Annual Report 2018 uniQure N.V. Amsterdam

Amsterdam, May 3, 2019

A Report of the Board of Directors

a) Forward-looking statements

This Annual Report and the Consolidated Financial Statements contain forward-looking statements as defined under U.S. federal securities laws. Forward-looking statements are based on our current expectations of future events and many of these statements can be identified by the use of terminology such as believes, expects, anticipates, plans, may, will, projects, continues, estimates, potential, opportunity and similar expressions.

Forward-looking statements are only predictions based on management s current views and assumptions and involve risks and uncertainties, and actual results could differ materially from those projected or implied. The most significant factors known to us that could materially adversely affect our business, operations, industry, financial position or future financial performance include those described under Risk Factors and elsewhere in this Annual Report and in our Annual Report on Form 10-K filed with the U.S. Securities and Exchange Commission. You should carefully consider that information before you make an investment decision.

You should not place undue reliance on these statements, which speak only as of the date that they were made. Our actual results or experience could differ significantly from those anticipated in the forward-looking statements and from historical results, due to the risks and uncertainties described under Risk Factors and elsewhere in this Annual Report as well as others that we may consider immaterial or do not anticipate at this time. These cautionary statements should be considered in connection with any written or oral forward-looking statements that we may make in the future. We do not undertake any obligation to release publicly any revisions to these forward-looking statements after completion of the Annual Report to reflect later events or circumstances or to reflect the occurrence of unanticipated events. All forward-looking statements attributable to us are expressly qualified in their entirety by these cautionary statements.

In addition, with respect to all of our forward-looking statements, we claim the protection of the safe harbor for forward-looking statements contained in the U.S. Private Securities Litigation Reform Act of 1995.

b) History and development of uniQure

uniQure (the Company ) was incorporated on January 9, 2012 as a private company with limited liability (besloten vennootschap met beperkte aansprakelijkheid) under the laws of the Netherlands. We are a leader in the field of gene therapy and seek to deliver to patients suffering from rare and other devastating diseases single treatments with potentially curative results. Our business was founded in 1998 and was initially operated through our predecessor company, Amsterdam Molecular Therapeutics (AMT) Holding N.V ( 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 the initial public offering, the Company converted into a public company with limited liability (naamloze vennootschap) and changed its legal name from uniQure B.V. to uniQure N.V.

The Company is registered in the trade register of the Dutch Chamber of Commerce (Kamer van Koophandel) in Amsterdam, the Netherlands under number 54385229. The Company s headquarters are in Amsterdam, the Netherlands, and its registered office is located at Paasheuvelweg 25a, Amsterdam 1105 BP, the Netherlands and its telephone number is +31 20 240 6000. Our website address is www.uniqure.com. Our ordinary shares are listed on the NASDAQ Global Select Market and trade under the symbol QURE .

c) Business overview

We are a leader in the field of gene therapy, seeking to develop one-time administered treatments with potentially curative results for patients suffering from genetic and other devastating diseases. We are working to advance a focused pipeline of innovative gene therapies that have been developed both internally and through partnerships, such as our collaboration with Bristol Myers-Squibb focused on cardiovascular diseases. In January 2019, we commenced the dosing phase of a pivotal study of AMT-061, our lead product candidate for patients with hemophilia B. Also, in January 2019, we received notice from the U.S. Food and Drug Administration ( FDA ) of the

clearance of our Investigational New Drug ( IND ) application for AMT-130, our product candidate for patients with Huntington s disease, thereby enabling us to initiate our Phase I/II clinical study. In November 2018, we announced the expansion of our research pipeline to include additional novel gene therapy candidates for treating hemophilia A, Fabry disease and spinocerebellar ataxia Type 3 ( SCA3 ).

We believe our gene therapy technology platform and manufacturing capabilities provide us distinct competitive advantages, including the potential to reduce development risk, cost and time to market. We produce our adeno-associated virus ( AAV ) based gene therapies in our own facilities with a proprietary, commercial-scale, current good manufacturing practices ( cGMP ), compliant, manufacturing process. We believe our Lexington, Massachusetts-based facility is one of the world s leading, most versatile, gene therapy manufacturing facilities.

