Summary Basis of Decision for Givlaari

Clinical Pharmacology

The acute hepatic phorphyria (AHP) family consists of four subtypes, each involving a genetic mutation in a distinct heme pathway enzyme. The subtypes are as follows:

• acute intermittent porphyria (AIP) - caused by mutations in the hydroxymethylbilane synthase (also known as porphobilinogen [PBG] deaminase) gene;
• hereditary coproporphyria (HCP) - caused by mutations in the coproporphyrinogen oxidase gene;
• variegate porphyria (VP) - caused by mutations in the protoporphyrinogen oxidase gene; and
• aminolevulinic acid (ALA) dehydratase-deficient porphyria (ADP) - caused by mutations in the ALA dehydratase gene.

Several lines of evidence indicate that ALA and PBG are central to the pathophysiology of AHP disease and are causal mediators of injury. Both ALA and PBG have been shown to directly induce oxidative stress, inflammation, vasoconstriction, and cell death in vitro in multiple cell types and tissues, including the kidney, liver and nervous system. In patients who received a liver transplantation due to severe recurring porphyria attacks, ALA and PBG levels normalized within a few days of surgery and porphyria attacks and chronic porphyria-related symptoms resolved.

Givosiran, the medicinal ingredient in Givlaari, is a double-stranded small interfering ribonucleic acid (siRNA) that causes degradation of aminolevulinate synthase 1 (ALAS-1) messenger ribonucleic acid (mRNA) in hepatocytes through RNA interference, reducing the elevated levels of liver ALAS-1 mRNA. This leads to reduced circulating levels of the elevated toxic heme intermediates ALA and PBG thereby preventing or reducing neurovisceral attacks and ongoing symptoms in all AHP disease subtypes.

The clinical pharmacology program consisted of biomarker, pharmacokinetic, pharmacodynamics, and dose-titration studies to assess the subcutaneous administration of givosiran 2.5 mg/kg once monthly in healthy volunteers and in AHP patients.

Clinical data showed that following subcutaneous administration, givosiran was rapidly absorbed into the plasma and was primarily distributed to the liver where it was metabolized by nucleases to shorter oligonucleotides and an equipotent active metabolite, AS (N-1)3' givosiran that represents 45% of givosiran exposures.

In givosiran dose ranges of 0.035 to 5 mg/kg, dose-dependent reductions in urinary ALAS-1 mRNA, ALA and PBG levels were observed. In AHP patients receiving monthly doses of 2.5 mg/kg givosiran, maximal reductions of ALA and PBG levels were achieved by 3 months. Modelling of the urinary ALA reduction and clinical activity, as measured by the incidence of porphyria attack (i.e., the annualized attack rate [AAR]) demonstrated that givosiran 2.5 mg/kg monthly dosing reduced the AAR to 2.9 attacks/year compared to 4.2 attacks/year with 2.5 mg/kg quarterly dosing and 12.5 attacks/year with placebo. These data support givosiran 2.5 mg/kg monthly dosing as the optimal dose regimen.

Given its mechanism of action, givosiran can lower hepatic heme levels and could reduce the activity of heme-dependent proteins in the liver such as drug metabolizing cytochrome P450 (CYP450) enzymes. The review of data showed that givosiran treatment had an important impact on some CYP450 enzyme activity. In vitro studies indicated that givosiran does not directly inhibit or induce CYP enzymes. However, clinical drug interaction studies demonstrated that the concomitant use of a single subcutaneous dose of givosiran 2.5 mg/kg:

• increased caffeine (sensitive CYP1A2 substrate) blood concentration with time [area under the concentration versus time curve (AUC)] by 3.0‑fold and maximum concentration (C_max) by 1.3-fold, and
• increased dextromethorphan (sensitive CYP2D6 substrate) blood concentration with time (AUC) by 2.4‑fold and maximum concentration (C_max) by 2.0‑fold.

This is important as multi-drug therapy is common in AHP patients due to multiple comorbidities, such as chronic pain, depression, and hypertension. As such, patients should avoid concomitant use of givosiran with CYP1A2 or CYP2D6 substrates for which minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, a decrease in CYP1A2 or CYP2D6 substrate drug dosage is recommended.

No dosage adjustment of CYP2C9, CYP2C19 and CYP3A4 substrates is recommended when coadministered with givosiran.

