What changed in this filing

/stocks — the workspaceLOADING

Item 7. Management’s Discussion and Analysis

2021-03-01 compared with 2020-03-02 · 400 added, 356 removed, 248 unchanged (75% of the section changed)

4 unchanged sentences

GAAP”) and unless otherwise indicated are presented in U.S.

Except for the historical information contained herein, the matters discussed this MD&A may be deemed to be forward-looking statements.

Except for the historical information contained herein, the matters discussed in this MD&A may be deemed to be forward-looking statements.

Forward-looking statement 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.

7 unchanged sentences

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, including product candidates for the treatment of hemophilia and Huntington’s disease.

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, 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 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.

We produce our AAV-based gene therapies in our own facilities with a proprietary, commercial-scale, cGMP-compliant, manufacturing process.

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

Business developments

Below is a summary of our recent significant business developments:

CSL Behring commercialization and license agreement

On June 24, 2020, uniQure biopharma B.V., a wholly owned subsidiary of uniQure N.V., entered into the CSL Behring Agreement with CSL Behring pursuant to which CSL Behring will receive exclusive global rights to etranacogene dezaparvovec, 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 DNA and 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 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.

On November 11, 2020, the 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 HSR Act.

On January 4, 2021, the FTC issued 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 Requests 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.

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 such regulatory approvals.

Regulatory approval in the United States has not occurred to date.

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 from the second half of 2022 into the second half of 2024 (assuming a full repayment of funds borrowed from 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.

BMS collaboration

We and Bristol-Myers Squibb entered into a collaboration and license agreement in May 2015.

BMS 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.

In April 2019, following an assessment of the progress of this collaboration and our expanding proprietary programs, we notified BMS that we did not intend to agree to an 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.

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 the research, development, and regulatory milestone payments related to the fifth to 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 the Company to receive a $4.4 million research milestone payment.

The Company 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.

The amended BMS CLA also terminated two warrants to increase BMS ownership in the Company to 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, we (or our 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.

Hemophilia B program – Etranacogene dezaparvovec (AMT-061)

Etranacogene dezaparvovec is our lead gene therapy candidate and includes an AAV5 vector incorporating the 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 United States FDA and access to the PRIME initiative by the EMA.

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.

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

The primary endpoint of the study will be based on the 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 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 Phase III HOPE-B hemophilia B pivotal trial and in September 2019, we completed the enrollment of approximately 60 patients in the lead-in phase of the trial.

In August 2018, we initiated a Phase IIb dose-confirmation study of etranacogene dezaparvovec.

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 etranacogene dezaparvovec 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 2x10 13 gc/kg.

In February, May, July and December 2019, we presented updated data from the 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, with two of the three patients maintaining FIX activity in the normal range.

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 in the third patient was 41% of normal.

The second and third patients 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 perioperatively with short-acting factor replacement.

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

In December 2019, we also presented four-year follow-up data related to our first-generation hemophilia B program.

AMT-060, which incorporated a wild-type FIX gene.

All 10 patients enrolled in the Phase I/II study continue to show long-term meaningful clinical impact, including sustained increases in FIX activity and improvements in their disease state as measured by reduced usage of FIX replacement therapy and decreased bleeding frequency.

At up to four years of follow-up, AMT-060 continues to be well-tolerated, with no new serious adverse events and no development of inhibitors since the last reported data.

All five patients in the high dose cohort of 2x10 13 gc/kg continue to be free of routine FIX replacement therapy at up to three and a half years after treatment.

Based on the last six months of data collected during the fourth year of follow-up, the mean annualized bleeding rate was zero compared to an average of four bleeds during the year prior to treatment, representing a 100% reduction.

Steady state mean yearly FIX activity at three and a half years was 7.5% compared with 7.1% in the first year, 8.4% in the second and 7.9% in the third year.

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.

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 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 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.

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 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.

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.

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.

We enrolled five patients into a low dose cohort in the third quarter 2015.

Another five patients were enrolled into a high dose cohort between March and May 2016.

In December 2020, we presented five-year follow-up data related to this Phase I/II clinical trial.

All 10 patients enrolled continue to show long-term clinical benefit, including sustained increases in FIX activity, reduced usage of FIX replacement therapy, and decreased bleeding frequency.

At up to five years of follow-up, AMT-060 continues to be well-tolerated, with no new treatment-related adverse events since the last reported data and no development of inhibitors during the study.

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 TM proprietary, gene-silencing platform and incorporates an AAV vector carrying a 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.

AMT-130 is our gene therapy candidate targeting Huntington’s disease that utilizes an AAV vector carrying an engineered miRNA designed to silence HTT and exon 1 HTT, a potentially highly toxic protein fragment that may also contribute to disease pathology.

AMT-130 comprises a recombinant AAV5 vector carrying a DNA cassette, encoding a miRNA that non-selectively lowers or knocks-down HTT and exon 1 HTT in Huntington’s disease patients.

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 primary objective of the study is to evaluate the safety, tolerability, and efficacy of AMT-130 at two doses.

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.

In the fourth quarter of 2019, we initiated patient screening.

Additionally, cGMP clinical material has been manufactured at our Lexington facility and has been released for shipment.

In January 2019, the U.S.

Patent and Trademark Office issued U.S.

Patent 10,174,321 and in May 2019 the European Patent Office issued EP 3237618, both with granted claims that cover the RNA constructs specifically designed to target exon1 and the embedding of these Huntington’s disease RNA sequences into the miR451 scaffold, which we exclusively license from CSHL.

The claims also cover certain expression cassettes comprising the RNA constructs and the use of gene therapy vectors including AAV vectors encompassing the described expression cassettes.

In February 2019, we presented new preclinical data at the 14th Annual CHDI Huntington’s disease Therapeutics Conference that illustrated the therapeutic potential of AMT-130 to restore the function of damaged brain cells in Huntington’s disease and provide a sustained reduction of mutant huntingtin protein.

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 has 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 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.

Preclinical programs

In November 2018, we announced the expansion of our research pipeline with novel AAV gene therapy approaches to treating hemophilia A, Fabry disease and Spinocerebellar Ataxia Type 3.

Hemophilia A program (AMT-180)

AMT-180 is our novel hemophilia A gene therapy that we believe has the potential to treat all hemophilia A patients including those with past and current inhibitors.

Approximately 30% of patients with severe hemophilia A will develop an inhibitor that neutralizes the infused Factor VIII activity.

This patient population has in the past been excluded from gene therapy approaches in clinical development.

AMT-180 utilizes an AAV vector incorporating a proprietary, exclusively licensed, modified FIX gene that has been demonstrated in preclinical studies to convey Factor VIII-independent activity and circumvent inhibitors to Factor VIII.

In May 2019, we presented preclinical proof-of-concept data at the ASGCT Annual Meeting, demonstrating that AMT-180 induced thrombin activation, and up to 29% of Factor VIII-independent activity, in FVIII-depleted human plasma.

The studies further demonstrated that a single intravenous administration of AMT-180 resulted in sustained, dose-dependent hemostatic effect as measured by one-stage clotting assay, and that AMT-180 shows activation kinetics similar to native FIX and is not hyperactive.

A pilot study in non-human primates demonstrated that administration of AMT-180 resulted in sufficient FIX protein expression that may translate to Factor VIII-independent activity in humans.

No elevation of coagulation activation markers or signs of thrombi formation were observed.

We are currently conducting safety and toxicology studies of AMT-180 to support the submission of a clinical trial application in 2020.

Spinocerebellar Ataxia Type 3 program (AMT-150)

AMT-150 is our novel gene therapy candidate for the treatment of SCA3, also known as Machado-Joseph disease, which is caused by a CAG-repeat expansion in the ATXN3 gene that results in an abnormal form of the protein ataxin-3.

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.

At the 2019 American Academy of Neurology Annual Meeting, we presented preclinical data on AMT-150 demonstrating mechanistic proof-of-concept of the non-allele-specific ataxin-3 protein-silencing approach by using artificial miRNA candidates engineered to target the ataxin-3 gene in a SCA3 knock-in mouse model.

In this proof-of-concept study, a single AMT-150 injection in the cerebrospinal fluid resulted in AAV transduction and mutant ataxin-3 lowering at the primary sites of disease neuropathology, the cerebellum (up to 53%) and the brainstem (up to 65%).

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

In May 2020, we presented preclinical data at the ASGCT Annual Meeting, on our gene therapy candidate SCA3.

In an in vivo preclinical study, six NHP received a one-time injection of AMT-150 via the cisterna magna to assess expression and distribution.

Samples taken after eight weeks showed widespread transduction of the brain and spinal cord, with the highest genome copies found in the posterior fossa and cortical regions.

In other preclinical studies, researchers evaluated AMT-150 in SCA3 mouse models, as well as human iPSC-derived neurons and astrocytes, to investigate potential off-target effects of AAV5-miATXN3.

The iPSC-derived cell cultures, which were derived from two SCA3 patients, represent the most disease-relevant cell type for therapeutic targeting of AMT-150.

A clear dose-dependent expression of miATXN3 was observed in the iPSC-derived neurons and astrocytes transduced with AMT-150.

Mature miATXN3 molecules were also associated with extracellular vesicles that strongly correlated with the dose and miATXN3 expression, suggesting the potential therapeutic spread of the engineered miATXN3.

Additionally, AMT-150 demonstrated ATXN3 knockdown in human neurons and various SCA3 mouse models with subsequent neuropathology improvement.

In September 2020, we initiated a safety and toxicology study of AMT-150 in NHP.

Fabry disease program (AMT-190)

AMT-190 is our novel gene therapy candidate for the treatment of Fabry disease that comprises of an AAV vector incorporating a proprietary, exclusively licensed, ModNAGA variant.

ModNAGA may have several advantages over other therapies for Fabry disease, including higher stability in blood, circumvention of inhibitors, better biodistribution in the target organs, secondary toxic metabolite reduction and improved cross-correction of neighboring cells.

At the ASGCT Annual Meeting in May 2019, we presented data from in vitro and in vivo studies showing that AMT-190 has the potential to become a one-time treatment option that could be an improvement upon the enzyme replacement standard of care with more efficient uptake in the kidney and heart and an improved immunogenicity profile.

