uniQure N.V. operates in the field of gene therapy, seeking to deliver to patients suffering from rare and other devastating diseases single treatments with potentially curative results.
The company is advancing a focused pipeline of innovative gene therapies, including its clinical candidates for the treatment of Huntington's disease, amyotrophic lateral sclerosis (ALS), refractory mesial temporal lobe epilepsy (MTLE) and Fabry disease. The company's internally developed HEMGENIX, a gene thera...
uniQure N.V. operates in the field of gene therapy, seeking to deliver to patients suffering from rare and other devastating diseases single treatments with potentially curative results.
The company is advancing a focused pipeline of innovative gene therapies, including its clinical candidates for the treatment of Huntington's disease, amyotrophic lateral sclerosis (ALS), refractory mesial temporal lobe epilepsy (MTLE) and Fabry disease. The company's 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. The company licenses HEMGENIX to CSL Behring LLC (CSL Behring), which is responsible for its commercialization. The company is manufacturing HEMGENIX for CSL Behring and is entitled to specific milestone payments and royalties on net sales of the product, a portion of which it sold to a royalty acquisition company in 2023 in exchange for up-front cash.
The company produces its adeno-associated virus-based gene therapies in its own facilities with a proprietary, current good manufacturing practices (GMP) -compliant manufacturing process.
Recent Product Candidate Developments
Huntington's disease program (AMT-130)
AMT-130 is the company's novel gene therapy candidate for the treatment of Huntington's disease, which utilizes its 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.
The company is 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, the company 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.
The company is 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. study. 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.
The company completed the enrollment of all 26 patients in the first two cohorts of its Phase I/II clinical trial of AMT-130 in the U.S. in March 2022. In June 2022, the company 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, the company 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, the company 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. 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.
Amyotrophic Lateral Sclerosis program (AMT-162)
In January 2023, the company announced that it 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 includes 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 Investigational New Drug (IND) application for APB-102 and has granted Orphan Drug and Fast Track designation.
Strategy
The key elements of the company's strategy are to advance the development of AMT-130, a potential one-time gene-therapy approach for the treatment of Huntington's disease; advance the company's pipeline of clinical-stage gene therapy candidates; support the commercialization and global expansion of HEMGENIX; and prioritize technology development on next-generation AAV capsids and novel cargo technologies.
Central Nervous System Diseases
Development of AMT-130 for Huntington's Disease
AMT-130 is the company's novel gene therapy candidate for the treatment of Huntington's disease. AMT-130 utilizes its 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.
The company is 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.
On March 21, 2022, the company announced that it completed the enrollment of all 26 patients in the first two cohorts of its 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). In July 2022, the company 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, the company announced that in its 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, the company 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 the company has 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, the company announced safety and biomarker data from the 10 patients enrolled in the lower-dose cohort.
On June 21, 2023, the company 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.
On December 19, 2023, the company 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.
In November 2023, the company 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.
Development of AMT-260 for Temporal Lobe Epilepsy
In July 2021, the company acquired uniQure France SAS (uniQure France) and its lead program 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 the company.
AMT-260 is a gene therapy using an AAV9 vector. The use of AAV9 to deliver any sequence that affects the expression of the GRIK2 gene in humans has been exclusively licensed from Regenxbio Inc (Regenxbio).
AMT-260, employs miRNA silencing technology to target suppression of aberrantly expressed GluK2 containing kainate receptors in the hippocampus of patients with MTLE.
In October 2021, the company 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, the company initiated IND-enabling, GLP toxicology studies in non-human primates for its gene therapy candidate in MTLE.
On September 5, 2023, the company announced that the FDA had cleared the IND application for AMT-260. The first-in-human Phase I/IIa clinical trial will be conducted in the United States and consist of two parts. The first part is a multicenter, open-label trial with two dosing cohorts of six patients each to assess safety, tolerability, and first signs for efficacy of AMT-260 in patients with refractory MTLE. The second part is expected to be a randomized, controlled trial to generate proof of concept (POC) data.
