Regulatory Decision Summary for Givlaari

Review decision

The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.


Product type:

Drug

Medicinal ingredient(s):

Givosiran

Therapeutic area:

Other Alimentary Tract and Metabolism Products

Type of submission:

Priority New Drug Submission (New Active Substance)

Control number:

237194
What was the purpose of this submission?

This New Drug Submission (NDS) was filed to obtain market authorization for Givlaari, for the treatment of acute hepatic porphyria (AHP) in adults.

This NDS was reviewed according to the Health Canada Priority Review of Drug Submissions policy.

Why was the decision issued?

Acute hepatic porphyrias (AHP) is a rare debilitating disease that results from defects in the heme biosynthesis pathway leading to induction of ALA synthase-1 (ALAS1), which results in increased production of the neurotoxic heme intermediates delta-aminolevulinic acid (ALA) and porphobilinogen (PBG). These toxic heme intermediates cause clinical expression of the disease through neuro-visceral attacks characterized by severe abdominal pain, muscle weakness, seizures, psychiatric dysfunction, irreversible neurological damage, hyponatremia, and frequent visits for medical care. Acute intermittent porphyria (AIP) is the most common subtype of AHP and represents approximately 80% of all symptomatic cases.

The only current targeted treatment for AHP with market approval is intravenous (IV) Hemin derived from processed red blood cells. Hemin is used to abort attacks of AHP and has been used clinically for prophylaxis in AHP in patients with temporal acute attacks related to the menstrual cycle when carbohydrate therapy is inadequate. Intravenous fluids, analgesic medications (opioids and non-opioids), diet modifications, and avoidance of triggers are part of the mainstay of treatment in these patients. Until the development of Givlaari (givosiran), hemin has been the only targeted therapy and carries with it long-term risks of iron overload. Additional treatments for AHP include chemically induced menopause with hormonal suppressive therapy (e.g. gonadotropin-releasing hormone agonists) and in patients with liver failure, a liver transplant is the only other therapy available.

Givlaari is a chemically synthesized and modified, double-stranded, small interfering ribonucleic acid (siRNA) that binds to a genetically conserved sequence in ALAS1 mRNA in the liver. Givosiran is administered subcutaneously (SC) and is delivered to the liver via uptake by asialoglycoprotein receptors (ASGPRs) which are highly expressed on the hepatocytes. Givlaari inhibits the synthesis of ALAS1 in the liver through the mechanism of RNA interference (RNAi), thereby leading to a substantial and sustained reduction in ALA and PBG.

The sponsor submitted the pivotal phase 3 study (ENVISION), which was a randomized, double-blind (DB), placebo-controlled multicenter trial. Patients were randomized 1:1 (givosiran 2.5 mg/kg vs. placebo) over a 6-month double-blinded period. The study enrolled 94 adults; 46 patients were randomized to placebo and 48 to givosiran. Results of the study indicated a statistically significant decrease in the mean composite AAR (annualized attack rate), which was also clinically important and consistently produced significant reductions in all 3 composite components of the AAR (hospitalization, urgent care visit, IV hemin use). Over the 6-month DB period, the mean AAR was 3.2 (95% CI, 2.3-4.6) in those receiving givosiran and 12.5 (95% confidence interval [CI], 9.4-16.8) in placebo. This represented a 73% lower AAR for the full analysis set of all AHP subtypes in the givosiran group (p<0.001). The study was adequately powered and showed consistent results in the majority of the sub-analyses and multiple secondary outcomes favouring Givlaari over placebo. Among the secondary endpoints with statistically significant benefits, favouring Givlaari, included mean annualized days of IV hemin use, reduced ALA and PBG levels, and reduced worst daily pain scores.

Other patient-reported outcomes analyzed as secondary endpoints were the change from baseline in the score on the Physical Component Summary of the 12-item Short-Form Health Survey, version 2 (SF-12). With respect to the SF-12, the results across all the domains showed a consistent effect favoring givosiran over placebo with the largest differences seen with bodily pain, social functioning, and role limitations due to physical problems. These are all important patient-oriented outcomes. 

Patients who were on the ENVISION study were allowed to continue onto the open-label extension study (OLE) which is ongoing for 29 months (full data collection not available at the time of this submission). Patients in the ENVISION placebo arm were permitted to cross over to givosiran 2.5 mg/kg every month and patients on givosiran 2.5 mg every month were permitted to reduce their dose to 1.25 mg/kg secondary to transaminase elevations. Preliminary results from the OLE study are consistent with the results in the pivotal ENVISION trial with continued benefit from treatment with givosiran.