In particular, data from a study in wild-type mice showed a single intravenous administration of AMT-190 resulted in a ten- to twenty-fold higher alpha-galactosidase (“GLA”) activity in the plasma compared to the control group.

Additionally, in a study in a diseased mouse model, GLA activity significantly increased in plasma, and globotriaosylsphingosine (“Lyso-Gb3”) was significantly reduced in target organs after a single dose of AMT-190.

Based on the results of these in silico and in vitro studies, the modifications introduced into NAGA appear to pose a very low immunogenicity risk.

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

BMS collaboration

We entered into a collaboration and license agreement with BMS in May 2015.

We have been supporting BMS in the discovery, non-clinical, analytical and process development efforts of Collaboration Targets.

For any Collaboration Targets that are advanced, we will be responsible for manufacturing of clinical and commercial supplies using our vector technologies and industrial, proprietary insect-cell based manufacturing platform.

BMS has been reimbursing us for all our research and development costs in support of the collaboration during the initial research term.

BMS will lead the development, regulatory and commercial activities for all four currently active Collaboration Targets as well as additional Collaboration Targets that may be advanced.

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

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

We are currently in discussions with BMS potentially to restructure or amend the collaboration and license agreement and other related agreements following the expiration of the research term.

Although such discussions are ongoing and may not result in any change to these arrangements, we believe that the final resolution of these discussions may result in material changes to our collaboration with BMS.

Padua mutation in human Factor IX patent family

We own a patent family, including patents and patent applications, directed to the use of the Padua mutation in human FIX for gene therapy.

A patent cooperation treaty application was filed on September 15, 2009, and patents have been issued in the United States, Europe, and Canada.

Further applications are pending in the United States, Europe, and Hong Kong.

The issued patents include claims directed to FIX protein with a leucine at the R338 position of the protein sequence, nucleic acid sequences coding for this protein, and therapeutic applications, including gene therapy.

The standard 20-year patent term of patents in this family will expire in 2029.

On November 5, 2019, the USPTO granted us a third patent, U.S.

Patent Number 10,465,180, which covers any AAV comprising a nucleic acid encoding a FIX-Padua protein, and promoter sequences, transcription termination and control elements.

The claims also cover FIX-Padua variants with at least 70% sequence identity to FIX-R338L.

On June 13, 2018, we were granted European Patent 2337849 directed to a FIX polypeptide protein.

The opposition period with respect to such patent expired on March 13, 2019, by which time five parties had filed an opposition.

On July 25, 2019, we submitted responses to such oppositions with the European Patent Office, or EPO, and expect that oral proceeding with respect to such oppositions will take place in June and July 2020.

In addition, on May 15, 2019, a divisional European patent application in the FIX-Padua family, EP 3252157, was refused.

In September 2019, we filed a notice of appeal with respect to such refusal.

We are also pursuing a European divisional patent application that was filed on May 14, 2019.

On January 4, 2020, a petition seeking Inter Partes Review of the ‘405 Patent was filed by Pfizer, Inc.

The petition seeks to invalidate claims 6 and 9-15 of the ‘405 Patent.

We are in the process of responding to the petition.

Intellectual Property Portfolio in Manufacturing

We continue to strengthen the intellectual property related to our proprietary insect cell-based AAV manufacturing process.

In May 2018, we announced that the USPTO granted U.S.

Patent Number 9,840,694, which includes claims covering nanofiltration to selectively remove potential residual baculovirus from the product.

We believe this nanofiltration step is important for product quality and safety and that nanofiltration generally may be required to comply with viral clearance standards established by global regulatory authorities.

Related patents were previously granted in Europe, Japan and several other jurisdictions.

The 9,840,694 patent expands our intellectual property portfolio directed to large-scale manufacturing of AAV in insect cells using baculovirus vectors.

Our portfolio includes multiple important molecular and process-related patents, as well as extensive know-how covering essential production, purification, and processing steps that are necessary for the large-scale insect cell-based manufacturing and for compliance with the regulatory authorities.

Technology and Manufacturing Platform Developments

In November 2018, we presented our miQURE™ gene silencing platform, which is designed to degrade disease-causing genes, without off-target toxicity, and induce silencing of the entire target organ through secondary exosome-mediated delivery.

Gene therapy candidates designed with miQURE ™ incorporate proprietary, therapeutic miRNA constructs that can be delivered using AAVs to potentially provide long-lasting activity.

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 to the cellular miRNA or messenger RNA transcriptome.

miQURE ™ technology has been incorporated in AMT-130, our investigational gene therapy for Huntington’s disease, and is expected to be applied to AMT-150 for SCA3.

In October 2018, we presented non-clinical data demonstrating that a next-generation synthetic promoter developed for liver-directed gene therapy is capable of generating up to a 40-fold increase in expression compared to a reference promoter.

A “promoter” is an essential component of a gene therapy construct that controls expression of a therapeutic protein.

Most gene therapies incorporate natural promoters, which have limitations and may not optimize the expression of genes in specific target cells.

Consequently, natural promoters may not be appropriate for gene therapies that require higher levels of gene expression and tissue specificity.

The new promoter may enable us to tailor expression levels required for a specific therapeutic transgene.

Also, in October 2018, we presented new data demonstrating the ability to manufacture gene therapies using a 500-liter single-use, stirred tank reactor that has the potential to significantly increase manufacturing capacity and enhance scalability.

We produce our AAV-based gene therapies in our state-of-the-art, Lexington-based manufacturing facility using a proprietary baculovirus expression vector system.

On September 10, 2019, we completed a follow-on public offering of 4,891,305 ordinary shares at a public offering price of $46.00 per ordinary share, and on September 13, 2019, we completed the sale of an additional 733,695 ordinary shares at a public offering price of $46.00 per ordinary share pursuant to the exercise by the underwriters of the option to purchase additional ordinary shares, resulting in total gross proceeds to us of $258.8 million.

The net proceeds from this offering were $242.7 million, after deducting underwriting discounts and commissions and other offering expenses payable by us.

We deducted $0.6 million of expenses incurred related to this offering from additional paid-in capital in the accompanying consolidated balance sheets and reflected this within the proceeds from public offering of shares, net of issuance costs within the cash flows from financing activities.

Manufacturing Facility

In November 2018, we entered into an amendment to the lease on our facility in Lexington, Massachusetts.

Pursuant to the terms of the original lease, we leased approximately 53,343 rentable square feet for a term through April 30, 2024.

Pursuant to the amended lease, we have leased approximately 30,655 additional square feet of contiguous space for a term that commenced on June 1, 2019 and runs through June 30, 2029.

Additionally, we extended the term of the lease of the original space through June 2029.

The amended lease provides for an aggregate of $15.8 million of rent for the expansion space and $25.8 million of rent for the original space over the extended term.

The amended lease provides for an additional contribution from the landlord of $1.5 million, which may be used for alterations to the entire premises for a period of 18 months from the commencement of the term on the expansion space.

We have two options to renew the amended lease for terms of five years each, as well as a right of first offer to lease any of the remaining approximately 20,000 square feet of space in the same building, if that space becomes available for rent.

In August 2019, we promoted Sander van Deventer, M.D., Ph.D., to Executive Vice President, Research and Product Development, and Alex Kuta, Ph.D., to Executive Vice President, Operations.

van Deventer, in addition to his responsibilities to being responsible for research, will now also be responsible for our product development.

Kuta, in addition to regulatory affairs, will now also be responsible for global quality as well as GMP manufacturing at our state-of-the-art facility in Lexington, Massachusetts.

As a result of these changes, we eliminated the Chief Operating Officer role, and Scott McMillan, Ph.D.

AMT-190 is our novel gene therapy candidate for the treatment of Fabry disease.

AMT-190 is a one-time, IV-administered, AAV5-based gene therapy.

In September 2020, we selected a lead gene therapy candidate (AMT-190) for the treatment of Fabry disease to advance into IND-enabling studies.

The lead candidate is a one-time administered AAV5 gene therapy incorporating the α-galactosidase A (GLA) transgene.

In preclinical studies comparing multiple product candidates, including constructs incorporating a modified alpha-N-acetylgalactosaminidase transgene (modNAGA), AMT-190 demonstrated the most robust and sustained increases in GLA activity.

Hemophilia A program (AMT-180)

In June 2020, we announced that we plan to de-prioritize our research program of AMT-180 for patients with hemophilia A, as part of our effort to focus on those gene therapy programs that have the greatest potential to improve patients’ lives and generate long-term value for shareholders.

Term loan facility

As of December 31, 2020, a $35.0 million term loan was outstanding in accordance with the 2018 Amended Facility between us and Hercules.

On January 29, 2021 we and Hercules entered into the 2021 Amended Facility.

Pursuant to the 2021 Amended Facility, Hercules agreed to 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.

End of term charges in respect of advances under the 2021 Term Loan range from 1.65% to 6.85%, depending on the maturity date.

COVID-19 measures

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 that 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.

Related party transaction

In August 2019, we entered into an Amended CLA as well as an additional New CLA with our related party 4DMT.

In the Amended CLA, we received from 4DMT an exclusive, sublicensable, worldwide license under certain 4DMT intellectual property rights to research, develop, make, use, and commercialize previously selected AAV capsid variants and certain associated products using 4DMT proprietary AAV technology for delivery of gene therapy constructs to cells in the Field.

In the New CLA, the parties agreed to research and develop, at 4DMT’s cost, new AAV capsid variants using 4DMT proprietary AAV technology for delivery of up to six additional transgene constructs in the Field that will be selected by us.

On December 1, 2020, we and BMS entered into the amended BMS CLA.

All transactions subsequent to the effective date of the amended BMS CLA are considered to no longer be with a related party.

2020 Financial Highlights

10 unchanged sentences

$659.7 million).

We anticipate that our loss from operations will increase in the future as we:

● Build-out our commercial infrastructure and seek marketing approval for any product candidates (including etranacogene dezaparvovec) that successfully complete clinical trials;

We anticipate that our expenses will increase substantially as we:

● Advance the clinical development of AMT-130 for our Huntington’s disease gene therapy program;

● Continue to build-out our clinical, medical and regulatory capabilities;

● Build-out our commercial and medical affairs infrastructure and seek marketing approval for any product candidates (including etranacogene dezaparvovec in the event that the transactions contemplated by the CSL Behring Agreement do not close) that successfully complete clinical trials;

● Advance multiple research programs related to gene therapy candidates targeting liver-directed and CNS diseases;

5 unchanged sentences

In preparing our consolidated financial statements in accordance with U.S.

