Summary Basis of Decision for Alprolix
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:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Alprolix is located below.
Recent Activity for Alprolix
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.
Post-Authorization Activity Table (PAAT) for Alprolix
Updated:
The following table describes post-authorization activity for Alprolix, a product which contains the medicinal ingredient recombinant human coagulation factor IX-FC fusion protein (rFIXFc). For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the list of abbreviations that are found in PAATs.
For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.
Drug Identification Number (DIN):
- DIN 02422905 - 250 IU/vial, recombinant human coagulation factor IX-FC fusion protein (rFIXFc), powder for solution, intravenous
- DIN 02422913 - 500 IU/vial, recombinant human coagulation factor IX-FC fusion protein (rFIXFc), powder for solution, intravenous
- DIN 02422921 - 1,000 IU/vial, recombinant human coagulation factor IX-FC fusion protein (rFIXFc), powder for solution, intravenous
- DIN 02422948 - 2,000 IU/vial, recombinant human coagulation factor IX-FC fusion protein (rFIXFc), powder for solution, intravenous
- DIN 02422956 - 3,000 IU/vial, recombinant human coagulation factor IX-FC fusion protein (rFIXFc), powder for solution, intravenous
- DIN 02474034 - 4,000 IU/vial, recombinant human coagulation factor IX-FC fusion protein (rFIXFc), powder for solution, intravenous
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| SNDS # 222096 | 2018-11-19 | Issued NOC2019-10-16 | Submission filed as a Level I - Supplement to update the PM. Revisions were made to the Adverse Reactions, and Clinical Trials sections of the PM, The submission was reviewed and considered acceptable, and an NOC was issued. |
| NC # 226447 | 2019-04-03 | Issued NOL2019-07-05 | Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the specifications for the drug substance and drug product. The submission was reviewed and considered acceptable, and an NOL was issued. |
| SNDS # 219896 | 2018-09-18 | Issued NOC2018-11-23 | Submission filed as a Level I - Supplement to meet the Plain Language Labelling requirements. The updates to the inner and outer labels for all of the strengths were reviewed and considered acceptable, and an NOC was issued. |
| NC # 221021 | 2018-10-16 | Cancellation Letter Received2018-10-23 | Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with additional long-term safety and efficacy data. The proposed revisions exceeded the scope of a Notifiable Change. The submission was therefore cancelled administratively by the sponsor so as to be filed as a SNDS. |
| SNDS # 215257 | 2018-04-06 | Cancellation Letter Received2018-04-19 | Submission filed as a Level I - Supplement to update the label for Alprolix. The changes were not in scope of an SNDS but were considered to be Level III changes. The submission was cancelled by the sponsor. |
| SNDS # 204981 | 2017-04-21 | Issued NOC2018-04-05 | Submission filed as a Level I - Supplement to add a new strength of Alprolix (4,000 IU/vial) and to make changes to the drug substance and drug product manufacturing process. The data were reviewed and considered acceptable, and an NOC was issued. DIN 02474034 was issued pursuant to section C.01.014.2(1) of the Food and Drug Regulations. |
| Drug product (DIN 02422948) market notification | Not applicable | Date of first sale:2018-03-13 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NC # 212246 | 2017-12-19 | Issued NOL2018-01-30 | Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with safety-related changes. As a result of the NC, modifications were made to the Warnings and Precautions, and Adverse Reactions sections of the PM. The submission was reviewed and considered acceptable, and an NOL was issued. |
| Drug product (DIN 02422956) market notification | Not applicable | Date of first sale:2018-01-23 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| Drug product (DIN 024229913) market notification | Not applicable | Date of first sale:2018-01-18 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NDS # 203852 | 2017-03-27 | Issued NOC2017-05-17 | Submission filed to transfer ownership of the product (that is [i.e.] drug sponsor name) from Biogen Canada Inc. to Bioverativ Canada Inc. An NOC was issued. |
| NC # 200290 | 2016-11-15 | Issued NOL2016-12-28 | Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM to reflect revisions in the company core data sheet. As a result of the NC, additions were made to the Warnings and Precautions, Adverse Reactions, and Dosage and Administration sections of the PM, and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and a No Objection Letter was issued. |
| NC # 197875 | 2016-08-19 | Issued NOL2016-12-07 | Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to change the expiry dates for the drug substance, drug product and diluent, to seek approval for a change in the manufacturing site, and a change to the working reference standard qualification protocol. The submission was reviewed and considered acceptable, and an NOL was issued. |
