MANAGEMENT INSIGHT - The Davids of Drug Development

Inspiration from Malcolm Gladwell’s latest book, David and Goliath

We are an entire industry of Davids. Every one of us is a little guy, facing insurmountable odds, scouring the countless compounds of the universe in search of a cure. Every scientist in every lab labors through the seasons in pursuit of that single spark. Every project manager, receptionist, human resources officer, and manager works in tandem for the same cause. Once in a while, we achieve a flicker of light, and spirits soar. Most of them sizzle and die out. And yet we move on, like addicts in search of a buzz, pursuing that moment again; that one incredible high that is drug discovery.

Malcolm Gladwell’s latest book, David and Goliath, is a feel-good book to inspire our industry. It isn’t remarkably new. It is about the concepts of creative destruction and disruption. We’ve seen it in Richard Foster’s, Attacker’s Advantage, and in some of the concepts from Nassim Taleb’s Antifragile.

The author of Tipping Point, Blink and Outliers begins this book by telling us that everything we know about the story of David and Goliath is wrong. We’ve learned about a scrap of a shepherd boy who was the only Israelite brave enough to take on the massive Goliath. Powered by faith, he met his better on the field of battle and bested the mighty giant with only a slingshot. Actually, writes Gladwell, Goliath never had a chance. Sure, David broke the rules, but he knew he had a good shot at taking Goliath out if he did. As a shepherd, David was skilled with the sling. Not a slingshot – that’s a child’s toy. A sling is a leather pouch with two long cords and a pouch. He would swing that pouch around a few times and let fly his projectile at speeds approaching 35 meters per second. That’s much faster than the best pitcher in major league baseball. He would slip a piece of local stone into the sling: barium sulphate is twice as dense as a normal rock. This combination gave his weapon the stopping power of a 45-mm handgun. He was practiced at using it at great distances for the protection of his flock.

Goliath, meanwhile, was nearly immobilized by metal. He was also almost certainly visually impaired. The text hints at this, and so does the science. Whenever an individual deviates largely from the cultural norms of height, the most likely explanation is acromeglia, a disease in which the body never ceases producing growth hormones. Measuring 6 feet 9 inches, Goliath almost certainly suffered from acromeglia and its common side effect—double vision or debilitating near sightedness, caused by a pituitary tumor compressing visual nerves. The result is double vision or debilitating near sightedness.

This is the problem with giants, Gladwell surmises. “The same qualities that appear to give them strength are often the sources of greatest weakness.” Underdogs, meanwhile, take risks and chart paths that the powerful elite would never contemplate.

Gladwell provides numerous anecdotes demonstrating how the underdog tries harder. A David, by his definition, is someone who doesn’t have the resources or the authority to make a difference in the conventional way; and yet, they are so desperate to succeed that they think differently than Goliath. Therein lies their strength. They see the world differently, and that mindset frees them to come up with unconventional ideas.

Disadvantage becomes advantage. Dyslexia, for example, is abnormally prevalent in high-performing people – Richard Branson, Charles Schwab, and Brian Glazer among others. Such individuals are forced from a young age to work differently from others. The early loss of a parent is another disadvantage, yet nearly a quarter of all US Presidents (12 of 44) lost a parent at a young age – including George Washington and Barack Obama. The impressionists of Europe were a largely impoverished group of artists with a shocking artistic style. Tossed out of conventional salons, they created their own art shows. Eventually, their works surpassed in popularity most of the greatest traditional artists of that time.

Drug developers fight incredible odds every day. Every step in our path is fraught with failure. Here are three moving stories of Davids who overcame significant challenges to advance medical science.

JAY FREIREICH – LEUKEMIA: DAVID VS. THE ESTABLISHED BODY OF MEDICAL OPINION

Born to Hungarian immigrants, Dr. Jay Freireich’s father died in his youth, and his family lost everything in the Great Depression. He scraped through medical school. A notoriously bad-tempered and callous man, he made few friends. His disinterest in social niceties thwarted his career. He was fired seven times.

In 1955, he began work in the children’s leukemia ward of the National Cancer Institute. It’s hard to imagine a more heartbreaking place to work. Ninety percent of his patients bled to death within 6 weeks of arriving. They bled from their ears, skin, mouth, and noses. Medical science was failing them.

