What changed in this filing

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Item 1. Business

2021-03-01 compared with 2020-03-02 · 575 added, 342 removed, 546 unchanged (63% of the section changed)

We are a leader in the field of gene therapy, seeking to develop single treatments with potentially curative results for patients suffering from genetic and other devastating diseases.

We are advancing a focused pipeline of innovative gene therapies.

Our lead program, etranacogene dezaparvovec for the treatment of hemophilia B, is currently being evaluated in a Phase III HOPE-B pivotal trial.

In September 2019, we completed the enrollment of the lead-in phase of the HOPE-B pivotal trial.

We are also developing a novel gene therapy product candidate, AMT-130, for patients with Huntington’s disease.

In January 2019, we received notice from the United States Food and Drug Administration (“FDA”) of the clearance of our Investigational New Drug (“IND”) application and recently initiated a Phase I/II clinical study of AMT-130.

Beyond our lead clinical program for hemophilia B and our Huntington’s disease program, we have a pipeline of additional AAV-based gene therapy programs in various stages of preclinical development.

We are advancing a focused pipeline of innovative gene therapies, including product candidates for the treatment of hemophilia B, which we intend to license to CSL Behring pursuant to the CSL Behring Agreement (as defined below), and Huntington’s disease.

We believe our validated 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.

Conducting a pivotal study of hemophilia B lead candidate – Etranacogene dezaparvovec (AMT-061)

Etranacogene dezaparvovec is our lead gene therapy candidate and includes an AAV5 vector incorporating the Factor IX-Padua variant.

We believe our Lexington, Massachusetts-based facility is one of the world’s most versatile gene therapy manufacturing facilities.

CSL Behring commercialization and license agreement

On June 24, 2020, uniQure biopharma B.V., a wholly-owned subsidiary of uniQure N.V., entered into a commercialization and license agreement (as amended, the “CSL Behring Agreement”) with CSL Behring LLC (“CSL Behring”) pursuant to which CSL Behring will receive exclusive global rights to etranacogene dezaparvovec, our investigational gene therapy for patients with hemophilia B (the “Product”).

Under the terms of the CSL Behring Agreement, we will receive a $450.0 million upfront cash payment upon the closing of the CSL Behring Agreement and be eligible to receive up to $1.6 billion in additional payments based on regulatory and commercial milestones.

The CSL Behring agreement also provides that we will be eligible to receive tiered double-digit royalties in a range of up to a low-twenties percent of net sales of the Product based on sales thresholds.

Pursuant to the CSL Behring Agreement, we will be responsible for the completion of the HOPE-B clinical trial, manufacturing process validation, and the manufacturing supply of the Product until such time that these capabilities may be transferred to CSL Behring or its designated contract manufacturing organization.

Concurrently with the execution of the CSL Behring Agreement, we and CSL Behring entered into a development and commercial supply agreement, pursuant to which, among other things, we will supply the Product to CSL Behring at an agreed-upon price.

Clinical development and regulatory activities performed by us pursuant to the CSL Behring Agreement will be reimbursed by CSL Behring.

CSL Behring will be responsible for global regulatory submissions and commercialization requirements for the Product.

Other than under the CSL Behring Agreement, neither we nor CSL Behring may perform any clinical trials, with the exception of trials required to extend the label or gain marketing authorization outside the United States or the European Union, for any gene therapy product, gene-editing product, or any other product comprising an AAV vector to conduct nucleotide transfer (including deoxyribonucleic acid (“DNA”) and ribonucleic acid (“RNA”)) for the treatment, prevention, or cure of hemophilia B for a period commencing on June 24, 2020 and continuing for a period of four years following the first commercial sale of the Product in the United States, and neither we nor CSL Behring may commercialize such a product for a period commencing as of June 24, 2020 and continuing for a period of seven years following the first commercial sale of the Product in the United States.

This exclusivity commitment would not bind an acquirer of us that owns or controls such a product so long as certain precautions are followed to ensure that CSL Behring’s confidential information and our proprietary technology related to the Product are not used or accessed by personnel of such acquirer who are developing or commercializing such competing product.

Unless earlier terminated as described below, the CSL Behring Agreement will continue on a country-by-country basis until expiration of the royalty term in a country.

The royalty term expires in a country on the later of (a) 15 years after the first commercial sale of the Product in such country, (b) expiration of regulatory exclusivity for the Product in such country and (c) expiration of all valid claims of specific licensed patents covering the Product in such country.

Either we or CSL Behring may terminate the CSL Behring Agreement for the other party’s material breach if such breach is not cured within a specified cure period.

