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Item 1. Business

2025-02-27 compared with 2024-02-28 · 191 added, 296 removed, 694 unchanged (41% 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”), refractory mesial temporal lobe epilepsy (“MTLE”) and Fabry disease.

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

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

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

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

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

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

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

A summary of our key development programs is provided below:

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.

Recent Product Candidate Developments

Huntington’s disease program (AMT-130)

AMT-130 is our novel gene therapy candidate for the treatment of Huntington’s disease, which utilizes our proprietary, gene-silencing miQURE platform and incorporates an AAV vector carrying a miRNA specifically designed to silence the huntingtin gene and the potentially highly toxic exon 1 protein fragment.

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

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

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

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

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

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

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

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

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

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

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

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

in March 2022.

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

Phase I/II clinical trial of AMT-130.

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

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

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

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

The combined U.S.

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

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

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

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

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

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

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

Amyotrophic Lateral Sclerosis program (AMT-162)

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

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

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

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

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

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.

Other Business Developments

Reorganization

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

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

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

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

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

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

Royalty Financing Agreement

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

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

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

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

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

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

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.

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.

Our Mission and Strategy

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Our strategy to achieve this mission is to:

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

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

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

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

We enrolled 39 patients into our U.S.

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

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

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

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

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

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

Advance the development and 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.

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

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

Support the commercialization and global expansion of HEMGENIX ® .

HEMGENIX ® is an FDA and EMA approved one-time administered gene therapy for the treatment of patients with severe and moderately severe hemophilia B.

In 2020 we licensed the commercial rights to HEMGENIX ® to CSL Behring .

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

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

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.

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.

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Huntington’s Disease

Huntington’s Disease and Market Background

Huntington’s Disease

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.

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Our Development of AMT-130 for Huntington’s Disease

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

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

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

and a Phase Ib/II study in the EU.

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

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

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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Phase I/II clinical trial of AMT-130.

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

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

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

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

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

and European Phase I/II clinical trials:

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 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, 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”).

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

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

Exploratory efficacy data

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

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

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

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

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

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

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

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

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

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

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

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

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

Biomarkers and Volumetric Imaging Data

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

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

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

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

These transient increases were not dose dependent.

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

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

Total Brain Volume :

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

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

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

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

Temporal Lobe Epilepsy Program (AMT-260)

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

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

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

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 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”).

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

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

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

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

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

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

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

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.

Amyotrophic Lateral Sclerosis (“ALS”)

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

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

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

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

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

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

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.

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Our Development of AMT-162 for ALS – SOD1

On January 31, 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).

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.

Our Development of AMT-161 for ALS – C9ORF72

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

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

Alzheimer’s Disease (AMT-240)

Alzheimer’s Disease and Market Background

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

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

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

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

Our Development of AMT-240 for Alzheimer’s disease

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

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

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

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).

Liver-directed diseases

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CSL Behring collaboration

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

The transaction became fully effective on May 6, 2021.

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.

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

In March and April 2022, we received the total $55.0 million owed to us by CSL Behring related to CSL Behring’s submissions of marketing applications for HEMGENIX ® in the EU in March 2022 and the U.S.

in April 2022.

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

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

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Our Development of AMT-191 for Fabry Disease

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

The lead candidate is a one-time administered AAV5 gene therapy incorporating the GLA transgene under control of our proprietary strong liver-specific promoter.

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

On November 29, 2023 we announced that the FDA had cleared the IND application for AMT-191 and the first-in-human Phase I/IIa clinical trial will be conducted in the United States.

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.

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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.

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

New Technology Development

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The existing miQURE gene silencing strategy was expanded by linking several miRNA molecules in a single construct, resulting in the new linQURE platform.

Commercial-Scale Manufacturing Capabilities

The ability to reliably produce our products and product candidates at a high quality and at commercial scale is critical to the development of our AAV-based gene therapies.

With the exception of AMT-260 and AMT-162, we produce our gene therapies either at our Amsterdam, the Netherlands facility (the “Amsterdam Facility”) or our commercially licensed Lexington, Massachusetts-based manufacturing facility (the “Lexington Facility”) using our proprietary baculovirus expression vector system.

We believe our integrated manufacturing and process development capabilities provide us several potential advantages, including:

(1) Know-how.

Since our founding in 1998, we have invested heavily in developing optimized processes, methods and formulations to reliably and reproducibly manufacture AAV-based gene therapies at commercial scale.

During this time, we have accumulated significant internal experience and knowledge of the underlying manufacturing technology and critical quality attributes of our products.

