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Item 1. Business

2024-02-28 compared with 2023-02-27 · 361 added, 333 removed, 629 unchanged (52% of the section changed)

We are a leader in the field of gene therapy and seek to deliver to patients suffering from rare and other devastating diseases single treatments with potentially curative results.

We are advancing a pipeline of innovative gene therapies, including our clinical candidate for the treatment of Huntington’s disease and amyotrophic lateral sclerosis (“ALS”) as well as preclinical product candidates, including candidates for the treatment of refractory temporal lobe epilepsy (“rTLE”) and Fabry disease.

In November 2022 and February 2023, our internally-developed HEMGENIX Ô , a gene therapy for the treatment of hemophilia B, was approved for commercialization by the United States Food and Drug Administration (“FDA”) and the European Medicines Agency (“EMA”), respectively.

In June 2020, we agreed to license HEMGENIX Ô to CSL Behring LLC (“CSL Behring”), which is now responsible for the commercialization of HEMGENIX Ô .

We are manufacturing HEMGENIX Ô for CSL Behring and are entitled to specific milestone payments and royalties on net sales.

We believe our validated technology platform and manufacturing capabilities provide us distinct competitive advantages, including the potential to reduce development risk, cost, and time to market.

We produce our Adeno-associated virus (“AAV”) -based gene therapies in our own facilities with a proprietary, commercial-scale, current good manufacturing practices (“cGMP”)-compliant, manufacturing process.

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

CSL Behring collaboration

On June 24, 2020 (the “Signing Date”), uniQure biopharma B.V., a wholly owned subsidiary of uniQure N.V., entered into a commercialization and license agreement (the “CSL Behring Agreement”) with CSL Behring, pursuant to which CSL Behring received exclusive global rights to etranacogene dezaparvovec (the “Product”).

The transaction became fully effective in May 2021 (the “Closing”).

In March and April 2022, CSL Behring submitted marketing applications for the Product in the United States (“U.S.”) and European Union (“EU”).

In March and April 2022, we received the $55.0 million owed to us by CSL Behring related to the submission of these marketing applications.

In November 2022, the FDA approved the marketing application for the U.S., and in February 2023 the EMA approved the marketing application for the EU.

We are eligible to receive a $100.0 million payment from CSL Behring following the first sale of the Product in the U.S.

We are also eligible to receive a $75.0 million payment from CSL Behring following the first sale of the Product in any of five major European countries, namely France, Germany, Italy, Spain, and the United Kingdom, provided the first sale occurs prior to July 2, 2023.

We recorded the $100.0 million milestone payment we are eligible to receive from CSL Behring associated with the first sale in the U.S.

as license revenue in the year ended December 31, 2022, as we expect this event to occur in 2023.

We did not record license revenue related to a $75.0 million payment in the year ended December 31, 2022, as the accomplishment of this milestone prior to July 2, 2023 is contingent on factors outside our control.

We are eligible to receive up to $1.3 billion in additional commercial milestones, and tiered double-digit royalties of up to a low-twenties percentage of net product sales arising from the Product.

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

We are advancing a focused pipeline of innovative gene therapies, including our clinical candidates for the treatment of Huntington’s disease, amyotrophic lateral sclerosis (“ALS”), refractory mesial temporal lobe epilepsy (“MTLE”) and Fabry disease.

Our internally developed HEMGENIX®, a gene therapy for the treatment of hemophilia B, has been approved for commercialization by the United States Food and Drug Administration (the “FDA”) and the European Medicines Agency (“EMA”).

The approval of HEMGENIX® follows more than a decade of research and clinical development, represents a major milestone in the field of gene therapy and ushers in a new treatment approach for patients living with hemophilia B.

We license HEMGENIX® to CSL Behring LLC (“CSL Behring”), which is responsible for its commercialization.

We are manufacturing HEMGENIX® for CSL Behring and are entitled to specific milestone payments and royalties on net sales of the product, a portion of which we sold to a royalty acquisition company in 2023 in exchange for up-front cash.

We believe our validated technology platform and manufacturing capabilities provide us with distinct competitive advantages, including the potential to reduce development risk, cost, and time to market.

We produce our adeno-associated virus-based gene therapies in our own facilities with a proprietary, current good manufacturing practices (“GMP”) -compliant manufacturing process.

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

A summary of our key development programs is provided below:

Recent Product Candidate Developments

Huntington’s disease program (AMT-130)

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

We are currently conducting a randomized, controlled and blinded Phase I/II clinical trial for AMT-130 in the U.S.

The lower-dose cohort of this trial includes 10 patients, of which six patients received treatment with AMT-130 and four patients received imitation surgery.

The higher-dose cohort includes 16 patients, of which 10 patients received treatment with AMT-130 and six patients received imitation surgery.

Patients receiving imitation surgery have the option to cross over after 12 months if they meet the inclusion criteria for the study.

We are also conducting an open-label Phase Ib/II study in the EU, which includes six patients in the lower-dose cohort and nine patients in the higher-dose cohort.

All 15 patients in the EU study will receive AMT-130.

On March 21, 2022, we announced that we completed the enrollment of all 26 patients in the first two cohorts of our Phase I/II clinical trial of AMT-130 in the U.S.

In July 2022, we began crossing over patients who received the imitation surgical procedure.

On June 23, 2022, we announced safety and biomarker data from the 10 patients enrolled in the low-dose cohort.

At 12 months of follow-up on the patients in the low-dose cohort:

● AMT-130 was generally well-tolerated with no serious adverse events related to AMT-130 reported in the treated patients.

There were two serious adverse events unrelated to AMT-130, including a deep-vein thrombosis in the elbow of one patient that was resolved with anticoagulants and transient post-operative delirium in the second patient that was resolved through supportive care.

