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Summary Basis for Regulatory Action - ALPROLIX

 Summary Basis for Regulatory Action

Date

28 March 2014

From

Nancy Kirschbaum, PhD, Committee Chair

Subject

Summary Basis for Regulatory Action

BLA #

BL STN 125444/0

Applicant

Biogen Idec, Inc.

Date of Submission

28 December 2012

PDUFA Goal Date

29 March 2014

Trade Name/Proper Name

ALPROLIX™/Coagulation Factor IX (Recombinant), Fc Fusion Protein

Dosage form

Lyophilized powder with nominal potencies: 500 IU, 1000 IU, 2000 IU or 3000 IU per vial

Proposed Indication(s)

Indicated in adults and children with Hemophilia B for:

  • Control and prevention of bleeding episodes,
  • Perioperative management,
  • Routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

ALPROLIX™ is not indicated for induction of immune tolerance in patients with Hemophilia B.

Recommended Action

Approval

Signatory Authority Action

Jay Epstein, MD___________________
Offices Signatory Authority
 I concur with the summary review
 I concur with the summary review and include a separate review or addendum to add further analysis
 I do not concur with the summary review and include a separate review or addendum

Mary Anne Malarkey___________________
Offices Signatory Authority
 I concur with the summary review
 I concur with the summary review and include a separate review or addendum to add further analysis
 I do not concur with the summary review and include a separate review or addendum

 

Discipline Review

Clinical Review

Stephanie Omokaro

Clinical Pharmacology Review

Carl-Michael Staschen

Statistical Review

Judy Li

Chemistry, Manufacturing and Controls Review

Ellen Huang, Nancy Kirschbaum, Andrey Sarafanov, Ze Peng

Establishment Inspection Report

Priscilla Pastrana, Marion Michaelis, Jie He, Nancy Kirschbaum

Pharmacology / Toxicology Review

La’Nissa Brown

Bioresearch Monitoring Review

Anthony Hawkins

Pharmacovigilance Review

Bethany Baer

Labeling Review

Loan Nguyen, Nisha Jain, Stephanie Omokaro, Nancy Kirschbaum, Carl-Michael Staschen, Bethany Baer

Lot Release Coordination /In-Support Testing

Catherine Poole, Alfred Del Grosso, Igor Bacik, Hyesuk Kong, Hsiaoling Wang

Regulatory Project Manager

Edward Thompson

1.     Introduction
Biogen Idec, Inc. (Biogen)has submitted an original biologics license application (BLA) to seek US licensure for Coagulation Factor IX (Recombinant), Fc Fusion Protein. The intended commercial product is a lyophilized powder in a crimp-sealed, stoppered, glass vial, available in nominal dosage strengths of 500, 1000, 2000 or 3000 international units of Factor IX potency.  The product is reconstituted with the provided diluent [0.325% (w/v) sodium chloride], for intravenous administration. The proprietary name of the intended US marketed product is ALPROLIX™.

ALPROLIX™ is indicated in adults and children with Hemophilia B (congenital Factor IX deficiency) for: (1) control and prevention of bleeding episodes, (2) perioperative management, and (3) routine prophylaxis to prevent or reduce the frequency of bleeding episodes. ALPROLIX™ is not indicated for induction of immune tolerance in patients with Hemophilia B.

2.     Background
Hemophilia B (Christmas disease) is a rare, hereditary, hematologic disorder caused by deficiency or dysfunction of Coagulation Factor IX, resulting in bleeding secondary to abnormal clot formation. Because the Factor IX gene is located on the X-chromosome, Hemophilia B has an X-linked inheritance pattern, affecting 1 in 100,000 male births. There is no available cure for Hemophilia B. To promote clotting, treatment includes replacement of the deficient Factor IX by intravenous administration of a purified Coagulation Factor IX concentrate. Both plasma-derived and recombinant DNA-derived Coagulation Factor IX concentrates are commercially available. In recent years, treatment regimens have shifted from on-demand treatment of bleeding episodes to routine prophylaxis because of observed improvement in long-term, clinical outcome. Patients on routine prophylaxis regimens have been non-compliant, however, because of the short molecular half-life of infused Factor IX, (mean 18 to 22 hours), necessitating frequent product infusions. ALPROLIX™, Coagulation Factor IX (Recombinant), Fc Fusion Protein [rFIXFc], was designed to provide a long acting, coagulation active Factor IX for less frequent dosing in routine prophylaxis regimens for Hemophilia B patients.

Coagulation Factor IX (Recombinant), Fc Fusion Protein [rFIXFc], the active ingredient in ALPROLIX™, is a recombinant fusion protein comprising the human Coagulation Factor IX sequence linked to the Fc domain of human immunoglobulin G1 (IgG1). The Factor IX portion of rFIXFc has a primary amino acid sequence that is identical to the Thr148 allelic form of plasma-derived Factor IX and has structural and functional properties similar to endogenous Factor IX. The Fc domain of rFIXFc contains the hinge, CH2, and CH3 regions of IgG1. The Fc portion of the rFIXFc fusion protein allows it to bind the neonatal Fc receptor (FcRn), which is part of a naturally occurring pathway that prolongs circulating half-life.

Clinical trials that provided the evidence for safety and efficacy of ALPROLIX™ were conducted under IND 13487. To support licensure for the proposed indications, the clinical development program included: (1) a single dose pharmacokinetic (PK) study, (2) a non-randomized, open-label treatment phase where subjects received either one of two prophylaxis regimens (every 7 days or every 10 days) or on-demand treatment for at least 50 exposure days (ED), and (3) a perioperative prophylaxis study. Interim analysis data from an ongoing PK and safety study in pediatric subjects were also considered. Biogen has agreed to complete an ongoing extension study evaluating the long-term efficacy and safety of ALPROLIX™ as a post-marketing commitment. Study completion is anticipated for December 2018. A final study report will be submitted to FDA by December 2019.

ALPROLIX™ is not currently approved or marketed in any country.

This original BLA was reviewed under the PDUFA V program (Standard 12 Month) and included the review milestones listed in Table 1.
Table 1: Review Milestones


Milestone

Date

Received

28 December 2012

Filing date

28 February 2013

Mid-cycle communication

11 June 2013

Late cycle meeting

12 September 2013

Advisory Committee

Waived

Major amendment

20 November 2013

Action Due

29 March 2014

Chemistry, Manufacturing and Controls issues discussed and resolved during BLA review
Validation of the lyophilization process
Biogen initially provided the lyophilization technical runs, lyophilization parameter operating range studies, and process consistency validation runs to demonstrate validation of the lyophilization process. The studies provided insufficient data to support the final lyophilization cycle. Deficiencies included: failure to provide an adequate empty chamber shelf temperature mapping study, failure to perform a full-scale product temperature mapping study, and failure to perform any extended sampling of either the maximum or minimum lyophilization loads. Furthermore, none of the initial studies provided evaluated the final lyophilization production cycle the firm employed to lyophilize the conformance lots. Discussions about the validation of the lyophilization process began on July 1, 2013 and eight teleconferences were held with the firm to resolve these deficiencies. The firm submitted a total of nine amendments about lyophilization. Biogen provided additional empty chamber shelf temperature mapping studies in amendments 39 and 41. Product temperature mapping studies and extended sampling results of the maximum and minimum lyophilization loads for the (b)(4) IU and 3000 IU product strengths were provided in amendments 45 and 48.

