Annual Report 2014 uniQure N.V. Amsterdam

Amsterdam, May 1, 2015

uniQure N.V. Annual Report 2014

Management Board Report

Introductory statements

Forward-Looking Statements

This Annual Report and the consolidated Financial Statements on Form 20-F as filed with the SEC contain forward-looking statements. The Private Securities Litigation Reform Act of 1995 provides a safe harbor from civil litigation for forward-looking statements accompanied by meaningful cautionary statements. Except for historical information, this report contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, which may be identified by words such as estimates , anticipates , projects , plans , seeks , may , will , expects , intends , believes , should and similar expressions, or the negative versions thereof, and which also may be identified by their context. Such statements, whether expressed or implied, are based upon our current expectations and speak only as of the date made. We assume no obligation to update or revise any forward-looking statements even if experience or future changes make it clear that any projected results expressed or implied therein will not be realized. These statements are subject to various risks, uncertainties and assumptions. Our actual results of operations may differ materially from those stated in or implied by such forward-looking statements as a result of a variety of factors, including those described under Risk Factors and elsewhere in this Annual Report.

Explanatory Note to Shareholders

On January 20, 2014, the general meeting of shareholders of the Company approved, and on January 21, 2014 the Supervisory Board of the Company confirmed, a 5- for-1 consolidation of shares, which had the effect of a reverse share split, that became effective on January 31, 2014.

All share, per-share and related information presented in the financial statements and accompanying footnotes has been retroactively adjusted, where applicable, to reflect the impact of the reverse share split.

Bristol-Myers Squibb Collaboration

On April 6, 2015, we entered into an agreement with Bristol-Myers Squibb, or BMS, that provides BMS exclusive access to uniQure s gene therapy technology platform for multiple targets in cardiovascular and other target-specific disease areas. The collaboration includes our proprietary congestive heart failure gene therapy candidate, which has demonstrated in advanced preclinical models that it can restore the ability to synthesize S100A1, a calcium sensor and master regulator of heart function, and increase survival rates after myocardial infarction. In addition, we will collaborate with BMS on up to nine additional gene therapy targets addressing a broad range of heart conditions and other target-specific disease areas. We will be responsible for discovery, preclinical development, and CMC, and will provide BMS our vector technologies and access to our industrial, proprietary insect-cell based manufacturing platform. uniQure will be responsible for CMC portions of regulatory filings and will co-operate with BMS in the preparation of all regulatory materials and interactions with regulatory authorities. BMS will be responsible for clinical development and all commercial activities across all programs.

The financial terms include guaranteed, near-term payments to us of approximately $102 million, including an upfront payment of $50 million to be made at the closing of the transaction. The closing of the transaction is expected to occur in the second quarter of 2015 subject to Hart-Scott-Rodino clearance and customary closing conditions. An additional $15 million payment is to be received following the selection of three additional collaboration targets, in addition to the S100A1 program, within three months of the closing. An initial equity investment in uniQure will

be made for a number of shares that will equal 4.9% of the total number of shares outstanding following such issuance, at a purchase price of $33.84 per share, or approximately$37 million in total. This investment is expected to be completed in the second quarter of 2015. BMS is also obligated to make an additional equity investment in uniQure for a number of shares that will equal 5.0% of the total number of shares outstanding following such issuance by December 31, 2015 and will be granted two warrants to acquire at its option up to an additional 10% equity interest, at a premium to market, based on additional targets being introduced into the collaboration.

The parties have also agreed to enter into a supply contract, under which uniQure will undertake the manufacturing of all gene therapy products under the collaboration. uniQure will be eligible to receive research, development and regulatory milestone payments, including up to $254 million for the lead S100A1 therapeutic and up to $217 million for each other gene therapy product potentially developed under the collaboration, assuming designation of all targets by BMS and achievement of all milestones. uniQure is also eligible to receive target designation fees, net sales based milestone payments and compensation on net product sales based on single- to double-digit percentages of net sales.

On April 9, 2015 the Company announced the pricing of its follow-on public offering of 3,000,000 ordinary shares at price to the public of $29.50 per ordinary share. After deducting underwriting discounts but before share issuance expenses, the net proceeds of the follow-on public offering were $83.2 million ( 77.2 million). In addition, uniQure granted the underwriters a 30-day option to purchase up to an additional 450,000 ordinary shares from uniQure at the public offering price, less underwriting discounts. The offering closed on April 15, 2015. The securities are being offered pursuant to a shelf registration statement on Form F-3 filed with the Securities Exchange Commission (the SEC ) on March 3, 2015 and declared effective on March 13, 2015.