● In the four treated patients with evaluable data, mean levels of mutant Huntingtin protein in the cerebral spinal fluid (“CSF mHTT”) declined at all timepoints compared to baseline, and decreased by 53.8% at 12 months of follow-up (range from 44% decrease to 71% decrease).

In the three control patients with evaluable data, mean levels of CSF mHTT showed an increase compared to baseline at one, three, six and nine months of follow-up, and decreased by 16.8% compared at 12 months of follow-up (range 35% increase to 47% decrease).

● In the six treated patients, measurements of neurofilament light chain in the cerebral spinal fluid (“CSF NfL”), a biomarker of neuronal damage, initially increased as expected following the AMT-130 surgical procedure and declined thereafter, nearing baseline at 12 months of follow-up.

At 12 months, mean CSF NfL showed an 8% increase compared to baseline (range 46% increase to 14% decrease).

Two of the six treated patients were at or below baseline at 12 months of follow-up, with an additional patient below baseline at 15 and 18 months of follow-up.

In the four control patients, mean CSF NfL remained stable or slightly declined over 12 months (range 1% increase to 35% decrease).

Also on June 23, 2022, we announced that 10 patients in our Phase Ib/II study in the EU had been treated with AMT-130.

In August 2022, we announced a voluntary postponement of AMT-130 higher-dose procedures due to suspected unexpected severe adverse reactions (“SUSARs”) reported in three of the 14 patients that were treated with the higher dose of AMT-130.

In October 2022, after completing a comprehensive safety investigation, the Data Safety Monitoring Board (“DSMB”) recommended resuming treatment at the higher dose of AMT-130 for the remaining five European patients and any patients in the U.S.

trial eligible to cross over from the control arm to the treatment.

All three patients have experienced full resolution of the reported SUSARs.

Preclinical programs

In May 2022, we presented certain preclinical findings on our gene therapy candidates for refractory temporal lobe epilepsy, Fabry disease, Parkinson’s disease, Amyotrophic lateral sclerosis, and Alzheimer’s disease at the American Society of Gene and Cell Therapy Hybrid Congress.

In July and August 2022, respectively, we initiated Investigational New Drug-enabling (“IND-enabling”), Good Laboratory Practice (“GLP”) toxicology studies in non-human primates for our gene therapy candidates in rTLE and Fabry disease.

In November 2022, we hosted a virtual investor event focused on the target candidate for the treatment of temporal lobe epilepsy (“AMT-260”).

The presentation highlighted preclinical data on AMT-260 and our initial plans for clinical development, as well as our miQURE™ and linQURE™ technology platforms that utilize micro ribonucleic acids (“miRNAs”) to reduce the expression of abhorrent genes.

We also highlighted our progress in developing a commercial-scale AAV manufacturing platform.

Termination of Bristol-Myers Squibb Agreement

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

BMS had initially designated four Collaboration Targets in 2015.

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 (the “Amended BMS CLA”).

The Amended BMS CLA did not extend the initial research term, and BMS did not replace any of the active Collaboration Targets.

On November 21, 2022, we received written notice that BMS was terminating the BMS CLA as amended (“Termination Notice”), effective on February 21, 2023 (“Termination Date”).

As a result of the termination of the BMS CLA, the contractually defined payment set for in the Amended BMS CLA that would have required us to make a payment to BMS in the event of a change of control transaction is of no further force or effect.

The Investor Agreement dated April 2015 between the Company and BMS remains in force according to its terms, but various provisions of the Investor Agreement have been terminated.

Amyotrophic Lateral Sclerosis (AMT-162)

On January 31, 2023, we announced that we have entered into a global licensing agreement for a one-time, intrathecally administered gene therapy for ALS with Apic Bio.

With this agreement, we have added to our pipeline of gene therapies to treat neurological disorders.

We made an initial cash payment of $10.0 million.

In addition, we will pay Apic Bio up to $43.0 million in milestones upon achievement of regulatory approvals in the U.S.

and Europe and pre-specified annual net sales, and a tiered royalty on net sales ranging from the mid-single digits to low double digits.

AMT-130 is our novel gene therapy candidate for the treatment of Huntington’s disease, which utilizes our proprietary, gene-silencing miQURE 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.

We are currently conducting a multi-center randomized, controlled, and blinded Phase I/II clinical trial for AMT-130 in the U.S.

in which 26 patients with early-manifest Huntington’s disease have been enrolled.

The low-dose cohort of this trial includes 10 patients, of which six patients received treatment with AMT-130 and four patients received imitation surgery.

The high-dose cohort includes 16 patients, of which 10 patients received treatment with AMT-130 and six patients received imitation surgery.

Patients in the high-dose cohort that received imitation surgery had the option to cross over after 12 months if they met the inclusion criteria for the study.

In July 2022, we began crossing over patients in the high-dose cohort who received the imitation surgical procedure.

Four of the six control patients in the high-dose cohort have been crossed over to treatment (three patients received the high dose and one patient received the low dose).

The remaining two control patients in the high-dose cohort did not meet all the inclusion criteria for the study and were not eligible for crossover.

All four crossover patients received a short course of immunosuppression therapy concurrent with the administration of AMT-130.

We are also conducting an open-label Phase Ib/II study in the EU and the United Kingdom, which has enrolled 13 patients with the same early-manifest criteria for Huntington’s disease as the U.S.

Six of these patients were treated with AMT-130 in the initial low-dose cohort and seven patients were treated in the subsequent high-dose cohort.

We completed the enrollment of all 26 patients in the first two cohorts of our Phase I/II clinical trial of AMT-130 in the U.S.

in March 2022.

