The development & approval of Novoeight, a case study

A STORY OF

NOVOEIGHT®

WITH THE FDA

Overview of the Approval of Novoeight by the FDA for Hemophilia A management in Adults and Children's

Final Project Presentation for RGA 6200, Winter 2014 Class

Qinglin Che

Mach 20, 2014

What’s the Story

On October 15th, 2013, The FDA approved Novoeight ®, a

recombinant Antihemophilic Factor developed by Novo Nordisk for

adult and children patients with hemophilia A for the following three

indications.

Control & prevention of bleeding episodes

Perioperative management

Routine prophylaxis to prevent or reduce the frequency of

bleeding episodes.

Background: The Indications

What is Hemophilia A? Hemophilia A is a chronic, inherited bleeding disorder

that mainly affects males. 1 of every 5,000 male births with Hemophila A.

Global Patients Population: ~400,000

U.S. Patients Population: ~20,000

What Causes Hemophila A? Hemophia A patients has no or malfunctional

Factor VIII protein in the plasma. Classified based on FVIII activity in plasma.

Sever (<1%)

Moderate (1-5%)

Mild (>5%)

How to Manage? patient would take Factor VIII to replace the missed or

malfunctioning FVIII protein.

Background: About the Target FVIII

Plasma based FVIII Concentrate

widely used before 1990s,

Safety Concern: viral contamination.

Recombinant Full-Length FVIII

First Gen. Using human albumin as stabilizer. Transmission issue remains.

Second Gen. synthetic stabilizers, but human/animal proteins used in manuf.

Third Gen. No human/animal plasma-based products used in process

Recombinant B-Domain Deleted Recombinant FVIII (BDDrFVIII):

Replaced heavy B-domain with a short amino acid sequence

Reducing the size of the protein, making manufacturing much easier

Greater stability, eliminating the need for human albumin as stabilizer, thus

reducing the risk of viral pathogen transmission.

Safety Concern: Immunogenicity-development of inhibitor and antibody

Historical Evolution to FVIII products

Plasma-derived FVIII concentrates become commercially available.

HIV epidemic results in viral contamination of plasma-derived products and widespread infection of more than half of all hemophiliacs with HIV.

Recombinant FVIII products become commercially available

1st Generation: Recombinant (Baxter)

2nd Generation: Advate (Baxter)

3rd Generation: Kogenate FS (Bayer)

ReFacto, the first BDDrFVIII is licensed by FDA: elimination of the B-Domain

Xyntha, a BDDrFVIII albumin-free cell culture product is licensed by FDA and replaces ReFacto in the US market

NovoNordisk submits BLA for NovoEight

Regulatory Chronology of NovoEight ®

Jun 15, 2009

• IND submitted (BB-IND14059)

July 9, 2009

• Telecon on Study Design: Immunogenicity testing and surgical study evaluation revised

July 16, 2009

• Telecon to discuss deficiencies; study can’t proceed until revisions are submitted and approved by FDA

August 14, 2009

• Study may proceed; non-hold items communicated

June 13, 2012

• Pre-BLA meeting response: dataset to be arranged by study site

August 3, 2012

• 2012 Telecon to discuss Pre-BLA responses; clarification on the site-specific data set format requested by sponsor

Oct 16, 2012

BLA

Submitted

BLA Review: CMC and PLI

CMC Review. No use of any serum or other animal-derived

components in the manufacturing and formulation process

Drug substance: cell culture, capture of protein, purification of protein.

Durg product: Filtration, filling and lyophilization

Pre-license Inspection

Inspected the facility in Denmark for the manufacturing of NovoEight

Form FDA 483 Issued with following observations

Deficiencies in following aseptic tech in the seed lab

Insufficient control over the cell culture process

Lack of quantitative criteria in the qualification of purification

equipment

Inadequate cleaning validation

August 16, 2013. NovoNordisk response with corrective actions.

