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Summary Basis for Regulatory Action - ATryn

Summary Basis for Regulatory Action

Date

February 04, 2009

From

Roman Drews, Committee Chair

Subject

Summary Basis for Regulatory Action

BLA #
Supplement#

STN 125284/0

Applicant

GTC Biotherapeutics, Inc (GTC)

Date of Submission

August 08, 2008

PDUFA Goal Date

February 07, 2009

Proprietary Name /
Established (USAN) names

ATryn/ Antithrombin (Recombinant)

Dosage forms

Lyophilized powder; approximately 1750 IU/vial

Proposed Indication(s)

Prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin deficient patients

Recommended Action:

Approval

Signatory Authority(ies)
Action

Offices Signatory Authority:

Basil Golding____________________________

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 Malarkey __________________________

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

 

Material Reviewed/ Consulted     List of specific documentation used in compiling SBRA
Clinical Review Nisha Jain
Statistical Review Paul Hsieh
Clinical Pharmacology Iftekhar Mahmood
Pharmacology/ Toxicology Review Evi Struble
CMC Review/Facilities
Roman Drews/Chiang Syin
Biomonitoring Review Joseph Manik
Veterinary Medicine Philip Snoy
Labeling Maryann Gallagher
EIR Chiang Syin/ Roman Drews
Advisory Committee Transcript January 9, 2009
Center of Veterinary Medicine FONSI January 29, 2009

1. Introduction

ATryn, for Injection, Antithrombin (Recombinant) is a nanofiltered, sterile, terminally heat-treated product. ATryn is supplied as a lyophilized powder in single-use glass vials. ATryn is administered by intravenous injection after reconstitution with the appropriate volume of Sterile Water for Injection (USP). ATryn is indicated for the prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin deficient patients.

2. Background

Antithrombin (AT) plays a central role in the regulation of hemostasis. AT is the principal inhibitor of thrombin and Factor Xa, serine proteases, which play a pivotal role in blood coagulation. AT neutralizes the activity of thrombin and Factor Xa by forming a complex that is rapidly eliminated from the bloodstream. The ability of antithrombin to inhibit thrombin and Factor Xa can be enhanced by greater than 300 to 1000 fold when AT is bound to heparin.

The active ingredient in ATryn is a recombinant form of human AT (rAT). rAT is produced by recombinant DNA technology using genetically engineered goats into which the DNA sequence for human antithrombin has been introduced along with a mammary gland specific DNA sequence, which directs expression of the rAT in the milk. The goats in which rAT is produced are USDA certified scrapie-free, vaccinated, and controlled for specific pathogens.

The amino acid sequence of rAT is identical to that of human plasma-derived antithrombin (pdAT). rAT and pd AT both contain six cysteine residues forming three disulphide bridges and 3-4 N-linked carbohydrate moieties. But rAT differs from pdAT significantly in glycosylation profile. This results in an increased heparin affinity (about fourfold) and decreased half-life from 3 to 4 days for pdAT to around 10 hours for rAT. The functional in vitro assay for rAT potency is not affected because it is performed in the presence of excess heparin.

GTC Biotherapeutics (GTC) has submitted an original (rolling) Biologics License Application (BLA) for ATryn in January 2008. The clinical module that triggered the PDUFA time line has been submitted in August 2008. ATryn has been designated as an orphan drug. The fast- track and priority review has been granted in December 2007 and August 2008, respectively.

This application was presented at the Blood Products Advisory Committee (BPAC) meeting on January 9, 2009. The committee concurred with FDA’s assessment that there are sufficient safety and efficacy data to support the proposed indication. The committee also concurred with FDA’s assessment regarding the need for post marketing studies.

ATryn has been approved by the European Union regulatory authorities for prevention of peri-operative thromboembolism in hereditary deficient patients in August 2006.

3. Chemistry Manufacturing and Controls (CMC) and Facilities

General Manufacturing Summary

Herd of transgenic goats and collection of milk (source material)

The transgenic goat was obtained after microinjection of the DNA construct (transgene) into the pro-nucleus of a goat embryo. The transgene comprises of the cDNA of human AT and the regulatory elements (promoter) of the goat beta casein gene. The promoter drives the expression of rAT in the mammary gland. The selection of the first transgenic goat (male founder) was based on the DNA sequence integrity, ability of germline transmission of transgene, and level of rAT in the milk.

Goat breeding is accomplished through a combination of natural breeding and artificial insemination. To secure continuation of the manufacture, a --b(4)--- transgenic animal banking system has been established, -------------------b(4)------------------------------------------------------------------- containing qualified male and female goats, and the semen from qualified male goats. The genetic stability of the transgene has been demonstrated up to seven generations of goats. The additional steps to control genetic stability of production goats have been added following CBER recommendations. Qualification of goats to the production herd is based on genotyping, assessment of milk composition and content of rAT, microbiological and adventitious agent screening of the milk, and general examination of animal health. Source material (milk) is collected from qualified does, frozen, and shipped to ---------b(4)--------------- (contract manufacturer for BDS) facility for purification and further processing.

In order to optimize the consistency of the source material, which shows certain variability with regards to the milk composition and attributes of rAT molecule (i.e. glycosylation profile) depending on the production animal or lactation timing, a milk pooling strategy has been incorporated. Milk pool composition is tested before entering the purification process. The firm agreed on changes proposed by CBER concerning scope of testing and acceptance limits. The review of the submitted data demonstrated that the acceptable level of consistency has been achieved.