In June 2022, we announced initial safety and biomarker data from 10 patients enrolled in the low-dose cohort of the ongoing U.S.

Phase I/II clinical trial of AMT-130.

In June 2023, we announced additional interim data from U.S.

Phase I/II clinical trial of AMT-130, including up to 24-month follow-up from the 26 patients enrolled.

In December 2023 we announced updated interim data, including up to 30 months of follow-up from 39 patients enrolled in the ongoing U.S.

and European Phase I/II clinical trials, as described in more detail below under “— Our Development of AMT-130 for Huntington’s Disease ”.

The combined U.S.

and European interim data were subject to a September 30, 2023 cut-off date and did not include outcome or biomarker data from the control patients who crossed over to treatment with AMT-130 following the 12-month core study period.

● AMT-130 was generally well tolerated with a manageable safety profile at both doses.

Serious adverse events (“SAE”) cases of CNS inflammation attributable to AMT-130 have improved with the administration of glucocorticoids.

● Patients treated with both doses of AMT-130 showed evidence of preserved neurologic function relative to pre-treatment baseline measurements and potential clinical benefit relative to a non-concurrent natural history cohort, based in each case on certain clinical and functional measurements.

● CSF NfL trends for the low-dose cohort remained below baseline through month 30 and CSF NfL for the high-dose cohort also further declined and was near baseline at month 18, together suggesting a reduction in neurodegeneration when compared to an expected increase from baseline in CSF NfL based on natural history data.

Mean changes in Mutant Huntingtin Protein (“mHTT”) levels measured in CSF samples compared to baseline continued to be variable and impacted by baseline levels near or below the lower limit of quantification.

● Brain volumetric changes did not appear to be clinically meaningful or associated with protracted increases in neurodegeneration as measured by NfL.

Amyotrophic Lateral Sclerosis program (AMT-162)

In January 2023, we announced that we had entered into a global licensing agreement with Apic Bio, Inc.

(“Apic Bio”) for a one-time, intrathecally administered investigational gene therapy for ALS caused by mutations in superoxide dismutase 1 (“SOD1”), a rapidly progressing, rare motor neuron disease that leads to loss of everyday functions and is uniformly fatal (previously known as APB-102).

Mutations in the SOD1 gene of ALS account for approximately one-fifth of all inherited forms of this fatal disease.

APB-102 is comprised of a recombinant AAVrh10 vector that expresses a miRNA designed to knock down the expression of SOD1 with the goal of slowing down or potentially reversing the progression of ALS in patients with SOD1 mutations.

The FDA has cleared the IND application for APB-102 and has granted Orphan Drug and Fast Track designation.

Other Business Developments

Reorganization

In October 2023, we announced the implementation of a reorganization plan (the “Reorganization”).

As a result of the Reorganization, we discontinued investments in more than half of our then-existing research programs, including AMT-210 for the treatment of Parkinson’s disease, and certain other technology projects.

Following the Reorganization, we are prioritizing advancing our clinical-stage programs, including referenced in the pipeline graphic above, to clinical proof of concept.

As a result of the Reorganization, which was completed in December 2023, we eliminated approximately 20% of our total workforce and closed our research laboratory in Lexington, Massachusetts.

As part of the Reorganization we consolidated all good manufacturing practices (“GMP”) manufacturing into our Lexington manufacturing facility and consolidated process and analytical development into our Amsterdam, Netherlands facility.

In addition, we appointed Richard Porter, Ph.D., who previously served as our Chief Business Officer, to serve as our Chief Business and Scientific Officer, effective as of October 2023.

Royalty Financing Agreement

In May 2023, we entered into a royalty purchase agreement (the “Royalty Purchase Agreement”) with HemB SPV, L.P.

(the “Purchaser”) for the sale of a portion of the royalty rights due to us from CSL Behring under the commercialization and license agreement we entered into with CSL Behring in June 2020 (the “Commercialization and License Agreement”).

Under the terms of the Royalty Financing Agreement, we received an upfront payment of $375.0 million in exchange for the Purchaser’s rights to the lowest royalty tier on CSL Behring’s worldwide net sales of HEMGENIX® for certain current and future royalties due to us.

We are also eligible to receive an additional $25.0 million milestone payment under the Royalty Financing Agreement if 2024 net sales of HEMGENIX® exceed a pre-specified threshold.

We retained the rights to all other royalties, as well as contractual milestones totaling up to $1.3 billion, under the terms of the CSL Behring Agreement.

See Note 14, “ Royalty Financing Agreement ” for additional information on the terms of the Royalty Purchase Agreement and payments thereunder.

Our Mission and Strategy

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Advance the development of AMT-130, a potential one-time gene-therapy approach for the treatment of Huntington’s disease.

AMT-130 is the first AAV-based gene therapy to enter clinical development for Huntington’s disease.

AMT-130 is the first AAV-based gene therapy that entered into clinical development for Huntington’s disease.

It consists of an AAV5 vector carrying an artificial miRNA specifically tailored to silence the huntingtin gene and leverages our proprietary miQURE™ silencing technology.

The therapeutic goal of AMT-130 is to inhibit the production of the mutant HTT protein.

In June 2022, we announced initial data from patients in the lower-dose cohort of the U.S.

Phase I/II study.

Patient enrollment is ongoing in the U.S.

Phase I/II study as well as an EU Phase Ib/II study.

We enrolled 39 patients into our U.S.

Phase I/II and our European Phase Ib/II clinical trials.

We announced preliminary results from these clinical trials in June 2022, June 2023 and December 2023.

Together, these studies are intended to establish safety, proof of concept, and the optimal dose of AMT-130.

