Executive Summary / Key Takeaways

• uniQure is a gene therapy leader focused on single-treatment, potentially curative therapies for rare diseases, strategically pivoting towards a focused clinical pipeline led by AMT-130 for Huntington's disease.
• AMT-130 has achieved significant regulatory milestones, including FDA Breakthrough Therapy and RMAT designations, and alignment on an Accelerated Approval pathway utilizing clinical endpoints and natural history controls, positioning it for a planned BLA submission in Q1 2026.
• The company's proprietary AAV-based gene therapy platform and miQURE™ silencing technology provide key differentiators, enabling targeted delivery and specific gene knockdown, which are crucial competitive advantages in complex indications like Huntington's.
• Recent strategic actions, including the divestiture of manufacturing operations and organizational restructuring, coupled with a Q1 2025 financing, have strengthened the balance sheet, with cash and investments totaling $409.0 million as of March 31, 2025, expected to fund operations into the second half of 2027.
• Upcoming catalysts, including 3-year AMT-130 data in Q3 2025 and initial data from other pipeline programs (AMT-260, AMT-191), are critical milestones expected to drive value and further illuminate the potential of uniQure's gene therapy approach.

The Quest for Cures: uniQure's Gene Therapy Vision

uniQure N.V. stands at the forefront of genetic medicine, driven by a mission to develop and deliver single-treatment gene therapies with the potential to offer curative results for patients suffering from rare and devastating diseases. Founded on the legacy of Amsterdam Molecular Therapeutics (AMT) dating back to 1998, uniQure has evolved through corporate reorganizations and its 2014 IPO to become a publicly traded entity focused on harnessing the power of gene therapy. Its journey includes the pioneering achievement of gaining EU approval for Glybera, a gene therapy for a ultra-rare lipid disorder. While a landmark regulatory success, the commercial realities of Glybera highlighted the challenges of targeting extremely small patient populations and navigating complex reimbursement landscapes, ultimately leading uniQure to strategically prioritize a pipeline of programs addressing larger, albeit still rare, patient populations with high unmet needs.

This strategic evolution is underpinned by uniQure's differentiated technological foundation. The company leverages an Adeno-Associated Virus (AAV) vector platform, notably utilizing AAV5 and AAVrh10 serotypes, combined with its proprietary miQURE™ gene silencing technology. The AAV platform is designed for targeted delivery of therapeutic genes or gene-silencing elements to specific tissues. AAV5, in particular, has demonstrated a favorable immunogenicity profile in clinical trials, potentially allowing treatment in a broader patient population, including those with pre-existing antibodies to other AAV serotypes. The miQURE™ technology is engineered to specifically silence disease-causing genes, such as the huntingtin gene in Huntington's disease, while minimizing off-target effects. This targeted approach to gene silencing represents a crucial technological differentiator, aiming to address the root cause of certain genetic disorders. For AMT-130, the miQURE™ technology is designed to suppress both the full-length mutant huntingtin protein and the highly toxic exon 1 fragment, a mechanism the company believes provides a competitive edge. While specific quantifiable metrics on the comparative advantages of AAV5 immunogenicity or miQURE™ specificity over all competitor technologies are not explicitly detailed with precise figures across all programs, the company's focus on these platforms underscores their strategic importance and perceived benefits in patient eligibility and therapeutic precision.

The gene therapy landscape is intensely competitive, populated by large pharmaceutical companies, specialty biotechs, and academic institutions. Key publicly traded competitors include BioMarin Pharmaceutical (BMRN), CSL Limited (CSL), Novartis (NVS), and Pfizer (PFE), many of whom possess significantly greater financial resources and established commercial infrastructures. uniQure's strategic positioning emphasizes innovation in complex indications and leveraging its AAV and miQURE™ technologies. While competitors like CSL (through its partnership with uniQure on HEMGENIX) and Pfizer are active in the hemophilia gene therapy space, and others like BioMarin and Novartis have broad rare disease and gene therapy portfolios, uniQure aims to differentiate itself through its specific pipeline targets and the unique attributes of its technology platforms. For instance, in Huntington's disease, uniQure faces competition from companies like PTC Therapeutics (PTCT) and Roche (RHHBY), but believes its AMT-130 program, with its direct brain delivery and miQURE™ technology targeting the huntingtin gene, offers a potentially best-in-class approach. Financially, uniQure operates at a significant loss, reflecting its stage of development, with a TTM operating margin of -855.32% and a net margin of -1077.05%, starkly contrasting with the profitability of larger, diversified competitors like CSL (TTM operating margin 23%, net margin 26%) or Novartis (TTM operating margin 28%, net margin 23%). This financial disparity highlights the capital-intensive nature of gene therapy development and uniQure's reliance on successful clinical execution and financing to bridge the gap to potential commercialization.

