Summary Basis of Decision for Fabhalta

Clinical Pharmacology

Iptacopan binds to complement Factor B and inhibits the alternative complement pathway. This action inhibits the cleavage of the complement component 3 (C3) and the subsequent formation of the membrane attack complex (MAC).

In paroxysmal nocturnal hemoglobinuria (PNH), intravascular hemolysis (IVH) is mediated by the MAC. Under terminal complement inhibition extravascular hemolysis (EVH) emerges and is triggered by C3 fragment opsonization. Iptacopan acts proximally in the alternative pathway of the complement cascade to control both C3 fragment-mediated EVH and MAC-mediated IVH.

The clinical pharmacokinetic and pharmacodynamic profile of iptacopan was mainly characterized in healthy volunteers and patients with PNH. The results of the pharmacokinetic studies indicated that iptacopan was rapidly absorbed after oral administration, with steady state achieved in approximately 5 days after 200 mg twice daily (BID) dosing. Food intake had no clinically meaningful effect on the pharmacokinetics of iptacopan. Fabhalta may be taken with or without food.

Iptacopan showed concentration-dependent binding to plasma proteins due to its high affinity and saturable binding to the target Factor B in the systemic circulation. Consequently, at oral doses between 25 mg and 200 mg BID, the systemic exposure of iptacopan was overall less than dose proportional; however, oral doses of 100 mg and 200 mg were approximately dose proportional.

Results of exposure-pharmacodynamics and exposure-safety analyses of data from clinical studies supported the recommended 200 mg BID dosing regimen in PNH patients.

Iptacopan is primarily eliminated by hepatic metabolism. In a dedicated clinical study, unbound iptacopan exposure (area under the plasma concentration-time curve from 0 to infinity [AUC_inf]) increased by 3.7-fold in the severe hepatic impairment group versus the normal hepatic function group. Fabhalta is not recommended for use in patients with severe hepatic impairment.

Renal excretion is not a major route of elimination for iptacopan. Based on the population pharmacokinetic analysis, mild to moderate renal impairment had no clinically relevant effect on the pharmacokinetics of iptacopan. Until sufficient data become available, no dose recommendations can be given to patients with severe renal impairment or to those on dialysis.

Iptacopan is a substrate of cytochrome P450 (CYP) 2C8. Concomitant use of CYP2C8 inducers or strong CYP2C8 inhibitors may result in clinically relevant changes in iptacopan exposure. In vitro data showed that iptacopan has potential for induction of CYP3A4 and may decrease exposure of sensitive CYP3A4 substrates.

In a QT study in healthy volunteers, single supra-therapeutic iptacopan doses up to 1,200 mg (which provided greater than 4-fold peak concentration of the 200 mg BID dose) had no effect on cardiac repolarization or QT interval.

Overall, the review of clinical pharmacology studies did not identify issues that would preclude the approval of Fabhalta in the intended patient population. Key clinical pharmacology findings, relevant risks, and uncertainties are properly addressed in the Fabhalta Product Monograph approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Fabhalta for the treatment of adult patients with PNH was evaluated in the pivotal Phase III Study APPLY-PNH and in the key supportive Phase III Study APPOINT-PNH.

The APPLY-PNH study was a multicentre, randomized, open-label, active comparator-controlled, parallel group study designed to evaluate the efficacy and safety of Fabhalta in adult patients with PNH who had residual anemia (i.e., a hemoglobin [Hb] level of 10 g/dL [100 g/L] or less) despite previous treatment with a stable dose of an anti- complement component 5 (C5) therapy for a minimum of 6 months prior to randomization. Ninety-seven patients were randomized in an 8:5 ratio to either switch to Fabhalta 200 mg taken orally twice per day (BID; total number [n] = 62), or to remain on their current anti-C5 therapy (total number [n] = 35; eculizumab – n = 23 or ravulizumab n = 12) throughout the duration of the 24-week randomized treatment period. Randomization was stratified based on prior anti-C5 treatment and transfusion history within the last 6 months. Following completion of the 24-week randomized treatment period, all patients were eligible to enroll in a 24-week treatment extension period and receive Fabhalta monotherapy. Subsequently, patients were eligible to enter a separate long-term extension study.

Patients were required to be vaccinated against Neisseria meningitidis and were recommended to be vaccinated against Streptococcus pneumoniae and Haemophilus influenzae type B. If the patient had not been previously vaccinated or if a booster was required, vaccination was administered at least 2 weeks prior to first dosing. If Fabhalta treatment was initiated earlier than 2 weeks after vaccination, antibacterial drug prophylaxis was administered. In total, 97%, 86% and 89% of patients in the Fabhalta arm were vaccinated against Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae type B, respectively, either before or during treatment with Fabhalta. All patients in the Fabhalta arm were vaccinated against meningococcal serotype A, C, W-135, and Y.