Establishment of in-process controls that reflect manufacturing capability
Biogen’s originally proposed in-process specifications (IPS) for bioburden and endotoxin far exceeded values obtained during manufacture with the validated process. They were, therefore, considered inadequate for proper routine, commercial process control. At mid-cycle, the Agency requested that Biogen establish IPS more reflective of manufacturing experience. Biogen proposed revised acceptance limits in amendment 21; however, the proposed limits still far exceeded manufacturing experience. Biogen further revised IPS for bioburden and endotoxin in amendment 28, which were accepted by the Agency.

Establishment of release specifications that reflect clinical use, ensure clinical safety and product quality, and reflect the validated manufacturing process
At mid-cycle, the Agency requested that Biogen establish enhanced routine release testing for     --------(b)(4)------ and impurities --------------------(b)(4)------------------- in the drug product, and that acceptance criteria be revised to reflect clinical and manufacturing experience. Biogen proposed enhanced release testing in amendment 21 that was accepted by the Agency.

Definition of a compendial assay
Biogen had originally claimed that it was not necessary to fully validate its Factor IX potency assay because it complied with the applicable ---------------------(b)(4)------------------. At mid-cycle, the Agency informed Biogen that the US statutory definition of compendial did not include the -----------(b)(4)----------- and that complete method validation was required. Biogen provided complete method validation in amendment 21.

3. Chemistry, Manufacturing and Controls (CMC)
a) Product Quality and Manufacturing Control
Product Quality Attributes
Description
ALPROLIX™ is a sterile, non-pyrogenic, preservative-free, white to off-white, lyophilized powder for reconstitution with the provided diluent, for intravenous injection. After reconstitution, the solution has a clear to slightly opalescent appearance and contains the excipients: sucrose, mannitol, sodium chloride, L-histidine and polysorbate 20. ALPROLIX™ is available in single-use vials containing nominal Factor IX potencies of 500, 1000, 2000 or 3000 international units (IU). Each ALPROLIX™ vial is labeled with the actual IU of Factor IX potency.

Analytical Characterization
Coagulation Factor IX (Recombinant), Fc Fusion Protein is the active ingredient in ALPROLIX™. It is a recombinant DNA-derived fusion protein. It is not purified from human blood. The active fusion protein contains full-length human Factor IX sequence linked to the disulfide bonded human IgG1 Fc sequence. It contains 867 amino acids and has a molecular weight of approximately 98 kilodaltons. Several batches of clinical and commercial scale drug substance and drug product were characterized for ----------------(b)(4)---------------------------- modifications including ------------------------------------(b)(4)----------------------------------------------------. Drug substance batches were also characterized by --------------------(b)(4)---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

Impurities
Product and process related impurities were identified and characterized in several batches of      --------(b)(4)-------- drug product that were studied in clinical trials. Removal of product and process related impurities by the commercial manufacturing process was demonstrated during process development and process validation.

Endogenous Factor IX circulates as an inactive zymogen. Upon cleavage at two specific sites within the molecule, Factor IX becomes an activated serine protease. Premature cleavage and activation of rFIXFc leads to product impurity, rFIXaFc (activated Factor IX, Fc fusion protein). rFIXaFc is considered a critical product related impurity because activated Factor IX in other products has been reported to be associated with thromboembolic adverse events. Therefore, Biogen was asked to establish rFIXaFc specifications for ---------(b)(4)-------- drug product release to reflect levels in lots studied in clinical trials.

Coagulation Factor IX (Recombinant), Fc Fusion Protein is produced from a human embryonic kidney (HEK) cell line. Host cell protein impurities are considered critical because of their potential for immunogenicity even when derived from a cell line of human origin. Therefore, Biogen was asked to establish a -------(b)(4)------ release specification for HEK proteins.

Drug Product Release Specification
The drug product release specification was derived from characterization data for (b)(4) commercial scale lots, many of which were studied in clinical trials. The final product release specification in Table 2 is considered adequate to confirm product quality and manufacturing consistency.
Table 2: Final Product Release Specification


Test

Method

Acceptance Criteria

Quality

Appearance

Visual inspection

White to off-white powder to cake

Appearance after reconstitution

Visual inspection

Color: (b)(4)
Clarity: (b)(4)
Practically free from visible particles

Reconstitution time

-(b)(4)-

(b)(4)

(b)(4)

--(b)(4)--

-(b)(4)-

---(b)(4)----

  • ----(b)(4)----
  • --(b)(4)--

--(b)(4)--

 

---------(b)(4)----------
--------------------------

Identity

Factor IX potency

-----(b)(4)-----

Meets biological activity specification

Protein profile

--------(b)(4)--------

Compares to reference

Protein profile

----------(b)(4)---------

Compares to reference

Potency

Factor IX potency

One stage clotting

500 IU vial: -(b)(4)- IU/vial
1000 IU vial: -(b)(4)- IU/vial
 2000 IU vial: -(b)(4)- IU/vial
 3000 IU vial: -(b)(4)- IU/vial
(b)(4) IU/mg

FcRn potency

----(b)(4)----

----(b)(4)----

Protein

(b)(4)

-(b)(4)-

Purity

Residual Moisture

--------(b)(4)--------

---------(b)(4)----------

Purity

----------(b)(4)----------

-----(b)(4)------
------------------------------------------

Product impurities

---------(b)(4)----------

-----(b)(4)-----
------------------------------
-----------------------
-------------------------------------

Product impurities

----(b)(4)----

-----(b)(4)-----
-----------------------
------------------------------
----------------------

Activated rFIXFc

-(b)(4)-

≤0.035 mol% rFIXFc

Excipients

L-histidine

----(b)(4)----

------------(b)(4)-------------

D-mannitol

---------(b)(4)---------

------------(b)(4)-------------

Sucrose

-----------(b)(4)------------

------------(b)(4)-------------

Polysorbate 20

------------(b)(4)-----------

------------(b)(4)-------------

Safety

Particulates

---(b)(4)---

-------(b)(4)----------
------------------------

Endotoxin

---(b)(4)---

  -------(b)(4)------------
 ------------------------------------------

Sterility

---(b)(4)---

----(b)(4)----

At each significant phase of pre-market development, product quality was linked to manufacturing control through a robust comparability program that integrated nonclinical animal studies and clinical trial experience with extensive analytical characterization.

