Pathogenic infections are understandable. A foreign organism invades your body and you get sick. The immune system eventually takes care of it, sometimes with the help of other drugs. Autoimmune disorders, on the other hand, are much more frustrating. Why would your body suddenly start attacking itself? How would you even theoretically go about preventing such a thing?
In most cases autoimmune diseases are painful nuisances that can be managed. The autoimmune disease with the highest prevalence is Graves disease (page 11), which is when immune cells make the thyroid basically go berserk, speeding up the body's metabolism into turbo overdrive. The only way to manage it is to kill the thyroid gland and take supplemental thyroxin instead. The second most common is rheumatoid arthritis at around 1% of the global population (link above). Here the immune system attacks joints, destroying them and making it painful and difficult to move. The only long term treatment available is immune suppression.
While Graves is certainly unpleasant, it is manageable. And while RA is painful, if caught early, joint destruction can be mitigated. While it is debatable which is the "most debilitating" autoimmune disorder, multiple sclerosis is certainly high on the list. Like RA, MS makes it difficult to move, but rather than attacking joints, it attacks nerves. Some major joints like knees and hips can be replaced. Nerves cannot. Once they die, that's it.
There are currently 10 FDA approved drugs for MS on the market, 5 of which have been approved in the last 5 years. I will go over those five and their sales numbers for the respective companies, and cover two others which could gain approval soon, one which looks especially exciting. First, however, a little digression into a possible cause of MS and other autoimmune diseases, a theory called...
The Old Friends Hypothesis
The prevalence of MS in Europe is 80 per 100,000 according to WHO. In Africa, it is .5 per 100,000. What accounts for this 160-fold increase in MS in Europe over Africa? Some researchers have theorized what is known as the "Old Friends Hypothesis," namely that the reason for this wide divergence is that parasites, in order to survive in humans, must suppress the human immune system so it wouldn't attack them. (Old friends being humans and parasites.) Most people back in the day had parasites of one form or another, and therefore the immune system had to evolve under the conditions of natural parasitic suppression.
In the Western world where parasites have been all but eradicated, this exposes the body to a potentially overactive immune system unchained from its natural suppression by parasites under which it evolved. In Africa, however, parasites still thrive, so autoimmune diseases are much rarer. On the whole, evidence suggests that a moderate number of intestinal hookworms improves the symptoms of MS.
Each autoimmune disease has a different trigger, but in theory it is the unsuppressed immune system empty of all parasitic worms that enables the condition once a trigger is hit. In that sense all autoimmune diseases including allergies can be seen as the same root disease, just with different expressions caused by different triggers, much like cancer is one disease with different expressions.
In 2004, one Dr. David Pritchard decided to test the Old Friends Hypothsis on himself to cure his allergies, and actually infected himself with hookworms. He found that in low numbers, the hookworms do not pose a threat, but do modulate the immune system. The New York Times reported in 2008 that after one hookworm clinical trial, results showed that the T-cells in the hookworm arm produced lower levels of inflammation than those with the "placebo worms."
Essentially, the worms act as a natural immune suppressant, as suggested by the theory.
Western culture, unfortunately, is more a fan of lab-developed immune suppressants that cost orders of magnitude more than the average hookworm, which is pretty cheap. Nevertheless, the Old Friends Hypothesis is crucial in that it does point towards immune suppression as the proper way to treat MS. (It is also crucial to the conclusion of this article, as you will soon see.) If humans evolved with natural immune suppression but lost it with the loss of parasitic worms, then immune suppression seems to be the way to go. In that field, here's what has happened in MS over the last five years, followed by what may happen in the next few, and ultimately how it connects back to the Old Friends Hypothesis.
Approvals since 2009
1) Extavia by Novartis (NYSE:NVS) - this drug is a form of interferon, a naturally occurring protein produced by the immune system. Approved in August 2009, its precise mechanism of action is unknown, but is believed to reduce inflammation by reducing certain cytokines that attack myelin, the lipid sheath surrounding nerve fibers attacked in MS patients. Sales were $159M in 2013 (page 121). In its first full year on the market, sales were $124M. This is by no means a best seller for the pharma giant, but judging by consistent sales, it is a steady niche market that brings along reliable income.
