What changed in this filing

/stocks — the workspaceLOADING

Item 1. Business

2026-03-02 compared with 2025-02-27 · 369 added, 326 removed, 559 unchanged (55% of the section changed)

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”) caused by mutations in superoxide dismutase 1 (“SOD 1”), refractory mesial temporal lobe epilepsy (“mTLE”), and Fabry disease.

We are advancing a focused pipeline of innovative gene therapies, including our clinical candidates for the treatment of Huntington’s disease, refractory mesial temporal lobe epilepsy (“MTLE”), Fabry disease, and amyotrophic lateral sclerosis caused by mutations in superoxide dismutase 1 (“SOD1-ALS”).

Recent Product Candidate Developments

Huntington’s disease program (AMT-130)

RMAT Designation

In June 2024, we announced that the U.S.

Food and Drug Administration (“FDA”) granted us Regenerative Medicine Advanced Therapy (“RMAT”) designation for AMT-130 based on the potential of AMT-130 to address the major unmet medical need among patients with Huntington’s disease.

The designation followed the FDA’s review of interim Phase I/II clinical data for AMT-130 announced in December 2023 and was based on an analysis comparing these 24-month clinical data to a non-concurrent criteria-matched natural history cohort.

Updated Interim Data

In July 2024, we announced updated interim clinical data, including up to 24 months of follow-up data from 29 patients enrolled in the U.S.

study and the European study as of a March 31, 2024 cut-off date.

As summary of key observations from the July 2024 interim update is set forth below.

● A statistically significant, dose-dependent, slowing in disease progression measured by composite Unified Huntington’s Disease Rating Scale (“cUHDRS”) was observed through 24 months in patients receiving the high dose of AMT-130.

● Trends in measurements of motor and cognitive function showed near-baseline stability throughout the 24 months of follow-up in patients receiving the high dose of AMT-130.

● A statistically significant reduction of neurofilament light chain (“NfL”) in cerebrospinal fluid (“CSF”) was observed in patients treated with AMT-130.

● Based on data observed as of the July 2024 update, AMT-130 remained generally well-tolerated, with a manageable safety profile at both high and low doses.

There were no new AMT-130-related serious adverse events reported.

Regulatory Alignment

In December 2024, following our initial Type B meeting, we announced that we had reached agreement with FDA on key elements of an Accelerated Approval pathway for AMT-130.

In correspondence leading up to and following the Type B meeting, FDA agreed that data from the ongoing Phase I/II studies of AMT-130, compared to a natural history external control, may serve as the primary basis for a Biologics License Application, (“BLA”), submission under FDA’s accelerated approval pathway.

The FDA also agreed that cUHDRS may be used as an intermediate clinical endpoint and that reductions in NfL measured in CSF may serve as supportive evidence of therapeutic benefit in the application for such accelerated approval.

We have initiated BLA-readiness activities and plan to have additional interactions with the FDA to discuss the primary statistical analysis plan and chemistry, manufacturing, and controls (“CMC”) requirements for a BLA submission.

In addition, we plan to initiate regulatory interactions with the European Medicines Agency (“EMA”) in the first half of 2025.

Other clinical candidates

In November 2024, we announced that the that the first patient was dosed in the GenTLE Phase I/IIa clinical trial of AMT-260 for the treatment of refractory mTLE.

In addition, the FDA recently approved a protocol amendment expanding the inclusion criteria for certain patients in the first cohort to include patients with non-lesional mesial temporal lobe epilepsy in the non-dominant hemisphere.

In August 2024, we announced that the first patient had been dosed in a Phase I/IIa clinical trial of AMT-191 for the treatment of Fabry disease.

In October 2024, we announced the first patient had been dosed in a Phase I/IIa clinical trial of AMT-162 for the treatment of SOD1-ALS.

In September 2025, we announced p ositive topline data from the pivotal Phase I/II study of AMT-130 for the treatment of Huntington’s disease.

We analyzed clinical outcomes for 29 patients treated with AMT-130 (n=17 high-dose;

n=12 low-dose) of which 12 patients per dose group had attained 36 months of follow-up and were evaluated at that time point.

Outcomes for each dose group were compared to a propensity score-matched external control drawn from the Enroll-HD natural history data set (n=940 for high-dose;

n=626 for low-dose).

Topline 36-month efficacy results for patients receiving high-dose AMT-130 were as follows (data cutoff as of June 30, 2025):

● A statistically significant 75% slowing of disease progression as measured by composite Unified Huntington’s Disease Rating Scale (“cUHDRS”) (p=0.003), which met the primary endpoint of the study.

Treated patients had a mean change in cUHDRS from baseline of -0.38 compared to a change of -1.52 for patients in the propensity score-matched external control.

● A statistically significant 60% slowing of disease progression as measured by Total Function Capacity (“TFC”) (p=0.033), which met a key secondary endpoint of the study.

Treated patients had a mean change in TFC from baseline of -0.36 compared to a change of -0.88 for patients in the propensity score-matched external control.

● Favorable trends in other secondary endpoint measures of motor and cognitive function, including Symbol Digit Modalities Test (“SDMT”), Stroop Word Reading Test (“SWRT”) and Total Motor Score (“TMS”).

o An 88% slowing of disease progression as measured by SDMT (p=0.057), with a mean change in SDMT from baseline of -0.44 compared to a change of -3.73 for patients in the propensity score-matched external control.

o A 113% slowing of disease progression as measured by SWRT (nominal p=0.002), with a mean change in SWRT from baseline of 0.88 compared to a change of -6.98 for patients in the propensity score-matched external control.

o A 59% slowing of disease progression as measured by TMS (nominal p=0.174), with a mean change in TMS from baseline of 2.01 compared to a change of 4.88 for patients in the propensity score-matched external control.

A mean reduction from baseline in cerebrospinal neurofilament light protein (“CSF NfL”) of -8.2% was observed at 36 months in the high-dose of AMT-130 of the Phase I/II studies.

CSF NfL is a well-characterized, supportive biomarker of neurodegeneration.

Elevation in CSF NfL has been shown to be strongly associated with greater clinical severity of Huntington’s disease.

We believe that the consistently favorable results in functional, motor and cognitive endpoints at 36 months observed in the high-dose group, compared to the variable trends observed in the low-dose group, reflect a dose-dependent response to AMT-130.

Various other supportive analyses of the results from the AMT-130 high-dose treatment group, including those using a propensity score-weighted external control and comparisons to the TRACK-HD and PREDICT-HD datasets, were consistent with the primary analysis.

AMT-130 was generally well-tolerated in the Phase I/II studies, with a manageable safety profile at both doses with no new drug-related serious adverse events (“SAEs”) observed since December 2022.

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

In 2025, we treated six patients with the high-dose of AMT-130 in a fourth cohort to evaluate the safety and efficacy of AMT-130 in patients with lower baseline striatal volumes compared to previous cohorts in the U.S.

Phase I/II study.

In April 2025, we announced that the FDA granted Breakthrough Therapy designation to AMT-130 for the treatment of Huntington’s disease.

The Breakthrough Therapy designation was supported by clinical data from the ongoing Phase I/II trials of AMT-130 for the treatment of Huntington’s disease showing the potential for meaningful slowing of disease progression.

Breakthrough Therapy designation is intended to expedite the development and review of investigational therapeutic candidates that are intended to treat a serious condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s).

In general, the preliminary clinical evidence should show a clear advantage over available therapy.

In addition to the Breakthrough Therapy designation, the FDA previously granted RMAT designation, Orphan Drug designation and Fast Track designation to AMT-130.

In October 2025, we met with the FDA at a pre-BLA meeting to discuss the application for AMT-130.

In December 2025, we announced that in the final meeting minutes, the FDA conveyed that data submitted from the Phase I/II studies of AMT-130 are currently unlikely to provide the primary evidence to support a BLA submission.

In January 2026, we met with the FDA at a Type A meeting to discuss AMT-130.

In March 2026, following receipt of the final meeting minutes from the Type A meeting, we announced that the FDA stated that it cannot agree that data from the Phase I/II studies, compared to an external control, are sufficient to provide the primary evidence of effectiveness required to support a marketing application for AMT-130.

The FDA strongly recommended we conduct a prospective, randomized, double-blind, sham surgery-controlled study.

We intend to continue engaging with the FDA regarding Phase III development considerations and plan to request a Type B meeting in the second quarter of 2026 to further discuss potential study design approaches.

Temporal lobe epilepsy program (AMT-260)

In May 2025, we presented initial safety and exploratory efficacy data from the first treated patient in our Phase I/IIa clinical trial (“GenTLE”) of AMT-260 for the treatment of MTLE in the United States (“U.S.”).

As of the April 17, 2025 cutoff date, the patient showed a 92% reduction in seizure frequency observed through the first five months of follow-up with no serious safety events as of the data announcement.

In September 2025, we completed enrollment of the first three patients in the first cohort administering AMT-260 to the non-dominant hemisphere of the brain.

Following a positive review by the independent data monitoring committee (“IDMC”), we expanded the first cohort into MTLE in the dominant hemisphere.

We completed enrollment of the first cohort in 2025.

We also initiated enrollment of a second cohort in 2025, which is expected to include an additional six patients.

Fabry disease program (AMT-191)

In February 2025, we announced a favorable recommendation from the IDMC following a review of safety data from the first two patients treated in the Phase I/II clinical trial of AMT-191 for the treatment of Fabry disease.

The IDMC’s review did not identify any significant safety concerns and recommended proceeding with enrollment in the second cohort.

During 2025, we enrolled three patients in a second, lower dose cohort in our Phase I/II clinical trial of AMT-191 for the treatment of Fabry disease, as well as enrolled four patients in a third cohort.

In September 2025, we announced initial safety and exploratory efficacy data from the first cohort.

The data presented in respect of the July 24, 2025 cutoff date, at which date all patients had less than three months of follow-up, was as follows:

● All patients in the first dose cohort showed sustained increases in α-galactosidase A (“α-Gal A”) enzyme activity, ranging from 27- to 208-fold above the mean normal range (1.38-8.66 nmol;

mean normal of 3.57 nmol).

All four patients were withdrawn from enzyme replacement therapy (“ERT”) and maintained stable plasma lyso-Gb3 levels through the cutoff date.

● AMT-191 showed a manageable safety profile.

At the high dose, two SAEs unrelated to AMT-191 (stroke, diplopia), two related SAEs (chest pain, increased troponin), and one possibly related SAE (leptomeningeal enhancement) were observed in two patients.

Additionally, one patient experienced an asymptomatic Grade 3 liver enzyme elevation that resolved with corticosteroid therapy.

This event, classified as a dose-limiting toxicity per protocol, was not considered serious and did not require hospitalization.

No loss of α-Gal A expression was observed in this patient.

In February 2026, we announced updated preliminary data from the Phase I/II study of AMT-191 for Fabry disease.

Updated preliminary safety and exploratory efficacy data included the following, with a data cutoff date as of January 8, 2026:

● Dose-dependent elevations were observed across 11 patients in three dose levels with α-Gal A activity ranging from 0.34- to 82.2-fold above mean normal range (1.38-8.66 nmol;

mean normal of 3.57 nmol) at the lowest dose, 1.6- to 312.52-fold at the mid dose, and 27.7- to 223.7-fold at the highest dose.

These increases were durable for the measured time period ranging from the longest follow-up period of more than a year in a treated patient (high-dose cohort) to the shortest follow-up period of four-months in a treated patient (mid-dose cohort).

● Six of 11 dosed patients were withdrawn from ERT.

● Plasma lyso-Gb3 levels were stable post-dose across all dose cohorts, regardless of ERT status through the cutoff date.

AMT-191 continued to show a manageable safety profile.

No SAEs related to AMT-191 were observed at the 4x10 13 gc/kg and 2x10 13 gc/kg doses.

No additional SAEs were observed at the 6x10 13 gc/kg dose beyond the five previously reported in September 2025 in two patients.

Per protocol, additional dosing in the mid- and high-dose cohorts has been paused pending further evaluation following asymptomatic Grade 3 liver enzyme elevations observed in two patients in the mid-dose cohort, which were confirmed dose-limiting toxicity.

Amyotrophic Lateral Sclerosis (AMT-162)

In September 2025, we voluntarily paused enrollment of our Phase I/II multi-center, open-label trial of AMT-162 for the treatment of SOD1-ALS (“EPISOD1”) in the U.S.

upon the recommendation of the IDMC following a review of available preliminary data related to the safety and efficacy of AMT-162 in the context of a dose limiting toxicity, which resulted in an SAE determined to be related to AMT-162, that was observed in one patient in the second cohort.

We continue to collect and evaluate data from the five patients dosed in EPISOD1 to date.

Other Business Developments

Sale of commercial manufacturing activities

In June 2024, our affiliates, uniQure Inc.

and uniQure biopharma B.V., entered into an asset purchase agreement (the “APA”) with Genezen Holdings Inc.

and its subsidiary, Genezen MA, Inc.

(together “Genezen”) to sell certain assets and assume certain liabilities related to uniQure’s manufacturing facility and operations in Lexington, Massachusetts (“Lexington Transaction”).

The Lexington Transaction closed in July 2024 (“Closing”).

In connection with the Closing, Genezen extended offers of employment to a significant majority of our employees located at the Lexington facility and our Chief Executive Officer, Matthew Kapusta, joined the board of directors of Genezen.

At the Closing, we entered into a commercial supply agreement (“CSA”) with Genezen for the commercial manufacture of HEMGENIX®.

Pursuant to the CSA, Genezen manufactures and supplies CSL Behring’s commercial demand for HEMGENIX® on our behalf.

The CSA includes a minimum term of three years and minimum purchase commitments of HEMGENIX® commercial supplies of $43.3 million over the first three years, unless certain contractual provisions are triggered.