Activities related to transgenic production of rAT in goats have been inspected by CBER. Furthermore, safety of the farm operation and its potential environmental impact has been verified during the site visit performed by Center of Veterinary Medicine (CVM) of the FDA.

Purification of ATryn drug substance (DS)

Purification begins with thawing, pooling and clarification of the source material, followed by filtration steps, three chromatography columns (-----------b(4)-------------------------------------------------------------------), and filtration though a virus retention nano-filter. The DS is formulated before for the final production steps. Lots of rAT are manufactured on a campaign basis.

The purification process for rAT has been validated in a series of scaled-down and full scale process validation studies. The studies were performed according to the protocol and samples derived from each operation units were subjected to the microbiological and biochemical tests. Special emphasis was placed on removal of process and product related impurities, product purity, and yield. In addition, the product glycosylation profile has been monitored throughout the purification process. The proposed in-process testing and acceptance criteria limits were evaluated and determined to be acceptable.

During the development of rAT purification process, GTC incorporated a nanofiltration step. In addition to revalidation of the purification steps, the firm demonstrated physical and biochemical comparability of non nano-filtered and nano-filtered rAT material. Furthermore, GTC executed a nonclinical and clinical pharmacokinetics studies which demonstrated bioequivalence between the rAT materials.

The release and enhanced analytical data deriving from the three consecutive batches of DS and additional batches manufactured at commercial scale were submitted in the BLA and verified during the FDA inspection. The presented data support consistency of the manufacturing process.

Removal of milk-derived impurities by the purification process was adequately validated by analyses of milk production pools-------b(4)------------------- steps, and DS batches derived from the validation studies or designated for commercial distribution. Validated analytical assays were used to demonstrate the efficient removal of milk related impurities. Furthermore, safety of the impurities profile of ATryn has been confirmed by the nonclinical and clinical studies.

Characterization of structure and function

rAT is a 432 amino acid glycoprotein with a molecular weight of approximately 57,215 Daltons. The structure of rAT is consistent with published data on pdAT. The four methionine residues have been identified as potential oxidation sites.

rAT and pdAT are glycosylated with each containing 3-4 N-linked carbohydrate moieties. However, they significantly differ in the monosaccharide composition and oligosaccharide structure. These differences account for the increased affinity to heparin (about fourfold) and shorter half-life of rAT compared to pdAT. The functional in vitro assays for rAT activity (inhibition of thrombin and Factor Xa) are not affected since they are performed in the presence of excess heparin.

Specifications

Specifications and validation of analytical methodology have been evaluated by CBER and discussed with the firm during the review process. The final specifications tests and acceptance limits provided by GTC for control of DS batches were determined to be acceptable. Each batch of BDS is tested for identity, purity, and potency. Testing include measurements of product quality attributes, product and process related impurities, and safety parameters. The specifications are established based on the results of conformance batches, additional batches of product designated for commercial distribution, and outcome of nonclinical and clinical studies. All routine methods used as control or release test of starting materials, process intermediates, drug substance, drug product, and stability samples were validated as appropriate.

Although milk contaminants were shown to be removed to trace levels by evaluation/ validation studies and safety of the product has been demonstrated by nonclinical and clinical studies, milk components are known allergens. Therefore, the levels of ----------------------------------b(4)------------------------------------------------------------------------- are monitored at product release. Furthermore, a statement is included in the product label to preclude patients with hypersensitivity to goat proteins or goat milk components.

Stability of ATryn Drug Substance

The submitted studies demonstrated that formulated ATryn DS is stable up to ----------------b(4)---------------------- before sterile filtration and lyophilization. The study protocol specified tests and time points of the routine stability studies. The stability studies will be conducted according to approved protocol, as captured in the post-marketing commitment.

Manufacture of Final Drug Product (FDP)

The final product is manufactured by ---------b(4)-------------------------------, The ----b(4)------, where product is aseptically filled, lyophilized, and subjected to a terminal sterility and viral inactivation step by heat-treatment.

The terminal heat-treatment step has been incorporated over the course of product development. The comparability studies for non-heat-treated and heat-treated material encompasses biochemical, nonclinical, and clinical studies. The biochemical studies demonstrated that ATryn lots that were subjected to the terminal heat-treatment step were comparable to the non-heated material, but small changes occurred for the following attributes-----------------------------------b(4)---------------------------------------------------------------------------------------------------------. However, one nonclinical rat pharmacokinetic/biodistribution study and two human studies performed in healthy volunteers demonstrated bioequivalence of the heated and non-heated material.

The analytical control of the finished product is similar to that performed on the BDS. The in vitro assay of product potency is based on the ability of ----------------------------------------b(4)----------------------------------------------------. The assay is performed in the presence of an excess of heparin. This is consistent with the assay routinely used to measure the potency of pdAT.

Using a reference standard calibrated against a World Health Organization international standard for antithrombin concentrate, each vial of ATryn contains the potency stated on the product label expressed in IU (approximately 1750 IU). In addition to rAT, each vial of product contains 100 mg glycine, 79 mg sodium chloride, and 26 mg sodium citrate. When reconstituted with 10 mL Sterile Water for Injection, the pH is 7.0. Following reconstitution, the solution may be further diluted into 0.9 % sodium chloride for injection.

ATryn does not contain any preservatives nor is it formulated with human plasma proteins. It contains trace amounts of heparin.

Stability of ATryn Final Drug Product

Stability studies were performed on four lots of ATryn stored at 2 0C - 8 0C. Results of the studies support the shelf-life of the product for 36 months.