The recent divestiture of manufacturing operations to Genezen in July 2024 represents a strategic operational shift, aiming to reduce costs and streamline the business, although it introduces reliance on a third party for manufacturing, a potential risk point.

Advancing the Pipeline: Focus on AMT-130

The core of uniQure's current investment narrative revolves around AMT-130, its investigational gene therapy for Huntington's disease. This devastating, inherited neurodegenerative disorder currently lacks disease-modifying treatments, representing a significant unmet medical need. AMT-130 is being evaluated in ongoing Phase I/II clinical studies in the U.S. and Europe. The program has garnered significant regulatory support, receiving FDA designations including Orphan Drug, Fast Track, Regenerative Medicine Advanced Therapy (RMAT), and, notably, Breakthrough Therapy designation in April 2025.

Recent interactions with the FDA have been particularly encouraging, leading to alignment on key elements of an Accelerated Approval pathway. This includes the potential use of data from the ongoing Phase I/II studies, compared to a natural history external control, as the primary basis for a Biologics License Application (BLA) submission. The FDA has agreed that the composite Unified Huntington's Disease Rating Scale (cUHDRS), a measure of functional and motor decline, may serve as an acceptable intermediate clinical endpoint for accelerated approval, with reductions in neurofilament light chain (NfL), a biomarker of neuronal damage, potentially serving as supportive evidence. The company plans to use a propensity score-adjusted external control derived from the large ENROLL-HD dataset for the primary efficacy analysis, with sensitivity analyses using other datasets like TRACK-HD and PREDICT-HD.

Clinical data presented in July 2024 from the ongoing studies showed dose-dependent slowing of disease progression based on cUHDRS at 24 months compared to natural history, suggesting a meaningful therapeutic effect. While specific quantitative figures for the cUHDRS change were not detailed, management highlighted an approximately 80% slowing of disease progression based on composite UHDRS in prior data. The company completed enrollment in the third cohort of the Phase I/II trial in February 2025, which is evaluating AMT-130 in combination with prophylactic immunosuppression. Initial safety data from this cohort showed AMT-130 continued to be generally well-tolerated, with no treatment-related serious adverse events, although three SAEs related to the immunosuppression regimen were observed (mania, MRSA infection, fever), all of which resolved. Management believes a short two-week course of steroids may be an appropriate optimized immunosuppression strategy going forward.

Preparations for the BLA submission are actively underway. Productive Type B meetings with the FDA in Q1 and Q2 2025 addressed critical aspects, including the pivotal statistical analysis plan and Chemistry, Manufacturing and Controls (CMC) requirements. The FDA agreed that validation of the AMT-130 manufacturing process can leverage experience from the HEMGENIX process, supplemented by additional GMP batches and a single Process Performance Qualification (PPQ) batch. Based on these interactions, uniQure plans to submit an updated SAP to the FDA in Q2 2025 and is targeting a BLA submission for AMT-130 in the first quarter of 2026. The company expects to release 3-year top-line data from the ongoing Phase I/II study in the third quarter of 2025, which will be critical in further supporting the planned BLA.

Beyond AMT-130, uniQure is advancing a pipeline of other gene therapy candidates, each targeting severe diseases with high unmet needs. AMT-260, utilizing the miQURE™ technology for refractory mesial temporal lobe epilepsy (mTLE), is in a Phase IIIa trial (GenTLE). The first patient was dosed in November 2024, and preliminary results from this patient are anticipated at a scientific meeting on May 29, 2025. AMT-191, an AAV5-based therapy for Fabry disease, is in a Phase IIIa trial. Following a favorable IDMC review in February 2025, enrollment in the second dose cohort is proceeding, with initial patient data expected in the second half of 2025. AMT-162, an AAVrh10-based miQURE™ therapy for SOD1-ALS, is in a Phase III EPISOD1 trial. The IDMC recommended proceeding after reviewing initial safety data in January 2025, and enrollment in the third dose cohort is expected to begin in Q3 2025. These programs represent potential future value drivers and highlight the breadth of uniQure's gene therapy platform across different indications and delivery methods.

Financial Position and Strategic Realignment

uniQure's financial strategy is currently focused on funding the advancement of its clinical pipeline, particularly the costly late-stage development and BLA preparation for AMT-130, while managing its cash burn. As of March 31, 2025, the company held a solid cash and investments position of $409.0 million, an increase from $367.5 million at the end of 2024. This increase was significantly bolstered by the net proceeds of $80.5 million from a follow-on public offering completed in the first quarter of 2025.

