uniQure: is the gene therapy pioneer en route to becoming a biotech rebuff?

uniQure layoffs

Once thought to be a frontrunner in gene therapy, uniQure’s fame may no longer be coveted, as the biotech looks to reorganize by slashing its workforce, in an attempt to stay afloat. But how did things go awry for the company that was once in its prime in the DNA game?

The Danish company, which was founded nearly two and a half decades ago and called Amsterdam Molecular Therapeutics back then, was on a mission to advance research and development in gene therapy, at the time. In 2008, its FIX gene cassette was used in the first-ever clinical trial for hemophilia B. The FIX gene is what codes for the human clotting factor IX, and the absence of this gene, often due to a spontaneous mutation, is what results in hemophilia B.

uniQure makes strides in gene therapy program

Meanwhile, uniQure’s gene therapy focus was expanding to other indications as well. Its treatment for lipoprotein lipase deficiency (LPLD), Glybera, became the first gene therapy to obtain the European Union (EU) nod in 2012. uniQure also went on to snap up cardiology gene therapy company InoCard, which specialized in treating congestive heart failure (CHF), for €3 million ($3.25 million).

Affecting one in a million, LPLD is a rare genetic disorder of lipid metabolism, that is characterized by symptoms like abdominal pain, loss of appetite, and high levels of fat in the blood, typically due to the lack of an enzyme called lipoprotein lipase. Apart from sticking to a low fat diet, there weren’t any effective cures for the disease. So, Glybera, a one-off solution – with an efficacy of at least six years –  which worked by introducing copies of the lipoprotein lipase gene to produce the deficient enzymes, drew attention. When Glybera made its big entrance into the market, it offered promise, but at the hefty cost of $1 million.

Glybera exits market

Despite riding on the success of several ‘firsts,’ things began to go downhill. Glybera was soon – in 2017 – pulled from the market when uniQure chose not to renew its marketing authorization in Europe. This was largely because sales had gone down the drain, because its cost and demand didn’t match up. Moreover, the approval of the drug had come with maintenance costs, since patients were required to be monitored over a long period of time, and, on top of that, the drug had to undergo a phase 4 trial. All this had led to several years of virtually no sales, before it was abandoned.

This was also around the time when its chief executive officer (CEO) abruptly quit, making it two CEOs who jumped ship in the span of a year.

Following these setbacks, both with regards to pipeline and management woes, uniQure decided to lean towards some other indications that were in the works at the time, like its hemophilia B, Huntington’s disease and heart disease candidates. 

But its partner in the gene therapy program for congestive heart failure, Bristol Myers Squibb, called it quits after seven years of collaboration. While uniQure did not owe any money to its former partner, it lost its chance to make hundreds of millions in potential milestone payments, when the latter failed to renew the partnership. 

Huntington’s disease candidate sees mixed results, uniQure stocks drop

In the meantime, uniQure was invested in bringing its Huntington’s disease candidate to the market. AMT-130 consists of an adeno-associated virus serotype 5 (AAV5) vector carrying an artificial micro-RNA specifically tailored to silence the huntingtin gene. Huntington’s disease is an inherited disorder that causes the damage and death of certain neurons in the brain. This is because of a mutation that occurs in the gene coding for a protein called huntingtin. uniQure’s candidate works to inhibit the production of the mutant protein mHTT – which disregulates homeostasis in cells as well as impairs transcription. 

While the candidate showed encouraging results in preclinical studies published in 2019, where AMT-130 lowered mHTT levels in the frontal areas of the brain, the results this time around have been met with scrutiny.

For starters, the phase 1/2 clinical trial was initially halted for three months following safety concerns, where three patients were hospitalized after experiencing nausea and vomiting. It was then resumed, where the trial saw participation from 26 patients with early-stage Huntington’s disease, where 10 patients were in a low-dose group – 6 treated and 4 in control – and the rest in a high-dose group. Interim data from the blinded 12-month study showed an increase in the total motor score – a scale that measures motor symptoms in Huntington’s – in patients. Those in the low-dose and high-dose cohort demonstrated a mean improvement of 1.8 and 2.7 points respectively, whereas those in the control group had a declining score. 

The company documented neurofilament light chain levels – a hallmark of neurodegenerative diseases, where its abundance is associated with the disease – in the low-dose group, which dropped 12.9% below baseline. But levels in the high-dose arm rose by 51.5% after one year, with two patients in the cohort experiencing a reduction after one and a half years. Although, this could mean that the neurofilament light chain levels would decrease with time.

Besides that, a baffling 39.7% jump in mHTT levels in the high-dose group was also measured, although an 8.1% mHTT decrease in the low-dose cohort was seen after two years.

And while there were four adverse effects observed during the trial, including post-operative, and major depression and back pain, uniQure claimed that they were unrelated to AMT-130. 

Although these results seemed to be favorable in the eyes of the biotech, stockholders weren’t too pleased, which resulted in a six-year low 40.2% plummet in stocks, earlier this year.

HEMGENIX hits snag in U.K. 

To add to that, the National Institute for Health and Care Excellence (NICE) in the U.K. – a public body that measures the cost-effectiveness of drugs that hit the market – has put a damper on its hemophilia drug HEMGENIX, which was approved by the U.S. Food and Drug Administration (FDA) last year, and the European Union this year. uniQure passed the baton to pharma giant CSL Behring to distribute the drug globally.

The $3.5 million drug – making it the most expensive medicine in the world – will not be recommended by NICE to the U.K.’s National Health Service (NHS), owing to concerns about its effectiveness, particularly in comparison with the standard of care prophylaxis treatment. 

HEMGENIX, the one-time fix for hemophilia B, was designed to eliminate the need for prophylactics. The AAV5-based therapy contains the active ingredient etranacogene dezaparvovec, which delivers a copy of the factor IX gene, in an effort to elevate factor IX levels, and facilitate the formation of blood clots.

Despite positive phase 3 trial results encouraging 96% of the participants to quit routine prophylaxis, NICE said that the data wasn’t strong enough, especially with regards to long-term efficacy, to gain a recommendation. Plus, its cost-effectiveness wasn’t compelling enough, according to a draft guidance issued in August.

uniQure cuts pipeline and workforce

And most recently, things have boiled down to significant restructuring within the company, with the biotech taking an ax to not only its pipeline but also to more than a quarter of its workforce. As a means to save $180 million over the next three years and focus on its amyotrophic lateral sclerosis (AML) and Fabry disease candidates, it will shut down a research lab in Massachusetts in the U.S., as well as pull the plug on more than half of its research and technology projects – but without affecting Hemgenix manufacture.

However, whether this vow to recapture its dwindling stardom will hold true, we will have to wait and watch.

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