Based upon in-use stability studies, the reconstituted product should be administered within 8 - 12 hours of preparation stored at room temperature (up to 25 0C).

Following the FDA recommendations, as captured in the post-marketing commitments, the firm will perform ----------------------b(4)----------------------------------------------------------------------------------- per the approved protocol.

Control of Adventitious Agents

Viral safety and control of scrapie agents are adequately addressed. The pathogen safety of ATryn relies on the screening of goats, starting material (milk), and documented clearance of pathogens by the manufacturing process.

The goat herd is closed and is comprised of selected animals with limited origins ( USA and New Zealand). The GTC goats are scrapie-free certified by the United States Department of Agriculture (USDA). The herd is vaccinated and monitored for general health status and pathogens. The milk pools used for the purification of ATryn are tested for pathogens. The clearance evaluation of enveloped and non-enveloped viruses with different physico-chemical properties by the manufacturing process is acceptable, as demonstrated in the table attached below.

  Log 10 Reduction
Process step

Pseudo-rabies

Virus

Xenotropic

Murine

Retrovirus

Human Adenovirus Porcine Parvovirus
Tangential Filtration ≥5.1 NA NA NA
Affinity column 1.6 1.2 NA 1.4
Nano-filtration NA ≥3.8 ≥6.3 ≥3.7
Ion Exchange column 3.6 1.0 ≥7.1 NA
HIC column ≥5.6 ≥4.4 ≥4.8 ≥5.7
Heat treatment 2.8 ≥5.0 ≥1.8 2.4
Total reduction ≥18.7 ≥15.4 ≥20.0 ≥13.2

NA- not applicable

Furthermore, the removal rates of scrapie agents by the major steps of the purification process were demonstrated. The manufacturing steps were shown capable of achieving the following log 10 reductions: 2.0 (tangential filtration), 2.2 (affinity cchromatography), ≥ 3.3 (ion exchange chromatography), ≥ 3.8 (HIC hydrophobic interaction chromatography).

Conclusion

The CMC reviewer (Roman Drews) finds that sufficient data and information has been provided on the chemistry, manufacturing, and controls to support licensure of ATryn.

Facilities

  The following facilities are used in the manufacture of ATryn:

GTC Biotherapeutics, Inc. facility, located at 175 Crossing Boulvard, Framingham, MA 01702, USA is used for ----b(4)-----------------.

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

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

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

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

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

CBER conducted the pre-approval inspection of GTC and -b(4)-- facilities located in Massachusetts USA from ---b(4)---------------, 2008. The inspections resulted in the citation of five FDA 483 observations for -b(4)- facility and six FDA 483 observations for GTC facilities. The FDA 483 observations concerned manufacturing and quality issues. The responses to the FDA items were received, reviewed and found to be acceptable by CBER.

 The inspection of the ----b(4)-------------- for the production of final drug product was conducted by CDER from --b(4)---------, 2008. Based on the outcome of this inspection the pre-approval inspection of ---b(4)---- facility was waived.

There are no ongoing or pending investigations or compliance actions with respect to the above facilities or their products. Therefore, the Office of Compliance and Biologics Quality, Division of Case Management does not object to the approval of this submission.

Categorical exclusion under 21 CFR § 25.31(c)

The request for a categorical exclusion submitted by GTC from an environmental assessment under 21 CFR 25.31(c) is justified because this product falls into the category of substances that occur naturally in the environment and the action (approval of the BLA) would not alter significantly the concentration or distribution of the substance, its metabolites, or degradation products in the environment. In addition, FDA's Center For Veterinary Medicine (CVM) (based on information submitted by GTC) has prepared an Environmental Assessment (EA), pursuant to 21 CFR 25.20(m) and 21 CFR 25.40, concerning GTC's new animal drug application (NADA) for the rDNA construct that directs the expression of recombinant antithrombin (ATryn) in the milk of lactating does (female goats). CVM has issued a finding of no significant impact, 21 CFR 25.41, stating that the approval of GTC's New Animal Drug Application (NADA) will not significantly affect the human environment.

Conclusion

The facilities reviewer (Chiang Syin) considers this submission approvable on the basis of the facilities information provided.

4. Nonclinical Pharmacology/Toxicology

Toxicology

 The highest dose in 14-day repeat toxicity study in monkeys was 300 mg/kg/day or ~8 times maximum daily dose (MDD). At this dose, female monkeys exhibited liver toxicity and internal bleeding both of which were not seen in males. On day 15 increased aspartate aminotransferase (AST) and alkaline phosphatase (ALK) were observed in the highest dose animals. The AST increase was likely due to muscle damage associated with injection site reaction; both parameters returned to normal by day 22. Hematological findings in females at the highest dose were a decrease of red cells, hematocrit and hemoglobin and an increase in reticulocytes and polymorphonucleocytes. These changes could be due to multiple blood samples collected during the first day of the study; they returned to normal by day 22. NOAEL in monkeys was 36 mg/kg or approximately equal to MDD. A dose of 120 mg/kg/day caused swelling and bruising at administration sites, but no other effects, including no gross necropsy or microscopic findings.

The highest dose in the 28-day repeat-dose toxicity study in rats was 360 mg/kg/day, ~ 10 times MDD. The observed toxicity at this dose was transient limb swelling and local injection site bruising/swelling.