GAAP and pursuant to the rules and regulations promulgated by the Securities and Exchange Commission (“SEC”) we make assumptions, judgments and estimates that can have a significant impact on our net income/loss and affect the reported amounts of certain assets, liabilities, revenue and expenses, and related disclosures.

On an ongoing basis, we evaluate our estimates and judgments, including those related to the implementation of ASC 842 Leases, recognition of License Revenue in accordance with ASC 606, BMS warrants, share-based payments and corporate income taxes related to valuation allowance.

GAAP and pursuant to the rules and regulations promulgated by the SEC we make assumptions, judgments and estimates that can have a significant impact on our net income/loss and affect the reported amounts of certain assets, liabilities, revenue and expenses, and related disclosures.

On an ongoing basis, we evaluate our estimates and judgments, including those related to the treatment of the CSL Behring Agreement, the amended BMS CLA, share-based payments, corporate income taxes related to valuation allowance and accounting for operating leases under ASC 842.

We base our assumptions, judgments and estimates on historical experience and various other factors that we believe to be reasonable under the circumstances, the results of which form the basis for making judgments about the carrying values of assets and liabilities that are not clear from other sources.

2 unchanged sentences

We also discuss our critical accounting policies and estimates with the Audit Committee of our Board of Directors.

We believe that the assumptions, judgments and estimates involved in the recognition of License Revenue in accordance with ASC 606, BMS warrants, share-based payments, corporate income taxes related to valuation allowance and accounting for operating leases under ASC 842 to be our critical accounting policies.

We believe that the assumptions, judgments, and estimates involved in the treatment of the CSL Behring Agreement, the amended BMS CLA, share-based payments, corporate income taxes related to valuation allowance and accounting for operating leases under ASC 842 to be our critical accounting policies.

Historically, our assumptions, judgments and estimates relative to our critical accounting policies have not differed materially from actual results.

Adoption of ASC 842 Leases on January 1, 2019

On January 1, 2019, we adopted ASC 842, “Leases (Topic 842)”.

We adopted the standard using the modified retrospective approach with an effective date as of the beginning of the fiscal year, January 1, 2019, to operating leases that existed on that date.

Prior year comparative financial information was not recast under the new standard and continues to be presented under ASC 840.

We elected to utilize the package of practical expedients available for expired or existing contracts which allowed us to carryforward historical assessments of (1) whether contracts are or contain leases, (2) lease classification, and (3) initial direct costs.

We performed an assessment and identified the lease facilities as material leases to be accounted for under ASC 842 as of January 1, 2019.

The impact of implementing ASC 842 is summarized below:

- Recognized a $19.0 million operating right-of-use asset and a $28.1 million operating lease liability in relation to the facilities leased at the Amsterdam and Lexington sites in the Consolidated balance sheet as of January 1, 2019;

- Presented deferred rent of $9.1 million as of December 31, 2018, as a reduction of the right-of-use asset as from January 1, 2019 onwards in the Consolidated balance sheet and as a change within operating cash flows within accrued expense, other liabilities and operating leases;

We measured the lease liability at the present value of the future lease payments as of January 1, 2019.

We used an incremental borrowing rate to discount the lease payments.

We derived the discount rate, adjusted for differences such as in the term and payment patterns, from our Hercules loan which was refinanced immediately prior to the January 1, 2019 adoption date in December 2018.

We valued the right-of-use asset at the amount of the lease liability reduced by the remaining December 31, 2018 balance of lease incentives received.

We subsequently measure the lease liability at the present value of the future lease payments as of the reporting date with a corresponding adjustment to the right-to-use asset.

Absent a lease modification we will continue to utilize the January 1, 2019, incremental borrowing rate.

We will continue to recognize lease cost on a straight-line basis and will continue to present these costs as operating expenses within our Consolidated statements of operations and comprehensive loss.

We will continue to present lease payments and landlord incentive payments within cash flows from operations within our Consolidated statements of cash flows.

Adoption of ASC 606 revenue recognition on January 1, 2018

On January 1, 2018 we adopted new revenue recognition policies in accordance with ASC 606.

The new revenue recognition policies replace the existing policies in accordance with ASC 605.

We elected to implement ASC 606 by applying it to active collaboration arrangements as of January 1, 2018 and to record a cumulative adjustment of revenue previously recognized to our accumulated loss as of December 31, 2017.

The impact of implementing ASC 606 is summarized below:

- Recognized $7.5 million of license revenue during the twelve months ended December 31, 2018, related to the collaboration with BMS compared to $4.2 million that would have been recognized in accordance with the previous revenue recognition policies;

- Continued to present revenue recognized during the twelve months ended December 31, 2017, in accordance with the previous revenue recognition policies;

- Decreased the accumulated loss by $24.9 million as of January 1, 2018 and decreased deferred revenue as of the same date by $24.9 million.

In accordance with the previous revenue recognition policies we had concluded that the BMS collaboration agreement consisted of three performance obligations, (i) technology (license and target selections), know-how and manufacturing in the field of gene therapy and development and active contribution to the development through the joint steering committee participations, (ii) provision of employees, goods and services for research, and (iii) clinical and commercial manufacturing.

We determined that these three performance obligations are substantially identical with the performance obligations in accordance with our new revenue recognition policies:

Providing access to our technology and know-how in the field of gene therapy as well as actively contributing to the target selection, the collaboration as a whole, the development during the target selection, the pre-clinical and the clinical phase through participating in joint steering committee and other governing bodies (“License Revenue”);

(ii) Providing pre-clinical research activities (“Collaboration Revenue”);

(iii) Providing clinical and commercial manufacturing services for products (“Manufacturing Revenue”).

License Revenue

We generate license revenue from a $60.1 million upfront payment recorded on May 21, 2015, as well as $15.0 million received in relation to the designation of the second, third and fourth collaboration target in August 2015.

We are also entitled to an aggregate $16.5 million in target designation payments upon the selection of the fifth to tenth collaboration target.

We will also be eligible to receive research, development and regulatory milestone payments of up to $254.0 million for a lead candidate target (which has been AMT-126) and up to $217.0 million for each of the other selected targets, if milestones are achieved.

We will include the variable consideration related to the selection of the fifth to tenth collaboration target, or any of the milestones, in the transaction price once it is considered probable that including these payments in the transaction price would not result in the reversal of cumulative revenue recognized.

We might recognize significant amounts of License Revenue for services performed in prior periods if and when we consider this probable.

Due to the significant uncertainty surrounding the development of gene-therapy product candidates and the dependence on BMS’s performance and decisions we so far did not consider this probable.

Additionally, we are eligible to receive net sales-based milestone payments and tiered mid-single to low double-digit royalties on product sales.

The royalty term is determined on a licensed-product-by-licensed-product and country-by-country basis and begins on the first commercial sale of a licensed product in a country and ends on the expiration of the last to expire of specified patents or regulatory exclusivity covering such licensed product in such country or, with a customary royalty reduction, ten years after such first commercial sale if there is no such exclusivity.

These revenues will be recognized when performance obligations are satisfied.

Under the previous revenue standard, we recognized License Revenue over the expected performance period on a straight-line basis commencing on May 21, 2015.

In accordance with the new revenue recognition standards, we recognize License Revenue over the expected performance period based on our measure of progress towards the completion of certain activities related to our services.

We determine such progress by comparing activities performed at the end of each reporting period with total activities expected to be performed.

We estimate total expected activities using a number of unobservable inputs, such as the probability of BMS designating additional targets, the probability of successfully completing each phase and estimated time required to provide services during the various development stages.

If available, we use product candidate-specific research and development plans.

Alternatively, we assume that completion of the pre-clinical phase requires an average of four years and that clinical development and commercial launch on average require 8.5 years to complete.

CSL Behring Agreement

We obtained regulatory approvals in Australia and the United Kingdom prior to January 6, 2021.

We received a Second Request from the FTC on January 4, 2021, and as such, regulatory approval in the United States has not occurred to date.

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.

As of December 31, 2020, we concluded that we have no enforceable right to receive the $450.0 million upfront payment, in accordance with the CSL Behring Agreement as payment is contingent upon the successful completion of reviews under the HSR Act.

Therefore, we determined we will not recognize any revenue in relation to the upfront payment, the regulatory and sale milestone payments, or the royalties (together “CSL Behring License Revenue”) in accordance with ASC 606.

We incurred $2.1 million of expenses related to obligations related to the CSL Behring Agreement that had not been satisfied as of December 31, 2020.

We capitalized these expenses as we believe these qualify as contract fulfillment costs.

As of December 31, 2020, we also recognized a $2.1 million receivable from CSL Behring for expenses for which we have a right of reimbursement as well as a contract liability for the same amount.

In accordance with ASC 606, we cannot recognize any revenue in connection with the CSL Behring Agreement as of this date.

In accordance with our existing license and other agreements, we are contractually required to pay in total a low to high single digit percentage of any upfront payment to our licensors and financial advisor (“License Fees”).

We did not record any License Fees in the year ended December 31, 2020, as we had not recognized the upfront payment as of this date.

Amended BMS CLA

In May 2015, we entered into a collaboration and license agreement and various related agreements with BMS, which we collectively refer to as the BMS CLA, which provided BMS with exclusive access to our gene therapy technology platform for the research, development and commercialization of therapeutics aimed at multiple targets in cardiovascular and other diseases.

The BMS CLA provided that we and BMS could have potentially collaborated on up to ten Collaboration Targets in total.

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

During the initial research term of the BMS CLA, BMS, at its option, could purchase non-clinical, analytical and process development effort services.

For any Collaboration Targets that might have been advanced, BMS could have purchased clinical and commercial supplies from us.

BMS reimbursed us for the services in support of the collaboration during the initial research term, and leads the development, regulatory and commercial activities for any Collaboration Targets that are advanced.

On December 1, 2020, we and BMS amended the 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 or research, development, and regulatory milestone payments related to the fifth and tenth Collaboration Targets.

