Few companies have attempted to traverse the largely uncharted and treacherous gene therapy regulatory waters, and none have yet crossed it. Currently finding its way is Amsterdam Molecular Therapeutics (AMT), which expects to hear in the middle of next year whether Glybera, a therapy for lipoprotein lipase deficiency (LPLD), has won approval in Europe.
A green light would be a huge event not only for the company, but for the field in general; other than products approved in the Philippines and China a gene therapy product has yet to reach a Western market. Jörn Aldag, chief executive of AMT, tell EP Vantagethat he believes the company has made a strong case for approval. Given past failures not all will share his faith, but no doubt eyes across the world will be watching the outcome (Therapeutic focus - Will hopes evaporate as gene therapy pipeline flows?,August 25, 2010).
LPLD is caused by a genetic mutation which diminishes, to varying degrees, the activity of lipoprotein lipase, an enzyme needed to break down large fat-carrying particles that circulate in the blood after each meal. If these particles, called chylomicrons, are not broken down they block blood vessels, particularly in the pancreas.
As such, repeated episodes of pancreatitis are the hallmark of this disease, although sufferers are also likely to develop severe diabetes and cardiovascular problems at an early age.
Glybera works by using an adeno-associated virus (AAV) as a delivery vehicle, which carries the missing gene into the cell nucleus. These genes do not integrate with the host cell’s DNA, but do prompt the cell to start producing the missing enzyme.
AMT has managed to achieve this without immunogenicity reactions, a major stumbling block for many gene therapies.
The administration of Glybera is not particularly pleasant, but it does have a huge advantage in that patients only need to go through the process once. Over three hours, 40 intramuscular injections are given in the thigh; a patient is only required to stay in hospital for a morning.
The cells in the thigh then start to produce LPL, and enough can be generated to substantially improve a patient’s condition, AMT believes.
The company has measured the therapy’s efficacy through monitoring chylomicron levels and the frequency of pancreatitis events. Its pivotal trial demonstrated a 70% reduction in the incidence of pancreatitis, a significant improvement for these patients who can sometimes suffer more than one event a year.
The link between chylomicrons and pancreatitis is well established, and AMT has tracked both in the Glybera trials.
“We have a pretty good case to say the clinical evidence is well described. That’s what gives us confidence in that we have a clinical benefit and means to prove it, and we have not seen any side effects.
“You can never prove anything easily, what happens in the body, but I think we have all the bits and pieces needed to have a good explanation that should be acceptable for the European authorities,” he says.
Another plus point is that the regulators recently confirmed that data from the 27 patients enrolled in the pivotal trial will be sufficient. More data on these patients will be fed to the EMA over the coming months, but a bigger study will not be required.
The small trial reflects the small patient population; AMT believes only 1,600 patients worldwide suffer from the homozygous form of the disease.
Although the Glybera decision is clearly the biggest event on the horizon for AMT, other projects are underway. In particular, a number of projects that it believes might attract big pharma partners have been identified, as the company hopes to capitalise on a shift in opinion towards gene therapy (Gene therapy players sensing light at the end of the tunnel, August 25, 2010).
Mr Aldag highlights haemophilia and Parkinson’s disease as two areas where partners are being sought. The former in particular he believes is looking promising.
“We have actively selected a couple of projects that we think would be interesting to big pharma because they are disruptive to existing markets. In haemophilia, currently it’s a lousy treatment, you have to get three injections a week and that’s not the standard of care you expect. We think if you can bring a gene therapy to patients this should substitute the protein replacement market. And I think now we are in an environment where this could be partnered,” he says.
The first patient has been dosed with good results, Mr Aldag says, adding that early stage discussions have already started. In Parkinson’s, where a gene has been licenced from Amgen, the company expects to be in the clinic in a couple of months.
“We have a few people dancing around us and looking at this,” Mr Aldag says.
In terms of a deal for Glybera, Mr Aldag says they are not actively seeking a partner at the moment, acknowledging that nothing would happen anyway until approval is in the bag.
“We have seen people looking at it, but they are not willing to take the approval risk,” he says. If all goes well things might change.
“If someone takes away the risk by giving us a huge down payment that would keep us going for ages, then yes we would consider [doing a deal]. But we would probably only need 10 people to market this in Europe,” he says.
The company plans to end the year with a year of cash, meaning the subject of financing will also soon have to be addressed. Mr Aldag believes that his investors would step up, but funds will probably have to be found before the outcome of the regulatory review is known. As such, investors will be taking a lot of risk.
“At this point of development the company has a huge potential if it works out and at the moment I consider the risk take-able."
Popping the corks
Whether investors agree remains to be seen. AMT shares are currently trading at €2.36, giving the company a market value of €35m. The stock has lost a quarter of its value so far this year and three-quarters since floating on the Amsterdam Stock Exchange in mid-2007 at €10, and gene therapy is still considered one of the most high-risk areas of biotech.
Of course the fate of AMT shares has also been closely aligned to the fate of others in the gene therapy space, a high-risk space that has taken down many biotechs, if not completely than certainly their market value.
As such, much pivots on the Glybera decision.
“Approval would be the validation of gene therapy in principle and for all our efforts. It will be like pulling the cork out of the bottle,” Mr Aldag says.
If it does happen, the sounds of champagne corks popping will no doubt be heard loud and clear at AMT and beyond.