The highest doses in the single dose toxicity studies in rats and dogs were 360 mg/kg and 210 mg/kg, respectively. The observed toxicities at these doses were transient swelling observed in rats and dogs at the highest doses tested, and increased AST at highest dose in the dog study, both resolved during recovery period. AST increase was likely due to soft tissue damage due to local injection site reaction.

The highest dose used in reproductive toxicity studies and administered during most of pregnancy was 210 mg/kg/day – i.e. ~6 times MDD (~37 mg/kg/day) in pregnant women. At this dose, a slight, statistically significant decrease in pup viability or an increase in pup mortality - 4% - was observed. The same dose is NOAEL in rats when used peripartum and during lactation. A dose of 21 mg/kg/day or 0.6 times MDD used so far in pregnant women is NOAEL when used during most of the pregnancy in rats. Based on the results and conclusions of the reproductive toxicity studies the product is classified as Pregnancy Category C.

Genotoxicity

ATryn shows neither genotoxicity nor cytotoxicity potential. The genotoxicity was studied in an in vivo mouse micronucleus assay up to 360 mg/kg/day and in two in vitro studies, i.e. Ames test in Salmonella typhimurium and E.coli strain (dose up to 0.05 mg/plate) and Chinese hamster ovary cells (dose up to 5 mg/mL). The results of the referenced studies were negative.

Pharmacokinetics

Five pharmacokinetic and three toxicokinetic (1 single-, 2 repeated-dose) studies were performed by intravenous route in mice, rats, dogs and monkeys.

Pharmacokinetic (PK) and Biodistribution (BD) profiles of non-heat-treated and nanofiltered heat-treated materials have been analyzed in two studies -b(4)- -100 (non-heat treated) and 04-0585P (heat-treated and nanofiltered heat treated). There is no difference in PK and BD of non-nanofiltered and nanofiltered rAT. PK parameters are comparable for the non-heat treated (-b(4)- -100) and heat treated (04-0585P) animal studies. BD in the rat was generally similar for rAT and pdAT. There was one difference in the BD disposition of rAT. Namely, there was more drug related radioactivity associated with the gastrointestinal tract following b(4)-rAT than b(4)- pd AT administration suggesting higher bile elimination for the recombinant product.

In toxicokinetic rat studies, Area Under Curve (AUC) increased with dose in a non-linear manner. AUC values were greater after 4 weeks of dosing compared with initial values, suggesting accumulation. The clearance for pdAT was lower when compared to rAT at each dose and could be due to the different glycosylation pattern.

AUC measured in toxicokinetic study in ---b(4)----- monkeys was 3-4 times greater than in the rat at all doses used. Evidence of accumulation in monkeys was observed at dose levels ≥ 300 mg/kg/day. Other kinetic parameters in the primate underscore the cross-species difference: the clearance in monkeys is slower and the elimination half-life is longer than those measured in the rat model. All PK values in the monkey were comparable with the ones measured in the dog.

Formulation, Excipients

Formulations used in pre-clinical studies differ from the FDP. The pre-clinical formulations contained non-nanofiltered and non-heat treated rAT. The exceptions are the reproductive toxicity studies #-b(4)-007-001 and #6354-13, and bioequivalence study #04-0585P which used the nanofiltered and terminal heat treated product. Due to the terminal dry heat treatment increase in aggregation deamidated forms was observed. But the values stay within the proposed release specification limits. These changes do not significantly affect PK parameters in rat studies. Furthermore, the comparability of these lots has been demonstrated in the clinical PK studies ( GTC AT PK 011-04).

The composition of FDP contains excipients that are present in other FDA approved drugs administered via the same ROA and having the same concentration and exposure found in the ATryn formulation (data obtained from Inactive Ingredients Database and the Physician Desk Reference).

Conclusion

he reviewer for nonclinical studies (Evi Struble) identified no issues that would prevent this BLA from being approved

5. Clinical Pharmacology

Pharmacokinetics studies

 “AT III-009-00: Randomized Pharmacokinetics of AT III in Patients with hereditary AT III deficiency receiving two doses 50 and 100 IU/kg”.

This was an open-label, single dose pharmacokinetic study in male and female patients (≥ 18 years of age) with hereditary AT deficiency. The patients received either 50 (n = 9 all females) or 100 (n = 6, 2 males and 4 females) IU/kg ATryn intravenously. Blood samples were collected before the administration of the drug and at 5, 10, 15, 30, 45, and 60 minutes and at 2, 4, 6, 8, 24, 48, and 72 hours. The clearance and half-life of ATryn were 9.6 and 7.2 mL/hr/kg and 11.6 and 17.7 hours following 50 and 100 IU/kg dose, respectively. The incremental recovery was 2.07 ± 1.54 %/IU/kg .

 “AT III-009-00: Population pharmacokinetic analysis of recombinant antithrombin and comparison to human plasma-derived antithrombin.”

The objective of this investigation was to compare the pharmacokinetics of ATryn and plasma-derived antithrombin (pdAT) using population-pharmacokinetic approach.

  The pharmacokinetics of ATryn were evaluated in 15 patients with congenital antithrombin deficiency following a short intravenous infusion of 50 or 100 IU/kg. The pharmacokinetics of pdAT were evaluated from a study performed in 1984 in the USA in 8 patients with congenital AT deficiency, following intravenous infusion of administration of 25 to 225 IU/kg pdAT. The following table summarizes the PK parameters of the two products.

A PK comparison between ATryn and pdAT

Parameters

rAT

pdAT

CL (mL/hr/kg)

9.5

1.3

Half-life (hrs)

10.2

91.2

Vss (liters)

7.7

9.8

ATryn has almost a 9-fold shorter half-life and 7-fold faster clearance than p d AT.