But Dr. Freireich cared nothing for the usual way of doing things. Like so many Davids, he didn’t feel constrained by his colleagues’ opinions. In fact, Gladwell asserts that his previous suffering was essential to his later achievements. His colleagues couldn’t do or say anything he hadn’t seen or heard before. He had nothing to lose. He launched a series of unorthodox methodologies, including the daily sampling of bone marrow from his young patients without anesthetic. He wasn’t intentionally cruel, it was simply that anesthetic had little effect in this procedure.

His priority was to stop the bleeding, which he was certain was caused by low platelet counts. His supervisors disagreed. Against their objections, he transfused patients with platelets. He succeeded in temporarily stopping the bleeding. Once the children weren’t bleeding to death, he could consider treatment. Frustrated by the lack of success with a single chemotherapy drug, Freireich proposed a mix of four medications: Methotrexate (an antifolate), vincristine (a Vinca alkaloid), 6-mercaptopurine (6-MP), and prednisone – together referred to as the POMP regimen. Again, his colleagues rigorously objected. If a single chemo served only to prolong a child’s agony, four was inhumane! When the NCI approved his regimen for initial testing, several doctors on the ward refused to participate. But by giving the doses in combination, he was able to reduce the dose to 60%. This lower dose reduced toxicity while maintaining efficacy.

Today, combination chemotherapy is the basis for any chemotherapy regimen. The cure rate for the type of leukemia Freireich treated is 90%. We owe both of these advances largely to the fact that Dr. Jay Freireich had nothing to lose, and so was willing to risk everything to find a cure only he believed in.

SYNTA – ELESCLOMOL: DAVID VS. STATISTICAL IMPROBABILITY

This story, particularly relevant to our industry, comes from Gladwell’s blog. A Taiwanese-born cell biologist in his mid-60s, Dr. Lan Bo Chen, a founding partner of Synta Pharmaceuticals, saw countless compounds in industries outside of drug development just sitting around untested. He felt the search for new drugs should be as far and wide as possible.

The first improbability Dr. Chen surmounted was in finding a philanthropist to give him $4 million dollars to spend as he saw fit. He immediately purchased a batch of 22,000 chemicals gathered from all over Russia and the Ukraine and a machine to screen 96 compounds at a time, a hundred batches a day.

At first, the chemicals killed everything, normal and cancerous. When he found a compound that killed only cancer cells, he reduced the amount of chemical on the plate a 1000-fold and tried again. One chemical withstood the tests. The cancer cells reacted to it “like a blowtorch.” It was a strange little chemical called elesclomol, something no one ever would’ve thought to try. The chemical gathered up copper from the bloodstream and deposited it in the mitochondria, causing an electrochemical reaction. The idea of using copper to cause this kind of reaction was bizarre. No one ever would have come up with it through a rational approach.

Still more improbabilities lay ahead. No one had any idea what the new drug should target. It showed promise for ovarian cancer, sarcoma, even melanoma. But cost was a factor. They couldn’t test it on everything. They zeroed in for Phase II on lung cancer, soft-tissue sarcomas, and melanoma.

Still more decisions had to be made – decisions that could significantly affect the trial’s outcome. What if the drug only worked on low-LDH patients and not high-LDH? What if it worked against a melanoma that adhered to the skin but not the kind that invaded the liver? What if it only worked well in second-stage cancers, or on patients who have not been treated with other forms of chemo? Even a major pharma house can’t afford multiple Phase II trials on a single disease. The company settled on a single trial allowing for the presence of the full myriad of variables.

In the world of cancer research, melanoma is something of a holy grail. It’s one of the most complex and variable cancers, and in the previous 35 years, there had been some 70 large-scale Phase II trials for metastatic-melanoma. None made it to the next phase. Synta, meanwhile, had other problems. Its other, more statistically probable candidates had all failed. The company began discussing lay-offs.

Two days later, Chief Medical Officer Dr. Eric Jacobson gathered Sytna’s 130 staff in the company lobby to present the Phase II results for elesclomol. The data was rigorously detailed. The staff was silent slide after slide, waiting for the one and only thing that mattered: the Kaplan-Meier graph. This two-line graph would show patients who received treatment on one line, and those who received the control on another. If the two lines separated, the drug was a success.

When Dr. Jacobson flipped to the Kaplan-Meier, his audience gasped. He continued talking. A few slow claps erupted, Gladwell reports. There were tears. Their lives had changed. Patient lives had changed. Their little company had a chance to win. It was the type of moment drug developers live for. But it was only Phase II.