Glybera Regulatory Status

On April 8, 2015, the Company received a copy of a preliminary assessment report on Glybera prepared by the rapporteur designated by the Committee for Advanced Therapies (CAT), which is the committee that advises the Committee for Human Medicinal Products (CHMP) on gene therapies. The preliminary report was a response to the Company s submission to the European Medicines Agency (EMA) on September 5, 2014 of a Type II variation, which proposed an amendment to the Glybera Summary of Product Characteristics (SPC) to reflect certain information from the six year follow up data included in the Company s final clinical study report. The preliminary assessment report, which represented the sole view of the rapporteur, stated that Glybera lacked efficacy and therefore the benefit-risk balance was negative. The rapporteur s preliminary report was provided to the CAT for further discussion in advance of the CAT s monthly meeting on April 16-17.

On April 24, the Company received a copy of the final assessment report prepared by the CAT and endorsed by the CHMP, which states the following:

At the April CAT meeting, the CAT discussed the negative rapporteur recommendation on the benefit risk of Glybera. The CAT did not agree with the negative view of the rapporteur and concluded by majority on the following recommendation presented below:

The efficacy of Glybera needs to be considered in its totality as defined in the initial approval taking into account, the criteria considered at time of initial approval:

the persistence of LPL (lipoprotein lipase) activity

the evidence of an effect on lipids, in particular the post prandial CM (chylomicron),

the evidence presented on the reduction in the rate of pancreatitis

In accordance with the Company s Type II variation request, the CAT will continue to evaluate the six year follow up data and has requested supplemental information, which the Company is currently preparing.

On April 28, the Company informed the Federal Joint Committee (G-BA), which is responsible for the commercialization of Glybera in Germany, of its receipt of the final assessment report from the CAT. Previously, the G-BA had put its ongoing benefit assessment of Glybera on hold to await the final assessment of the CAT and the CHMP regarding benefit/risk. Based on the recommendations stated in the final assessment report, the Company has requested the G-BA to immediately resume its benefit assessment of Glybera.

The Company continues to believe that the clinical data from its Glybera development program, including the six-year follow-up data, support the long-term value and efficacy. However, the Company can provide no assurance regarding the final conclusions of the EMA and G-BA. Any adverse outcomes could require the Company to expend significant additional resources to support its conclusions or could have a material negative impact on the revenue expectations for Glybera.

2014 Corporate Highlights

2014 was an important year as we continued to strengthen our financial position and leadership in the field of gene therapy.

Hemophilia B: As of the end of the first quarter 2015, the Company has initiated the first clinical trial site in Germany for its clinical trial in Hemophilia B patients and anticipates providing top-line data and initial results on this trial in the second half of 2015.

Sanfilippo B: The Company expects clinical data from its collaborator-sponsored Sanfilippo B program with Institut Pasteur will be available in the second half of 2015 and plans to present those results at a relevant scientific meeting.

Glybera : In early 2016, the Company expects to commence an additional clinical evaluation of Glybera (alipogen tiparvovec) to be included in a future BLA submission with the FDA. The clinical trial will include next-generation manufacturing process enhancements, which are currently being implemented.

In June 2014, uniQure presented six-year follow-up data with commercialization partner Chiesi from Glybera-treated patients. The analysis demonstrated that after a single administration of Glybera, patients have experienced reductions in both the frequency and severity of pancreatitis, long-term clinical benefits that reduce the burden on healthcare resources.

Acute Intermittent Porphyria (AIP): In October 2014, the Company announced together with the AIPGENE Consortium top-line, one year follow-up analysis of a completed Phase I dose-escalation clinical trial testing an AAV5-PBGD gene therapy candidate (AMT-021) in AIP patients. The preliminary analysis of the data confirmed the safety and successful transduction of patient s liver cells with the porphobilinogen deaminase gene (PBGD) using uniQure s proprietary AAV5 viral vector, as previously indicated in the interim analysis presented in May.

Parkinson s Disease: As of mid-year 2014, uniQure s partnership with UCSF and NIH for Parkinson s disease completed dosing of all six patients in the first cohort of the ongoing clinical trial.

