Developing new medicines is an amazingly difficult undertaking. The research portion alone is daunting, and for those of us who have actually attempted it, humbling. A recent article reminded me just how little many people understand about the drug discovery process. The basic premise of “Pharma Needs an Innovation Intervention” was that pharma should change its focus from “finding druggable targets” to “deliver a consumer-focused product and service and a business model that goes beyond the product itself.”
Unfortunately, the article doesn’t address two critical issues; one grounded in the past, the other the future. First off, why has Big Pharma, after being one of the most profitable industries for decades, suddenly become so remarkably unproductive in coming up with new medicines? Second, if Big Pharma walked away from the difficult task of “finding druggable targets,” then who would take over the job of creating new medicines? From a business point of view, one can see a clear need to alter a revenue model that may not be working for Big Pharma any longer. However, from a practical and societal perspective, there needs to be some way of innovating new medicines, not just new business models.
I wish I could provide a definitive reason why Big Pharma, as a group, has become so unproductive in recent years. These companies are not monolithic and have distinct styles for running their businesses. To paraphrase Tolstoy’s Anna Karenina “Productive drug companies are all alike; every unproductive drug company is unproductive in its own way.” It’s easy to congregate a lineup of the usual non-productivity suspects: excessive layers of bureaucracy, fear of making the wrong (or any) decisions, entrenched industrial group-thinking, failure to recognize and support an innovative culture, and new regulatory uncertainties. I suspect that all of these concerns contribute to the productivity problem, but it’s difficult to quantitate exactly how important each of these factors really is.
I think Big Pharma is still hung over after a difficult transition from a decades-long focus on screening chemical libraries to more of a recombinant DNA/genomic biology mindset. It may very well be that after a century or so of effort, all of the “low hanging fruit” really has been picked off of the medicinal tree. Finally, consider that Big Pharma’s recent attention was focused on developing blockbuster drugs that would bring in sufficient revenues to feed their bloated organizations. Genzyme’s marked success in treating rare diseases (along with its recent acquisition by Sanofi) illustrates how that thinking has changed.
So why is coming up with new drugs so difficult? The answer is actually pretty straightforward: because biology is amazingly complex. It’s not rocket science; it’s much harder. With all due respect to the people that design and build our space vehicles, uncovering the functional role of thousands of unique biological molecules is a significantly more complicated undertaking. Twelve years is about the average length of time it takes for a single drug to be discovered, developed, tested, and approved by the FDA. Twelve years also defines the time period between the start of the space age (the launch of Sputnik 1 in 1957) and humans landing on the moon in 1969.
Even more difficult than figuring out the function of biological molecules is coming up with a way to alter, in an appropriate way, the divergent activities of selected subsets of these molecules to treat various diseases. People can be afflicted with literally thousands of different ailments. As living organisms, we reflect eons of genetic diversification and are vulnerable to rogue viruses, bacteria, fungi, and environmental pollutants. No two of us are alike, not even identical twins. People also suffer from pain, are susceptible to psychological disorders including addictions, and are at risk of unintentional side effects brought on by numerous medications. The biological and rocket sciences do share one primary characteristic: they are both very expensive, high cost-of-entry businesses.
Mechanistically, how do medicines work? In general terms, most drugs act by either stimulating something (these are called agonists) or blocking something (these are called antagonists). These effects are generally directed against specific molecules, even if the exact target remains unidentified. Within these broad definitions, however, lies a great diversity of approaches that drug makers have taken to treat diseases. Let me share some examples:
Drugs can directly stimulate (e.g. morphine) or block (HIV protease inhibitors) enzymes. They can bind to and sequester molecules (TNF blockers for rheumatoid arthritis). Drugs can replace missing molecules (insulin, hemophilia) and alter the rate of movement of molecules into or out of cells (anti-arrhythmics like sodium channel blockers). Some drugs stimulate the immune system (Provenge, Yervoy), change the pH balance in the body (sodium bicarbonate for acidosis), or interfere with the assembly or function of intracellular structures (anti-cancer drugs like taxanes). Drugs can stimulate the release of stored molecules (epinephrine), or interfere with DNA synthesis (sulfa antibiotics). Drugs can perturb cell membranes (anesthetics), and effect the modification of proteins, thereby altering their function (histone deacetylase inhibitors). In gene therapy, the drug is often a replacement gene; anti-sense drugs block the formation of proteins by binding up specific mRNAs.