Conclusions

The clinical pharmacology reviewer (Iftekhar Mahmood) considers this submission approvable on the basis of the information provided.

6. Clinical/Statistical-Efficacy

Efficacy

 GTC AT III 01002: “Phase 2 study to assess the incidence of thromboembolic events following prophylactic intravenous (iv) administration of antithrombin (rAT) to hereditary antithrombin (AT) deficient patients in high-risk situations.”

This was a single arm, multicenter, multinational, open-label study with blinded evaluation of the ultrasonographic images. 15 hereditary AT deficient patients (documented AT activity ≤ 60% of normal and with previous history of thromboembolism) scheduled for surgery, Caesarean section, or vaginal delivery qualified for the study were treated prophylactically with ATryn. Dosing with ATryn was individualized to increase and maintain target AT activity levels between 80% and 120% of normal. Functional AT activity levels were used to monitor and adjust dosing.

ATryn administration to patients scheduled for surgery and patients scheduled for Caesarean section or delivery was initiated approximately 24 hours before the planned procedure and continued for a minimum of 3 days. ATryn therapy was continued, until effective chronic anticoagulation therapy was established and the patient was mobilized and ready for hospital discharge.

In pregnant patients not scheduled for Caesarean section or induction of delivery, treatment was initiated only when the patient was hospitalized and in active labor. Treatment of these patients was also continued for a minimum of 3 days and continued until effective chronic anticoagulation therapy was established and the patient was mobilized and ready for hospital discharge.

A blinded, independent determination of the incidence of acute DVT based on duplex ultrasound examination was the primary measurement of the outcome of treatment with ATryn. Standardized duplex ultrasound examination of the lower extremities was used to establish the presence or absence of acute DVT Duplex ultrasound studies were performed and interpreted by qualified specialists within the same hospital/institution on a real time basis for the timely and appropriate clinical care of the patient. Venography could be used, when clinically indicated, if the study investigator felt that duplex ultrasound results were inconclusive. For other TE relevant diagnostic modalities were used.

GTC AT HD 012-04: “Phase 3 study multicenter, multinational study to assess the safety and efficacy of antithrombin III in hereditary antithrombin (AT) deficient patients in high-risk situations for thromboembolic events”

 The trial design for this study was similar to the phase 2 study. This was a single arm, open-label multi-center, multinational study in 18 patients. Congenital AT deficient patients scheduled for surgical procedures (with personal histories of TE and documented AT levels less than 60%) and pregnant patients were enrolled in the study.

Dosing with ATryn was to be individualized to increase and maintain target AT activity levels between 80% and 120% of normal. Functional AT activity levels were used to monitor and adjust dosing. For elective procedures (i.e. non-pregnant surgery patients and pregnant patients scheduled for Caesarean section or delivery induction), treatment with ATryn was initiated up to 24 hours prior to the scheduled procedure. For pregnant patients not scheduled for Caesarean section or delivery induction, treatment with ATryn was started as soon as they were admitted to the hospital and active labor had begun. The dosing algorithm was revised for pregnant patients based on phase 2 results.

Administration of ATryn was continued for a minimum of 3 days for all study patients and continued until effective chronic anticoagulation therapy was established and the patient was mobilized and ready for hospital discharge. The protocol-specified maximum duration of treatment was limited to 14 days.

The incidence of thromboembolic events was assessed clinically in all patients who were treated with ATryn. Signs and symptoms indicative of the occurrence of a thromboembolic event were monitored during treatment with ATryn and up to and including 7 days after cessation of ATryn treatment. If signs and symptoms indicated the occurrence of a thromboembolic event appropriate diagnostic tests were performed to confirm or exclude the presence of the event.

GTC AT HD-R 013-04: “Historical cohort study to assess the incidence of thromboembolic events following prophylactic intravenous administration of plasma-derived antithrombin to hereditary antithrombin (AT) deficient patients in high-risk situations. Both studies (GTC ATIII 01002 and GTC ATHD 012-04) were compared to the historical control.”

This was an international, multi-center, prospectively designed retrospective cohort study of hereditary AT deficient patients who had a history of thromboembolic events, an elective procedure performed since 1 January 1997 that placed them at high risk for the occurrence of a thromboembolic event, and at that time, were treated prophylactically with intravenous administration of pd AT for a minimum of 2 days.

Approximately 5 to15 sites were planned for participation in the study. All eligible study sites had a listing or automated medical record system that identified patients who had hereditary AT deficiency and/or those patients who had received plasma AT during high-risk elective procedures since 1 January 1997.

All the patients identified were selected. A minimum of 35 up to a maximum of 70 patients identified from the listing or automated medical record system of all patients eligible patients at the sites were included in the study. The eligibility criteria were the same as for the study conducted with ATryn. Clinical outcomes in terms of TE were noted in the case report form.

Statistical Methods for Determining the Efficacy End-Point

The statistical approach used was to establish non-inferiority by comparing the incidence of any TE event with pdAT vs. ATryn (results were combined from Phase 2 and 3 studies). The non inferiority margin was set at 20%. Use of a one-sided lower confidence bound, instead of a confidence interval, consistent with use of a one-sided test for a non-inferiority study was adopted (see table below). The 95% confidence interval based on the exact (Clopper-Pearson) method for the proportion of patients with presence of DVT for both groups was presented.

