Summary Basis of Decision for Ultomiris

Review decision

The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.


Product type:

Drug

Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Ultomiris is located below.

Recent Activity for Ultomiris

SBDs written for eligible drugs approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Summary Basis of Decision (SBD) for Ultomiris

Date SBD issued: 2020-03-02

The following information relates to the new drug submission for Ultomiris.

Ravulizumab

Drug Identification Number (DIN):

  • DIN 02491559 - 10 mg/mL solution, intravenous administration

Alexion Pharma Canada

New Drug Submission Control Number: 217955

On August 28, 2019, Health Canada issued a Notice of Compliance to Alexion Pharma Canada for the drug product Ultomiris.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit-risk profile of Ultomiris is favourable for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH).

1 What was approved?

Ultomiris, a selective immunosuppressant, was authorized for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH).

Ultomiris is not authorized for use in pediatric patients (<18 years of age), as its safety and efficacy have not been evaluated in this population.

Ultomiris may be administered to patients with PNH aged 65 years and over. There is no evidence indicating any special precautions are required for treating a geriatric population.

Ultomiris is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.

Ultomiris was approved for use under the conditions stated in its Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Ultomiris (10 mg/mL ravulizumab) is presented as a concentrate for solution for infusion. In addition to the medicinal ingredient ravulizumab, the concentrate contains Polysorbate 80 (vegetable origin), sodium chloride, sodium phosphate dibasic, sodium phosphate monobasic, and water for injection.

For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Ultomiris Product Monograph, approved by Health Canada and available through the Drug Product Database.

2 Why was Ultomiris approved?

Health Canada considers that the benefit-risk profile of Ultomiris is favourable for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria (PNH).

Paroxysmal nocturnal hemoglobinuria is a very rare acquired hematopoietic stem cell disorder. Patients with PNH lack naturally occurring complement inhibitors, which normally protect red blood cells from destruction by the complement system. The lack of complement inhibitors results in continuous complement activation and uncontrolled hemolysis, which can lead to thrombosis, anemia, kidney disease, and pulmonary hypertension. This condition is potentially life-threatening. If left untreated, an estimated one third of PNH patients do not survive more than five years, and approximately half of patients die within 10 years from the time of diagnosis. The global prevalence of PNH is 3 to 4 individuals per million. The estimated number of PNH patients in Canada is 572.

The clinical efficacy of Ultomiris was demonstrated primarily in two Phase III pivotal studies, ALXN1210-PNH-301 and ALXN1210-PNH-302. Each of these studies were 26 weeks long, open-label, randomized, and active-controlled, with the aim of assessing the non-inferiority of Ultomiris compared to eculizumab in adult patients with PNH. In both pivotal studies, four infusions of Ultomiris were administered according to the recommended dosing regimen. Eculizumab was administered according to its approved dosing regimen and was the standard of care for PNH at the time of the studies.

Study ALXN1210-PNH-301 was conducted in 246 patients with PNH who were naïve to complement inhibitor treatment and had active hemolysis. Patients were randomized in a 1:1 ratio to receive either Ultomiris (ravulizumab) or eculizumab. The co-primary endpoints of this study were transfusion avoidance (TA) and the reduction of hemolysis, as directly measured by the normalization of lactate dehydrogenase (LDH) levels. The TA rates were 73.6% and 66.1% in the Ultomiris and eculizumab treatment groups, respectively. The proportion of patients who achieved LDH normalization was 53.6% in the Ultomiris treatment group, and 49.4% in the eculizumab treatment group.

Study ALXN1210-PNH-302 was conducted in 195 patients with PNH who were clinically stable after having been treated with eculizumab for at least the previous six months. Patients were considered clinically stable if they had an LDH level ≤1.5 times the upper limit of normal (ULN) at screening. Patients were randomized in a 1:1 ratio to either continue treatment with eculizumab, or to switch to Ultomiris. The primary endpoint was hemolysis, measured by the percent change in LDH from baseline. The percent change in LDH was determined to be -0.82% in the Ultomiris treatment group and 8.4% in the eculizumab treatment group.

In both studies, all primary and secondary endpoints were met, thereby demonstrating evidence of non-inferiority of Ultomiris to eculizumab. This evidence of non-inferiority was shown in each patient population examined: in the complement inhibitor-naïve treatment population, and in patients with PNH who were previously treated with eculizumab.