Manufacturing Control
Process Description
Coagulation Factor IX (Recombinant), Fc Fusion Protein drug substance is produced --(b)(4)--
---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------           ---------------------------------------------------------------------------------------------------------------       ------------------------------------------------------------------------------------------------------------------   ------------------------------------------------------------------------------------------------------------           ------------------------------------------------------------------------------------------------------------------   --------------------------------------------------------------------------------
 
Drug product manufacture is performed at a contract manufacturer. -------------(b)(4)--------------------------------------------------------------------------------------------------------------------------------     ---------------------------------------------------------------------------------------------------------------       ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------. Final vial labeling and packaging of the commercial drug product kit are performed at Biogen Idec or other designated sites. Each drug product kit contains a product vial, pre-filled diluent syringe, plunger rod and vial adapter.

Source material quality and control
Human Embryonic Kidney, ---------------------------------(b)(4)-----------------------------------          ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------  ---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------    --------------------------------------------------------------------------------------------------------------------- adventitious agents safety, genotypic quality and phenotypic quality consistent with recommendations in ICH and FDA guidance. ---------------------------(b)(4)-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------. The manufacturing process for rFIXFc does not use materials or reagents of animal or human origin.

Critical Process Steps
The manufacturing process for rFIXFc incorporates two manufacturing steps validated to clear relevant viruses: (1) a nanofiltration step and (2) a column chromatography step.
Critical Process Parameters and Their Control
Biogen implemented quality risk assessment tools and process characterization studies to define an in-process control strategy and terminology consistent with definitions in the Q8(R2) guideline and accepted industry practice. Process inputs (operational controls) and process outputs (quality controls) have been categorized as critical, key or non-key parameters according to determined potential product or process performance impact. Non-key process inputs (N-KCP) are controlled by monitoring operating ranges. Critical (CCP) or key (KCP) inputs are controlled by action limits. Critical outputs [termed, “critical in-process controls (CIPC)” or “critical in-process tests (CIPT)”] are controlled through action limits or in-process specifications (IPS). In-process controls for each manufacturing operation have been established and justified.

Process Validation
Three drug substance conformance batches were manufactured at Biogen Idec’s Large Scale Manufacturing facility located in -------------(b)(4)-------------. The conformance batches were manufactured through -----------------------------------------(b)(4)--------------------------------------------------------------------------. The three drug substance conformance batches are listed in Table 3. Only batch -----(b)(4)----- was monitored for long-term stability.

Table 3: Drug Substance Conformance Batches


Batch Number

Date of Manufacture

-------(b)(4)-------

-------(b)(4)-------

-------(b)(4)-------

-------(b)(4)-------

-------(b)(4)-------

-------(b)(4)-------

For drug product, conformance lot validation was conducted at the contract manufacturing facility, ------------------------------------------------(b)(4)---------------------------------------------------, through manufacture of: (a) three (b)(4) IU lots, (b) three 3000 IU lots and (c) one lot each of the 500 IU, 1000 IU or 2000 IU dosage presentations, covering minimum and maximum lot sizes. Conformance lot information is listed in Table 4.   
Table 4: Drug Product Conformance Lots


Lot

Dose

DS Batch

Date of Manufacture

Batch size

Bulk (L)

Number of vials

--(b)(4)--

--(b)(4)--

--(b)(4)--

------(b)(4)------

--(b)(4)--

--(b)(4)--

--(b)(4)--

--(b)(4)--

--(b)(4)--

------(b)(4)------

--(b)(4)--

--(b)(4)--

--(b)(4)--

--(b)(4)--

--(b)(4)--

------(b)(4)------

--(b)(4)--

--(b)(4)--

--(b)(4)--

500 IU

--(b)(4)--

------(b)(4)------

--(b)(4)--

--(b)(4)--

--(b)(4)--

1000 IU

--(b)(4)--

------(b)(4)------

--(b)(4)--

--(b)(4)--

--(b)(4)--

2000 IU

--(b)(4)--
-----------

------(b)(4)------

--(b)(4)--

--(b)(4)--

--(b)(4)--

3000 IU

--(b)(4)--
------------

------(b)(4)------

--(b)(4)--

--(b)(4)--

--(b)(4)--

3000 IU

--(b)(4)--
-----------
-----------

------(b)(4)------

--(b)(4)--

--(b)(4)--

--(b)(4)--

3000 IU

--(b)(4)--
------------

------(b)(4)------

--(b)(4)--

--(b)(4)--

Process and quality controls for conformance batch/lot manufacture complied with prospectively defined acceptance criteria for successful process validation.

Analytical Methods
Suitable analytical methods have been validated to support quality control throughout manufacture, final product release and stability monitoring. An acceptable reference standard qualification and maintenance program has been established.

Container/Closure System
The primary container closure system for ALPROLIX™ drug product comprises a 10 mL, -----(b)(4)-------- glass vial sealed with a 20 mm, --------(b)(4)-------, chlorobutyl stopper crimped with an aluminum seal with a ------(b)(4)------- flip-off cap. A different cap color identifies each vial dosage. Dimensional drawings, specifications and letters of authorization to applicable drug master files for each component were provided. Container closure safety and performance were qualified through extractables, leachables and container closure integrity testing (CCIT) in addition to final product monitoring in the established stability program.

Stability
Stability data submitted to BL STN 125444/0 supported a final container shelf-life of 36 months when stored at 2 – 8oC. During this 36 month shelf-life, the product may be stored for up to 6 months at room temperature not to exceed 30oC. The available stability data indicated no negative trends during the observed long-term storage period. The reconstituted product may be stored at 2 – 30oC for up to 3 hours. The product should be protected from light. 

Adventitious Agents Safety
Non-viral pathogen safety
Microbial safety is ensured through control of bioburden in source materials, adherence to current Good Manufacturing Practice, in-process quality control monitoring, validated sterile filtration and aseptic filling processes, and release and stability testing for sterility and endotoxin.

Viral safety
All cell banks have been demonstrated to be free of infectious viruses. The manufacturing process does not use animal-derived raw materials. The -----------(b)(4)------------ from every cell production campaign is directly tested for infectious virus on relevant cell culture systems. The manufacturing process incorporates a -(b)(4)- nanofiltration step and a column chromatography step, which collectively have been validated to remove at least 10 logs of enveloped virus and at least 6 logs of non-enveloped virus. The viral safety profile for ALPROLIX™ is considered acceptable. Biogen committed to submission of a prior approval supplement to FDA for the implementation of a second generation rFIXFc process, which includes incorporation of a -----(b)(4)------ step.

b) CBER Lot Release and In-support testing
Routine lot-by-lot release by CBER is not required for ALPROLIX™ because it is a well-characterized recombinant product.

The Division of Biological Standards and Quality Control has performed in-support testing of commercial scale ALPROLIX™ product lots of –(b)(4)- IU, 1000 IU and 3000 IU nominal potency. Test results for (b)(4), appearance, reconstitution, endotoxin, ---(b)(4)--- and Factor IX potency were deemed consistent with the proposed commercial release specification.
c) Facilities review and inspection
The manufacture of rFIXFc drug substance is performed at Biogen Idec’s ---------(b)(4)-------------------------------------- facility. Manufacture of the drug product is performed at the contract manufacturer, -----------------------------------------------(b)(4)-------------------------------------------. Manufacture of the diluent is performed at the contract manufacturer, ------------(b)(4)-----------------------------------------------------------------.