Our obligations with respect to the supply of HEMGENIX® to CSL Behring remain in effect notwithstanding the subcontracting to Genezen.

Additionally, we entered into a development and other manufacturing services agreement (“DMSA”) with Genezen at Closing.

Pursuant to the DMSA, we are entitled to preferred customer status to receive manufacturing and development services to support our investigational gene therapy programs and other services related to HEMGENIX® (other than our manufacturing and supply obligations under the CSA).

The DMSA has a minimum term of three years and requires us to purchase services for a total minimum of $14.0 million.

We recorded a $1.2 million gain from the divestment.

We paid a total of $8.3 million to Genezen and CSL related to adjustments of working capital and to obtain consent to proceed with the divestiture.

Organizational restructuring

In August, 2024, we announced a global organizational restructuring (the “Restructuring”).

These actions were the outcome of a comprehensive review of our operations with the goals of conserving capital and streamlining the organization.

As a result of the Restructuring and the Lexington Transaction, we eliminated approximately 300 positions or 65% of our workforce.

We substantially completed the Restructuring at the end of 2024.

We have incurred $5.2 million employee severance costs in the year ended December 31, 2024 and estimate that we will incur additional costs in the range of $0.5 million to $1.0 million in 2025.

Hercules loan repayment and amendment

In connection with the July 2024 closing of the Lexington Transaction we and Hercules amended our existing term loan facility whereby we prepaid $50.0 million of the total $100.0 million principal outstanding.

The remaining $50.0 million principal outstanding will need to be repaid in January 2027.

Public Offerings

In January 2025, we received net proceeds of $70.1 million, after deducting underwriting discounts and commissions and other offering expenses payable by us, through a follow-on public offering of 4.4 million ordinary shares at a public offering price of $17.00 per ordinary share.

In February 2025, we received an additional $10.6 million in net proceeds upon the underwriters’ exercise of their option to purchase an additional 0.7 million ordinary shares at the public offering price.

We expect that net proceeds and our existing cash, cash equivalents and investments will be sufficient to fund our operating expenses and capital requirements into the second half of 2027.

In February 2025, we received an additional $10.4 million in net proceeds, after related offering expenses, upon the underwriters’ exercise of their option to purchase an additional 0.7 million ordinary shares at the public offering price.

In September 2025, we received net proceeds of $323.7 million, after deducting underwriting discounts and commissions and other offering expenses payable by us, through a follow-on public offering of 6.7 million ordinary shares at a public offering price of $47.50 per ordinary share, and, in lieu of ordinary shares to certain investors, pre-funded warrants to purchase 0.5 million of our ordinary shares at the public offering price per share less the $0.0001 per share exercise price of each pre-funded warrant.

Hercules Loan Amendment

In September 2025, we entered into a $175.0 million senior secured term loan facility (the “2025 Amended Facility”) with Hercules Capital, Inc.

(“Hercules”).

The 2025 Amended Facility consists of three tranches including a first tranche of $50.0 million replacing the debt outstanding as per the loan amendment date, an additional term loan tranche of $100.0 million, which can be drawn at our option, subject to the BLA approval of AMT-130 prior to June 2027, provided that confirmatory trials to the extent and in the manner required to support full approval (if applicable) remain ongoing or are being planned, and a third tranche of up to $25.0 million, subject to Hercules’ approval.

All tranches have a floating interest rate of the greater of 9.45% and the prime rate plus 2.45%, reflecting a floating rate of 9.45% as of December 31, 2025.

The tranches mature on October 1, 2030.

Our Mission and Strategy

2 unchanged sentences

Our strategy to achieve this mission is to:

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

Advance the development and potential commercialization 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 for the treatment of Huntington’s disease to have entered into clinical development.

In November 2024, we aligned with the FDA on core elements of an Accelerated Approval pathway for AMT-130.

In 2025, we intend to further engage with the FDA regarding a potential BLA submission and to initiate discussions with EMA regarding the registrational pathway for AMT-130.

We also intend to initiate commercial planning and readiness activities in the U.S.

in anticipation of a potential Accelerated Approval.

Advance our pipeline of clinical-stage gene therapy candidates.

We have dosed the first patients in the clinical studies of our product candidates for the treatment of MTLE (AMT-260), SOD1-ALS (AMT-162), and Fabry disease (AMT-191).

We intend to complete enrollment and generate clinical data to assess the safety, tolerability and potential efficacy of these product candidates.

Advance our pipeline of clinical-stage gene therapy candidates and research programs.

We have dosed patients in the clinical studies of our product candidates for the treatment of MTLE (AMT-260), Fabry disease (AMT-191), and SOD1-ALS (AMT-162).

We intend to generate clinical data to assess the safety, tolerability and potential efficacy of these product candidates.

We also continue to advance early-stage research candidates with a focus on gene therapies for severe diseases.

Develop next-generation delivery and 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 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.

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 after systemic delivery, as well as novel cargo technologies such as miQURE ® , our one-time administered gene silencing platform, LinQURE ® , a single AAV carrying multiple micro ribonucleic acids (“miRNAs”) designed 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.

2 unchanged sentences

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.

Approximately 75,000 people have Huntington’s disease in the U.S., European Union (“EU”), and United Kingdom (“UK”), with approximately 40,000 symptomatic Huntington’s disease patients in the U.S.

In addition to this, there are hundreds of thousands of others at risk of inheriting the 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.

Although some symptomatic treatments are available, they are only transiently effective and are often associated with 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, which utilizes our proprietary, gene-silencing miQURE platform and incorporates an AAV vector carrying a micro ribonucleic acid (“miRNA”), specifically designed to silence the huntingtin gene and the potentially highly toxic exon 1 protein fragment.

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 a miRNA, specifically designed to silence the huntingtin gene and the potentially highly toxic exon 1 protein fragment.

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;

(1) one-time administration of a 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.

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

study”), as well as an open-label Phase Ib/II study in Europe (“European study”) with the same early-manifest criteria for Huntington’s disease as the U.S.

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

study”), as well as an open-label Phase Ib/II study in Europe (the “European study”) with the same early-manifest criteria for Huntington’s disease as the U.S.

We completed the enrollment of all 26 patients in the first two cohorts of the U.S.

study in March 2022 and the enrollment of 13 patients in the two cohorts of the European study in June 2023.

study in March 2022 and the enrollment of 13 patients in the first two cohorts of the European study in June 2023.

study, 26 patients with early manifest Huntington’s disease were randomized to treatment (six low-dose patients, 10 high-dose patients) or an imitation (sham) surgical procedure (10 patients).

study consists of a blinded 12-month core patient study period followed by an unblinded long-term follow-up period of five years.

Four imitation surgery patients from the U.S.

study crossed over to treatment (“Crossover patients”).

An additional four control patients crossed over to treatment.

In the European study, 13 patients were enrolled and treated with AMT-130 (six low-dose patients and seven high-dose patients).

As of February 2025, we have enrolled 12 patients across the U.S.

into a third cohort to further investigate both doses of AMT-130 together with perioperative immunosuppression using the current, established stereotactic administration procedure.

The focus of this third cohort is to evaluate the near-term safety and tolerability.

In July 2024, we announced updated interim clinical data including up to 24 months of follow-up data from 29 patients enrolled in the U.S.

study and the European study as of a March 31, 2024 cut-off date.

In conjunction with the July 2024 update, we conducted a post-hoc statistical analysis of clinical outcomes for the 21 treated patients at 24 months compared to a propensity-weighted external control developed in collaboration with the Cure Huntington’s Disease Initiative using data from the TRACK-HD, TRACK-ON and PREDICT-HD natural history studies.

The external control includes 154 patients that met the Phase I/II clinical trial eligibility criteria and whose data contributions were statistically weighted using propensity scoring to closely match the baseline characteristics of patients treated with AMT-130.

Disease-related outcomes for these well-balanced cohorts were then compared after 24 months follow-up.

Measures of statistical significance in this analysis were based on nominal p values and are unadjusted.

A summary of key observations related to efficacy from the July 2024 interim update is set forth below:

● A statistically significant, dose-dependent, slowing in disease progression measured by cUHDRS was observed through 24 months in patients receiving the high dose of AMT-130.

o At 24 months, the mean change in cUHDRS for patients receiving the high-dose of AMT-130 was -0.2 compared to -1.0 for patients in the propensity score-weighted external control, representing an 80% slowing of disease progression (p=0.007);

o At 24 months, the mean change in cUHDRS for patients receiving the low-dose of AMT-130 was -0.7 compared to -1.0 for patients in the propensity score-weighted external control, representing a 30% slowing of disease progression (p=0.21);

o cUHDRS has been demonstrated to be the most sensitive measurement of clinical progression in Huntington’s disease patients.

● Trends in measurements of motor and cognitive function showed near-baseline stability throughout the 24 months of follow-up in patients receiving the high dose of AMT-130.

● A statistically significant reduction of NfL in CSF was observed in patients treated with AMT-130.

o Patients treated with AMT-130 had a mean reduction in CSF NfL of 11% compared to baseline (p=0.02) at 24 months;

o Mean CSF NfL levels for both high and low doses were below baseline at 24 months;

o CSF NfL is a well-characterized biomarker of neurodegeneration that has been shown to be strongly associated with the clinical severity of Huntington’s disease.

An independent natural history study demonstrated a 26% increase in CSF NfL at 24 months in 19 patients with early manifest Huntington’s disease.

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.

In 2023, we initiated patient dosing in a third cohort consisting of up to 12 patients to further investigate both doses of AMT-130 together with perioperative immunosuppression using the current, established stereotactic administration procedure.

In February 2025, we completed enrollment of all 12 patients in the third cohort.

Phase I/II study .

Temporal Lobe Epilepsy Program (AMT-260)

Temporal Lobe Epilepsy Disease and Market Background

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

Temporal Lobe Epilepsy (“TLE”) affects approximately 0.5 million people in the U.S.

alone, of which approximately 0.3 million U.S.

2 unchanged sentences

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.

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.

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

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.

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

AMT-260 is comprised of an AAV9 vector that locally delivers two engineered miRNAs designed to degrade the GRIK2 gene and suppress the aberrant expression of glutamate receptor subtype GLUK2 that is believed to trigger seizures in patients with refractory MTLE.

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”).

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

We initiated a Phase I/IIa clinical trial that is being 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 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”).

We initiated a Phase I/IIa clinical trial that is being conducted in the U.S.

and is intended to consist of two parts.

The first active part of the clinical trial is a multicenter, open-label trial with two dosing cohorts of six patients each to assess safety, tolerability, and initial 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 data.

The FDA-approved study protocol provides that the first three patients to be enrolled in the study are required to have MRI-confirmed unilateral, hippocampal sclerosis.

In November 2024 we announced that the first patient had been dosed in the GenTLE Phase I/IIa clinical trial of AMT-260 for the treatment of mTLE.

The FDA-approved study protocol provides that the first three patients to be enrolled in the study are required to have Magnetic Resonance Imaging (“MRI”)-confirmed unilateral, hippocampal sclerosis.

In September 2025, we completed enrollment of the first three patients in the first cohort administering AMT-260 to patients with lesions in the non-dominant hemisphere of the brain.

Following a positive review by the IDMC, we expanded the first cohort into MTLE in the dominant hemisphere and initiated a second cohort.

We completed enrollment of six patients into the first cohort in 2025.

We also initiated enrollment of a second cohort in 2025, which is expected to include an additional six patients.

Amyotrophic Lateral Sclerosis (“ALS”)

4 unchanged sentences

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.

ALS affects up to approximately 35,000 adults in the U.S.

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

1 unchanged sentence

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

One 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.

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

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

While the exact mechanism for the 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 SOD1 have been identified.

1 unchanged sentence

Mutations can be both dominant and recessive.

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

The most common mutations in the SOD1 gene are D90A, G93A, A4H and D46R.

Patients with different mutations progress at different rates.

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

It is estimated that there are approximately 300 to 600 patients with SOD1-ALS in the U.S.

Our Development of AMT-162 for ALS – SOD1

In January 2023 we announced that we entered into a global licensing agreement with Apic Bio for a novel, one-time, intrathecally administered gene therapy for ALS caused by SOD1 mutations (formerly APB-102).

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

The FDA cleared the Investigational New Drug (“IND”) application for APB-102 and granted it Orphan Drug and Fast Track designation.

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 AMT-162 and has granted Orphan Drug and Fast Track Designation.

In October 2024, we announced the first patient had been dosed in a Phase I/IIa clinical trial of AMT-162 (“EPISOD1”) for the treatment of SOD1-ALS.

In January 2025, we announced that the independent data monitoring committee had recommended to proceed with enrollment of the second cohort after a review of the 28-day safety data from the first cohort.

EPISOD1 is a Phase I/II multi-center, open-label trial of AMT-162 for the treatment of SOD1-ALS being conducted in the United States consisting of three dose-escalating cohorts with up to four patients each receiving a short course of immunosuppression prior to and after an intrathecal infusion of AMT-162.

The trial will explore the safety and tolerability of AMT-162 and will assess exploratory signs of efficacy by measuring neurofilament light chain, a biomarker of neuronal damage, and SOD1 protein.

Additional details are available on www.clinicaltrials.gov (NCT06100276).

The FDA cleared the IND application for AMT-162 and has granted Orphan Drug and Fast Track Designation.

EPISOD1 is our Phase I/II multi-center, open-label trial of AMT-162 for the treatment of SOD1-ALS conducted in the U.S.

consisting of three dose-escalating cohorts with up to four patients in each cohort.

The trial is designed to explore the safety and tolerability of AMT-162 and assess exploratory signs of efficacy by measuring neurofilament light chain, a biomarker of neuronal damage, and SOD1 protein.