| SNDS # 188247 | 2015-10-19 | Issued NOC2016-08-16 | Regulatory Decision Summary published. |
| Drug product (DINs 02422921, 02422956) market notification | Not applicable | Date of first sale:2016-01-15 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| Drug product (DINs 02422913, 02422948) market notification | Not applicable | Date of first sale:2015-12-11 | The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations. |
| NC # 187846 | 2015-09-16 | Issued No Objection Letter2015-12-09 | Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to update excipient release specifications based on a post-market commitment. The company also provided adequate information to support alternate test sites. The submission was reviewed and a No Objection Letter was issued. |
| NC # 187267 | 2015-09-01 | Issued No Objection Letter2015-11-19 | Submission filed as a Level II (90 day) Notifiable Change (Safety Change) to update the Warnings and Precautions and Toxicology sections of the Product Monograph based on post-market safety information. The company also corrected the company name on the Product Monograph cover to Biogen Canada Inc. The submission was reviewed and a No Objection Letter was issued. |
| NC # 186966 | 2015-08-14 | Issued No Objection Letter2015-11-13 | Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to provide information to support implementation of a new working reference standard (WRS) and the extension of the expiry date of the WRS. The submission was reviewed and a No Objection Letter was issued. |
| NC # 177229 | 2014-08-14 | Issued No Objection Letter2014-11-25 | Submission filed as a Level II (90 day) Notifiable Change (Moderate Quality Changes) to add quality control testing sites, clarify shipping information, extend the reference standard shelf life, revise stability testing, and respond to post-marketing commitments described in Health Canada’s post-decision letter. The submission was reviewed and a No Objection Letter was issued. |
| NDS # 163614 | 2013-03-28 | Issued NOC2014-03-20 | Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Alprolix
Date SBD issued: 2014-08-20
The following information relates to the new drug submission for Alprolix.
Recombinant Human Coagulation Factor IX-FC Fusion Protein (rFIXFc)
250, 500, 1,000, 2,000 and 3,000 IU/vial
Powder for solution
Intravenous
Drug Identification Number (DIN):
- DIN #02422905 - 250 IU/vial, powder for solution
- DIN #02422913 - 500 IU/vial, powder for solution
- DIN #02422921 - 1,000 IU/vial, powder for solution
- DIN #02422948 - 2,000 IU/vial, powder for solution
- DIN #02422956 - 3,000 IU/vial, powder for solution
Biogen Idec Canada Inc.
New Drug Submission Control Number: 163614
On March 20, 2014, Health Canada issued a Notice of Compliance to Biogen Idec Canada Inc. for the drug product, Alprolix.
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 Alprolix is favourable for use in adults and children (≥12 years) with hemophilia B (congenital factor IX deficiency or Christmas disease) for:
- Routine prophylactic treatment to prevent or reduce the frequency of bleeding episodes.
- Control and prevention of bleeding episodes.
1 What was approved?
Alprolix, a long-acting recombinant coagulation factor IX Fc fusion protein, was authorized for adults and children (≥12 years) with hemophilia B (congenital factor IX deficiency or Christmas disease) for:
- Routine prophylactic treatment to prevent or reduce the frequency of bleeding episodes.
- Control and prevention of bleeding episodes.
Clinical studies did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Dose selection for an elderly patient should be individualized.
No data are available for patients below the age of 12 years.
Alprolix is contraindicated for individuals who have manifested severe hypersensitivity reactions, including anaphylaxis, to the product or its components. Alprolix was approved for use under the conditions stated in the Alprolix Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Alprolix (250, 500, 1,000, 2,000, and 3,000 IU/vial Recombinant Human Coagulation Factor IX-FC Fusion Protein (rFIXFc)) is presented as powder for solution. Alprolix is administered by intravenous injection after reconstitution with 0.325% sodium chloride solution. When reconstituted, the non-medicinal ingredients are L-histidine, mannitol, polysorbate 20, sodium chloride, and sucrose.
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 Alprolix Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Alprolix approved?
Health Canada considers that the benefit/risk profile of Alprolix is favourable for adults and children (≥12 years) with hemophilia B (congenital factor IX deficiency or Christmas disease) for:
- Routine prophylactic treatment to prevent or reduce the frequency of bleeding episodes.