The safety profile of Ultomiris was comparable to that of eculizumab in both patient populations examined in the pivotal trials. The most frequently reported adverse drug reaction in the clinical studies was headache. Serious adverse reactions were reported in 6.8% of patients treated with Ultomiris during clinical studies.

Meningococcal infection and meningococcal sepsis were the most serious adverse reactions reported, and were life-threatening in some cases. Patients who contracted meningococcal infections or meningococcal sepsis were treated with antibiotics, and recovered from these conditions while also remaining on treatment with Ultomiris.

The Serious Warnings and Precautions box in the Ultomiris Product Monograph highlights the risk of serious meningococcal infection. Instructions and recommendations are included to minimize the risk and promote the early detection of signs of meningococcal infection. Patients should also be informed of the signs and symptoms of meningococcal septicemia and advised to seek medical care immediately. Additionally, Ultomiris will be available in Canada through a controlled distribution program.

A Risk Management Plan (RMP) for Ultomiris was submitted by Alexion Pharma Canada 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 be put in place to minimize risks associated with the product.

The submitted inner and outer labels, package insert and Patient Medication Information section of the Ultomiris Product Monograph meet the necessary regulatory labelling, plain language and design element requirements.

A Look-alike Sound-alike brand name assessment was performed and the proposed name Ultomiris was accepted.

Ultomiris has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling, adequate monitoring, and controlled distribution of the drug. Warnings and precautions are in place in the Ultomiris Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

3 What steps led to the approval of Ultomiris?

Submission Milestones: Ultomiris

Submission MilestoneDate
Submission filed:2018-09-13
Screening
Screening Acceptance Letter issued:2018-11-02
Review
Review of Risk Management Plan complete:2019-06-13
On-Site Evaluation:2019-06-24 - 2019-06-28
Clinical/Medical Evaluation complete:2019-08-09
Labelling Review complete, including Look-alike Sound-alike brand name assessment:2019-08-13
Quality Evaluation complete:2019-08-23
Notice of Compliance issued by Director General, Biologics and Genetic Therapies Directorate:2019-08-28

The Canadian regulatory decision on the review of Ultomiris was based on a critical assessment of the data package submitted to Health Canada. Review reports from the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) were consulted for relevant supplementary information.

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

4 What follow-up measures will the company take?

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

5 What post-authorization activity has taken place for Ultomiris?

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAAT will continue to be updated during the product's life cycle.

At this time, no PAAT is available for Ultomiris. When available, the PAAT will be incorporated into this SBD.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

6 What other information is available about drugs?

Up to date information on drug products can be found at the following links:

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision

Clinical Pharmacology

Ultomiris (ravulizumab), is a recombinant monoclonal antibody (mAb) that binds to the complement protein C5 with high affinity. This inhibits the cleavage of C5 into C5a (the proinflammatory anaphylatoxin) and C5b which is a component of the terminal complement complex, C5b-9, that promotes cell lysis. Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by uncontrolled complement activation. By binding to complement C5, Ultomiris blocks terminal complement-mediated inflammation, cell activation, and cell lysis.

The pharmacokinetics of ravulizumab was characterized in five Phase I/II studies. Three of these studies were conducted in healthy subjects, and the other two studies were conducted in patients with PNH. The pharmacodynamic effect of ravulizumab was assessed based on the reduction in serum concentrations of free C5 and the lowering of serum lactate dehydrogenase (LDH) levels.

A pharmacokinetic/pharmacodynamic (PK/PD) model-based simulation was performed at the end of Phase II studies to determine the dosing regimen to be used in Phase III studies. Additionally, a population PK/PD modelling analysis was conducted based on pooled data, including concentration data obtained through Phase III studies, to support the proposed dosing regimen.

Ravulizumab has dose-linear and time-independent pharmacokinetics over a dosage range of 200 mg to 5,400 mg when administered up to once every 12 weeks. The recommended dosing regimen is weight-based, as body weight was found to significantly affect drug clearance. No clinically meaningful differences in PK of Ultomiris were observed in subjects with mild to severe hepatic impairment or mild to moderate renal impairment. There were no patients with severe renal impairment enrolled in the studies.