The demographics and baseline disease characteristics were generally well balanced between treatment groups. The mean age of enrolled patients was 51.0 years and most patients were female (69.1%). The majority of patients had lactate dehydrogenase (LDH) levels at baseline that were less than or equal to 1.5-times the upper limit of normal, which is expected in patients receiving a stable dose of anti-C5 treatment for at least 6 months. However, more than half of the enrolled patients had a history of transfusion within the last 6 months prior to randomization, and the mean absolute reticulocyte count was elevated at 192.27 x 10⁹/L. The mean time on prior anti-C5 treatment was 3.8 and 4.2 years for Fabhalta and anti-C5 groups, respectively. The baseline mean PNH red blood cell (RBC) clone size (Type II + III) was 64.6% for Fabhalta and 57.4% for the anti-C5 group.

The evaluation of efficacy was based on two primary endpoints to demonstrate superiority of switching to Fabhalta compared to continuing on anti-C5 therapy. These endpoints involved achieving a hematological response after 24 weeks of treatment, without a need for RBC transfusion, and were assessed as: 1) the proportion of patients achieving a sustained increase in Hb levels of 2 g/dL (20 g/L) or higher from baseline (Hb improvement) and/or 2) the proportion of patients achieving sustained Hb levels of 12 g/dL (120 g/L) or higher.

The study met its two primary endpoints. After 24 weeks, adult PNH patients with residual anemia treated with Fabhalta monotherapy 200 mg BID demonstrated statistically significant superiority to those treated with anti-C5 therapy without a need for RBC transfusion. The results indicated a significant difference in response rate of 80.2% (82.3% Fabhalta arm versus [vs.] 2% anti-C5 arm; 95% Confidence Interval [CI]: 71.2, 87.6; p <0.0001) for the number of patients achieving Hb improvement as indicated by a sustained increase of hemoglobin levels of 2 g/dL (20 g/L) or higher from baseline. Furthermore, a significant difference in response rate of 67% (68.8% Fabhalta arm vs. 1.8% anti-C5 arm; 95% CI: 56.4, 76.9; p<0.0001) was demonstrated for the number of patients achieving a sustained increase in Hb level of 12 g/dL (120 g/L).

Fabhalta also showed statistically significant superiority to anti-C5 therapy for the following key secondary endpoints: a 68.9% difference in the number of patients avoiding transfusions between Day 14 and Day 168; an adjusted mean difference of +3.66 g/dL (+36.6 g/L) in Hb level change from baseline between Day 126 and Day 168; an adjusted mean difference of -116.15 x 10⁹/L in absolute reticulocyte counts change from baseline in absolute reticulocyte count between Day 126 and Day 168; an adjusted mean difference of +8.29 points in change from baseline in the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score between Day 126 and Day 168; and an annualized adjusted rate of clinical breakthrough hemolysis with a rate ratio of 0.10.

The APPOINT-PNH Study was a key supportive Phase III, multicentre, single-arm, open-label study in adult PNH patients naive to complement inhibitor therapy (anti-C5 antibody treatment). A total of 40 patients were enrolled to receive Fabhalta 200 mg orally BID during the 24-week open-label core treatment period. Subsequently, patients were eligible to enroll in a 24-week treatment extension period and continue to receive Fabhalta, followed by a separate long-term extension study. Adult patients with a confirmed diagnosis of PNH and an Hb level of 10 g/dL (100 g/L) or less and LDH more than 1.5-times the upper limit of normal were eligible for enrollment.

The mean age of enrolled patients was 42.1 years and a slight majority of patients were male (57.5%). The mean baseline LDH level was 1,698.8 U/L and the mean absolute reticulocyte count was 154.33 x 10⁹/L, both of which are markers of hemolysis.

The primary endpoint of the study was the proportion of patients achieving a sustained Hb increase of 2 g/dL (20 g/L) or higher from baseline without a need for RBC transfusions after 24 weeks. This endpoint was met as Fabhalta treatment resulted in a response rate of 92.2% (95% CI: 82.5, 100.0). The lower bound of the two-sided 95% CI was 82.5%, which exceeded the pre-specified threshold of 15% by a factor of more than five-fold.