Biogen Idec ----------------------(b)(4)---------------------- Facility
Biogen Idec Building -------------------------------(b)(4)--------------------------- is used for the manufacture of the rFIXFc drug substance. -----------------------------(b)(4)-------------------------------------------------------------------------------------------------------------------------------------               ---------------------------------------------------------------------------. This facility was inspected by the FDA for the rFIXFc BLA.

----------------(b)(4)-------------- Facility
------------------------------------------------------(b)(4)-------------------------------------------------------------------------------- is a contract manufacturing facility for drug product manufacture.  The facility was last inspected by ORA from ----(b)(4)----- for manufacturing processes similar to that of rFIXFc, and the inspection was classified as, “No Action Indicated (NAI).”  The previous inspection of the facility (---------(b)(4)-------------) was classified as, “Voluntary Action Indicated (VAI).”

-----------------(b)(4)-------------- Facility
--------------------------------------------------------(b)(4)------------------------------------------------------------------------------- is a contract manufacturing facility for syringes pre-filled with the diluent for reconstitution [0.325% (w/v) sodium chloride].  The facility was last inspected by ORA from ----------(b)(4)------- and the inspection was classified as VAI. The previous inspections of the facility (----------------------------(b)(4)-------------------------------) were also classified as VAI. Manufacturing operations that were similar to those used to produce the diluent for rFIXFc were included in the scope of those inspections.

CBER Pre-license Inspection
CBER performed a pre-license inspection (PLI) of Biogen Idec’s ---------------(b)(4)---------------- facility from -------(b)(4)-------. The inspections of -------------------(b)(4)------------------- facilities in ---(b)(4)--- were waived per SOPP 8410.

The PLI of the ----------(b)(4)---------- facility covered the manufacturing process for rFIXFc drug substance, which includes --------------------------------(b)(4)-------------------------------------------------------------------------------------------------------------------------. The PLI covered Quality, Facility & Equipment, Materials Management, Production, Packaging & Labeling, and Laboratory Controls Systems with respect to the manufacture of rFIXFc drug substance. At the conclusion of the inspection, CBER issued Form FDA 483 with six observations. A summary of the issues is as follows: (i) deficient segregation of pre-viral and post-viral manufacturing processes, (ii) lack of instructions for the ------------------------(b)(4)------------------------, (iii) inappropriate labeling of the manufacturing -----(b)(4)-----, (iv) inadequate control of Factor IX Fc potency assay, (v) inadequate program for qualification and use of analytical control preparations in the determination of Factor IX Fc potency and activated Factor IX Fc impurity, and (vi) inadequate procedures to address false positive samples for the ----------(b)(4)--------------------------------------------------. Biogen Idec provided corrective actions to address the 483 items. The corrective actions were reviewed and found to be adequate. All inspectional issues are considered to be satisfactorily resolved.

d) Environmental Assessment
The BLA included a request for a categorical exclusion from an Environmental Assessment under 21 CFR § 25.31(c). The FDA concluded that this request was justified as the manufacture of this product will not alter, significantly, the concentration and distribution of naturally occurring substances and no extraordinary circumstances exist that would require an environmental assessment.

e) Recommendation
The manufacturing process for ALPROLIX™ is considered validated at the commercial scale and is sufficiently controlled to assure consistent manufacture of commercial product meeting acceptable release specification. Inspectional issues were adequately addressed. The reviewers from the Division of Hematology, the Division of Manufacturing and Product Quality and the Division of Biological Standards and Quality Control have concluded that Biogen has provided sufficient data and information on chemistry, manufacturing and controls to support the licensure of ALPROLIX™.

4. Nonclinical Pharmacology/Toxicology
a) Pharmacological/Toxicological Findings
The nonclinical program consisted of a series of studies to demonstrate the safety and effectiveness of rFIXFc in animals including: (a) safety pharmacology in mice and dogs, (b) proof-of-principle in Hemophilia B mice and dogs, (c) dose range finding in mice, (d) repeat dose toxicity, including toxicokinetics, in rats and monkeys, (e) immunogenicity in rats and monkeys, (f) local tolerance in rabbits, (g) thrombogenic potential in rabbits, (h) subchronic toxicity with toxicokinetics in monkeys, (i) pharmacokinetics in rats, monkeys, mice and dogs and (j) hemostasis activity of rFIXFc in Hemophilia B mice and dogs to support the proposed clinical indications. Relevant animal models were studied, including: Hemophilia B mice and dogs, wild-type Factor IX expressing rats, mice, rabbits and dogs, and ----(b)(4)---- monkeys.

Overall, the nonclinical safety profile of rFIXFc did not identify any unexpected findings or significant concerns; toxicities that were observed were due to exaggerated pharmacological effect of excess amounts of Coagulation Factor IX, which are expected for products in this class. rFIXFc was tested acutely in animals at doses up to 1000 IU/kg, (i.e., 12.5 times the intended median perioperative clinical dose of 80 IU/kg). Repeat-dose toxicity studies were completed with daily dosing of up to 1000 IU/kg for up to 27 weeks, (i.e., 13.3 times the intended, median prophylactic clinical dose of 75 IU/kg). Animal study results supported results from clinical trials investigating safety and efficacy of rFIXFc prophylaxis regimens.  In animal studies, the exaggerated pharmacological effects of rFIXFc that were considered adverse included hypersensitivity, thrombogenic events and local reactions at the treatment site, and were reported after repeat dosing with rFIXFc doses 10-fold greater (i.e., 1000 IU/kg rFIXFc) than the proposed maximum (median) clinical dose of 100 IU/kg in the repeat dose setting. Toxicokinetic profiles demonstrated a linear dose-dependent increase in the levels of Factor IX, followed by a time-dependent decrease in product levels. This profile was maintained until anti-product antibody formation occurred, resulting in decreased Factor IX activity. The formation of anti-product antibodies in animals is not unexpected and is not predictive of an immunogenic response to rFIXFc in humans. There were no reports of neutralizing anti-Factor IX antibodies or anaphylaxis in clinical trials of rFIXFc.

Based on the intended use of rFIXFc, nonclinical reproductive or developmental toxicity studies, long-term animal studies to evaluate carcinogenic potential, and studies to determine genotoxicity and effects of ALPROLIX™ on fertility were neither required according to ICH guidelines nor performed. A toxicological risk assessment was completed on extractables and leachables associated with the ALPROLIX™ manufacturing process and container closure system. There were no concerns regarding impurities or unexpected toxic effects that would require additional studies.

b) Recommendation
The results from the nonclinical program suggested that treatment of Hemophilia B patients with ALPROLIX™ will be reasonably safe for use for the labeled clinical indications. The toxicological risk assessment and results from nonclinical studies support approval of BL STN 125444/0.