FDA accepted the response, and considered it satisfactory

BLA Review: Clinical Programs

Based on 3 clinical trials including a pivotal and an expansion trials

Trial ID Number of

subjects Study design Regimen

NN7008-3543 150 adolescents

and adults

Pivotal trial

For prevention and

treatment of bleeds

Prevention: 20-50 IU/kg every second day or 20-

60 IU/kg 3 times weekly

Treatment: per guidelines

Surgery: based on individual PK

PK: 50 IU/kg (single dose)

NN7008-3545 63 children <12

years

Pediatric study,

previously treated

patients with hemophilia

A

Prevention: same as NN7008-3543

Treatment: per guidelines

Surgery: based on individual PK

PK: 50 IU/kg (single dose)

NN7008-3568

188 pediatric,

adolescent or

adult

Extension trial

For prevention and

treatment of bleeds

Routine prophylaxis: 20-50 IU/kg every second

day or 20-60 IU/kg 3 times weekly

Treatment: per guidelines

Surgery: based on individual PK

BLA Review: Efficacy Assessment

Objectives: assess the efficacy for reducing the number of acute bleeding

events per year on prophylactic treatment when compared to on demand treatment

and for treatment of breakthrough bleeds using the following endpoints:

Annualized bleeding rate of prophylactic vs on-demand treatment

Hemostatic effect for intra- and post-operative management and for

treatment of spontaneous and traumatic bleeding episodes

The number of infusions required per bleeding episode

Efficacy Conclusion: The outcomes of the study support the efficacy of

Novoeight in adults with hemophilia A for control and prevention of bleeding,

perioperative management, and routine prophylaxis to prevent or reduce the

frequency of bleeding episodes.

Reviewer Comment: A success rate was not pre-specified in the protocol; however, a response rate

of >80% is clinically significant. The success rate of 80.8% is lower than the sponsor’s report of

84.5%, which was calculated with missing data excluded. The protocol did not specify how missing

data would be handled, therefore in my analysis all missing data were considered failures.

BLA Review: Safety Assessment

Endpoints: The safety concerns for this product are hypersensitivity and

allergic reactions, thromboembolic events, and inhibitor development. The safety

was assessed using the endpoints:

• Frequency of adverse events

• Vital signs (blood pressure, pulse, temperature, and respiratory rate)

• Clinical laboratory tests

Results: 783 AEs reported in 179 subjects (2.29/subject); 30 were evaluated as

related to the product by the investigator. The majority of the AEs were mild or

moderate; 28 severe AEs in 22 subjects were all unrelated. No confirmed inhibitor

development.

Safety Conclusion: Data from the three efficacy and safety trials and from

the three PK studies were pooled to allow for an integrated prioritized review of

safety topics. The product appears well-tolerated. No new safety concerns were

identified.

Compliance with GCP: BIMO Inspection

Who were inspected?

Four clinical sites were chosen. Selection of sites was based on

Highest No. of subject enrolled (6,6,6,10, totally 28, 22% of total), &

Previous inspection history

What were Inspected? Focused on

the study protocol

comparison of data submitted in the BLA to source

Results:

Form FDA 483 was issued notifying NovoNordisk of objectionable conditions were issued at the sites.

A number of deviations from protocol adherence, &

Data discrepancies between the source document and BLA.

However, the FDA consider that the inspections did not reveal any

issue that would impact the data submitted in the BLA.

BLA Review: PeRC Assessment

PREA requirements were triggered as a new indication was being sought.

Subjects: From the pivotal and pediatric trials, the safety and efficacy of

Novoeight was evaluated in 79 children between 0 and <16 years, including 4 from

0 to <2 years, 27 from 2 to <6 years, 32 from 6 to <12 years, and 16 from 12 to

<16 years of age.

Reviews: Sep 11, 2013. The data from the pediatric trial and pediatric patients in

the pivotal trial were presented to the Pediatric Review Committee (PeRC)

PeRC: Pediatric Research Equity Act

Conclusion: No confirmed inhibitors were reported in any

pediatric subject. Hemostatic response in 54 subjects was

excellent or good for 210/244 (86%) of bleeds. The ABR (95%

CI) for the 79 subjects was 4.8. Based on these data, PeRC

agreed with the review decision that Novoeight is safe and

efficacious for children with hemophilia A.

Advisory Committee? Not this time!

FDA didn’t refer to the Blood Products Advisory Committee (BPAC) for

approval recommendation, because:

NovoEight is not a NME (new molecular entity). Sveral products already been

licensed in the U.S. since 1992.

The MOA (mechanism of action) of FVIII and its function in blood coagulation is

well studied and understood.

Novoeight is identical to human plasma derived FVIII in heavy and light chain

amino acid sequence and major post-translational modifications.

The Manufacturing process already includes two viral clearance steps.

The proposed indication are identical or similar

to those of other US licensed FVIII products.