In November 2023 we commenced enrollment of a third cohort to further investigate both doses in combination with perioperative immune suppression with a focus on evaluating near-term safety.

Up to 12 patients will be treated in this cohort, all of whom will receive AMT-130 using the current, established stereotactic neurosurgical delivery procedure.

We intend to use these additional data from our ongoing clinical trials to define our regulatory and ongoing clinical development strategy for AMT-130.

Advance our pipeline of clinical-stage gene therapy candidates.

The INDs for our product candidates AMT-260 for the treatment of MTLE, AMT-162 for the SOD1-ALS, and AMT-191 for the treatment of Fabry disease were accepted by the FDA in 2023.

We have initiated clinical trials for these three programs with the objective of generating initial safety and tolerability data and generating clinical proof-of concept.

Support the commercialization and global expansion of HEMGENIX ® .

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We will be supplying CSL Behring with HEMGENIX ® for a number of years.

We are eligible to receive up to $1.3 billion in additional commercial milestones, and tiered double-digit royalties of up to a low-twenties percentage of net product sales arising from HEMGENIX Ô .

Advance our pipeline of other preclinical and clinical-stage gene therapy candidates into first-in-human trials.

We expect to advance additional one-time administered gene therapy product candidates into clinical studies, including AMT-260 for the treatment of rTLE, AMT-162 for the treatment of superoxide dismutase 1 (“SOD1”)-ALS, and AMT-191 for the treatment of Fabry disease.

AMT-260 and AMT-162 utilize an AAV9 vector to deliver customized miRNAs to suppress the expression of the glutamate inotropic receptor kainate type subunit 2 (“GRIK2”) and SOD1 genes, respectively.

AMT-191 is an AAV5 gene therapy incorporating the α-galactosidase A (“GLA”) transgene.

Initiate additional gene therapy programs leveraging validated technologies and focused on central-nervous system (“CNS”) and other debilitating disorders.

We are leveraging proven enabling technologies, including AAV vectors, promoters, and manufacturing capabilities, to develop gene therapies that have the potential to be best or first-in-class.

Many of our gene therapy product candidates incorporate AAV5 or AAV9 vectors, which are currently being utilized in commercially available, approved gene therapies, as well as extensively studied in the clinical setting.

We believe AAV5 may potentially offer a favorable immunogenicity profile and the ability to confer therapeutic effect in patients with pre-existing antibodies.

We have also developed substantial know-how around optimizing delivery of gene therapies to the central nervous system and the liver, which can be leveraged across multiple product candidates.

Maintain our leadership position in commercial-scale AAV manufacturing.

We have established cGMP, commercial-scale manufacturing capabilities for AAV-based gene therapies in our commercially-licensed Lexington, Massachusetts facility and completed construction of a second cGMP manufacturing facility in Amsterdam, the Netherlands that complements our work in Lexington.

We believe our manufacturing platform enables us to rapidly produce new products for clinical investigation, minimize time between clinical phases and complete scale-up as product candidates advance into late-stage development and commercialization.

Invest in next-generation technologies with the goal of enhancing safety, improving efficacy, and expanding the applicability of gene therapy to patients.

Prioritize technology development on next-generation AAV capsids and novel cargo technologies.

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

These technologies include next-generation delivery approaches, such as smart AAV capsids potentially capable of improved CNS transduction and crossing the blood-brain barrier, as well as novel cargo technologies such as miQURE, our one-time administered gene silencing platform.

We are expanding our cargo platforms to include additional technologies, such as linkQURE to combine multiple miRNAs to suppress different genes, goQURE for simultaneous silencing of a disease gene and replacement with a healthy gene, and abQURE for the delivery of therapeutic antibodies.

We are also developing novel administration approaches, such as QUREDose, to enable dosing through neutralizing antibodies and re-dosing.

These various technologies are developed both in-house by our experienced research team in Amsterdam, the Netherlands, as well as via collaborations with third parties.

Continue to expand our intellectual property portfolio.

We have established what we believe is a leading intellectual property portfolio covering various aspects of our technology and programs, including (i) elements of our gene therapy constructs, such as AAV vectors, promoters and transgenes;

(ii) innovative delivery technologies, such as re-administration of AAV gene therapy;

and (iii) proprietary manufacturing processes covering key components of our upstream and downstream capabilities.

We expect to continue to expand our intellectual property portfolio by aggressively seeking patent protection for promising aspects of our technology platform and product candidates.

Our Product Candidates

A summary of our key development programs is provided below:

These technologies include next-generation delivery approaches, such as smart AAV capsids potentially capable of improved central nervous system (“CNS”) transduction and crossing the blood-brain barrier, as well as novel cargo technologies such as miQURE, our one-time administered gene silencing platform, linkQURE to combine multiple miRNAs to suppress different genes, and goQURE for simultaneous silencing of a disease gene and replacement with a healthy gene.

Central Nervous System Diseases

Huntington’s Disease

Huntington’s Disease and Market Background

Huntington’s disease is a severe genetic neurodegenerative disorder causing loss of muscle coordination, behavioral abnormalities, and cognitive decline, often resulting in complete physical and mental deterioration over a 12 to 15-year period.

The median survival time after onset is 15 to 18 years (range:

5 to >25 years).

Huntington’s disease is caused by an inherited defect in a single gene that codes for a protein called Huntingtin (“HTT”).

The estimated prevalence of Huntington’s disease is three to seven per 100,000 in the general population, similar in men and women, and it is therefore considered a rare disease.

Huntington’s disease mutation carriers can be identified decades before onset.

There is currently no available therapy that can delay onset or slow progression of the disease.

Although some symptomatic treatments are available, they only are transiently effective despite significant side effects.