2) Ampyra by Acorda (NASDAQ:ACOR) - Ampyra was approved in January 2010, and takes a different approach. Rather than suppress the immune system, it enhances conduction in damaged nerves, allowing MS sufferers improved walking ability. Sales were $303M in 2013. Its first year on the market saw $133M (page 1) in sales. In 3 years sales have more than doubled.
3) Gilenya by Novartis - Approved September 2010, this is another immune suppressant that prevents white blood cells from migrating into the central nervous system. By all accounts Gilenya is a blockbuster, with global sales of nearly $2B in 2013 (page 116). Its first full year on the market saw nearly $500M in sales (page 137).
4) Aubagio by Sanofi (NYSE:SNY) - Approved September 2012, like Gilenya, an immune suppressant thought to block white blood cell activation in the central nervous system. Like all of its cousins, the exact mechanism of action is unknown. Sales in 2013, its first full year on the market were $166M (page 98).
5) Tecfidera by Biogen Idec (NASDAQ:BIIB) - Approved just last March, this is also an immune modulator, but nobody knows exactly how it works. However, it looks to be a blockbuster, with the first 3 quarters of sales totaling $876M (page 1).
One Likely Imminent Approval
In 1995, Biogen got Avonex through the FDA, a drug very similar to Extavia in that they are both interferon. Avonex is a mega blockbuster at over $3B in 2013 (page 39). Biogen and Novartis are actually in a patent litigation duel over this very issue, and Avonex coming to market 14 years earlier is probably the biggest reason that Extavia sales are comparatively so thin. This past January, Biogen announced positive results on a phase 3 trial for a slightly different version of Avonex that has a longer half life and therefore has higher effectiveness at lower dosages. This is likely to be approved and could replace Avonex as Biogen's MS blockbuster, since it is basically the same thing but has a higher potency.
Back to Old Friends
But by far the most exciting (at least in my opinion) and possibly disruptive candidate is coming out of left field by Synthetic Biologics (NYSEMKT:SYN). The leading MS treatment today is Teva's (NASDAQ:TEVA) Copaxone at $4.3B in 2013. It is Teva's #1 seller and its patent has expired. Generics will soon start eating into its revenues. Synthetic Biologics is testing of all things an estrogen hormone called estriol in conjunction with Copaxone for synergistic interaction.
Copaxone is a polymer of only four amino acids. Nobody knows exactly how it works, but a leading theory is also anti inflammatory immunosuppression, just as parasites do.
At first glance this sounds a bit mundane and random. What's the big deal about a natural estrogen hormone and why would it work with Copaxone? If, however, we bring ourselves back to the Old Friends Hypothesis, it actually makes a whole lot of sense.
Remember that the theory is that MS is enabled by an overactive immune system that would normally be suppressed by parasites. Consider that MS is twice as common in women than in men. Consider further that women are also programmed to grow a parasite of sorts inside themselves, namely a fetus during pregnancy, and not have the immune system attack that fetus, which would not be good for the human species at all.
Estriol is a specific type of estrogen produced in large amounts only during pregnancy, and studies have shown that pregnancy actually reduces MS relapses in women.
The following is speculation, but I can't but help put 2 and 2 together. If twice as many women get MS than men, could it be that on top of parasitic immune suppression, women evolved to have additional immune suppression during pregnancy to make sure the fetus is not attacked? This would mean that female immune system evolved under double suppression, that of parasites and pregnancy. Nowadays pregnancy is also controllable, meaning the modern ability of birth control and sanitation could be doubly unchaining their immune systems, making women twice as prone to autoimmune diseases than men, who only evolved under one layer of immunosuppression.
If the Old Friends Hypothesis is correct, the combination of Copaxone with estriol could indeed be synergistic, especially in women. Interestingly, Synthetic Biologics's estriol plus Copaxone phase 2 trial is the only MS trial currently active that is only testing women.
Results will be presented on April 29, in less than 3 weeks time. Could a possible syergistic interaction between Copaxone and estriol catapult Synthetic Biologics to a blockbuster by piggybacking off of Teva's $4.3B Copaxone market?
It's a tantalizing possibility. Though approval is likely a few years off even if phase 2 is successful, we'll know much more in about three weeks, and the $136M company could get quite a big boost.
Disclosure: I am long SYN. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.