We evaluated the impact of the amendment of the BMS CLA in relation to our performance obligation related to:

- providing access to our technology and know-how in the field of gene therapy and participating in joint steering committee and other governing bodies (materially satisfied as of December 1, 2020) (“License Revenue”).

We did not identify any new distinct performance obligations and determined the amended BMS CLA did not represent a separate contract in accordance with ASC 606.

We evaluated the effect the modification has on our measure of progress towards the completion of our performance obligation in relation to License Revenue and recorded an adjustment to License Revenue as of December 1, 2020.

The estimation of total services at the end of each reporting period involves considerable judgement.

The estimated number of product candidates that BMS will pursue, significantly impacts the amount of License Revenue we recognize.

For example, if we would increase the probability of all additional targets being designated by 10% then the revenue for the twelve months ended December 31, 2019 would have decreased by approximately $1.9 million to $3.1 million, as we would be required to render more services in relation to the consideration received.

Collaboration and Manufacturing Revenue

The adoption of the new revenue recognition policies did not materially impact the recognition of Collaboration or Manufacturing Revenue.

We continue to recognize Collaboration Revenues associated with pre-clinical Collaboration Target specific, non-clinical, analytical and process development activities that are reimbursable by BMS under our collaboration agreement during the initial research term (that ended on May 21, 2019).

We are currently in discussions with BMS potentially to restructure or amend the collaboration and license agreement and other related agreements following the expiration of the research term.

During these discussions, which may be terminated by us or BMS at any time, we have agreed to continue providing support of the pre-clinical Collaboration Targets, and any related costs will be reimbursed by BMS.

Pursuant to the BMS CLA, we granted BMS two warrants:

● A warrant allowing BMS to purchase a specific number of our ordinary shares such that its ownership will equal 14.9% immediately after such purchase.

The warrant can be exercised on the later of (i) the date on which we receive from BMS the Target Designation Fees (as defined in the BMS CLA) associated with the first six new targets (a total of seven Collaboration Targets);

and (ii) the date on which BMS designates the sixth new target (the seventh Collaboration Target).

● A warrant allowing BMS to purchase a specific number of our ordinary shares such that its ownership will equal 19.9% immediately after such purchase.

The warrant can be exercised on the later of (i) the date on which we receive from BMS the Target Designation Fees associated with the first nine new targets (a total of ten Collaboration Targets);

and (ii) the date on which BMS designates the ninth new target (the tenth Collaboration Target).

As of December 31, 2019, BMS had designated a total of four Collaboration Targets, and as such, the warrants were not exercisable.

Pursuant to the terms of the BMS CLA, the exercise price in respect of each warrant is equal to the greater of (i) the product of (A) $33.84, and (B) a compounded annual growth rate of 10% (or approximately $52.39 as of December 31, 2019) and (ii) the product of (A) 1.10, and (B) the VWAP for the 20 trading days ending on the date that is five trading days prior to the date of a notice of exercise delivered by BMS.

For fair value measurement, we applied a Monte-Carlo simulation.

The valuation model incorporates several inputs, including the underlying share price the reporting date, the risk free rate adjusted for the period affected, an expected volatility based on our historical volatility, the expected yield on any dividends, and management's expectations on the timelines of reaching certain defined trigger events for the exercising of the warrants, as well as our expectations regarding the number of ordinary shares that would be issued upon exercise of the warrants.

Additionally, the model assumes BMS will exercise the warrants only if it is financially rational to do so.

Given the nature of these input parameters, we have classified the analysis as a level 3 valuation.

The estimated annualized volatility for fair value measurement is 72.5% as of December 31, 2019 (December 31, 2018:

75%) for the warrants.

The Company conducted a sensitivity analysis to assess the impact on changes in assumptions on the fair value.

Specifically, the Company examined the impact on the fair market value of the warrants by increasing the volatility by 10% to 82.5%.

A further sensitivity analysis was performed assuming the warrants would be exercised a year later than currently estimated.

The table below illustrates the impact on the fair market valuation associated with these changes in assumptions as of December 31, 2019.

Total warrants

Increase volatility by 10% to 82.5%

Extend exercise dates by one year

The amount of services we expect to provide is significantly impacted by the number of Collaboration Targets that we estimate BMS would pursue.

We considered that BMS may no longer designate potentially up to six Collaboration Targets in addition to the currently four active targets.

We evaluated our obligations with respect to the two replacement cardiovascular indications that BMS might potentially designate until November 30, 2021, and the services we expected to perform in relation to participating in joint steering committee and other governing bodies as well as the effort required to actively contribute to the target selection process or the collaboration as a whole.

Based on this we concluded that our remaining performance obligation is immaterial and adjusted our measure of progress accordingly.

As such we recognized the remaining balance of unrecognized License Revenue as of November 30, 2020 of $27.8 million in profit and loss during the year ended December 31, 2020 as License Revenue from a related party.

In 2015 we granted BMS two warrants, which were terminated in connection with the amendment to the BMS CLA.

We granted to BMS:

● A warrant that allowed BMS to purchase a specific number of our ordinary shares such that its ownership would have equaled 14.9% immediately after such purchase (1 st warrant”).

The 1 st warrant could have been exercised on the later of (i) the date on which we received from BMS the Target Designation Fees (as defined in the BMS CLA) associated with the first six new targets (a total of seven Collaboration Targets);

and (ii) the date on which BMS designated the sixth new target (the seventh Collaboration Target).

● A warrant that allowed BMS to purchase a specific number of our ordinary shares such that its ownership would have equaled 19.9% immediately after such purchase (“2 nd warrant” and together with the 1 st warrant, the “warrants”).

The warrant could have been exercised on the later of (i) the date on which we received from BMS the Target Designation Fees associated with the first nine new targets (a total of ten Collaboration Targets);

and (ii) the date on which BMS designated the ninth new target (the tenth Collaboration Target).

Pursuant to the terms of the BMS CLA the exercise price in respect of each warrant was equal to the greater of (i) the product of (A) $33.84, multiplied by (B) a compounded annual growth rate of 10% (or approximately $57.32 as of November 30, 2020) and (ii) the product of (A) 1.10 multiplied by (B) the volume weighted average price (“VWAP”) for the 20 trading days ending on the date that is five trading days prior to the date of a notice of exercise delivered by BMS.

We used Monte-Carlo simulations to determine the fair market value of the BMS warrants.

The valuation model incorporated several inputs, the risk-free rate adjusted for the period affected, an expected volatility based on our historical volatility, the expected yield on any dividends and management’s expectations on the timelines of reaching certain defined trigger events for the exercising of the warrants, as well as management’s expectations regarding the number of ordinary shares that would be issued upon exercise of the warrants.

All of these represent Level 3 inputs.

Additionally, the model assumed BMS would exercise the warrants only if it were financially rational to do so.

The warrants could only have been exercised following the occurrence of events contractually defined in the warrant agreements.

The probability of the occurrence of these events represented another significant unobservable input used in the calculation of the fair value of the warrants.

The fair value of the warrants as of December 31, 2019 was $3.1 million.

During the year ended December 31, 2020, we recognized a $3.1 million gain in non-operating income / expense (December 31, 2019:

$2.3 million loss;

December 31, 2018:

$0.5 million gain) related to fair value changes of the BMS warrants.

The gain recognized in the year ended December 31, 2020 includes $0.8 million from the derecognition of the BMS warrants on December 1, 2020.

On December 1, 2020, we and BMS terminated the BMS warrants and 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 (5.0%) 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 (“CoC-payment”).

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

We determined that the CoC-payment should be recorded as a derivative financial liability as of December 1, 2020 and that subsequent changes in the fair market value of this derivative financial liability should be recorded in profit and loss.

The fair market value of the derivative financial liability is materially impacted by probability that market participants assign to the likelihood of the occurrence of a change of control transaction that would give rise to a CoC-payment.

This probability represents an unobservable input.

We determined the fair market value of the derivative financial liability by using a present value model based on expected cash flow.

The expected cash flows are materially impacted by the probability that market participants assign to the likelihood of the occurrence of a change of control event within the biotechnology industry.

We estimated this unobservable input using the best information available as of December 1, 2020 and December 31, 2020.

We obtained reasonably available market information that we believe market participants would use in determining the likelihood of the occurrence of a change-of control transaction within the biotechnology industry.

Selecting and evaluating market information involves considerable judgement and uncertainty.

Based on all such information and our judgment we estimated that the fair market value of the derivative financial liability (presented within “Other non-current liabilities”) as of December 1, 2020 and December 31, 2020 was $2.6 million.

We recorded a $2.6 million loss within “other non-operating expenses” in the twelve-month period ended December 31, 2020 related to the initial recognition of this derivative financial liability.

Share-based payments

15 unchanged sentences

We have been incurring net operating losses in accordance with the respective corporate tax laws in almost all years since we founded our business.

As of December 31, 2019, the total amount of tax losses carried forward under the Dutch tax regime was $414.0 million and $46.7 million in the United States of America.

We believe that there is insufficient positive evidence of sufficient taxable profits available to us, including the implementation of possible and feasible tax strategies, to overcome the negative evidence of our loss-making history.

We have therefore recorded a $109.9 million valuation allowance and have not recorded a net deferred tax asset in our Consolidated Balance Sheet.

Recent Accounting Pronouncements

ASC 842 - Leases (Topic 842)

In February 2016, the FASB issued ASU 2016-02, “Leases (Topic 842)”.

In July 2018, the FASB issued ASU No.

2018-10, “Codification Improvements to Topic 842, Leases” (ASU 2018-10), which provides narrow amendments to clarify how to apply certain aspects of the new lease standard, and ASU No.

2018-11, “Leases (Topic 842) – Target Improvements” (ASU 2018-11), which address implementation issues related to the new lease standard.

The standard is effective for interim and annual reporting periods beginning after December 15, 2018.

Under the new standard, lessees are required to recognize the right-of-use assets and lease liabilities that arise from operating leases on the Consolidated balance sheet.

As of December 31, 2020, the total amount of net operating losses carried forward under the Dutch tax regime was $588.2 million and $42.3 million in the United States of America.

We reassessed the need for a full valuation allowance in conjunction with entering into the CSL Behring Agreement.

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.