These learnings have been essential in developing a modular, third generation manufacturing platform that can be used to produce all our future gene therapy products.

(2) Flexibility.

Controlling cGMP allows us to rapidly adapt our production schedule to meet the needs of our business.

With the exception of AMT-260 and AMT-162 programs, we do not rely on contract manufacturers, nor do we require costly and time-consuming technology transfers to third parties.

Our facility is designed to commercially supply multiple products and is flexibly designed to accommodate expansion and scale up as our needs change.

(3) Faster Path to Market.

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

(4) Scalability.

We have demonstrated our manufacturing process is reproducible at volumes ranging from 2 liters to 500 liters and believe it is possible to achieve higher scale production with our insect-cell, baculovirus system.

(5) Low Cost of Goods.

We believe that our ability to scale production has the potential to significantly reduce unit costs.

Our manufacturing process only utilizes disposable components, which enables faster change-over times between batches and avoid costs associated with cleaning and sterilization.

Additionally, our production system does not require the use of plasmids, which can be a costly raw material.

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 countries 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 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.

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In addition, we have filed manufacturing patent applications with claims directed to alternative compositions of matter and manufacturing processes to seek better protection from competitors.

We file the initial patent applications for our commercially important technologies in both Europe and the U.S.

For the same technologies, we typically file international patent applications under the PCT within one year.

We file the initial patent applications for our commercially important technologies in Europe and/or the U.S.

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.

As of December 31, 2023, our intellectual property portfolio included 123 issued patents (including 30 U.S.

patents and 14 patents granted by the European Patent Office (“EPO”)) and 129 pending patent applications (including 23 U.S.

patent applications and 31 EPO patent applications).

These patents relate to a variety of technologies including our product candidates that are in development and our manufacturing and technology platform.

Our Patent Portfolio Related to Our Key Development Programs

Hemophilia B program (HEMGENIX®)

We own a patent family, including patents and patent applications, directed to the use of the Padua mutation in human Factor IX (“hFIX”) for gene therapy in etranacogene dezaparvovec.

CSL Behring received exclusive global rights to etranacogene dezaparvovec pursuant to the CSL Behring Agreement and is responsible for the prosecution and enforcement of the underlying patent portfolio pursuant to its obligations thereunder.

See “Liver-directed diseases—Hemophilia B (HEMGENIX® or etranacogene dezaparvovec)” for more information on the CSL Behring collaboration.

Huntington’s disease program (AMT-130)

We own three patent families directed to gene therapy treatment of Huntington’s disease, including with AMT-130 and its formulation.

This miQURE gene silencing technology platform is designed to degrade disease-causing genes without off-target toxicity and induce silencing of the entire target organ through secondary exosome-mediated delivery.

Temporal Lobe Epilepsy (AMT-260)

We co-own three patent families directed to gene therapy treatment of TLE, including with AMT-260 of which the other owners have exclusively licensed their rights to us.

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

prior to the grant or issue of the patent.

For patent families which are considered particularly important, we may also file divisional applications in other jurisdictions.

As of December 31, 2024, our fully owned intellectual property portfolio included 128 issued patents (including 27 U.S.

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

patent applications and 27 patent applications pending at the EPO).

These patents relate to a variety of technologies including our product candidates that are in development as well as to our manufacturing and technology platforms.

We own three published patent families directed to gene therapy treatment of Huntington’s disease, including AMT-130 and its formulation.

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.

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

Additionally, we are the exclusive licensee to two other patent families directed to the Gluk2/Gluk5 antagonists and their use in TLE.

Amyotrophic Lateral Sclerosis (AMT-162)

We have obtained an exclusive license to two patent families directed to gene therapy treatment of ALS, including AMT-162.

Fabry’s Disease (AMT-191)

We own a patent family directed to potent liver-specific promoters including the promoter present in our gene therapy treatment of Fabry product AMT-191.

We have obtained an exclusive license to two patent families directed to gene therapy treatment of ALS, including our product candidate AMT-162.

We own a patent family directed to potent liver-specific promoters, including the promoter present in our product candidate AMT-191.

Additionally, we own a patent family directed to the formulation of AMT-191 for intravenous infusion.

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Technology Used for Specific Development Programs

Hemophilia B program (HEMGENIX®)

In April 2017, we entered into an Assignment and License Agreement with Dr.

Simioni (the “Padua Assignment”).

Pursuant to the Padua Assignment, we acquired from Dr.