In addition, if CSL Behring fails to commercialize the Product in any of a group of major countries for an extended period of time following the first regulatory approval of the Product in any of such group of countries (other than due to certain specified reasons) and such failure has not been cured within a specified cure period, then we may terminate the CSL Behring Agreement.

CSL Behring may also terminate the CSL Behring Agreement for convenience.

The effectiveness of the transactions contemplated by the CSL Behring Agreement is contingent on completion of review under antitrust laws in the United States, Australia, and the United Kingdom, and certain provisions of the CSL Behring Agreement will not become effective until after we receive all such regulatory approvals.

On November 11, 2020, the Australian Competition and Consumer Commission (“ACCC”) determined, pursuant to section 50 of the Competition and Consumer Act 2010 of Australia, that it will not intervene in the CSL Behring Agreement.

Thus, the ACCC has completed its review of the CSL Behring Agreement, and the transactions contemplated by the CSL Behring Agreement may close from the perspective of the Australian competition authority.

On November 24, 2020, the Competition and Markets Authority in the United Kingdom (the “CMA”) adopted a decision not to refer the CSL Behring Agreement for proceedings under section 33 of the Enterprise Act 2002 of the United Kingdom.

The decision was made public by the CMA on January 6, 2021.

Thus, the CMA has completed its review of the CSL Behring Agreement, and the transactions contemplated by the CSL Behring Agreement may close from the perspective of the United Kingdom competition authority.

On December 3, 2020, we and CSL Behring filed a premerger notification and report form under the Hart-Scott-Rodino Antitrust Improvements Act of 1976 (the “HSR Act”).

On January 4, 2021, the United States Federal Trade Commission (“FTC”) issued to us a request for additional information and documentary material (a “Second Request”) under the HSR Act.

The FTC similarly issued a Second Request to CSL Behring also with respect to the antitrust review of the CSL Behring Agreement.

The effect of the Second Request is to extend the waiting period imposed under the HSR Act until 30 days after all parties to the CSL Behring Agreement have substantially complied with the requests unless the waiting period is terminated earlier by the FTC or voluntarily extended by the parties.

We do not believe that the FTC will determine that the consummation of the transaction will result in a violation of the HSR Act.

However, there can be no assurance as to the outcome of the Second Request.

Closing of the transaction is expected to materially impact our profitability and cash flows.

Receipt of the $450.0 million payment due on closing would extend the funding of our operations into the second half of 2024 (assuming a full repayment of funds borrowed from Hercules Capital Inc.

(“Hercules”) under our term loan facility by 2023).

However, we expect to continue to incur losses and to generate negative cash flows beyond the fiscal year in which we would close the transaction.

Hemophilia B program – Etranacogene dezaparvovec (AMT-061)

Etranacogene dezaparvovec is our lead gene therapy candidate and includes an Adeno-associated virus (“AAV”) serotype 5 (together “AAV-5”) vector incorporating the functional human Factor IX (“FIX”) Padua variant.

We are currently conducting a pivotal study in patients with severe and moderately-severe hemophilia B.

Etranacogene dezaparvovec has been granted Breakthrough Therapy Designation by the FDA and access to the PRIME initiative by the European Medicines Agency (“EMA”).

In June 2018, we initiated our Phase III HOPE-B pivotal trial of etranacogene dezaparvovec for hemophilia B.

In January 2019, we dosed the first patient in the trial and in September 2019, we completed the enrollment of approximately 60 patients in the lead-in phase of this trial.

The trial is a multinational, multi-center, open-label, single-arm study to evaluate the safety and efficacy of etranacogene dezaparvovec.

After the six-month lead-in period, patients are receiving a single intravenous administration of etranacogene dezaparvovec.

The primary endpoint of the study will be based on the Factor IX (“FIX”) activity level achieved following the administration of etranacogene dezaparvovec, and the secondary endpoints will measure annualized FIX replacement therapy usage, annualized bleed rates and safety.

Patients enrolled in the HOPE-B pivotal trial have been tested for the presence of pre-existing neutralizing antibodies to AAV5 but are not being excluded from the trial based on their titers.

In February, May, July and December 2019, we presented updated data related to the three patients treated in our Phase IIb dose-confirmation study of etranacogene dezaparvovec.

Data from the Phase IIb study of etranacogene dezaparvovec show that all three patients experienced increasing and sustained FIX levels after a one-time administration of etranacogene dezaparvovec.

Mean FIX activity was 41% of normal at 52 weeks of follow-up, exceeding threshold FIX levels generally considered sufficient to significantly reduce the risk of bleeding events.

The first patient achieved FIX activity of 50% of normal.

