Summary Basis of Decision for Voydeya

Clinical Pharmacology

The submitted clinical pharmacology data support the use of Voydeya (danicopan) for the specified indication.

Danicopan administered 150 mg three times daily or 200 mg three times daily as an add-on treatment in patients with paroxysmal nocturnal hemoglobinuria (PNH) receiving ravulizumab or eculizumab led to inhibition of the complement alternative pathway activity, reduced plasma Bb fragment levels, and decreased the proportion of circulating erythrocytes with complement component 3 (C3) fragment deposition.

Following oral administration of 150 mg danicopan in patients with PNH, the median time to maximum observed plasma concentration (t_max) was 3.7 hours. The maximum observed plasma concentration (C_max) and the area under concentration-time curve (AUC) showed approximately dose-proportional increases within the clinical dose range (150 mg three times daily to 200 mg three times daily). Limited (less than twofold) systemic accumulation of danicopan was observed following repeated administration compared to a single-dose regimen. The mean half-life of danicopan is approximately 8 hours. It is primarily eliminated via feces, and to a lesser extent, via urine.

Danicopan is metabolized by amide hydrolysis and carbonyl reduction. It is not metabolized to any major extent by cytochrome P450 (CYP) enzymes, which suggests a very low likelihood of Voydeya as a victim of CYP-based drug-drug interactions. Danicopan was shown to be an inhibitor of P-glycoprotein (P-gp). Therefore, concomitant administration of Voydeya with a P-gp substrate known to have a narrow therapeutic range (e.g., digoxin) may require dose adjustment of the P-gp substrate.

The exposure to danicopan (as measured by the AUC and C_max) was higher when the drug was administered concomitantly with food compared to when administered under fasting conditions. However, the differences were not considered to have a meaningful impact on the safety profile and efficacy of the drug. Therefore, Voydeya may be taken without regard to food.

Based on pharmacokinetic data, dose escalation of Voydeya to 200 mg three times a day is not recommended in patients with severe renal impairment. Voydeya has not been studied in patients with end-stage renal disease requiring hemodialysis and in patients with severe hepatic impairment.

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

Clinical Efficacy

The evidence of efficacy of Voydeya as an add-on to ravulizumab or eculizumab for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH) who have residual hemolytic anemia due to extravascular hemolysis is primarily derived from one randomized, double-blind, placebo-controlled study (ALXN2040-PNH-301).

Study ALXN2040-PNH-301 enrolled 86 adults with PNH and clinically evident anemia (defined by hemoglobin less than or equal to 9.5 g/dL [95 g/L] with absolute reticulocyte count of greater than or equal to 120 x 10⁹/L) who were receiving a complement component 5 (C5) inhibitor (ravulizumab or eculizumab). The patients were randomized in a ratio of 2:1 to receive Voydeya or placebo in addition to their background C5 inhibitor for 12 weeks. The starting dose of Voydeya was 150 mg three times a day and could be escalated up to a maximum of 200 mg three times a day depending on the clinical response. After Week 12, all patients from the placebo group were switched to Voydeya as an add-on to their background C5 inhibitor. Then, after Week 24, patients could enter a long-term extension period and continue to receive Voydeya at the same dose received at Week 24 in addition to their background C5 inhibitor.

The primary endpoint of the study was the change in hemoglobin from baseline to Week 12. Key secondary endpoints were the proportion of patients with an increase in hemoglobin levels of at least 2 g/dL at Week 12 in the absence of transfusions, the proportion of patients with transfusion avoidance through Week 12, the change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores at Week 12, and the change from baseline in absolute reticulocyte count at Week 12. Transfusion avoidance was considered to be achieved only by the patients who did not receive a transfusion and did not meet the protocol-specified guidelines for transfusion from baseline through Week 12.

A prespecified interim analysis was performed when 63 participants reached the end of the 12-week, randomized, double-blind, placebo-controlled treatment period (including patients who completed and those who discontinued treatment). The interim analysis set comprised 42 participants from the Voydeya group and 21 participants from the placebo group. Demographic and baseline clinical characteristics were generally balanced between treatment groups. At baseline, the mean age of the patients was 54.3 years (range: 25 to 80 years) and 58.7% of patients were female.