For the key secondary endpoints, the response rate for patients achieving an Hb level of 12 g/dL (120 g/L) or higher without a need for RBC transfusion, after 24 weeks was 62.8% (95% CI: 47.5, 77.5). Fabhalta treatment led to a transfusion avoidance rate of 97.6% (95% CI: 92.5, 100.0) between Day 14 and Day 168. The adjusted mean change from baseline in Hb, absolute reticulocyte count, LDH levels, and FACIT-Fatigue scores were also consistent with and supportive of the primary endpoint.

Overall, the efficacy results from pivotal study APPLY-PNH and supportive study APPOINT-PNH adequately demonstrate the ability of Fabhalta to provide benefit for adult patients with PNH who have hemolytic anemia.

Indication

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

Fabhalta (iptacopan hard capsules) is indicated for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH).

Upon review, the proposed indication was revised to reflect the clinical study patient population. Accordingly, Health Canada approved the following indication:

Fabhalta (iptacopan capsules) is indicated as monotherapy in the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH) who have hemolytic anemia.

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

Clinical Safety

The clinical safety of Fabhalta for the treatment of adult patients with PNH was primarily evaluated in the pivotal Phase III APPLY-PNH Study. Additional safety data included pooled data from the pivotal study and supportive studies which included one Phase III study (APPOINT-PNH) and two Phase II studies in patients with PNH.

The safety analysis set for the randomized treatment period of APPLY-PNH included all patients who received at least one dose of study treatment; all 62 patients in the Fabhalta arm were included. The median duration of exposure was 169 days (range: 141 to 171 days) for the Fabhalta group for a total of 28.58 patient years.

Overall, the proportion of patients experiencing treatment emergent adverse events (TEAEs) in the randomized treatment period of APPLY-PNH was comparable between the Fabhalta and anti-C5 treatment groups (Fabhalta: 51/62, 82.3%; anti-C5: 28/35, 80.0%). The most frequently reported TEAEs in the Fabhalta group during the randomized treatment period were: headache (10/62, 16.1%), diarrhea (9/62, 14.5%), nasopharyngitis (7/62, 11.3%) and nausea (6/62, 9.7%). The most commonly reported (in 3% or more of patients) adverse events (AEs) suspected to be related to Fabhalta treatment per investigator assessment were headache (6.5%), arthralgia (4.8%), nausea (4.8%), thrombocytopenia (3.2%), diarrhea (3.2%) and hot flush (3.2%).

In APPLY-PNH, severe AEs in patients treated with Fabhalta were anemia, pyelonephritis, and sinus node dysfunction with transient ischemic attack, reported in one patient each. Overall, 6/62 patients (9.7%) in the Fabhalta treatment group experienced serious AEs (SAE) in the randomized treatment period. Serious AEs in patients treated with Fabhalta were sinus node dysfunction and transient ischemic attack, coronavirus disease 2019 (COVID-19), pyelonephritis and urinary tract infection, increased blood creatinine phosphokinase, basal cell carcinoma, and myelodysplastic syndrome. One SAE in the Fabhalta group (blood creatine phosphokinase increase) was suspected to be related to Fabhalta. None of the SAEs had a fatal outcome. There were no deaths in the randomized treatment period (RTP) and no TEAEs leading to dose interruption or discontinuation.

In the pooled PNH studies, 170 patients received Fabhalta 200 mg BID for a total of 185.1 patient-treatment years, and the median duration of exposure was 10.6 months (range: 0.9 to 51.9 months). The mean duration of exposure to Fabhalta 200 mg BID was 13.1 months (SD = 9.71 months). The proportion of patients from the pooled PNH studies that had a duration of exposure of 12 months longer and 24 months or longer was 33.5% (57/170) and 10.6% (18/170), respectively.

Across the pooled PNH studies, the most frequent TEAEs were COVID-19 (40/170, 23.5%), headache (29/170, 17.1%), diarrhea (19/170, 11.2%), and nasopharyngitis (15/170, 8.8%). Other AEs that were reported in 5% or more of patients were nausea, pyrexia, abdominal pain, arthralgia, vomiting and thrombocytopenia. The common TEAEs observed in the pooled data were generally consistent with those reported in APPLY-PNH randomized treatment period and APPOINT-PNH core treatment period.

Three patients in the PNH pool died. All three patients had medical histories and/or confounding factors for the event leading to death. There were no deaths in the randomized treatment period of APPLY-PNH or in the core treatment period of APPOINT-PNH.

Adverse events of special interest were identified based on the mechanism of action of iptacopan, class effects associated with complement inhibition, and available non-clinical and clinical data. Key risks for Fabhalta include serious breakthrough hemolysis or hemolysis following treatment discontinuation, and infections caused by encapsulated bacteria.