Following the intravenous loading dose and the last maintenance dose of the Phase III dosing regimen, the observed trough concentration (Ctrough) and maximum concentration (Cmax) of ravulizumab were above the target threshold values at all times. Additionally, these concentrations were comparable between complement inhibitor-naïve PNH patients previously treated with eculizumab, across all body weight categories.

The mean terminal elimination half-life (±standard deviation [SD]) of ravulizumab in patients with PNH was estimated at 49.7 (±8.9) days, based on the population pharmacokinetic modelling results. Complete inhibition of serum-free C5 levels was observed after the first dose and sustained throughout the entire 26-week treatment period. These data support the proposed dosing regimen for Ultomiris in adult PNH patients.

Overall, the clinical pharmacological data support the use of Ultomiris according to the recommended dosing regimen and for the approved indication.

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

Clinical Efficacy

The clinical efficacy of Ultomiris was demonstrated primarily in two non-inferiority Phase III pivotal studies, ALXN1210-PNH-301 and ALXN1210-PNH-302. Each of these studies were 26 weeks long, open-label, randomized, and active-controlled, with the aim of assessing the non-inferiority of Ultomiris to eculizumab in adult patients with PNH. In both pivotal studies, four infusions of Ultomiris were administered over the 26 weeks, according to the recommended dosing regimen. Eculizumab was administered as 15 infusions over 26 weeks according to its approved dosing regimen, which was the standard of care for PNH at the time of the studies.

Study ALXN1210-PNH-301

Study ALXN1210-PNH-301 was conducted in 246 patients with PNH who were naïve to complement inhibitor treatment. Patients enrolled in this study had high disease activity, which was defined as a lactate dehydrogenase (LDH) level ≥1.5 times the upper limit of normal (ULN) at screening, along with the presence of one or more PNH-related signs or symptoms within three months of screening. PNH-related signs or symptoms which would fulfill these criteria were fatigue, hemoglobinuria, abdominal pain, shortness of breath (dyspnea), anemia (hemoglobin <10 g/dL), history of a major adverse event (including thrombosis), dysphagia or erectile dysfunction; or a history of packed red blood cell (pRBC) transfusion due to PNH.

Patients were randomized in a 1:1 ratio to receive either Ultomiris (ravulizumab) or eculizumab. Transfusion history in the 12 months prior to study entry was similar between the two treatment groups, and over 80% of patients in both treatment groups had a history of blood transfusion during this time period.

The co-primary endpoints of this study were transfusion avoidance (TA) and the reduction of hemolysis, as directly measured by the normalization of LDH levels. Transfusion avoidance was considered achieved only by patients who did not receive a transfusion and did not meet the protocol-specified guidelines for transfusion from baseline to Day 183 (end of the 26-week study). The TA rates were 73.6% and 66.1% in the Ultomiris and eculizumab treatment groups, respectively. The proportion of patients who achieved LDH normalization was 53.6% in the Ultomiris treatment group, and 49.4% in the eculizumab treatment group.

Key secondary endpoints included the percent change from baseline LDH levels, change in quality of life as measured by the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale, the proportion of patients with breakthrough hemolysis, and the proportion of patients with stabilized hemoglobin.

Both co-primary endpoints and all secondary endpoints were met, which provided evidence of the non-inferiority of Ultomiris to eculizumab in the complement inhibitor-naïve treatment population.

Study ALXN1210-PNH-302

Study ALXN1210-PNH-302 was conducted in 195 patients with PNH who were clinically stable after having been treated with eculizumab for at least the previous six months. Patients were considered clinically stable if they had an LDH level ≤1.5 times the ULN at screening.

Patients were randomized in a 1:1 ratio to either continue treatment with eculizumab, or to switch to Ultomiris. Transfusion history in the 12 months prior to study entry was similar between the two treatment groups, and over 87% of patients in both treatment groups had a history of blood transfusion during this time period.

The primary endpoint was hemolysis, measured by the percent change in LDH from baseline. The percent change in LDH was determined to be -0.82% in the Ultomiris treatment group and 8.4% in the eculizumab treatment group.