Our Development of AMT-130 for Huntington’s Disease

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

AMT-130 utilizes our proprietary, gene-silencing miQURE 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.

We are currently conducting a Phase I/II clinical trial for AMT-130 in the U.S.

and a Phase Ib/II study in the EU.

Together, these studies are intended to establish safety, proof of concept, and the optimal dose of AMT-130.

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

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

(1) one-time administration of disease-modifying therapy into the striatum, the area of the brain where Huntington’s disease is known to manifest;

(2) biodistribution of the therapy in both the deep and cortical structures of the brain via transport of the AAV vector and through secondary exosome-mediated delivery;

(3) safe, on-target and durable knockdown of HTT and exon 1 HTT.

On March 21, 2022, we announced that we completed the enrollment of all 26 patients in the first two cohorts of our randomized, double-blinded, Phase I/II clinical trial of AMT-130 taking place in the U.S.

In the study, patients are randomized to either treatment with AMT-130 or to an imitation surgical procedure.

The treated patients have received a single administration of AMT-130 using MRI-guided, convection-enhanced stereotactic neurosurgical delivery directly into the striatum (caudate and putamen).

The trial consists of a blinded 12-month period followed by unblinded long-term follow-up for five years.

The lower-dose cohort includes 10 patients, of which six patients received treatment with AMT-130 and four patients received imitation surgery between June 19, 2020 and April 5, 2021.

The higher-dose cohort includes 16 patients, of which 10 patients received treatment with AMT-130 and six patients received imitation surgery between June 13, 2021 and March 21, 2022.

In July 2022, we began crossing over patients in the high-dose cohort who received the imitation surgical procedure.

Four of the six control patients in the high-dose cohort have been crossed over to treatment (three patients received the high dose and one patient received the low dose).

The remaining two control patients in the high-dose cohort did not meet all the inclusion criteria for the study and were not eligible for crossover.

All four crossover patients received a short course of immunosuppression therapy concurrent with the administration of AMT-130.

On June 23, 2022, we announced that in our open-label, Phase Ib/II study in Europe all six patients in the lower-dose cohort and five out of the nine patients in the higher-dose cohort had been treated with AMT-130.

On August 8, 2022, we announced a voluntary postponement of AMT-130 higher-dose procedures due to suspected unexpected serious adverse reactions (“SUSARs”) reported in three of the 14 patients that were treated with the higher dose of AMT-130.

In October 2022, after completing a comprehensive safety investigation, the DSMB recommended resuming treatment at the higher dose of AMT-130.

All three patients have experienced full resolution of the reported SUSARs.

following the investigation we have added additional risk mitigation procedures including closer patient monitoring during the first two weeks after the administration of AMT-130 and a seven-day, post-surgical in-person visit.

The DSMB recommended that the use of immunosuppression remain at the discretion of the treating physician.

On June 23, 2022, we announced safety and biomarker data from the 10 patients enrolled in the lower-dose cohort.

At 12 months of follow-up on the patients in the lower-dose cohort:

● AMT-130 was generally well-tolerated with no serious adverse events related to AMT-130 reported in the treated patients at the lower dose of 6x10 12 vector genomes;

● Measurements of CSF NfL increased as expected following the AMT-130 surgical procedure and approached baseline at 12 months;

● Measurements of mHTT protein in the CSF of evaluable treated patients showed potential decreases compared to baseline through 12 months

On June 21, 2023, we announced interim data, including up to 24-month follow-up, from 26 patients enrolled in the ongoing U.S.

Phase I/II clinical trial of AMT-130.

Efficacy and biomarker data from the crossover patients are not included in the following summary.

● AMT-130 continues to be generally well-tolerated across both dose cohorts;

● Patients treated with AMT-130 potentially show preserved function compared to baseline and clinical benefits relative to natural history of the disease;

● NfL in the CSF was below baseline at 24 months in patients treated with the low-dose of AMT-130 and declining towards baseline at 12 months in patients treated with the high-dose of AMT-130;

On December 19, 2023 ,we announced updated interim data, including up to 30 months of follow-up from 39 patients enrolled in the ongoing U.S.

and European Phase I/II clinical trials:

Safety and tolerability

We believe AMT-130 was generally well-tolerated, with a manageable safety profile in patients treated with the lower dose of 6x10 12 vector genomes and the higher dose of 6x10 13 vector genomes.

The most common adverse events in the treatment groups were related to the surgical procedure.

There were four serious adverse events (SAE) unrelated to AMT-130 (post-operative delirium, major depression, suicidal ideation and epistaxis) in the low-dose cohort, six unrelated SAEs in the high-dose cohort (back pain, hypothermia, post procedural hematoma, post-lumbar puncture syndrome (n=2), pulmonary embolism), and one SAE (deep vein thrombosis) in the control group.

In addition, there were four AMT-130-related SAEs in the high-dose cohort (central nervous system inflammation (n=3), and severe headache (n=1) that, retrospectively, also was attributable to central nervous system inflammation.

Patients with symptomatic central nervous system inflammation improved with glucocorticoid medication.

Additionally, six high-dose patients have received preoperative steroids with the administration of AMT-130 to reduce the risk of inflammation.

Exploratory efficacy data

Clinical and functional measurements for treated patients in each dose cohort were compared to baseline measurements, as well as to control patients (up to 12 months) and a non-concurrent criteria-matched natural history cohort.

The natural history cohort was developed by us in collaboration with the Cure Huntington’s Disease Initiative (CHDI) using the TRACK-HD natural history study of patients with early Huntington’s disease.

The cohort includes 31 patients that met our clinical trial inclusion criteria of i) total functional capacity, ii) diagnostic classification level and (iii) minimum striatal volumes.