- Control and prevention of bleeding episodes.
Hemophilia B is a congenital bleeding disorder occurring predominantly in males, characterized by a deficiency of functional coagulation factor IX (FIX). Hemophilia B results in abnormal clot formation, causing prolonged and abnormal bleeding which may be life-threatening or result in significant morbidity. There is no available cure for hemophilia B; treatment focuses on the replacement of FIX with FIX-containing coagulation products to maintain hemostasis. The current recommended standard of care involves the regular administration (routine prophylaxis) of recombinant FIX (rFIX) to minimize the number of bleeding episodes. Routine prophylaxis has been associated with improvements in long-term outcomes, but is hindered by the need for frequent intravenous (IV) administration of currently available FIX products.
Alprolix has been shown to be efficacious in hemophilia B patients in routine prophylactic treatment and in controlling and preventing bleeding episodes. The market authorization was based on one Phase III study (998HB102) for routine prophylactic and on-demand treatment of bleeding episodes and perioperative management in patients aged 12 years and older with hemophilia B. Additionally, results from a Phase I/IIa safety and pharmacokinetic (PK) study of intravenous FIXFc in previously treated hemophilia B patients (SYN-FIXFc-0007-01) were used as supplementary safety data.
Study 998HB102 was a Phase III multicentre, open-label study that evaluated the safety, pharmacokinetics, and efficacy of rFIXFc in 123 previous treated patients (PTPs) with severe hemophilia B (defined as ≤2 IU/dL endogenous FIX), ≥12 years of age, with ≥100 exposure days (EDs). Patients were assigned to one of four treatment arms based on the clinical site's standard of care and investigator decision. Patients assigned to Arm 1 received fixed weekly prophylaxis with personalized doses, while those on Arm 2 received fixed dose which was administered through an individualized injection interval prophylaxis regimen. Patients assigned to Arm 3 receive an on-demand regimen for treatment of bleeding episodes and those on Arm 4 patients received perioperative management. The primary endpoints of the study for safety and tolerability were clinically notable changes from baseline in laboratory values, incidence of adverse events (AEs), and incidence of inhibitor development. The primary endpoint for efficacy was the number of bleeding episodes (spontaneous and traumatic) with rFIXFc per subject annualized over the study period [comparison between Arms 1 and 2 versus (vs) Arm 3]. Results showed that the subjects in Arms 1 and 2, who received a prophylaxis treatment regimen, had fewer bleeding episodes compared to the subjects in Arm 3 with on-demand treatment regimen. There were 12 subjects included in Arm 4 (perioperative management). One of the subjects in this arm was withdrawn from the study due to multiple injections of a non-study factor IX product during the postoperative period. Based on the submitted information regarding the perioperative management, the current available data was not considered sufficient to support this indication. The safety profile showed that rFIXFc was generally well tolerated. While the comparison of Arms 1 and 2 to Arm 3 was the intended primary analysis, the indication of bleeding prevention was ultimately based on the comparison of the estimated number of bleeding episodes in the 12-month period prior (captured through retrospective collection of data) to study start and the estimated number of on-study bleeding episodes per subject for those subjects in Arms 1 and 2.
The primary objective of the SYN-FIXFc-07-001 study was to assess safety of rFIXFc at doses ranging from 1 to 100 IU/kg. The primary endpoint of safety was evaluated in all treated patients by physical examination, vital signs, electrocardiogram (ECG), laboratory changes over time, AEs, and antibody development. Dose-proportional increases in maximum plasma concentration (Cmax) and area under the curve (AUCinf) were observed for both rFIXFc concentration and FIX activity following the administration of 50 or 100 IU/kg. The mean CL was found to be 3.77 ± 1.12 mL/h/kg in the 50 IU/kg group and 2.89 ± 0.62mL/h/kg in the 100 IU/kg group. In addition, in the 50 IU/kg and 100 IU/kg group respectively, the mean volume of distribution at steady state (Vss) was 264 ± 77.6 and 179 ± 31.0 mL/kg and the mean terminal t1/2 were 52.1 ± 10.4 and 52.5 ± 10.1 hours. The study did have some limitations which included only 10 patients receiving 50 or 100 IU/kg of rFIXFc, the reporting of some protocol deviations, the use of only one lot of frozen liquid drug product, and not re-testing the PK parameters after 3-6 months. Due to these limitations, the results from this study could only be used as supplementary data.