Commencing a pivotal study of hemophilia B lead candidate ( AMT-061 )

On February 4, 2019, we announced the dosing of the first patient in our Phase III HOPE-B hemophilia B pivotal trial. The trial is a multinational, multi-center, open-label, single-arm study to evaluate the safety and efficacy of AMT-061. After the six-month lead-in period, patients will receive a single intravenous administration of AMT-061. The primary endpoint of the study will be based on the Factor IX ( FIX ) activity level achieved following the administration of AMT-061, and the secondary endpoints will measure annualized FIX replacement therapy usage, annualized bleed rates and safety. Patients enrolled in the HOPE-B trial will be tested for the presence of pre-existing neutralizing antibodies to AAV5 but will not be excluded from the trial based on their titers.

In February 2019, we presented updated data from our Phase IIb dose-confirmation study of AMT-061, which demonstrated that all three patients experienced increasing and sustained FIX levels after a one-time administration of AMT-061. Twelve weeks after administration, mean FIX activity for the three patients was 38% of normal, exceeding threshold FIX levels generally considered sufficient to significantly reduce the risk of bleeding events. The first patient achieved FIX activity of 48% of normal at 16 weeks after administration. FIX activity in the second patient was 25% of normal at 14 weeks following administration and in the third patient was 51% of normal at 12 weeks after administration. Based on the data obtained through December 13, 2018, no patient experienced a material loss of FIX activity, reported any bleeding events or required any infusions of FIX replacement therapy. AMT-061 has been well-tolerated, with no serious adverse events reported and no patients requiring any immunosuppression therapy.

Preparing for the clinical development of Huntington product candidate ( AMT-130 )

In January 2019, our IND application for AMT-130 was cleared by the FDA, thereby enabling us to initiate our planned Phase I/II clinical study. The Phase I/II study is expected to be a randomized, double-arm, blinded, imitation surgery-controlled trial conducted at three surgical sites and at least two non-surgical sites in the U.S. The primary objective of the study is to evaluate the safety, tolerability and efficacy of AMT-130 at two doses.

Expanding our preclinical pipeline and proprietary technology platform

In November 2018, we announced the expansion of our research pipeline with three new AAV-based product candidates. Our lead preclinical candidate, AMT-180, is a novel hemophilia A gene therapy candidate that we believe has the potential to treat all hemophilia A patients, including those with past and current inhibitors. Our next most advanced preclinical candidates, AMT-190 and AMT-150, are differentiated gene therapy candidates for the treatment of Fabry disease and SCA3, respectively.

Also, in November 2018, we presented our miQURE gene silencing technology platform. miQURE is uniQure s novel technology platform designed to degrade disease-causing genes, without off-target toxicity, and induce silencing of the entire target organ through secondary exosome-mediated delivery. Preclinical studies of miQURE-based gene therapies have demonstrated several important advantages, including enhanced tissue-specificity, improved nuclear and cytoplasmic gene lowering and no off-target effects associated with impact on the normal cellular miRNA or mRNA mechanisms. Gene therapy candidates designed with miQURE incorporate proprietary, therapeutic miRNA constructs that can be delivered using AAVs to potentially provide long-lasting activity. miQURE technology has been incorporated in our gene therapy product candidate for Huntington s disease, and is expected to be applied to our gene therapy candidate for SCA3.

In May 2018, we raised $138.4 million through a follow-on public offering of 5.2 million ordinary shares at $28.50 per ordinary share.

In December 2018, we increased our existing $20 million credit facility to $35 million, extended the maturity by three years to May 31, 2023 and extended the interest-only period by at least two years to January 1, 2021.

Our Mission and Strategy

Our mission is to deliver curative gene therapies that transform the lives of patients.

