uniQure N.V. (QURE): A Bear Case Theory 

We came across a bearish thesis on uniQure N.V. on augur’s substack. In this article, we will summarize the bulls’ thesis on QURE. uniQure N.V.’s share was trading at $27.51 as of November 28th. QURE’s forward P/E was 27.93 according to Yahoo Finance.

uniQure N.V. develops treatments for patients suffering from rare and other devastating diseases in the United States. QURE’s AMT-130 gene therapy faces significant scientific and strategic challenges in the rapidly evolving Huntington’s disease (HD) landscape. Allele-selective approaches, such as Wave Life Sciences’ WVE-003, achieve comparable or superior mutant huntingtin (mHTT) reduction while preserving wild-type HTT, are intrathecal, and require quarterly dosing, demonstrating mechanistically coherent biomarker changes without serious adverse events.

Oral splicing modulators like SKY-0515, protein degradation therapies from Arvinas, and MSH3-targeting approaches from Latus Bio diversify the field away from invasive, non-selective, one-time interventions. The underlying huntingtin hypothesis itself is increasingly questioned. Disease progression is influenced by CAG repeat length, somatic expansion, and multiple genetic modifiers, with substantial variability among patients sharing identical repeats.

Non-selective HTT lowering risks disrupting essential wild-type function, potentially triggering neuroinflammation or compensatory responses, and previous attempts like tominersen have failed. UniQure provides minimal data on modifier genotyping, somatic expansion, or target engagement, leaving critical confounds unresolved. AMT-130 carries inherent miRNA and AAV risks. miRNAs can produce off-target effects and saturate RNAi machinery, while preclinical AAV5 studies show peripheral biodistribution and potential long-term immune responses.

Human trials remain small (n=12), rely on external controls, and omit key mechanistic endpoints such as striatal volume and mHTT reduction. Post-hoc analyses and nominal p-values without multiplicity correction further weaken the evidence. Operationally, UniQure is constrained by debt and regulatory timelines, limiting feasibility of a rigorous Phase 3 trial.

Market optimism has been fueled by hope, FDA alignment, and the “right to try” framework, but objective data gaps and mechanistic uncertainties persist. Broader implications include heightened scrutiny for gene therapies, higher regulatory standards, and the need for robust, reproducible evidence to validate permanent interventions in HD. AMT-130 remains a high-risk, potentially obsolete approach amid safer, more targeted, and mechanistically supported therapies advancing toward approval.

Previously we covered a bullish thesis on CRISPR Therapeutics AG (CRSP) by MADD-Scientis in March 2025, which highlighted Casgevy’s commercial potential, strong institutional backing, a robust pipeline, and low dilution risk. The company’s stock price has appreciated approximately by 30.51% since our coverage. The thesis still stands as CRSP advances multiple near-term catalysts. A_May_MD shares a contrarian view, emphasizing uniQure’s AMT-130 risks and competing allele-selective therapies.

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Disclosure: None.