Regulatory approval in the United States has not occurred to date.

We recognize deferred tax assets to the extent that we determine that these assets are more likely than not to be realized.

In making such a determination, we weighed all available positive and negative evidence, including future income projections from the CSL Behring Agreement, and concluded that it is more likely than not that the deferred tax assets will not be realized.

Accordingly, we continued to record a full valuation allowance as of December 31, 2020 in the Netherlands.

As of December 31, 2020, our valuation allowance amounted to $150.1 million (2019:

$109.9 million).

We recorded $16.4 million of deferred tax income in the year ended December 31, 2020 from releasing the full valuation allowance against our net deferred tax assets in the United States as of December 31, 2020.

entity has generated taxable income in the fiscal years 2018, 2019 and 2020.

Based on the current design of our worldwide operations, we expect to continue to generate taxable income in the U.S.

during the foreseeable future and therefore determined that it is more likely than not that our U.S.

deferred tax assets will be realized.

deferred tax assets as of December 31, 2020 amount to $16.4 million.

On January 1, 2019, we adopted ASC 842, “Leases (Topic 842)”.

We adopted the standard using the modified retrospective approach with an effective date as of the beginning of our fiscal year, January 1, 2019, to operating leases that existed on that date.

Prior year comparative financial information was not recast under the new standard and continues to be presented under ASC 840.

ASC 606 Revenue from Contracts with Customers

Effective January 1, 2018 we adopted new revenue recognition policies in accordance with ASC 606.

The new revenue recognition policies replace the existing policies in accordance with ASC 605.

ASC 825 Recognition and Measurement of Financial Assets and Financial Liabilities

In January 2016, the FASB issued ASU 2016-01, Financial Instruments - Overall (Subtopic 825-10):

Recognition and Measurement of Financial Assets and Financial Liabilities (“ASU 2016-01”).

ASU 2016-01 addresses certain aspects of recognition, measurement, presentation and disclosure of financial instruments.

ASU 2016-01 is effective for fiscal years, and interim periods within those years, beginning after December 15, 2017, which for the Company is January 1, 2018.

ASU 2016-01 did not have a material impact on our consolidated financial statements.

Derivatives and Hedging:

Effect of Derivative Contract Novations on Existing Hedge Accounting Relationships

In March 2016, the FASB issued ASU 2016-05, Derivatives and Hedging:

Effect of Derivative Contract Novations on Existing Hedge Accounting Relationships (“ASU 2016-05”) and ASU 2016-06, Derivatives and Hedging:

Contingent Put and Call Options in Debt Instruments.

Both ASUs address issues regarding hedge accounting.

The ASUs are effective for fiscal years, and interim periods within those years, beginning after December 15, 2017, which for the Company is January 1, 2018.

Neither ASU 2016-05 nor ASU 2016-06 had a material impact on our consolidated financial statements.

Compensation (topic 718)- scope of modification accounting

In May 2017, the FASB issued ASU 2017-09, Compensation-stock compensation (topic 718)- scope of modification accounting (“ASU 2017-09”), which provides clarity regarding the applicability of modification accounting in relation to share-based payment awards.

Under the new guidance, modification accounting is required only if the fair value, the vesting conditions, or the classification of the award (as equity or liability) changes as a result of the change in terms or conditions.

The effective date for the standard is for fiscal years beginning after December 15, 2017, which for the Company is January 1, 2018.

Early adoption is permitted.

The new standard is to be applied prospectively.

ASU 2017-09 did not have a material impact on our consolidated financial statements.

Codification Updates to SEC Sections

In July 2019, the FASB issued ASU 2019-07, Codification Updates to SEC Sections (“ASU 2019-07”), which provides amendments to SEC Paragraphs Pursuant to SEC Final Rule Releases No.

33-10532, Disclosure Update and Simplification, and Nos.

33-10231 and 33-10442, Investment Company Reporting Modernization, and Miscellaneous Updates.

The effective date for the standard is upon issuance.

ASU 2017-09 did not have a material impact on our consolidated financial statements.

Recent Accounting Pronouncements Not Yet Effective

Comparative financial information related to profit and loss and cash flows for the twelve-month period ended December 31, 2018, was not recast under the new standard, and continues to be presented under ASC 840.

We measured the lease liability at the present value of the future lease payments as of January 1, 2019.

We used an incremental borrowing rate to discount the lease payments.

We derived the discount rate, adjusted for differences such as in the term and payment patterns, from our loan from Hercules Capital, which was refinanced immediately prior to the January 1, 2019 adoption date in December 2018.

We valued the right-of-use asset at the amount of the lease liability reduced by the remaining December 31, 2018 balance of lease incentives received.

The lease liability is subsequently measured at the present value of the future lease payments as of the reporting date with a corresponding adjustment to the right-to-use asset.

Absent a lease modification, we will continue to utilize the January 1, 2019, incremental borrowing rate.

We recognize lease cost on a straight-line basis and present these costs as operating expenses within our Consolidated statements of operations and comprehensive loss.

We present lease payments and landlord incentive payments within cash flows from operations within our Consolidated statements of cash flows.

Recent Accounting Pronouncements

Fair Value Measurement

4 unchanged sentences

All other amendments should be applied retrospectively.

We do not expect ASU 2018-13 to have a material impact on our consolidated financial statements except for the inclusion of potentially additional disclosures for Level 3 inputs.

ASU 2018-13 did not have a material impact on our consolidated financial statements.

Recent Accounting Pronouncements Not Yet Effective

Results of Operations

10 unchanged sentences

Non-operating items, net

Loss before income tax expense

Income tax expense

We recognize total collaboration revenues associated with development activities that are reimbursable by Chiesi (up to the July 2017 termination of the collaboration) and BMS under our respective collaboration agreements.

In July 2017, we reacquired development and commercial rights in Europe and other select territories for our gene therapy in hemophilia B from Chiesi, our previous co-development partner.

The BMS collaboration revenues are associated with pre-clinical Collaboration Target specific, non-clinical, analytical and process development activities that are reimbursable by BMS under our collaboration agreement during the initial research term (that ended on May 21, 2019).

We are currently in discussions with BMS potentially to restructure or amend the collaboration and license agreement and other related agreements following the expiration of the research term.

We recognize license revenues associated with the amortization of the non-refundable upfront payment, target designation fees and research and development milestone payments we received or might receive from BMS and, until June 2017, Chiesi.

The timing of these cash payments may differ from the recognition of revenue, as revenue is deferred and recognized over the duration of the performance period.

We recognize other revenue, such as sales milestone payments, when earned.

Loss before income tax income / (expense)

Income tax income / (expense)

We recognize collaboration revenues associated with Collaboration Target-specific pre-clinical analytical development and process development activities that are reimbursable by BMS under the BMS CLA and the amended BMLS CLA as well as other related agreements.

Collaboration Revenue related to these contracted services is recognized when performance obligations are satisfied.

We recognized license revenues associated with the amortization of the non-refundable upfront payment and target designation fees we received from BMS in 2015.

We evaluated our outstanding performance obligation following the amendment of the BMS CLA on December 1, 2020 and determined that our remaining performance obligation is immaterial.

We updated our measure of progress accordingly and amortized the remaining balance of unrecognized revenue as of December 1, 2020.

In accordance with the amended BMS CLA, we continue to be eligible to receive research, development, and regulatory milestone payments as well as sales milestone payments and royalties for each of the four active Collaboration Targets if defined milestones are achieved in relation to the license to our technology and know-how.

We will recognize revenue from these payments when earned or as sales occur.

Our revenue for the years ended December 31, 2020, 2019 and 2018 was as follows:

Year ended December 31,

(in thousands)

License revenue

Collaboration revenue

Collaboration revenue Chiesi

Total revenues

We recognized $5.0 million and $7.5 million of BMS license revenue for the year ended December 31, 2019 and 2018, respectively, in accordance with our new revenue recognition policies we adopted effective January 1, 2018.

We recognized $4.1 million of license revenue for the year ended December 31, 2017 in accordance with our previous revenue recognition policies.

Following the termination of our collaboration with Chiesi in July 2017, we no longer recognize license revenue in association with the upfront fees received in 2013.

We recognized $0.0 million license revenue from Chiesi during the year ended December 31, 2017.

We recognized our license revenue during the year ended December 31, 2017, net of a $0.5 million reduction for amounts previously amortized in relation to a $2.3 million up-front payment that we were required to repay in 2017 in accordance with the Glybera Termination Agreement.

Collaboration revenue generated during year ended December 31, 2019, from research activities associated with our BMS-partnered programs, was $2.3 million compared to $3.8 million and $4.3 million for the years ended December 31, 2018 and December 31, 2017, respectively.

We have been providing research services to BMS since the May 2015 effective date of our collaboration.

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

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 the Company’s expanding proprietary programs, we notified BMS that we did not intend to agree to an extension of the research term but rather preferred to restructure the collaboration to reduce or eliminate certain of our obligations under it.

During the aforementioned discussions with BMS potentially to restructure or amend the BMS CLA and other related agreements, which may be terminated by us or BMS at any time, we have agreed to continue providing support of the pre-clinical Collaboration Targets, and any related costs will be reimbursed by BMS.

Following the termination of our collaboration with Chiesi in July 2017, we no longer recognize collaboration revenue from our co-development of hemophilia B with Chiesi.

We recognized $4.6 million collaboration revenue for the year ended December 31, 2017.

We recognized $37.3 million, $5.0 million, and $7.5 million of license revenue for the year ended December 31, 2020, 2019 and 2018, respectively.

The increase in license revenue in 2020 of $32.2 million compared to 2019 primarily resulted from $27.8 million of license revenue that we recognized as of the December 1, 2020 effective date of the amended BMS CLA as well as $4.4 million research milestone payment that we recorded in December 2020 following the designation of one of the four Collaboration Targets as a candidate to advance into IND-enabling studies.

The decrease in license revenue in 2019 of $2.5 million compared to 2018 resulted from the termination of the S100A1 Collaboration Target and subsequent designation of a replacement target in 2019.

We recognized $0.2 million, $2.3 million, and $3.8 million of collaboration revenue for the years ended December 31, 2020, 2019 and 2018, respectively.