The population pharmacokinetics and the pharmacokinetic/pharmacodynamic analysis did not reveal any clinically meaningful differences in the pharmacokinetics or pharmacodynamics of givosiran based on age, sex, or race/ethnicity.

For adolescent (≥12 to <18 years old) patients, predictive pharmacokinetic and pharmacodynamic simulations were conducted assuming a body weight of 40 kg (the median body weight for 12-year old boys and girls based on Centers for Disease Control and Prevention [CDC] growth charts) and compared with adults (≥18 years old; a body weight of 66 kg) for monthly doses of givosiran 2.5 mg/kg. Predicted mean plasma exposures (C_max and AUC) of givosiran in adolescents were within 22% of that in adults. The predicted mean urinary ALA level in adolescents after 2.5 mg/kg once-monthly doses of givosiran was 1.26 mmol/mol creatinine which was comparable to 1.18 mmol/mol creatinine in adults.

While age is not a covariate in population pharmacokinetic analysis, clinical studies of givosiran did not include a sufficient number of patients to determine the effectiveness of the drug in the geriatric population.

Based on the population pharmacokinetic and the pharmacokinetic/pharmacodynamic (percent reduction in urinary ALA and PBG) analyses, caution is recommended in patients with severe renal impairment. No dosage adjustment is necessary in patients with mild or moderate renal impairment. Population pharmacokinetic data indicated that the exposures of givosiran were predicted to increase by 14% for givosiran and by 43% for AS(N-1)3' givosiran (an active metabolite with equal potency as givosiran) in patients with mild-to-severe renal impairment compared to patients with normal renal function, which is not considered clinically significant. The effect of end-stage renal disease (estimated glomerular filtration rate <15 mL/min/1.73 m²) on givosiran pharmacokinetics is unknown.

No dosage adjustment is necessary in patients with mild hepatic impairment based on the population pharmacokinetics and pharmacokinetic/pharmacodynamic analysis. Hepatic impairment was not a significant covariate in the population pharmacokinetic analysis. The effect of moderate to severe hepatic impairment on the pharmacokinetics of givosiran has not been evaluated.

A dedicated thorough QT study has not been conducted with givosiran. The effect of givosiran on the corrected QT interval (QTc) was evaluated in a double blind, placebo-controlled study and the open-label extension study. No large mean increase in QTc (i.e., >20 ms) was detected at the 2.5 mg/kg once monthly dose level. The administration of single or multiple doses of givosiran was not associated with clinically relevant changes in the QTc interval, including at plasma concentrations approximately 2- to 3-fold higher than the expected plasma C_max at the therapeutic dose of 2.5 mg/kg once monthly in AHP patients.

The clinical pharmacology data support the use of Givlaari for the recommended indication. For further details, please refer to the Givlaari Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Givlaari was evaluated in the pivotal study ENVISION, a randomized, double-blind, placebo-controlled, multicentre, Phase III study with a subsequent open-label extension period.

The ENVISION study enrolled 94 adult patients with acute hepatic porphyria. These patients were randomized in a ratio of 1:1 to receive 2.5 mg/kg Givlaari (48 patients) or a placebo (46 patients) over a 6-month double-blind period.

Key inclusion criteria for the study were: patients aged 12 years and older, who had experienced a minimum of two porphyria attacks requiring hospitalization, an urgent healthcare visit, or intravenous hemin administration at home in the 6 months prior to study entry. Patients had to be willing to discontinue and/or not initiate prophylactic hemin. Hemin use was permitted during the study for the treatment of acute porphyria attacks. Patients were required to have a diagnosis of AHP (AIP, HCP, VP or ADP) based on clinical features, at least one documented urinary or plasma PBG or ALA value greater than or equal to the upper limit of normal within the past year prior to or during screening, and documented genetic evidence of a mutation in a porphyria-related gene. For patients whose genetic testing did not identify a mutation in a porphyria-related gene (<5% of cases), the patient could be eligible for inclusion if they had both clinical features and diagnostic biochemical criteria consistent with AHP.

The primary endpoint of the study was the effect of subcutaneously administered Givlaari as compared to placebo in AIP patients for the composite annualized porphyria attack rate (AAR) during the 6-month double-blind period. The composite annualized porphyria attack rate was defined as the annualized rate of porphyria attacks requiring hospitalization, an urgent healthcare visit, or intravenous hemin administration at home. Porphyria attacks were defined as:

• an acute episode of neurovisceral pain in the abdomen, back, chest, extremities and/or limbs, with no other medically determined cause, and
• requiring treatment with intravenous dextrose or hemin, carbohydrates, analgesics, or other medications such as antiemetics at a dose or frequency beyond the participant's usual daily porphyria management.