Our strategy to achieve this mission is to:

Advance the development of AMT-061, a potentially best-in-class treatment of hemophilia B. AMT-061 combines the advantages of AAV5 with an enhanced Padua-FIX transgene, and may provide optimized clinical and tolerability benefits to all, or nearly all patients with hemophilia B. We have achieved alignment with the FDA and European Medicines Agency ( EMA ) on what we believe is an expedited clinical development plan. We initiated the lead-in phase of our pivotal study program in June 2018 and dosed the first patient in January 2019.

Maintain our leadership position in commercial-scale AAV manufacturing. We have established cGMP, commercial-scale manufacturing capabilities for AAV-based gene therapies in our state-of-the-art Lexington, Massachusetts facility. We successfully produced batches of multiple gene therapy products using the same fundamental manufacturing process, methods and controls. We believe the modularity of our platform provides us with distinct advantages, including the potential for reduced development risk and faster times to market.

Build a pipeline of gene therapy programs focused on rare and orphan diseases targeting liver-directed and central-nervous system ( CNS ) diseases. Beyond our lead clinical program for hemophilia B and our Huntington s program, we have a pipeline of additional AAV-based gene therapy programs in various stages of preclinical development. We are leveraging our leading technology platform, which includes novel vectors, promoters and manufacturing capabilities, to develop gene therapies primarily focused on rare, monogenic liver-directed, and CNS diseases as well as cardiovascular diseases.

Leverage the favorable immunogenicity profile of AAV5-based gene therapies to develop multiple products. We have demonstrated AAV5-based gene therapies to be generally safe and well-tolerated in four clinical trials conducted in 25 patients. No patient treated with AAV5-based gene therapies experienced a confirmed immune response to the capsid or complications associated with T-cell activation, such as a material loss of efficacy. Clinical trials also demonstrated that AAV5 has the lowest prevalence of preexisting neutralizing antibodies ( Nab ) compared to other AAV vectors, which may enable all, or nearly all patients to be eligible for treatment with AAV5-based gene therapies.

Invest in next-generation technologies to expand the applicability of gene therapy to patients. We are developing proprietary technologies that have the potential to enhance safety and efficacy of our product candidates and may broaden the applicability of our gene therapies to a wider range of diseases and patients. These technologies include (i) tailored vectors and promoters; (ii) optimized delivery and administration techniques and (iii) novel transgenes. These technologies are developed both in-house by our experienced research team in Amsterdam, the Netherlands, as well as via collaborations with third parties.

Continue to expand our intellectual property portfolio. We have established what we believe is a leading intellectual property portfolio covering various aspects of our technology and programs, including (i) elements of our gene therapy constructs, such as AAV vectors, promoters and transgenes, including the novel Padua-FIX gene we utilize in AMT-061 for hemophilia B; (ii) innovative delivery technologies, such as re-administration of AAV gene therapy; and (iii) proprietary manufacturing processes covering key components of our upstream and downstream capabilities. We expect to continue to expand our intellectual property portfolio by aggressively seeking patent protection for promising aspects of our technology platform and product candidates.

We have developed and communicated throughout the Company our key values in support of our vision and strategy. The key values are also published at our website and are also taken into account in the annual employee performance and appraisal review. These key values drive our Code of Business Conduct and Ethics, which must be acknowledged annually by each employee.

Our Product Candidates

A summary of our key development programs as of December 31, 2018 is provided below:

Liver-directed diseases

Hemophilia B Disease and Market Background

Hemophilia B is a serious and 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 following accidental trauma or medical interventions. Severe hemophilia is characterized by recurrent episodes of spontaneous joint bleeds that cause long-term damage to the joints resulting in disabling arthropathy. Bleeds may be fatal if they occur in the brain. The deficient blood clotting results from the lack of functional human Factor IX ( hFIX ). Treatment of hemophilia B today consists of prophylactic or on-demand protein replacement therapy, in which one to three times weekly intravenous administrations of plasma-derived or recombinant hFIX are required to prevent bleeding and once daily infusions in case bleeding occurs. Hemophilia B occurs in approximately 1 out of 30,000 live male births.