Development of AMT-162 for ALS - SOD1
On January 31, 2023, the company announced that it 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. APB-102 includes 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.
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 ribonucleic acid (RNA) aggregates and prevent dipeptide protein formation. AMT-161 uses the company's miQURE and linQURE gene silencing technology to target the toxic sense and antisense alleles of C9ORF72 as a potential treatment for ALS.
Development of AMT-240 for Alzheimer's disease
AMT-240 is the company's preclinical product candidate for the treatment autosomal dominant Alzheimer's disease. AMT-240 is a one-time intra cerebrospinal fluid-administered AAV gene therapy overexpressing a protective APOE variant with or without a miQure designed to knockdown the toxic APOE4 variant. It is initially targeted as a treatment for autosomal dominant Alzheimer's disease patients but may be effective for a broader population of patients.
Liver-Directed Diseases
CSL Behring collaboration
On June 24, 2020, the company 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.
The company and CSL Behring also entered into a development and commercial supply agreement, pursuant to which, among other things, the company will supply the Product to CSL Behring. The company is contractually obligated to supply the Product until such time that these capabilities are transferred to CSL Behring or its designated contract manufacturing organization. On September 6, 2022, CSL Behring notified the company of its intent to transfer manufacturing technology in the coming years related to HEMGENIX to a third-party contract manufacturer designated by CSL Behring.
Development of AMT-191 for Fabry Disease
In September 2020, the company 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 the company's proprietary strong liver-specific promoter.
In October 2021, the company 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, the company 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. The multicenter, open-label clinical trial consists of two dose-escalating cohorts of three patients each to assess safety, tolerability, and efficacy of AMT-191 in patients with Fabry disease. Three patients will be dosed in the initial dose. If no dose-limiting toxicology is identified, the dose will be escalated. If dose-limiting toxicology occurs in one of the three initial patients, three additional patients will be enrolled at the same dose level. If no additional patients in the cohort experience a dose-limiting toxicology, the dose will be escalated. Assessments will be made at three- and six-months post-treatment.
Intellectual Property
Patent Portfolio
The company's gene therapy programs are protected by patents and patent applications directed to various aspects of its technology.
The company files the initial patent applications for its commercially important technologies in both Europe and the U.S. For the same technologies, it typically files international patent applications under the PCT within one year. The company 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, the company's 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 its product candidates that are in development and the company's manufacturing and technology platform.
Patent Portfolio Related to Key Development Programs
Hemophilia B program (HEMGENIX)
The company owns 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.
Huntington's disease program (AMT-130)
The company owns 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)
The company co-owns 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 the company. Additionally, the company is the exclusive licensee to two other patent families directed to the Gluk2/Gluk5 antagonists and their use in TLE.
Amyotrophic Lateral Sclerosis (AMT-162)
The company has obtained an exclusive license to two patent families directed to gene therapy treatment of ALS, including AMT-162.
Fabry's Disease (AMT-191)
The company owns a patent family directed to potent liver-specific promoters including the promoter present in its gene therapy treatment of Fabry product AMT-191. Additionally, the company owns a patent family directed to the formulation of AMT-191 for intravenous infusion.
Licenses
Licensed Technology Used for Multiple Programs
The company is exploiting technology from third-party sources described below in more than one of its programs.
Cold Spring Harbor Laboratory
In 2015, the company entered into a license agreement with CSHL in which CSHL granted to it an exclusive, sublicensable license to develop and commercialize certain of CSHL's patented RNAi-related technology for use in connection with the treatment or prevention of Huntington's disease. The company expanded the scope of the license agreement with CSHL in 2018 beyond Huntington's disease to include the diagnosis, treatment, or prevention of all CNS diseases in the field. Under the amended license agreement CSHL granted to the company an exclusive license to develop and commercialize therapeutic products for the additional disease classifications in the field of liver diseases, neuromuscular diseases, and cardiovascular diseases, and the company has subsequently added such products to its pipeline.
