1. Hemophilia B:
The Emerging Gene Therapy
Evangelia Argentou
Aisha Asra
Patcha Chainiwatana
Yau Kiat Lee
Damiano Migani
Muhammad Mustaqim
Chien-Yu Ting

2. Background - Science
● X-linked recessive bleeding disorder
○ due to a mutation of the coagulation factor IX gene
○ Serine protease critical for blood clotting
○ Hence, factor IX deficiency
○ Much more common in males
● Factor levels <1% is considered a severe Hemophilia
● Current treatments:
○ Transfusion of plasma from a healthy individual
○ Recombinant factor IX intravenous infusion every 2-3 days
■ E.g. Pfizer’s BeneFix
■ Not curative, invasive, inconvenient
■ Costs $250,000/patient/year (2014)
http://www.hog.org/publications/detail/new-factor-concentrates-the-future-is-now

3. Source: novo nordisk

4. Market Analysis
● 12,000 Hemophilia B patients in the U.S. and EU
○ 75% of the patients with severe and moderate conditions
○ 40% of those is expected to choose our durable
response
○ Market size of 3,600 patients during the first 4 years
● Steady market but increasing market share over
time with potential expansion to global market
● Market penetration:
○ Competitors - other companies at different
developmental stages and similar products
○ No other long term treatment commercially available
http://www.hog.org/publications/detail/new-factor-concentrates-the-future-is-now

5. Solution and Concept
● HemB, Somatic in vivo gene therapy
○ transfer of a normal copy of factor IX gene via an AAV8 vector
○ Single intravenous infusion which remains relatively stable for a period of 4 years
○ Novel and improved biobetter version
○ Corrects the problem at the genetic level
Nathwani, Amit C. et al. "Long-Term Safety And Efficacy Of Factor IX Gene Therapy In Hemophilia B". New England Journal of Medicine 371.21 (2014): 1994-2004. Web.
● Advantages:
○ Persistent, endogenous production of factor IX
○ Factor IX expression at 1-6% of the normal value
○ Patients no longer have severe Hemophilia B; less
bleeding episodes
○ Weekly infusions no longer required → more
convenient; financial savings
○ Improved quality of life

6. About the Vector
● 4.8 kb ssDNA Adeno-associated virus genome
○ Inverted terminal repeats (ITRs)
- synthesis of complementary DNA strand
○ Rep/Cap - proteins required for AAV life cycle and capsid
○ Helper plasmid - mediates AAV replication
● Important features:
○ Safe, non-pathogenic, produces lowest immune response
○ High gene transfer efficiency; enables long-term transgene persistence in hosts
○ Preferentially transduces specific cell type (AAV8 - containing liver-specific promoters)
● Pseudotyping
○ Production of viral vectors in combination with foreign viral envelope proteins (capsid)
○ scAAV2/8 - self-complementary; preferred over WT-vectors
https://www.addgene.org/viral-vectors/aav/aav-guide/

7. http://bioviva-science.com/gene-therapy/
Gene Therapy

8. Current stage of development
● Phase I clinical trial successful
○ 10 patients
■ All showed an increase of factor IX production from <1% to 1-6% normal levels
■ Patients given the high dosage of HemB experienced a 90% reduction in both bleeding
episodes and requirement for the factor IX concentrate treatment
■ Patients were able to maintain an active lifestyle including playing sports which would
have been out of the question without treatment
■ No long term toxicity observed - observation still ongoing
■ No significant side effects
● An increase in alanine aminotransferase (ALT) was observed which is
asymptomatic and reduced to normal levels after a short course of prednisoline
■ Patients hemophilia B symtpoms were transformed from severe to mild

9. Phase II clinical trial
● Total of 60 patients with severe hemophilia B will be recruited over 3 years
● 40 patients will receive HemB
○ These patients will receive HemB with either capsid A or capsid B
■ Two capsids are being trialled in case of development of inhibitors to the initial capsid
after treatment
● 20 patients will continue on the current factor IX concentrate treatment
(control group)
● The study will take place in 3 specialist hemophilia centres across the USA
● Factor IX levels will be used as surrogate endpoint12 months after the patient
has received treatment
○ Post marketing surveillance - patients will be monitored up to 4 years post treatment

10. Current Competitors - Issue
https://www.linkedin.com/pulse/hemophilia-market-boiling-new-players-products-drug-wars-eran-or