Our Development of AMT-061 for Hemophilia B

We are currently developing AMT-061, a gene therapy for patients with hemophilia B that is designed to restore Factor IX ( FIX ) activity, an essential protein for blood clotting. AMT-061 includes an AAV5 vector incorporating our patent-protected FIX-Padua variant ( FIX-Padua ). AMT-061 is identical in structure to our first-generation hemophilia B product candidate, AMT-060, apart from two nucleotide substitutions in the coding sequence for FIX. The FIX-Padua variant expresses a protein with a single amino acid substitution that has been reported in multiple preclinical and nonclinical studies to provide an approximate eight- to ninefold increase in FIX activity compared to the wild-type protein, which was incorporated in AMT-060. All other critical quality attributes of AMT-061 are expected to be comparable to those of AMT-060, as AMT-061 utilizes the same AAV5 capsid and proprietary insect cell-based manufacturing platform.

AMT-061 is intended to be delivered by IV-infusion, without immunosuppressant therapy, through the peripheral vein in a single treatment session for approximately 30 minutes.

Our goal for AMT-061 is to develop a gene therapy with the following profile:

long-term safety, including a favorable immunogenicity profile;

predictable, sustained and potentially curative increases in FIX activity;

significant reductions in both bleeding rates and the need for FIX replacement therapy; and

broad patient eligibility, including the potential to treat all or nearly all patients with hemophilia B

AAV5-based gene therapies have been demonstrated to be generally safe and well-tolerated in a multitude of clinical trials, including four uniQure trials conducted in 25 patients in hemophilia B and other indications. In contrast to data reported using other AAV capsids delivered systemically via IV infusion, no patient treated in clinical trials with our AAV5 gene therapies has experienced any confirmed, cytotoxic, T-cell-mediated immune response to the capsid or material loss of FIX activity. An independent clinical trial has demonstrated that AAV5 has the lowest prevalence of preexisting neutralizing antibodies compared to other AAV vectors. Data from our clinical, preclinical and nonclinical studies suggest that all, or nearly all patients may be eligible for treatment with AMT-061.

The FDA has agreed that AMT-061 will fall under the existing Breakthrough Therapy Designation and IND for AMT-060, and the EMA has also agreed that AMT-061 will fall under the current priority medicines ( PRIME ) designation.

In June 2018, we announced the enrollment of the first patient in the Phase III HOPE-B pivotal study of AMT-061. The Phase III HOPE-B pivotal trial is a multinational, multi-center, open-label, single-arm study to evaluate the safety and efficacy of AMT-061. Approximately 50 adult hemophilia B patients classified as severe or moderately severe will be enrolled in a six-month observational period during which time they will continue to use their current standard of care to establish a baseline control. After the six-month lead-in period, patients will receive a single IV-administration of AMT-061. The primary endpoint of the study will be based on the FIX activity level achieved following the administration of AMT-061, and the secondary endpoints will measure annualized FIX replacement therapy usage, annualized bleed rates and safety. Patients enrolled in the HOPE-B trial will be tested for the presence of pre-existing neutralizing antibodies to AAV5 but will not be excluded from the trial based on their titers. In January 2019 we dosed the first patient in our HOPE-B pivotal trial.

In September 2018, we completed the dosing of a Phase IIb dose-confirmation study of AMT-061. The Phase IIb study is an open-label, single-dose, single-arm, multi-center trial being conducted in the United States. The objective of the study was to evaluate the safety and tolerability of AMT-061 and confirm the dose based on FIX activity at six weeks after administration. Three patients with severe hemophilia were enrolled in this study and received a single intravenous infusion of 2x1013 genome copies per kilogram ( gc/kg ). Patients are evaluated for the presence of pre-existing neutralizing antibodies to AAV5 but not excluded from the trial on this basis. We will continue to follow patients for a total of 52 weeks to assess FIX activity, bleeding rates and usage of FIX replacement therapy, and will monitor patients for five years to evaluate the safety of AMT-061.