A total of 123 subjects were included in the safety analysis Study 998HB102; 94 of them (76.4%) reported at least 1 AE for a total of 320 AEs. The bleeding episodes in this study were not reported as AEs, and only bleeding events that met serious adverse event (SAE) criteria were reported as SAEs. There were two bleeding related SAEs that were reported: upper gastrointestinal (GI) hemorrhage and obstructive uropathy/hematuria. These two events were resolved under the treatment of rFIXFc, without other non-study FIX and blood products. No SAEs of allergic reactions or anaphylaxis were reported during the study. One subject reported dizziness and oral paraesthesia that may represent a non-serious allergic reaction. Additionally, no thrombotic events were reported.
The efficacy of rFIXFc in the control and prevention of bleeding was also evaluated in Study 998HB102. This study found that, for the control and prevention of bleeding, rFIXc was efficacious. For the control of bleeding, this conclusion was supported by the fact that 90.4% (575 episodes) of bleeding episodes required a single dose of rFIXFc for resolution and that response to the first injection was considered to be excellent or good in 83.7% of bleeding episodes. For the prevention of bleeding, this conclusion was based on the comparability of the observed annualized bleeding rates for subjects on a prior prophylaxis regimen with their prior bleeding rates.
In Study SYN-FIXFc-07-001, after a single dose of rFIXFc, 16 AEs were reported by 7/14 subjects. All AEs were reported by 1/14 subject, except thrombin-antithrombin III complex increased, chills, and hypertension/blood pressure increased, which were reported by 2/14 subjects. Adverse events considered to be at least possibly related to the rFIXFc were dysgeusia and headache which were reported by one subject. No subjects developed inhibitor to FIX activity during either the 998HB102 study or the SYN-FIXFc-07-001 study.
A Risk Management Plan (RMP) for Alprolix was submitted by Biogen Idec Canada Inc. 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 therapeutic benefits seen in the pivotal study are promising and the benefits of Alprolix therapy seem to outweigh the potential risks. Alprolix has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling, and adequate monitoring. Appropriate warnings and precautions are in place in the Alprolix 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 Alprolix?
The sponsor filed a request for Priority Review Status under the Priority Review Policy for the review of the New Drug Submission (NDS) for Alprolix. An assessment was conducted to determine if sufficient evidence was provided demonstrating that the drug provides:
- an effective treatment, prevention or diagnosis of a disease or condition for which no drug is presently marketed in Canada; OR
- a significant increase in efficacy and/or significant decrease in risk such that the overall benefit/risk profile is improved over existing therapies, preventatives or diagnostic agents for hemophilia B, a disease or condition that is not adequately managed by a drug marketed in Canada.
There was insufficient evidence to show that the use of Alprolix results in better clinical outcomes. In addition, based on the information provided in the request, it is unknown if Alprolix with an extended half-life would hold an advantage over the approved therapies in Canada. For these reasons, the informal adjudicator committee determined that the submission did not meet the criteria for Priority Review and therefore the request was denied. The submission was subsequently filed and reviewed as a regular NDS.
Submission Milestones: Alprolix
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2013-01-31 |
| Request for priority status | |
| Filed: | 2013-02-13 |
| Rejection issued by Director, Centre for Blood Tissues Evaluation | 2013-03-06 |
| Submission filed: | 2013-03-28 |
| Screening | |
| Screening Acceptance Letter issued: | 2013-05-24 |
| Review | |
| On-Site Evaluation: | 2014-02-03 - 2014-02-07 |
| Quality Evaluation complete: | 2014-03-20 |
| Clinical Evaluation complete: | 2014-03-19 |
| Biostatistics Evaluation complete: | 2014-03-18 |
| Labelling Review complete: | 2014-03-18 |
| Notice of Compliance issued by Director General: | 2014-03-20 |
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.
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada and have been market notified (that is, the company has told Health Canada the product is being marketed).
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance Document, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision
Clinical Pharmacology
Alprolix, a recombinant coagulation factor IX Fc (rFIXFc) fusion protein, is a long-acting anti-hemophilic factor (recombinant) indicated for patients that have a Factor IX (FIX) deficiency. The FIX portion of Alprolix has similar structural and functional characteristics as endogenous FIX and promotes hemostasis by correcting the deficiency of functional FIX.