In September 2025, we voluntarily paused enrollment in EPISOD1 upon the recommendation of the IDMC following a review of available preliminary data related to the safety and efficacy of AMT-162 in the context of a dose limiting toxicity, which resulted in an SAE determined to be related to AMT-162, that was observed in one patient in the second cohort.

We continue to collect and evaluate data from the five patients dosed in EPISOD1 to date .

Liver-directed diseases

Hemophilia B (HEMGENIX® or etranacogene dezaparvovec)

Hemophilia B Disease and Market Background

Hemophilia B is a rare, lifelong bleeding disorder caused by a single gene defect, resulting in insufficient production of factor IX, a protein primarily produced by the liver that helps blood clots form.

Treatments for moderate to severe hemophilia B include prophylactic infusions of factor IX replacement therapy to temporarily replace or supplement low levels of blood-clotting factor and, while these therapies are effective, those with hemophilia B must adhere to strict, lifelong infusion schedules.

They may also still experience spontaneous bleeding episodes as well as limited mobility, joint damage or severe pain as a result of the disease.

For appropriate patients, HEMGENIX® allows people living with hemophilia B to produce their own factor IX, which can lower the risk of bleeding.

CSL Behring collaboration

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

The transaction became fully effective in May 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.

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

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

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

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

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.

We are contractually obligated to supply the Product until such time that these capabilities are transferred to CSL Behring or its designated contract manufacturing organization.

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.

Fabry disease program (AMT-191)

15 unchanged sentences

Fabry disease occurs in all racial and ethnic populations and affects males and females.

It is estimated that type 1 classic Fabry disease affects approximately one in 40,000 males and approximately one in 20,000 females.

It is estimated that type 1 classic Fabry disease affects at least one in 40,000 males and approximately one in 20,000 females.

In the U.S., there may be approximately 7,000 type 1 Fabry patients.

The type 2 later-onset phenotype is more frequent, and in some populations may occur as frequently as about 1 in 1,500 to 4,000 males.

1 unchanged sentence

AMT-191 is our investigational gene therapy candidate for the treatment of Fabry disease.

AMT-191 is comprised of an AAV5 capsid that incorporates the α-galactosidase A (GLA) transgene and a proprietary, highly potent, liver-specific promoter.

In November 2023 we announced that FDA had cleared the investigation new drug application (“IND”) for AMT-191.

We are conducting a Phase I/IIa clinical trial in the United States.

The multicenter, open-label clinical trial consists of two dose-escalating cohorts of three patients each to assess safety, tolerability, and efficacy of AMT-191 in patients with Fabry disease.

Three patients will be dosed in the initial dose.

If no dose-limiting toxicology is identified, the dose will be escalated.

If dose-limiting toxicology occurs in one of the three initial patients, three additional patients will be enrolled at the same dose level.

If no additional patients in the cohort experience a dose-limiting toxicology, the dose will be escalated.

Assessments will be made at three- and six-months post-treatment.

In August 2024, we announced that the first patient has been dosed in a Phase I/IIa clinical trial of AMT-191 for the treatment of Fabry disease.

In September 2024, we announced the FDA granted Orphan Drug Designation to AMT-191 and in October 2024, the FDA granted Fast Track Designation to AMT-191.

In February 2025, we announced the completion of enrollment in the first cohort of the Phase I/IIa trial.

Additionally, the Independent Data Monitoring Committee reviewed safety data from the initial two patients enrolled in the first cohort.

AMT-191 is comprised of an AAV5 capsid that incorporates the GLA transgene and a proprietary, highly potent, liver-specific promoter.

In 2023 we announced that the FDA had cleared the IND for AMT-191, and in 2024 we announced that the FDA granted Orphan Drug Designation and Fast Track Designation to AMT-191.

We are conducting a Phase I/II clinical trial in the U.S.

The multicenter, open-label clinical trial consists of three dose-ranging cohorts of three or more patients each to assess safety, tolerability, and efficacy of AMT-191 in patients with Fabry disease.

In February 2025, we announced the completion of enrollment in the first cohort of the Phase I/II trial.

Additionally, the IDMC reviewed safety data from the initial two patients enrolled in the first cohort.

The IDMC’s review did not identify any significant safety concerns and recommended proceeding with enrollment in the second cohort.

In 2025, we enrolled three patients in a second cohort and four patients in a third cohort in our Phase I/II clinical trial of AMT-191.

Hemophilia B (HEMGENIX ® or etranacogene dezaparvovec)

Hemophilia B Disease and Market Background

They may also still experience spontaneous bleeding episodes as well as limited mobility, joint damage or severe pain as a result of the disease.

For appropriate patients, HEMGENIX allows people living with hemophilia B to produce their own factor IX, which can lower the risk of bleeding.

CSL Behring collaboration

In June 2020, we entered into a commercialization and license agreement with CSL Behring LLC (the “CSL Behring Agreement”) pursuant to which CSL Behring LLC (“CSL Behring”) received exclusive global rights to HEMGENIX.

The transaction became fully effective in May 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.

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

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

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

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

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

We are contractually obligated to supply the product until such time that these capabilities are transferred to CSL Behring or its designated contract manufacturing organization.

In September 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.

In addition, in July 2024, as part of the closing of the asset purchase agreement among our affiliates, uniQure Inc.

and uniQure biopharma B.V.

(“uniQure biopharma”), and Genezen Holdings Inc.

and its subsidiary Genezen MA, Inc.

(together “Genezen”) to sell certain assets and assume certain liabilities related to our former manufacturing facility and operations in Lexington, Massachusetts (the “Lexington Transaction”), we transferred the manufacturing and supply activities to Genezen such that Genezen manufactures and supplies CSL Behring’s commercial demand for HEMGENIX on our behalf.

New Technology Development

2 unchanged sentences

(i) the capsid, or the outer viral protein shell that encloses the target deoxyribonucleic acid (“DNA”);

(ii) the cargo, including the transgene or therapeutic gene, and promoters, or the DNA sequence that drives the expression of the transgene;

(ii) the cargo, including the transgene or therapeutic gene, and promoters, or the DNA sequence that drives or regulates the expression of the transgene;

and (iii) administration techniques.

5 unchanged sentences

We have also demonstrated the ability to deliver engineered DNA constructs that can silence or suppress disease-causing genes.

Our miQURE gene silencing platform, based on exclusively licensed technology from Cold Spring Harbor Laboratory (“CSHL”), is designed to degrade mutated genes without off-target toxicity and induce silencing of the mutated gene in the entire target organ through secondary exosome-mediated delivery.

Our miQURE gene silencing platform, based on exclusively licensed technology from Cold Spring Harbor Laboratory (“CSHL”), is designed to degrade mutated genes without producing a “passenger strand” thereby mitigating potential off-target toxicity and induce silencing of the mutated gene in the entire target organ through secondary exosome-mediated delivery.

miQURE-based gene therapy candidates, such as AMT-130, incorporate proprietary, therapeutic miRNA constructs that can be delivered using AAVs to potentially provide long-lasting activity.

2 unchanged sentences

Our Intellectual Property

We strive to protect the proprietary technologies that we believe are important to our business, including by seeking and maintaining patent protection in the U.S., Europe, and other jurisdictions for novel components of our gene therapies, the chemistries of and processes for manufacturing these gene therapies, the use of these components in gene therapies, our technology platform, and other inventions and related technology.

We also rely on trade secrets, security measures and careful monitoring of our proprietary information to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection.

We expect that our probability of success will be significantly enhanced by our ability to obtain and maintain patent and other proprietary protection for commercially important technology, inventions and know-how related to our business, defend and enforce our patents, maintain our licenses to use intellectual property owned by third parties, preserve the confidentiality of our trade secrets and operate without infringing the valid and enforceable patents and other proprietary rights of third parties.

To the extent applicable, we also rely on trade secrets, know-how protection measures and monitoring of our proprietary information to protect aspects of our business that are not amenable to, or that we do not consider appropriate for, patent protection.

We expect that our probability of success will be enhanced by our ability to obtain and maintain patent and other proprietary protection for commercially important technology, inventions and know-how related to our business, defend and enforce our patents, maintain our licenses to use intellectual property owned by third parties, preserve the confidentiality of our trade secrets and operate without infringing the valid and enforceable patents and other proprietary rights of third parties.

We also rely on know-how, continuing technological innovation and in-licensing opportunities to develop, strengthen and maintain our proprietary position in the field of AAV-based gene therapies.

3 unchanged sentences

We anticipate that we will require licenses to additional technology in the future.

Because most patent applications throughout the world are confidential for 18 months after the earliest claimed priority date, and since the publication of discoveries in the scientific and patent literature often lags actual discoveries, we cannot be certain that we were the first to invent or file applications for the inventions covered by our pending patent applications.

Because most patent applications throughout the world are confidential for 18 months after the earliest claimed priority date, and since the publication of discoveries in scientific and patent literature often lags actual discoveries, we cannot be certain that we were the first to invent or file applications for the inventions covered by our pending patent applications.

Moreover, we may have to participate in post-grant proceedings in the patent offices of the U.S.

10 unchanged sentences

For the same technologies, we typically file international patent applications under the Patent Cooperation Treaty (“PCT”) within one year.

After the PCT phase, we file patent applications in Europe (EPO) or the U.S., as applicable based on the jurisdiction in which we file the first patent application.

We also may seek, usually on a case-by-case basis, local patent protection in Canada, Australia, Japan, China, India, Israel, South Africa, New Zealand, South Korea, and Eurasia, as well as South American jurisdictions such as Brazil and Mexico.

During prosecution of the patent applications, we may file divisional applications at the EPO or divisionals or continuations in the U.S.

After the PCT phase, we file patent applications in Europe or the U.S., as applicable based on the jurisdiction in which we file the first patent application.

We also may seek, usually on a case-by-case basis, local patent protection in other jurisdictions, including Canada, Australia, Japan, China, India, Israel, South Africa, New Zealand, South Korea, and Eurasia, as well as South American jurisdictions, such as Brazil and Mexico.

During prosecution of the patent applications, we may file divisional applications at the European Patent Office (“EPO”) or divisionals or continuations in the U.S.

prior to the grant or issue of the patent.

1 unchanged sentence

As of December 31, 2025, our fully owned intellectual property portfolio included 147 issued patents (including 32 U.S.

patents and 15 patents granted by the European Patent Office (“EPO”)) and 127 (published) pending patent applications (including 27 U.S.

patents and 21 patents granted by the EPO) and 173 (published) pending patent applications (including 36 U.S.

patent applications and 31 patent applications pending at the EPO).

2 unchanged sentences

AMT-130 is a miQURE®-based gene-transcript silencing technology designed to degrade disease-causing gene transcripts without off-target toxicity while inducing silencing throughout the entire target organ through secondary exosome-mediated delivery.

We co-own two patent families, and fully own one patent family, directed to gene therapy-mediated treatment of TLE, including our product candidate AMT-260.

We co-own two patent families, and fully own one patent family, directed to the gene therapy-mediated treatment of TLE, including our product candidate AMT-260.

Of the two co-owned patent families, the co-owners have exclusively licensed their rights to us.

12 unchanged sentences

In 2015, we entered into a license agreement with CSHL in which CSHL granted to us an exclusive, sublicensable license to develop and commercialize certain of CSHL’s patented RNAi-related technology for use in connection with the treatment or prevention of Huntington’s disease.

We expanded the scope of the license agreement with CSHL in 2018 beyond Huntington’s disease to include the diagnosis, treatment, or prevention of all CNS diseases in the field.

Under the amended license agreement CSHL granted to us an exclusive license to develop and commercialize therapeutic products for the additional disease classifications in the field of liver diseases, neuromuscular diseases, and cardiovascular diseases, and we have subsequently added such products to our pipeline.

We expanded the scope of the license agreement with CSHL in 2018 beyond Huntington’s disease.

In addition, pursuant to the 2018 amendment, we were granted a license to use the RNAi-related technology for research in the fields of liver diseases, neuromuscular diseases, and cardiovascular diseases.

Under this license agreement, as amended, annual fees, development milestone payments and future single-digit royalties on net sales of a licensed product are payable to CSHL.

4 unchanged sentences

Temporal Lobe Epilepsy (AMT-260)

In June 2020, uniQure France SAS entered into an agreement, subsequently amended in June 2021, with Regenxbio for an exclusive (in the field of using AAV9 to expression of the GRIK2 gene in humans (the “Field”)), sublicensable, royalty-bearing, worldwide license under Regenxbio’s interest in EU patent application 19185533.7 (the “Foreground Patents”) and related patents, as well as patents covering inventions developed during the collaboration and certain patents and know-how relating to AAV9.

In June 2020, uniQure France entered into an agreement, subsequently amended in June 2021, with Regenxbio for an exclusive (in the field of using AAV9 to expression of the GRIK2 gene in humans (the “Field”)), sublicensable, royalty-bearing, worldwide license under Regenxbio’s interest in EU patent application 19185533.7 (the “Foreground Patents”) and related patents, as well as patents covering inventions developed during the collaboration and certain patents and know-how relating to AAV9.

The license also includes non-exclusive rights to exploit the licensed Foreground Patents and certain related patents know-how developed in collaboration pursuant to the license agreement outside the Field.

2 unchanged sentences

The agreement also calls for sublicense fees in the low-double digit range.

The royalty is paid on sales of license products using any of licensed patents or know-how for as long as the agreement is in effect.

The royalty is paid on sales of licensed products using any of licensed patents or know-how for as long as the agreement is in effect.

Royalty and milestone payments may continue to be owed under the license, following termination of the agreement if licensed products are sold following termination of the license.

Under the agreement, uniQure France SAS has certain diligence obligations and Regenxbio has certain obligations related to the pre-clinical development of manufacturing technology.