5. Clinical Pharmacology

  1. Mechanism of Action

ALPROLIX™ is a recombinant fusion protein that temporarily replaces the missing Coagulation Factor IX needed for effective hemostasis. ALPROLIX™ contains the Fc region of human IgG1, which binds to the neonatal Fc receptor (FcRn). FcRn is part of a naturally occurring pathway that delays lysosomal degradation of immunoglobulins by cycling them back into circulation, and prolonging their plasma half-life.

  1. Pharmacokinetics

The pharmacokinetics (PK) of ALPROLIX™ were evaluated in 22 previously treated patients (PTP) for up to 240 hr., following a 10 minute intravenous infusion of a single dose of 50 IU/kg. The PK parameters presented in Table 5 were based on plasma Factor IX activity measured by a one-stage clotting assay.
Table 5: Pharmacokinetic Parameters


PK Parameters

Arithmetic Mean (CV)

Cmax (IU/dL)

46.04 (68.3%)

AUCinf (h*IU/dL)

1619.1 (26.1%)

CL (mL/kg/h)

3.304 (28.4%)

Vss (mL/kg)

327.0 (28.2%)

Terminal T1/2 (h)

86.52 (37.2%)

MRT (h)

101.96 (29.7%)

IR (IU/dL per IU/kg)

1.0154 (58.7%)

Time to 1% Factor IX activity (days)

11.489 (23.8%)

Abbreviations: IR = incremental recovery; AUCinf = area under the FIX activity time curve;
T1/2 = elimination half-life; MRT = mean residence time; CL = body weight adjusted clearance;
Vss = body weight adjusted volume of distribution at steady-state,

The PK parameters following a 100 IU/kg dose of ALPROLIX™ were evaluated in a subset of 27 subjects in study 998HB102.   For this subset, the mean drug clearance (CL) was 2.65 (21.7%) mL/kg/h, the maximum activity (Cmax) was 99.89 IU/dL (20.1%) and the time to 1% Factor IX activity was 15.8 days (21.3%). The ALPROLIX™ PK profile was comparable at week 26 with the PK profile after the first dose. 

PK parameters for adolescents (12 to 17 years of age) and children (2 to 11 years of age) were evaluated in open-label, multicenter studies of previously treated patients. In one study, PK parameters were evaluated in 11 adolescents for up to 336 hr. (14 days) following a single, 10 minute infusion of ALPROLIX™. In a separate study, PK parameters were evaluated in 18 children, 2 to 11 years of age, for up to 168 hr. (7 days) following a single dose of ALPROLIX™. PK parameters were estimated based on the plasma Factor IX activity over time profile. Table 6 presents the PK parameters calculated from the pediatric data of 29 subjects, 2 to 17 years of age.

Table 6: Pharmacokinetic Parameters by Age (CV)


PK parameter1

2 to 5 years
(N = 5)

6 to 11 years
(N = 13)

12 to 17 years
(N = 11)

IR (IU/dL per IU/kg)

0.5980  (15.7%)

0.7422  (29.2%)

0.8929  (36.4%)

AUC/Dose (IU*h/dL per IU/kg)

23.18  (15.9%)

29.38  (26.6%)

30.23 (22.2%)

T½ (h)

66.40  (32.1%)

72.23  (23.1%)

83.59  (19.1%)

MRT (h)

80.52  (22.3%)

84.06  (18.6%)

95.13  (19.4%)

CL (mL/h/kg)

4.406 (16.8%)

3.613  (25.1%)

3.483  (25.6%)

Vss (mL/kg)

349.0  (19.2%)

303.0  (28.5%)

326.0  (24.9%)

1PK parameters are presented as the arithmetic mean (CV%); Abbreviations: IR = incremental recovery; AUC = area under the FIX activity time curve; T ½= elimination half-life; MRT = mean residence time; CL = body weight adjusted clearance; Vss = body weight adjusted volume of distribution at steady-state

For adults, the arithmetic mean increase in circulating Factor IX activity after treatment with ALPROLIX™ was 1.02 IU/dL per IU/kg, with an elimination half-life of 87 hours. Pediatric PK studies indicated that children under 12 may need dose and interval adjustments due to observed lower incremental recovery and higher body weight-adjusted clearance.

  1. Recommendation

Pharmacokinetic studies with ALPROLIX™ support the recommended dose and dosing schedule of the product.

6. Clinical Safety and Efficacy
a) Clinical Program
Summary of Clinical Studies
The clinical development program for ALPROLIX™ is summarized in Table 7
Table 7: Summary of Clinical Studies


Study

ID #

Objective

Design

Dosing

Subjects

Treatment

Status

Safety
PK

SYN-FIXFc-07-001

Safety of single rFIXFc IV administration at 1 – 100 IU/kg;

Estimate PK at doses ranging from 12.5 – 100 IU/kg

Open-label
Multicenter
Dose escalation
Uncontrolled

Single IV
dose at:

1 IU/kg
5 IU/kg
12.5 IU/kg
25 IU/kg
50 IU/kg
or
100 IU/kg

PTP
Age ≥18 years
Severe Hemophilia B
15 enrolled
14 completed*

One day,
Single dose,
30 day follow-up

Complete
Reported

Safety
Efficacy
PK

998HB
102

Prophylaxis vs. on-demand treatment by comparing ABR

PK parameter estimates at baseline and week 26: rFIXFc vs. BeneFIX®

Response to treatment and product consumption

Open-label
Multicenter
Nonrandomized
Uncontrolled

BeneFIX® active comparator for sequential PK subgroup

Arm 1
50 IU/kg weekly, initially
Arm 2
100 IU/kg every 10 days, initially; individualize interval
Arm 3
20 – 100 IU/kg on-demand
Arm 4
40 – 100 IU/kg for perioperative management

PTP
Age ≥12 years
Severe Hemophilia B
123 enrolled
115 completed

Arm 1
At least 52(±1) weeks
Arm 2
At least 26 weeks, up to ~50 ED
Arm 3
At least 52(±1) weeks
Arm 4
Pre-operative period, surgery and rehabilitation

Pivotal trial for licensure
Complete
Reported

Safety
Efficacy
PK

9HB02
PED

Pediatric subjects

Evaluation based on patient-reported and health outcomes

Open-label
Multicenter
Nonrandomized
Uncontrolled

Weekly prophylaxis:
IV, ~50 to 60 IU/kg initially

PTP
Age <12 yr. old
Severe Hemophilia B

20 planned
10 <6 yr. old
10 6  to <12 yr. old

As of March 2014:
15 enrolled, 6 to <12 yr. old
8 enrolled, 2-5 years old
0 completed

~50 weeks, at least 50 ED

Ongoing
Progress Report

Safety
Efficacy

9HB01
EXT

Long-term safety and efficacy

Open-label
Multicenter
Long term extension study
Uncontrolled

Option 1
Weekly prophylaxis, 20 – 100 IU/kg

Option 2
Individualize prophylaxis interval with 100 IU/kg every 8 – 16 days or twice a month

Option 3
On-demand treatment

Option 4
Perioperative management

Adult and pediatric PTP with severe Hemophilia B who have completed studies 998HB102 or 9HB02PED

~120 planned

As of 09 Oct 2012:
87 enrolled
0 completed

Up to ~ 4 yr.

