Hemophilia B:The Emerging Gene Therapy

Evangelia ArgentouAisha Asra

Patcha ChainiwatanaYau Kiat Lee

Damiano MiganiMuhammad Mustaqim

Chien-Yu Ting

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

Source: novo nordisk

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

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

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/

http://bioviva-science.com/gene-therapy/

Gene Therapy

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

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

Current Competitors - Issue

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

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

Product development, manufacturing & operations

Our Team

Team Hiring Timeline

Production Process

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

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

Risk AssessmentRISK 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

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 MARKETINGCLINICAL PHASEPRECLINICAL PHASE REGULATORY REVIEW

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%

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

Key Milestones Payment

Financial Evaluation

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