The trials moved to Phase III, enrolling 650 patients in 15 countries, backed by GlaxoSmithKline. There were problems with making a water-soluble version of the drug, but compromise was achieved, and the trial continued. Too soon, another call came. More patients in the treatment group were dying than in the control group. The study was halted. The data revealed that the drug was failing patients with high-LDH tumors. Glaxo ended the collaboration.

Synta, like so many biotechs, continues to fight the odds. The company has regrouped and is moving forward with further clinical trials on elesclomol for other cancers, and their website reports early promise. They’ve since added another drug, ganetespib, to their oncology portfolio. They continue to pursue that high. It takes a certain kind of person to drive forward through such unbearable odds. It takes a David mentality. In drug development, we see this attitude everyday.

DR. DEVI SHETTY – HEART TRANSPLANTS: DAVID VS. POVERTY

Dr. Devi Shetty, a cardiothoracic surgeon, has been dubbed “The Henry Ford of Heart Surgery” by The Wall Street Journal. When he first returned to his native India in 1989, very few patients could pay the $2,400 cost of his surgery, even if their lives depended upon it, writes Davis Lui, a physician blogger who expanded on Gladwell’s ideas in a recent blog. This combination of urgency of need and lack of resources begged for Dr. Shetty’s David mindset, says Lui.

Many surgeons before him had walked away from the problem, but Dr. Shetty chose to explore a different tact. Maximizing economies of scale to reduce costs, Dr. Shetty now oversees 42 cardiac surgeons who performed 3,174 cardiac bypass surgeries in 2008, more than double than the 1,367 performed by the Cleveland Clinic in the US that year, according to Dr. Liu’s blog.

The sheer volume of surgeries performed at Dr. Shetty’s hospitals allows each doctor to zero in on a specific area of specialty. Surgeon Colin John, for example, has performed nearly 4,000 Tetralogy of Fallot procedures, a complex procedure that corrects four different heart defects simultaneously. He has almost certainly achieved the 10,000 hours of practice necessary to achieve mastery of a field.

Dr. Shetty’s team now performs 12% of all cardiac surgeries in India. That reality gives him tremendous buying power. When a European manufacturer failed to lower the cost of hospital gowns, he convinced a group of Indian entrepreneurs to take up the job, reducing costs by 60%. A new hospital cuts costs by pumping air conditioning only into operating theaters and intensive care units. Urgency and lack of resources combined to create an environment ripe for a David mindset. Dr. Shetty reduced the cost of surgery to $1600. Compare that to the $106,000 regularly paid for the same surgery in the US. Even accounting for differences in the cost of living (Delhi’s cost of living is 54% of Atlanta’s), this achievement is staggering.

THE IMPORTANCE OF GOLIATH

Innovation involves taking risks and breaking rules. This is something individuals do. Companies do the opposite. The larger the company, the more the rules. Gigantic cash flows can smother the incentive to find better ways of doing things. Institutional memory can inhibit new ideas at their source. Lipinski’s Rules, hERG liabilities, and other rules of drug selection do more to stifle development than to facilitate it.

Goliath shouldn’t try to be David. And yet, we very much need our Goliaths in this industry. So too did the armies in the time of David. In fact, as Gladwell points out, every army had their massive foot soldiers, clad like Goliath with swords and armor, leading the army into battle. But they also had infantry – those sling-bearing soldiers like David, in the rear. Together they formed a powerful combination.

We have thousands of Davids out there slogging away at their science in pursuit of a spark. Most of them are in biotech. But biotech needs big pharma to takes those ideas that work to the next level. Only big pharma can bankroll a trial of hundreds of rare patients across 15 nations.

Drug development is an industry uniquely replete with Davids. They provide the spark that drives development. David and Goliath, working for the same common cause, form a potent army in the war against disease. This is the model for our generation.

To view this issue and all back issues online, please visit www.drug-dev.com.

Derek G. Hennecke is President and CEO of Xcelience, a CDMO in formulation development and clinical packaging located in Tampa, FL. Mr. Hennecke launched Xcelience as a management buyout in 2006, and the company has more than doubled in size. Prior to starting Xcelience, Mr. Hennecke worked for DSM as a turn-around manager in the global drug development community, managing an anti-infectives plant in Egypt, technical and commercial operations in a JV in Mexico, and a biologics facility in Montreal. He developed the formulation and business strategy of several drug compound introductions such as clavulanic acid, erythromycin derivatives and Tiamulin. A Canadian, he covets the Florida sun, but can’t be kept away from the rink for long. He is an avid fan of the Tampa Bay Lightning.