The clinical pharmacology of Recombinant Human Coagulation Factor IX-FC Fusion Protein (rFIXFc) in patients with severe hemophilia B was evaluated in the Phase I/IIa study (SYN-FIXFc-07-001) and a subset of subjects in Phase III study (998HB102), and compared with currently available FIX products (BeneFIX).
Together, the clinical and pharmacological data support the use of Alprolix for routine prophylaxis and control of bleeding episodes in patients aged 12 years and older with hemophilia B.
For further details, please refer to the Alprolix Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
The clinical efficacy of Alprolix was evaluated in a Phase III, multicentre, open-label, prospective study (998HB102). The study was designed to assess the efficacy of Alprolix in the treatment and prevention of bleeding episodes. A total of 123 previously-treated patients (PTPs) with severe hemophilia B (defined as ≤2 IU/dL endogenous FIX activity), ≥12 years of age, with ≥100 Exposure Days (EDs) were assigned to one of four treatment arms: Arm 1 (63 patients) had fixed weekly prophylaxis regimen with personalized dose. Arm 2 (29 patients) had individualized injection interval prophylaxis regimen with fixed dose [100 IU/kg (IV)]. Arm 3 (27 patients) had on-demand regimen for treatment of bleeding episodes. Arm 4 (12 patients) was for perioperative management.
Routine Prophylaxis
Patients in Arm 1 received an initial dose of 50 IU/kg once every 7 days and subjects in Arm 2 received a fixed dose of 100 IU/kg at an initial interval of once every 10 days. Following initial pharmacokinetic (PK) evaluation in each subject in Study 998HB102, the dose (for subjects in Arm 1) and dosing interval (for subjects in Arm 2) were further adjusted to achieve trough levels in the range of 1% to 3% above baseline, or higher as clinically indicated for ongoing bleeding.
The primary efficacy analysis in the Phase III multicentre study was the comparison of the annualized bleeding rate per subject between the prophylaxis (Arms 1 and 2) and episodic (Arm 3) regimens. While this comparison was the intended primary analysis, the efficacy of Alprolix for routine prophylaxis was evaluated comparing the on-study bleeding rates to subject-reported retrospective data on prior bleeds. The number of bleeding episodes in the 12 months prior to the study start was collected in the study by the investigator and was derived from source documentation in the subject's medical records. The on-study median (range) annualized bleeding rates for the prophylactic treatment regimens were 2.95 (0.0, 12.8) for Arm 1 [patient number (n) = 61] and 1.38 (0.0, 8.9) for Arm 2 (n = 26). Out of 87 patients who received prophylactic treatment regimen during the study (Arm 1 and 2), 39 patients received prophylactic treatment 12 months prior study. When compared to the number of bleeding episodes in the 12 months prior to study start, the observed annualized bleeding rates for subjects on a prior prophylaxis regimen were comparable to their prior frequency. Those who were treated on a prior episodic regimen experienced a decrease in their annualized bleeding rates when treated with a prophylaxis regimen on study.
In summary, data from Arms 1 and 2 of the study demonstrated that in subjects with hemophilia B, regimens starting at 50 IU/kg every 7 days and 100 IU/kg every 10 days were found to be clinically effective. A regimen of 50 IU/kg once per week or 100 IU/kg every 10 to 14 days will maintain FIX activity levels >1% in the majority of patients with severe hemophilia.
Control and Prevention of Bleeding
The efficacy of Alprolix in the control and prevention of bleeding was evaluated in Study 998HB102. The dose of Alprolix recommended for the treatment of bleeding episodes in the study was based on clinical practice guidelines for patients with severe hemophilia. The recommended target FIX activity level for the treatment of bleeding in the study was 20% to 100% based on the subject's clinical condition, known pharmacokinetics (PK), and type and severity of the bleeding event.
Overall, 575 (90.4%) bleeding episodes required one dose of Alprolix for resolution, and the response to the first injection was considered to be excellent or good in 83.7% of bleeding episodes. The median dose per injection required for resolution of bleeding was 46.1 IU/kg (range 7.9 to 111.1 IU/kg), and the median total dose required per bleeding episode was 47.0 IU/kg (range 7.9 to 263.9 IU/kg). These doses were within the range expected for effective FIX replacement, and were supported by the PK analysis demonstrating incremental recovery (K) values close to 1 IU/dL per IU/kg. Thus, the dose used to control bleeding in the study was approximately 50 IU/kg.