Simioni all rights, title and interest in a patent family covering the variant of the FIX gene, carrying an R338L mutation (FIX-Padua;

Under the Padua Assignment, we have also licensed certain know-how included in the Padua IP.

We provided Dr.

Simioni with an initial license fee and reimbursement of past expenses.

Under the agreement, additional payments may come due upon the achievement of certain milestone events related to the development of the Padua IP or as royalties on a percentage of certain revenues.

We have granted a license of the Padua IP back to Dr.

Simioni for therapeutic or diagnostic use of a modified Factor IX protein (other than in connection with gene therapy) and any application for non-commercial research purposes.

We have agreed to indemnify Dr.

Simioni for claims arising from our research, development, manufacture, or commercialization of any product making use of the Padua IP, subject to certain conditions.

The Padua Assignment will remain in effect, unless otherwise terminated pursuant to the terms of the Padua Assignment, until the later of (i) the expiration date of the last of the patents within the Padua IP and (ii) the expiration of the payment obligations under the Padua Assignment.

Jude Children’s Research Hospital

In 2008, we entered into a license agreement with St.

Jude Children’s Research Hospital (“St.

Jude”), which we amended in 2012.

Under this license agreement, St.

Jude has granted us an exclusive license, with a right to sublicense, to patent rights relating to expression of hFIX in gene therapy vectors, to make, import, distribute, use, and commercialize products containing hFIX covered by a valid patent claim in the field of gene therapy for treatment or prophylaxis of hemophilia B.

In addition, we have a first right of negotiation regarding any patent applications that are filed by St.

Jude for any improvements to the patent rights licensed to us.

patent rights will expire in 2028 and the European patents will expire in 2025.

We have agreed to pay St.

Jude a royalty equal to a low single-digit percentage of net sales by us or our sublicensees of products covered by the licensed patent rights, and a portion of certain amounts we receive from sublicensees ranging from a mid-single digit to a mid-teen double-digit percentage of such amounts.

With respect to our collaboration with CSL Behring, we have agreed with St.

Jude on an apportionment of certain amounts we receive from CSL Behring as sublicensing revenue that is equivalent to a low-single digit percentage of such amounts.

The agreement will remain in effect until no further payment is due relating to any licensed product under this agreement or either we or St.

Jude exercise our rights to terminate it.

Jude may terminate the agreement in specified circumstances relating to our insolvency.

We may terminate the agreement for convenience at any time subject to a specified notice period.

Temporal Lobe Epilepsy (AMT-260)

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The biotechnology and pharmaceutical industries, including in the gene therapy field, are characterized by rapidly advancing technologies, intense competition, and a strong emphasis on intellectual property.

We face substantial competition from many different sources, including large and specialty pharmaceutical and biotechnology companies, academic research institutions and governmental agencies and public and private research institutions.

We face worldwide competition from larger pharmaceutical companies, specialty pharmaceutical companies and biotechnology firms, universities and other research institutions and government agencies that are developing and commercializing pharmaceutical products.

Our key competitors focused on developing therapies in various indications, include among others, Pfizer, Freeline Therapeutics, Intellia Therapeutics, Sangamo Biosciences, Voyager Therapeutics, Passage Bio, Roche, PTC Therapeutics, Prilenia Therapeutics, CombiGene, Caritas Therapeutics, Alnylam, Wave Life Sciences, Bayer AG (AskBio), Amicus Therapeutics, 4D Molecular Therapeutics, Sanofi, Idorsia, Amicus, Spark, Takeda, Chiesi, CANbridge, Abeona, Annexon, Vico, Alexion (AZ), Neurona, Combigene, NeuExcell, EpiBlok, Biogen, ionis, Eisai and Lexeo,

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.

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and foreign laws.

For other countries outside of the U.S.

and the EU, marketing approval and pricing and reimbursement requirements vary from country to country.

If we fail to comply with applicable regulatory requirements, we may be subject to, among other things, civil penalties, refusal to approve pending applications, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions, and criminal prosecution.

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● 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 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 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;

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

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the chemistry, manufacturing, and controls;

the design and conduct of clinical trials;

the design and conduct of clinical trials and product development;

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

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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, or CARES, Act to include the volume of drugs produced during the prior year.

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.

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

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

The FDA will not approve an application unless it determines that the manufacturing processes and facilities are following cGMP requirements and adequate to assure consistent production of the product within required specifications.

FDA Programs to Expedite Product Development

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By the date of approval of an accelerated approval product, FDA must specify the conditions for the required post approval studies, including enrollment targets, the study protocol, milestones, and target completion dates.