In the Voydeya group, the least squares mean increase in hemoglobin from baseline to Week 12 was 2.94 g/dL compared with 0.50 g/dL in the placebo group. Therefore, the treatment difference (Voydeya group versus placebo group) was 2.44 g/dL (95% confidence interval [CI]: 1.69, 3.20; p<0.0001). Treatment differences were observed as early as Week 1. These results represent a clinically meaningful improvement in hemoglobin levels with the addition of Voydeya to a C5 inhibitor in patients with PNH and hemolytic anemia when compared to a C5 inhibitor alone. Results were generally consistent between patient subgroups (defined by age, sex, number of transfusions prior to screening, hemoglobin level at screening, and background C5 inhibitor).

In the Voydeya group, there were also statistically significant improvements (based on a prespecified hierarchical testing strategy) in the key secondary endpoints compared to the placebo group. The proportion of patients with an increase in hemoglobin levels of at least 2 g/dL at Week 12 in the absence of transfusions was 59.5% versus 0% in the placebo group, and the proportion of patients with transfusion avoidance through Week 12 was 83.3% versus 38.1% in the placebo group. Furthermore, the change from baseline in FACIT-Fatigue scores at Week 12 was 7.97 versus 1.85 in the placebo group, and the change from baseline in absolute reticulocyte count at Week 12 was -83.8 x 10⁹/L versus 3.5 x 10⁹/L in the placebo group.

Other secondary endpoints that showed improvements in the Voydeya group compared to the placebo group were change in the number of red blood cell (RBC) units transfused and transfusion instances during the 12-week treatment compared to the 12 weeks prior to treatment initiation, changes in total and direct bilirubin levels from baseline to Week 12, changes in PNH RBC clone size from baseline to Week 12, and changes in C3 fragment deposition on PNH RBCs from baseline to Week 12. In addition, the proportion of participants who achieved hemoglobin normalization at Week 12 was higher in the Voydeya group. While lactate dehydrogenase (LDH) levels at Week 12 were numerically decreased in the Voydeya group, the treatment difference between Voydeya and placebo did not reach statistical significance.

In patients who crossed over from the placebo group to receive Voydeya after Week 12, the least squares mean change in hemoglobin from baseline at Week 24 was 2.26 g/dL. Reductions in the number of transfusion instances and units transfused, the increase in the proportion of patients with transfusion avoidance, the improvement in the FACIT-Fatigue score, and an increase in the proportion of patients achieving a hemoglobin increase of at least 2 g/dL in the absence of transfusion were consistent with the efficacy findings in the 12-week, randomized, double-blind period.

Supportive data for the efficacy of Voydeya in combination with a C5 inhibitor were provided from a Phase II, open-label, multiple-dose, multicentre study (ACH471-101) in 11 participants with PNH who had an inadequate response to eculizumab monotherapy. In these patients, the mean hemoglobin change from baseline after 24 weeks of treatment with Voydeya as an add-on therapy to eculizumab was 2.39 g/dL, which was considered clinically meaningful. Ten of the 11 participants remained transfusion free at Week 24, and 6 patients remained transfusion free for at least 152 weeks. The results are suggestive of a durable reduction in transfusion needs with the addition of Voydeya to a background C5 inhibitor.

Importantly, a single-arm study of Voydeya monotherapy in untreated patients with PNH (Study ACH471-100) suggested that Voydeya should not be used as monotherapy in patients with PNH, because it did not provide adequate control of intravascular hemolysis (at Day 84, 70% of patients had LDH levels greater than 1.5 times the upper limit of normal).

Overall, the pivotal study (ALXN2040-PNH-301) of Voydeya demonstrated the superiority of Voydeya used in combination with a C5 inhibitor over a C5 inhibitor alone in increasing hemoglobin in patients with PNH who have hemolytic anemia while receiving a C5 inhibitor.

Indication

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

Voydeya (danicopan) is indicated as an add-on to Ultomiris or Soliris for the treatment of signs or symptoms of extravascular hemolysis in adult patients with paroxysmal nocturnal hemoglobinuria.