Other Business Development and Commercial Updates

Glybera Commercialization: uniQure s commercialization partner Chiesi has submitted price and reimbursement dossiers in key European countries in order to make Glybera accessible to patients. Glybera is officially available to doctors in Germany. The price has also been accepted by the Department of Health and published in the United Kingdom. Based on an assessment report provided to uniQure and the Committee for Advanced Therapeutics (CAT) by the MHRA, a designated rapporteur, the Federal Joint Committee (G-BA), the regulators responsible for the commercialization of Glybera in Germany, have put the ongoing benefit assessment of Glybera on hold to await the final assessment of the CAT and the CHMP regarding benefit/risk later this month.

Acquisition of InoCard: In August 2014, uniQure announced the acquisition of InoCard GmbH, an innovative, early-stage biotechnology company focused on the development of gene therapy approaches for cardiac diseases. InoCard has developed a novel gene therapy for the one-time treatment of congestive heart failure, a rapidly progressing disease affecting 26 million people worldwide. InoCard founders Prof. Patrick Most and Prof. Hugo Katus joined uniQure as

Managing Director of uniQure Germany and Chairman of the Scientific Advisory Board, for Cardiovascular Diseases, respectively.

Collaboration with Treeway: In January 2015, uniQure entered into a license and collaboration agreement with Treeway B.V., a private company founded by entrepreneurs Bernard Muller and Robbert Jan Stuit, both diagnosed with amyotrophic lateral sclerosis, or ALS, to develop a gene therapy treatment for ALS.

Technology Platform Collaborations: In January 2014, uniQure entered into a collaboration and license agreement with 4D Molecular Therapeutics ( 4D ) for the discovery and optimization of next-generation AAV vectors. uniQure gained exclusive access to 4D s AAV vector discovery and optimization technology for gene delivery to the central nervous system and liver. The Company expects to make a preliminary selection of new synthetic vectors in the first half of 2015.

In January 2015, uniQure entered into a collaborative license agreement with Synpromics Limited to strengthen its technology platform with respect to therapeutic indications that require high-level therapeutic gene expression or comprise large therapeutic genes. uniQure will exclusively own the results of this collaborative effort.

Other Corporate Highlights

Human Resources: In January 2015, uniQure announced the appointment of Matt Kapusta to Chief Financial Officer.

In April 2014, uniQure announced the appointment of Eric Goossens as its Chief Operating Officer and Deya Corzo, M.D. as its Vice President, Medical Affairs for the U.S.

In June 2014, uniQure announced Will Lewis will join the Company s supervisory board.

Infrastructure: As of early 2015, the Company completed the build out of the Lexington, Massachusetts 53,000 sq. ft. (4,924 m2) manufacturing facility which now houses over 40 employees.

Financial Highlights

On February 5, 2014, uniQure completed IPO on NASDAQ, placing 5,400,000 shares at $17 per share, raising a total of gross $91.8 million ( 67.3 million). On such date the Company also reclassified its class A, B and C ordinary shares as ordinary shares.

In July 2014, uniQure announced the closing of an additional $10 million venture debt loan with Hercules Technology Growth Capital, Inc.

Licensing and collaboration revenues for the 12 months ended December 31, 2014 were 4.7 million, compared with 2.9 million in 2013. The collaboration revenues are related to development activities that were reimbursable by Chiesi under the Company s co-development agreement for hemophilia B. The license revenues reflect the amortization of the upfront received from Chiesi in July 2013.

Research and development expenses were 33.9 million for the 12 months ended December 31, 2014, compared to 13.2 million for the comparable period in 2013. This increase reflected the expansion of our research and development activities to support our hemophilia B program and our other product candidates and research programs, as well as the build-up of staff in our Lexington facility. In addition, as part of our strategic collaboration with 4D Molecular Therapeutics, entered into in January 2014, we incurred increased research and development expenses related to certain share-based payments of 6.3 million in relation to the management of 4D Molecular Therapeutics.

Selling, general and administrative expenses were 11.2 million for the 12 months ended December 31, 2014, compared to 11.6 million in 2013. This decrease resulted principally from higher legal and audit related expenses incurred in 2013 associated with the preparation of our initial public offering, partially offset by an increase in expenses related to being a public company, and the continued build-out of the administrative functions.