In December 2018, the study s Data Monitoring Committee evaluated initial data from the Phase IIb study and confirmed the dose of 2x1013 gc/kg for the Phase III pivotal trial. In February 2019, we presented updated data from the Phase IIb dose-confirmation study, which demonstrated that all three patients experienced increasing and sustained FIX levels after a one-time administration of AMT-061. Twelve weeks after administration, mean FIX activity for the three patients was 38% of normal, exceeding threshold FIX levels generally considered sufficient to significantly reduce the risk of bleeding events. The first patient achieved FIX activity of 48% of normal at 16 weeks after administration. FIX activity in the second patient was 25% of normal at 14 weeks following administration and in the third patient was 51% of normal at 12 weeks after administration. Based on the data obtained through December 13, 2018, no patient experienced a material loss of FIX activity, reported any bleeding events or required any infusions of FIX replacement therapy. AMT-061 has been well-tolerated, with no serious adverse events reported and no patients requiring any immunosuppression therapy.

Intellectual Property for AMT-061

In 2017, we acquired intellectual property from Professor Paolo Simioni ( Dr. Simioni ), a hemophilia expert at the University of Padua, Italy. The intellectual property includes U.S. Patent Number 9,245,405, which covers compositions of FIX-Padua nucleic acids and polypeptides (proteins), as well as their therapeutic uses.

In May 2018, the U.S. Patent and Trademark Office ( USPTO ) granted us a second patent, U.S. Patent Number 9,982,248, which covers methods of treating coagulopathies (bleeding disorders), including hemophilia B, using AAV-based gene therapy with nucleic acid encoding the hyperactive FIX Padua variant. The FIX Padua variant is a Factor IX protein carrying a leucine at the R338 position, often called the FIX-Padua or Padua mutant .

In addition to the U.S. patent, in February 2018, the Canadian Intellectual Property Office granted Patent Number 2,737,094, which covers FIX-Padua nucleic acids for use in gene therapy and FIX-Padua polypeptides for use in FIX replacement therapy. We are also currently pursuing European patents directed toward therapeutic uses of FIX-Padua nucleic acids and polypeptides.

Phase I/II Clinical Trial of AMT-060

In the third quarter of 2015, we initiated a Phase I/II clinical trial of AMT-060, our first-generation hemophilia B product candidate, in patients with severe or moderately-severe hemophilia B. AMT-060 consists of an AAV5 vector carrying a codon-optimized, wild-type, human Factor IX gene cassette licensed from St. Jude Children s Research Hospital. The study is a five-year, open-label, uncontrolled, single-dose, dose-ascending multi-center trial that includes two cohorts, with the low-dose cohort using a treatment of 5x1012 gc/kg and the second-dose cohort using 2x1013 gc/kg. We enrolled five patients into the low dose cohort in the third quarter 2015. Another five patients were enrolled into the high dose cohort between March and May 2016.

In December 2018, we presented long-term clinical data from our ongoing Phase I/II study of AMT-060, including up to two and a half years of follow-up. The data demonstrated that AMT-060 continues to be safe and well-tolerated, with no new serious adverse events and no development of inhibitors. All ten patients sustained increases in FIX activity and improvements in their disease state as measured by reduced usage of FIX replacement therapy and decreased bleeding frequency.

All five patients in the second dose cohort of 2x1013 gc/kg continue to be free of routine prophylaxis at up to two years after treatment. During the last 12 months of observation, the mean annualized bleeding rate was 0.5 bleeds, representing an 88% reduction compared to the year prior to treatment. During the same period, the usage of FIX replacement therapy declined 93% compared to the year prior to treatment. Mean FIX activity increased from 7.1% in the first year after treatment to 8.3% in the second year and was 8.9% of normal at the last measurement.