Key secondary endpoints included the proportion of patients that experienced breakthrough hemolysis, quality of life as measured by the FACIT-Fatigue scale, TA, and the proportion of patients with stabilized hemoglobin.

The primary endpoint and all secondary endpoints were met, which provided evidence of the non-inferiority of Ultomiris to eculizumab in patients with PNH who were previously treated with eculizumab.

Indication

The New Drug Submission for Ultomiris was filed by the sponsor with the following indication, which Health Canada subsequently approved:

  • Ultomiris (ravulizumab) is indicated for the treatment of adult patients with paroxysmal nocturnal hemoglobinuria.

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

Clinical Safety

The data reviewed for the safety evaluation were derived predominantly from 261 patients with PNH who had received Ultomiris in Phase II and III clinical studies, including the two pivotal studies described in the Clinical Efficacy section. Cumulatively, these patients represent 177 patient-years.

The safety profile of Ultomiris was comparable to that of eculizumab in complement inhibitor-naïve adult patients with PNH, and in adult patients with stable PNH who have previously received eculizumab. The most frequently reported adverse drug reaction in the clinical studies was headache. Serious adverse reactions were reported in 6.8% of patients treated with Ultomiris during clinical studies.

Meningococcal infection and meningococcal sepsis were the most serious adverse reactions reported, and were life-threatening in some cases. Patients who contracted meningococcal infections or meningococcal sepsis were treated with antibiotics, and recovered from these conditions while also remaining on treatment with Ultomiris.

The Serious Warnings and Precautions box in the Ultomiris Product Monograph highlights the risk of serious meningococcal infection. Instructions and recommendations are included to minimize the risk and promote the early detection of signs of meningococcal infection. Patients should also be informed of the signs and symptoms of meningococcal septicaemia and advised to seek medical care immediately. Additionally, Ultomiris will be available in Canada through a controlled distribution program.

As with any therapeutic protein, immunogenicity (the development of anti-drug antibodies [ADAs]) may occur. One treatment-emergent ADA was reported with Ultomiris in the PNH patient studies (261 patients).

Health Canada has determined that appropriate risk management measures are in place to address the safety concerns identified for Ultomiris, and to promote its safe and effective use. For more information, refer to the Ultomiris Product Monograph, approved by Health Canada and available through the Drug Product Database.

7.2 Non-Clinical Basis for Decision

The repeat-dose toxicology and reproductive and developmental toxicology studies included in this submission were previously reviewed as part of another submission. The sponsor previously obtained authorization for a drug product containing the closely related antibody, eculizumab.

As ravulizumab (the medicinal ingredient in Ultomiris) does not bind to non-human C5, there are no animal species which exhibit a pharmacologically active response to it. Therefore, a surrogate antibody directed against murine C5 was generated for use in a 26-week repeat-dose toxicity study and reproductive studies in mice.

In the repeat-dose toxicity study, the treatment was well-tolerated, and no clinical signs of drug-related toxicities were detected. Reproductive toxicity was evaluated at a dose of 30 mg/kg either once or twice weekly; however, maximal inhibition of hemolysis could not be attained in the majority of treated animals. With that limitation noted, no treatment-related effects were observed on male or female fertility, embryo-fetal toxicity, or maternal function.

Two cases of retinal dysplasia and one case of umbilical hernia were observed among 230 offspring born to mothers exposed to the higher antibody dose (30 mg/kg twice weekly) during organogenesis; however, these findings were not clearly test-article related.

Although no clear signs of developmental or reproductive toxicity were detected in these studies, the results of animal studies are not always indicative of human response. It is not known whether ravulizumab can cause fetal harm if administered to a pregnant woman, but human immunoglobulins are known to cross the placental barrier. It is therefore recommended that pregnant or lactating women should not be treated with ravulizumab, unless the potential benefit justifies or outweighs the potential risk to the mother and the fetus.

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

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

7.3 Quality Basis for Decision

Characterization of the Drug Substance

Ravulizumab, the drug substance, is a modified monoclonal antibody based on the structure of eculizumab (which is based on the structure of immunoglobulin G [IgG] 2 and 4). It is produced by recombinant deoxyribonucleic acid (DNA) technology in Chinese hamster ovary (CHO) cells, and has been engineered to increase its similarity to natural human antibodies (humanized). Additionally, ravulizumab has been genetically modified to lengthen its serum half-life relative to eculizumab (a comparator drug).