Net loss for the full year 2014 was 37.0 million or 2.16 per share, compared to 26.8 million or 2.48 per share for the full year 2013.

History and Development of the Company

uniQure was incorporated on January 9, 2012 as a private company with limited liability (besloten vennootschap met beperkte aansprakelijkheid) under the laws of the Netherlands. Our business was founded in 1998 and was initially operated through our predecessor company, Amsterdam Molecular Therapeutics (AMT) Holding N.V, or AMT. In 2011, AMT undertook a corporate reorganization, pursuant to which uniQure B.V. acquired the entire business and assets of AMT and completed a share-for-share exchange with the shareholders of AMT in the first half of 2012.

Effective February 10, 2014, in connection with our initial public offering and pursuant to a deed of amendment and conversion, we converted into a public company with limited liability (naamloze vennootschap). Our legal name changed from uniQure B.V. to uniQure N.V. at the time of the conversion.

Our company is registered with the Dutch Trade Register of the Chamber of Commerce (handelsregister van de Kamer van Koophandel en Fabrieken) in Amsterdam, the Netherlands under number 54385229. Our corporate seat is in Amsterdam, the Netherlands, and our registered office is located at Meibergdreef 61, Amsterdam 1105 BA, the Netherlands, and our telephone number is +31 20 240 6000. Our website address is www.uniqure.com.

Information on our website is not incorporated by reference into this Annual Report or any other report we file with or furnish to the SEC. Our ordinary shares are traded on the NASDAQ Global Select Market under the symbol QURE .

We are a leader in the field of gene therapy and have a technology platform that we use as the basis for our proprietary and collaborative product lines across multiple therapeutic areas. Our core gene therapies include AMT-060 for the treatment of hemophilia B, in which we initiated a Phase I/II clinical trial in the first quarter of 2015; our preclinical S100A1 therapeutic for the treatment of congestive heart failure and Glybera, the first and currently the only gene therapy product to receive regulatory approval in the European Union.

Our aim is to make gene therapy a mainstay of modern medicine by:

using our technology platform to develop our own programs in liver-based diseases, cardio/metabolic diseases, and central nervous system, or CNS, diseases. Our focus is on areas in which we believe the modular nature of our approach offers the potential to reduce development risk, cost and time to market by allowing us to advance multiple programs using validated components of our technology and relying on safety and efficacy data from earlier clinical studies;

sponsoring and acquiring additional early-stage programs in these areas from other biopharmaceutical companies and academic investigators;

enhancing and accelerating these programs through our modularized research and development platform and our experience in the EU and FDA regulatory environments for gene therapies;

applying our proprietary, commercial-scale manufacturing process to produce high quality material for our own and our collaborators programs; and

collaborating with pharmaceutical companies with the necessary expertise to enhance our late-stage therapy development and maximize the value of our therapies at the commercialization stage.

We believe that our technology platform and strategic collaborations place us at the forefront of gene therapy within our chosen therapeutic areas. Our transgene delivery system is based on common, adeno-associated viruses, or AAV, which we believe are safe and effective delivery methods for efficient expression of transgenes. We have the exclusive or non-exclusive rights to natural AAV serotypes for lipoprotein lipase deficiency, or LPLD, liver and CNS applications and the capability to identify and develop synthetic AAV vectors that are designed to optimize the expression of a particular transgene in specific tissue types. We produce our AAV-based vectors in our own facilities with a proprietary, commercial-scale, consistent, manufacturing process using insect cells and baculoviruses, a common family of viruses found in invertebrates.

We believe our Lexington, Massachusetts-based facility, which is currently being qualified, is one of the world s leading, most versatile, gene therapy manufacturing facilities. We believe this technology platform, combined with our know-how derived from achieving the first regulatory approval of a gene therapy in the European Union, provides us a significant advantage in bringing our gene therapy products to the market ahead of our competitors.

We seek to develop gene therapies targeting a range of liver-based, cardio/metabolic and CNS indications, from ultra-orphan diseases, such as LPLD (for which Glybera is designated), to orphan diseases such as hemophilia B and Sanfilippo B syndrome, to common diseases that affect far larger populations, such as congestive heart failure and Parkinson s disease. The core of our approach is our modular technology backbone, which allows us to advance our programs in multiple therapeutic areas using validated components of our technology and safety and efficacy data from earlier clinical studies, in multiple therapeutic areas, with the potential to reduce development risk, cost and time to market. As part of our strategy, we are accessing important medical expertise for our therapeutic focuses through strong ties with academic thought leaders and clinical institutions.