A key secondary endpoint was the effect of Givlaari as compared to placebo in all AHP patients for the composite AAR during the 6-month double-blind period. Other secondary endpoints included an evaluation of the effects of Givlaari compared to placebo with respect to urinary ALA and PBG levels and hemin usage in AIP patients. The rate of porphyria attacks requiring hospitalization, an urgent healthcare visit, or intravenous hemin administration at home in patients was also evaluated in AHP patients.

Other patient-reported outcomes analyzed as secondary endpoints were the change from baseline in score on the Physical Component Summary (PCS) of the 12-item Short-Form Health Survey, version 2 (SF-12).

The primary endpoint of the study was met as the results demonstrated a statistically significant reduction of 74% in the composite AAR in AIP patients compared to placebo (rate ratio [RR] = 0.26, p <0.0001). These results were clinically meaningful and consistently produced significant reductions in all three composite components of the composite AAR (hospitalization, urgent care visit, and intravenous hemin use). In addition, a 73% reduction was observed in the composite AAR among all AHP patients, a key secondary endpoint (RR = 0.27, p <0.0001).

Decreases in the composite AAR were observed after the first dose of Givlaari and were maintained throughout the study. The statistically significant difference of treatment with Givlaari versus placebo was observed for each non-overlapping component of the composite AAR endpoint, pre-specified sensitivity analyses, and all pre-specified subgroup analyses (by age, sex, race, region, baseline body mass index, prior hemin prophylaxis status, historical attack rate, prior chronic opioid use, and the presence of prior chronic symptoms when not having attacks). Of the patients treated with Givlaari, 50% had no attacks that met the criteria for the endpoint of composite porphyria attacks versus 16.3% who received placebo.

Further, treatment with Givlaari led to rapid and sustained reductions in elevated baseline levels of ALA and PBG without evidence of recovery between dosing. For median urinary ALA levels, a clinically meaningful and statistically significant reduction was demonstrated with Givlaari compared with placebo in AIP patients, with median of treatment differences of 14.6 mmol/mol creatinine at Month 3 (p <0.0001) and of 12.8 mmol/mol creatinine at Month 6 (p <0.0001). For median urinary PBG levels, a clinically meaningful and statistically significant reduction was demonstrated for Givlaari compared with placebo in AIP patients at Month 6, with a median of treatment difference of 27.5 mmol/mol creatinine (p <0.0001).

For AIP patients, a clinically meaningful and statistically significant reduction in the annualized days of hemin use was observed in patients treated with Givlaari (RR = 0.23, p <0.0001). Overall, 54.3% of Givlaari-treated patients with AIP and 23.3% of placebo-treated patients with AIP had 0 days of hemin use.

With respect to the SF-12, the results across all the domains showed a consistent effect favouring Givlaari over placebo with the largest differences seen with bodily pain, social functioning, and role limitations due to physical problems.

Supportive Studies

The preliminary results from the open-label extension period are consistent with the results from the double-blind period from the pivotal ENVISION study and have demonstrated continued benefit from treatment with Givlaari. Following the completion of treatment and assessments in the 6-month double-blind period, patients enrolled in the ENVISION study were allowed to continue in the open-label extension period. This period was ongoing at the time of the review, therefore, the full data collection was not available to Health Canada. Patients from the placebo arm of the ENVISION study were permitted to cross over to receive Givlaari 2.5 mg/kg every month or Givlaari 1.25 mg/kg every month. Patients who were in the treatment arm of the ENVISION study receiving Givlaari 2.5 mg/kg every month were permitted to reduce their dose to 1.25 mg/kg due to transaminase elevations. All patients were eligible to receive treatment with Givlaari for up to 29 months in the open-label extension period.

Although the study was ongoing at the time of this submission, the available data for AIP and AHP patients who received long-term treatment with Givlaari (median of 7.61 months of exposure) demonstrated:

• maintenance of the decreased porphyria attack composite endpoint AAR,
• maintenance of the stable and durable lowering of urinary ALA and PBG levels,
• maintenance of decreased days of intravenous hemin administration,
• maintenance of the improvements in the weekly pain score, the PCS of the SF-12, and the EQ-5D-5L score.