Across the pooled PNH studies, no adverse events of hemolysis were reported post-discontinuation. All three patients who discontinued Fabhalta monotherapy switched to eculizumab treatment. There were decreases of 2 g/dL (20 g/L) or more in hemoglobin levels but all were clinically managed. Across the pooled PNH studies, 9/170 (5.3%) patients had one or more events of breakthrough hemolysis, hemolysis or extravascular hemolysis. None of the hemolysis events led to Fabhalta interruption or discontinuation. Most of the hemolysis events did not require any intervention, with the exception of two patients who received RBC transfusions and one patient who received treatment for painful crisis. All hemolysis events on Fabhalta were of mild or moderate severity, except one which was severe and serious. The serious event of breakthrough hemolysis on Fabhalta in the extension period of the APPOINT-PNH study was reported in association with COVID-19 infection and cold agglutinins. The event was not suspected to be related to Fabhalta. The patient received RBC transfusions and the breakthrough hemolysis resolved while continuing treatment with iptacopan.

In total, there were 7/170 patients in the pooled PNH studies with infections caused by encapsulated bacteria. Serious infections were seen in three patients with PNH treated with Fabhalta (two cases of bacterial pneumonia and one Pseudomonas aeruginosa urinary tract infection). The remaining patients with infections caused by encapsulated bacteria in the PNH pool had non-serious infections (staphylococcal skin infection, hemophilus bronchitis, erysipelas, furuncle, and otitis media), each seen in only one patient. There was no pattern or type of infection reported more frequently. All patients with infections caused by, or likely to be caused by, encapsulated bacteria were vaccinated as per protocol. All were successfully treated, and the infections resolved whilst continuing treatment with Fabhalta.

In order to minimize this risk of serious infections caused by encapsulated bacteria, Fabhalta will only be available through a Controlled Distribution Program under which prescribers must enrol patients and confirm vaccination against encapsulated bacteria and treatment with a prophylactic antibiotic, as applicable. Prescribers must also counsel patients about the risk of serious infection and provide them with a Patient Safety Card and a Patient/Caregiver Guide. A Serious Warnings and Precautions box describing the risk of serious infections caused by encapsulated bacteria has been included in the Product Monograph for Fabhalta.

Overall, the safety profile of Fabhalta appears to be acceptable for the treatment of adult patients with PNH who have hemolytic anemia. The identified safety issues can be managed through risk minimization measures including a Controlled Distribution Program, labelling, and post-market pharmacovigilance. For more information, refer to the Product Monograph for Fabhalta, approved by Health Canada and available through the Drug Product Database.

Iptacopan is a selective inhibitor of complement Factor B. The binding of iptacopan to complement Factor B results in the inhibition of the alternative complement pathway, the cleavage of component C3, and the downstream formation of the membrane attack complex.

Iptacopan was evaluated in safety pharmacology, repeat-dose toxicity, genotoxicity, carcinogenicity, reproductive toxicity, and phototoxicity studies. The pharmacokinetic characteristics of iptacopan in the tested animal species supported their use for toxicological assessment.

Repeat-dose toxicity studies in rats and in dogs identified the thyroid, male reproductive organs, and cardiovascular system as the principal targets of toxicity for iptacopan.

Iptacopan is not mutagenic, genotoxic, or carcinogenic. In rat fertility and early embryonic studies, iptacopan had no effect when administered to males, but increased pre- and post-implantation loss when administered to females. Iptacopan did not demonstrate embryofetal toxicity or teratogenicity when administered to pregnant female rats and rabbits during organogenesis, or adverse effects on pre- and post-natal development in offspring from iptacopan-treated female rats.

Iptacopan absorbs light in the ultraviolet B and ultraviolet A range and induced transient and minimal skin reactions to irradiation in mice. This suggests iptacopan may have a weak potential for phototoxicity. 

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

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

The quality (chemistry and manufacturing) information submitted for Fabhalta has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper pharmaceutical development and supporting studies were conducted and an adequate control strategy is in place for the commercial processes. Changes to the manufacturing process and formulation (if any) 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 below 30 ºC.

The proposed drug-related impurity limits are considered adequately qualified (e.g., within International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH] limits and/or qualified from toxicological studies, as needed).

A risk assessment for the potential presence of nitrosamine impurities was conducted according to requirements outlined in Health Canada’s Guidance on Nitrosamine Impurities in Medications. 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.

One excipient in the capsule shell, gelatin, is of animal origin. Letters of attestation confirming that the materials are not from a bovine spongiform encephalopathy and transmissible spongiform encephalopathy (BSE/TSE) affected country/area have been provided for this drug product indicating that it is considered to be safe for human use.