FIX activity in the second patient was 31% of normal and the third patient was 41% of normal.

In August 2018, we initiated a Phase IIb dose-confirmation study of etranacogene dezaparvovec and in September 2018, we completed the dosing for that study.

In February, May, July, and December 2019, and in December 2020, we presented updated data from the Phase IIb dose-confirmation study of etranacogene dezaparvovec.

The most recent data that we announced from the Phase IIb study of etranacogene dezaparvovec show that all three patients experienced increasing and sustained FIX levels after a one-time administration of etranacogene dezaparvovec.

Mean FIX activity was 44.2% of normal two years after administration, exceeding threshold FIX levels generally considered sufficient to significantly reduce the risk of bleeding events.

The first patient achieved FIX activity of 44.7% of normal, the second patient was 51.6% of normal and the third patient was 36.3% of normal.

The second and third patients had previously screen-failed and were excluded from another gene therapy study due to pre-existing neutralizing antibodies to a different AAV vector.

Based on the data obtained through October 24, 2019, no patient experienced a material loss of FIX activity, reported any bleeding events or required any infusions of FIX replacement therapy for bleeds.

One patient underwent hip surgery due to a pre-existing condition and was treated pre-operatively with short-acting factor replacement.

This was reported by the investigator as a serious adverse event unrelated to etranacogene dezaparvovec.

Enrolling Phase I/II clinical study of Huntington product candidate (“AMT-130”)

At two years after dosing, two of the three participants remain free from bleeds and use of FIX replacement therapy.

A single bleed has been reported in one participant, who has used a total of two FIX infusions (excluding surgery).

All patients have remained free of prophylaxis in the two years since receiving etranacogene dezaparvovec.

In June 2018, we initiated the six-month lead-in period of our Phase III HOPE-B pivotal trial of etranacogene dezaparvovec (the “HOPE-B trial”).

The HOPE-B trial is a multinational, multi-center, open-label, single-arm study to evaluate the safety and efficacy of etranacogene dezaparvovec.

After the six-month lead-in period, patients received a single intravenous administration of etranacogene dezaparvovec.

Patients enrolled in the HOPE-B trial were tested for the presence of pre-existing neutralizing antibodies to AAV5 but not excluded from the trial based on their titers.

The primary endpoints of the study are based on the FIX activity level achieved following the administration of etranacogene dezaparvovec after 26 weeks and 52 weeks after dosing as well as annualized bleed rates during the 52 weeks after dosing.

In March 2020, we completed dosing of the 54 patients in the HOPE-B trial.

The targeted number of patients to be dosed per the clinical trial protocol was 50.

As set forth below, we have implemented and continue to implement various measures to allow us to closely monitor the trial within the guidance provided by the U.S.

Food and Drug Administration (“FDA”) regarding the impact of the COVID-19 coronavirus pandemic (“COVID-19”) to minimize any risk or disruption in patient follow-up visits.

In December 2020, we announced top-line data from the HOPE-B trial.

The 26-week follow-up date from the trial showed that FIX activity in the 54 patients increased after dosing from ≤ 2% to a mean of 37.2% at 26 weeks, meeting a first primary endpoint of the HOPE-B trial.

No correlation between pre-existing neutralizing antibodies and FIX activity was found in patients with neutralizing antibody titers up to 678.2, a range expected to include more than 95% of the general population;

one patient with a neutralizing antibody titer of 3,212.3 did not show an increase in FIX activity.

Less than 1% of the general population is expected to have neutralizing antibody titers of greater than 3,000.

During the 26-week period after dosing, 15 patients (28%) reported a total of 21 bleeding events, representing a reduction of 83% compared to the 123 bleeding events reported by 38 patients (70%) during the observational lead-in phase of the trial.

Total bleeds include any bleeding event reported after the treatment of etranacogene dezaparvovec, including spontaneous, traumatic, and those associated with unrelated medical procedures, whether or not FIX treatment was required.

Of the total bleeding events reported during the 26-week period after dosing, only three were classified as spontaneous bleeds requiring treatment, representing a reduction of 92% compared to the 37 such bleeding events reported during the observational lead-in phase.

Mean annualized usage of FIX replacement therapy, a secondary endpoint in the clinical trial, declined by 96% during the 26-week period after dosing compared to the observational lead-in phase.

Etranacogene dezaparvovec was generally well-tolerated.

As of the November 2020 cut-off date, most adverse events were classified as mild (81.5%).

The most common events included transaminase elevation treated with steroids per protocol (9 patients;

17%), infusion-related reactions (7 patients;

13%), headache (7 patients;

13%) and influenza-like symptoms (7 patients;

Liver enzyme elevations resolved with a tapering course of corticosteroids and FIX activity remained in the mild range in the steroid treated patients.

