Economies of Scales

The benefits of essential fatty acids have long been established, but introducing them into the pharmaceutical sphere is a relatively recent phenomenon. Hilda Steineger explains how Pronova’s use of omega-3 from fish oil has transformed an age-old remedy into a potential blockbuster.

“The human race has eaten fish for hundreds of thousands of years, so we have the metabolism and the system in place”
-Hilde Steineger

Norway has traditionally used fish oil as a natural remedy, most notably cod liver oil, but it wasn’t until the late 1970s that a Danish scientist discovered that the large intake of fats by Eskimos did not have the normal correlation of cardiovascular problems that are seen in the Western world. Further analysis of the types of fat uncovered large quantities of omega-3, and the understanding of its cardiovascular properties was born.

“There has been a lot of scientific research in Norway on lipids and omega-3s since the late 1980s,” explains Hilde Steineger of Norwegian-based Pronova BioPharma. “Between the late 1980s and early 1990s, Norsk Hydro looked into omega-3 to produce it in a very high concentration, and this is what makes our product different than the supplements from those you can buy in the pharmacy: we have a much higher concentration of omega-3. A normal supplement would be somewhere between 30-50 percent concentration, while our product is above 90 percent concentration of omega-3.

“At that time Norsk Hydro, which is a large conglomerate in Norway, filed patents on this concentration and they started to do clinical trials. When they started they had an open mind about which indication and diseases this could be used towards, and what they observed was that it was quite effective on lowering triglycerides. So that was one of the indications that we ended up with in the clinical trials going forward.”

Steineger also notes the work of a large cardiologist group in Italy, the GISSI Group, who began work on the effects of omega-3 at a similar time. They also began studying the effects of omega-6, and whether it would work, as well as if similar results could be produced from Vitamin E.

Clinical trials
Following this, the GISSI Group then took the lead with Pronova and began performing large-scale clinical trials, with over 7000 post-myocardial infarction patients. For instance, patients who had previously experienced heart attacks would receive either a placebo drug, omega-3 or Vitamin E to determine the effects. The Vitamin E groups proved to show no effects, whilst the highly concentrated omega-3 groups showed tremendous effects on all-cause mortality, new cardio arrests and heart attacks, as well as on sudden deaths.

Most astonishingly, the trials showed a four to five percent relative risk reduction in sudden death groups and a 20 percent reduction in all-cause mortality. Steineger notes that these results were responsible for the formation of the basis of post-myocardial infarction in Europe, the other indication present being a lowering of triglycerides.

She explains the results of omega-3 on cardiac prevention as being due to a regulation of heart rhythms – electrocardiac signals – in the body. “On cardiac prevention, you must remember the human race has eaten fish for hundreds of thousands of years, so we have the metabolism and the system in place, and fish oil and omega-3 are involved in extremely high number of different pathways in the body,” says Steineger.

“There are many modes of action of this drug; we can’t pinpoint one and say, ‘This is one of them. This is how it works.’ We can pinpoint several, but which of these modes of action is the most important is difficult to say. However, on the prevention of cardiac events, the scientists and we believe that this is a regulation of heart rhythms, electrocardiac signals.

“How would that come to be? Well, it’s believed that every cell membrane of phospholipids has lipids in it, and if you exchange the lipids from saturated or monounsaturated with polyunsaturated, they get more liquid: the membranes get more higher fluidity. Because the more saturated fat is, the harder it gets.

“If you then go to the other extreme and have a polyunsaturated fatty acid, like omega-3, and you incorporate this into the phospholipid layers it has been shown that the lipid layer will get a higher fluidity. This fluidity has an effect on the electrocardiac channels, such as the calcium potassium channels conducting the electric signals between the cells. That’s one change in the phospholipid layer and how that might change electrocardiac signals.

“After the GISSI-Prevenzione study the GISSI Group also performed a study reported in 2008 called the GISSI Heart Failure study. There they showed the reduction in all-cause mortality to be around nine percent this time, however heart failure patients are quite sick and are on a lot of different drugs, so it was an add-on therapy and not a switch. This is the mode of action on the cardiac prevention.