Safety

In referenced studies the patients were evaluated for laboratory parameters of coagulation (INR, aPTT, and anti-Xa activity) and immunogenicity (up to 90 days after treatment). Active assessment of any bleeding complications was performed and included a brief physical examination, hemoglobin and hematocrit measurements, and urinalysis every day during ATryn administration through the last day treatment. In addition, blood serum samples were collected to allow for retrospective infectious or immunological evaluations in the future, if indicated.

 

ATryn treatment duration, rAT dose administration and dose adjustments

Group/Patient

Number

Treatment Duration (days) Total loading doses (IU/kg)

Dose per day

(IU/kg/day)

Dose adjustments

Surgery group

 

-b(6)-

-b(6)-

-b(6)-

-b(6)-

-b(6)-

 

 

12

8

13

19

10

 

 

50.0

47.1

38.2

35.1

21.0

 

 

166.0

157.1

79.5

179.9

113.7

 

 

3

4

4

8

1

Pregnant Group

-b(6)-

-b(6)-

-b(6)-

-b(6)-

-b(6)-

-b(6)-

-b(6)-

-b(6)-

-b(6)-

 

 

10

3

3

3

4

4

5

3

3

 

48.6

21.0

26.9

27.2

19.7

23.7

81.4

25.3

20.3

 

293.0

222.0

331.6

207.0

249.5

286.5

451.7

167.0

277.4

 

12

2

4

14

2

2

6

1

15

 

IU= international units

Results of the Phase 3 GTC AT HD 012-04 study:

A total of 23 patients were enrolled in the study with 18 (78.3%) of the 23 patients receiving treatment with ATryn. All 18 (100.0%) ITT population patients completed the study. The reasons for five of the enrolled patients who were not included as ITT population of the study were: (i) ineligible due to DVT at baseline, (ii) went into spontaneous labor, (iii) spontaneous amniorrhexis, (iv) fetal Doppler results were pathological hence withdrew consent and (v) signed an informed consent form and had some study procedures performed and then withdrew consent.

In the safety and the ITT population, six of the ATryn-treated patients were non-pregnant surgery patients and 12 were pregnant patients. The Per Protocol population was comprised of 6 non-pregnant surgery patients and 11 pregnant patients. One patient was not included in the Per Protocol population because the patient’s treatment started after delivery, instead of before delivery as specified in the protocol.

The mean patient age was 37.2 years (21-62 years). The mean screening AT activity level was 50.9% and ranged from 29.0% to 65.7% with Although some screening AT activity levels were above 60%, patients met all the inclusion criteria, and had historical levels confirming hereditary AT deficiency.

Concomitant medications for all patients included the heparin group of anticoagulants.

For the primary efficacy endpoint, the Intent-to-Treat Population (ITT) was defined as those patients who received ATryn and had at least one follow-up assessment after initiation of treatment with ATryn. The ITT population included 6 non-pregnant surgery patients and 12 pregnant patients.

The Per Protocol Population included those patients who received ATryn and met inclusion criteria of a personal history of venous thromboembolic events and a history of congenital deficiency that included 2 or more plasma AT activity values ≤ 60% of normal, and received at least 3 (calendar) days of treatment with ATryn with at least one follow-up. The Per Protocol population included 6 non-pregnant surgery patients and 11 pregnant patients.

  Safety Population: This population included all patients who received at least 1 dose of ATryn. The Safety population included 6 non-pregnant surgery patients and 12 pregnant patients.

The efficacy of ATryn for the prophylaxis of thromboembolic events in surgical and pregnant patients with congenital deficiency undergoing medical high risk procedures was evaluated by assessment for clinical signs and symptoms of any thromboembolic events. This was followed by the appropriate diagnostic testing. The occurrence of a thromboembolic event was confirmed if symptoms occurred and diagnostic testing was positive.

During treatment and during the follow-up period of 7 days after cessation of treatment with ATryn, no thromboembolic events occurred in the intent to treat population (n = 18). The patients included in this study all had significant prior personal histories of venous thromboembolic events which elevated the risk for recurrence of such events in this study.

On the basis of the efficacy results, FDA concludes that ATryn is effective in preventing potentially life-threatening thromboembolic events in patients with hereditary AT deficiency during the peri-operative or peri-partum period.

There were 2 venous thromboembolisms reported in the study after the 7-day post-treatment follow-up period. A DVT was reported 11 days after discontinuation of treatment with ATryn and a PE occurred 14 days after stop of ATryn treatment. Given the short half-life of ATryn (approximately 10 hours), it is not expected that ATryn will have a beneficial effect that long after stopping treatment. It can, therefore, be concluded that these events were not due to a lack of efficacy of ATryn, but due to the potential lack of efficacy of the anticoagulant medication being administered at the time of each event.

In conclusion, the data from the current study demonstrates the efficacy of ATryn for the prevention of thromboembolic events in congenital deficient patients in high risk situations and the effectiveness of the dosing formula for both surgical patients and pregnant women (shown in graph and table below)

the data from the current study demonstrates the efficacy of ATryn for the prevention of thromboembolic events in congenital deficient patients in high risk situations and the effectiveness of the dos

Treatment duration and dose administration and dose adjustments

Group Treatment Duration (days) Total loading doses (IU/kg)

Dose per day

(IU/kg/day)

Dose adjustments

 

Surgery group

N=6

Mean

Median

Range

 

 

 

 

7

3

3-14

 

 

21.6

19.2

13.5-34.4

 

 

 

37.8

21.2

15-78.5

 

 

2.5

2.0

1-6.0

Pregnant Group

N=12

Mean

Median

Range

 

 

4.4

3.6

1-14.0

 

 

36.3

35.5

13.0-57.6

 

 

38.9

30.2

7.2-139.9

 

 

1.5

1.0

0.0-6.0

Please note with the revised dosing algorithm for pregnant patients, the number of dose adjustments needed was significantly reduced compared to the Phase 2 Study.