For cardio/metabolic diseases we are building a center of expertise in our German subsidiary, uniQure GmbH, in close cooperation with leading academic clinicians and surgeons at the university hospital and heart center in Heidelberg, Germany. Our CNS activities are based on collaborations with the University of California at San Francisco, the National Institutes of Health, and the Institut Pasteur, Paris, France. Our hemophilia B product originates from St. Jude Children s research Hospital in Memphis, Tennessee. We also seek to collaborate with or acquire emerging companies within our chosen therapeutic areas that are conducting or sponsoring early-stage clinical trials.

Our collaborations allow us to cost-effectively obtain access to pre-clinical and early-stage programs without expending significant resources of our own. We generally have the rights to the data generated in these collaborator-sponsored programs, but do not control their design or timing. Our collaboration programs include gene therapy candidates for Parkinson s disease, Sanfilippo B syndrome, Acute Intermittent Porphyria and amyotrophic lateral sclerosis.

Bristol-Myers Squibb Collaboration

On April 6, 2015, we entered into an agreement with BMS that provides BMS exclusive access to uniQure s gene therapy technology platform for multiple targets in cardiovascular and other target-specific disease areas. The collaboration includes our proprietary congestive heart failure gene therapy candidate, which has demonstrated in advanced preclinical models that it can restore the ability to synthesize S100A1, a calcium sensor and master regulator of heart function, and increase survival rates after myocardial infarction. In addition, we will collaborate with BMS on up to nine additional gene therapy targets addressing a broad range of heart conditions and other target-specific disease areas. We will be responsible for discovery, preclinical development, and CMC, and will provide BMS our vector technologies and access to our industrial, proprietary insect-cell based manufacturing platform. uniQure will be responsible for CMC portions of regulatory filings and will co-operate with BMS in the preparation of all regulatory materials and interactions with regulatory authorities. BMS will be responsible for clinical development and all commercial activities across all programs.

The financial terms include guaranteed, near-term payments to us of approximately $102 million, including an upfront payment of $50 million to be made at the closing of the transaction. The closing of the transaction is expected to occur in the second quarter of 2015 subject to Hart-Scott-Rodino clearance and customary closing conditions. An additional $15 million payment is to be received following the selection of three additional collaboration targets, in addition to the S100A1 program, within three months of the closing. An initial equity investment in uniQure will be made for a number of shares that will equal 4.9% of the total number of shares outstanding following such issuance, at a purchase price of $33.84 per share, or approximately $37 million in total. This investment is expected to be completed in the second quarter of 2015. BMS is also obligated to make an additional equity investment in uniQure for a number of shares that will equal 5.0% of the total number of shares outstanding following such issuance by December 31, 2015 and will be granted two warrants to acquire at its option up to an additional 10% equity interest, at a premium to market, based on additional targets being introduced into the collaboration. The parties have also agreed to enter into a supply contract, under which uniQure will undertake the manufacturing of all gene therapy products under the collaboration.

uniQure will be eligible to receive research, development and regulatory milestone payments, including up to $254 million for the lead S100A1 therapeutic and up to $217 million for each other gene therapy product potentially developed under the collaboration, assuming designation of all targets by BMS and achievement of all milestones. uniQure is also eligible to receive target designation fees, net sales based milestone payments and compensation on net product sales based on single- to double-digit percentages of net sales.

Our Gene Therapy Development Platform

Our gene therapy approach seeks to treat the causes of genetic diseases by enabling patients to effectively express a missing or deficient protein. To accomplish this, Glybera and our product candidates are designed to deliver a functional gene, or transgene, through a delivery system called a vector. Our approach is designed to be modular, in that it may allow us to efficiently develop, manufacture and seek regulatory approval for multiple gene therapies generally using the same principal components and manufacturing platform. In some cases, we believe that the disease-specific gene and potentially the tissue-specific promoters will be the only components we need to change to target a new disease in a particular tissue. Combining this with the validated quality and safety of our manufacturing platform across our products, we believe that we can cross-reference data between products, and thereby on a case by case basis we may be able to reduce the overall preclinical and clinical development activities required to obtain regulatory approval, and reduce significantly the overall development risk, time and cost.