No relationship between safety and neutralizing antibody titers was observed.

Based on interactions with the FDA and the European Medicines Agency (“EMA”), we plan to incorporate FIX activity and bleeding rates at 52 weeks as additional co-primary endpoints in the study.

On December 21, 2020, our clinical trials of etranacogene dezaparvovec, including our HOPE-B trial, were placed on clinical hold by the FDA.

The clinical hold was initiated following the submission of a safety report in mid-December relating to a possibly related serious adverse event associated with a preliminary diagnosis of hepatocellular carcinoma (“HCC”), a form of liver cancer, in one patient in the HOPE-B trial that was treated with etranacogene dezaparvovec in October 2019.

The patient has multiple risk factors associated with HCC, including a twenty-five-year history of hepatitis C (“HCV”), hepatitis B virus (“HBV”), evidence of non-alcoholic fatty liver disease and advanced age.

Chronic infections with hepatitis B and C have been associated with approximately 80% of HCC cases.

The liver lesion was detected during a routine abdominal ultrasound conducted as part of the required study assessments in patients at one-year post dosing.

A surgical resection of the lesion has occurred, and an analysis of the tissue samples was initiated in early 2021.

On February 19, 2021, we reported initial results from this analysis to the FDA in accordance with pharmacovigilance requirements.

We are gathering final data from these molecular analyses and will be preparing a detailed response to the FDA’s clinical hold questions regarding this event.

Currently, we do not have adequate data to determine a possible causal relationship, especially in the context of the other known risk factors.

We currently do not anticipate any impact on our regulatory submission timelines, including the filing of a BLA.

No other cases of HCC have been reported in our clinical trials conducted in more than 67 patients in hemophilia B, with some patients dosed more than 5 years ago.

Etranacogene dezaparvovec has been granted Breakthrough Therapy Designation by the FDA and access to the current priority medicines (“PRIME”) initiative by the EMA.

Huntington’s disease program (AMT-130)

AMT-130 is our novel gene therapy candidate for the treatment of Huntington’s disease.

AMT-130 utilizes our miQURE™ proprietary, gene-silencing platform and incorporates an AAV vector carrying a microRNA (“miRNA”) specifically designed to silence the huntingtin gene and the potentially highly toxic exon 1 protein fragment.

AMT-130 utilizes our proprietary, gene-silencing miQURE platform and incorporates an AAV vector carrying an miRNA specifically designed to silence the huntingtin gene and the potentially highly toxic exon 1 protein fragment.

AMT-130 has received orphan drug and Fast Track designations from the FDA and Orphan Medicinal Product Designation from the EMA.

In January 2019, our IND application for AMT-130 was cleared by the FDA enabling us to initiate our planned Phase I/II clinical study.

The Phase I/II protocol is a randomized, imitation surgery-controlled, double-blinded study.

The study will include three surgical sites and multiple referring, non-surgical sites in the U.S.

In June 2020, we announced the completion of the first two patient procedures in the Phase I/II clinical trial of AMT-130 for the treatment of Huntington’s disease.

These procedures occurred after a postponement that resulted from the COVID-19 pandemic and the associated states of emergency declarations in the United States.

The Phase I/II protocol is a randomized, imitation surgery-controlled, double-blinded study conducted at three surgical sites, and multiple referring, 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.

Patient screening for the study is currently underway.

Additionally, we manufactured cGMP clinical material at our Lexington facility during 2019 and have released the clinical material for shipment.

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.

We are currently conducting safety and toxicology studies of AMT-180 to support the submission of an IND application.

Our next most advanced preclinical candidates, AMT-190 and AMT-150, are differentiated gene therapy candidates for the treatment of Fabry disease and Spinocerebellar Ataxia Type 3 (“SCA3”), respectively.

We are currently preparing to initiate safety and toxicology studies of AMT-150 to support the submission of an IND application.

We are currently conducting additional preclinical studies to identify a lead candidate for AMT-190 for further safety testing.

We are actively engaged in the research and development of other potential product candidates that are currently in the pre-clinical stage of development as well as other related technologies in the field of gene therapy.

In September 2019, we raised $242.7 million of net proceeds, after deducting underwriting discounts and commissions and other offering expenses payable by the Company, through a follow-on public offering of 5,625,000 ordinary shares at a public offering price of $46.00 per ordinary share.