The clinical PK data indicated bioequivalence

with a licensed full-length recombinant FVIII

No safety Concern revealed from the clinical data

Other Regulatory Related Items

Pharmacovigilance and Post-marketing Commitments

Stated in NDA Amendments (STN 125466/0.26 and STN 125466/0.34)

To conduct additional stability studies for the commercial batches.

To conduct an trial of 50 subjects for a minimum of 100 Eds over four years

To conduct a trial in at least 50 PUPs who will be treated for a minimum of 50

Eds over 3.5 years,

To submitted the final study report by March 31, 2017, and March 31, 2009,

respectively.

Labeling

The proposed proprietary name, Novoeight, was reviewed by APLB

(Advertising and Promotional Labeling Branch) and accepted.

The FPI (Full Prescribing Information) was reviewed by BLA committee,

comments conveyed to NovoNordisk, modification accepted.

Review Conclusions

Novoeight appears reasonably safe and likely to provide therapeutic benefit

to patients with hemophilia A.

No reports of hypersensitivity/allergic reactions, thromboembolic events or

confirmed inhibitor development were reported.

Hemostasis was successfully achieved in the treatment of acute bleeds and

during surgery.

Prophylaxis reduced the ABR for subjects previously treated with on-

demand therapy by greater than fifty percent.

Post-Approval Activities

Global Approval Landmarks

Sep. 2013, NovoEight was approved by EMA

Oct 16, 2013, NovoEight was approved by FDA

Nov 18, 2013, NovoEight passed the review by the Committee on Drugs of

Pharmaceutical Affairs in Japan

Wait until April 2014 to launch in Europe

Wait until Early 2015 to launch in the U.S.

Why not launch immediately after approval?

Novo Nordisk is afraid of stepping on some unspecified

third-party patents, would wait until the expiration of the

patent before launch.

Why Not Biosimilar?

As an follow-on BDDrFVIII drug, why not go through biosimilar

pathway?

To date, no application submitted via abbreviated BLA pathway yet.

Unclear requirement for clinical Data in 2009 when IND initiated

Need for public disclosure with originator drug company (patent

dance)

No extended exclusion right

Price dropped to ~70% of originator biologic

Why Normal BLA Pathway?

Treated as innovator drug, not copycat, can keep

manuf. Process confidential

Huge pricing advantage, still Brand-Name

12-year exclusion benefit

What Does NovoEight Mean to NovoNordisk

Aiming to be a leader in Hemophilia Management

Current lead product NovoSeven for Hemophilia A & B management.

2012 Sale of Novoseven reached 1.5 Billion.

Patent expiring in US and EU, sale from NovoSeven will decline.

What’s Next? NovoNordisk’s long-acting FVIII product (N8-GP) is in Phase III clinical trial now. This is next generation of FVIII products that can work longer in the body (with extended T-half).

NovoNordisk approach: glyco-PEGylated rFVIII

Intensed Competition. Rivols include include Baxter, Bayer and Biogen Idec.

BAX 855

PhIII Trail ELOCTATETM BLA review

BAY 94-9027

PhI Trial N8-GP, Phase III Trail

What We Learned from NovoEight Story?

A up-to-date case study on how biologics are developed and approved in the U.S.

The historical evolution of NovoEight and other FVIII products demonstrated that

scientific Innovation drives the development of safer and more efficient therapeutics.

Safety and efficacy are the two major aspects that the review focuses on. They are

the basis of risk/benefit assessment which determines the fate of the BLA

application.

For the sponsor, intelligent properties consideration is very important in the process

of drug development. Protect your own, not step on the others.

Biosimilar pathway in the U.S. is still immature, additional efforts from the regulator

are needed to accelerate the progress.

References & Additional Readings

Final Review Memo of Original Application http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM375275.pdf

Long-lasting recombinant factor VIII proteins for hemophilia A http://asheducationbook.hematologylibrary.org/content/2013/1/37.full.pdf

The Hemophilia Market: Steep but Surmountable Barriers for New Entrants http://corporate.morningstar.com/us/html/pdf/Healthcare-Observer-Jan-2013.pdf

Biologics License Application Memo, March 28, 2013 - Novoeight (PDF - 232KB) http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM374795.pdf

Approval History, Letters, Reviews and Related Documents for Novoeight

http://www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/ucm374010.htm

NovoEight (turotocog alfa) page on European Medicines Agency

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002719/human_med_001701.jsp&mid=WC0b01ac058001d124