The key components of our gene therapy approach are:

Therapeutic genes. We design our gene therapies to deliver into the body s cells a transgene that encodes, or provides the blueprint for the expression of, a therapeutic protein. The transgene is carried in a gene cassette, or DNA sequence that encodes the specific genes and that includes DNA promoters that direct expression in specific tissues. We either develop our own gene cassettes or in-license them, often as part of our collaborations with academic research institutions and biotechnology and pharmaceutical companies. In-licensing gene cassettes provides us access to key intellectual property and allows us to build upon our collaborators scientific expertise and financial investment, as well as their preclinical and, in some cases, clinical development efforts.

AAV-based vector delivery system. We deliver the gene cassette to the target tissue using an engineered, non-replicating viral vector delivery system based on AAV, a common virus that affects humans but does not cause disease. We believe that AAV is the vector of choice for most in vivo gene therapy applications, such as ours, in which the functional gene is introduced directly into the patient s body. We use different variants, or serotypes, of AAV, each of which selectively targets particular tissues. In the case of diseases for which relatively modest levels of gene expression may result in therapeutic benefit, we expect that we will be able to achieve adequate levels of expression using existing, naturally derived AAV serotypes. In the case of diseases for which higher levels of gene expression may be required for therapeutic benefit; however, we believe we may need access to more potent vectors than are currently available.

To complement our internal development efforts in this regard, in January 2014 we entered into a collaboration and license agreement with 4D Molecular Therapeutics, or 4D, a private biotechnology company with a team that we believe is a leader in AAV vector discovery and optimization. 4D uses directed evolution techniques, which involve an iterative selection process in which researchers screen libraries of mutant AAV variants to identify those that are expected to have optimal properties for achieving higher levels of gene expression.

In January 2015, we entered into a collaborative license agreement with Synpromics Limited to strengthen our technology platform with respect to therapeutic indications that require high-level therapeutic gene expression or comprise large therapeutic genes. We will exclusively own the results of this collaborative effort. In more than 80 gene therapy clinical studies conducted by us or third parties, AAV-based vectors raised no material safety concerns. AAV-based vectors have also demonstrated sustained expression in target tissue in non-human primates for more than five years. In the hemophilia B Phase I/II clinical trial described below, St. Jude Children s Research Hospital in Memphis, Tennessee, or St. Jude, has reported expression in target tissue in humans for more than four years after a single treatment.

Administration technologies. We and our collaborators are developing expertise in utilizing a variety of administration technologies to optimize the introduction of our gene therapy vectors to effectively deliver the transgene into the tissues and organs relevant to the indications we are targeting.

Scalable, proprietary manufacturing process. We produce our AAV-based vectors in our own facilities with our proprietary manufacturing process, which uses insect cells and baculoviruses, a common family of viruses found in invertebrates. Our insect cell-based manufacturing process, which uses cells that can be grown in a suspension culture, is designed to produce higher yields of vectors more cost effectively and efficiently than the mammalian cell-based approaches that many of our competitors utilize. We believe that our manufacturing process, developed over ten years, demonstrates a high standard of safety and predictability. We have a manufacturing facility in Amsterdam, which has obtained EU regulatory approval for clinical and commercial grade production, and a facility in Lexington, Massachusetts, which we have

recently equipped and which offers a 500-liter capacity that can be further expanded to 2,000L capacity when needed. We expect to commence internal GMP validation of this facility in the first half of 2015 and anticipate GMP production in the second half of 2015. We believe these two facilities will enable us to produce gene therapies cost effectively at commercial scale.

Product and Development Pipeline

The following table sets out the status of our approved product and each of our and our collaborators development projects:

AMT-060 for Hemophilia B

Hemophilia B Disease and Market Background

Hemophilia B is a serious rare inherited disease in males characterized by insufficient blood clotting. The condition can lead to repeated and sometimes life-threatening episodes of external and internal bleeding, either spontaneous or following accidental trauma or medical interventions. The episodes can cause long-term damage, for example to the joints, and can be fatal if they occur in the brain. The deficient blood clotting results from the lack of functional human hFIX as a result of mutations in the relevant gene. The presence of hFIX at greater than 1% of normal levels eliminates the risk of spontaneous bleeds. The current standard of care for hemophilia B is prophylactic or on-demand protein replacement therapy, in which frequent intravenous administrations of plasma-derived or recombinant hFIX are required to stop or prevent bleeding. Prophylactic protein replacement therapy is expensive, with an estimated annual cost ranging from $300,000 to $440,000 in the United States, but this can vary depending on disease severity and inhibitor status (this can be as high as $1,126,000 for a patient with severe disease and inhibitors). Hemophilia B affects approximately 1 in 20,000 live male births. A 2012 World Federation of Hemophilia, or WFH, survey identified 28,008 hemophilia B patients across 109 countries. An earlier WFH survey found that around 35% of identified hemophilia B patients were located in the European Union or the United States.