Protein Sciences
In 2016, the company revised its existing license contract with Protein Sciences Corporation for the use of its expresSF+ insect cell line and associated technology for human therapeutic and prophylactic uses (except influenza) to provide the company with a royalty free, perpetual right and license to the technology in the field of AAV-based gene therapy.
Technology Used for Specific Development Programs
Hemophilia B program (HEMGENIX)
Padua
In April 2017, the company entered into an Assignment and License Agreement with Dr. Simioni (the Padua Assignment). Pursuant to the Padua Assignment, the company 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; Padua IP). Under the Padua Assignment, the company also licensed certain know-how included in the Padua IP.
St. Jude Children's Research Hospital
In 2008, the company entered into a license agreement with St. Jude Children's Research Hospital (St. Jude), which it amended in 2012. Under this license agreement, St. Jude has granted the company 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, the company a first right of negotiation regarding any patent applications that are filed by St. Jude for any improvements to the patent rights licensed to the company. The U.S. patent rights will expire in 2028 and the European patents will expire in 2025.
Temporal Lobe Epilepsy (AMT-260)
Regenxbio
In June 2020, uniQure France SAS entered into an agreement, subsequently amended in June 2021, with Regenxbio for an exclusive (in the field of using AAV9 to expression of the GRIK2 gene in humans (the Field)), sublicensable, royalty-bearing, worldwide license under Regenxbio's interest in EU patent application 19185533.7 (the Foreground Patents) and related patents, as well as patents covering inventions developed during the collaboration and certain patents and know-how relating to AAV9. The license also includes non-exclusive rights to exploit the licensed Foreground Patents and certain related patents know-how developed in collaboration pursuant to the license agreement outside the Field. The license also includes retained and license back rights that permit Regenxbio and its upstream licensors to exploit for any research, development, commercialization, or other purposes certain patents, inventions and know-how (other than the Foreground Patents) subject to or created pursuant to the license agreement.
Inserm Transfert
In January 2020, uniQure France SAS entered into license agreement with Inserm Transfert SA (also acting as a delegate for the French National Institute of Health and Medical Research) and La societe SATT Aquitaine (the counterparties collectively referred to as Inserm Transfert). Under the license agreement, uniQure France SAS is granted an exclusive, sublicensable, royalty-bearing, worldwide license under European Patent (EP) patent application 13306265.3 in the field of the prevention and treatment of epilepsy, and in Inserm Transfert's share in EP patent application 19185533.7 (which is co-owned by Regenxbio) in the field of all human use. uniQure France SAS also is granted a non-exclusive, sublicensable, royalty-bearing, worldwide license under certain know-how in the fields that may be developed by Inserm pursuant to the agreements. Under the agreements, Inserm retains certain rights for teaching, academic and/or research purposes.
Amyotrophic Lateral Sclerosis (AMT-162)
Apic Bio, Inc. (Apic Bio)
In January 2023, the company announced that it had entered into a global licensing agreement with Apic Bio for a one-time, intrathecally administered investigational gene therapy for ALS caused by mutations in SOD-1, pursuant to which the company acquired an exclusive global license (including a sublicense of rights granted to Apic Bio pursuant to an exclusive license agreement with a certain U.S.-based academic institution) to Apic Bio's rights under certain licensed technology to develop, manufacture, and commercialize any product incorporating a licensed construct (including APB-102, certain constructs expressing a SOD1-targeting microRNA or AAV that codes for a microRNA that silences SOD1 expression), in any dosage strength, formulation, concentration or method of delivery in the applicable field.
Trademarks
The company has a number of material registered trademarks, including 'uniQure', that it has registered in various jurisdictions including the United States (U.S.) and the EU.
Research and Development
The company's research and development expenses included $214.9 million for the year ended December 31, 2023.
Competition
The company's 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.
Government Regulation
All the company's product candidates are subject to regulation by the FDA as biologics.
The U.S. Foreign Corrupt Practices Act, to which the company is subject, imposes certain recordkeeping requirements and prohibits corporations and individuals from engaging in certain activities to obtain or retain business or to influence a person working in an official capacity.
History
uniQure N.V. was founded in 1998.
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