● Updated clinical data through 30 months for the low-dose cohort and 18 months for the high-dose show ongoing evidence of potential dose-dependent clinical benefit relative to the non-concurrent criteria-matched natural history.

● For patients receiving the high dose, neurological function as measured by composite Unified Huntington’s Disease Rating Scale (“cUHDRS”) and each of its individual components was preserved or improved at 18 months compared to pre-treatment baseline measurements.

● For patients receiving the low dose, neurological function as measured by Total Motor Score (TMS) and Total Functional Capacity (TFC) was preserved at 30 months compared to pre-treatment baseline measurements.

● When compared to the expected rate of decline from the natural history cohort, AMT-130 showed favorable trends in cUHDRS, TFC and TMS.

AMT-130 showed a favorable difference in cUHDRS of 0.39 points at 30 months and 1.24 points at 18 months for the low- and high-dose, respectively (baseline values:

14.1 in low-dose and 14.9 in high-dose).

AMT-130 showed a favorable difference in TFC of 0.95 points at 30 months in the low-dose and 0.49 points at 18 months in the high-dose (baseline values:

11.9 in low-dose and 12.2 in high-dose).

AMT-130 showed a favorable difference in TMS of 2.80 points at 30 months in the low-dose and 1.70 points in the high-dose at 18 months (baseline values:

13.3 in low-dose and 12.1 in high-dose).

Biomarkers and Volumetric Imaging Data

Mean CSF NfL for the low-dose cohort remained below baseline through month 30 and was 6.6% below baseline.

Mean CSF NfL for the high-dose cohort also further declined and is near baseline at month 18.

These data suggest a reduction in neurodegeneration when compared to an expected increase from baseline in CSF NfL based on natural history data.

As expected, all patients treated with AMT-130 experienced a transient increase in CSF NfL related to the surgical procedure that peaked at approximately one month following the procedure and declined thereafter.

These transient increases were not dose dependent.

Given AMT-130 is directly administered deep within the brain, the pharmacodynamics of mHTT in the CSF are not believed to be materially representative of mHTT in the targeted brain regions.

Mean changes in mHTT levels measured in CSF samples compared to baseline continue to be variable and impacted by baseline levels near or below the lower limit of quantification.

Total Brain Volume :

Changes in the total brain volume of patients treated with AMT-130 were observed after the surgical procedure and trended below natural history.

The volumetric changes do not appear to be clinically meaningful or associated with protracted increases in neurodegeneration as measured by NfL.

In November 2023 we commenced enrollment of a third cohort to further investigate both doses in combination with perioperative immune suppression with a focus on evaluating near-term safety.

Up to 12 patients will be treated in this cohort, all of whom will receive AMT-130 using the current, established stereotactic neurosurgical delivery procedure.

Temporal Lobe Epilepsy Program (AMT-260)

Temporal Lobe Epilepsy Disease and Market Background

TLE affects approximately 1.0 million people in the U.S.

alone, of which approximately 0.3 million U.S.

patients are inadequately treated through anti-seizure medications and are considered refractory.

240,000 of U.S.

refractory TLE patients have a lesion in the mesial temporal lobe (hippocampus), which is expressed as sclerosis, atrophy or scarring.

Mesial TLE (“MTLE”) is often caused by brain injury, infections or prolonged febrile seizures which can lead to hyperexcitability of the hippocampus and repeated seizures which can further damage the hippocampus over time.

Refractory MTLE patients have a poor quality of life and a reduced lifespan.

Surgical treatment for refractory patients is lobectomy or laser tissue ablation but only 1-2% of eligible patients undergo surgery.

Our Development of AMT-260 for Temporal Lobe Epilepsy

In July 2021, we acquired uniQure France SAS (“uniQure France,” formerly Corlieve Therapeutics SAS) and its lead program now known as AMT-260 to treat refractory MTLE.

AMT-260 is being developed based on exclusive licenses to certain patents uniQure France SAS obtained following its formation in 2019 from two French research institutions that continue to collaborate with us.

AMT-260 is a gene therapy using an AAV9 vector.

The use of AAV9 to deliver any sequence that affects the expression of the GRIK2 gene in humans has been exclusively licensed from Regenxbio Inc (“Regenxbio”).

AMT-260, employs miRNA silencing technology to target suppression of aberrantly expressed GluK2 containing kainate receptors in the hippocampus of patients with MTLE.

In October 2021, we presented preclinical data for AMT-260 at the European Society of Gene and Cell Therapy (“ESGCT”).

AMT-260 reduces the expression of GluK2 in cortical neurons, reduces epileptiform activity and hyperlocomotion in a preclinical model of epilepsy and blocks epileptiform discharges in organotypic slices from patients with MTLE .

In July 2022, we initiated IND-enabling, GLP toxicology studies in non-human primates for our gene therapy candidate in MTLE.

On September 5, 2023 we announced that the FDA had cleared the IND application for AMT-260.

The first-in-human Phase I/IIa clinical trial will be conducted in the United States and consist of two parts.

The first part is a multicenter, open-label trial with two dosing cohorts of six patients each to assess safety, tolerability, and first signs for efficacy of AMT-260 in patients with refractory MTLE.

The second part is expected to be a randomized, controlled trial to generate proof of concept (“POC”) data.

Amyotrophic Lateral Sclerosis (“ALS”)

ALS Disease and Market Background

ALS commonly known as Lou Gehrig’s disease, is a progressive and fatal neuromuscular disease with the majority of ALS patients dying within 2 to 5 years of receiving a diagnosis.

Familial ALS, a hereditary form of the disease, accounts for 5-10% of cases, whereas the remaining cases (sporadic ALS) have no clearly defined etiology.