On September 25, 2020, we announced that the independent Data Safety Monitoring Board (“DSMB”) overseeing the Phase I/II clinical trial of AMT-130 for the treatment of Huntington’s disease had met and reviewed 90-day safety data from the first two patients enrolled in the trial.

No significant safety concerns were noted to prevent further dosing.

On October 13, 2020, we announced the completion of the third and fourth patient procedures in the Phase I/II clinical trial.

On February 8, 2021, we announced that the DSMB had met and reviewed the six-month safety data from the first two enrolled patients and the 90-day safety data from the next two enrolled patients in the study.

No significant safety concerns were noted to prevent further dosing, and the final six patients in the first cohort are now cleared for enrollment.

BMS collaboration

We and Bristol-Myers Squibb (“BMS”) entered into a collaboration and license agreement in May 2015 (“BMS CLA”).

BMS had initially designated four Collaboration Targets in 2015 and in accordance with the terms of the BMS CLA could have designated a fifth to tenth Collaboration Target.

In February 2019, BMS requested a one-year extension of the initial research term.

Accordingly, the initial four-year research term under the collaboration terminated on May 21, 2019.

On December 1, 2020, we and BMS amended the BMS CLA (“amended BMS CLA”).

Following the amendment BMS is no longer entitled to designate a fifth to tenth Collaboration Target and as such we are no longer entitled to receive an aggregate $16.5 million in target designation payments for research, development, and regulatory milestone payments related to the fifth and tenth Collaboration Targets.

For a period of one-year from the effective date of the amended BMS CLA, BMS may replace up to two of the four active Collaboration Targets with two new targets in the field of cardiovascular disease.

We continue to be entitled to receive up to $217.0 million for each of the four Collaboration Targets if defined milestones are achieved, as well as royalties on net sales associated with any Collaboration Target.

On December 17, 2020, BMS designated one of the four Collaboration Targets as a candidate to advance into IND-enabling studies entitling us to receive a $4.4 million research milestone payment.

We recorded the $4.4 million as License Revenue in the twelve-month period ended December 31, 2020.

The amended BMS CLA does not extend the initial research term.

BMS may place purchase orders to provide limited services primarily related to analytical and development efforts in respect of the four Collaboration Targets.

BMS may request such services for a period not to exceed the earlier of (i) the completion of all activities under a Research Plan and (ii) either (A) three years after the last replacement target has been designated by BMS during the one-year replacement period following the amended BMS CLA effective date or (B) three years if no replacement targets are designated during this one-year period and BMS continues to reimburse us for these services.

For as long as any of the four Collaboration Targets are being advanced, BMS may place a purchase order to be supplied with research, clinical and commercial supplies.

Subject to the terms of the amended BMS CLA, BMS has the right to terminate the research, clinical and commercial supply relationships, and has certain remedies for failures of supply, up to and including technology transfer for any such failure that otherwise cannot be reasonably resolved.

Both we and BMS may agree to a technology transfer of manufacturing capabilities pursuant to the terms of the amended BMS CLA.

We have agreed to certain restrictions on our ability to work independently of the collaboration, either directly or indirectly through any affiliate or third party, on certain programs that would be competitive with a Collaboration Target.

We have agreed to indication exclusivity for the current four Collaboration Targets.

BMS may add or change the exclusive indications in the process of replacing Collaboration Targets as described above.

We can opt out of the indication exclusivity by giving up certain economic rights under the amended BMS CLA for each such indication that is affected by us opting out.

If we opt out of an exclusive indication, we could pursue other targets for such indication other than a Collaboration Target.

The amended BMS CLA also terminated two warrants to increase BMS ownership in the Company up to 19.9% through purchasing a specific number of our ordinary shares following the designation of a seventh, and a tenth Collaboration Target, respectively.

We and BMS agreed that upon the consummation of a change of control transaction of uniQure that occurs prior to the earlier of (i) December 1, 2026 and (ii) BMS’ delivery of a target cessation notice for all four Collaboration Targets, uniQure (or its third party acquirer) shall pay to BMS a one-time, non-refundable, non-creditable cash payment of $70.0 million, provided that (x) if $70.0 million is greater than five percent of the net proceeds (as contractually defined) from such change of control transaction, the payment shall be an amount equal to five percent of such net proceeds, and (y) if $70.0 million is less than one percent of such net proceeds, the change of control payment shall be an amount equal to one percent of such net proceeds.

We have not consummated any change of control transaction as of December 31, 2020 that would obligate us to make a payment to BMS.

The amended BMS CLA did not change any of the provisions of the Investor Agreement with BMS that we entered into in 2015.

We have granted BMS certain registration rights that allow BMS to require us to register our securities beneficially held by BMS under the U.S.