Hemophilia A program (AMT-180)

Hemophilia A Disease and Market Background

Hemophilia A, also called factor VIII ( FVIII ) deficiency or classic hemophilia, is a genetic disorder caused by missing or defective factor VIII, a clotting protein. Although it is passed down from parents to children, about 1/3 of cases are caused by a spontaneous mutation, a change in a gene. More than half of the patients have the severe form of hemophilia A. Patients with severe hemophilia A experience bleeding following an injury and may have frequent spontaneous bleeding episodes, often into their joints and muscles. Hemophilia A occurs in approximately one in 5,000 live births. Approximately 30 percent of patients with severe hemophilia A will develop an inhibitor that neutralizes the infused FVIII activity. Historically, this patient population has been underserved due to past exclusion from gene therapy research in clinical development.

Our Development of AMT-180 for Hemophilia A

AMT-180 is a novel hemophilia A gene therapy that we believe has the potential to treat all hemophilia A patients including those with past and current inhibitors. AMT-180 is a one-time, intravenously-administered, AAV5-based gene therapy incorporating a proprietary modified Factor IX gene, Super9 , that has been demonstrated in preclinical studies to circumvent inhibitors to FVIII. A proof-of-concept study indicated that administration of Super9 resulted in clinically relevant FVIII mimetic activity in hemophilia A mice and was not associated with hypercoagulability in wild-type mice. Another study in non-human primates indicated that a single dose of AMT-180 resulted in expression levels that translate into FVIII mimetic activity expected to be clinically relevant in hemophilia A patients with or without inhibitors. In addition, Super9 induced clinically relevant thrombin activation in FVIII-depleted human plasma with or without inhibitors. These data indicate that AMT-180 may lead to durable expression in hemophilia A patients and may provide long-term prevention of bleeds. In early 2019, we initiated a large animal study, safety and toxicology study of AMT-180 to support a planned IND submission.

Fabry disease program (AMT-190)

Fabry Disease and Market Background

Fabry disease is a progressive, inherited, multisystemic lysosomal storage disease characterized by specific neurological, cutaneous, renal, cardiovascular, cochleo-vestibular and cerebrovascular manifestations. Fabry disease is caused by a defect in a gene that encodes for a protein called -galactosidase A ( GLA ). The GLA protein is an essential enzyme required to breakdown globotriaosylsphingosine ( Gb3 ) and lyso-globotriaosylsphingosine ( lyso-Gb3 ). In patients living with Fabry disease, Gb3 and lyso-Gb3 accumulate in various cells throughout the body causing progressive clinical signs and symptoms of the disease. Current treatment options, which consist of bi-weekly intravenous enzyme replacement therapy, typically have no therapeutic benefit in patients with advanced renal or cardiac disease. Studies have also shown that a majority of male patients develop antibodies that inhibit the GLA protein and interfere with therapeutic efficacy.

Fabry disease has two major disease phenotypes: the type 1 classic and type 2 later-onset subtypes. Both lead to renal failure, and/or cardiac disease, and early death. Type 1 males have little or no functional a-Gal A enzymatic activity (<1% of normal mean), and marked accumulation of GL-3/Gb3 and related glycolipids in capillaries and small blood vessels which cause the major symptoms in childhood or adolescence. In contrast, males with the type 2 later-onset phenotype (previously called cardiac or renal variants) have residual a-Gal A activity, lack GL-3/Gb3 accumulation in capillaries and small blood vessels, and do not manifest the early manifestations of type 1 males. They experience an essentially normal childhood and adolescence. They typically present with renal and/or cardiac disease in the third to seventh decades of life. Most type 2 later-onset patients have been identified by enzyme screening of patients in cardiac, hemodialysis, renal transplant, and stroke clinics and recently by newborn screening. Fabry disease occurs in all racial and ethnic populations and affects males and females. It is estimated that type 1 classic Fabry disease affects approximately one in 40,000 males. The type 2 later-onset phenotype is more frequent, and in some populations may occur as frequently as about 1 in 1,500 to 4,000 males.