While the study was not designed to evaluate major bleeding episodes, the robust clinical efficacy in controlling bleeding and the incremental recovery close to 1 IU/dL per IU/kg, supports a dose of 100 IU/kg to target a FIX activity level of 80% to 120% for the treatment of major bleeding episodes. Consistent with the prolonged half-life of Alprolix, few subjects required a second injection to control bleeding in the study but in the small number that did, the median time to the second injection was 45.0 hours. Population PK analysis demonstrated a predicted median activity level of 8.62 (5th, 95th percentile: 5.36, 13.2) 48 hours following a 50 IU/kg dose. Thus the clinical data and the population PK analysis both support a 48-hour interval for repeat injection to control bleeding if necessary.
In summary, for the control and prevention of bleeding, Alprolix was efficacious and the dose used was approximately 50 IU/kg with a range of 8 to 111 IU/kg. Taken together, these clinical and PK data support the recommendation that a second dose can be administered, if necessary after 48 hours.
Perioperative Management
A total of 14 surgical procedures, which were performed in 12 subjects and were classified as "major surgery", were provided to support the proposed perioperative management indication. The inclusion as "major surgery" for 8/14 procedures was questionable. The remaining 6 surgeries were knee replacement for 5 subjects, and a large intestine fistula closure for 1 subject. The subject who underwent the large intestine fistula closure received a 2,000 mL blood transfusion during and within 14 days post-surgery, and was subsequently withdrawn from study due to multiple injections of a non-study factor IX product during the postoperative period. The perioperative management using rFIXFc to this patient cannot be considered successful. Therefore, the data submitted was not considered sufficient to support the proposed "perioperative management" indication.
Persistence of Efficacy
Pharmacokinetic (PK) data from Study 998HB102 demonstrated a comparable FIX activity time profile, when measured by the one-stage clotting assay, from baseline to the second Alprolix PK evaluation at approximately 26 weeks in patients in the Sequential PK subgroup of Arm 1. These data support the persistence of efficacy. Data on bleeding episodes continue to be collected in the ongoing extension study.
For more information, refer to the Alprolix Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The clinical safety of Alprolix was evaluated in a Phase I/IIa open-label study (SYN-FIXFc-07-001) and a Phase III open-label study (998HB102).
Study SYN-FIXFc-07-001 evaluated the safety of a single dose of Alprolix in previous treated patients (PTPs) with severe hemophilia B [defined as ≤2 IU/dL (≤2%) endogenous FIX], ≥18 years of age, with ≥100 exposure days (EDs). Ten patients were included in the PK analysis, five of them received 50 IU/kg and five received 100 IU/kg of Alprolix. After a single dose of Alprolix, 16 adverse events (AEs) were reported by 7/14 patients. All AEs were reported by 1/14 subject, except thrombin-antithrombin III complex increased, chills, and hypertension/blood pressure increased, which were reported by 2/14 subjects. AEs considered to be at least possibly related to the Alprolix were dysgeusia and headache that were reported by one patient. No inhibitor has been reported.
The SYN-FIXFc-07-001 study had the following limitations, according to the internationally accepted European Medicines Agency's (EMA) requirement for Factor IX products. First, only 10 patients (not 12 or more) received 50 or 100 IU/kg of Alprolix. Second, only one lot (not 3 or more lots) of frozen liquid, which is not the proposed market drug product, was used. Due to these limitations, the results from this study can only be used as supplementary data.
Study 998HB102 evaluated the safety of Alprolix in 123 previously treated patients (PTPs) with severe hemophilia B (defined as ≤2 IU/dL endogenous FIX), ≥12 years of age, with ≥100 EDs. Patients were to use an electronic patient diary (eDiary) throughout the study to record details of rFIXFc administration, any bleeding episodes, and responses to Alprolix for bleeding episodes. Of the 123 PTPs, 94 of them (76.4%) reported at least 1 AE with a total of 3,230 AEs. Adverse Events (AEs) judged by the Investigator as least possibly related to Alprolix were reported in 10/119 subjects (8.4%) in Arms 1, 2, and 3 combined. These included oral paraexthesia, headache, palpitation, breath odor, fatigue, infusion site pain, dizziness, dysgeusia, obstructive uropathy (hematuria), and hypotension. No subjects (55 subjects with ≥50 EDs) developed an inhibitor to FIX activity during the study. No Serious Adverse Events (SAEs) of allergic reactions or anaphylaxis were reported during the study. One subject reported dizziness and oral paresthesia that may represent a non-serious allergic reaction. No thrombotic events were reported in the study. The bleeding episodes in this study were not reported as AEs, and only bleeding events that met SAE criteria were reported as SAEs. There were two bleeding related SAEs that have been reported: upper gastrointestinal (GI) hemorrhage and obstructive uropathy/hematuria. These two events were resolved under the treatment of rFIXFc, without other non-study FIX and blood products.