FDA may also require that the confirmatory Phase 4 studies be commenced prior to FDA granting a product accelerated approval.

FDA may also require, and frequently does require, that the confirmatory Phase 4 studies be commenced prior to FDA granting a product accelerated approval.

Reports on the progress of the required Phase 4 confirmatory studies must be submitted to FDA every 180 days after approval.

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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 audits and monitoring conducted by the sponsor, among other conditions.

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.

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

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a 510(k) premarket notification is generally required for moderate risk devices classified as Class II.

A de novo request may be used for novel devices not previously classified by the FDA (and hence are automatically Class III) but are low or moderate risk (due to the application of special controls) and thus are classified as Class II.

Low risk devices classified as Class I generally do not require any FDA premarket authorization, with limited exceptions.

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”).

Recent regulatory and legislative proposals, however, may cause the FDA to actively regulate LDTs.

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.

Post-approval Requirements

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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, and a guidance on communication of off-label scientific information about approved products.

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.

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.

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Anti-Kickback Provisions and other Fraud and Abuse Requirements

The federal Anti-Kickback Statute is a criminal statute that prohibits, among other things, knowingly and willfully offering, paying, soliciting, or receiving remuneration directly or indirectly, overtly or covertly, in cash or in kind, to induce or in return for purchasing, leasing, ordering, or arranging for the purchase, lease or order of any healthcare item or service reimbursable under Medicare, Medicaid or other federally financed healthcare programs, in whole or in part.

The federal Anti-Kickback Statute (“AKS”) is a criminal statute that prohibits, among other things, knowingly and willfully offering, paying, soliciting, or receiving remuneration directly or indirectly, overtly or covertly, in cash or in kind, to induce or in return for purchasing, leasing, ordering, or arranging for the purchase, lease or order of any healthcare item or service reimbursable under Medicare, Medicaid or other federally financed healthcare programs, in whole or in part.

The term “remuneration” has been interpreted broadly to include anything of value.

The Anti-Kickback Statute has been interpreted to apply to arrangements between biopharmaceutical industry members on the one hand and prescribers, purchasers, and formulary managers on the other.

The AKS has been interpreted to apply to arrangements between biopharmaceutical industry members on the one hand and prescribers, purchasers, and formulary managers on the other.

The Beneficiary Inducement Civil Monetary Penalties Law imposes similar restrictions on interactions between the biopharmaceutical industry and federal healthcare program beneficiaries.

There are certain statutory exceptions and regulatory safe harbors to the Anti-Kickback Statute protecting some common activities from prosecution.

There are certain statutory exceptions and regulatory safe harbors to the AKS protecting some common activities from prosecution.

The exceptions and safe harbors are drawn narrowly, and practices that involve remuneration that may be alleged to be intended to induce or reward prescribing, purchases, or recommendations may be subject to scrutiny if they do not qualify for an exception or safe harbor.

Failure to meet all the requirements of a particular applicable statutory exception or regulatory safe harbor does not make the conduct per se illegal under the Anti-Kickback Statute.

Failure to meet all the requirements of a particular applicable statutory exception or regulatory safe harbor does not make the conduct per se illegal under the AKS.

Instead, the legality of the arrangement will be evaluated on a case-by-case basis based on a cumulative review of all its facts and circumstances.

Several courts have interpreted the statute’s intent requirement to mean that if any one purpose of an arrangement involving remuneration is to induce or reward referrals of federal healthcare program business, including purchases of products paid by federal healthcare programs, the statute has been violated.

The Patient Protection and Affordable Care Act, of 2010, as amended, (the “ACA”) modified the intent requirement under the Anti-Kickback Statute to a stricter standard, such that a person or entity no longer needs to have actual knowledge of the statute or specific intent to violate it to have committed a violation.

In addition, the ACA also provided that a violation of the federal Anti-Kickback Statute 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 Patient Protection and Affordable Care Act, of 2010, as amended, (the “ACA”) modified the intent requirement under the AKS to a stricter standard, such that a person or entity no longer needs to have actual knowledge of the statute or specific intent to violate it to have committed a violation.

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.

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 Anti-Kickback Statute discount 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.

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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 the overpayment, even if the overpayment was not caused by a false or fraudulent act.

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.

The majority of states also have statutes similar to the federal Anti-Kickback Statute 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.

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.

The government may further prosecute conduct constituting a false claim under the criminal False Claims Act.

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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.

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

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”).