Securities Exchange Act of 1934, as amended (“Exchange Act”).

BMS may make up to two such demands for us to register the shares, provided that we may deny such demand if (i) the market value of the shares to be registered is less than $10.0 million (provided however, if BMS holds less than $10.0 million worth of our shares, we must comply with their demand for registration), (ii) we certify to BMS that we plan to effect a registration within 120 days of their demand or we are engaged in a transaction that would be required to be disclosed in a registration statement and that is not reasonably practicable to be disclosed at that time, or (iii) we have already effected one registration statement within the twelve months preceding BMS’s demand for registration.

In addition, independent of their demand registration rights, upon the occurrence of certain events, we must also provide BMS the opportunity to include their ordinary shares in any registration statement that we effect.

We also continue to grant BMS certain information rights under the Investor Agreement, although these requirements may be satisfied by our public filings required by U.S.

securities laws.

BMS also continues to be subject to a lock up pursuant to the Investor Agreement for as long as BMS holds more than 4.9% of our ordinary shares (as of December 31, 2020 BMS holds 5.3%).

Without our prior consent, BMS may not sell or dispose any of its current ordinary shares.

The Investor Agreement also continues to require BMS to vote all of our ordinary shares it beneficially holds in favor of all items on the agenda for the relevant general meeting of shareholders of our company as proposed on behalf of our company, unless, in the context of a change of control or similar transaction, BMS has itself made an offer to our company or our board in connection with the transaction that is the subject of the vote, in which case it is free to vote its shares at its discretion.

This voting provision will terminate upon the later of the date on which BMS no longer beneficially owns at least 4.9% of our outstanding ordinary shares, the closing of a transaction that provides BMS exclusive and absolute discretion to vote our shares it beneficially holds, or the termination of the amended BMS CLA for breach by us.

Term loan facility

As of December 31, 2020, a $35.0 million term loan was outstanding in accordance with the Second Amended and Restated Loan and Security Agreement (“2018 Amended Facility”) between us and Hercules.

On January 29, 2021 we and Hercules entered into amendments to the 2018 Amended Facility (the “2021 Amended Facility”).

Pursuant to the 2021 Amended Facility, Hercules agreed to make additional term loans in the maximum aggregate amount of $100.0 million (the “2021 Term Loan”), increasing the aggregate principal amount of the term loan facility from $35.0 million to up to $135.0 million.

On January 29, 2021 we drew down $35.0 million of the 2021 Term Loan.

We may draw down the remaining $65.0 million under the 2021 Term Loan in a series of one or more advances of not less than $20.0 million each until December 15, 2021.

Advances under the 2021 Term Loan bear interest at a rate equal to the greater of (i) 8.25% or (ii) 8.25% plus the prime rate, less 3.25% per annum.

The principal balance and all accrued but unpaid interest on advances under the 2021 Term Loan is due on June 1, 2023, which date may be extended by us by up to two twelve-month periods.

Advances under the 2021 Term Loan may not be prepaid until six-months after the Closing Date, following which we may prepay all such advances without charge.

In addition to the 2021 Term Loan, the amendment also extends the interest only payment period of the previously funded $35.0 million term loan from January 1, 2022 to June l, 2023.

COVID-19 measures

The coronavirus disease (“COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (“Sars-CoV 2 virus) was characterized as a pandemic by the World Health Organization (“WHO”) on March 11, 2020.

During late 2020 various, potentially more infectious, variants of the Sars-CoV 2 virus causing COVID-19 were identified.

Starting March 2020, we implemented measures to address the impact of COVID-19 on our business.

We mandated a work-from-home policy for all non-essential employees at our Amsterdam and Lexington facilities when the pandemic began.

We implemented a series of protocols governing the operations of our Lexington facility to comply with the requirements of the various orders and guidance from the Commonwealth of Massachusetts and other related orders, guidance, laws, and regulations.

We supported our employees in setting up a healthy and efficient remote working environment.

In conjunction with implementing this policy, we accelerated the roll-out of several information technology security measures, such as dual factor authentication, to address the increased risks to which we might be exposed as a result of remote working conditions.

In addition, we conducted awareness training around cybersecurity for critical functions involved in making payments to vendors such as finance and supply chain.

We continue to monitor local government rules and recommendations and office protocols will be aligned with these rules and recommendations.

We conduct frequent status video-meetings of local management at our two sites as well as leadership-team video meetings to implement these measures and to monitor the evolving situation.

In addition, we inform our employees through periodic newsletters and have organized virtual local and global townhalls to share information and provide direction and support to our employees.