 Conclusion of overall Efficacy:

Patients for the control group (pdAT) were matched, as for as possible, for demographics, medical/surgical history, history of prior TEs, surgical procedure, baseline AT activity levels and concomitant medication with the ATryn group. The two studies conducted with ATryn, when pooled together, show that Atryn is as effective as pdAT in preventing peri-operative and peri-partum thromboembolism in hereditary AT deficient patients when analyzed by prespecified statistical parameters and methods (see table below)

  Test (31) Control (35)
TE Outcome    
Positive 1 0
Negative 30 35

 

Binomial Proportions [col1]: piHat_1 0.03226
Binomial Proportions [col2]: piHat_2 0
Difference of Proportions: piHat_2 - piHat_1 -0.03226
Std. Error: (pooled estimate of std dev of piHat_2-piHat_1) 0.03013
Standardized Difference: (piHat_2-piHat_1)/Stderr -1.071

 

 

 

 

P-value

 

95% Confidence Interval

(P 2-P 1)

Type 1-sided 2*1-sided Lower Limit Upper limit
Asymptotic 0.1422 0.2843 -0.1634 0.0698
Exact 0.2401 0.4802 -0.167 0.0778

The primary efficacy endpoint is the incidence of any thromboembolic event after the start of treatment (pdAT or rAT) and within 7 days following discontinuation of treatment. Clopper Pearson exact 95% confidence interval for the proportion of patients with a thromboembolic event is presented for each treatment group, as well as the exact 95% lower confidence bound for the difference between treatments. Non-inferiority is demonstrated as the lower 95% confidence bound of the difference (pdAT vs. rAT) is ≥ -0.20.

7. Safety

There were two patients who did not experience any treatment emergent adverse events (TEAEs) during their participation in the study. During dosing, five (83.3%) of the six surgery patients and nine (75.0%) of the 12 pregnant patients experienced one or more TEAE. The majority of TEAEs reported during dosing with ATryn were of mild or moderate severity. Four (22.2%) of the 18 study patients experiencing a TEAE were rated severe (shown below). The AE rated as severe included one surgery patient and three pregnant patients:

Table showing AEs that were severe in intensity

Patient Type of AE Relationship to ATryn
Surgery Severe headache Not related
Pregnant

Dilutional anemia with no evidence of bleeding.

Muscle spasm

Not related

 

Not related

Pregnant Enterobacter sepsis Not related
Pregnant Vaginal tear Not related

TEAE occurring in two or more patients treated with ATryn due to all causes are presented below:

Body System/ preferred term

TEAE incidence (%)

(Total patients n = 18)

Number of events (%)
Total number of patients with TEAE 16 (88.9) 63
Anemia 3 (16.7) 3 (4.8)
Vaginal laceration 3 (16.7) 3 (4.8)
Non cardiac chest pain 2 (11.1) 2 (3.2)
Edema peripheral 2 (11.1) 2 (3.2)
Urinary tract infection 2 (11.1) 2 (3.2)
Post procedural hemorrhage 2 (11.1) 2 (3.2)
Headache 2 (11.1) 5 (7.9)
Syncope 2 (11.1) 2 (3.2)
Hematoma 2 (11.1) 2 (3.2)

Immunogenicity:

No patients developed anti AT antibodies. Data on repeat exposure to the product is very limited and is being evaluated in post marketing studies. Because of the infrequency with which patients may require treatment with ATryn on more than one occasion additional clinical data assessing the immunogenic potential of ATryn, especially in those patients requiring re-exposure to ATryn, will be evaluated in a post-marketing immunosurveillance program. The sponsor has proposed to implement a patient registry in which physicians will collect serum samples from patients treated with ATryn and have the samples analyzed for the development of IgE, IgM and/or IgG antibodies to recombinant antithrombin. Testing of the serum samples for antibodies to recombinant antithrombin will be offered as a free service to physicians and patients. In this postmarketing immunosurveillance study a total of 50 patients or over a period of five years, whichever occurs first will be evaluated.

The details of the information captured in the registry are outlined below:

 Physicians Information

  • Name, title, affiliation, phone/fax numbers and addresses (mail and e-mail)
  • Reason for request (i.e., because of an adverse event or for routine
    immunosurveillance)
  • Date sample(s) submitted

Patient Information

  • Patient identifier (initials only)
  • Demographics (date of birth, sex, ethnic origin, known thrombotic disorders, etc
  • Indication for treatment and type of medical procedure (surgical or obstetric)
  • Date of treatment (start and stop)
  • Dates and time of serum sample collections
  • Dosing information (loading dose, continuous infusion, etc.)
  • Number of prior treatments with ATryn or human pd antithrombin, if
    any, and dates of such treatments
  • Use of concomitant anti-coagulants
  • •Date(s) and time of adverse drug reactions, if any, including lack of efficacy

Forms will be provided to the physician to capture the detailed baseline information. Thebaseline information form will be completed by the treating physician and forwarded to the sponsor via telefax. The sponsor will check it for completeness.