The above examples demonstrate the variety of approaches drug makers have taken in coming up with new medicines. Their goal: design in characteristics that enable the drugs to achieve the desired effects, while at the same time designing out their ability to bind to and effect secondary molecules. These secondary interactions (and sometimes primary ones as well) often lead to side effects that can be sufficiently serious to prevent a drug from ever being used in the marketplace. This particular aspect of designing small molecules is daunting. X-ray crystallography and other techniques often enable scientists to generate 3D images of the protein that wish to target. This information is extremely valuable in tailoring the design of a drug that is meant to bind to and modulate the function of this particular protein. Ideally, the drug only attaches itself to this one (or in some cases, a few closely related) target(s). Often, the primary challenge isn’t finding a chemical that can bind to the chosen protein, it’s identifying one that doesn’t bind well to the other 21,000 or so proteins that it might also interact with. Imagine trying to design a mask that will precisely fit your face, but won’t fit well on the faces of thousands of other individuals. This inherent difficulty has fueled the rise of biologics (protein-based drugs), where such discriminatory specificity is much easier to achieve because the appropriate molecules have already been selected for by the powerful forces of evolution.
For a number of medical conditions, the exact molecular defect that is responsible for the disease is now well understood. In a best-case scenario, the genetic defect that causes chronic myelogenous leukemia was identified and led to the development of an amazingly effective drug with a very high cure rate. Knowing exactly what causes a disease is useful, but this information doesn’t always translate into curative medicines. The mutated protein that causes cystic fibrosis was discovered after years of intensive research in 1989. In the two decades since this discovery was made, however, no one has developed a reliable method for replacing, correcting, or bypassing the single defective gene that encodes this key protein (although a recent trial looks somewhat promising for one specific subset of patients).
A recent study suggested that mutations in genes that are essential to survival are the cause of many rare diseases, whereas alterations in non-essential genes are the primary drivers of more common illnesses, such as heart disease. Many health problems, however, result not from a single defective gene, but from numerous mutations throughout the genome. It is estimated that the average tumor contains 15 or more altered genes that are responsible for its unchecked growth and metastasis. Other diseases may arise simply from a combination of what turns out to be an “unhealthy mix” of genetic variations acting in concert, or in combination with environmental factors. Finding effective treatments for these types of diseases is much more difficult than those caused by single genetic alteration (not that these are necessarily easy to treat either).
The various molecules that exist within our cells don’t function independently of each other. There are numerous interconnections between them, the study of which has spawned a recent approach referred to as systems biology. The complex nature of these interactions makes them extremely difficult to study. It’s obviously simpler to design a drug that affects a protein that operates within a single defined pathway than one that functions at the intersection of numerous metabolic junctions. Drugs that are directed at proteins that function at biological intersections may affect any and all of the pathways that lead to and away from the target.
It’s important to have a clear understanding of the drug discovery process if we hope to accelerate the pace of creating new medicines. Prior to the past 120 years or so, virtually all medicines were derived from naturally occurring plant materials. These eventually gave way to chemically synthesized molecules, which ruled a large share of the market for the better part of a century. Drugs these days may still come from these sources, but many of the newer medicines are biologics (purified recombinant proteins, including monoclonal antibodies). Insulin, the first protein drug, was originally purified from cadaver pigs, but bacteria growing in brewery-sized stainless steel tanks now generate most of it. Biology has usurped chemistry as the dominant force behind many of the newest drugs, even though most biologics are incredibly expensive compared to small, chemically synthesized drugs. Some of the newest types of medicines (most of which are still in development) are comprised of various types of DNA or RNA, and they may be packaged in viruses, liposomes, or as nanoparticles for administration to people. Various medicines require distinct routes for drug delivery: they can be swallowed, inhaled, sniffed, injected, or supplied via a skin patch.
This tremendous degree of biological diversity and complexity demands that pharma and biotech companies devise new and pioneering approaches in both research and development. This will take guts, which some feel many of these companies are lacking. Sequencing of the human genome was a great milestone in biology, but it only served to underscore just how much work remains to be done in solving biological problems. The “innovation intervention” approach mentioned at the beginning of this article was actually targeted at business models, not drug discovery. What is abundantly clear is that the industry needs to change its modus operandi, and several new initiatives have been launched.
One popular approach that a number of Big Pharma companies have adopted is to align themselves financially with university researchers to take advantage of the expertise contained within academia. If properly done, this tactic should undoubtedly be helpful. Many of the most innovative drug development papers that I’ve seen recently originated in academia. Another approach has been for Big Pharma to re-align and narrow the focus of their internal research programs; some companies have made significant cuts in their research and development spending. This can be successful if the aim is to focus on fewer research areas, but increased spending, not less, will be needed going forward to support the remaining avenues of investigation.
I believe that all of these changes are necessary, but I have doubts as to whether they will be sufficient to reinvigorate Big Pharma’s drug discovery efforts. As novelist Ellen Glasgow put it “All change is not growth, as all movement is not forward.” I have no doubt that “bushels of fruit” remain to be picked from the medicinal tree, although reaching those higher branches will require the industry to wisely adapt a long term perspective. They need to establish an innovative culture, correctly employ new technologies, reward smart thinking, and have a brave heart. Though many are loath to admit it, the truth is plain to see: there will be no shortcuts on the long and difficult journey towards the medicines of tomorrow.
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