Ongoing
Progress Report
PMC

Abbreviations: ABR = annualized bleeding rate; ED = exposure days; IU/kg = international units per kilogram;
 IV = intravenous; PK = pharmacokinetics; PTP = previously treated patients; PMC = post-marketing commitment
*One patient did not return for study drug infusion after screening.

A total of 123 subjects were enrolled in one or more study phases and 114 were used for the full analysis set of safety and efficacy in the treatment phase. Eight subjects (6.5%) discontinued the study prematurely and one subject was treated both in the prophylaxis and surgery arm. The reasons for premature discontinuation were withdrawn consent in three subjects, AEs in two subjects (device infection and motor vehicle accident in a country where the study drug could not be imported), protocol violation in two subjects, and one subject lost to follow-up.

Study 9HB01EXT is an extension of the Phase 3 study 998HB102 and the pediatric study
9HB02PED. It is an open-label, multicenter study to evaluate the long-term safety and efficacy
of ALPROLIX™ for prophylaxis and on-demand treatment of bleeding episodes in previously treated patients (PTPs) with hemophilia B. Subjects on-demand  were given the option to switch to the prophylaxis regimen. Subjects will continue in this study for up to 4 years or until rFIXFc is commercially available in the applicable participating country. The primary endpoint is the frequency of inhibitor development with secondary endpoints of annualized number of bleeding episodes and incidence of AEs and SAEs. Dosing will be individualized based on the clinical and pharmacokinetic profile from prior studies.

b) Efficacy Analysis
Prophylaxis vs. On-demand Treatment
Efficacy was determined by the number of bleeding episodes per subject annualized over the study period, and assessment of treatment response by subjects and physicians. Overall, ALPROLIX™ was effective in preventing bleeding by achieving a target Factor IX activity level of 1-3% above baseline in severe Hemophilia B subjects undergoing either of two prophylaxis regimens: once weekly or once every 10 days. The mean annualized bleeding rates (ABR) were determined in subjects dosed with one of three study regimens: (Arm 1) 50 IU/kg every 7 days, (Arm 2) 100 IU/kg every 10 days, with individualized dosing interval adjustment or (Arm 3) on-demand treatment of bleeding episodes, with the following summary results in Table 8.

Table 8: Mean Annualized Bleeding Rates For Different Study Groups


Treatment Regimen

Mean ABR (N)

Reduction from On-demand

On-demand

18.67 (N=27)

---

50 IU/kg every 7 days

3.12 (N=63)

83%

100 IU/kg every 10 days

2.4 (N=29)

87%

Prophylaxis subjects in Arm 1 were administered a median dose of 40.70 IU/kg once weekly for 9 months. Subjects in the individualized prophylaxis Arm 2 were initiated at a dosing interval of 10 days but averaged a median interval of 12.53 days (range 7.8 to 15.9 days) during the efficacy period. A total of 12 subjects (46.2%) achieved a dosing interval of 14 days or longer during the last six months of the study. There were 402 bleeds recorded for on-demand subjects, 167 bleeds for subjects in prophylaxis Arm 1, and 67 bleeds in prophylaxis Arm 2 totaling 636 bleeds treated during the efficacy period. Ninety percent of all bleeds required one infusion, 7% were treated with two infusions and 3% required three infusions. Of all subjects on prophylaxis, 44% experienced no bleeds.

For each bleeding episode, subjects and investigators were asked to rate the efficacy of ALPROLIX™ on a 4-point scale from excellent to no response. Subjects reported as follows: 2% gave no rating for efficacy, 80% gave a rating of excellent or good, and 18% rated the efficacy as moderate. Investigators reported for their patients: 71% excellent, 27.8% effective and 1.2% partially effective, with no reported lack of effect.

Perioperative Management
Surgery phase analyses included 12 subjects who underwent 14 major surgeries and 13 subjects with 15 minor surgical procedures. The types of major surgical procedures and efficacy outcomes are listed in Table 9. ALPROLIX™ was administered by bolus infusion only. Continuous infusion was not evaluated.
Table 9: Perioperative Hemostasis Response


Major Procedures

Assessment of Hemostasis Response

Total Knee Replacement (n=5)

Excellent (4), Good (1)

Arthroscopic Procedure (n=2)

Excellent (2)

Closure of Rectal Fistula (n=1)

Excellent (1)

External Fixation of Knee (n=1)

Excellent (1)

Tendon Transfer (n=1)

Excellent (1)

I & D1 of Dental Abscess with Extractions (n=1)

Excellent (1)

I & D1 Pilonidal Cyst (n=1)

Excellent (1)

Amputation of Finger (n=2)

Excellent (2)

1Incision and Drainage

Subjects who had major surgery received bolus infusions at initial pre-surgery doses of 142-265 IU/kg with subsequent dosing ranging from 22-83 IU/kg. The median rFIXFc consumption was 146.1 IU/kg on the day of major surgery; 168.2 IU/kg for the first 3 days following surgery and 277.1 IU/kg for Days 4 through 14 following surgery. Overall, 85.7% of all major surgeries required a single injection of rFIXFc to maintain hemostasis during the operative period.  The major surgery population represented patients from both the prophylaxis and treatment groups. The number of infusions required to maintain hemostasis is not expected to be influenced by the treatment regimen the patient was on prior to surgery.  The median average dose per injection for the 14 surgeries was 90.9 IU/kg.

Hemostasis control and blood loss were considered excellent or good in all major surgical procedures and acceptable Factor IX levels were achieved before, during and after surgery. Transfusion support was required in two subjects; the first was administered concurrent anticoagulants because of a prior history of DVT and the second was withdrawn for study non-compliance due to multiple injections of a non study factor IX product. There were two subjects who developed a total of three bleeding episodes during the post-operative period but did not require transfusion. One of them developed a spontaneous bleeding episode post-operatively and the remaining two bleeding episodes were classified as traumatic in the second subject.

c) Safety Analysis
Safety of study subjects was monitored in terms of adverse events (AEs), immunogenicity, history and physical examination, laboratory measurements, assessments of bleeding and viral safety. Adverse events were coded using MedDRA Version 15.0 and were analyzed based on the principle of treatment emergence. Although bleeding was monitored and considered an efficacy outcome, subjects were also monitored for development of inhibitors that might predispose to bleeding. Pre-infusion (baseline) and post-infusion levels of Factor IX inhibitory (neutralizing) antibodies and non-inhibitory (non-neutralizing) antibodies were assessed. As of December 2012, 123 subjects age 12-71 had received at least one infusion of ALPROLIX™. The population was diverse in terms of race and geography and included subjects with significant comorbidities associated with hemophilia such as a history of HCV and/or HIV. A total of 60 subjects achieved at least 50 exposure days in 77 weeks. There were an additional 24 enrolled subjects in the pediatric pharmacokinetic sub-study. The youngest subject was 2 years of age. The demographics were similar to the pivotal study with regards to race and geography. The median duration of treatment for pediatric subjects was 21.3 weeks.