Based on clinical review of the efficacy and safety data submitted, the overall benefit/risk profile of Alprolix is considered favorable for routine prophylaxis and control of bleeding episodes in patient aged 12 years and older with hemophilia B.
For more information, refer to the Alprolix Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
An extensive non-clinical program with Alprolix was performed in mice, rats, dogs, rabbits and monkeys to support clinical development and registration for the proposed indications, as well as to support manufacturing changes. The non-clinical program included pharmacokinetic, pharmacology, and toxicology studies. The route of administration in the non-clinical program was intravenous (IV) which matched the route of administration in clinical studies.
Based on the results of these PK studies, in vitro and in vivo pharmacology studies, and toxicology studies, Alprolix has been adequately characterized. Therefore, the non-clinical program supports the clinical development and marketing authorization of Alprolix for the treatment of hemophilia B.
The results of the non-clinical studies as well as the potential risks to humans have been included in the Alprolix Product Monograph. In view of the intended use of Alprolix, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.
For more information, refer to the Alprolix Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.3 Quality Basis for Decision
The Chemistry and Manufacturing information submitted for Alprolix has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes. Changes to the manufacturing process and formulation 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.
All sites involved in production are compliant with Good Manufacturing Practices.
All non-medicinal ingredients (described earlier) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.
No human or animal derived raw materials are used to manufacture the drug substance (25 mM Histidine with 0.01% weight/volume) Polysorbate 20). Similarly, the drug product (Alprolix) is not composed of novel excipients or excipients of human or animal origin.
Characterization of the Drug Substance
The rFIXFc molecule is a heterodimer comprised of the rFIXFc single chain (rFISFc-sc) and an Fc single chain bound together by two disulfide bonds. The rFIXFc subunit is a fusion protein comprised of full length coagulation Factor IX linked to the Fc domain of a human antibody (IgG1 isotype). Experiments including sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), digestion following liquid chromatography mass-spectrometry (LC-MS), ultraviolet-visible (UV-Vis) spectroscopy, fluorescence spectroscopy, circular dichroism, differential scanning calorimetry and analytical ultra-centrifugation as well as various in vitro assays were carried out to characterize this drug substance. All physicochemical and in vitro biological characterization studies were supportive of the proposed rFIXFc structure.
Several product-related impurities were investigated by SDS-PAGE (reducing and non-reducing), analytical ultra-centrifugation, native gel analysis and peptide mapping. Of the impurities tested, levels of oxidation for the five methionine residues in rFIXFc were determined, but were deemed to have negligible effects on coagulation activity. Thus, they were not among the release specifications. The other potential product-related impurities tested are controlled in the release specifications, which is considered acceptable.
Several process related impurities were also investigated; most of which were found to be within acceptable limits and not included among the release specifications. Levels of host cell protein, however, were noted and will be controlled in the release specifications.
Thus, results from process validation studies indicate that the processing steps adequately control the levels of product- and process-related impurities. The impurities that were reported and characterized were found to be within established limits.
Manufacturing Process and Process Controls of the Drug Substance and Drug Product
The manufacturing process of the drug substance consists of a series of stages which include fermentation, cell processing, purification, cell culture, product recovery, filtration, dispensing and storage. The purification process includes the isolation of inclusion bodies and a combination of chromatographic (viral clearance) steps. The materials used in the manufacture of the drug substance are considered suitable and/or meet standards appropriate for their intended use.
The manufacturing process of the drug substance was updated during review to restrict limits for bioburden for cell harvest and downstream processes. As a result, this process is considered to be well-defined and appropriately controlled for critical steps and intermediates.
The manufacturing process for the drug product consists of three main steps: compounding, sterile filtration and aseptic filling, and lyophilisation. The drug product is a sterile lyophilized powder. It is supplied in aseptically filled single use vials which contain nominally 250, 500, 1,000, 2,000, and 3,000 IU per vial.
