Stephane Huberty won an award as young entrepreneur of the year in Brussels, Belgium, in 1993. His thriving start-up company developed specialised 3D scanners, software and machines for custom made and orthopaedic shoes. But in 1996 on a bus trip to Hanover in Germany, the Belgian medical doctor began to experience double vision and feel unwell. At the weekend, he had difficulty standing up while trying to fit a wooden floor in his apartment with his father. Later that evening he had trouble eating dinner. “I thought maybe I had a bad flu, or I was exhausted from work,” he remembers.
But a few days later, a friend had some strong advice: “You must go see a doctor, doctor.” A neurologist promptly diagnosed him as having myasthenia gravis (MG), a rare neurological condition. He could not even crouch and stand up. MG is an autoimmune disease involving severe muscle weakness. Within a few months, he had been on a respiratory machine, had lost 20 kg and had trouble moving around; he was put on cortisone. “It was a miserable time,” he recalls.
He wanted to get better. Being a medical doctor, he read the literature. He came across the work of Edwin Blalock, professor of medicine at the University of Alabama at Birmingham, USA, who had developed a therapeutic vaccine against the blood cells that produce those antibodies that sometimes turn rogue and attack the body. He tested out his vaccine against rats with MG.
Huberty tracked the US researcher down. And he convinced him to form a start-up company—CuraVac. Its aim is to develop a vaccine for humans that specifically targets the rogue antibodies involved in the disease, attacking a specific protein at an important neuromuscular junction – specifically, the alpha-chain of the acetylcholine receptor. Blalock had already cured a pet dog sick with MG and had begun a trial on pet dogs. “I thought it was all wrapped up. It was a matter of making sure the patent was owned by the company, it would rapidly go into Phase I trials in patients and we could pass it on to a pharma or biotech company to take it from there,” says Huberty. “That proved to be very, very wrong.” There was little interest from industry; MG is an orphan disease and affects 1 in 5,000 people, so the market is small.
The approach seemed outside the box. The publication of the successful trial in dogs came out in 2006. Still nobody picked up the baton. And the company struggled to find the funds required to push the candidate drug forward. One problem was that pharma companies and venture capitalists mistakenly believed there were already treatments for MG and that severe MG was rare, Huberty recalls.
In the face of disinterest from potential funders, Huberty forged ahead with his idea. Scraping together funding, including a €200,000 investment from a neighbour, CuraVac’s vaccine was manufactured to Good Manufacturing Practice standards, which makes it suitable for administration. “This was one question we had from the pharmaceutical companies. Could this be done?” But once this was achieved, and the vaccine injected into rats, pharma companies just came up with yet more questions.
Then, Huberty did something unusual and either brave or desperate.
“No rats died. At the same time I knew we didn’t have the money in 2009 or 2010 to move forward to Phase I toxicity trials in humans. But I had some of the new batch of vaccine in my fridge. So I decided to take it myself. I asked a friend, who was a specialist in emergency care, to be by my side,” says Huberty.
That was in June 2009 and his condition began to rapidly improve. Within a few months he was able to swim long distances, and the following winter went skiing for the first time since 1996. However, he began to weaken again so had three subsequent injections with a higher dosage, the last in 2010. “Since then I have lowered my cortisone intake to a quarter of what it was and reached a dosage that is safe in the long term,” he says.
CuraVac applied and received orphan drug designation for the therapeutic vaccine drug in 2009.
The question is whether there a business case for orphan diseases, with relatively small numbers of patients. There are an estimated 250,000 patients in the US, Europe and Japan combined.
A recent study in Drug Discovery Today asked if orphan drugs make sense from a business point of view. “There has been a stark increase in the number of drugs getting approved over the last couple of decades, and we wanted to know if that was economically viable,” says study author Kiran Meekings at Thomson Reuters, based near Geneva, Switzerland. “There is a whole new business model that has emerged, based around rare diseases and involving a large number of small biotechs.” Her research indicated that orphan drugs or no more or less profitable than non-orphan drugs. However, she says companies need a lot of support and it can be difficult to recruit patients.