Under the agreement, uniQure France has certain diligence obligations and Regenxbio has certain obligations related to the pre-clinical development of manufacturing technology.

Inserm Transfert

In January 2020, uniQure France SAS entered into license agreement with Inserm Transfert SA (also acting as a delegate for the French National Institute of Health and Medical Research) and La societe SATT Aquitaine (the counterparties collectively referred to as “Inserm Transfert”).

Under the license agreement, uniQure France SAS is granted an exclusive, sublicensable, royalty-bearing, worldwide license under European Patent (“EP”) patent application 13306265.3 in the field of the prevention and treatment of epilepsy, and in Inserm Transfert’s share in EP patent application 19185533.7 (which is co-owned by Regenxbio) in the field of all human use.

uniQure France SAS also is granted a non-exclusive, sublicensable, royalty-bearing, worldwide license under certain know-how in the fields that may be developed by Inserm pursuant to the agreements.

Under the agreements, Inserm retains certain rights for teaching, academic and/or research purposes.

In January 2020, uniQure France entered into a license agreement with Inserm Transfert SA (also acting as a delegate for the French National Institute of Health and Medical Research) and La société SATT Aquitaine (the counterparties collectively referred to as “Inserm Transfert”).

Under the license agreement, uniQure France is granted an exclusive, sublicensable, royalty-bearing, worldwide license under European Patent (“EP”) patent application 13306265.3 in the field of the prevention and treatment of epilepsy, and in Inserm Transfert’s share in EP patent application 19185533.7 (which is co-owned by Regenxbio) in the field of all human use.

uniQure France is also granted a non-exclusive, sublicensable, royalty-bearing, worldwide license under certain know-how in the fields that may be developed by Inserm pursuant to the agreements.

Under the agreements, Inserm Transfert retains certain rights for teaching, academic and/or research purposes.

Payment obligations under the agreements include a royalty on the net sales of license products in the low single digits, milestone payments associated with clinical trial and regulatory approval milestones of multiple licensed products totaling in the low-single digit millions of Euros.

2 unchanged sentences

Amyotrophic Lateral Sclerosis (AMT-162)

In January 2023, we announced that we had entered into a global licensing agreement with Apic Bio for a one-time, intrathecally administered investigational gene therapy for ALS caused by mutations in SOD-1, pursuant to which we acquired an exclusive global license (including a sublicense of rights granted to Apic Bio pursuant to an exclusive license agreement with a certain U.S.-based academic institution) to Apic Bio’s rights under certain licensed technology to develop, manufacture, and commercialize any product incorporating a licensed construct (including APB-102, certain constructs expressing a SOD1-targeting microRNA or AAV that codes for a microRNA that silences SOD1 expression), in any dosage strength, formulation, concentration or method of delivery in the applicable field.

In January 2023, we announced that we had entered into a global licensing agreement with Apic Bio for a one-time, intrathecally administered investigational gene therapy for ALS caused by mutations in SOD-1, pursuant to which we acquired an exclusive global license (including a sublicense of rights granted to Apic Bio pursuant to an exclusive license agreement with a certain U.S.-based academic institution) to Apic Bio’s rights under certain licensed technology to develop, manufacture, and commercialize any product incorporating a licensed construct (including APB-102, certain constructs expressing a SOD1-targeting miRNA or AAV that codes for a miRNA that silences SOD1 expression), in any dosage strength, formulation, concentration or method of delivery in the applicable field.

We made an initial cash payment of $10.0 million to Apic Bio.

3 unchanged sentences

In addition to patents and licenses, we rely on trade secrets and know-how to develop and maintain our competitive position.

For example, significant aspects of the process by which we manufacture our gene therapies are based on unpatented trade secrets and know-how.

We seek to protect our proprietary technology and processes and obtain and maintain ownership of certain technologies, in part, through confidentiality agreements and invention assignment agreements with our employees, consultants, scientific advisors, contractors and commercial collaborator.

For example, significant aspects of the process by which we manufacture certain of our gene therapies are based on unpatented trade secrets and know-how.

We also seek to preserve the integrity and confidentiality of our data, trade secrets and know-how by maintaining physical security of our premises and physical and electronic security of our information technology systems.

3 unchanged sentences

We face substantial competition from many different sources, including large and specialty pharmaceutical and biotechnology companies, academic and other research institutions and governmental agencies and public and private research institutions that are developing and commercializing pharmaceutical products that may be competitive with ours.

Our key competitors focused on developing therapies in various indications, include among others, PTC Therapeutics, Roche, Wave Life Sciences, Alnylam Pharmaceuticals, Regeneron Pharmaceuticals and Skyhawk Therapeutics (for Huntington’s disease), Neurona Therapeutics and CombiGene (for TLE), Biogen, Ionis Pharmaceuticals, Neurimmune, Regeneron Pharmaceuticals, Alnylam Pharmaceuticals and Voyager Therapeutics (for ALS) and Amicus Therapeutics, Sanofi, Takeda, Chiesi, Idorsia, Sangamo Therapeutics, 4D Molecular Therapeutics, Skyline Pharmaceuticals and CANbridge (for Fabry disease).

We also compete with existing standards of care, therapies, and symptomatic treatments, as well as any new therapies and novel technologies, that may become available in the future for the indications we are targeting.

Our key competitors, focused on developing therapies in various indications, include among others, Novartis, Roche, Wave Life Sciences, Alnylam Pharmaceuticals, Regeneron Pharmaceuticals, Skyhawk Therapeutics and Sarepta Therapeutics (for Huntington’s disease), Neurona Therapeutics, EpilepsyGTx and Xenon Pharmaceuticals (for TLE), Biogen, Ionis Pharmaceuticals, Neurimmune, Regeneron Pharmaceuticals, Alnylam Pharmaceuticals, Coya Therapeutics, Amylyx Pharmaceuticals, NeuroSense Therapeutics, AL-S Pharma and Voyager Therapeutics (for ALS) and Amicus Therapeutics, Sanofi, Takeda, Chiesi, Idorsia, Sangamo Therapeutics, 4D Molecular Therapeutics, Skyline Pharmaceuticals and CANbridge (for Fabry disease).

We also compete with existing standards of care, therapies, and symptomatic treatments, as well as any new therapies and novel technologies, which may become available in the future for the indications we are targeting.

Many of our current or potential competitors, either alone or with their collaborators, have significantly greater financial resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials regulatory affairs, and marketing approved products than we do.

25 unchanged sentences

● approval by an independent institutional review board (“IRB”) and, for some studies, Institutional Biosafety Committee (“IBC”) before each clinical trial may be initiated;

● performance of adequate and well-controlled human clinical trials in accordance with the FDA’s cGCP to establish substantial evidence of the safety and efficacy for the proposed biological product for each indication;

● performance of adequate and well-controlled human clinical trials in accordance with the FDA’s current Good Clinical Practice regulations (“cGCP”) to establish substantial evidence of the safety and efficacy for the proposed biological product for each indication;

● preparation and submission to the FDA of a Biologics License Application (“BLA”);

● satisfactory completion of one or more FDA inspections or remote regulatory assessments of the manufacturing facility or facilities at which the product, or components thereof, are produced to assess compliance with current Good Manufacturing Practice (“cGMP”) requirements and to assure that the facilities, methods, and controls are adequate to preserve the product’s identity, strength, quality, and purity, as well as selected clinical trial sites and investigators to determine cGCP compliance;

● satisfactory completion of one or more FDA inspections of the manufacturing facility or facilities at which the product, or components thereof, are produced to assess compliance with current Good Manufacturing Practice (“cGMP”) requirements and to assure that the facilities, methods, and controls are adequate to preserve the product’s identity, strength, quality, and purity, as well as selected clinical trial sites and investigators to determine cGCP compliance;

● approval of the BLA by the FDA, in consultation with an FDA advisory committee, if deemed appropriate by the FDA;

4 unchanged sentences

Nonclinical studies include laboratory evaluation of chemistry, pharmacology, toxicity, and product formulation, as well as animal studies to assess potential safety and efficacy.

Such studies must generally be conducted in accordance with the FDA’s GLPs.

Clinical trials involve the administration of the investigational biologic to human subjects under the supervision of qualified investigators in accordance with current GCP requirements, which includes requirements for informed consent, study conduct, and IRB review and approval.

Such studies must generally be conducted in accordance with the FDA’s Good Laboratory Practices.

In 2025, however, the FDA announced a plan to reduce the need for animal testing, with an initial focus on monoclonal antibodies.

Clinical trials involve the administration of the investigational biologic to human subjects under the supervision of qualified investigators in accordance with cGCP requirements, which includes requirements for informed consent, study conduct, and IRB review and approval.

Special clinical trial ethical considerations also must be considered if a study involves children.

A protocol for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of an IND.

Sponsors will be required to provide the FDA with diversity action plans.

INDs include nonclinical study reports, together with manufacturing information, analytical data, any available clinical data, or literature, and proposed clinical study protocols among other things.

17 unchanged sentences

This may result in a need to modify an ongoing clinical trial to incorporate this feedback or even a clinical hold of the trial.

There is also risk that FDA may not provide comments or feedback but may ultimately disagree with the design of the study once a BLA is submitted.

There is also risk that the FDA may not provide comments or feedback but may ultimately disagree with the design of the study once a BLA is submitted.

Human clinical trials are typically conducted in three sequential phases, which may overlap or be combined:

2 unchanged sentences

The biological product is administered to an expanded patient population, generally at geographically dispersed clinical trial sites, in adequate and well-controlled clinical trials to generate sufficient data to statistically confirm the potency and safety of the product for approval, to establish the overall risk-benefit profile of the product and to provide adequate information for the labelling of the product.

Typically, two Phase III trials are required by the FDA for product approval.

Under some limited circumstances, however, the FDA may approve a BLA based upon a single Phase III clinical study plus confirmatory evidence or a single large multicenter trial without confirmatory evidence.

Recent legislation further established a new program that may be used to facilitate future marketing applications and development programs following a first product approval.

The FDA typically requires that a BLA include data from adequate and well-controlled clinical trials which provide substantial evidence of efficacy.

Legislation further established a new program that may be used to facilitate future marketing applications and development programs following a first product approval.

Specifically, the Consolidated Appropriations Act, 2023 established a program whereby a platform technology that is incorporated within or utilized by an approved drug or biologic product may be designated as a platform technology, provided that certain conditions are met, in which case development and approval of subsequent products using such technology may be expedited.

In addition, under the Pediatric Research Equity Act (the “PREA”), a BLA or BLA supplement for a new active ingredient, indication, dosage form, dosage regimen, or route of administration, must contain data that are adequate to assess the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

In addition, under the Pediatric Research Equity Act of 2003 (the “PREA”), a BLA or BLA supplement for a new active ingredient, indication, dosage form, dosage regimen, or route of administration, must contain data that are adequate to assess the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements.

10 unchanged sentences

Regulation and FDA Guidance Governing Gene Therapy Products

The FDA has and continues to issue various guidance documents with respect to the development and commercialization of gene therapies.

These include guidance on, among other things, the proper preclinical and nonclinical assessment of gene therapies;

the chemistry, manufacturing, and controls;

the design and conduct of clinical trials and product development;

the design and analysis of shedding studies for virus or bacteria based gene therapies;

the proper design of tests to measure product potency in support of an IND or BLA application;

and measures to observe delayed adverse effects in subjects and patients who have been exposed to gene therapies via long-term follow-up with associated regulatory reporting.

The FDA has also issued guidance on the development of gene therapies for the treatment of neurodegenerative diseases, rare diseases, and hemophilia, as such products may face special challenges.

The FDA has and continues to issue various guidance documents with respect to the development and commercialization of gene therapies, including for specific diseases, such as neurodegenerative diseases, rare diseases, and hemophilia, as such products may face special challenges.

Certain gene therapy studies are also subject to the National Institutes of Health’s Guidelines for Research Involving Recombinant DNA Molecules, (“NIH Guidelines”).

4 unchanged sentences

Manufacturers and others involved in the manufacture and distribution of such products must also register their establishments with the FDA and certain state agencies and provide the FDA a list of products manufactured at the facilities.

Recently, the information that must be submitted to the FDA regarding manufactured products was expanded through the Coronavirus Aid, Relief, and Economic Security (CARES) Act to include the volume of drugs produced during the prior year.

Establishments may be subject to periodic unannounced inspections and remote regulatory assessments by government authorities to ensure compliance with cGMPs and other laws.

Discovery of non-compliance may result in the FDA placing restrictions on a product, manufacturer, or holder of an approved BLA, and may extend to requiring withdrawal of the product from the market, recall, shutdown, enforcement letters, among other consequences.

Sponsors must further submit information to the FDA regarding manufactured products, including the volume of drugs produced during the prior year.

Establishments may be subject to periodic unannounced inspections by government authorities to ensure compliance with cGMPs and other laws.

Discovery of non-compliance may result in the FDA issuing a Form 483, placing restrictions on a product, manufacturer, or holder of an approved BLA, and may extend to requiring withdrawal of the product from the market, recall, shutdown, or enforcement letters, among other consequences.

Noncompliance with the applicable manufacturing requirements may also require costly corrective and preventative actions.

6 unchanged sentences

This may be demonstrated by clinical or nonclinical data.

If granted, the benefits include greater interactions with the FDA and potentially rolling review of sections of the BLA.

If granted, the benefits include more frequent interactions with the FDA and potentially rolling review of sections of the BLA.

In some cases, a fast track product may be eligible for accelerated approval or priority review.

2 unchanged sentences

Products designated as breakthrough therapies are potentially eligible for rolling review, as well as intensive guidance on an efficient development program beginning as early as Phase I trials, and a commitment from the FDA to involve senior managers and experienced review staff in a proactive collaborative, cross disciplinary review.