The decrease in collaboration revenue in 2020 of $2.1 million compared to 2019 was primarily related to the reduction of activities following the termination of the initial research term under the BMS CLA in May 2019.

The decrease in collaboration revenue in 2019 of $1.5 million compared to 2018 resulted from the termination of the initial research term in May 2019 as well as the discontinuation of the S100A1 program in October 2018.

Research and development expenses

13 unchanged sentences

In June 2018, we initiated a pivotal study.

We completed enrollment of the lead-in phase of the pivotal study in September 2019.

We completed enrollment of the lead-in phase of the pivotal study in September 2019 and dosed a total of 54 patients between January 2019 and March 2020.

Following the completion of dosing we initiated activities related to the preparation of marketing authorization applications in the U.S.

and EU, as well as other related undertakings.

In September 2018, we completed patient dosing in our Phase IIb dose-confirmation study;

Since we and Chiesi terminated our Hemophilia Collaboration Agreement in July 2017, all development expenses have been borne by us (previously Chiesi reimbursed us for 50% of such costs);

● AMT-130 (Huntington’s disease).

13 unchanged sentences

● our ability to agree to ongoing development budgets with collaborators who share the costs of our development programs.

A change in the outcome of any of these variables with respect to our product candidates that we may develop could mean a significant change in the expenses and timing associated with the development of such product candidate.

A change in the outcome of any of these variables with respect to our product candidates that we may develop, including as a result of the COVID-19 pandemic, could mean a significant change in the expenses and timing associated with the development of such product candidate.

Research and development expenses for the year ended December 31, 2020 were $122.4 million, compared to $94.7 million and $74.8 million for the years ended December 31, 2019 and 2018, respectively.

3 unchanged sentences

(in thousands)

Hemophilia B (AMT-060/061)

Etranacogene dezaparvovec (AMT-060/061)

Huntington's disease (AMT-130)

4 unchanged sentences

Facility expenses

Other expenses

Termination benefits

1 unchanged sentence

Impairment loss in process research and development asset

Other expenses

Total other research and development expenses

2 unchanged sentences

Hemophilia B (AMT-060/061)

In the years ended December 31, 2018 and 2019, our external costs for our hemophilia B program were primarily related to the planning and execution of our Phase III and Phase IIb clinical trials.

Regarding the Phase III pivotal trial, the first patient was enrolled into the lead-in phase in June 2018 and dosed in January 2019.

In September 2019, we completed enrollment of approximately 60 patients in the lead-in phase of the trial.

In the year ended December 31, 2020, the external costs for our hemophilia B program were primarily related to the execution of our Phase III clinical trial and the preparations related to submissions of marketing authorization applications in the U.S.

We enrolled patients into a six-month lead in phase between January 2018 and September 2019 and dosed a total of 54 patients between January 2019 and March 2020.

Our expenses related to etranacogene dezaparvovec were largely unaffected by the COVID-19 pandemic as we completed enrollment prior to the lockdowns in those countries that we enroll patients.

We implemented additional measures to minimize any risk, disruption, or delay on follow-up visits, and as of September 2020, we completed almost all follow-up visits according to our initial plan.

In addition, we continue to incur costs for the long-term follow-up of patients in our Phase I/II clinical trial of AMT-060 and our Phase IIb clinical trial of etranacogene dezaparvovec.

Our Phase IIb dose-confirmation study was initiated in January 2018 and dosing occurred in July and August 2018.

In 2017 and early 2018, we incurred costs related to bridging studies to demonstrate the comparability of our first-generation product candidate for the treatment of Hemophilia B (AMT-060) with our current product candidate AMT-061.

In addition, we continue to incur cost for the long-term follow-up of patients we dosed as part of our Phase I/II clinical trial of AMT-060 in 2015 and 2016.

Patients were dosed as part of our Phase I/II clinical trial of AMT-060 in 2015 and 2016.

In the years ended December 31, 2018 and 2019, our external costs for our hemophilia B program were primarily related to the planning and execution of our Phase III and Phase IIb clinical trials.

Following the completion of patient enrollment into our HOPE-B trial we also started incurring costs related to preparation of a BLA and MAA and for commercialization of etranacogene dezaparvovec.

Huntington disease (AMT-130)

In the year ended December 31, 2020, our external costs for the development of Huntington’s disease were primarily related to the execution of our Phase I/II clinical trial as well as expenses related to the procedures of the first two patients in June 2020.

In the year ended December 31, 2019, our external costs for the development of Huntington’s disease were primarily related to the preparation of our Phase I/II clinical trial.

During 2018 and 2017, the majority of costs were related to the planning and execution of a GLP toxicology study.

During 2018, the majority of costs were related to the planning and execution of a GLP toxicology study.

In addition, we incurred cost related to the filing of our IND in late 2018 and early 2019.

In the year ended December 31, 2017, we primarily incurred cost related to various preclinical research activities.

Preclinical programs & platform development

In the year ended December 31, 2019, we incurred $5.7 million of costs related to related to our preclinical activities for product candidates including Hemophilia A (AMT-180), SCA3 (AMT-150) and Fabry (AMT-190) and enhancement of our technology compared to $2.5 million in 2018 and $5.8 million in 2017

In the year ended December 31, 2020, we incurred $6.5 million of costs related to related to our preclinical activities for product candidates including Hemophilia A (AMT-180), SCA3 (AMT-150) and Fabry disease (AMT-190), as well as various other research programs and technology innovation projects compared to $5.7 million in 2019 and $2.5 million in 2018.

Other research & development expenses

● We incurred $41.7 million in employee and contractor expenses in the year ended December 31, 2020 compared to $34.0 million in 2019 and $28.9 million in 2018.

Our cost increased in 2019 by $5.1 million primarily as a result of the recruitment of personnel to support the preclinical and clinical development of our product candidates.

Our cost increased in 2018 by $0.8 million primarily because of new personnel added during the year in our manufacturing and development organizations;

Our cost increased in 2020 by $7.7 million compared to 2019 as a result of the recruitment of personnel to support the preclinical and clinical development of our product candidates.

For the same reason our costs increased by $5.1 million in 2019 compared to 2018;

● We incurred $12.0 million in share-based compensation expenses in the year ended December 31, 2020 compared to $8.1 million in 2019 and $4.0 million in 2018.

The increase in 2020 compared to 2019 of $3.9 million was primarily driven by grants to newly recruited personnel as well as share-based compensation expenses recorded in relation to the termination of one of our executives.

The increase in 2019 compared to 2018 of $4.1 million was driven primarily by the appreciation of our share price and increase in number of grants;

1 unchanged sentence

The increase in 2020 compared to 2019 of $2.2 million primarily relates to extending and expanding (as of June 2019) the lease of our Lexington facility.

The decrease in 2018 compared to 2017 of $1.4 million was largely the result of our decision to sublet part of our Amsterdam facility in 2018, as well as the costs incurred in 2017 from the termination of lease contracts associated with our former Amsterdam facilities;

● We recorded no expenses associated with termination benefits attributable to our November 2016 restructuring in 2019, compared to $0.1 million in 2018 and $1.8 million in 2017;

● We recorded no results related to a change in the fair value of the contingent consideration owed to the sellers of the InoCard business, compared to an income of $3.8 million in 2018 and compared to an expense of $3.0 million in 2017;

● We incurred no impairment losses in 2019, compared to an impairment loss of $5.4 million on the in-process research and development asset acquired in the InoCard business combination in 2018.

We recorded no such charge in 2017;

● We incurred $10.7 million in costs compared to $10.1 million in 2018 and $8.9 million in 2017 related to disposables that we consume to produce materials to conduct our pre-clinical and clinical trials and other expenses.

The increase in 2019 compared to 2018 of $2.2 million also primarily relates to extending and expanding (as of June 2019) the lease of our Lexington facility;

● We incurred $10.2 million in costs in the year ended December 31, 2020 compared to $8.8 million in the year ended December 31, 2019 and $9.5 million in the year ended December 31, 2018 related to miscellaneous other costs we incur as a result of expanding our organization;

● We incurred $6.2 million in other expenses in the year ended December 31, 2020 compared to $2.0 million in 2019 and $0.6 million in 2018.

The increase in 2020 compared to 2019 of $4.2 million primarily relates to license payments of $3.4 million that we determined during 2020 to have no alternative future use.

The increase in 2019 compared to 2018 of $1.4 million primarily relates to extending and expanding (as of June 2019) the lease of our Lexington facility;

● We recorded no results related to a change in the fair value of the contingent consideration owed to the sellers of the InoCard business in the years ended December 31, 2020 and 2019 compared to a gain of $3.8 million in 2018;

● We incurred no impairment losses in the years ended December 31, 2020 and 2019 compared to an impairment loss of $5.4 million on the in-process research and development asset acquired in the InoCard business combination in 2018.

Selling, general and administrative expenses

1 unchanged sentence

We incur expenses associated with operating as a public company, including expenses for personnel, legal, accounting and audit fees, board of directors’ costs, directors' and officers' liability insurance premiums, Nasdaq listing fees, expenses related to investor relations and fees related to business development and maintaining our patent and license portfolio.

Our selling costs in 2019 include employee expenses as well as professional fees related to the preparation of a commercial launch of etranacogene dezaparvovec.

Our selling costs include employee expenses as well as professional fees related to the preparation of a commercial launch of etranacogene dezaparvovec.

Selling, general and administrative expenses for the year ended December 31, 2020 were $42.6 million, compared to $33.5 million and $25.3 million for the years ended December 31, 2019 and 2018, respectively.

● We incurred $13.6 million in personnel and consulting expenses in 2020 compared to $10.5 million in 2019 and $8.9 million in 2018.

The increase of $1.6 million in 2019 compared to 2018 was primarily driven by an increase in personnel and consulting related expenses to support our growth;

The increase of $3.1 million in 2020 compared to 2019 and the increase of $1.6 million in 2019 compared to 2018 was primarily driven by an increase in personnel and consulting related expenses to support our growth;

● We incurred $9.8 million of share-based compensation expenses in 2020 compared to $9.4 million in 2019 and $6.7 million in 2018.

The increase in 2019 compared to 2018 of $2.7 million was primarily driven by the appreciation of our share price and increase in number of grants.

