Annual Report 2015 uniQure N.V. Amsterdam

Amsterdam, May 2, 2015

A Management Board Report

a) Forward-looking statements

This Annual Report and the Consolidated Financial Statements 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 and in our Annual Report on Form 20-F filed with the U.S. Securities and Exchange Commission.

b) History and development of uniQure

uniQure N.V. 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 2012, 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. Effective February 10, 2014, in connection with our initial public offering we converted into a public company with limited liability (naamloze vennootschap) and changed our legal name from uniQure B.V. to uniQure N.V. ( uniQure )

uniQure 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. Our ordinary shares are traded on the NASDAQ Global Select Market under the symbol QURE .

c) Business overview

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 candidates across three therapeutic focus areas.

Liver/Metabolic Disease

AMT-060 for the treatment of hemophilia B, in which we are currently conducting a Phase I/II clinical trial;

Our preclinical product candidate for the treatment of Hemophilia A, for which we have demonstrated mechanistic proof of concept and are in the process of selecting a lead candidate; and

Glybera, the first gene therapy product to receive regulatory approval in the European Union

Central Nervous System (CNS) Disease

AMT-110 for the treatment of Sanfilippo B syndrome, in which our collaboration partner, Institute Pasteur, recently completed a Phase I/II clinical study;

A product candidate based on glial cell line-derived neurotrophic factor (GDNF) for the treatment of Parkinson s disease, which is currently being studied in an investigator-sponsored Phase I clinical study led by Kristof Bankiewicz, MD, PhD, at the University of California, San Francisco;

AMT-130 for the treatment of Huntington s disease, in which we have demonstrated preclinical proof of concept and have initiated IND-enabling studies;

Cardiovascular Disease

Our preclinical product candidate based on the S100A1 gene, a master regulator of heart function, for the treatment of congestive heart failure and currently being developed with BMS;

With our focus on the patients within these three therapeutic categories, we aim to make gene therapy a mainstay of modern medicine by:

targeting 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 clinical and commercial 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, manufacturing capabilities, broad product pipeline 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 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-metabolic, cardiovascular and CNS indications, from ultra-orphan diseases, such as LPLD (for which Glybera is designated), to orphan diseases such as hemophilia B, Huntington disease 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 the 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 in our therapeutic focus areas through strong ties with commercial collaborators, academic thought leaders and clinical institutions. In cardiovascular disease, we have a collaboration with Bristol-Myers Squib. 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 and amyotrophic lateral sclerosis (ALS).

d) Our gene therapy development platform

Our gene therapy approach seeks to treat the causes of genetic diseases by enabling patients to (i) effectively express a missing or deficient protein, or (ii) reduce or eliminate the abnormal overexpression of a protein. To express a missing or deficient protein, our product candidates are designed to deliver a functional gene, or transgene, through a delivery system called a vector. To address the over-expression of a protein, we are also developing product candidates that utilize vectors to deliver microRNAs that can knock-down , or silence, the abnormal overexpression of certain proteins.

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 multiple products, we believe that we can cross-reference data between products, and thereby on a case by case basis reduce the overall development activities required to obtain regulatory approval and potentially decrease the overall risk, time and cost of our development programs.

The key components of our gene therapy approaches are:

Therapeutic genes. We design most of 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.

microRNAs. We are also designing therapies designed to knock-down or silence abnormal genes underlying certain diseases. For the knock-down approach we are using miRNAs delivered via AAV5. Our lead program in Huntington s disease has demonstrated proof of concept in preclinical animal models and other potential applications are being explored.

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 more than ten years, demonstrates a high standard of safety and predictability. We have a GMP manufacturing facility in Amsterdam, which has obtained EU regulatory approval for clinical and commercial grade production, and a facility in Lexington, Massachusetts with 500-liter capacity that can be further expanded to 2,000L capacity when needed. We believe these two facilities will enable us to produce gene therapies cost effectively at commercial scale.

a) 2015 Business highlights

On May 26, 2015, we announced the closing of a collaboration with BMS that provides BMS with exclusive access to our gene therapy technology platform for multiple targets in cardiovascular and other targeted diseases, including our proprietary gene therapy program for congestive heart failure.