Biologics studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit over existing treatments may receive accelerated approval, which means the FDA may approve the product based upon a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.

Biologics studied for their safety and effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit over existing treatments may receive accelerated approval, which means the FDA may approve the product based upon a surrogate endpoint that is reasonably likely to predict clinical benefit, or on an intermediate clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.

A biologic candidate approved on this basis is subject to rigorous post-marketing compliance requirements, including the completion of Phase 4 or post-approval clinical trials to confirm the effect on the clinical endpoint.

24 unchanged sentences

The FDA may also refer certain applications to an advisory committee.

Before approving a product candidate for which no active ingredient (including any ester or salt of active ingredients) has previously been approved by the FDA, the FDA must either refer that product candidate to an external advisory committee or provide in an action letter, a summary of the reasons why the FDA did not refer the product candidate to an advisory committee.

The FDA may also refer other product candidates to an advisory committee if the FDA believes that the advisory committee’s expertise would be beneficial.

An advisory committee is typically a panel that includes clinicians and other experts, which review, evaluate, and make a recommendation as to whether the application should be approved and under what conditions.

An advisory committee is typically a panel that includes clinicians and other experts, which reviews, evaluates, and makes recommendations as to whether the application should be approved and under what conditions.

The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

The FDA reviews applications to determine, among other things, whether a product candidate meets the agency’s approval standards and whether the manufacturing methods and controls are adequate to assure and preserve the product’s identity, strength, quality, potency, and purity.

Before approving a marketing application, the FDA typically will inspect or conduct remote regulatory assessments of the facility or facilities where the product is manufactured.

Before approving a marketing application, the FDA typically will inspect the facility or facilities where the product is manufactured.

The FDA will not approve an application unless it determines that the manufacturing processes and facilities, including contract manufacturers and subcontractors, are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.

Additionally, before approving a marketing application the FDA will inspect or conduct remote regulatory assessments of one or more clinical trial sites to assure compliance with good clinical practices (“GCPs”).

After evaluating the marketing application and all related information, including the advisory committee recommendation, if any, and inspection and remote regulatory inspection reports regarding the manufacturing facilities and clinical trial sites, the FDA may issue an approval letter or a complete response letter.

Additionally, before approving a marketing application the FDA will inspect one or more clinical trial sites to assure compliance with cGCPs.

After evaluating the marketing application and all related information, including the advisory committee recommendation, if any, and inspection reports regarding the manufacturing facilities and clinical trial sites, the FDA may issue an approval letter or a complete response letter.

An approval letter authorizes commercial marketing of the biological product with specific prescribing information for specific indications.

A complete response letter generally outlines the deficiencies in the submission and may require substantial additional testing or information for the FDA to reconsider the application.

In 2025, the FDA began publicly releasing complete response letters after issuance, for both products that eventually obtained approval and products that have not yet received approval.

Even with submission of this additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.

11 unchanged sentences

Following product approval, a REMS may also be required by the FDA if new safety information is discovered, and the FDA determines that a REMS is necessary to ensure that the benefits of the product outweigh the risks.

In guidance, FDA stated that during the review of a BLA for a gene therapy, it will assess whether a REMS is necessary.

Several gene therapy products that have been approved by FDA have required substantial REMS, which included requirements for dispensing hospital and clinic certification, training, adverse event reporting, documentation, and regulatory audits and monitoring conducted by the sponsor, among other conditions.

During the review of a BLA for a gene therapy, the FDA will assess whether a REMS is necessary.

Several gene therapy products that have been approved by the FDA have required substantial REMS, which included requirements for dispensing hospital and clinic certification, training, adverse event reporting, documentation, and regulatory audits and monitoring conducted by the sponsor, among other conditions.

REMS, such as these, can be expensive and burdensome to implement, and burdensome for hospitals, clinics, and healthcare providers to comply with.

19 unchanged sentences

To increase competition in the drug and biologic product marketplace, Congress, the executive branch, and the FDA have taken certain legislative and regulatory steps.

By example, the FDA finalized a guidance to facilitate biologic product importation.

For example, the FDA finalized certain guidance documents to facilitate biologic product importation.

Moreover, the 2020 Further Consolidated Appropriations Act included provisions requiring that sponsors of approved biologic products, including those subject to REMS, provide samples of the approved products to persons developing biosimilar products within specified timeframes, in sufficient quantities, and on commercially reasonable market-based terms.

Failure to do so can subject the approved product sponsor to civil actions, penalties, and responsibility for attorney’s fees and costs of the civil action.

This same bill also includes provisions with respect to shared and separate REMS programs.

This same legislation also includes provisions with respect to shared and separate REMS programs.

Orphan Drug Exclusivity

Under the Orphan Drug Act of 1983, the FDA may designate a biological product as an orphan drug if it is intended to treat a rare disease or condition that affects fewer than 200,000 individuals in the U.S., or more in cases in which there is no reasonable expectation that the cost of developing and making a biological product available in the U.S.

for treatment of the disease or condition will be recovered from sales of the product.

for treatment of the disease or condition will be recovered from sales of the product, and where there is a medically plausible basis for the use of the drug for the rare disease or condition.

Additionally, sponsors must present a plausible hypothesis for clinical superiority to obtain orphan drug designation if there is a product already approved by the FDA that is considered by the FDA to be the same as the already approved product and is intended for the same indication.

2 unchanged sentences

Specifically, whether two products are deemed to be the same by the FDA will depend on the products’ transgene expression, viral vectors groups and variants, and additional product features that may contribute to therapeutic effect.

Minor product differences will not, generally, result in a finding that two products are different and there are some factors that FDA will consider on a case-by-case basis.

Minor product differences will not, generally, result in a finding that two products are different and there are some factors that the FDA will consider on a case-by-case basis.

Any of the FDA sameness determinations could impact our ability to receive approval for our product candidates and to obtain or retain orphan drug exclusivity.

1 unchanged sentence

Competitors may receive approval of different products for the indication for which the orphan product has exclusivity and may obtain approval for the same product but for a different indication.

Notably, a 2021 judicial decision, Catalyst Pharms., Inc.

Becerra , 14 F.

4 th 1299 (11th Cir 2021), challenged and reversed an FDA decision on the scope of orphan product exclusivity for the drug, Firdapse .

Under this decision, orphan drug exclusivity for Firdapse blocked approval of another company’s application for the same drug for the entire disease or condition for which orphan drug designation was granted, not just the disease or condition for which approval was received.

In a January 2023 Federal Register notice, however, FDA stated that it intends to continue to apply its regulations tying the scope of orphan-drug exclusivity to the uses or indications for which a drug is approved.

The exact scope of orphan drug exclusivity will likely be an evolving area.

Orphan drug designation does not change the FDA’s standard for product approval.

The FDA’s regulations, however, provide flexibility in meeting such approval standards such that the FDA may exercise scientific judgment in determining the kind and quantity of data required for approval and during development programs.

Per guidance issued by the FDA in 2023, “[t]his flexibility extends from the early stages of development to the design of adequate and well-controlled clinical investigations required to demonstrate effectiveness to support marketing approval and to establish safety data needed for the intended use.” The FDA states that it “is committed to helping sponsors create successful drug development programs that address the particular challenges posed by each disease.”

Pediatric Exclusivity

Under the Pediatric Research Equity Act of 2003, pediatric exclusivity provides for the attachment of an additional six months of marketing protection to the term of any existing regulatory exclusivity in the US, including orphan exclusivity and reference biologic exclusivity.

Under the PREA, pediatric exclusivity provides for the attachment of an additional six months of marketing protection to the term of any existing regulatory exclusivity in the US, including orphan exclusivity and reference biologic exclusivity.

This six-month exclusivity may be granted if the FDA issues a written request to the sponsor for the pediatric study, the sponsor submits a final study report after receipt of the written request and meets the terms and timelines in the FDA’s written request.

Regenerative Advanced Therapy Designation

The 21 st Century Cures Act became law in December 2016 and created a new program under Section 3033 in which the FDA has authority to designate a product as a regenerative medicine advanced therapy (“RMAT”).

Regenerative Medicine Advanced Therapy Designation

The 21 st Century Cures Act became law in December 2016 and created a new program under Section 3033 in which the FDA has authority to designate a product as a RMAT.

A drug is eligible for a RMAT designation if:

3 unchanged sentences

A RMAT designation request must be made with the submission of an IND or as an amendment to an existing IND.

FDA will determine if a product is eligible for RMAT designation within 60 days of submission.

The FDA will determine if a product is eligible for RMAT designation within 60 days of submission.

Advantages of the RMAT designation include all the benefits of the fast track and breakthrough therapy designation programs, including early interactions with the FDA.

2 unchanged sentences

FDA Regulation of Companion Diagnostics and Other Combination Products

We may seek to develop companion diagnostics for use in identifying patients that we believe will respond to our gene therapies.

We may seek to develop companion diagnostics for use in identifying patients who we believe are more likely to respond to our gene therapies.

Similarly, our product candidates may require delivery devices.

2 unchanged sentences

In some cases, the medical device component may require a separate premarket submission.

Moreover, clinical trial sponsors using investigational devices in their studies must comply with FDA’s investigational device exemption regulations.

Moreover, clinical trial sponsors using investigational devices in their studies must comply with the FDA’s investigational device exemption regulations.

If the device component (e.g., in vitro diagnostic device) is not packaged with the drug component and authorized by the FDA as a combination product, or approved or cleared as a medical device, the device component must comply with the FDA general controls applicable to a medical device, including establishment registration, device listing, device labeling, unique device identifier, quality system regulation, medical device reporting, and reporting of corrections and removals requirements.

7 unchanged sentences

Except in some limited circumstances, the FDA generally will not approve a biologic that is dependent upon the use of a companion diagnostic device if the device is not contemporaneously FDA-approved or -cleared.

It’s also possible that an in vitro diagnostic device could be subject to FDA enforcement discretion from compliance with the FDCA if it meets the definition of a Laboratory Developed Test (“LDT”).

However, FDA issued a final rule in April 2024 to end enforcement discretion for LDTs and actively regulate such products as medical devices.

Under this final rule, LDTs are required to come into compliance with FDA’s medical device regulatory requirements in a staged approach over the course of four years.

The implementation of this LDT final rule could potentially be affected by the Executive Order, Regulatory Freeze Pending Review, issued by President Trump on January 20, 2025 and/or the anticipated change in leadership at FDA under the new administration.

It is also possible that a diagnostic test could be considered outside the scope of the FDA’s regulatory authority if it meets the definition of a Laboratory Developed Test (“LDT”).

The FDA attempted to actively regulate all LDTs as medical devices through a final rule in April 2024, but this rule was challenged in the US District Court for the Eastern District of Texas, which found that LDTs are not medical devices and thus not subject to the FDA’s device authority.

Nonetheless, LDTs remain subject to the regulatory requirements under the Clinical Laboratory Improvement Amendments.

Post-approval Requirements

Any products manufactured or distributed pursuant to the FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements related to manufacturing, recordkeeping, and reporting, including adverse experience reporting, deviation reporting, shortage reporting, and periodic reporting, product sampling and distribution, advertising, marketing, promotion, certain electronic records and signatures, and post-approval obligations imposed as a condition of approval, such as Phase 4 clinical trials, REMS, and surveillance to assess safety and effectiveness after commercialization.

Any products manufactured or distributed pursuant to the FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements related to manufacturing, recordkeeping, and reporting, including adverse experience reporting, deviation reporting, shortage reporting, and periodic reporting, product sampling and distribution, long term follow-up, advertising, marketing, promotion, certain electronic records and signatures, and post-approval obligations imposed as a condition of approval, such as Phase 4 clinical trials, REMS, and surveillance to assess safety and effectiveness after commercialization.

After approval, most changes to the approved product, such as adding new indications or other labeling claims, are subject to prior FDA review and approval.

2 unchanged sentences

Changes to the manufacturing process are strictly regulated and often require prior FDA approval or notification before being implemented.

In fact, in 2023, the FDA issued a guidance specifically on demonstrating product comparability, and the management and reporting of manufacturing changes for investigational and licensed cellular and gene therapy products.

For example, in 2023, the FDA issued a guidance specifically on demonstrating product comparability, and the management and reporting of manufacturing changes for investigational and licensed cellular and gene therapy products.

FDA regulations also require investigation and correction of any deviations from cGMP and specifications and impose reporting and documentation requirements upon the sponsor and any third-party manufacturers that the sponsor may decide to use.

Accordingly, manufacturers must continue to expend time, money, and effort in production and quality control to maintain cGMP compliance.

In addition to the above manufacturing requirements, the FDA and the current U.S.

presidential administration have taken actions to encourage the use of U.S.

domestic manufacturing and supply chains.

This includes executive orders intended to facilitate and streamline the development of U.S.

manufacturing, enhance the inspection of foreign manufacturing facilities, and increase foreign manufacturing facility user fees.

The FDA also strictly regulates marketing, labeling, advertising, and promotion of products that are placed on the market.

3 unchanged sentences

Companies must also provide adequate balancing information on a product’s risks in its advertising and promotional pieces.

In 2023, the FDA took a few actions in the advertising and promotional spaces, including issuing a final rule and a guidance on risk and efficacy disclosures in direct-to-consumer advertising.

At the beginning of 2025, FDA also finalized guidance on communication of off-label scientific information about approved products.

In 2023, the FDA took certain regulatory actions in the advertising and promotional spaces, including issuing a final rule and a guidance on risk and efficacy disclosures in direct-to-consumer advertising.

At the beginning of 2025, the FDA also finalized guidance on communication of off-label scientific information about approved products.