Placebo crossover patients demonstrated rapid and sustained improvements in the porphyria attack composite endpoint AAR, urinary ALA and PBG levels, hemin use, and PCS of the SF-12 on Givlaari in the open-label extension period, with effects and a time course consistent with those observed for Givlaari during the 6‑month double blind period. Patients who crossed over from placebo in the 6‑month double blind period to 1.25 mg/kg or 2.5 mg/kg Givlaari in the open-label extension period had substantial reductions in ALA at Month 7. Lower reductions were observed with the 1.25 mg/kg Givlaari dose.

Indication

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

• Givlaari (givosiran) is indicated for the treatment of acute hepatic porphyria (AHP) in adults and adolescents 12 years and older.

Based on the review of the data submitted, Health Canada determined that the safety and efficacy of Givlaari in pediatric (<18 years of age) patients have not been established. Accordingly, Health Canada approved the following indication:

• Givlaari (givosiran) is indicated for the treatment of acute hepatic porphyria (AHP) in adults.

In addition, the clinical studies did not included sufficient numbers of patients to determine if the use of Givlaari in geriatric patients is associated with differences in safety or effectiveness.

Overall Analysis of Efficacy

The clinical efficacy of Givlaari has been demonstrated pharmacodynamically and clinically through significant reductions in the frequency of severe porphyria attacks. The pivotal study was adequately powered and showed consistent results for the majority of the sub-analyses and multiple secondary outcomes favouring Givlaari over placebo.

Overall, until the present time, treatment of acute porphyria attacks in patients with AHP has been limited. The development of Givlaari fulfills a therapeutic need for these patients as clinically significant benefits have been demonstrated including reductions in acute attacks, reduced pain and analgesic use (including opioid analgesics), reduced intravenous hemin use, reduced time in hospital or off work, and improved quality of life measures.

One of the limitations of the development program and the ENVISION study with open-label extension study was the brief duration of therapy for a chronic disease (6 months for the double-blind period). Secondly, the study did not provide a large representative sample for every subtype of AHP as patients with AIP represented 95% of the population in the pivotal study. It is unclear if the benefits outweigh the uncertainty of potential long-term safety in patients with lower frequencies of attacks (i.e., adolescents); however, it is likely an important therapeutic in patients with a high frequency (>4) of attacks over the course of a calendar year.

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

Clinical Safety

The clinical safety of Givlaari was primarily evaluated in the double-blind period in the pivotal study (ENVISION) and the subsequent open-label extension period described in the Clinical Efficacy section. Additional data were obtained from a supportive study (Study 002).

Safety data were obtained from patients receiving monthly doses of Givlaari 2.5 mg/kg as well as patients receiving monthly doses of Givlaari 1.25 mg/kg, a reduced dose for patients in the open-label extension period who had experienced elevated transaminases. As porphyria attacks were evaluated as a measure of efficacy for Givlaari, symptoms/signs consistent with acute porphyria attacks were not treated as adverse events (AEs) or serious adverse events (SAEs) in the safety evaluations.

Data from the double-blind period in the pivotal ENVISION study demonstrated that in the AHP population, 89.6% of patients in the Givlaari group and 80.4% of patients in the placebo group reported at least one AE. Serious adverse events were reported in 20.8% of patients in the Givlaari-treatment group and 8.7% of patients in the placebo-treatment group. There were no patient deaths during the study.

The most common AEs reported in >10% of patients in the Givlaari group vs. the placebo group were nausea (27% vs. 11%), injection site reactions (25% vs. 0%), headache (12.5% vs 15.2%), chronic kidney disease (10.4% vs. 0%), fatigue (10% vs. 4%), transaminase increased (13% vs 2%) blood creatinine increase (15% vs 4%) and rash (17% vs 4%).

Adverse events reported with ≥5% higher frequency in the Givlaari group included injection site reactions, nausea, fatigue, transaminase increased, increased blood creatinine (includes chronic kidney disease and decreased estimated glomerular filtration rate) and rash (includes pruritus, eczema, erythema, and urticarial rash). All injection site reactions were mild or moderate in severity. Nausea experienced by patients in this study was mainly mild in severity. Of the five Givlaari-treated patients with adverse events of increased chronic kidney disease (increased creatinine and/or decreased estimated glomerular filtration rate), four had a pre-existing medical history of chronic kidney disease, renal impairment, and/or hypertension, and the AEs reported were a worsening of the condition. None of these AEs led to treatment discontinuation or study withdrawal.