Our Development of AMT-190 for Fabry Disease

AMT-190 is a one-time, intravenously-administered, AAV5-based gene therapy designed to circumvent GLA antibodies that can inhibit efficacy in Fabry patients. AMT-190 incorporates a modified version of -N-acetylgalactosaminidase ( NAGA ), a protein that is structurally similar to the GLA protein but is not recognized by GLA-neutralizing antibodies. As such, AMT-190 has the potential to be a more effective, longer-term treatment of Fabry disease. In cultured cells and in a study in wild-type mice, AMT-190 resulted in clinically relevant GLA activity. In a preclinical proof-of-concept study, Fabry mice were injected with a single dose of AMT-190, resulting in modified NAGA expression with subsequent GLA-activity in plasma. At two- and four-weeks post-dosing, this GLA activity already translated to up to fifty percent reduction in lyso-Gb3 levels. We believe that these studies demonstrate proof-of-concept of AMT-190 as a gene therapy candidate for Fabry disease. We believe that a one-time administration of AMT-190 could potentially lead to long-term expression of GLA in the liver, kidneys and heart, with no loss of expression due to inhibitors. We are currently conducting preclinical studies of AMT-190 and plan additional studies to further demonstrate safety and efficacy.

Central Nervous System diseases

Huntington s Disease

Huntington s Disease and Market Background

Huntington s disease is a severe genetic neurodegenerative disorder causing loss of muscle coordination, behavioral abnormalities and cognitive decline, often resulting in complete physical and mental deterioration over a 12 to 15-year period. The median survival time after onset is 15 to 18 years (range: 5 to >25 years). Huntington s disease is caused by an inherited defect in a single gene that codes for a protein called Huntingtin ( HTT ). The prevalence of Huntington s disease is three to seven per 100,000 in the general population, similar in men and women, and it is therefore considered a rare disease. Despite the ability to identify Huntington s disease mutation carriers decades before onset, there is currently no available therapy that can delay onset or slow progression of the disease. Although some symptomatic treatments are available, they only are transiently effective despite significant side effects.

Our Development of AMT-130 for Huntington s Disease

AMT-130 is our gene therapy candidate targeting Huntington s disease that utilizes an AAV vector carrying an engineered micro-RNA ( miRNA ) designed to silence both HTT and HTT exon 1, a highly toxic protein directly linked with genetic modifiers of Huntington s disease. AMT-130 is our lead product candidate developed using our miQURE technology, a proprietary, one-time administered gene silencing platform. AMT-130 has received orphan drug designation from the FDA and Orphan Medicinal Product Designation from the EMA. AMT-130 is intended to be administered directly into the brain via a stereotactic, magnetic resonance imaging guided catheter.

Our goal for AMT-130 is to develop a gene therapy with the following profile:

One-time administration in the striatum of disease modifying therapy;

Strong knockdown of both mutant HTT ( mHTT ) and HTT exon 1 in the deep structures of the brain and cortex; and

Leverages proprietary miQURE gene silencing platform.

In April 2017, we presented preclinical data on AMT-130 in transgenic mini pigs. The data demonstrated widespread, dose-dependent distribution of the vector throughout the mini pig brain that corresponded strongly with the mHTT expression. Researchers also observed a dose-dependent reduction in mHTT protein levels, as well as similar trends in cerebral spinal fluid. Both the surgical procedure and AMT-130 treatment were well tolerated with no adverse events.

In October 2017, we presented preclinical data on AMT-130 in a mouse model with a highly aggressive form of Huntington s disease which demonstrated significant improvements in both motor-coordination and survival, as well as a dose-dependent, sustained reduction in mHTT.

In April 2018, we presented an overview of preclinical data establishing proof-of-concept for AMT-130 at the 2018 American Academy of Neurology Annual Meeting in Los Angeles, California. Data from multiple studies in Huntington s disease animal models across three different species showed that a single intraparenchymal administration of AMT-130 into the striatum, resulted in a dose-dependent and sustained reduction of mHTT in both the deep structures of the brain and the cortex. Specifically, we presented data from the ongoing preclinical study in transgenic minipigs, one of the largest Huntington s disease animal models available, demonstrating significant reductions in human mHTT by a median of 68% in the striatum and a median of 47% in the frontal cortex at 6 months after administration of AMT-130.