Approximately 60% of individuals with the disease have severe hemophilia, according to the National Hemophilia Foundation, characterized by functional hFIX levels that are less than 1% of normal; 15% of the hemophilia population have moderately severe disease, with 1% to 5% of normal levels; and the remainder have mild disease, with 5% to 50% of normal levels. Based on these estimates we believe that the approximately 60% to 70% of the worldwide patient population with severe to moderate disease would be eligible for treatment with gene therapy.

Our Development of AMT-060

In collaboration with Chiesi, we are developing AMT-060, a gene therapy for the treatment of hemophilia B. The goal of our AMT-060 program is to restore blood clotting and to shift patients from the severe to the mild phenotype on a long-term and potentially curative basis through the delivery of the functional gene for hFIX into the patient s liver cells. We have entered into a co-development agreement with Chiesi for the development and commercialization of AMT-060 in the European Union and other specified countries. AMT-060 consists of the AAV5 vector carrying an hFIX gene that we have exclusively licensed from St. Jude, in which we have altered the codons to maximize expression, together with the insertion of a liver-specific promoter, LP1. We produce this vector with our insect cell-based manufacturing process. We are designing this therapy for systemic administration through intravenous infusion in a single treatment.

We believe our AAV5 vector, exclusively licensed from NIH, carries a favorable safety and immunological profile compared with the AAV8 vector used by our competitors. We also believe that AMT- 060 is currently the only gene therapy program using AAV5 vector for liver indications. We initiated a Phase I/II clinical trial with this product candidate, described below, in the first quarter of 2015. Our collaborator St. Jude is currently conducting a Phase I/II clinical trial in this indication with an hFIX gene carried by an AAV8 vector. The vectors used by St. Jude are manufactured in a third party mammalian cell-based manufacturing process.

We filed an IND for AMT-060 with the FDA in December 2014 which has now been accepted. We also filed a CTA in Germany which was approved by the Paul-Ehrlich-Institute (PEI) in December 2014. We have pending approvals of CTAs and pending Environmental Safety approvals in Denmark, Sweden and the Netherlands.

Phase I/II Clinical Trial

In the first quarter of 2015, we initiated our Phase I/II, open-label, uncontrolled, single-dose, dose-ascending multi-center clinical trial of AMT-060 in patients with severe or moderately severe hemophilia B. In this trial we are targeting sustained gene expression levels of over 5% with long term durability, a 90% reduction in both consumption of FIX replacement therapy and bleeding rates, as well as long-term safety. Our AMT-060 product candidate uses the same hFIX gene cassette being used in the St. Jude trial described below. One of our goals is to improve on the safety profile demonstrated by the St. Jude study through the use of our AAV5 vector, under exclusive license from NIH, manufactured using our validated baculovirus-based expression vector system. We also believe that AAV5 from the insect cell based manufacturing system may lead to a reduced incidence of organ toxicity compared with AAV8 from the mammalian based manufacturing system, potentially due to differences in the risk of induction of an immune response. This outcome is supported by data from the ongoing clinical trial in AIP, described below, which uses the same dosage of the AAV5 vector as will be used in our hemophilia B trial, in which no immune response related liver toxicity occurred.

The key elements of our approved Phase I/II protocol are as follows:

Trial Population. The trial will consist of two dosing cohorts, with five patients in each cohort. We will enroll male patients from multiple countries with either severe or moderately severe hemophilia B, but in either case with a severe bleeding phenotype. A maximum of two subjects with moderately severe hemophilia B will be enrolled per cohort.

Expedited Patient Enrollment. Within each dosing cohort, we will allow a safety monitoring period of 24 hours between treating each patient. We will allow a period of 12 weeks for the first three patients between concluding treatment of the first cohort and commencing treatment of the second cohort.