The proposed indication was revised to more accurately reflect the studied population in the pivotal trial. Accordingly, Health Canada approved the following indication:

Voydeya (danicopan tablets) is indicated as an add-on to ravulizumab or eculizumab for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria who have residual hemolytic anemia due to extravascular hemolysis.

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

Clinical Safety

The assessment of the safety profile of Voydeya as an add-on therapy to ravulizumab or eculizumab for the treatment of adult patients with PNH who have residual hemolytic anemia due to extravascular hemolysis was primarily based on data from the pivotal study (ALXN2040-PNH-301, described in the Clinical Efficacy section).

During the 12-week, randomized, double-blind period of the pivotal study, 57 participants received Voydeya and 29 participants received placebo. In the Voydeya group, 3 participants started on Voydeya 100 mg three times a day; 56 participants started on Voydeya 150 mg three times a day; and for 14 out of the 57 participants, the Voydeya dose was escalated to 200 mg three times a day. The median (range) exposure to Voydeya was 84.0 (23.0 to 85.0) days. During the entire study through the data cut-off date, 80 participants received Voydeya and the overall median (range) exposure to Voydeya was 264.0 (5.0 to 623.0) days.

In the Voydeya group, treatment-emergent adverse events reported in at least 3% of patients and at a higher incidence than in the placebo group in the first 12 weeks of treatment were headache, increased hepatic enzyme (grouped term), vomiting (grouped term), arthralgia, pyrexia, hypertension, pain in extremity, hemolysis, constipation, pancreatitis, coronavirus disease 2019 (COVID-19), urinary tract infection, viral infection, increased blood bilirubin, decreased white blood cell count, myalgia, oropharyngeal pain, and rhinorrhea. Treatment with Voydeya was associated with increases in median total cholesterol and low-density lipoprotein (LDL) cholesterol levels starting at Week 1 of treatment.

Four serious adverse events (irrespective of causality) were reported in three patients who received Voydeya during the placebo-controlled 12-week period. These included pancreatitis, increased blood bilirubin, cholecystitis, and COVID-19.

In the 12-week treatment period, four patients had treatment-emergent adverse events leading to treatment discontinuation: three (5.3%) from the Voydeya group and one (3.4%) from the placebo group. All four treatment discontinuations were due to treatment-emergent adverse events related to hepatic abnormalities. The treatment discontinuation in one of the Voydeya-treated patients was due to the serious adverse events of increased blood bilirubin level and pancreatitis.

No deaths and no meningococcal infections were reported in the study at the time of data cut-off. However, one death due to pneumonia occurred after the data cut-off date.

Additional safety data were obtained from Phase II studies in patients with PNH receiving Voydeya monotherapy or Voydeya in combination with a C5 inhibitor, as well as Phase II studies of Voydeya monotherapy in patients with C3 glomerulopathy (C3G) and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN). In the pooled PNH and C3G/IC-MPGN population, the most commonly reported treatment-emergent adverse events (occurring in at least 10% of patients) were headache (22.3%), pyrexia (21.6%), diarrhea (16.5%), COVID-19 (15.1%), nausea (14.4%), fatigue (12.2%), upper respiratory tract infection (12.9%), anemia (11.5%), arthralgia (10.1%), and oropharyngeal pain (10.1%). Most of these treatment-emergent adverse events were also commonly reported in the pivotal study of Voydeya in patients with PNH. There appeared to be no clinically meaningful differences in the adverse event profile of Voydeya between sexes, racial groups, or age groups.

The evaluation of the potential for drug-induced hepatotoxicity in patients with PNH is confounded by the fact that liver enzyme elevations in these patients may be the result of hemolysis. Notably, in a multiple ascending dose study in healthy volunteers (ACH471-002), Grade 3 and Grade 4 elevations in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) were reported in two participants (one who received Voydeya 500 mg twice daily and one who received Voydeya 800 mg twice daily), suggesting that Voydeya may cause liver enzyme elevations. In addition, in the pooled PNH and C3G/IC-MPGN population of 139 patients who received at least one dose of Voydeya, 17.3% of patients had treatment-emergent adverse events related to liver abnormalities, more than a third of which were considered to be related to treatment. Most occurred during the first 12 weeks of treatment. While 10 potential Hy’s Law cases were identified, none of the cases appeared to be true Hy’s Law cases.