The increase in 2018 compared to 2017 of $0.4 million is primarily related to the appreciation of our share price;

The increase in 2020 compared to 2019 of $0.4 million was primarily driven by newly recruited personnel and the increase in 2019 compared to 2018 of $2.7 million was primarily driven by the appreciation of our share price and increase in number of grants;

● We incurred $8.0 million in professional fees in 2020 compared to $6.0 million in 2019 and $4.2 million in 2018.

We regularly incur accounting, audit and legal fees associated with operating as a public company.

Additionally, in the year ended December 31, 2020, we incurred professional fees in relation to our licensing transaction with CSL Behring.

Other items, net

2 unchanged sentences

We present expenses related to such income as other expense.

Following the termination of our collaboration with Chiesi in July 2017, we recognized $13.8 million of income that was previously treated as deferred revenue.

We recognized no such income in 2019 and 2018.

In 2017, we recognized other expense of $1.7 million related to our decision to not seek renewal of the marketing authorization for the Glybera program, as well as the termination of our collaboration agreements with Chiesi.

We did not recognize any such expenses in 2019 or 2018.

In 2017, we accrued $0.6 million in contract termination costs related to vacated facilities at our Amsterdam site.

We did not recognize any such expenses in 2019 or 2018.

In 2017, we accrued $0.8 million related to various exit activities conducted during the year.

We did not recognize any such expenses in 2019 or 2018.

Other non-operating items, net

2 unchanged sentences

We recognize foreign exchange results related to changes in these foreign currencies.

We issued warrants to Hercules and lenders of a convertible loan in 2013 and to BMS in 2015.

We issued warrants to Hercules in 2013 and to BMS in 2015.

We recognize changes in the fair value of these warrants within other non-operating income / (expense).

Following the termination of the BMS warrants on December 1, 2020, we no longer recognize changes in the fair value of these warrants within other non-operating (expense) / income.

As of the same date, we recognized a derivative financial liability related to the CoC-payment .

Following the exercise of the warrants by Hercules in February 2019 we no longer recognize changes in the fair value of these warrants within other non-operating (expense) / income.

5 unchanged sentences

Foreign currency (losses) / gains, net

Other non-operating (losses) / gains, net

Total non-operating income, net

We raised $85.3 million in October 2017, $138.4 million in our May 2018 and $242.7 million in our September 2019 public follow-on offering.

The resulting increase in our cash on hand increased our interest income in the year ended December 31, 2019 to $3.5 million compared to $2.7 million in 2018 and $0.1 million in 2017.

In 2019, we recognized a net foreign currency loss of $0.3 million related to our borrowings from Hercules and our cash and cash equivalents, compared to a net gain of $4.4 million in 2018 and a net loss of $3.6 million in 2017.

In 2019, we recognized a $2.5 million loss related to fair value changes of warrants, compared to a gain of $0.2 million in 2018 and a loss of $2.2 million in 2017.

The loss is primarily driven by the increase in fair value of the BMS warrants.

Other non-operating gains / (losses), net

Total non-operating income / (loss), net

We recognized $0.9 million interest income in 2020, $3.5 million in 2019 and $2.7 million in 2018.

Our interest income in 2020 decreased by $2.6 million compared to 2019 due to a reduction in market interest rates in 2020 as well as a reduction in cash and cash equivalents.

Our interest income in 2019 increased by $0.8 million as a result of an increase in our cash and cash equivalents through our September 2019 $242.7 million public follow-on offering.

We recognized $3.8 million interest expense in 2020, $3.8 million in 2019 and $2.2 million in 2018.

Our interest income in 2020 was unchanged compared to 2019 as our outstanding debt remained unchanged.

Our interest expense in 2019 increased by $1.6 million as we increased our outstanding debt from $20.0 million to $35.0 million on December 6, 2018.

In 2020, we recognized a net foreign currency loss of $13.6 million related to our borrowings from Hercules and our cash and cash equivalents as well as loans between entities within the uniQure group, compared to a net loss of $0.3 million in 2019 and a net gain of $4.4 million in 2018.

In 2020, we recognized a $0.5 million net gain related to fair value changes of derivative financial instruments, compared to a net loss of $2.5 million in 2019 and a gain of $0.2 million in 2018.

The changes in 2020 compared to 2019 result from a $3.1 million gain that we recognized related to fair value changes of the BMS warrants (compared to $2.5 million loss in 2019), which includes an $0.8 million gain that we recognized related to the termination of the BMS warrants in December 2020, and a loss of $2.6 million to recognize the derivative financial liability for the CoC-payment on December 1, 2020.

We recognized $16.4 million of deferred tax income in 2020, $0.0 million in 2019 and income tax expense of $0.2 million in 2018.

Deferred tax income recorded in 2020 results from the release of the valuation allowance recorded for our net deferred tax assets by our U.S.

We did not record changes in valuation allowances in 2019 and 2018.

Financial Position, Liquidity and Capital Resources

As of December 31, 2020, we had cash, cash equivalents and restricted cash of $247.7 million.

We currently expect that our cash and cash equivalents will be sufficient to fund operations into mid-2022.

We believe our cash and cash equivalents as of December 31, 2020, combined with the $100.0 million 2021 Amended Facility will enable us to fund our operating expenses, including our debt repayment obligations, as they become due and capital expenditure requirements into the second half of 2022.

In the event that we receive the $450.0 million payment due on the closing of the CSL Behring Agreement, we expect that our cash and cash equivalents will be sufficient to fund operations into the second half of 2024 (assuming a full repayment of funds borrowed from Hercules under our term loan facility by 2023).

The table below summarizes our consolidated cash flow data for the years ended December 31:

7 unchanged sentences

Cash, cash equivalents and restricted cash at the end of period

We have incurred losses and cumulative negative cash flows from operations since our business was founded by our predecessor entity AMT Therapeutics Holding N.V.

(“AMT”) in 1998.

We have incurred losses and cumulative negative cash flows from operations since our business was founded by our predecessor entity AMT in 1998.

We had a net loss of $125.0 million in 2020, $124.2 million in 2019, and $83.3 million in 2018.

5 unchanged sentences

On December 6, 2018, we signed an amendment to the Second Amended and Restated Loan and Security Agreement (the “2018 Amended Facility”) that both refinanced our existing $20 million credit facility and provided us with an additional commitment of $30 million (of which $15 million is subject to the discretion of Hercules).

On December 6, 2018, we signed an amendment to the Second Amended and Restated Loan and Security Agreement (the “2018 Amended Facility”) with Hercules that both refinanced our then-existing $20.0 million credit facility and provided us with an additional unconditional commitment of $15.0 million as well as a conditional commitment of $15.0 million that expired on June 30, 2020.

At signing, we drew down an additional $15.0 million, for a total outstanding amount of $35.0 million.

We have the right to draw another $15 million through June 30, 2020 subject to the terms of the 2018 Amended Facility.

The 2018 Amended Facility extends the loan’s maturity date until June 1, 2023.

The 2018 Amended Facility extended the loan’s maturity date until June 1, 2023.

The interest-only period was initially extended from November 2018 to January 1, 2021.

The interest-only period was further extended to January 1, 2022 as a result of meeting the provision in the 2018 Amended Facility of raising more than $90.0 million in equity financing.

We met this provision as a result of the follow-on public offering completed in September 2019.

As of December 31, 2019, $35 million was outstanding under the 2018 Amended Facility (2018:

The interest-only period was further extended to January 1, 2022 as a result of raising more than $90.0 million in equity financing in September 2019.

As of December 31, 2020, $35.0 million was outstanding under the 2018 Amended Facility (December 31, 2019:

$35.0 million).

We are required to repay the facility in equal monthly installments of principal and interest between the end of the interest-only period and the maturity date.

We are required to repay the f acility in equal monthly installments of principal and interest between the end of the interest-only period and the maturity date.

The variable interest rate is equal to the greater of (i) 8.85% or (ii) 8.85% plus the prime rate less 5.50%.

Under the 2018 Amended Facility, we paid a facility fee equal to 0.50% of the $35,000,000 loan outstanding and will owe a back-end fee of 4.95% of the outstanding debt.

On January 29, 2021 we and Hercules entered into the 2021 Amended Facility.

Pursuant to the 2021 Amended Facility, Hercules agreed to 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.

On May 7, 2018, we completed a follow-on public offering of 5,175,000 ordinary shares at a public offering price of $28.50 per ordinary share, resulting in gross proceeds to us of $147.5 million.

1 unchanged sentence

We deducted $0.2 million of expenses incurred related to this offering from additional paid-in capital in the accompanying consolidated balance sheet and reflected this within the proceeds from public offering of shares, net of issuance costs with the cash flows from financing activities.

On October 27, 2017, we completed a follow-on public offering of 5,000,000 ordinary shares at a public offering price of $18.25 per ordinary share, resulting in gross proceeds to us of $91.3 million.

The net proceeds from this offering were $85.3 million, after deducting underwriting discounts and commissions and other offering expenses payable by us.

We deducted $0.5 million of expenses incurred related to this offering from additional paid-in capital in the accompanying consolidated balance sheet and reflected this within the proceeds from public offering of shares, net of issuance costs with the cash flows from financing activities.

We expect to continue to incur losses and to generate negative cash flows.

We have no firm sources of additional funding.

Until such time, if ever, as we can generate substantial cash flows from successfully commercializing our product candidates, we expect to finance our cash needs through a combination of equity offerings, debt financings, collaborations, strategic alliances and marketing, distribution and licensing arrangements.

We are subject to covenants under our 2018 Amended Facility and may become subject to covenants under any future indebtedness that could limit our ability to take specific actions, such as incurring additional debt, making capital expenditures or declaring dividends, which could adversely impact our ability to conduct our business.

In addition, our pledge of assets as collateral to secure our obligations under the 2018 Amended Facility may limit our ability to obtain debt financing.

documentation, as well as credit and debt market conditions, and we may not be able to obtain such financing on terms acceptable to us or at all.

The $450.0 million upfront payment we expect to receive on the closing of the CSL Behring Agreement would fund operations into the second half of 2024 (assuming a full repayment of funds borrowed from Hercules under our term loan facility by 2023).

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

We expect to generate positive cash flows in the period of closing and to recognize material revenue related to the CSL Behring Agreement.