Financially, Q1 2025 results reflect the company's strategic shifts and ongoing R&D focus. Total revenues decreased to $1.6 million from $8.5 million in Q1 2024. This decline was primarily due to the cessation of contract manufacturing revenue (which was $4.0 million in Q1 2024) and a decrease in collaboration revenue ($3.3 million in Q1 2024) following the divestiture of the Lexington facility and changes in service provision to CSL Behring. Cost of contract manufacturing was nil in Q1 2025 compared to $9.1 million in Q1 2024, also a direct result of the divestiture. Research and development expenses saw a decrease to $36.1 million in Q1 2025 from $40.7 million in the prior year period, driven by lower employee and facility costs resulting from the August 2024 restructuring and Lexington divestiture, partially offset by increased external spending on the AMT-130 BLA preparation.

Selling, general, and administrative expenses also decreased to $10.9 million from $13.9 million, primarily due to reduced personnel costs from the restructuring. The net loss for the quarter was $43.6 million, an improvement from the $65.6 million net loss in Q1 2024, reflecting the impact of cost reduction efforts and changes in revenue mix. Other income in Q1 2025 included a one-time $6.0 million sale of critical reagents to Genezen.

The company's liquidity is further impacted by its material cash requirements. These include a $50.0 million principal balance on the Hercules debt facility due in January 2027, associated future interest payments ($14.5 million total, $8.6 million within 12 months), fixed lease obligations ($22.8 million total, $4.2 million within 12 months), and a guarantee of $19.6 million in fixed lease payments for the divested Lexington facility until May 2029. Additionally, there are potential contingent milestone payments of up to EUR 160 million related to the uniQure France acquisition, expected between 2029 and 2033, which could be settled partly with shares. Minimum purchase commitments under agreements with Genezen amount to $33.1 million for supply services and $11.6 million for development services as of March 31, 2025. The liability from the royalty financing agreement related to HEMGENIX royalties stood at $446.66 million, with an effective interest rate of 12.0% to 13.5%, expected to be satisfied prior to December 31, 2038.

Based on its current operating plan and expected progress, uniQure projects its existing cash and investments will be sufficient to fund operations into the second half of 2027. This guidance is predicated on successful execution of its development plans and timing expectations, but is subject to change based on numerous factors, particularly the timing and costs associated with the AMT-130 BLA submission and potential commercialization.

Risks and Challenges

Despite the promising pipeline and strategic focus, investing in uniQure carries significant risks inherent in the biotechnology sector, particularly for a company focused on novel gene therapies. The success of the investment thesis is heavily reliant on the successful development and regulatory approval of AMT-130. Failure to demonstrate sufficient safety or efficacy in ongoing or future clinical trials, or challenges in the regulatory review process, could severely impact the company. The reliance on an Accelerated Approval pathway, while potentially expediting review, is not guaranteed, and the acceptance of intermediate clinical endpoints and external controls by regulatory authorities carries inherent uncertainty. The use of exploratory biomarkers like NfL and post-hoc analyses of clinical data are also subject to regulatory scrutiny and may not be sufficient for approval.

Manufacturing complex gene therapies poses ongoing challenges, and uniQure's reliance on third parties like Genezen introduces supply and quality risks that are outside of its direct control. The competitive landscape is intense, and larger competitors with greater resources could bring competing therapies to market sooner or more effectively. Pricing and reimbursement for high-cost, single-administration therapies, particularly for rare diseases, remain uncertain and could limit commercial success even if approved. The need for additional funding beyond the current runway is anticipated, and the ability to raise capital on favorable terms is not assured, potentially forcing delays or curtailment of development programs. Furthermore, macroeconomic conditions, changes in healthcare legislation, and potential negative public perception of gene therapy could adversely affect the business. The company's existing debt obligations also impose covenants and repayment requirements that could impact financial flexibility.

Conclusion

uniQure is positioning itself for a potentially transformative period, centered on the planned BLA submission for its lead Huntington's disease candidate, AMT-130, in the first quarter of 2026. The company's strategic realignment, including the divestiture of manufacturing and organizational restructuring, coupled with recent financing, has bolstered its financial runway, providing the necessary resources to advance its focused clinical pipeline. The differentiated AAV and miQURE™ technology platforms offer a compelling scientific foundation, particularly for complex neurological disorders.

While significant risks remain, particularly concerning clinical trial outcomes, regulatory hurdles, and the competitive landscape, the recent progress with AMT-130, including Breakthrough Therapy designation and alignment on an Accelerated Approval pathway, underscores the program's potential. Upcoming data readouts from AMT-130 and other pipeline assets in the near term represent critical milestones that could further validate uniQure's approach and unlock significant value. For discerning investors, uniQure represents a high-risk, high-reward opportunity tied to the successful execution of its gene therapy development strategy and the potential to bring the first disease-modifying treatment to patients suffering from Huntington's disease. The company's ability to navigate the remaining clinical, regulatory, and commercialization challenges will be paramount in realizing this potential.