ALS affects persons of all races and ethnicities;

however, persons of certain demographics (Caucasians, males, non-Hispanics and persons aged 60 years or older) and those with a family history of ALS are more likely to develop the disease.

ALS affects approximately 17,800 to 31,800 adults in the U.S.

and a similar number of adults in Europe.

Evidence from prevalence studies suggests that prevalence and incident rates can vary significantly between regions and ethnicities.

Most cases are sporadic (“sALS”) but approximately 10% are found to have a familial, i.e., dominant genetic causation (“fALS”).

fALS can be caused by mutations in various genes including chromosome 9 open reading frame 72 (“ C9ORF72”), SOD1, tyrosyl-DNA phosphodiesterase 2 and others.

The most common genetic mutation that causes ALS is a G4C2 hexanucleotide repeat expansion in the chromosome 9 open reading frame 72 (“ C9ORF72”) gene.

The hexanucleotide expansion causes the formation of ribonucleic acid (“RNA”) aggregates and the production of toxic dipeptides that ultimately lead to neuronal death.

It is estimated that there are approximately 600 incident cases per year in the U.S.

Another genetic mutation that causes ALS are pathogenic mutations in the superoxide dismutase enzyme 1(“SOD1”).

SOD1 is an enzyme that that is responsible for catalyzing toxic superoxide to hydrogen peroxide and dioxygen.

While the exact mechanism for disease is not known, it is believed that a toxic gain of function in SOD1 results in oxidative stress and cell death of motor neurons.

More than 100 pathogenic SOD-1 have been identified.

Mutations are concentrated in a few regions of the protein.

Mutations can be both dominant and recessive.

Most common mutations occur in the D90A, G93A, A4H and D46R genes.

Patients with different mutations progress at different rates.

It is estimated that there are approximately 300 incident cases per year in the U.S.

Our Development of AMT-162 for ALS – SOD1

The FDA has cleared the IND for APB-102 and has granted it Orphan Drug and Fast Track designation.

Our Development of AMT-161 for ALS – C9ORF72

AMT-161 is a one-time, intra cerebrospinal fluid-administered AAV gene therapy that targets the repeat-expanded C9ORF72 allele to lower toxic RNA aggregates and prevent dipeptide protein formation.

AMT-161 uses our miQURE and linQURE gene silencing technology to target the toxic sense and antisense alleles of C9ORF72 as a potential treatment for ALS.

Alzheimer’s Disease (AMT-240)

Alzheimer’s Disease and Market Background

Alzheimer’s disease causes loss of memory and dementia and is the most common neurodegenerative disease.

Human genetic studies suggest that the Apolipoprotein E (APOE) gene is an important factor in the pathogenesis of Alzheimer’s disease.

APOE consists of 3 major isoforms that are structurally and functionally different.

The APOE4 isoform is associated with earlier onset of Alzheimer’s disease while APOE2 and variants of APOE3 are protective.

Our Development of AMT-240 for Alzheimer’s disease

AMT-240 is our preclinical product candidate for the treatment autosomal dominant Alzheimer’s disease.

AMT-240 is a one-time intra cerebrospinal fluid-administered AAV gene therapy overexpressing a protective APOE variant with or without a miQure designed to knockdown the toxic APOE4 variant.

It is initially targeted as a treatment for autosomal dominant Alzheimer’s disease patients but may be effective for a broader population of patients.

Liver-directed diseases

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On June 24, 2020, we entered into the CSL Behring Agreement pursuant to which CSL Behring received exclusive global rights to HEMGENIX ® .

The transaction became fully effective on May 6, 2021, one day after the waiting period under the HSR Act expired on May 5, 2021.

The transaction became fully effective on May 6, 2021.

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.

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in April 2022.

In November 2022 the FDA approved the marketing application for the U.S.

and in February 2023 the EMA approved the marketing application for the EU.

We are eligible to receive a $100.0 million payment from CSL Behring following the first sale of the Product in the U.S.

We recorded the $100.0 million payment associated with the first sale in the U.S.

as license revenue in the year ended December 31, 2022 as we expect this event to occur in 2023.

In July 2023 we collected a $100.0 million payment from CSL Behring following the first sale of the Product in the U.S in June 2023.

We and CSL Behring also entered into a development and commercial supply agreement, pursuant to which, among other things, we will supply the Product to CSL Behring.

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On September 6, 2022, CSL Behring notified us of its intent to transfer manufacturing technology in the coming years related to HEMGENIX ® to a third-party contract manufacturer designated by CSL Behring.

CSL Behring also informed us of its intent to retain us as a source for manufacturing after the completion of the technology transfer.

Development of HEMGENIX™ (etranacogene dezaparvovec) for Hemophilia B

HEMGENIX™ is approved for adults 18 years or older with hemophilia B who currently use factor IX prophylaxis therapy or have current or historical life-threatening hemorrhage or have repeated, serious spontaneous bleeding episodes.

HEMGENIX™ includes an AAV5 vector incorporating the FIX-Padua variant (“FIX-Padua”).

The product is intended to be delivered by intravenous (“IV”)-infusion, without immunosuppressant therapy, through the peripheral vein in a single treatment session for approximately 30 minutes.

The approvals were based in part on data from our Phase III HOPE-B pivotal trial to evaluate the safety and efficacy of HEMGENIX™.

In the open-label, single arm, HOPE-B study, 54 adult male hemophilia B patients with severe or moderately severe hemophilia B, with or without pre-existing AAV5 neutralizing antibodies, were infused with a single dose of HEMGENIX™.

HEMGENIX™ produced mean factor IX activity of 39.0 IU/dL at six months and 36.9 IU/dL at 18 months post infusion, which was sustained at 36.7 IU/dL in the long-term follow-up data at two years.