The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly promoted off-label uses may be subject to significant liability, including, but not limited to, criminal fines and civil penalties under the FDCA and False Claims Act, exclusion from participation in federal healthcare programs, mandatory compliance programs under corporate integrity agreements, suspension and debarment from government procurement and non-procurement programs, and refusal of orders under existing government contracts.

1 unchanged sentence

Among the requirements of this legislation, sponsors are required to provide certain information regarding the products to individuals and entities to which product ownership is transferred, are required to label products with a product identifier, and are required to keep certain records regarding the product.

The transfer of information to subsequent product owners by sponsors is also required to be done electronically and will be required to allow interoperable electronic product tracing at the package level.

The transfer of information to subsequent product owners by sponsors is also required to be done electronically and allow interoperable electronic product tracing at the package level.

Sponsors must also verify that purchasers of the sponsors’ products are appropriately licensed.

Further, under this legislation, manufactures have product verification responsibilities, as well as investigation, quarantine, disposition, and notification responsibilities related to counterfeit, diverted, stolen, and intentionally adulterated products that would result in serious adverse health consequences or death to humans, as well as products that are the subject of fraudulent transactions or which are otherwise unfit for distribution such that they would be reasonably likely to result in serious health consequences or death.

Similar requirements additionally are also imposed through this legislation on other companies within the biopharmaceutical product supply chain, such as distributors and dispensers, as well as certain sponsor licensees and affiliates.

Further, under this legislation, manufacturers have product verification responsibilities, as well as investigation, quarantine, disposition, and notification responsibilities related to counterfeit, diverted, stolen, and intentionally adulterated products that would result in serious adverse health consequences or death to humans, as well as products that are the subject of fraudulent transactions or which are otherwise unfit for distribution such that they would be reasonably likely to result in serious health consequences or death.

Similar requirements are also imposed on other entities in the biopharmaceutical supply chain, including distributors and dispensers, as well as certain sponsor licensees and affiliates.

Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements before or after approval, may result in significant regulatory actions.

14 unchanged sentences

Patent and Trademark Office and granted, patent term restoration extends the patent life of a single unexpired patent, that has not previously been extended, for a maximum of five years.

The total patent life of the product with the extension also cannot exceed fourteen years from the product’s approval date.

Subject to the prior limitations, the period of the extension is calculated by adding half of the time from the effective date of an IND to the initial submission of a complete marketing application, and all the time between the submission of the marketing application and its approval.

This period may also be reduced by any time that the applicant did not act with due diligence.

The total patent life of the product with the extension cannot exceed fourteen years from the product’s approval date.

Subject to the prior limitations, the period of the extension is calculated by factoring in half of the time from the effective date of an IND to the initial submission of a complete marketing application, all the time between the submission of the marketing application and its approval, and any period that the applicant did not act with due diligence.

Anti-Kickback Provisions and other Fraud and Abuse Requirements

10 unchanged sentences

In addition, the ACA also provided that a violation of the AKS is grounds for the government or a whistleblower to assert that a claim for reimbursement submitted to a federal healthcare program for payment of items or services resulting from such violation constitutes a per se false or fraudulent claim for purposes of the federal civil False Claims Act.

The Department of Health and Human Services (“HHS”) promulgated a regulation in November 2020 with respect to the safe harbors that is effective in two phases.

The Department of Health and Human Services promulgated regulations in November 2020 with respect to the safe harbors that are effective in two phases.

First, the regulation excludes from the definition of “remuneration” limited categories of (a) Pharmacy Benefit Manager (“PBM”) rebates or other reductions in price to a plan sponsor under Medicare Part D or a Medicaid Managed Care Organization plan reflected in point-of-sale reductions in price and (b) PBM service fees.

Second, the regulation expressly provides that rebates to plan sponsors under Medicare Part D, either directly to the plan sponsor under Medicare Part D or indirectly through a PBM, will not be protected under the AKS discounts safe harbor.

The Inflation Reduction Act of 2022 extended a moratorium on the implementation, administration or enforcement of this final rule until January 1, 2032.

The Inflation Reduction Act of 2022 (“IRA”) extended a moratorium on the implementation, administration or enforcement of this final rule until January 1, 2032.

The federal civil False Claims Act prohibits any person from knowingly presenting, or causing to be presented, a false or fraudulent claim for payment to, or approval by, the federal government, knowingly making, using, or causing to be made or used a false record or statement material to a false or fraudulent claim to the federal government, or avoiding, decreasing, or concealing an obligation to pay money to the federal government.

1 unchanged sentence

The civil False Claims Act has been used to assert liability on the basis of kickbacks and other improper referrals, improperly reported government pricing metrics such as Best Price or Average Manufacturer Price, improper use of Medicare provider or supplier numbers when detailing a provider of services, improper promotion of off-label uses not expressly approved by the FDA in a product’s label, and allegations as to misrepresentations with respect to products, contract requirements, and services rendered.

In addition, private payers have been filing follow-on lawsuits alleging fraudulent misrepresentation, although establishing liability and damages in these cases is more difficult than under the FCA.

In addition, private payers have been filing follow-on lawsuits alleging fraudulent misrepresentation, although establishing liability and damages in these cases is more difficult than under the False Claims Act.

Intent to deceive is not required to establish liability under the civil False Claims Act.

3 unchanged sentences

If the government declines to intervene, the individual may pursue the case alone.

The civil FCA provides for treble damages and a civil penalty for each false claim, such as an invoice or pharmacy claim for reimbursement, which can aggregate into tens and even hundreds of millions of dollars.

The civil False Claims Act provides for treble damages and a civil penalty for each false claim, such as an invoice or pharmacy claim for reimbursement, which can aggregate into tens and even hundreds of millions of dollars.

For these reasons, since 2004, False Claims Act lawsuits against biopharmaceutical companies have increased significantly in volume and breadth, leading to several substantial civil and criminal settlements, as much as $3.0 billion, regarding certain sales practices and promoting off label uses.

Civil False Claims Act liability may further be imposed for known Medicare or Medicaid overpayments, for example, overpayments caused by understated rebate amounts, that are not refunded within 60 days of the identification of the overpayment, even if the overpayment was not caused by a false or fraudulent act.

In addition, civil judgment for violating the FCA may result in exclusion from federal healthcare programs, suspension and debarment from government procurement and non-procurement programs, and refusal of orders under existing government contracts.

In addition, civil judgment for violating the False Claims Act may result in exclusion from federal healthcare programs, suspension and debarment from government procurement and non-procurement programs, and refusal of orders under existing government contracts.

The majority of states also have statutes similar to the AKS and civil False Claims Act, which apply to items and services reimbursed under Medicaid and other state programs, or, in several states, apply regardless of the payer.

2 unchanged sentences

The Civil Monetary Penalties Law is another potential statute under which biopharmaceutical companies may be subject to enforcement.

Among other things, the civil monetary penalties statue imposes fines against any person who is determined to have knowingly presented, or caused to be presented, claims to a federal healthcare program that the person knows, or should know, is for an item or service that was not provided as claimed or is false or fraudulent.

Among other things, the civil monetary penalties statute imposes fines against any person who is determined to have knowingly presented, or caused to be presented, claims to a federal healthcare program that the person knows, or should know, is for an item or service that was not provided as claimed or is false or fraudulent.

Payment or reimbursement of prescription therapeutics by Medicaid or Medicare requires sponsors to submit certified pricing information to the Centers for Medicare and Medicaid Services (“CMS”).

5 unchanged sentences

A Department of Defense regulation requires sponsors to provide this discount on therapeutics dispensed by retail pharmacies when paid by the TRICARE Program.

All these price reporting requirements create risk of submitting false information to the government, potential FCA liability and exclusion from certain of these programs.

All these price reporting requirements create risk of submitting false information to the government, potential False Claims Act liability and exclusion from certain of these programs.

The VHCA also requires sponsors of covered therapeutics participating in the Medicaid program to enter into Federal Supply Schedule contracts with the VA through which their covered therapeutics must be sold to certain federal agencies at FCP.

2 unchanged sentences

The 340B program has its own regulatory authority to impose sanctions for non-compliance, adjudicate overcharge claims against sponsors by the purchasing entities, and impose civil monetary penalties for instances of overcharging.

The federal Health Insurance Portability and Accountability Act of 1996, (“HIPAA”), also created federal criminal statutes that prohibit, among other actions, knowingly and willfully executing, or attempting to execute, a scheme to defraud or to obtain, by means of false or fraudulent pretenses, representations or promises, any of the money or property owned by, or under the custody or control of, a healthcare benefit program, regardless of whether the payor is public or private, in connection with the delivery of or payment for healthcare benefits, knowingly and willfully embezzling or stealing from a healthcare benefit program, willfully obstructing a criminal investigation of a healthcare offense and knowingly and willfully falsifying, concealing, or covering up by any trick or device a material fact or making any materially false statements in connection with the delivery of, or payment for, healthcare benefits, items, or services relating to healthcare matters.

The federal Health Insurance Portability and Accountability Act of 1996, (“HIPAA”), also created federal criminal statutes that prohibit, among other actions, knowingly and willfully executing, or attempting to execute, a scheme to defraud or to obtain, by means of false or fraudulent pretenses, representations or promises, any of the money or property owned by, or under the custody or control of, a healthcare benefit program, regardless of whether the payer is public or private, in connection with the delivery of or payment for healthcare benefits, knowingly and willfully embezzling or stealing from a healthcare benefit program, willfully obstructing a criminal investigation of a healthcare offense and knowingly and willfully falsifying, concealing, or covering up by any trick or device a material fact or making any materially false statements in connection with the delivery of, or payment for, healthcare benefits, items, or services relating to healthcare matters.

Additionally, the ACA amended the intent requirement of certain of these criminal statutes under HIPAA so that a person or entity no longer needs to have actual knowledge of the statute, or the specific intent to violate it, to have committed a violation.

13 unchanged sentences

HIPAA privacy rules governing disclosures of protected health information by covered entities for research purposes may apply to gene therapy studies.

In addition, other federal and state laws, such as the California Consumer Privacy Act and state security breach notification laws and state consumer healthcare privacy laws, may govern the privacy and security of health and other information in certain circumstances, many of which differ from each other in significant ways, thus complicating compliance efforts.

Many states have also adopted laws similar to each of the above federal laws, which may be broader in scope and apply to items or services reimbursed by any third-party payor, including commercial insurers.

In addition, other federal and state laws, including state health information privacy laws, state security breach notification laws, and state consumer privacy laws (e.g., the California Consumer Privacy Act), may govern the privacy and security of health and other information in certain circumstances.

Some states, like Washington State, have passed healthcare-specific privacy laws.

For example, the My Health My Data Act became effective March 31, 2024 and restricts how entities collect, use, and process “consumer health data,” defined broadly as personal information that is linked or reasonably linkable to a consumer and that identifies the consumer's health status.

While HIPAA-regulated entities may be exempt from this act, the exemption is based on the data collected and used rather than on the entity’s status as a HIPAA covered entity or business associate.

As such, some data may be subject to this act and HIPAA, while other data may only be subject to HIPAA.

State laws may be more stringent, broader in scope or offer greater individual rights with respect to health-related information or other personal information than HIPAA.

Complying with these various state laws and regulations, which may differ from state to state, requires significant resources and may complicate our compliance efforts.

Penalties for violation of any of these laws and regulations may include civil and/or criminal penalties.

Additionally, U.S.

federal and state consumer protection laws may, among other things, require us to publish statements that describe how we handle personal information and choices individuals may have about the way we handle their personal information.

Many states have also adopted laws similar to each of the above federal laws, which may be broader in scope and apply to items or services reimbursed by any third-party payer, including commercial insurers.

Certain state laws also regulate sponsors’ use of prescriber-identifiable data.

17 unchanged sentences

GDP per capita.

While this rule now has been rescinded, government negotiation of certain Medicare drug pricing continues to be the focus of recent proposed legislation.

Although this rule was subsequently rescinded, in November 2025, CMS introduced the GENEROUS Model, which is expected to launch in 2026, and which requires manufacturers to provide rebates aligned with Most Favored Nation pricing to participating state Medicaid programs that opt into the program.

Further, government negotiation of certain Medicare drug pricing continues to be the focus of recent proposed legislation.

The Budget Control Act of 2011, among other things, created measures for spending reductions by Congress.

2 unchanged sentences

While President Biden previously signed legislation to eliminate this reduction through the end of 2021, a 1% payment adjustment was implemented from April 1 – June 30, 2022, and a 2% payment adjustment took effect beginning July 1, 2022.

The Inflation Reduction Act of 2022 requires manufacturers of selected drugs to negotiate discounted prices with the Secretary of the Department of Health and Human Services.

The IRA requires manufacturers of selected drugs to negotiate discounted prices with the Secretary of the Department of Health and Human Services.

Failure to reach an agreement can subject manufacturers to an excise tax or withdrawal of all drug products from coverage under Medicare and Medicaid.

In addition to entering into direct agreements with manufacturers, on December 1, 2025, the U.S.

entered into a trade agreement with the UK to permit tariff-free imports of pharmaceutical products in exchange for reductions in certain rebates paid by manufacturers to the UK Department of Health and Social Care.

Adoption of additional healthcare reform controls and measures and tightening of restrictive policies in jurisdictions with existing controls and measures, could limit payments for pharmaceuticals.

3 unchanged sentences

Decisions regarding whether to cover any of our products, the extent of coverage and amount of reimbursement to be provided are made on a plan-by-plan basis.

Further, no uniform policy for coverage and reimbursement exists in the U.S., and coverage and reimbursement can differ significantly from payor to payor.

Further, no uniform policy for coverage and reimbursement exists in the U.S., and coverage and reimbursement can differ significantly from payer to payer.

Coverage policies, third-party reimbursement rates and drug pricing regulation may change at any time.