Adverse Events
Of the 119 subjects evaluated for safety, each of whom received at least one dose of the product, there were 94 subjects who reported at least one AE. Table 10 provides a summary of adverse events.
Table 10: Summary of Adverse Events


System Organ Class

Adverse Event

Number of Subjects (%)

Nervous system disorders

Headache
Dizziness
Dysgeusia

2 (1.7)
1 (0.8)
1 (0.8)

Gastrointestinal disorders

Paresthesia oral
Breath odor

2 (1.7)
1 (0.8)

General disorders and administration site conditions

Fatigue
Infusion site pain

1 (0.8)
1 (0.8)

Cardiac disorders

Palpitations

1 (0.8)

Renal and urinary disorders

Obstructive uropathy*

1 (0.8)

Vascular disorders

Hypotension

1 (0.8)

 Total number of subjects who reported at least one AE was 94. The total number of subjects assessed for safety,all of whom received at least one dose was 119
* Obstructive uropathy was reported in one subject with hematuria who developed an obstructing clot in the urinary collecting system. The event resolved with hydration and the subject continued prophylactic treatment with ALPROLIX™. The causal relationship to ALPROLIX™ was not established.

Of the 119 subjects evaluated for safety, twenty serious adverse events (SAE) were reported in 16 subjects. All were considered unrelated to ALPROLIX™ based on a detailed review of each subject’s case report. Table 11 provides a summary of the SAEs.

Subject ID
Study Arm
Age (yr)

Preferred Term

Judged Relationship to rFIXFc

Onset Day in relation to study entry (rFIXFc was ongoing)

110-001
Arm 1
68

Arthralgia

Unrelated

348

118-001
Arm 3
62

Inguinal hernia

Unrelated

297

150-007
Arm 3
37

Cellulitis

Unrelated

255

300-006
Arm 3
19

Road traffic accident

Unrelated

119

521-001
Arm 3
19

Small intestinal obstruction

Unrelated

30

522-004
Arm 1
62

Hepatic neoplasm malignant

Unrelated

310

556-001
Arm 1
58

Cellulitis

Unrelated

83

863-001
Arm 2           
20

Peritonsillar abscess

Unrelated

304

871-003
Arm 1
50

Device related infection

Unrelated

136

872-003
Arm 1
24

Abdominal adhesions

Unrelated

366

892-002
Arm 1
71       

Angina pectoris

 

Unrelated

124

901-004
Arm 2
53

Upper GI hemorrhage

Unrelated

3

903-002
Arm 2
41

Obstructive uropathy

unrelated

496

102-004
Arm 4
61

Bacterial sepsis

Unrelated

290

Tachycardia

Unrelated

313

Bacterial sepsis

Unrelated

313

813-002
Arm 1 with surgical events in Arm 4
24

Pilonidal cyst

Unrelated

165

Tooth abscess

Unrelated

194

881-004
Arm 1 with surgical events in Arm 4

Limb crushing injury

Unrelated

330

 

There were no reports of death, nephrotic syndrome or  anaphylaxis. No case of confirmed inhibitor was reported. Thrombosis was reported in a single adult patient (see report of obstructive uropathy due to clot formation in the table above); the causal relationship to ALPROLIX™ was not established. There were no patterns of clinically significant laboratory abnormalities that could be ascribed to ALPROLIX™. Similarly, no patterns of abnormal vital signs or physical examination findings were noted.

Factor IX Inhibitors
There was no pattern of increased consumption of product, which might suggest the presence of neutralizing inhibitors against ALPROLIX™. Factor IX non-neutralizing antibodies, detected by -(b)(4)-, were present in 4 of 119 subjects both at screening prior to dosing, and during the pivotal study. One of the four subjects exhibited mild allergic symptoms (lip tingling) immediately after initial dosing but had neither progression nor recurrence of symptoms, and has continued as a subject in the extension study. A review of information on these four subjects did not reveal clinically significant adverse events, lack of therapeutic effect or alterations in pharmacokinetics.

d) Pediatric Studies and PREA requirements
Data for pediatric subjects were derived from an ongoing pharmacokinetics study in which 24 subjects received at least one dose of study drug. Eighteen subjects (five subjects <6 years of age and 13 subjects, 6 to <12 years of age) had evaluable rFIXFc PK profiles. Incremental recovery appeared to be lower and body weight-adjusted clearance appeared to be higher in children under 12 years of age when compared to adults. As a result, higher doses per kilogram body weight or more frequent dosing may be needed in pediatric patients less than 12 years of age. Efficacy can be extrapolated from pharmacokinetic data to subjects < 2 years of age.  Summary PK results are presented in the Clinical Pharmacology section. The safety profile in subjects less than 12 years of age is acceptable and no new safety issues were identified.

e) Bioresearch Monitoring
In consultation with the medical reviewer, five sites participating in pivotal trial 99HB102 were selected for Bioresearch Monitoring (BIMO) inspections by the Division of Inspections and Surveillance (DIS). Inspection outcomes did not reveal significant problems that impacted clinical data submitted to BL STN 125444/0.

f) Conclusion
ALPROLIX™ is effective or control and prevention of bleeding episodes, routine prophylaxis and perioperative prophylaxis. In 123 subjects, development of inhibitory antibodies and anaphylaxis were not observed. A single case of obstructive uropathy due to clot formation was observed. However, causal relationship to ALPROLIX™ was not established (please see Benefit-Risk assessment, below).

7. Pharmacovigilance
a) Reports of Serious Adverse Drug Reactions
ALPROLIX™ is not presently marketed in other countries. Consequently, the only adverse events available for analysis are those reported in the clinical studies noted above. Twenty (20) serious adverse events were reported in the pivotal clinical study (998HB 102). All reported adverse events were unlikely related to ALPROLIX™ based on detailed review of each subject’s case report. There were no reported deaths, immunogenicity, nephrotic syndrome or anaphylaxis. A single case of obstructive uropathy due to clot formation was observed. However, causal relationship to ALPROLIX™ was not established

b) Summary of the Pharmacovigilance Plan
The proposed pharmacovigilance plan includes routine pharmacovigilance, quarterly periodic adverse event reports for three years, 15-day expedited reports for serious, unlabeled adverse events as well as specific events of interest, and completion of the pediatric study 9HB02PED and the safety extension study 9HB01EXT. The pharmacovigilance plan for detecting important potential risks is acceptable, as proposed by Biogen.

8. Advisory Committee Meeting
The Division of Hematology in the Office of Blood Research and Review reviewed the information in BL STN 125444/0 and determined that referral to the Blood Products Advisory Committee (BPAC) prior to approval was not needed because: (1) the product’s mechanisms of action are well understood and (2) review of the data did not reveal safety or efficacy concerns, or pose unanswered scientific questions that would benefit from advisory committee discussion and recommendation. [FDAAA (HR 3580-138 SEC. 918: REFERRAL TO ADVISORY COMMITTEE)]

9. Other Relevant Regulatory Issues

There were no other regulatory issues raised during the review of BL STN 125444/0.