A unique patient ID number will be assigned by the Applicant for future reference and communicated to the treating physician. The unique patient ID number will be used to avoid potential complications in the database in the event that a patient has the same initials, is of the same sex and has the same date of birth. Data about the physician and the patient will be entered into a database for storage and subsequent generation of tables and reports.

Collection of Serum Samples

The sponsor will provide detailed instructions about the collection, processing, labeling and storage conditions of all serum samples. In addition, the sponsor will provide the collection and storage tubes, as well as labels to be affixed to tubes, and detailed shipping instructions. Upon receipt, the sponsor will acknowledge receipt of the samples.

Analysis of Samples

Serum samples will be collected from each patient prior to treatment and thenon days 1, 7 and 28 after initiation of treatment with ATryn. The samples will be tested for IgE, IgM and IgG antibodies to recombinant human antithrombin as described below.

Serum samples will be batched for periodic analysis. In the event of an adverse reaction that is suspected of being an IgE mediated event, the samples will be processed on an expedited manner.

CONCLUSIONS

ATryn has been shown to be efficacious, using the recommended dosing guidelines, for prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin deficient patients. Careful monitoring of AT activity levels during treatment is recommended. The safety profile appears to be acceptable.

The clinical reviewer (Nisha Jain) found clinical data to be acceptable and supportive of a ATryn’s approval.

8. Advisory Committee Meeting

The Blood Products Advisory Committee meeting convened on January 09, 2008 to discuss GTC Biopharmaceuticals’ clinical trials for the use of Atryn in prevention of peri-operative and peri-partum thromboembolic events (TE) in hereditary antithrombin deficient patients.

The Committee addressed two specific questions:

Q1

Do the data show safety and efficacy of the product in preventing peri-surgical and peri-partum TE events in congenital ATIII deficient patients?

  1. Is the safety profile acceptable?
    (Votes: Yes - 18; Abstain - 1)
  2. Is rATIII effective in preventing TE in non-pregnant surgical subjects and in pregnant subjects during the peri-partum period?
    (Votes: Yes - 16; No – 1; Abstain – 2)

The Committee agreed that the safety profile is acceptable and that rAT is effective in preventing TE in non-pregnant surgical objects and in pregnant subjects during the peri-partum period.

Q2

Should post-marketing studies be performed to assess safety and immunogenicity after repeat dosing?

The Committee unanimously agreed that post-marketing should be performed to address immunogenecity after repeat dosing.

9. Pediatric

ATryn was granted orphan drug status on December 7, 2007. Pediatric Research Equity Act (PREA) does not apply to orphan indications.

10. Other Relevant Regulatory Issues

No other regulatory issue to disclose.

11. Labeling

 The firm’s proprietary name, ATryn, was reviewed by the Advertising and Promotional Labeling Branch (APLB) from a promotional and comprehension perspective and was found to be acceptable on March 07, 2008. OBRR concurred.

Full Prescribing Information (FPI): APLB reviewed the original FPI submitted by GTC. Comments from a promotional and comprehension perspective were provided to OBRR on December 12, 2008. APLB comments regarding FPI were communicated to the firm on December 19, 2008. Subsequently the firm submitted the revised version of FPI on December 29, 2008. The CBER’s comments were communicated to the firm during the teleconference held on January 16, 2009. The revised version of FPLI was submitted by the firm on January 19, 2008. A subsequent teleconference was held on January 23, 2009. The firm accepted all of FDA’s remaining comments and recommendations and submitted revised version of FPLI on February 02, 2008. The FDA found it to be acceptable. The discussion between CBER and GTC concentrated on issues related to format and content of the FPI. All FPI issues have been adequately resolved to proceed with final approved labeling. FDA and the firm agreed that the following statement will be added in the Contraindication section: “Known hypersensitivity to goat and goat milk proteins”

Carton and immediate container labels submitted in the original application were reviewed by APLB. APLB reviewed content of carton and immediate labels from a promotional and comprehension perspective. APLB comments were submitted to OBRR on December 12, 2008 (for original submission) and on January, 23, 2009 (for the final version). Following CBER’s communication with the firm on December 19, 2008, the revised versions were submitted by GTC on December 29, 2008. The firm accepted all outstanding recommendations provided by the FDA. All carton/container labeling issues have been adequately resolved to proceed with final labeling.

12. Recommendations/Risk Benefit Assessment

Post-Marketing Requirement (PMR)

Because of the infrequency with which patients may require treatment with ATryn on more than one occasion additional clinical data assessing the immunogenic potential of ATryn, especially in those patients requiring re-exposure to ATryn, GTC is required to do the following:

  1. Evaluate immunogenicity in patients with repeat exposure to ATryn via an immunosurveillance program. Information on 50 patients over a period of 5 years will be collected. The completion dates as agreed upon are listed below:
Study start date: August 2009
Projected completion date: February 2014
Final study report date: August 2014

Post-Marketing Commitments (PMC)

In addition to the clinical PMR, the firm agreed to the following post-marketing commitments regarding ATryn stability testing and validation of the manufacturing process:

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13. Recommendation/Risk Benefit Assessment

 The review committee unanimously recommends approval of this BLA.

An extensive pharmacovigilance plan has been developed by GTC, and has been reviewed and is acceptable. Based on the known risks of this product, the proposed programs for post-marketing surveillance and immunosurveillance appear adequate to monitor for adverse outcomes in this patient population. There appear to be no known risks associated with ATryn treatment that require further assessment of risk reduction strategies, beyond what has already been proposed and established by the applicant.