We started to reopen the Amsterdam and Lexington facilities in phases, in line with the reopening plans that are prescribed by the local government.

Between June 1, 2020 until September 29, 2020, we encouraged our Amsterdam employees to work a minimum of two days per week from the office, and approximately 50% of local staff worked on site during that period.

As of September 29, 2020, we reinstated the mandatory work-from-home policy that was initiated in March in Amsterdam to align with the updated Dutch government’s measures.

Employees based in Amsterdam who cannot perform their duties outside of our Amsterdam facility will continue to work at our Amsterdam facility.

We adapted to operate our laboratories at our Amsterdam site to comply with social distancing rules and to ensure the health and wellbeing of our employees under the current circumstances.

All other employees in Amsterdam will work from home through at least the end of August 2021, partly in conjunction with the ongoing expansion of our laboratory space.

As a biopharma research and development company, we were deemed to provide essential services under the “stay at home” advisory that was issued by the Governor of Massachusetts on March 23, 2020 and we therefore have maintained our manufacturing operations at our Lexington site.

To ensure adequate social distancing in our Lexington facility, our COVID-19 protocols generally have limited occupancy to numbers below those allowed by the Massachusetts COVID-19 guidelines.

In our Lexington facility, we currently have implemented an occupancy limitation of approximately 25%.

Our employees that cannot perform their duties outside of our Lexington facility continue to work at our Lexington facility.

All other employees are required to work remotely to the extent possible through at least the end of the second quarter of 2021.

Our actual occupancy at the Lexington facility has been less than approximately 25% of our permitted occupancy during all phases of the Massachusetts reopening plan.

We have also implemented a mandatory COVID-19 PCR testing protocol effective February 11, 2021 that requires employees to have tested negative for COVID-19 prior to entering the Lexington facility.

We have adapted our ongoing clinical research activities based on the directions and flexibility provided by the “FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic” issued on March 18, 2020 and updated throughout the pandemic to minimize any risk, disruption, or delay in either patient dosing or follow-up visits.

These procedures occurred after a postponement that resulted from the COVID-19 pandemic and the associated states of emergency declarations in the United States.

The broader implications of COVID-19 on our results of operations and overall financial performance remain uncertain.

The COVID-19 pandemic and its adverse effects have become more prevalent in the locations where we, and our third-party business partners conduct business.

While we have experienced disruptions in our operations as a result of COVID-19, we are adapting to the current environment to minimize the effect to our business.

However, we may experience more pronounced disruptions in our operations in the future.

On September 14, 2020, we appointed Ricardo Dolmetsch, Ph.D.

as President, Research and Development.

Dolmetsch succeeded Sander van Deventer, M.D., Ph.D., our former Executive Vice President, Research and Product Development.

On October 14, 2020, our Chief Medical Officer, Robert Gut, M.D., Ph.D., resigned to allow him to return as a non-executive director on our Board of Directors.

Gut was appointed to our Board of Directors as a non-executive director at an extraordinary meeting of shareholders on December 1, 2020.

On June 17, 2020, our shareholders voted to approve the appointment of Leonard E.

as a non-executive director of the Board of Directors.

Post replaced Dr.

David Schaffer, whose term as a non-executive director of the Board of Directors ended on the same date.

Post has also assumed the role of chair of our Research & Development Committee of the Board of Directors.

Our Mission and Strategy

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Etranacogene dezaparvovec combines the potential 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.

In September 2019, we completed enrollment of approximately 60 patients in the lead-in phase of our Phase III HOPE-B pivotal study.

In March 2020, we completed dosing of 54 patients in our Phase III HOPE-B pivotal study.

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.

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We are developing proprietary technologies that have the potential to augment the safety and efficacy of our product candidates and broaden the applicability of our gene therapies to a wider range of diseases and patients.

These technologies include (i) miQURE TM , our one-time administered gene silencing platform, (ii) tailored vectors, promoters and other enhancers;

These technologies include (i) miQURE, our one-time administered gene silencing platform, (ii) tailored vectors, promoters, and other enhancers;

(iii) optimized delivery and administration techniques;

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Liver-directed diseases

Hemophilia B (etranacogene dezaparvovec)

Hemophilia B Disease and Market Background

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Hemophilia B occurs in approximately 1 out of 30,000 live male births.

CSL Behring collaboration

On June 24, 2020, we entered into the CSL Behring Agreement pursuant to which CSL Behring would receive exclusive global rights to etranacogene dezaparvovec.

Pursuant to the CSL Behring Agreement, we would be responsible for the completion of the HOPE-B clinical trial, manufacturing process validation, and the manufacturing supply of etranacogene dezaparvovec until such time that these capabilities may be transferred to CSL Behring or its designated contract manufacturing organization.