In the Givlaari-treatment group, 16.7% of patients experienced a severe AE vs. 10.9% of patients in the placebo group. The only severe AE reported in more than one patient was a device-related infection, which was reported in 4.2% of Givlaari-treated patients and 2.2% of patients receiving placebo.

Adverse events considered as related to the study drug occurred in 45.8% of patients in the Givlaari group versus 26.1% of placebo-treated patients. Study drug-related AEs reported in ≥5% of patients in the Givlaari-treated group vs. the placebo-treated group included nausea (16.7% vs. 4.3%), injection site reactions (14.6% vs. 0%), alanine aminotransferase (ALT) elevation (8.3% vs. 2.2%), headache (6.3% vs. 2.2%), asthenia (6.3% vs. 4.3%), aspartate aminotransferase (AST) elevation (6.3% vs. 2.2%) and chronic kidney disease (6.3% vs. 0%). The frequency of AEs seemed to remain stable over the study for both groups. The exception to this was the hepatic AEs (ALT/AST elevations) where there appeared to be a cluster in the Givlaari-treated group at the 3- to 5‑month period.

Two serious adverse events were reported in two patients: one patient experienced worsening chronic kidney disease and one patients discontinued treatment due to over 8‑times the upper limit of normal value for ALT.

In Phase I/II studies, one case of anaphylaxis was reported in Study 002 and this patient was adequately treated and withdrawn from the study. Another patient in Study 002 with low-titer antibodies developed injection site erythema that was moderate in intensity and related to the study drug. Following this event, based on a physician and patient decision, Givlaari treatment was discontinued due to a lack of marked response from the study drug.

Data from pediatric patients and adults 65 years of age and older were absent in the submission. Pharmacokinetic data suggested age was not a significant covariate in the pharmacokinetics of givosiran. Given that AHP is a life-long disease, Health Canada found it relevant to have a larger sample of patients followed for a longer period to authorize an indication in adolescents. No pediatric patients were enrolled in any stage of the development program or pivotal studies due to the low frequency of attacks and the rarity of this condition in the pediatric population. The identified potential risks and uncertainties of Givlaari treatment paired with the lack of pediatric data did not support authorization of an adolescent indication. Overall, the rather short follow-up and small sample size bring some uncertainties as to whether all the potential side effects of the treatment are captured within the study. Further, data on patients with various stages of renal or hepatic impairment are either absent or very limited.

Overall Analysis of Safety

Data from the double-blind period of the pivotal ENVISION study, the open-label extension period, the supportive study (Study 002) and the clinical development plan comprised the reviewed safety database. Overall exposure to Givlaari is limited in duration but this is considered acceptable, considering the rarity of these diseases. In general, the study population is representative of the target population for which treatment will be authorized. Data on adolescents (≥12 years of age and ≤18) were absent due to the extreme rarity of the condition presenting in that age group that, when identified, typically presents with infrequent attacks. Data in the elderly or in patients with various stages of hepatic impairment and severe renal impairment were either absent or limited. The use of Givlaari in patients with moderate or severe hepatic impairment and in patients with end stage renal disease or on dialysis were included as missing information in the risk management plan (RMP).

The main safety concerns with the use of Givlaari within the timeframe studied included a higher frequency of nausea, injection site reactions, rash, fatigue, increased creatinine and hepatic transaminases compared to placebo. Increased incidences of chronic kidney disease (increased creatinine and/or decreased estimated glomerular filtration rate), that in most cases were transient in nature are a concern for those with severe chronic kidney disease, as no dedicated study in this group was conducted. Furthermore, serious adverse events including worsening of chronic kidney disease and abnormal liver function tests occurred in some patients with the latter leading to discontinuation of Givlaari in one patient. In addition, one adverse drug reaction of anaphylaxis also occurred in a patient that was subsequently withdrawn from the study.

The potential risks of treatment with Givlaari are confounded by comorbid diseases that may exist in patients with AHP, including chronic kidney disease and liver dysfunction as long-term sequelae. Within the clinical studies, it appears that treatment with Givlaari may have exacerbated these conditions. The follow-up duration of 6 months during the double-blind period is relatively short for a life-long chronic disease. As such, an RMP will include a continued monitoring of patients for potential safety concerns and AEs that might reoccur or persist for longer periods of time than the study period.

Appropriate warnings and precautions are in place in the approved Givlaari Product Monograph to address the identified safety concerns.

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