11. Marketing and sales
● Pricing: $1.2 million per infusion
○ Installment plan available (e.g. $300,000 annually)
○ Anticipated annual revenue for the first 4 years is $1.08 billion
● Customers:
○ U.S. - National Hemophilia Foundation, Hemophilia Federation of America, Hemophilia
Treatment Center, insurance company
○ EU nations - local healthcare providers (e.g. NHS in UK), European Hemophilia Consortium,
Hemophilia Association in each country
● Marketing strategies:
○ Contact customers, support groups of Hemophilia B patients.
○ Advertisement via scientific/medical magazine, brochure in clinics
○ Hospital, NHS visits to inform authorities/healthcare professionals
○ Social media, internet (e.g. youtube), viral public stunt, support group website

14. Product development,
manufacturing & operations

15. Our Team

16. Team Hiring Timeline

17. Production Process

18. Images from: http://www.bioprocessintl.com/2012/bio-on-demand-333776/
http://www.hc-bios.com/en/about.php?sn=5
GMP Facility
Location: Cambridge, Massachusetts

19. Strengths Weaknesses
Opportunities Threats
● Innovative biobetter product
● Better quality of life
● Low manufacturing cost per dose
compared to selling cost
● Experienced management
● High return on investment
● Low patient number
● Problem with market access
● High initial investment
● Patient development of inhibitors or
antibodies to AAV
● Not a permanent treatment
● Larger global market share
● Potential development of new, similar
product to treat Hemophilia A
● Increasing market size due to expanding
population and longer life span of
patients
● Booming of competitors
● Development of inhibitors
● Possible leak of technology or important
information
● High investment could lead to business
failure, especially during recession
SWOT

20. Risk Assessment
RISK Likelihood Impact Total risk Mitigation Strategies
Immunogenicity Low Moderate Low Prescreen patients for AAV antibodies
Contamination of facility Low High Low Train personnel, follow SOPs carefully, ensure manufacturing workers
follow gowning access procedures carefully
Clinical trials fail Moderate High Moderate Not possible to de-risk. It can happen
Low market penetration moderate Low Low More promotions, closely contact customers
Leak of information High High High Stricter employment contract, increase security, registered access to the
information
Embezzling High Moderate High Stricter employment contract
Sudden inflation Moderate High High Cannot de-risk
Lack of venture capital Low High Low Solid business plan

21. Regulatory and IP framework
Documents
● CMC documentation
(chemical
manufacturing control)
● INDs (investigational
new drug)
● MSDSs (safety)
● Patents: 7 year
market exclusivity
from NDA
● Preclinical reports
● Research papers
Documents
● Clinical trials
agreements
● Global clinical trial
feasibility studies
● ICFs (informed
consent forms)
● Marketing material
● Patient recruitment
● SOPs (standard
operating procedures)
Documents
● Batch records
● eCTDs (common
technical document)
● MAA (marketing
authorization
application)
● NDA (new drug
application
● Manufacturing
documentation
Documents
● Adverse event report
● Pharmacovigilance
● Patient registries
● Pricing and
reimbursement
studies
SALES AND
MARKETING
CLINICAL PHASEPRECLINICAL PHASE REGULATORY REVIEW

22. Financial Assumptions
● Annual inflation rate is neglected
● Manufacturing cost of $15,000/dose
● 70-80% of product is administered in the first year; however, we assume that
900 patients receive the product each year
● The salaries of 90 employees are factored into the cost each year; however,
the employment contracts begin at different time points for each position
● Conditional part-time employment
● <5% annual depreciation rate; used equipment is purchased for
manufacturing
● Estimated tax and discount factor of 33% and 25%

23. Financial Evaluation
● Financial assumptions:
○ Expecting 60% of product is administered in the first year; however, we assume that 900
patients receive the product each year
○ The salaries of 90 employees are factored into the cost each year; however, the
employment contracts begin at different time points for each position
○ Constant wages
○ Disregard inflation and depreciation
● Initial Investment of ~$150M
● Manufacturing cost of ~$59,000/dose
● COG/SP ~ 6.5%
● Profit margin of ~93.5%
● Expected ~40 fold ROI at the end of year 10

24. Key Milestones Payment

25. Financial Evaluation

26. Final Proposal
● Required funding $62 million until product launch
● 4 Milestone Payments
● Clinical Trials & Product Development: Years 1-5; Product launch: Year 6
● Revenues commences in Year 6 and remains constant
● Introduction of the HemA treatment to maintain the market share
● Constant selling price $1.2 million/dose
● Begins with US market and expand to Europe
● Opportunity to move on to the global level
● Increasing market share until significant competitions hit in
● 10X Return of Initial Investment at years 6-7
Not only a financial but an investment for a better life