2 unchanged sentences

Even if favorable coverage and reimbursement status is attained for one or more products that receive regulatory approval, less favorable coverage policies and reimbursement rates may be implemented in the future.

Regulation in the European Union

Product development, the regulatory approval process and safety monitoring of medicinal products and their manufacturers in the European Union proceed broadly in the same way as they do in the U.S.

Therefore, many of the issues discussed above apply similarly in the context of the European Union.

In addition, drugs are subject to the extensive price and reimbursement regulations of the various EU member states.

The Clinical Trial Regulation EU 536/2014 (“CTR”), which replaced the Clinical Trials Directive 2001/20/EC, as amended (“CTD”), on January 31, 2022, provides a system for the approval of clinical trials in the European Union.

Regulation in the European Union and United Kingdom

The regulatory framework for medicinal products in the EU and the UK is broadly similar to that of the U.S., and many of the considerations described above apply in these jurisdictions.

Pharmaceutical products in the EU and UK are also subject to national pricing and reimbursement controls.

Following the UK’s withdrawal from the EU in January 2020 (“Brexit”) and the end of the transition period in December 2020, the Medicines and Healthcare products Regulatory Agency (“MHRA”) became the UK’s standalone medicines regulator as of January 1, 2021.

Under the Northern Ireland Protocol, different regulatory rules apply in Northern Ireland than in Great Britain, with Northern Ireland generally continuing to follow the EU regulatory regime.

On January 1, 2025, the Windsor Framework came into effect to simplify the supply of medicines between Great Britain and Northern Ireland, under which EU pharmaceutical legislation does not apply in all circumstances in Northern Ireland.

EU pharmaceutical legislation adopted after the end of the Brexit transition period generally does not apply in Great Britain (but may apply in Northern Ireland).

Clinical Trials

The CTR is directly applicable in all member states without the need for national implementation.

Whilst, for trials conducted in only one country, approval has to be obtained from the competent national authority of an EU member state in which the clinical trial is to be conducted before cross-border trials within the EU, it is possible to make a single harmonized electronic submission and have a single assessment process for clinical trials conducted in multiple member states.

Applicants make a single harmonized electronic submission and have a single assessment process for clinical trials conducted in multiple member states.

Furthermore, a clinical trial may only be started after a competent ethics committee has issued a favorable opinion on the Clinical Trial Application (“CTA”), which must be supported by an investigational medicinal product dossier with supporting information prescribed by the CTR and corresponding national laws of the member states and further detailed in applicable guidance documents.

In the case of Advanced Therapy Investigational Medical Products (“ATIMPs”) consisting of or containing Genetically Modified Organisms (“GMOs”), as is the case for our products, an additional approval for the environmental and biosafety aspects of the use and release of the GMO is required by the GMO competent authorities.

In the case of Advanced Therapy Investigational Medicinal Products (“ATIMPs”) consisting of or containing Genetically Modified Organisms (“GMOs”), as is the case for our products, an additional approval for the environmental and biosafety aspects of the use and release of the GMO is required by the GMO competent authorities.

Unlike EU Regulations, EU Directives require national implementation and GMO Directives have been implemented in different ways by Member States;

4 unchanged sentences

Under the CTR, member states may dispense with the requirement for a legal representative for a non-EU resident sponsor provided there is a contact person based in the EEA.

Under the CTR, the introduction of a new databased called the Clinical Trial Information System (“CTIS”), requires sponsors to upload and submit all data, including initial clinical trial application data and documentation, to the CTIS, with such data being publicly available, with few exceptions.

This means data transparency throughout the development process with the onus on sponsors to protect patient and commercial confidentiality at the point of submission.

Under the CTR, the introduction of a new database called the Clinical Trial Information System (“CTIS”), requires sponsors to upload and submit all data, including initial clinical trial application data and documentation, to the CTIS, with such data being publicly available, with few exceptions and with limited ability to redact the documents.

This means there is data transparency throughout the development process with the onus on sponsors to protect patient and commercial confidentiality at the point of submission.

The CTR does not apply in the UK.

Instead, the regulatory framework in relation to clinical trials is currently derived from the CTD (as implemented into UK law, through the Medicines for Human Use (Clinical Trials) Regulations 2004, as amended).

However, in April 2025, new Regulations – the Medicines for Human Use (Clinical Trials) (Amendment) Regulations 2025 – were finalized that will replace the current regulatory framework for clinical trials.

The new regulations aim to provide a more flexible regime to make it easier to conduct clinical trials in the UK, increase the transparency of clinical trials conducted in the UK and make clinical trials more patient centered.

The new regulations will take full effect in April 2026.

Marketing approval

Marketing approvals under the European Union regulatory system may be obtained through a centralized or decentralized procedure.

The centralized procedure results in the grant of a single marketing authorization that is valid for all 27 EU member states.

Marketing approvals under the EU regulatory system may be obtained through a centralized or decentralized procedure.

The centralized procedure results in the grant of a single marketing authorization that is valid in all 27 EU member states.

Pursuant to Regulation (EC) No 726/2004, as amended, the centralized procedure is mandatory for drugs developed by means of specified biotechnological processes, and advanced therapy medicinal products as defined in Regulation (EC) No 1394/2007, as amended.

4 unchanged sentences

Guidance on the factors that the EMA will consider in relation to the development and evaluation of ATMPs have been issued and include, among other things, the nonclinical studies required to characterize ATMPs;

the manufacturing and control information that should be submitted in a MAA;

the manufacturing and control information that should be submitted in an MAA;

and post-approval measures required to monitor patients and evaluate the long-term efficacy and potential adverse reactions of ATMPs.

1 unchanged sentence

The maximum timeframe for the evaluation of an MAA under the centralized procedure is 210 days after receipt of a valid application subject to clock stops during which the applicant deals with CHMP questions.

Market access can be expedited through the grant of conditional authorization for a medicine that may fulfil unmet needs which may be granted provided that the benefit-risk balance of the product is positive.

The benefit-risk balance is likely to be positive if the applicant can provide comprehensive data and the benefit to public health of the medicinal product's immediate availability on the market outweighs the risks due to need for further data.

Initially, a standard marketing authorization (“MA”) is valid for 5 years, but can be renewed for unlimited validity.

The EU also provides for a system of regulatory data and market exclusivity.

According to Article 14(11) of Regulation (EC) No 726/2004, as amended, and Article 10 of Directive 2001/83/EC, as amended, as well as European case law and guidance, upon receiving an MA, new active substances approved on the basis of complete independent data package benefit from eight years of data exclusivity and an additional two years of market exclusivity.

Data exclusivity prevents regulatory authorities in the EU from referencing the innovator’s data to assess a generic (abbreviated) application during the eight-year period from the date of notification of the MA.

During the additional two-year period of market exclusivity, a generic marketing authorization can be submitted, and the innovator’s data may be referenced, but no generic medicinal product can be placed on the market until the expiration of the market exclusivity.

The overall ten-year period will be extended to a maximum of eleven years if, during the first eight years of those ten years, the MA holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies.

Even if a compound is considered to be a new active substance and the innovator can gain the period of data exclusivity, another company nevertheless could also market another version of the drug if such company obtained marketing authorization based on an MAA with a complete independent data package of pharmaceutical test, preclinical tests, and clinical trials that does not reference the data within the original dossier.

The EMA has also issued guidelines for a comprehensive comparability exercise for biosimilars, and for specific classes of biological products and has recently conducted a consultation on streamlining this procedure.

In addition, under recently agreed revisions to the EU’s pharmaceutical legislation, the standard period of data protection will be reduced, but this may be extended if particular criteria are fulfilled.

The final text of the amendments is not yet available, so it is not certain when and in what form the new legislation will be adopted or how it will impact the development of our products or the protections they may receive.

Under Regulation (EC) No 141/2000 article 3 as amended (Orphan Drug Regulation, (“ODR”)) a product can benefit from orphan drug status if it is intended for the diagnosis, prevention, or treatment of a life-threatening or chronically debilitating condition affecting not more than five in 10,000 people in the European Community when the application is made and there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorized in the European Community or, if such method exists, that the medicinal product will be of significant benefit to those affected by that condition.

The principal benefit of such status, if confirmed at the time of marketing authorization, is 10 years’ market exclusivity once the MA is granted, during which the authorization shall not accept another application for a MA, or grant a MA or accept an application to extend an existing marketing authorization, for the same therapeutic indication, in respect of a similar medicinal product.

This may be reduced to six years under certain circumstances including if the product is sufficiently profitable not to justify maintenance of market exclusivity.

Under the above-mentioned proposed new legislation, the current 10-year period could be reduced for certain products, but may be extended by one year if certain conditions are met.

Additional rules apply to medicinal products for pediatric use under Regulation (EC) No 1901/2006, as amended.

This includes obligations to carry out pediatric research.

Potential incentives include a six-month extension of any supplementary protection certificate granted pursuant to Regulation (EC) No 469/2009;

however, this is not available in cases in which the relevant product is designated as an orphan medicinal product pursuant to the ODR.

Instead, medicinal products designated as orphan medicinal product may enjoy an extension of the ten-year market exclusivity period granted under Regulation (EC) No 141/2000, as amended, to twelve years subject to the conditions applicable to orphan drugs.

The proposed new legislation will retain the 6-month SPC extension but the current separate reward of two years market exclusivity for pediatric indications of orphan products would no longer apply.

The position in the UK is broadly similar, although based on UK legislation.

In order to obtain a UK MA to commercialize products in the UK, an applicant must be established in the UK and must follow one of the UK national authorization procedures or one of the post-Brexit international recognition procedures.

Applications are governed by the Human Medicines Regulations (SI 2012/1916).

While the review process and documentation are similar to the EU, the MHRA has introduced changes to national licensing procedures, including procedures to prioritize access to new medicinal products that will benefit patients, such as a 150-day assessment (subject to clock-stops) and a rolling review procedure.

In addition, an international recognition procedure (“IRP”) has been in place since January 1, 2024.

Pursuant to the IRP, the MHRA will take into account the expertise and decision-making of trusted regulatory partners (i.e., the regulators in Australia, Canada, Switzerland, Singapore, Japan, the U.S.

The MHRA will conduct a targeted assessment of IRP applications but retain the authority to reject applications if the evidence provided is considered insufficiently robust.

The IRP allows medicinal products approved by such trusted regulatory partners that meet certain criteria to undergo a fast-tracked MHRA review to obtain and/or update an MA in the UK.

There are also procedures in the UK for conditional approvals or approvals under exceptional circumstances that are similar to the procedures in the EU.

Regulatory data and market exclusivity operate in broadly the same way as in the EU.

However, there is no pre-MA orphan designation in the UK.

Instead, the MHRA reviews applications for orphan designation in parallel to the corresponding MA application.

The criteria are essentially the same, but have been tailored for the market, i.e., the prevalence of the condition in the UK, rather than the EU, must not be more than five in 10,000.

Should an orphan designation be granted, the period or market exclusivity will be set from the date of first approval of the product in the UK.

Once finalized, the changes to the framework in the EU will not apply in the UK, although may apply to certain products, depending on what basis they are placed on the market in the UK.

In addition, the UK has announced its intention to introduce a new regulatory pathway for orphan medicinal products to make it quicker and easier to get these therapies tested, manufactured and approved in the UK.

Consultation on this framework will take place in 2026.

Programs to expedite authorization in the EU and UK

In the EU, there is the possibility to obtain approval via an accelerated assessment whereby, on request, the CHMP can reduce the timeframe to 150 days if the applicant provides sufficient justification for an accelerated assessment by demonstrating that the medicinal product is expected to be of major public health interest, particularly from the point of view of therapeutic innovation.

Market access can also be expedited through various mechanisms, including the grant of conditional authorization on the basis of less comprehensive data for a medicine that may fulfil unmet needs, and which may be granted provided that the benefit-risk balance of the product is positive.

The benefit-risk balance is likely to be positive if the applicant can provide data that the benefit to public health of the medicinal product's immediate availability on the market outweighs the risks due to need for further data.

Such authorizations are valid for one year and can be renewed annually.

The holder will be required to complete specific obligations (ongoing or new studies, and in some cases additional activities) with a view to providing comprehensive data confirming that the benefit-risk balance is positive.

Once comprehensive data on the product have been obtained, the conditional authorization may be converted into a standard marketing authorization (“MA”) (not subject to specific obligations).

Initially, this is valid for 5 years, but can be renewed for unlimited validity.

Applicants for conditional authorizations can benefit from early dialogue with CHMP through scientific advice or protocol assistance and discuss their development plan well in advance of the submission of a MAA.

Once comprehensive data on the product have been obtained, the conditional authorization may be converted into a standard MA (not subject to specific obligations).

As noted above, a standard MA is initially valid for 5 years, but can be renewed for unlimited validity.

Other stakeholders (e.g., health technology assessment bodies) can be included.

2 unchanged sentences

Early dialogue and scientific advice also ensure that patients only participate in trials designed to provide the data necessary for an application, making the best use of limited resources.

The European Union also provides for a system of regulatory data and market exclusivity.

According to Article 14(11) of Regulation (EC) No 726/2004, as amended, and Article 10 of Directive 2001/83/EC, as amended, upon receiving marketing authorization, new chemical entities approved on the basis of complete independent data package benefit from eight years of data exclusivity and an additional two years of market exclusivity.

Data exclusivity prevents regulatory authorities in the European Union from referencing the innovator’s data to assess a generic (abbreviated) application during the eight-year period from when the first placement of the product on the EEA market.

During the additional two-year period of market exclusivity, a generic marketing authorization can be submitted, and the innovator’s data may be referenced, but no generic medicinal product can be marketed until the expiration of the market exclusivity.