In addition, 94 percent (51 out of 54) of patients treated with HEMGENIX™ discontinued use of prophylaxis and remained free of previous continuous routine prophylaxis therapy.

The data demonstrate the annualized bleeding rate (“ABR”) for all bleeds was reduced by 64% during months 7-24 of the study (mean ABR 1.51 vs.

4.18 during the lead-in period;

p=0.0002), sustaining the same bleed reduction that satisfied the study's primary endpoint.

The FDA-approved prescribing information for HEMGENIX™ shows that ABR for all bleeds was reduced by 54% during months 7-18 of the study.

Treatment with HEMGENIX™ also reduced mean unadjusted annualized factor IX consumption by 96% from the lead-in period (257,339 IU/year/participant) to months 19–24 (9751 IU/year/participant;

Of the 557 treatment-emergent adverse events reported 24-months post-infusion, 424 (76%) were mild, 115 (21%) were moderate and 18 (3%) were severe.

A total of 38 participants (70.4%) experienced 93 treatment-related adverse events, with only one occurring during months 18-24.

There were no serious adverse effects related to treatment and the most common side effects (incidence ≥5%) were liver enzyme elevations, headache, elevated levels of a certain blood enzyme, flu-like symptoms, infusion-related reactions, fatigue, nausea and feeling unwell.

Intellectual Property for etranacogene dezaparvovec

In 2017, we acquired intellectual property from Professor Paolo Simioni (“Dr.

Simioni”), a hemophilia expert at the University of Padua, Italy.

The intellectual property includes U.S.

Patent Number 9,249,405, (the “‘405 Patent”).

The ‘405 Patent was subject to Inter Partes Review (“IPR”) proceedings at the Patent Trials and Appeal Board (“PTAB”) of the United States Patent & Trademark Office (“USPTO”).

Ultimately, the challenged claims of the ‘405 Patent were withdrawn but the unchanged claims remain in force.

The ‘405 Patent thus covers compositions of FIX-Padua polypeptides (proteins), their therapeutic uses as well as nucleic acid sequences encoding FIX-Padua.

The FIX Padua variant is a FIX protein carrying a leucine at the R338 position, often called the “FIX-Padua” or “Padua mutant.”

On May 29, 2018, the USPTO granted us a second patent, U.S.

Patent Number 9,982,248, which covers methods of treating coagulopathies (bleeding disorders), including hemophilia B, using AAV-based gene therapy with nucleic acid encoding the hyperactive FIX Padua variant.

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.

In addition to the U.S.

patents, on February 20, 2018, the Canadian Intellectual Property Office granted Patent Number 2,737,094, which covers FIX-Padua nucleic acids for use in gene therapy and FIX-Padua polypeptides for use in FIX replacement therapy.

On October 14, 2022, Pfizer filed a Statement of Claim at the Federal Court in Canada to impeach our Canadian Patent CA 2,737,094.

We are currently defending this case.

On December 28, 2022, the European Patent Office granted Patent Number EP 3581650, which covers FIX-Padua nucleic acids and its uses in gene therapy.

That same day, Pfizer filed a Claim at the UK High Court, Patent Court seeking revocation of the UK part of EP 3581650.

We are currently defending this case.

Both in the U.S.

and in Europe, we have pending divisional applications still in prosecution phases.

On May 11, 2021, Pfizer, Inc.

filed three petitions at the USPTO seeking Inter Partes Review of U.S.

9,982,248 (the “‘248 Patent”) and 10,465,180 (the “‘180 Patent” and together with the ‘248 Patent, the “Patents”).

On November 15, 2022, the PTAB issued three Final Written Decisions (“FWD”) finding the claims of the challenged patents invalid.

On January 17, 2023, Notices of Appeal were filed at the Court of Appeal of the Federal Circuit (“CAFC”) contesting these FWDs.

Fabry disease program (AMT-191)

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In September 2020, we selected a lead gene therapy candidate (AMT-191) for the treatment of Fabry disease.

The lead candidate is a one-time administered AAV5 gene therapy incorporating the GLA transgene.

In preclinical studies comparing multiple product candidates, including constructs incorporating a modified alpha-N-acetylgalactosaminidase transgene (“modNAGA”), AMT-191 demonstrated the most robust and sustained increases in GLA activity and subsequent functional improvement.

In October 2021, we presented preclinical data for AMT-191 at the European Society of Gene and Cell Therapy (“ESGCT”), confirming efficiency and cross correction in a Fabry mouse model, with increased gamma-linolenic acid in the liver, kidney, heart, and brain and normalized lysoglobotriaosylceramide-3 levels in main target organs.

In August 2022, we initiated IND-enabling, GLP toxicology studies in non-human primates for our lead candidate.

Central Nervous System diseases

Huntington’s Disease

Huntington’s Disease and Market Background

The median survival time after onset is 15 to 18 years (range:

5 to >25 years).

Huntington’s disease is caused by an inherited defect in a single gene that codes for a protein called Huntingtin (“HTT”).

The prevalence of Huntington’s disease is three to seven per 100,000 in the general population, similar in men and women, and it is therefore considered a rare disease.

Despite the ability to identify Huntington’s disease mutation carriers decades before onset, there is currently no available therapy that can delay onset or slow progression of the disease.

Although some symptomatic treatments are available, they only are transiently effective despite significant side effects.

Our Development of AMT-130 for Huntington’s Disease

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

We are currently conducting a Phase I/II clinical trial for AMT-130 in the U.S.

and a Phase Ib/II study in the EU.

Together, these studies are intended to establish safety, proof of concept, and the optimal dose of AMT-130 to take forward into Phase III development or into a confirmatory study should an accelerated registration pathway be feasible.