As a complement inhibitor, Voydeya is expected to increase a patient’s susceptibility to serious infections caused by encapsulated bacteria (such as Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type B). This risk, along with a requirement for relevant vaccinations or prophylactic antibiotic therapy, is highlighted in a Serious Warnings and Precautions box in the Voydeya Product Monograph.

Furthermore, based on the mechanism of action of Voydeya, a greater proportion of PNH red blood cells is expected to remain in circulation, increasing the PNH clone size. When an event of breakthrough hemolysis occurs in a patient with a large PNH clone, it has the potential to be more severe due to the larger number of cells susceptible to complement-mediated destruction than in a patient with a smaller PNH clone. In light of the risk of breakthrough hemolysis, if Voydeya treatment discontinuation is necessary, the dose should be tapered before complete treatment cessation.

Overall, the safety profile of the addition of Voydeya to a C5 inhibitor is considered acceptable for the intended patient population. The identified risks have been adequately addressed in the Voydeya Product Monograph, which includes warnings related to the risks of serious infections caused by encapsulated bacteria, hemolysis after Voydeya treatment discontinuation, total cholesterol and LDL cholesterol elevations, and hepatotoxicity, as well as recommendations for relevant precautionary and monitoring measures.

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

Danicopan, the medicinal ingredient in Voydeya, binds reversibly to complement factor D (FD) and selectively inhibits its function. This complement factor is a serine protease that plays an essential role in the activation of the alternative pathway of the complement system. By inhibiting the FD function, danicopan prevents the cleavage of complement factor B into the Ba and Bb fragments required for the formation of the alternative pathway complement component 3 (C3) convertase C3bBb, the generation of downstream effectors including C3 fragments (which act as opsonins), and the amplification of the terminal complement pathway.

In enzymatic assays, danicopan was shown to bind reversibly and with high affinity to the active site of FD, thereby inhibiting the FD catalytic activity. Hemolysis assays and a functional enzyme-linked immunosorbent assay (ELISA) demonstrated that danicopan inhibited complement alternative pathway activity in human serum.

Repeat-dose toxicity, genotoxicity, carcinogenicity, reproductive and developmental toxicity, and phototoxicity studies were conducted to characterize the non-clinical toxicity profile of danicopan.

Danicopan-related reversible hepatobiliary cholestasis was observed in dogs at doses that produced systemic exposures corresponding to five times the exposure at the maximum recommended human dose of 200 mg three times a day (based on the area under the concentration-time curve [AUC]).

Danicopan was not found to be carcinogenic and genotoxic in carcinogenicity and genotoxicity studies, respectively.

Reductions in the male and female fertility and copulation/conception indices were observed in rabbits at systemic exposures corresponding to approximately 11 times the exposure at the maximum recommended human dose of danicopan (based on the AUC). There were no adverse effects of danicopan on organogenesis, embryo-fetal development, or postnatal development in rabbits up to mean maternal systemic exposures corresponding to approximately 15 times the exposure at the maximum recommended human dose (based on the AUC).

Following oral administration from lactation Day 4 to lactation Day 10, danicopan was found in the milk of lactating rabbits at higher concentrations compared to the concentrations measured in the plasma.

Ocular phototoxicity was observed in pigmented rats at systemic exposures to danicopan corresponding to 15 to 28 times the exposure at the maximum recommended human dose (based on the AUC and the maximum observed plasma concentration, respectively). Since danicopan can accumulate in the eye, there is a potential risk of ocular phototoxicity in patients who receive long-term danicopan therapy and are exposed to prolonged ultraviolet radiation without protection.

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

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

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

The 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). The risks relating to the potential presence of nitrosamine impurities in the drug substance and/or drug product are considered negligible or have been adequately addressed (e.g., with qualified limits and a suitable control strategy).

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

None of the non-medicinal ingredients (excipients) in the drug product are prohibited for use in drug products by the Food and Drug Regulations. The excipient lactose monohydrate is derived from milk obtained from healthy animals under the same conditions as milk collected for human consumption. Satisfactory information has been provided to establish that this excipient does not pose a risk of contamination with transmissible spongiform encephalopathy agents. No other excipient is of animal or human origin.