The Medicaid Drug Rebate statute requires sponsors to calculate and report price points, which are used to determine Medicaid manufacturer rebate payments shared between the states and the federal government and Medicaid payment rates for certain therapeutics.

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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 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 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.

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.

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teaching hospitals, as well as ownership and investment interests held by physicians and members of their immediate family.

Payments made to principal investigators and research institutions at teaching hospitals for clinical trials are also included within this law.

Payments made to principal investigators and research institutions for clinical trials are also included within this law.

Reported information is made publicly available by CMS.

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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, 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.

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.

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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.

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

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.

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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 and GMO directives have been implemented in different ways by Member States;

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

either following the Directive for “Contained use” (Directive 2009/41/EC) or “deliberate release” (Directive 2001/18/EC).

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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 confidentiality at the point of submission.

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

Marketing approval

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In the marketing authorization application (“MAA”) the applicant must properly and sufficiently demonstrate the quality, safety, and efficacy of the drug.

The Committee for Medicinal Products for Human Use (“CHMP”) is the European Medicines Agency's (“EMA”) committee responsible for human medicines.

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;

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Although these guidelines are not legally binding, we believe that our compliance will effectively be necessary to gain and maintain approval for any of our product candidates.

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 EMA 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.

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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 marketing authorization may be converted into a standard marketing authorization (not subject to specific obligations).

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 EMA through scientific advice or protocol assistance and discuss their development plan well in advance of the submission of a marketing-authorization application.

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.

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

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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.

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 marketing authorization 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.

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 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.

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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 marketing authorization (“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).

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.

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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 (EC) when the application is made.

The principal benefit of such status is 10 years’ market exclusivity once they are approved preventing 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 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.

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:

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Other Regulatory Requirements

A holder of a marketing authorization for a medicinal product is legally obliged to fulfill several obligations by virtue of its status as a marketing authorization holder (“MAH”).

A holder of a MA for a medicinal product is legally obliged to fulfill several obligations by virtue of its status as a marketing authorization holder (“MAH”).

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.

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● Manufacturing and Batch Release.

MAHs should guarantee that all manufacturing operations comply with relevant laws and regulations, applicable good manufacturing practices, with the product specifications and manufacturing conditions set out in the marketing authorization and that each batch of product is subject to appropriate release formalities.

MAHs should guarantee that all manufacturing operations comply with relevant laws and regulations, applicable GMP, with the product specifications and manufacturing conditions set out in the marketing authorization and that each batch of product is subject to appropriate release formalities.

● Pharmacovigilance.

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● Preparation, Filing and Maintenance of the Application and Subsequent Marketing Authorization.

MAHs must maintain appropriate records, comply with the marketing authorization’s terms and conditions, fulfill reporting obligations to regulators, submit renewal applications and pay all appropriate fees to the authorities.

We may hold any future marketing authorizations granted for our product candidates in our own name or appoint an affiliate or a collaborator to hold marketing authorizations on our behalf.

MAHs must maintain appropriate records, comply with the MA’s terms and conditions, fulfill reporting obligations to regulators, submit renewal applications and pay all appropriate fees to the authorities.

We may hold any future marketing authorizations granted for our product candidates in our own name or appoint an affiliate or a collaborator to hold MAs on our behalf.

Any failure by an MAH to comply with these obligations may result in regulatory action against an MAH and ultimately threaten our ability to commercialize our products.

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Orphan Drug Regulation

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

Regulation (EC) No 141/2000, as amended, states that a drug will be designated as an orphan drug if its sponsor can establish:

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.

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;

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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 marketing authorization application.

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 application for a marketing authorization, or grant a marketing authorization or accept an application to extend an existing marketing authorization, 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 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.

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.

Notwithstanding the foregoing, a marketing authorization may be granted, for the same therapeutic indication, to a similar drug if:

● the holder of the marketing authorization for the original orphan drug has given its consent to the second applicant;

● the holder of the marketing authorization for the original orphan drug is unable to supply sufficient quantities of the drug;

Notwithstanding the foregoing, a MA may be granted, for the same therapeutic indication, to a similar drug if:

● the holder of the MA for the original orphan drug has given its consent to the second applicant;

● the holder of the MA for the original orphan drug is unable to supply sufficient quantities of the drug;

● 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.

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

Note 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 future.

Human Capital Resources

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We invest in numerous learning opportunities focused on individual, management and team development and other initiatives to support our employees and build our culture.

In 2021 we initiated activities to coordinate our various ongoing activities and initiatives within an environmental, social and governance (“ESG”) framework.

Additional Information

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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