The method of manufacturing and the controls used during the manufacturing process for the drug product are valid and considered to be adequately controlled within justified limits.
Control of the Drug Substance and Drug Product
The drug substance and drug product release and stability testing are both performed at two separate facilities. All method validations are considered acceptable save for the rFIXFc assay, which was not formally validated. Adequate data were, however, provided to support the use of this assay for drug substance and drug product release testing at only one site. The sponsor has committed to provide further validation of the potency assay at the second site. The execution of this assay will be restricted to the first site in the interim.
Each lot of Alprolix drug product is tested against suitable reference standards to verify that they meet approved specifications. Sample testing of Alprolix and Certificate of Analysis testing confirm that the sponsor is able to manufacture Alprolix with consistent quality. However, supporting documentation including Certificates of Analysis and Certificates of Manufacture for the bulk Drug Substance batches and Drug Product lots must be submitted for review and testing prior to release on the Canadian market.
Stability of the Drug Substance and Drug Product
The results of the submitted stability data demonstrate that the drug substance is stable for at least 36 months when stored at 70°C ± 10°C.
With respect to the drug product, interim and completed stability studies for eleven commercial scale Alprolix lots were evaluated. Stability of drug product batches were evaluated at 5°C and 30°C. As well, additional studies support a 6-month period at 30°C following prolonged storage at 5°C. Stability data demonstrated that Alprolix is stable at 5°C; however, at 30ºC over 36 months, increasing moisture with decreasing rFIXFc activity and specific activity were noted. Based on these data, a shelf-life limit of 36 months when stored at 5°C ± 3°C, with 6 months at room temperature up to 30°C, and 3 hours in-use time for Alprolix is considered acceptable.
Data was provided to support the suitability of the container closure components and container closure integrity.
The proposed packaging and components are considered acceptable.
Facilities and Equipment
A pre-approval On-site-evaluation (OSE) was conducted at manufacturing facility for the drug substance, but not that for the Drug Product.
The OSE of the facilities involved in the manufacturing and testing of the drug substance was conducted by the Biologics and Genetic Therapies Directorate, Health Canada. Issues noted [particularly an issue related to deficient validation of the Factor IX-Fc activated partial thromboplastin time (aPTT) Potency assay] were successfully addressed by the manufacturer.
An OSE of the facilities involved in the manufacture and testing of the drug product was not conducted. Based on a previous pre-approval inspection of this site, its regular Good Manufacturing Process (GMP) inspections, the available information on the facility and the manufacturing history of the facility for other approved products, the facility was deemed to be acceptable for the Alprolix drug product manufacture.
Adventitious Agents Safety Evaluation
The rFIXFc manufacturing process incorporates adequate control measures to prevent contamination and maintain microbial control.
While the cell line used to manufacture the drug substance is human, cell bank testing showed it to be free of bacteria, fungi, mycoplasma and adventitious viruses (including bovine and porcine viruses, reverse transcriptase and human viruses). As well, raw materials are controlled and the unprocessed bulk harvest is tested regularly for the presence of bacteria, fungi, mycoplasma and adventitious viruses. Finally, purification columns and nanofiltration were identified as viral clearance steps.
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| ALPROLIX | 02422913 | SANOFI-AVENTIS CANADA INC | RECOMBINANT HUMAN COAGULATION FACTOR IX, FC FUSION PROTEIN 500 UNIT / VIAL |
| ALPROLIX | 02422948 | SANOFI-AVENTIS CANADA INC | RECOMBINANT HUMAN COAGULATION FACTOR IX, FC FUSION PROTEIN 2000 UNIT / VIAL |
| ALPROLIX | 02422956 | SANOFI-AVENTIS CANADA INC | RECOMBINANT HUMAN COAGULATION FACTOR IX, FC FUSION PROTEIN 3000 UNIT / VIAL |
| ALPROLIX | 02422905 | SANOFI-AVENTIS CANADA INC | RECOMBINANT HUMAN COAGULATION FACTOR IX, FC FUSION PROTEIN 250 UNIT / VIAL |
| ALPROLIX | 02422921 | SANOFI-AVENTIS CANADA INC | RECOMBINANT HUMAN COAGULATION FACTOR IX, FC FUSION PROTEIN 1000 UNIT / VIAL |