Even if a compound is considered to be a new chemical entity and the innovator can gain the period of data exclusivity, another company nevertheless could also market another version of the drug if such company obtained marketing authorization based on an MAA with a complete independent data package of pharmaceutical test, preclinical tests, and clinical trials.

The EMA has also issued guidelines for a comprehensive comparability exercise for biosimilars, and for specific classes of biological products.

Under European Commission proposals for revisions to the EU’s pharmaceutical legislation, the standard period of data protection may be reduced from eight to six years, but this may be extended by up to four years if particular criteria are fulfilled:

i.e., two additional years if the new product is available in all EU Member States;

an additional six months if the product addresses an unmet medical need;

an additional six months for new chemical entities where the supporting clinical trials use an evidence-based comparator based on EMA scientific advice;

and an additional year if, during the data protection period following authorization, the MA holder receives an authorization for an additional therapeutic indication for which there is a significant clinical benefit in comparison with existing therapies (replacing the additional year of marketing protection available under the current regime).

The additional period of marketing exclusivity protection (described above) will remain as two years following the expiry of the data protection period.

These proposals will be subject to continuing discussion so it is not certain when and in what form the new legislation will be adopted.

The principal benefit of such status is 10 years’ market exclusivity once the MA is granted the subsequent approval of similar medicines with similar indications although this may be reduced to six years under certain circumstances including if the product is sufficiently profitable not to justify maintenance of market exclusivity.

Under the above-mentioned proposed new legislation, other than for orphan drugs addressing a high unmet medical need, the current 10-year period would be reduced to nine years.

These periods may be extended by one year if either:

the new product is available in all EU member states;

or at least two years before the expiry of the orphan exclusivity period, the orphan MA holder obtains an MA for one or more further therapeutic indications for a different orphan condition.

Additional rules apply to medicinal products for pediatric use under Regulation (EC) No 1901/2006, as amended.

Potential incentives include a six-month extension of any supplementary protection certificate granted pursuant to Regulation (EC) No 469/2009, however not in cases in which the relevant product is designated as an orphan medicinal product pursuant to the ODR.

The proposed new legislation will retain the 6-month SPC extension but there would be an explicit obligation to place an authorized product with a pediatric indication on the market in every member state where the adult presentation is marketed.

Additionally, the current separate reward of two years market exclusivity for pediatric indications of orphan products would no longer apply under the proposed legislation.

MHRA has also introduced procedures to prioritize access to new medicinal products that will benefit patients, such as an expedited 150-day assessment (subject to clock-stops) and a rolling review procedure.

Further, similar to the position in the EU, the MHRA offers a national conditional marketing authorization scheme for new medicinal products that is available where comprehensive clinical data are not yet complete, but it is judged that such data will become available soon.

The criteria is similar to the position in the EU, and a conditional MA will be initially valid for one year and will be renewable annually.

There are also various schemes and pilots that are aimed at joining up the various steps in the authorization and access pathway in the UK, such as the Innovative Licensing and Access Pathway (“ILAP”) that provides coordinated advice from the MHRA, reimbursement authorities and the national healthcare system to try to speed up the time for authorized products to be accessed by patients.

Similarly, there are frameworks to provide patients with life-threatening or seriously debilitating conditions access to promising new medicines before they receive an MA, such as the Early Access to Medicines Scheme (“EAMS”).

Each of these schemes have different access criteria and requirements to be met, but are aimed at speeding up development and access to innovative products.

Manufacturing and promotion

Pursuant to European Commission Directive 2003/94/EC as transposed into the national laws of the member states, the manufacturing of investigational medicinal products and approved drugs is subject to a separate manufacturer’s license and must be conducted in strict compliance with cGMP requirements, which mandate the methods, facilities, and controls used in manufacturing, processing, and packing of drugs to assure their safety and identity.

Manufacturers must have at least one qualified person permanently and continuously at their disposal.

2 unchanged sentences

Failure to comply with these requirements could interrupt supply and result in delays, unanticipated costs, and lost revenues, and subject the applicant to potential legal or regulatory action, including but not limited to warning letters, suspension of manufacturing, seizure of product, injunctive action, or possible civil and criminal penalties.

In the European Union, the promotion of prescription medicines is subject to intense regulation and control, including a prohibition on direct-to-consumer advertising.

All medicines advertising must be consistent with the product’s approved summary of products characteristics, factual, accurate, balanced and not misleading.

The same principles apply in the UK.

In the EU, the promotion of prescription medicines is subject to intense regulation and control, including a prohibition on direct-to-consumer advertising.

All medicines advertising must be consistent with the product’s approved summary of products characteristics, and be factual, accurate, balanced and not misleading.

Advertising of medicines pre-approval or off-label is prohibited.

Some jurisdictions require that all promotional materials for prescription medicines be subjected to either prior internal or regulatory review & approval.

Some jurisdictions require that all promotional materials for prescription medicines be subjected to either prior internal or regulatory review and approval.

The same principles apply in the UK.

Other Regulatory Requirements

1 unchanged sentence

The MAH can delegate the performance of related tasks to third parties, such as distributors or marketing collaborators, provided that this delegation is appropriately documented and the MAH maintains legal responsibility and liability.

The obligations of an MAH include:

The obligations of an MAH in the EU and the UK include:

● Manufacturing and Batch Release.

1 unchanged sentence

● Pharmacovigilance.

MAHs are obliged to establish and maintain a pharmacovigilance system, including a qualified person responsible for oversight, to submit safety reports to the regulators and comply with the good pharmacovigilance practice guidelines adopted by the EMA.

● Advertising and Promotion.

1 unchanged sentence

● Medical Affairs/Scientific Service.

MAHs are required to disseminate scientific and medical information on their medicinal products to healthcare professionals, regulators, and patients.

MAHs are required to establish a scientific service that can disseminate scientific and medical information on their medicinal products to healthcare professionals, regulators, and patients.

● Legal Representation and Distributor Issues.

5 unchanged sentences

Reimbursement

In the European Union, the pricing and reimbursement mechanisms by private and public health insurers vary largely by country and even within countries.

In the EU and the UK, the pricing and reimbursement mechanisms by private and public health insurers vary largely by country and even within countries.

In respect of the public systems, reimbursement for standard drugs is determined by guidelines established by the legislature or responsible national authority.

2 unchanged sentences

The downward pressure on healthcare costs in general, particularly prescription drugs, has become very intense.

As a result, increasingly high barriers are being erected to the entry of new products and some of EU countries require the completion of studies that compare the cost-effectiveness of a particular product candidate to currently available therapies to obtain reimbursement or pricing approval.

As a result, increasingly high barriers are being erected to the entry of new products and some of EU countries and the UK require the completion of studies that compare the cost-effectiveness of a particular product candidate to currently available therapies to obtain reimbursement or pricing approval.

Special pricing and reimbursement rules may apply to orphan drugs.

2 unchanged sentences

In addition, results-based rules or agreements on reimbursement may apply.

Recently, a process has been formalized that allows sponsors to receive parallel advice from EMA and relevant national health technology assessment (“HTA”) bodies for pivotal clinical studies designed to support marketing approval.

Recently, in the EU, a process has been formalized that allows sponsors to receive parallel advice from EMA and relevant national health technology assessment (“HTA”) bodies for pivotal clinical studies designed to support marketing approval.

This process was followed for etranacogene dezaparvovec.

EU Regulation (EU) 2021/2282 also creates a framework for the joint clinical assessment of products where that assessment can be used for national pricing and reimbursement decisions.

Orphan Drug Regulation

We have been granted orphan drug exclusivity for AMT-130 for the treatment of Huntington’s disease subject to the conditions applicable to orphan drug exclusivity in the European Union.

We have been granted orphan drug exclusivity for AMT-130 for the treatment of Huntington’s disease subject to the conditions applicable to orphan drug exclusivity in the EU.

No pre-marketing authorization orphan designation step is required in the UK, but similar criteria will apply at the time of MA.

The ODR states that a drug will be designated as an orphan drug if its sponsor can establish:

● that it is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting not more than five in ten thousand persons in the community when the application is made, or that it is intended for the diagnosis, prevention or treatment of a life-threatening, seriously debilitating or serious and chronic condition in the European Union and that without incentives it is unlikely that the marketing of the drug in the European Union would generate sufficient return to justify the necessary investment;

● that there exists no satisfactory method of diagnosis, prevention, or treatment of the condition in question that has been authorized in the European Union or, if such method exists, that the drug will be of significant benefit to those affected by that condition.

that it is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting not more than five in ten thousand persons in the community when the application is made, or that it is intended for the diagnosis, prevention or treatment of a life-threatening, seriously debilitating or serious and chronic condition in the EU and that without incentives it is unlikely that the marketing of the drug in the EU would generate sufficient return to justify the necessary investment;

that there exists no satisfactory method of diagnosis, prevention, or treatment of the condition in question that has been authorized in the EU or, if such method exists, that the drug will be of significant benefit to those affected by that condition.

Regulation (EC) No 847/2000 sets out further provisions for implementation of the criteria for designation of a drug as an orphan drug.

An application for the designation of a drug as an orphan drug must be submitted at any stage of development of the drug before filing of a MAA.

If an EU-wide community marketing authorization in respect of an orphan drug is granted pursuant to Regulation (EC) No 726/2004, as amended, the European Union and the member states will not, for a period of 10 years, accept another MAA, or grant a MA or accept an application to extend an existing MA, for the same therapeutic indication, in respect of a similar drug.

An application for the designation of a drug as an orphan drug must be submitted at any stage of development of the drug before filing of an MAA and the criteria are also reassessed at the time of marketing authorization.

If an EU-wide community marketing authorization in respect of an orphan drug is granted pursuant to Regulation (EC) No 726/2004, as amended, the EU and the member states will not, for a period of 10 years, accept another MAA, or grant a MA or accept an application to extend an existing MA, for the same therapeutic indication, in respect of a similar drug.

Similar orphan exclusivity will be available in the UK if relevant criteria are met at the time of MA.

This period may however be reduced to six years if, at the end of the fifth year, it is established, in respect of the drug concerned, that the criteria for orphan drug designation are no longer met, in other words, when it is shown on the basis of available evidence that the product is sufficiently profitable not to justify maintenance of market exclusivity.

3 unchanged sentences

● the second applicant can establish in the application that the second drug, although similar to the orphan drug already authorized, is safer, more effective, or otherwise clinically superior.

Regulation (EC) No 847/2000 lays down definitions of the concepts similar drug and clinical superiority, which concepts have been expanded upon in subsequent European Commission guidance.

Other incentives available to orphan drugs in the European Union include financial incentives such as a reduction of fees or fee waivers and protocol assistance.

Regulation (EC) No 847/2000 sets forth definitions of the concepts of similar drug and clinical superiority, which concepts have been expanded upon in subsequent European Commission guidance and case law.

Other incentives available to orphan drugs in the EU include financial incentives such as a reduction of fees or fee waivers and protocol assistance.

Orphan drug designation does not shorten the duration of the regulatory review and approval process.

As described above, the above proposed legislation would, if implemented, impact orphan protection in the future.

As described above, the above proposed legislation would, if implemented, impact orphan protection in the EU in the future.

Human Capital Resources

1 unchanged sentence

and 12 in other European countries.

The split of employees between operations, clinical development, pre-clinical and technology and general and administrative functions are included below:

The split of employees between operations, clinical development, pre-clinical and technology and selling, general and administrative functions are included below:

Clinical development

Pre-clinical development and technology

General and administrative

Selling, general and administrative

As of December 31, 2025, 72 of our employees had an M.D.

3 unchanged sentences

We believe that we have good relations with all our employees and with the Works Council in the Netherlands.

Our values are to:

● Be passionate about the patient;

● Act with integrity and respect;

● Take ownership and act with urgency;

● Collaborate for success;

● Innovate every day;

● Focus relentlessly on quality.

We pride ourselves on our dedication to teamwork and uphold values that are:

● Passionate - Why we are here.

We are driven by a deep passion for making a difference in patients’ lives, channeling our energy and commitment into every project and celebrating the impact of our work together;

● Tenacious - How we move forward.

We push through challenges with grit, focus, and heart, relentlessly pursuing continuous improvement and scientific breakthroughs.

We never give up — because patients are counting on us;

● Honorable - How we behave.

We build trust with each other, and the wider patient community we serve, through honesty, integrity, and support for one another.

By acting with respect and compassion, we create a foundation for lasting success;

● Exceptional - What we deliver.

We give our best in everything we do, setting ambitious goals and holding ourselves to the highest standards.

Our patients deserve nothing less.

Our people are a critical component in our continued success.

3 unchanged sentences

Additional Information

(the “Company”) was incorporated on January 9, 2012 as a private company with limited liability (besloten vennootschap met beperkte aansprakelijkheid) under the laws of the Netherlands.

was incorporated on January 9, 2012 as a private company with limited liability (besloten vennootschap met beperkte aansprakelijkheid) under the laws of the Netherlands.

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

4 unchanged sentences

to uniQure N.V.

(the “Company”).

We are registered in the trade register of the Dutch Chamber of Commerce (Kamer van Koophandel) under number 54385229.

5 unchanged sentences

Also available through our website’s “Investors & Newsroom:

Corporate Governance” page are charters for the Audit, Compensation and Nominating and Corporate Governance committees of our board of directors (the “Board”), along with a copy of our Code of Business Conduct and Ethics, available at uniqure.com/investors-media/corporate-governance.

Corporate Governance” page are charters for the Audit, Compensation and Nominating and Corporate Governance committees of our board of directors (the “Board”), along with a copy of our Code of Conduct, available at uniqure.com/investors-media/corporate-governance.

The information on our website is not part of, nor shall it be deemed to be incorporated by reference into, this Annual Report on Form 10-K or any other filings with the SEC.

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 1. Business