uniQure (QURE): Gene Therapy Progress in Hemophilia B

Edward Kim  |

Hemophilia is a rare blood disorder caused by a deficiency in one of a group of clotting proteins that leads to excessive and prolonged bleeding from minor trauma or even spontaneously without injury. Most sufferers inherit the genetic deficiency, though about 30% have no family history of the disorder according to the Mayo Clinic. In these cases hemophilia is caused by a genetic change referred to as spontaneous mutation.

The Centers for Disease Control and Prevention (CDC) estimates that 20,000 people in the US suffer from hemophilia, with most diagnosed at a very young age. The median age at diagnosis is 36 months for people with mild hemophilia, 8 months for those with moderate hemophilia and 1 month for those with severe hemophilia. The disease is categorized into three types - A, B and C - depending on which clotting factor is deficient in the body.

uniQure (Nasdaq: QURE) is developing gene therapy treatments for hemophilia B (whose patients are deficient in, or have defective, clotting factor IX), Huntington's disease and cardiovascular disease. Its platform uses adeno-associated virus (AAV) vectors to deliver the therapeutic gene treatment to the affected regions in the body. We discussed gene therapy and AAV vectors last week in our article on Abeona Therapeutics (Nasdaq: ABEO). uniQure uses the AAV5 variant for its hemophilia B and Huntington's disease candidates and has exclusive, worldwide rights to AAV5 for use in therapeutic products delivered to the brain or liver.

Gene therapy pioneer

Readers may recall that uniQure made headlines - both good and bad - back in 2012 when it received the first ever marketing approval for a gene therapy in a regulated country. The company's Glybera therapy was approved by the European Medicines Agency (EMA) for the treatment of familial lipoprotein lipase deficiency (LPLD), a rare genetic disorder that disrupts the body's normal process of breaking down fats. Glybera was "famously initially priced at around $1 million in Europe, but just didn’t have a large commercial market to make it worth continuing to sell," according to Xconomy. uniQure announced in April 2017 that it wasn't going to pursue a renewal of its marketing authorization for Glybera, ending that program as a commercial failure but establishing a legacy, expensive though it may be, of a viable regulatory path for gene therapy.

Hemophilia B

In January 2017, uniQure's AMT-060 gene therapy for hemophilia B received Breakthrough Therapy Designation from the FDA. The EMA followed in April 2017 with PRIME Designation. Both are programs designed to expedite the development and review of drugs designed to treat serious conditions, based on preliminary clinical evidence.

In presentations last month at the International Society on Thrombosis and Haemostasis (ISTH) annual congress, uniQure presented updated, long-term clinical data from its Phase I/II trial of severe hemophilia B patients. All 10 patients in the study demonstrated improvements in their disease state as measured by reduced clotting factor IX replacement therapy and bleeding frequency. Across both low-dose and high-dose cohorts, cumulative annualized factor IX consumption decreased by 79%, and in the higher-dose cohort, no spontaneous bleeds were reported in the last six months of follow-up. The data also showed a reduction in the annualized spontaneous bleed rate of 84% compared to the one-year period prior to gene transfer.

The company also presented new clinical data showing the efficacy of AAV5 gene therapy in the presence of pre-existing neutralizing antibodies (NABs). All three patients with detected anti-AAV5 NABs presented increases in factor IX expression. To date, 18 patients across two clinical studies have received intravenous, systemic administration of AAV5-based gene therapies without any observed T-cell activation. The data suggest AAV5 may have a superior immunogenicity and safety profile compared to other AAV vectors.

uniQure also announced last month that it had reacquired the rights from Chiesi Group to co-develop and commercialize its hemophilia B gene therapy in Europe and other select territories and to terminate their co-development and license agreement. uniQure now has full global rights to the program.

Huntington's disease

Huntington's disease is a genetic disorder caused by a mutation in the huntingtin gene. Affected patients suffer progressive degeneration of nerve cells in the brain, leading to loss of muscle coordination, behavioral abnormalities and cognitive decline, and resulting in complete physical and mental deterioration over a 12- to 15-year period. uniQure expects to initiate an IND (Investigational New Drug Application)-enabling safety toxicology study of its AMT-130 gene therapy for Huntington's disease this fall.

The company published data last year that showed preclinical proof of concept of a one-time administration of AAV5-delivered gene therapy to successfully silence the huntingtin gene. Two additional preclinical studies were published in April 2017 that showed widespread transduction (transfer of genetic material) in the central nervous system and widespread and effective AAV5 vector distribution and extensive silencing of the mutant huntingtin gene in animal models.

Bristol-Myers Squibb collaboration in cardiovascular disease

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The company entered into a collaboration agreement with Bristol-Myers Squibb (NYSE: BMY) in 2015 that provides BMY with exclusive access to uniQure’s gene therapy technology platform for multiple targets in cardiovascular diseases. uniQure has received $140 million so far under this agreement, with the potential of achieving $2.3 billion in potential milestones and up to double-digit royalties. BMY has a 9.9% stake in uniQure with warrants to purchase an additional 10% of the company.

Last week, uniQure announced that preliminary data from a large animal study showed both DNA delivery and human expression of its cardiovascular gene therapy candidate in the myocardium after treatments with product produced from uniQure's proprietary manufacturing process. Based on this finding and others, BMY and uniQure intend to advance the product candidate into further preclinical studies, with a goal of initiating a preclinical therapeutic heart failure study as soon as possible.

Source: uniQure website

QURE stock

The stock has run up sharply since the publication of data two months ago that showed successful repeated liver-targeted gene delivery in non-human primates, but is still carrying a market valuation of only $225 million - less than a third of what it was two years ago. We applaud the company's decision in November 2016 to streamline the organizational structure and focus the development efforts on hemophilia, Huntington's disease and the BMY collaboration in cardivascular disease.

Despite the strong recent rally, we still like the risk-reward profile at this level, and the company guided investors to these upcoming anticipated milestones last week:

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