The most common adverse events reported more frequently in the givosiran group vs. placebo were injection-site reactions, nausea, liver dysfunction (alanine aminotransferase (ALT) increase), chronic kidney disease, decreased estimated glomerular filtration rate (eGFR), and rash. Two serious adverse events reported in at least 2 patients were worsening of chronic kidney disease and one patient that discontinued treatment due to >8 x upper limit of normal (ULN) for ALT. In Phase 1/2 studies, one case of anaphylaxis was reported in Study 002 and this patient was adequately treated and withdrawn from the study. Another patient developed anti-drug antibodies (ADA) in the development program and was taken off study. 

Potential risks with Givlaari are complicated by comorbid diseases that can exist in patients with AHP, including chronic kidney disease and liver dysfunction as long-term sequelae. Within the clinical studies, it appears that these conditions may have been exacerbated by treatment with Givlaari. Follow-up duration of 6 months during the double-blind period is relatively short for a life-long chronic disease; as such, a risk management plan will continue to monitor patients for potential safety concerns and adverse events that might re-occur or persist for longer periods of time than the study was conducted. Further, data on pediatric patients and adults ≥65 years were absent in the submission. Adult populations and pharmacokinetic data suggested age was not a significant covariate in the pharmacokinetics of givosiran. Given AHP is a life-long disease, Health Canada found it relevant to have a larger sample of patients followed for a longer duration 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 presenting in the pediatric age range. At the time of the submission, the potential risks and uncertainties of treatment paired with the lack of pediatric data did not provide enough evidence to support an adolescent indication. Overall, the rather short follow-up and small sample size bring some uncertainties 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 is either absent or very limited. 

While balancing the potential risks and uncertainties, there remains a need for targeted therapies for patients with AHP. Given the limited treatment options, the statistically and clinically significant benefits of treatment with Givlaari seen in the pivotal trial are favorable. Subcutaneous treatment may be more convenient and is an effective option for patients with AHP. Treatment has the potential to reduce or potentially replace a proportion of intravenous hemin administration. The reduced need for chronic indwelling central lines is an important potential benefit as well as the reduction in pain that could result in reduced opioid analgesic use. The collection and analysis of long-term data will be necessary along with the risk management plan to better characterize Givlaari related short and long-term effects.

The clinical efficacy of Givlaari has been demonstrated pharmacodynamically and clinically through significant reductions in the frequency of severe porphyria attacks. This reduction in attack frequency will likely significantly impact a patient’s quality of life. The overall safety profile of givosiran is considered acceptable and risks are managed by the proposed risk management plan and Product Monograph.

Considering the nature of the disease and the paucity of approved targeted treatments, the clinical benefits of Givlaari outweigh the currently known risks associated with its use. The long-term effect of treatment and safety in AHP patients will continue to be further evaluated.

The clinical pharmacology program contained biomarkers, pharmacokinetics, pharmacodynamics, and dose-titration studies to assess SC injection of givosiran 2.5 mg/kg once monthly in healthy volunteers and AHP patients.

The review of the non-clinical data revealed no special hazard for humans. Clinical data showed that givosiran was rapidly absorbed into plasma, primarily distributed to the liver, and metabolized by nucleases to shorter oligonucleotides. Only 14% of the givosiran dose was recovered in urine and the drug should be used with caution in patients with severe renal impairment. No dosing adjustment is necessary for mild, moderate, or severe renal impairment or mild hepatic impairment patients. The effect of givosiran on patients with end-stage disease or in moderate/severe hepatic impairment is unknown.

Maximal reductions of ALA and PBG level were achieved at Month 3 with givosiran 2.5 mg/kg once monthly in AHP patients. Based on these biomarkers and the modeling data from the urinary ALA reduction and the annualized porphyria attack rates, it was demonstrated that givosiran 2.5 mg/kg monthly dosing is significantly better than givosiran quarterly dosing or placebo (2.9 attacks/year, 4.2 attacks/year, and 12.5 attacks, respectively).

Given its mechanisms of action, givosiran can lower hepatic heme levels and could reduce 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. This is important since 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. If concomitant use cannot be avoided, patients will need to be monitored more frequently to determine if a dose adjustment of the concomitant medication is required.

A Risk Management Plan (RMP) for Givlaari was submitted by Alnylam Pharmaceuticals to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will put in place to minimize risks associated with the product.

Overall, the benefit risk assessment of Givlaari is considered favorable for use by qualified physicians for the treatment of adults with Acute Hepatic Porphyria.

Decision issued

Approved; issued a Notice of Compliance in accordance with the Food and Drug Regulations