10.   Labeling
The proposed proprietary name, ALPROLIX™, was reviewed by the Advertising and Promotional Labeling Branch (APLB) from a promotional and comprehension perspective and determined to be acceptable.. Carton and container labels submitted to BL STN 125444/0 were considered acceptable.

11.   Recommendations and Risk/Benefit Assessment
a) Recommended Regulatory Action
It is recommended that ALPROLIX™ be approved for use in adults and children with hemophilia B (congenital Factor IX deficiency) for:

  • Control and prevention of bleeding episodes,
  • Perioperative management,
  • Routine prophylaxis to prevent or reduce the frequency of bleeding episodes.

Biogen has agreed to implement a post-marketing commitment (PMC) for a cohort event efficacy and safety monitoring study Biogen will fulfill the PMC through the ongoing extension study entitled “An Open-Label, Multicenter Evaluation of the Long-Term Safety and Efficacy of Recombinant Human Coagulation Factor IX Fusion Protein (rFIXFc) in the Prevention and Treatment of Bleeding Episodes in Previously Treated Subjects with Hemophilia B.” Please refer to Section 6 for additional information on the study objectives and design.  A revised protocol was submitted to the BLA based on recommendations from the September 12, 2013 Late Cycle Meeting. A study completion date of December 2018 and a final complete study report submission date of December 2019 is anticipated.

b) Risk/Benefit Assessment
Hemophilia B is a blood clotting disorder caused by a mutation of the FIX gene, leading to a deficiency of FIX. Hemophilia B patients are at risk for acute bleeding episodes predominantly into joints, muscles, mucosa, body cavities, and central nervous system (CNS). Repeated bleeding into a joint can lead to disabling joint disease. Other bleeding episodes may be life-threatening such as intracranial bleeding.. ALPROLIX™ replaces the missing clotting FIX that is needed to achieve hemostasis in bleeding patients with Hemophilia B. In recent years, treatment regimens have shifted from on-demand treatment of bleeding episodes to routine prophylaxis because of observed improvement in long-term, clinical outcomes (such as joint damage). Patients on routine prophylaxis regimens have been non- compliant, however, because of the short half-life of infused Factor IX, (mean 18 to 22 hours), necessitating frequent infusions. ALPROLIX™ is designed to provide a long acting Factor IX to enable less frequent dosing in routine prophylaxis regimens for Hemophilia B patients.

Benefits:
The efficacy of ALPROLIX™ has been established for control and prevention of bleeding episodes, peri-operative management and routine prophylaxis to prevent or reduce the frequency of bleeding episodes, in clinical studies that enrolled 123 subjects. The PK profile of ALPROLIX™ shows an average 2.4-fold increase in half-life when compared to a licensed product. This allows for a weekly to every 10 day dosing schedule, instead of 2-3 times weekly, to maintain a plasma level of FIX above 5% that has been shown to prevent or reduce the frequency of bleeding. The weekly or every 10 day dosing schedule is considered a major contribution and improvement to patient care.

Risks:
ALPROLIX™ is a recombinant product synthesized in Human Embryonic Kidney, ---(b)(4)---, cells. Theoretically, the product could transmit infectious agents present in the cell line or materials used in the manufacturing. All cell banks have been demonstrated to be free of infectious viruses. The manufacturing process does not use animal-derived raw materials. The     -----------(b)(4)------------ from every cell production campaign is directly tested for infectious viruses on relevant cell culture systems. The manufacturing process incorporates a (b)(4) nanofiltration step and column chromatography steps that have been validated to remove at least 10 logs of enveloped virus and at least 6 logs of non-enveloped virus. The viral safety profile for ALPROLIX™ is considered acceptable. Additionally, as an added safety measure, the sponsor has agreed to add a -----(b)(4)----- step to the manufacturing process as a post marketing commitment.

The formation of Factor IX inhibitors was not observed during the pivotal, pediatric or extension studies. Binding Factor IX antibodies that were non-neutralizing were present in four of 119 total subjects at both screening prior to dosing and during the pivotal study. One of the four subjects exhibited mild allergic symptoms (lip tingling) immediately after initial dosing but had neither progression nor recurrence of symptoms, and has continued as a subject in the extension study. A risk analysis of these four subjects did not reveal clinically significant adverse events, lack of therapeutic effect or alterations in pharmacokinetics.

Neutralizing antibodies (inhibitors) are known to occur in PTPs treated with FIX containing product. Even though no subjects developed neutralizing antibodies to FIX in the pivotal clinical study, the potential for developing inhibitors is discussed in the Warnings and Precautions section of the Package Insert (PI).

The pediatric and extension studies are on-going. As of April 2013, there were no reports of inhibitors, anaphylaxis or hypersensitivity.

In the clinical program for rFIXFc that included 123 subjects, there were no reports of inhibitor formation, nephrotic syndrome or anaphylaxis. A single case of obstructive uropathy due to clot formation was observed. However, causal relationship to ALPROLIX™ was not established.

Overall, the risk/benefit profile of ALPROLIX™ is favorable. 
12.   Recommendation for Post-marketing Risk Management Activities
a) Pediatric Requirements
Study 9HB02PED is an ongoing, open-label, multi-center study of the safety, pharmacokinetics and efficacy of rFIXFc for routine prophylaxis and control of bleeding in previously treated patients (PTP) <12 years of age. Safety data for 24 patients were included in the Interim clinical Pharmacology Report (cut-off date: 23 April 2013). The median duration of treatment for the interim report was 21.3 weeks with a range of 1.1 to 45.7 weeks. The study will continue for approximately 50 doses of weekly prophylactic treatment and a final study report will be submitted to the Agency for review.

b) Post-marketing requirements under FD&C Act section 505(o)
The reviewed safety data do not substantiate a need for a post-marketing requirement (PMR) or a Risk Evaluation and Mitigation Strategy (REMS).

c) Post-marketing commitments

  1. To evaluate the safety and efficacy of ALPROLIX™ in study 9HB02PED, an ongoing open-label, multi-center, evaluation of safety, pharmacokinetics, and efficacy in the prevention and treatment of bleeding episodes in pediatric subjects (PUPs and PTPs) with Hemophilia B
  2. To evaluate the safety and efficacy of ALPROLIX™ in study 9HB01EXT, an ongoing open-label, multi-center evaluation of the long-term safety and efficacy in the prevention and treatment of bleeding episodes in previously treated patients with Hemophilia B
  3. To implement a second generation manufacturing process that incorporates a ----(b)(4)------------------- step
  4. To complete drug substance and drug product primary stability studies and to submit updates in annual reports

13.   References

  • Guidance for Industry: Q8(R2) Pharmaceutical Development, November 2009
  • Guidance for Industry: Q5A Viral Safety Evaluation of Biotechnology Products Derived From Cell Lines of Human or Animal Origin, September 1998
  • Points to Consider in the Characterization of Cell Lines Used to Produce Biologicals, July 1993
  • Guidance for Industry: S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals, July 1997