Getting a drug from conception to market is among the riskiest, hardest and most expensive of scientific and human endeavors, often requiring up to ten years of effort and anywhere between 1 and 5 billion dollars. And the chances of failure at every step are greater than in almost any other complex science or technology endeavor, including putting a man on the moon, designing a supercomputer or constructing the world's tallest skyscraper; as one article put it, "oil wildcatters have a sure thing by comparison". This is mainly because, unlike complex engineering or technological projects, even the basics of drug discovery - from simply getting drugs into cells to preventing side effects - are not well understood and every step is largely one into the great unknown. We aren't just fighting cost and complexity, we are fighting sheer ignorance. Ultimately the creation of a new drug is - whether scientists like to admit it or not - as much a function of good luck as anything else.

Considering the staggering amount of uncertainty and the failure rate in drug discovery, sometimes it seems miraculous that we have effective drugs for serious diseases like heart disease and cancer at all. But there's still a long way to go before we can declare triumph over major diseases, and one of the key steps in achieving this is in understanding new pathways and adopting new scientific strategies through which we can eradicate diseases. Unfortunately the overarching strategy pursued by drug discovery scientists in the last few decades has been the same - identify a protein that's malfunctioning and leading to a breakdown in the body's normal functions, and then discover a small molecule - an "inhibitor" - that will gum up this protein, essentially throwing a wrench in the works. This strategy has been marvelously successful, and almost every important drug from aspirin to Lipitor works this way, but from the viewpoint of modulating biological systems it represents only one strategy among many, in fact the tip of the iceberg.

What's much harder to do, and something which scientists have spent decades struggling to figure out, is to enhance or change the function of a protein rather than simply to block it. As with many other things in life, it's far easier to break something rather than fix it. There's a universe of possibilities out there waiting to be exploited, but until now we have been only scratching the surface.

That's why the latest news of a drug combination from Vertex Pharmaceuticals that treats the underlying cause of cystic fibrosis comes as a breath of fresh air. It's a victory both for innovative pharmaceutical research as well as for the era of genomics that helped identify a crucial gene for cystic fibrosis. In an era when pharmaceutical companies are often lambasted for producing "me too" therapies and then marketing the hell out of them to drive up profits, here's a genuinely breakthrough drug that works by a completely novel mechanism. Cystic fibrosis which affects about 30, 000 Americans and 75,000 patients worldwide was, until now, virtually untreatable in terms of therapies which attacked the underlying cause. It is characterized by the buildup of mucus in the lungs which leads to difficulties in breathing and the risk of deadly infections; many CF patients die painfully young. Most treatments for CF until now were symptomatic and ranged from sophisticated enzyme therapy to more primitive but somewhat effective measures like physical agitation of the lungs. They served only to delay the disaster rather than to prevent it.

Vertex took a totally different tack in approaching potential treatments for the disease, and one which might well have seemed impossible to seasoned drug discovery scientists. They decided to focus on a key protein in CF called the cystic fibrosis transmembrane conductance regulator (CFTR) which is responsible for transporting chloride ions to and from the lungs. The CFTR which is an ion channel essentially acts as a series of pores, regulating the fluid balance in the lungs and modulating the physiological environment. CF patients are born with a host of mutations in the CFTR protein that lead to a breakdown in the protein's functions. This breakdown can manifest itself in several ways. For instance it can involve misfolding of the protein, failure to transport it to the lung surface or failure to have it shuttle chloride ions into and out of the lungs.

There are several hundred known mutations afflicting the CFTR but two in particular are prominent. One, called G551D (in which the amino acid glycine is mutated to aspartic acid), causes the protein to correctly make it to the cell surface but hampers its ability to transport chloride. The other, called F508del (in which the amino acid phenylalanine is deleted) simply stops the protein from correctly being folded and transported to the surface. Vertex decided to tackle both these problems. Their effort not only showcases high-quality science but also the possibility of treating a neglected, small patient population with scarce resources; in this endeavor they were generously helped out by funds from the Cystic Fibrosis Foundation.

In 2012 the company came out with a drug called Kalydeco (ivacaftor) that addresses the first problem; it binds to the CFTR, tweaks its structure and function and enables it to start efficiently shutting chloride ions back and forth. It acts a little like a beam support for a walkway that was previously unable to smoothly transport pedestrians; in that analogy Kalydeco straightens out the walkway, clears its inner passages and makes walking through it much easier. In technical parlance Kalydeco is called a "potentiator".

When approved it was already considered a breakthrough and it had a major impact on patients' lifestyles; people who earlier were looking at a difficult, 40 year life, who had to spend extended periods in hospitals, who found it excruciatingly hard to perform basic functions like exercise, were now able to walk, run, exercise and spend quality time with their family and friends. There were glowing testimonials from patients who felt like they had been handed a new lease on life. This was as good a definition of "improved quality of life" as could be imagined for CF patients, and it is among the highest ideals that biomedical scientists and doctors can aspire to.

However, the problem with Kalydeco was that the G551D mutation which it corrected was present only in 4% of CF patients. This not only meant that the benefits of the drug would be limited to a small patient population, but that to compensate for discovery and development costs the drug would have to be priced very high, and indeed it was. At $300,000 dollars a year it was among the most expensive of drugs, although it was the insurance companies and the government who were paying for it; in fact Vertex offered to give the drug for free to anyone who could not afford it. The logic of the insurance companies was that it would still be cheaper to pay for the drug than to pay for extended hospital stays and other stopgap measures that CF patients had to previously undergo.

The latest drug from Vertex address some of these issues, both financial and medical. The new drug which is called lumacaftor treats the second of the two problems, correctly folding the protein and transporting it to the lung surface; in technical parlance it's a "corrector". This is a function that is very hard to engineer into a drug; as mentioned before, it's far easier to design a drug to simply block a protein than help it function correctly. From a scientific standpoint lumacaftor is an even bigger triumph than ivacaftor. The great thing about lumacaftor is that it targets a mutation that's present in a much larger patient population than ivacaftor, 50% instead of 4%. Thus it has been possible for the cost of the combination therapy to actually be lesser than that of ivacaftor alone. It's still not cheap, but considering its first-in-class nature and the breakthrough improvements in quality of life, it's a very good deal. There is still scope for the price of these therapies to drop if they address even larger populations.

The Vertex combination of ivacaftor/lumacaftor heralds a new age for disease treatments. The biggest message from the story is that there are still very attractive and challenging opportunities to discover and develop genuinely novel drugs for intractable treatments that work through hitherto unexplored mechanisms. From a scientific standpoint, the possibility of developing potentiators and correctors instead of just inhibitors opens up a whole brave new world of protein repair therapies for scientists and doctors. Given the sheer number of proteins in the human body that are involved in good health and disease, there is little doubt that the possibilities are staggering. Drug discovery is harder than aiming for the moon but as this story tells us, hope looms on the horizon when occasionally, just occasionally, we find that we can actually aim for Jupiter.