In an effort to drive greater patient focus and execution, we established three therapeutic focus areas in CNS, Liver/Metabolic and Cardiovascular disease indications. In July 2015, we announced the appointment of Charles W. Richard, M.D., Ph.D., to the position of Senior Vice President, Research and Development, Neuroscience, to lead our growing portfolio of gene therapies targeting CNS diseases, including current clinical trials for the treatment of Sanfilippo B syndrome and Parkinson s disease as well as preclinical programs in Huntington s disease and other rare CNS disorders. In August 2015, we announced the promotion of Deya Corzo, M.D., formerly Vice President, Medical Affairs at uniQure, to the position of Senior Vice President, Research and Development, Liver/Metabolic to lead our development efforts in liver-directed and metabolic diseases, including hemophilia B, hemophilia A, and other rare liver/metabolic diseases.

In October 2015, the Charit University Clinic in Berlin, Germany, announced the treatment of the first patient with Glybera as a commercially-available gene therapy, enabled by our commercialization partner in the EU, Chiesi Farmaceutici.

In January 2015, we 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. We will exclusively own the results of this collaborative effort.

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

In April 2015, we completed a follow-on public offering of 3,000,000 ordinary shares at $29.50 per ordinary share. After deducting the underwriting discounts and other offering expenses payable by us, the aggregate net proceeds to the Company were approximately $83.2 million.

Therapeutic development highlights

In October 2015, we completed dosing of the low-dose cohort in our Phase I/II study of AMT-060 in hemophilia B using our novel AAV5-based gene therapy. In January 2016, we announced encouraging preliminary topline results from the low-dose cohort.

meaningful increases in Factor IX expression, which validate the successful transduction of the liver using our proprietary AAV5 vector;

the first two of five patients in the low-dose cohort, who completed 20 and 12 weeks of follow up as of December 16, 2015, had central-lab-confirmed FIX expression levels of 5.5% and 4.5% of normal, respectively;

as of January 6, 2016, four of five patients in the low-dose cohort had fully discontinued prophylactic recombinant Factor IX therapy.

In September 2015, we announced positive topline results from a Phase I/II study of AMT-110 in Sanfilippo B Syndrome using our novel AAV5-based gene therapy.

safety, durable expression and positive signs of efficacy were demonstrated in all four patients;

restoration of catalytically activity of the NAGLU protein in the cerebrospinal fluid from 0% at baseline up to 14-17% of normal at three months with persistent effect at 12 months;

incremental cognitive development was maintained in all four patients;

no progression of brain atrophy in any of the four patients was observed in MRI tests.

In the third quarter of 2015, uniQure s investigator-sponsored Phase I clinical study of glial cell line-derived neurotrophic factor (GDNF) in Parkinson s disease, led by Kristof Bankiewicz, MD, PhD, at the University of California, San Francisco, completed enrolment of its first dosing cohort and commenced dosing of the second cohort.

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 more than $1 million 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

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 initiated a Phase I/II clinical trial with this product candidate, described below, in the third 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 have also filed CTAs in Germany, The Netherlands, and Denmark, the first of which was approved in December 2014.

Phase I/II Clinical Trial

In 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 3-5% with long term durability, a 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 adverse events compared with AAV8 from the mammalian based manufacturing system, potentially due to differences in the risk of induction of transaminase elevations. This outcome is supported by data from a previous clinical trial conducted in acute intermittent porphyria, which used the same dosage of the AAV5 vector as being used in our hemophilia B trial, in which no immune response related liver toxicity occurred.

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

Trial Population. The trial consists of two dosing cohorts, with five patients in each cohort. We are enrolling male patients from multiple countries with either severe (<1%) or moderately severe (<2%) hemophilia B on prophylaxis or on-demand recombinant factor IX treatment, but in either case with a severe bleeding phenotype.

Expedited Patient Enrollment. Within each dosing cohort, we are allowing a safety monitoring period of 24 hours between treating each patient. Additionally, we provided for a period of 12 weeks between concluding treatment of the first cohort and commencing treatment of the second cohort.

Therapeutically Relevant Dosing Levels. The low-dose cohort in our trial received a comparable dose to the highest-dose cohort in the St. Jude trial.

Preliminary top-line results

In January 2016, we announced the first preliminary, top-line results of the AMT-060 study. The first two out of five patients in the low dose cohort had completed at least 20 and 12 weeks of follow up and had central-lab-confirmed FIX expression levels of 5.5% and 4.5% of normal, respectively at the cutoff date of December 16, 2015. The three additional patients were treated, but had not achieved the full 12 weeks of follow-up at the cutoff date. However, as of January 6, 2016, four of the five patients, including the first two patients enrolled in the study, had met a secondary objective in the trial by fully discontinuing prophylactic rFIX. The 12 week follow-up, post AMT-060 administration, marks the period in which investigators in the trial attempt discontinuation of prophylactic rFIX, based on FIX expression levels. The first patient in the low-dose cohort experienced a mild, transient and asymptomatic elevation of transaminase levels at around 10 weeks post treatment. This patient received a short, 8-week course of tapering prednisolone doses with rapid return of transaminase levels to baseline values. No elevated transaminase levels have been observed in the other four patients with all patients being on therapy for at least 10 weeks as of January 6, 2016.