Comprehensive characterization studies were performed to provide assurance that ravulizumab consistently exhibits the desired characteristic structure and biological activity. Product identity, purity, size, structure, and glycosylation and charge profiles were all evaluated, and test results confirmed the expected composition and features of the molecule. The biological properties of ravulizumab were also assessed, especially as they relate to its binding affinity to C5, its relative potency to inhibit the complement alternative pathway, and binding kinetics to human C5 and the human neonatal Fc receptor (FcRn).

Manufacturing Process and Process Controls of the Drug Substance and Drug Product

Ravulizumab is manufactured from CHO cells using recombinant DNA technology. The process is initiated from a single working cell bank vial, and cells expressing ravulizumab are allowed to expand through a fed-batch process to reach commercial scale.

Cells are harvested from the culture medium through multiple filtration steps. Ravulizumab is isolated and purified through a series of chromatography, viral inactivation, and filtration steps, and then formulated with buffer. The formulated bulk drug substance is filtered into containers and stored at 2-8°C.

Manufacturing of the drug product, Ultomiris, begins with pooling and sterile filtration of the formulated drug substance. Vials are then aseptically filled with the appropriate volume.

All drug substance and drug product manufacturing facilities were found to be able to consistently manufacture drug substance or drug product of acceptable quality. The drug substance, which is manufactured at two sites, was found to be comparable across both sites.

Analytical methods were developed and validated according to International Council for Harmonisation (ICH) Guidelines. The specifications for stability and commercial release of the drug substance and drug product, as well as the overall control strategy, are sufficient to ensure that the production of Ultomiris meets quality expectations.

All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of ravulizumab with the excipients is supported by the stability data provided.

Control of the Drug Substance and Drug Product

Ultomiris is a Schedule D (biologic) drug and is, therefore, subject to Health Canada's Lot Release Program before sale as per Health Canada's Guidance for Sponsors: Lot Release Program for Schedule D (Biologic) Drugs.

As the formulation of ravulizumab occurs during the drug substance manufacturing process, most specifications set for the drug substance are also applicable to the drug product. The results of batch analyses for both the drug substance and the drug product indicate that all specifications were met. The results were similar from batch to batch, and provide evidence of consistency in the drug substance and drug product manufacturing processes.

For post-approval monitoring, Ultomiris is considered a low risk product because ravulizumab, the medicinal ingredient, is a well-characterized molecule. The risk level associated with a drug product is determined by factors including the nature of the product, its indication and target patient population, and the manufacturer's production and inspection history.

Stability of the Drug Substance and Drug Product

Based on the stability data submitted, the proposed shelf life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 24-month shelf life at 2-8°C for Ultomiris is considered acceptable.

Vials containing Ultomiris must be protected from light and must not be frozen or shaken. It is recommended that the product be used immediately after dilution. However, the diluted product remains chemically and physically stable for up to 24 hours at 2-8°C, and for up to six hours at room temperature.

Facilities and Equipment

An on-site evaluation (OSE) was conducted for one drug substance manufacturing facility, which received a compliant rating. An OSE was not conducted for the second drug substance manufacturing facility in connection with this submission, which was justified based on its manufacturing history of products regulated by Health Canada. Additionally, the sponsor's management of the quality agreement and oversight of the manufacturing process were similar between the two sites.

An OSE was not recommended for the drug product manufacturing facility, as it was considered a low-risk site at the time of review.

Adventitious Agents Safety Evaluation

The viral clearance studies were conducted using small-scale models which were representative of the commercial scale process. Under worst-case settings, the viral clearance strategy was found to be capable of consistently reducing contamination to levels below the acceptable limits.

L-cysteine hydrochloride monohydrate, which is of human origin, is used in the production of Ultomiris. L-cysteine hydrochloride monohydrate used for this purpose complies with requirements listed in the European Pharmacopoeia (Ph. Eur.) and the United States Pharmacopoeia (USP), and is processed at temperatures over 100°C. The risk of contamination with bovine spongiform encephalopathy (BSE), transmissible spongiform encephalopathy (TSE), or other adventitious agents of biological origin is considered low.

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