Concurrently with the execution of the CSL Behring Agreement we and CSL Behring entered into a development and commercial supply agreement, pursuant to which, among other things, we would supply etranacogene dezaparvovec to CSL Behring at an agreed-upon price.

Clinical development and regulatory activities performed by us pursuant to the CSL Behring Agreement would be reimbursed by CSL Behring.

CSL Behring would be responsible for global regulatory submissions and commercialization requirements for etranacogene dezaparvovec.

The CSL Behring Agreement continues to be subject to antitrust review in the U.S.

and as such is not yet effective.

Our Development of etranacogene dezaparvovec for Hemophilia B

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

AAV5-based gene therapies have been used in a multitude of clinical trials, including five clinical trials conducted by uniQure in patients with hemophilia B and other disorders.

AAV5-based gene therapies have been used in a multitude of clinical trials, including five clinical trials conducted by us in patients with hemophilia B and other disorders.

No patient treated in clinical trials with our AAV5-based gene therapies has experienced any confirmed, cytotoxic T-cell-mediated immune response to the capsid.

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Data from our clinical, preclinical, and nonclinical studies suggest that all, or nearly all patients may be eligible for treatment with etranacogene dezaparvovec.

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

In June 2018, we initiated our Phase III HOPE-B pivotal trial of etranacogene dezaparvovec.

The trial is a multinational, multi-center, open-label, single-arm study to evaluate the safety and efficacy of etranacogene dezaparvovec.

In January 2019 we dosed the first patient in our HOPE-B pivotal trial and in September 2019, we completed the enrollment of approximately 60 patients in the lead-in phase of the trial.

The adult hemophilia B patients, which were classified as severe or moderately severe, were 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 etranacogene dezaparvovec.

The primary endpoint of the study is based on the FIX activity level achieved following the administration of etranacogene dezaparvovec, and the secondary endpoints are

annualized FIX replacement therapy usage, annualized bleed rates and safety.

Patients enrolled in the HOPE-B trial were tested for the presence of pre-existing neutralizing antibodies to AAV5 but were not excluded from the trial based on their titers.

In March 2020, we completed dosing of the 54 patients in the HOPE-B trial.

The targeted number of patients to be dosed per the clinical trial protocol was 50.

As set forth previously, we have implemented and continue to implement various measures to allow us to closely monitor the trial within the guidance provided by the FDA regarding the impact of the COVID-19 coronavirus pandemic to minimize any risk or disruption in patient follow-up visits.

The adult hemophilia B patients, who were classified as severe or moderately severe, were enrolled in a six-month observational period prior to dosing during which time they continued to use their current standard of care to establish a baseline control.

After the six-month lead-in period, patients received a single IV-administration of etranacogene dezaparvovec.

Patients enrolled in the HOPE-B trial were tested for the presence of pre-existing neutralizing antibodies to AAV5 but not excluded from the trial based on their titers.

In December 2020, we announced top-line data from the HOPE-B trial.

one patient with a neutralizing antibody titer of 3,212.3 did not show an increase in FIX activity.

Less than 1% of the general population is expected to have neutralizing antibody titers of greater than 3,000.

Mean annualized usage of FIX replacement therapy, a secondary endpoint in the clinical trial, declined by 96% during the 26-week period after dosing compared to the observational lead-in phase.

Etranacogene dezaparvovec was generally well-tolerated.

As of the November 2020 cut-off date, most adverse events were classified as mild (81.5%).

The most common events included transaminase elevation treated with steroids per protocol (9 patients;

17%), infusion-related reactions (7 patients;

13%), headache (7 patients;

13%) and influenza-like symptoms (7 patients;

Liver enzyme elevations resolved with a tapering course of corticosteroids and FIX activity remained in the mild range in the steroid treated patients.

No relationship between safety and neutralizing antibody titers was observed.

Based on interactions with the FDA and the EMA, we plan to incorporate FIX activity and bleeding rates at 52 weeks as additional co-primary endpoints in the study.

On December 21, 2020, our clinical trials of etranacogene dezaparvovec, including our HOPE-B trial were placed on clinical hold by the FDA.

The clinical hold was initiated following the submission of a safety report in mid-December relating to a possibly related serious adverse event associated with a preliminary diagnosis of HCC, a form of liver cancer, in one patient in the HOPE-B trial that was treated with etranacogene dezaparvovec in October 2019.

The patient has multiple risk factors associated with HCC, including a twenty-five-year history of HCV, HBV, evidence of non-alcoholic fatty liver disease and advanced age.