St. Jude Clinical Trial

St. Jude is currently conducting a Phase I/II, open label, dose-escalation clinical trial in this indication with a gene therapy consisting of an AAV8 vector carrying the same therapeutic hFIX gene that we are using in AMT-060. In articles published in the New England Journal of Medicine in 2011 and 2014 reviewing interim data from six and 10 patients in the St. Jude clinical trial, respectively, the principal investigators reported that the vector used in the trial consistently led to long-term expression of the hFIX transgene at therapeutic levels in patients with severe hemophilia B, without acute or long-lasting toxicity.

AMT-110 for Sanfilippo B Syndrome

We and our collaborator Institut Pasteur are developing AMT-110 as a gene therapy for Sanfilippo B syndrome, a potentially fatal lysosomal storage disease that results in serious brain degeneration in children. This gene therapy consists of an AAV5 vector carrying a therapeutic N acetylglucosaminidase, or NaGLU, gene. We manufactured the material used in this clinical trial, which was sponsored by Institut Pasteur. We have executed a term sheet with Institut Pasteur/AFM/INSERM Consortium regarding the acquisition of the data from this study. We are currently in the process of negotiating a definitive agreement with the Consortium in accordance with the executed term sheet. We have assumed the sponsorship of the Phase I/II extension study, enabling us to continue the follow-up of the four patients treated to date.

The Institut Pasteur reported top line results at a scientific conference in September 2015 for four Sanfilippo B subjects aged 20 to 53 months at study entry with no detectable NAGLU enzyme activity. Subjects received 4e12th genome copies of AAV5-NAGLU gene therapy via intraparenchymal administration of our AAV5-NAGLU gene therapy into 16 different locations in the cerebrum and cerebellum. Patients receive tapering does of tacarolimus immunosuppession, to prevent an immune response to either the AAV vector capsid or the expressed protein. The neurosurgery and follow-up period was uneventful and well tolerated. Durable expression of the NAGLU transgene was measured in cerebrospinal fluid at 14-17% of normal levels at 1, 3 and 12 months post-dosing. All four subjects continued to gain neurocognitive skills throughout the 12 months, and none of the subjects demonstrated any measurable increase in brain atrophy as measured by MRI. We believe that if the results of this clinical trial constitute proof of concept of the administration to the brain of a gene therapy for lysosomal storage diseases.

AAV2/GDNF for Parkinson s Disease

We and our collaborator, the University of California at San Francisco, or UCSF, are developing a gene therapy for Parkinson s disease, a progressive neurodegenerative disorder. UCSF is collaborating with the NIH to conduct a Phase I clinical trial of a gene therapy in this indication consisting of an AAV2 vector carrying a therapeutic gene we have exclusively licensed in the gene therapy field from Amgen, Inc., or Amgen, that expresses a protein called glial cell line-derived neurotrophic factor, or GDNF. This clinical trial is being funded and sponsored by the NIH. The trial will involve 24 patients across four dosing cohorts (six patients per cohort). Treatment of the first of these cohorts is now complete and the second cohort is expected to complete enrollment in 2016. UCSF s product candidate has been manufactured by a third party using a mammalian cell-based process. In this clinical trial, the NIH is administering the gene therapy using convection enhanced delivery, which is a process developed by UCSF with the goal of achieving more precisely targeted administration than the methods used in earlier approaches, which may result in improved efficacy. We have a license under UCSF s rights to use all preclinical and clinical data from the UCSF program for any future development program. Based on the results of the UCSF program, we may decide to develop an AAV2-based gene therapy containing the GDNF gene manufactured with our insect cell based manufacturing process.

S100A1 for Congestive heart failure

Collaboration with Bristol-Myers Squibb (BMS)

In May 2015, we closed an agreement with BMS that provides exclusive access to our gene therapy technology platform for multiple targets in cardiovascular (and other) diseases. The collaboration included our proprietary gene therapy program for congestive heart failure which aims to restore the heart s ability to synthesize S100A1, a calcium sensor and master regulator of heart function, and thereby improve clinical outcomes for patients with reduced ejection fraction. Beyond cardiovascular diseases, the agreement also included the potential for a target exclusive collaboration in other disease areas. In total, the companies may collaborate on ten targets, including S100A1.