In 2013, the company won a European grant, under the FP7 funding scheme, with a consortium to develop the drug through Phase I and II trials. The research project, called MYASTERIX, is due to be completed by 2018. CuraVac is the consortium leader of a research group that involves Leiden University Medical Center, the reference centre for MG in the Netherlands, which follows around 600 patients. “This is a 5-year programme, and next year we begin phase I on 32 patients,” says Huberty. Phase II is forecasted for 2017-2018 on 50 patients. Given its orphan drug status, the Phase III trial might require only 200.
Nonetheless, Huberty is again surprised that, even with the seal of FP7 approval, potential investor companies remain reluctant to get involved. “This is a €6 million subsidised program over 5 years, but when we discuss with investors I sometimes get the impression that we must jump higher again and that the bar just keeps getting higher, until one day we must reach the market ourselves.”
However, an expert cautions that autoimmune disease can be particularly unpredictable. “A major problem is the translation of preclinical animal models into the clinic,” says Sander van Deventer, a professor of translational gastroenterology at Leiden University and an experienced venture capitalist who is managing director at Forbion Capital Partners, headquartered in Naarden, just outside Amsterdam, the Netherlands. “I do not know of any autoimmune disease where the animal models are really predictive of what happens in the clinic,” he says. One therapy, he recalls, worked for both Crohn’s disease and rheumatoid arthritis in animals, but then actually made the condition worse in people with Crohn’s. “The strategy is usually to test in patients as soon as you can, especially in spectrum diseases like multiple sclerosism, say.”
The nature of the treatment requires additional caution. “If you have a cancer monoclonal antibody, then they might buy it in early Phase II, but if you have an orphan product [like CuraVac’s], probably they will ask for more efficacy data. This is related to the fact that you are often the first to do anything of this kind for the disease. So the bar is higher,” says van Deventer.
He also says that taking too many stakeholders on board when developing a therapy can muddy the waters for investors. “Sometimes they end up splitting the intellectual property, and for us that would be a complete block. As VCs we need to have our hands free, because sometimes biotech companies need to change direction and this becomes difficult if your structure is complicated.”
Instead of seeking support from VC funds, the alternative is to make a development deal with the pharmaceutical industry, particularly to fund a phase III trial. Yet, Huberty is at times frustrated by the endless questions and wariness of pharmaceutical companies.
Critiques of the pharma sector already pointed out the extent to which the industry has become conservative and wary of taking risks. “If you look at drug approvals by the [US Food & Drug Administration] and the European Medicines Agency, there are only 25 new drugs approved. If I was to be demanding I would say only 5 of those are truly innovative,” says van Deventer.
Innovators are few and far between. “If you look at where they come from, the real innovators are in venture-backed biotech companies. But only 30% of even those companies are truly innovative. So I agree that there is a lack of innovation, particularly in view of the fact that there are so many diseases still not treated very well or not at all.”
Part of the blame, he says, lies with regulators. “These people are even more conservative than pharma, and they really don’t understand biotechnology. If you delay approval a couple of years for a small biotech, then you make the hurdle very high,” he adds. But part of the blame also lies with a culture of caution.
For now, Huberty is determined that the vaccine will overcome all obstacles and reach MG patients. He believes it could prove to be an effective approach for other autoimmune diseases like multiple sclerosis. “My dream is that a diabetes type I patient would just need three vaccine injections or that a MS patient goes to visit their doctor and is told they just need a few injections [to be cured],” he says enthusiastically. “If we can prove that the MG vaccine works it would be a new class of therapy. This could be a medical revolution.”
Already, he is contacted by new patients each week asking about the vaccine. “There is real hope and demand. I recently got a call from a mother asking for the vaccine for her 13 year old daughter. I had to tell her that we are working on it but that she had to wait. We are doing our best to provide it as a scientifically proven treatment as fast as possible.”
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