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

Until such time, if ever, as we can generate substantial cash flows from successfully commercializing our proprietary product candida tes, we expect to finance our cash needs through a combination of equity offerings, debt financings, collaborations, strategic alliances and marketing, distribution, and licensing arrangements.

We are subject to the same covenants under our 2018 Amended Facility and 2021 Amended Facility and may become subject to covenants under any future indebtedness that could limit our ability to take specific actions, such as incurring additional debt, making capital expenditures, or declaring dividends, which could adversely impact our ability to conduct our business.

In addition, our pledge of assets as collateral to secure our obligations under the 2018 Amended Facility and 2021 Amended Facility may limit our ability to obtain debt financing.

To the extent we need to finance our cash needs through equity offerings or debt financings, such financing may be subject to unfavorable terms including without limitation, the negotiation and execution of definitive documentation, as well as credit and debt market conditions, and we may not be able to obtain such financing on terms acceptable to us or at all.

If financing is not available when needed, including through debt or equity financings, or is available only on unfavorable terms, we may be unable to meet our cash needs.

2 unchanged sentences

Net Cash used in operating activities

Year ended December 31,

(in thousands)

Cash flows from operating activities

Adjustments to reconcile net loss to net cash used in operating activities:

Depreciation, amortization, and impairment losses

Share-based compensation expense

Change in fair value of derivative financial instruments and contingent consideration

Unrealized foreign exchange losses / (gains)

Deferred tax (income) / expense

Change in lease incentives

Change in deferred revenue

Changes in operating assets and liabilities:

Accounts receivable and accrued income, prepaid expenses, and other current assets

Accounts payable

Accrued expenses, other liabilities, and operating leases

Net cash used in operating activities

Net cash used in operating activities was $134.8 million for the annual period ended December 31, 2020, and consisted of a net loss of $125.0 million adjusted for non-cash items, including depreciation and amortization expense of $10.6 million, share-based compensation expense of $21.8 million, fair value gain of derivative financial instruments of $0.5 million, unrealized foreign exchange loss of $14.7 million, a change in deferred tax income of $16.4 million and a decrease in unamortized deferred revenue of $33.6 million.

Net cash used in operating activities also included unfavorable changes in operating assets and liabilities of $6.5 million.

These changes primarily related to a net increase in accounts receivable and accrued income, prepaid expenses, and other current assets of $7.0 million and a net increase in accounts payable, accrued expenses, other liabilities, and operating leases of $0.5 million.

Net cash used in operating activities was $98.7 million for the annual period ended December 31, 2019, and

1 unchanged sentence

Net cash used in operating activities also included changes in operating assets and liabilities of $2.9 million.

These changes primarily related to a net increase in accounts receivable and accrued income, prepaid expenses and other current assets of $4.8 million and a net increase in accounts payable, accrued expenses, other liabilities and operating leases of $7.7 million primarily related to our etranacogene dezaparvovec and AMT-130 clinical trials.

Net cash used in operating activities was $76.0 million for the annual period ended December 31, 2018, and

consisted of a net loss of $83.3 million adjusted for non-cash items, including depreciation and amortization expense of $12.4 million, share-based compensation expense of $10.7 million, fair value gain of derivative financial instruments and contingent consideration of $4.1 million, unrealized foreign exchange gain of $5.5 million, deferred tax of $0.2 million, a decrease in lease incentives of $0.3 million, and a decrease in unamortized deferred revenue of $8.5 million.

Net cash used in operating activities also included changes in operating assets and liabilities of $2.3 million.

These changes primarily related to a net increase in accounts receivable and accrued income, prepaid expenses, and other current assets of $4.8 million and a net increase in accounts payable, accrued expenses, other liabilities, and operating leases of $7.7 million primarily related to our clinical trials and facilities.

Net cash used in operating activities was $76.0 million for the annual period ended December 31, 2018, and

consisted of a net loss of $79.3 million adjusted for non-cash items, including depreciation and amortization expense of $7.5 million, share-based compensation expense of $10.3 million, fair value loss of derivative financial instruments and contingent consideration of $5.2 million, unrealized foreign exchange loss of $4.2 million, deferred tax of $0.2 million, an increase in lease incentives of $2.2 million, and a decrease in unamortized deferred revenue of $21.1 million.

Net cash used in operating activities also included changes in operating assets and liabilities of $6.4 million.

consisted of a net loss of $83.3 million adjusted for non-cash items, including depreciation and amortization expense of $12.4 million, share-based compensation expense of $10.7 million, fair value gain of derivative financial instruments and contingent consideration of $4.1 million, unrealized foreign exchange loss of $5.5 million, deferred tax of $0.2 million, an increase in lease incentives of $0.3 million, and a decrease in unamortized deferred revenue of $8.5 million.

Net cash used in operating activities also included changes in operating assets and liabilities of $2.3 million net.

Net cash used in investing activities

4 unchanged sentences

Build out of Amsterdam site

Acquisition of licenses and patents

Acquisition of licenses, patents and other rights

Total investments

In 2020, we invested $2.7 million in our facility in Lexington compared to $4.2 million in 2019 and $1.6 million in 2018.

Our investments in 2019 primarily relate to improvements we made to the additional space rented as from June 1, 2019.

Our investments in 2019 primarily relate to improvements we made to the additional space rented from June 1, 2019.

In 2020, we invested $4.5 million in our facility in Amsterdam compared to $1.5 million in 2019 and $0.8 million in 2018.

Our investments in 2020 primarily relate to the construction of additional laboratories to support the expansion of our preclinical activities.

Net cash generated from financing activities

We received net proceeds of $242.7 million associated with our public follow-on offering in September 2019, $138.4 million associated with our public follow-on offering in May 2018 and $85.3 million associated with our public follow-on offering in October 2017.

We received net proceeds of $242.7 million associated with our public follow-on offering in September 2019 and $138.4 million associated with our public follow-on offering in May 2018.

We received net proceeds of $0.5 million associated with the exercise of the Hercules warrants by Hercules in February 2019.

1 unchanged sentence

In 2020, we received $7.4 million from the exercise of options to purchase ordinary shares issued in accordance with our share incentive plans, compared to $5.6 million in 2019 and $4.8 million in 2018.

In 2017, we paid $0.6 million contingent consideration in relation to our 2014 acquisition of the InoCard business.

No such disbursements were made in 2019 and 2018.

Funding requirements

We believe our cash and cash equivalents as of December 31, 2019 will enable us to fund our operating expenses including our debt repayment obligations as they become due and capital expenditure requirements into mid-2022.

We believe our cash and cash equivalents as of December 31, 2020, combined with the $100.0 million 2021 Amended Facility, will enable us to fund our operating expenses, including our debt repayment obligations, as they become due and capital expenditure requirements into the second half of 2022.

In the event that we receive the $450.0 million payment due on the closing of the CSL Behring Agreement, we expect that our cash and cash equivalents would be sufficient to fund operations into the second half of 2024 (assuming a full repayment of funds borrowed from Hercules under our term loan facility by 2023).

Our future capital requirements will depend on many factors, including but not limited to:

● the closing of the transaction contemplated by the CSL Behring Agreement as well as achieving the milestones and royalties as defined therein;

● the cost and timing of future commercialization activities, including product manufacturing, marketing, sales, and distribution of any of our product candidates for which we receive marketing approval in the future;

● the amount and timing of revenue, if any, we receive from commercial sales of any product candidates for which we, or any collaboration partner, receive marketing approval in the future;

● the amount and timing of revenue, if any, we receive from commercial sales of any product candidates for which we, or our collaboration partner, receives marketing approval in the future;

● the scope, timing, results, and costs of our current and planned clinical trials, including those for etranacogene dezaparvovec in hemophilia B and AMT-130 in Huntington’s disease;

1 unchanged sentence

● the need for additional resources and related recruitment costs to support the preclinical and clinical development of our product candidates;

● the need for any additional tests, studies, or trials beyond those originally anticipated to demonstrate the safety or efficacy of our product candidates and technologies;

● the need for any additional tests, studies, or trials beyond those originally anticipated to confirm the safety or efficacy of our product candidates and technologies;

● the cost, timing and outcome of regulatory reviews associated with our product candidates;

1 unchanged sentence

● the costs and timing of preparing, filing, expanding, acquiring, licensing, maintaining, enforcing, and prosecuting patents and patent applications, as well as defending any intellectual property-related claims;

● the repayments of the principal amount of our venture debt loan with Hercules, which will contractually start in January 2022 and will run through June 2023;

● the repayments of the principal and other fees associated with our venture debt loan with Hercules, which following the January 29, 2021 amendment will be due in June 2023;

● the extent to which we acquire or in-license other businesses, products, product candidates or technologies;

● the costs associated with maintaining quality compliance and optimizing our manufacturing processes, including the operating costs associated with our Lexington, Massachusetts manufacturing facility;

● the costs associated with increasing the scale and capacity of our manufacturing capabilities;

● the costs associated in preparing for the BLA submission of etranacogene dezaparvovec, including process validation, inspection readiness and other regulatory expenses in the event that our collaboration and license agreement with CSL Behring does not close.

Contractual obligations and commitments

The table below sets forth our contractual obligations and commercial commitments as of December 31, 2020, that are expected to have an impact on liquidity and cash flows in future periods.

The obligations to repay debt do not reflect the extension of the interest-only period that we and Hercules agreed upon on January 29, 2021.

(in thousands)

3 unchanged sentences

We have not included these commitments on our balance sheet or in the table above because the achievement and timing of these milestones is not fixed and determinable.

We enter into contracts in the normal course of business with clinical research organizations (“CROs”) for preclinical research studies and clinical trials, research supplies and other services and products for operating purposes.

We will also have obligations to make future payments that become due and payable if we collect the upfront payment or milestone payments from CSL Behring.

We have not included these commitments on our balance sheet or in the table above because these payments only become due and payable upon the closing of the transaction with CSL Behring.

We enter into contracts in the normal course of business with CROs for preclinical research studies and clinical trials, research supplies and other services and products for operating purposes.

These contracts generally provide for termination on notice, and therefore are cancelable contracts and not included in the table of contractual obligations and commitments.

2 unchanged sentences

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 7. Management’s Discussion and Analysis