In January 2019 our IND application for AMT-130 was cleared by the FDA, thereby enabling us to initiate our planned Phase I/II clinical study. The Phase I/II study is expected to be a randomized, double-arm, blinded, imitation surgery-controlled trial conducted at three surgical sites in the U.S., with at least two non-surgical sites. The primary objective of the study is to evaluate the safety, tolerability and efficacy of AMT-130 at two doses.

In February 2019 we presented new preclinical data at the 14th Annual CHDI Huntington s disease Therapeutics Conference that illustrate the therapeutic potential of AMT-130 in restoring function of damaged brain cells in Huntington s disease and providing a safe and sustained reduction of mutant huntingtin protein.

On April 8, 2019, we announced that the FDA granted fast track designation for AMT-130.

Spinocerebellar Ataxia Type 3 program

Spinocerebellar Ataxia type 3 and Market Background

SCA3, also known as Machado-Joseph disease, is an inherited disorder caused by a CAG-repeat expansion in the ATXN3 gene that results in an abnormal form of the protein ataxin-3. Patients with SCA3 experience brain degeneration that results in movement disorders, rigidity, muscular atrophy and paralysis. There is currently no treatment available that slows the progressive course of this lethal disease.

Prevalence of SCA3 is estimated to be one to two per 100,000 with significant geographical and ethnic variations: the highest prevalence has been found in the Azores (Flores Island (1/239)), with intermediate prevalence

rates in Portugal, Germany, the Netherlands, China and Japan, and lower prevalence rates in North America, Australia and India. SCA3 is the most common form of type 1 autosomal-dominant cerebellar ataxia ( ADCA1 ) in most genetically characterized populations.

Our preclinical SCA3 program

AMT-150 is a one-time, intrathecally-administered, AAV gene therapy incorporating our proprietary miQURE silencing technology that is designed to halt ataxia in early manifest SCA3 patients. In an in-vitro study with human Induced Pluripotent Stem ( IPS ) derived neurons, AMT-150 has been shown to lower the human ataxin-3 protein by 65%, without any off-target effects. We also performed a proof-of-concept in-life study in SCA3 mice demonstrating that AMT-150 was able to lower toxic ataxin-3 protein by 65% in the brain stem after a single administration. Further studies in non-human primates demonstrate the ability to distribute and express a reporter gene at a clinically relevant level in the most degenerated brain regions in SCA3. These preclinical studies demonstrate that a single administration of AMT-150 results in sustained expression and efficient processing with on-target engagement. They also demonstrate that AMT-150 appears to be safe due to the lack of off-target activity. In early 2019, we initiated a large animal study of AMT-150 and anticipate additional preclinical studies to further demonstrate safety and efficacy.

Bristol-Myers Squibb Collaboration

In 2015, we entered into an agreement with BMS that provides exclusive access to our gene therapy technology platform for multiple targets primarily focused on cardiovascular diseases ( Collaboration and License Agreement ). We are supporting BMS in discovery, non-clinical, analytical and process development efforts in respect of the Collaboration Targets. For any Collaboration Targets that may be advanced, we are responsible for manufacturing of clinical and commercial supplies using our vector technologies and industrial, proprietary insect-cell based manufacturing platform. BMS reimburses us for all our research and development costs in support of the collaboration, and will lead development, regulatory and commercial activities for any Collaboration Targets that may be advanced.

In February 2019, BMS requested a one-year extension of the research term. In April 2019, following an assessment of the progress of this collaboration and our expanding proprietary programs, we notified BMS that we do not intend to agree to an extension of the research term. Accordingly, we are currently in discussions with BMS to potentially amend the collaboration and license agreement and other related agreements following the expiration of the research term.

Collaboration on cardiovascular and other diseases focused targets