“The lowering triglycerides is a bit more complicated in the sense that natural or fatty acids are natural ligands for PPARs. When the fatty acids bind to PPARs, the PPARs then regulate quite a lot of different metabolic pathways, stimulating the uptake of triglycerides in the blood and reducing the body’s own production of triglycerides, and also increasing the metabolism of fatty acids and triglycerides. So it has quite a lot of different modes of action, which all together give a reduction in the very high triglyceride group, because there’s differentiation on how high levels you have with triglycerides. Therefore, in the very high triglyceride we see a 45 percent reduction of triglycerides, which is comparable to Niaspan and Tricor, but without having the same side effect profile,” explains Steineger.

Regional attitudes
Pronova’s omega-3 product, known as Omacor in Europe and Asia and Lovaza in North America, is the first and only EU- and FDA approved omega-3 derived prescription drug. It is indicated in Europe for lowering all forms of triglycerides, as well as for use in post-myocardial infarction patients; whereas in the US it is indicated only for lowering very high triglycerides. However, the US market is expanding, following a recent re-launch. Reliant Pharmaceuticals launched Lovaza in 2005, and when GSK bought Reliant in 2007, a different sales team was put together, the sales force was doubled and the product was re-launched three months later – creating a bigger market. However, Steineger believes the pick-up rate to be the same at home as it is abroad, regardless of the long tradition of omega-3 use  in Norway. In fact, the greatest market currently for Pronova is the Mediterranean.

“They already eat a lot of fish there, so you would think that they wouldn’t need extra fish oil or extra omega-3, but the perception that fish oil and omega-3 are good for you is easier to penetrate there than in the more northern European countries,” says Steineger.

Although there is no scientific proof, she alludes to the fact that in a region where the intake of fish oil is already high, having extra is considered even more beneficial. It is this approach towards omega-3 that has received tremendous attention within the US, and she explains GSK is promoting the product, “very well and very professionally, it’s one of the growth drivers for GSK for the moment.”

So how is this steering the future of Pronova? Steineger explains that this area is due for even more growth, and there is certain to be a greater market in the future for these marine-derived omega-3 products.

“We have just scratched the surface of the potential, but it will of course be dependent on clinical trials and what we can prove. omega-3 has been coupled up with CNS diseases, like depression, Alzheimer’s and also dementia, as well as having shown to have anti-inflammatory effects. There’s a lot of research that shows there’s potential in omega-3, but of course, it all depends on the clinical trials you do to support your product. We have a business model whereby we don’t perform large clinical trials ourselves; it’s our partners that perform the clinical trials,” explains Steineger.

The timeframe for looking into such other potential applications is still uncertain. She notes that there is still a lot to do on the cardiac prevention and on the lowering of triglycerides, in the sense of harvesting all the potential. There is also a large clinical trial, known as ORIGIN and driven by sanofi-aventis, which includes Pronova’s product in two of the arms, and involves 12,000 pre-diabetic patients.

The remainder of 2009 looks promising for Pronova, and with March end-user sales hitting US$1.1 billion, the company is aiming for blockbuster status for Omacor/Lovaza, and as Steineger says, “There are not many products that can do that.”

Hilde Steineger has served as Head of Investor Relations at Pronova BioPharma since 2007. Before that, Steineger was Senior Associate at NeoMed Management from 2006 to 2007, Business Development Consultant at Maxfield/Amino from 2003 to 2006 and Senior Financial Analyst at Nordea Securities from 2001 to 2003. She graduated holds a PhD in medical biochemistry from the University of Oslo.

omega-3

Popularly known as fatty acids, omega-3s are a group of unsaturated acids that have a final carbon-carbon double bond in common. Awareness of their benefits to health has grown over the last few decades, and as a result, the number of foods enriched in omega-3 fatty acids has increased – such as milk and eggs that can be naturally enriched. They were deemed ‘essential’ when scientists found that they were indispensable to normal growth in young children and animals.

This article was first published in our European edition of Next Generation Pharmaceutical magazine: http://www.ngpharma.eu.com/article/Economies-of-scales/.