-administration with rifampin, a CYP3A4 inducer, resulted in a decrease in the AUC_0‑∞ and C_max of avacopan by approximately 93% and 79%, respectively. The AUC_0-∞ and C_max of M1 decreased similarly by approximately 93% and 73%, respectively. Co-administration of avacopan with a strong CYP3A4 inducer is anticipated to have a substantial effect on the pharmacokinetics of avacopan and its metabolite and should be avoided.

No dedicated drug-drug interaction study was conducted in patients with ANCA-associated vasculitis co-administered avacopan and prednisone. In two Phase II studies in patients with ANCA-associated vasculitis, avacopan did not appear to impact the exposure of prednisone and its metabolite prednisolone. Overall, there was no strong evidence to suggest a potential interaction between avacopan and glucocorticosteroids both in vitro and in vivo.

The available clinical pharmacology data support the use of avacopan for the specified indication.

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

Clinical Efficacy

The efficacy of Tavneos was evaluated in a 52-week, randomized, double-blind, active-controlled, pivotal Phase III trial (ADVOCATE) conducted in 330 patients with newly diagnosed or relapsing active ANCA-associated vasculitis.

Patients were randomized in a ratio of 1:1 in two treatment arms. In the Tavneos treatment arm (166 patients), Tavneos was used at a dose of 30 mg twice daily for 52 weeks as an adjunctive therapy to the standard of care at the time of the clinical trial (immunosuppressant cyclophosphamide or rituximab in the induction phase; in the maintenance phase, cyclophosphamide was replaced mainly by azathioprine after 13 weeks). In the prednisone-tapering arm (164 patients), oral prednisone was given according to a tapering plan (tapered from 60 mg/day to 0 mg/day over 20 weeks) with the aforementioned background immunosuppressive therapy. Patients in both treatment arms (i.e., 86% of patients in the prednisone-tapering arm and 83% of patients in the Tavneos treatment arm) received outside-of-study supplied glucocorticoids for the treatment of active vasculitis or for other reasons at the discretion of the investigator.

The two primary endpoints of the trial were: i) remission at Week 26; defined as a Birmingham Vasculitis Activity Score (BVAS) of zero and no glucocorticoids for ANCA-associated vasculitis within 4 weeks before Week 26, and ii) sustained remission at Week 52; defined as remission at Week 26 and Week 52, without relapse through Week 52, and no glucocorticoids for ANCA-associated vasculitis within 4 weeks before Week 52. The endpoints were tested for non-inferiority and superiority.

The percentage of patients achieving induction of remission at Week 26 was 72.3% in the Tavneos arm and 70.1% in the prednisone-tapering comparator arm. These results showed statistically significant (p<0.0001) non-inferiority of Tavneos versus the comparator in the endpoint of disease remission at Week 26. Statistically significant superiority of Tavneos versus the comparator was not demonstrated for this endpoint.

Sustained remission at Week 52 was achieved by 65.7% of patients in the Tavneos arm and 54.9% of patients in the prednisone-tapering comparator arm. Tavneos was shown to be statistically significantly (p = 0.0066) superior to the comparator with respect to the endpoint of sustained remission at Week 52.

Overall, data from the pivotal trial support the use of Tavneos as an adjunctive (add-on therapy) to current standard therapy (including glucocorticoids) for severe ANCA-associated vasculitis. Furthermore, the data indicate that treatment with Tavneos does not eliminate the need for use of glucocorticoids. These conclusions are reflected in the authorized indication for Tavneos (see below).

Indication

The New Drug Submission for Tavneos was filed by the sponsor with the following indication:

Tavneos (avacopan) is indicated for treatment of adult patients with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis or microscopic polyangiitis).

Health Canada revised the proposed indication to reflect the context of use of Tavneos in the pivotal trial, i.e., as an adjunctive therapy for severe active ANCA-associated vasculitis in combination with standard background therapy including glucocorticoids. Furthermore, the proposed indication was reworded to include the fact that Tavneos was not demonstrated to eliminate glucocorticoid use. Accordingly, Health Canada approved the following indication:

Tavneos (avacopan) is indicated for the adjunctive treatment of adult patients with severe active anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (granulomatosis with polyangiitis [GPA] and microscopic polyangiitis [MPA]) in combination with standard background therapy including glucocorticoids. Tavneos does not eliminate glucocorticoid use.

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

Clinical Safety

The safety of Tavneos was evaluated primarily based on data derived from the pivotal 52-week Phase III clinical trial (ADVOCATE, described in the Clinical Efficacy section). Additional safety data were obtained from two Phase II clinical trials, which were shorter in duration than the pivotal trial and involved smaller numbers of patients. In the three trials, 239 patients with ANCA-associated vasculitis received at least one dose of Tavneos.