We are leading the discovery, non-clinical, analytical and process development effort and are responsible for manufacturing of clinical and commercial supplies using our vector technologies and industrial, proprietary insect-cell based manufacturing platform, while BMS leads development and regulatory activities across all programs and is responsible for all research and development costs. BMS will be solely responsible for commercialization of all products from the collaboration.

In accordance with the terms of the agreement, BMS has to date made total payments to uniQure of $140 million. We will also 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. Additionally, we are eligible to receive net sales-based milestone payments and tiered single- to double-digit royalties on product sales. We have granted BMS two warrants, each to acquire up to an additional 5% equity interest, at a premium, based on additional targets being introduced into the collaboration. The parties have also agreed to enter into a supply contract, under which we will manufacture all gene therapy products under the collaboration.

In July 2015, three additional targets for development in cardiovascular indications were agreed with BMS. Development of two of these new targets is expected commence in 2016, starting with manufacture of materials for clinical and non-clinical studies.

S100A1 and Congestive Heart Failure

Heart failure is the inability of the heart to supply sufficient blood flow to meet bodily demand for oxygen and nutrition. Congestive heart failure, or HF, is the most common reason for hospitalization in Western societies and its 5-year mortality rate rivals most types of cancer. Maladaptive changes in the molecular composition of the diseased heart muscle contribute to its loss of contractile function, lethal tachyarrhythmia, energetic deficit, and maladaptive growth.

Current pharmacologic regimes are unable to directly target the molecular defects in cardiac muscle that are thought to determine the clinical course and prognosis of HF. Commonly used HF drugs, such as beta-adrenergic receptor blockers (beta-AR blockers), inhibitors of the renin angiotensin-aldosterone system (RAAS), mineralocorticoid receptor antagonist (MRA) and diuretics can slow, but cannot prevent, disease progression over time to advanced stages and prehospitalization, and the 1-year mortality rate remains high.

S100A1 is intended to fill this therapeutic gap by improving cardiac function and targets a novel molecular regulatory mechanism that differs from previous therapeutic attempts to enhance cardiac muscle function, such as beta-AR agonists (egg, dobutamine) or calcium sensitizers. S100A1 neither utilizes, nor relies on, components of the -adrenergic system to improve cardiac performance and conveys a cAMP-independent heightened systolic and diastolic contractile state. As such, S100A1 is intended to be fully compatible with current HF treatments due to its novel and independent mode of action. S100A1 s upstream position as a master regulator of a Ca2+-driven network in cardiomyocytes integrating contractility, metabolism, rhythm stability and growth, makes S100A1 a unique therapeutic target among other regulatory proteins in the heart.

S100A1 protein is downregulated in human CHF molecular analysis characterized the S100A1 protein as an upstream master regulator of the cardiomyocyte-calcium driven network. S100A1 deficient hearts show accelerated progression to severe heart failure and increase mortality after cardiac damage. Elevated cardiomyocyte S100A1 protein levels are protective and prolong survival in mouse CHF models.

Restoration of S100A1 protein expression deficit in a rat CHF by cardiac-targeted AAV-S100A1 gene therapy achieved long-term rescue of systolic and diastolic cardiac performance, reversed remodeling and was superior to the treatment with a clinically used CHF standard drug. Isolated cardiomyocytes from AAV-S100A1 treated rat heart showed superior systolic and diastolic performance. Cardiac-targeted delivery of AAV-S100A1 to failing hearts of domestic pigs by retrograde intravenous delivery resulted in widespread cardiac transduction and restoration of S100A1 protein expression that was contained to the heart. Long-term rescue of systolic and diastolic cardiac performance, improved energy metabolism, protection against maladaptive growth and tachyarrhythmia was achieved. Isolated cardiomyocytes from AAV-S100A1 treated pig heart showed superior systolic and diastolic performance.

A 12 month follow up study showed a profound survival benefit in the pig CHF model by retrograde intravenous AAV-S100A1 delivery. We believe that outcome data obtained in this model are readily applicable to clinical trial design and endpoint selection.

In 2015, we agreed with BMS to perform non-clinical studies that are expected to support an IND filing. Based on this plan, the following non-clinical studies will be conducted 2016:

GLP toxicology and biodistribution studies utilizing the same baculovirus-derived material that will be used in the clinical trials;