Incentives, IP and Smaller Companies: The Story of uniQure
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uniQure, based in Amsterdam in the Netherlands and Lexington, Massachusetts, USA, is developing curative gene therapies for patients with severe genetic diseases. The company had around 220 employees in 2017.
How uniQure wants to change patients’ lives with durable, curative benefits
uniQure has an ongoing clinical program in hemophilia B and preclinical proof of concept for a gene therapy for Huntington’s disease.
When the gene associated with the production of a protein required for blood clotting (Factor IX) is missing or mutated in patients with hemophilia B, a severe orphan blood clotting disorder, these patients’ blood cannot clot sufficiently to stop bleeding, even after a minor trauma or surgery. The condition can lead to repeated and sometimes life-threatening episodes of external and internal bleeding. The episodes can cause long-term damage, for example, to the joints, and can be fatal if they occur in the brain. Treatment of hemophilia B today consists of prophylactic or on-demand Factor IX replacement therapy with frequent and burdensome intravenous treatment that does not completely prevent bleeding.
The impact on patients, families, healthcare systems and society
Introducing a copy of the proper gene into the cell via gene therapy could restore the presence and natural function of the blood-clotting factor, which would prevent bleeding. Gene therapy is a technique that uses fragments of genetic material for the long-term treatment of genetic disorders. This may involve delivering a copy of a healthy or therapeutic gene, repairing a faulty gene, and/or altering the degree to which a gene is turned ‘on’ and ‘off’. Gene therapy can potentially be used to treat genetic disorders with one single or very few administrations rather than frequent dosing, thus improving quality of life and reducing the need for physician visits.
The uniQure gene therapy product candidate AMT-061 may be the first gene therapy to provide durable, curative benefits to nearly all patients with hemophilia B, along with optimized clinical and safety benefits. uniQure’s gene therapies deliver the gene to the target tissue using their proprietary AAV5 adeno-associated virus vector delivery system. They have been evaluated in three clinical trials conducted in more than two dozens of patients with hemophilia B and in other indications. No patient treated has experienced any confirmed adverse immune response, with no loss of efficacy at up to 18 months of observation. The therapy can therefore mean a “night and day” change to patients’ quality of lives: Instead of having frequent injections and an overly protected life in order to avoid any risk of provoking un-stoppable bleeding, they are now able to ride a bicycle, go on holiday or work in the garden.
Breaking new ground to bring new therapies faster to patients
In 2012, uniQure was the first company to succeed in obtaining marketing authorisation to treat familial lipoprotein lipase deficiency (LPLD), an ultra-rare genetic disorder, with Glybera® (alipogene tiparvovec), paving the way for gene therapy. uniQure was required to establish a global registry for the long-term surveillance of patients, conduct a post-approval clinical study, submit to annual regulatory reassessments and implement additional risk management procedures. All of these activities required significant infrastructure that included the company bearing the full costs of maintaining commercial manufacturing capabilities, managing development and validation of numerous assays and supporting regulatory interactions and inspections. uniQure did not pursue marketing authorization renewal of Glybera in Europe when it expired in October 2017, due to extremely limited patient demand which they do not envision increasing materially in the years ahead. As a result of the withdrawal of Glybera, uniQure expects to reduce future expenses related to the product by approximately $2 million annually, beginning in 2018 and net of any payments to the Chiesi Group, which has exclusive rights for the commercialization of Glybera in Europe and other selected countries.
UniQure will focus resources on advancing their hemophilia B program into a pivotal trial, moving their Huntington’s disease program into a clinical proof-of-concept trial, and progressing their research and development collaboration with Bristol-Myers Squibb. EU pharmaceutical incentives help enable innovation for the benefit of patients
EU pharmaceutical incentives have been instrumental in helping the company embark on these innovative development programs.
Based on the results of clinical Phase I/II studies (in 10 patients for AMT-060), the U.S. Food and Drug Administration granted a Breakthrough Therapy designation for the uniQure hemophilia B gene therapy in January 2017. In April 2017, the hemophilia B gene therapy also received PRIME designation by the European Medicines Agency (EMA). PRIME offers continuous support through early dialogue and scientific advice and guidance on the overall development plan and regulatory strategy. Developers of promising medicines that benefit from PRIME can expect to be eligible for accelerated assessment when applying for marketing authorisation, so that these medicines can reach patients earlier.
uniQure confirms that having focused conversations with health authorities is beneficial to both the patients and the company. Detailed knowledge of the development plans of novel therapies facilitates quicker access to new medicines for patients because authority representatives gain deep insight into the underlying research strategy. The prospect of accelerated market access – even only a few months are considered favourable – combined with other protective incentives is a very important factor for entrepreneurs when deciding which innovation pathway to pursue.
Benefits at multiple levels help bring innovations to the market
Patients in need of the new uniQure therapies also benefit from other special administrative and regulatory incentives. The orphan designation (OD) in Europe with ten years of market exclusivity for approved products also includes the possibility to seek scientific advice during development at no cost to the company. The Advanced Therapy Medicinal Product (ATMP) status also applies to uniQure’s innovative gene therapies. ATMP therapies are expected to bring important health benefits, but also to substantially impact the pharmaceuticals budget. To help get such therapies on the market, the EU offers a centralised marketing authorisation procedure that benefits from pooled expertise at European level and direct access to the entire EU market after registration. The combination of OD and ATMP status, and the EMA designation of uniQure as a small and medium-sized enterprise (SME) brings additional incentives. In combination, they can lead to up to 100% reductions in fees for administrative services, Scientific Advice procedures, Marketing Authorisation Application (MAA) and regulatory pre-inspections, as well as more than 80% reductions in post-authorisation procedures fees and fees for the monitoring and prevention of potential adverse effects (pharmacovigilance). uniQure also benefits from a MedDRA licence-fee waiver programme to facilitate electronic pharmacovigilance reporting in the pre- and post-authorisation phase.
A paediatric investigational plan (PIP) will also be discussed for each therapy in the uniQure pipeline, the company confirms. This helps children and juvenile patients to benefit as early as possible from novel therapies with the potential to improve quality of life sustainably by curing the disease rather than treating symptoms. With orphan designation (OD) at the time of marketing authorization for a given gene therapy, uniQure would benefit from a two-year extension to the standard ten-year market exclusivity upon completion of the PIP as agreed with the authorities.
Expanding development pipeline to benefit more patients with rare diseases
To transform the lives of even more patients with hemophilia, uniQure is planning a pivotal Phase III clinical study in 2018 for patients with severe and moderately severe hemophilia B, and also has a new gene therapy to treat hemophilia A in pre-clinical evaluation.
uniQure is also developing a gene therapy for Huntington’s disease (HD). HD is a rare, fatal, neurodegenerative genetic disorder that affects motor function and leads to behavioral symptoms and cognitive decline in young adults, resulting in total physical and mental deterioration over a 12- to 15-year period. HD is caused by a defect in multifunctional gene coding for a protein called huntingtin. There are no therapies available to treat the disease, delay its onset, or slow the progression of patient decline.
uniQure’s product candidate AMT-130 aims to inhibit the accumulation of the mutant huntingtin protein with the direct delivery to the brain of artificial micro-RNA to turn off the production. For this highly innovative approach to treating Huntington’s disease, uniQure achieved preclinical proof of concept in early 2016. In April 2017, uniQure published two additional preclinical studies that support moving forward with clinical trials of this promising gene therapy. The company received an orphan drug designation (ODD) by the US-FDA for this gene therapy program in September 2017, and expects to file an Investigational New Drug (IND) application and to enter clinical development for AMT-130 in Huntington’s disease in 2018.