In the pivotal trial, cases of hepatotoxicity (elevation of transaminases and hepatobiliary events, including serious and life-threatening events) were observed among the 166 patients who received Tavneos. Serious adverse reactions of abnormal hepatic function were reported in 1.2% of the patients in the Tavneos treatment arm versus 0% in the comparator treatment arm. Seven patients (4.2%) in the Tavneos treatment arm and two patients (1.2%) in the comparator treatment arm discontinued treatment due to adverse reactions of hepatotoxicity, including hepatobiliary adverse reactions and liver enzyme abnormalities.

Reactivation of hepatitis B virus infection was reported in the Tavneos treatment arm. Additionally, serious infections, including fatal infections, occurred among the Tavneos-treated patients. The most frequently reported serious infections in the Tavneos treatment arm were pneumonia (4.8% versus 3.7% in the comparator treatment arm) and urinary tract infections (1.8% versus 1.2% in the comparator treatment arm).

In the Tavneos treatment arm, two cases of angioedema occurred, including one serious event requiring hospitalization.

There were two deaths in the Tavneos treatment arm (due to worsening of vasculitis and pneumonia) and four deaths in the comparator treatment arm (due to myocardial infarction, infectious pleural effusion, generalized fungal infection, and unknown cause).

Common adverse events reported among the patients who received Tavneos in the pivotal trial included nausea, headache, hypertension, vomiting, diarrhea, nasopharyngitis, upper respiratory infection, urinary tract infection, abdominal pain, pneumonia, sinusitis, rash, and fatigue. In addition, common laboratory abnormalities were elevated liver function tests, elevated creatinine phosphokinase, and leukopenia.

Data on the safety profile of Tavneos beyond 52 weeks of treatment are not available. The sponsor has planned a post-authorization safety study to evaluate the long-term safety of Tavneos (beyond 1 year and up to 36 months) in patients with ANCA-associated vasculitis and to estimate the incidence rates of medical events of special interest, including liver injury, serious infections, malignancies, and cardiovascular events.

Appropriate warnings and precautions are included in the approved Tavneos Product Monograph to address the safety concerns identified in the pivotal trial. Liver function testing and hepatitis B serologic testing are recommended prior to initiation of therapy with Tavneos. Furthermore, Tavneos is not recommended for patients with active, untreated and/or uncontrolled chronic liver disease (e.g., chronic active hepatitis B, untreated hepatitis C, uncontrolled autoimmune hepatitis) and cirrhosis, or in patients with an active serious infection, including localized infections. Relevant monitoring recommendations and specific criteria for a temporary or permanent discontinuation of Tavneos are included in the Tavneos Product Monograph.

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

The medicinal ingredient in Tavneos, avacopan, was evaluated in repeat-dose toxicity studies conducted in rats (for up to 26 weeks in duration), hamsters (for up to 13 weeks in duration) and cynomolgus monkeys (for up to 44 weeks in duration). Avacopan was administered orally (by oral gavage or nasogastric intubation) at doses up to 100 mg/kg twice a day in rats, 500 mg/kg twice a day in hamsters, and 22.5 mg/kg twice a day in monkeys. None of the observed effects were considered adverse. Overall, avacopan was well tolerated up to the highest dose levels employed, with margins of exposure relative to patients with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis of 11.9 and 15.3 (rats), 4.6 and 4.9 (hamsters), and 3.8 and 4.7 (monkeys), for males and females, respectively.

Avacopan was not found to be genotoxic. Carcinogenicity of avacopan was assessed in 104-week studies in rats and hamsters with oral dosing of 10, 30, and 100 mg/kg/day. Studies in both species were terminated early (around weeks 92-98) due to decreased survival in the control group. Neoplastic findings in rats were not considered to be related to avacopan because they fell within historical control ranges. Maximal exposures in rats were 3.7- to 4.8-fold the clinical exposure for avacopan and around the clinical exposure for its major metabolite, M1. No neoplastic findings in hamsters were attributed to avacopan. Maximal exposures in hamster were 5- to 6-fold the clinical exposure for avacopan and around the clinical exposure for M1.

Embryo-fetal developmental toxicity studies were conducted in rabbits and hamsters. Reproductive and developmental effects were observed in both species (e.g., increased rate of abortions in rabbits and skeletal variations in hamsters); however, in general, they were not considered related to avacopan, because they were within historical control ranges or were not dose dependent. Nonetheless, avacopan is not recommended during pregnancy, during breastfeeding, and for women of child-bearing potential not using contraception.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Tavneos Product Monograph. In view of the intended use of Tavneos, there are no pharmacological or toxicological issues within this submission to preclude authorization of the product.

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

The chemistry and manufacturing information submitted for Tavneos has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf life of 36 months is acceptable when the drug product is stored at room temperature (15 ºC to 30 ºC).

Proposed limits of drug-related impurities are considered adequately qualified (i.e., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use limits and/or qualified from toxicological studies).

All sites involved in production are compliant with good manufacturing practices.

None of the non-medicinal ingredients (i.e., excipients, described earlier) found in the drug product are prohibited by the Food and Drug Regulations. Satisfactory information has been provided to establish that the excipient gelatine, which is of animal origin, does not pose a risk of contamination with transmissible spongiform encephalopathy agents.