Breakthroughs Blog: Medicines

Hing Sham, PhD, joined PATH recently as head of research and preclinical development for the Drug Development program. Hing has more than 30 years in the private pharmaceutical industry, where he led major projects for various diseases, including HIV, cancer, diabetes, and Alzheimer’s. In this guest post, Hing answers questions about the risks associated with drug development and the intricacies involved in bringing a drug to market. This is the second post in a three-part series on drug development. Q: Drug discovery and development is a long process. Estimates of the cost to develop a drug up to the point of regulatory approval can range from $150 million to $1.3 billion. Could you summarize drug development in just a few words? A: In a few words, drug development is not for the faint of heart! What I mean by that is drug development is one of the most complicated and high-risk businesses in the world. When you think about what we’re trying to do, which is basically to correct a physiological process so it functions the same way it would in a healthy individual, it’s very complex and riskier even than going to the casino. In drug development, from choosing the right target to successfully completing multiple phases of clinical trials to clearing regulatory hurdles, there are many things that can go wrong. Under the best circumstances, your success rate is around 20 percent. It’s definitely a worthwhile endeavor, but each new hurdle brings with it a new set of anxieties. Hing Sham, PhD, joined PATH recently as head of research and preclinical development for the Drug Development program. Credit: PATH/Elena Pantjushenko. Q: What is the most exciting part of drug discovery? A: For me, the most exciting moment is when the different puzzle pieces come together to form a clear profile of a potentially successful drug candidate. Before this can happen, you have to have already chosen the correct target to treat within the human body and then have chosen the right compound from thousands of possibilities to target that mechanism for the desired effect. In addition, you have to determine that the compound has gone through the right testing to ensure that it’s in the best position to clear clinical trials and other safety hurdles. When all of that begins to align for the first time, it’s very exciting. Q: One concept you’ve emphasized as inherent to successful drug development is the importance of “failing early.” What does it mean to fail early, and why is that a good thing? A: Failing early isn’t a new idea in the drug development industry, but it’s a term that’s gained popularity as philanthropic foundations have encouraged a shift to the left in the product development pipeline. It is important to answer core questions early to avoid spending resources on products that will not be able to move forward and will languish in the “valley of death,” the term for scientific discoveries that don’t fit the criteria for further development. Failing early doesn’t mean that a team is encouraged to fail. Instead, it means that when the data are discouraging, the team should accept that, and move on to more promising prospects. Q: Is it difficult to keep your judgment clear and make these tough calls? A: I think, even if the results indicate you’re heading in the wrong direction, the desire to see your efforts through is part of human nature. As a researcher, it’s tempting to come up with other experiments that could enhance your understanding of a drug, even though they aren’t necessarily critical to the core questions under investigation. Within a project, stakeholders must engage in rigorous debates to determine what the critical questions are for a project’s success. Making these determinations early on provides the best framework for evaluating a drug candidate’s promise at various stages of development. Q: What do you find most fulfilling about your work? A: After 30 years in the private pharmaceutical industry, I have an immense appreciation for what the private sector does in devoting resources to research for lifesaving therapies. Now with PATH, I feel I have the unique opportunity to bridge the best of the private and nonprofit sectors to tackle a tremendous need for efficacious drugs for diseases unique to poor countries. It’s fulfilling to know that our work is bringing the best science to bear on some of the world’s most challenging health issues.

  In this guest post, Joanna Breitstein, director of communications at the TB Alliance, highlights the response to a new study that indicates a novel tuberculosis (TB) combination drug may be on the horizon. Global press coverage this week cites a Lancet study suggesting that scientists have made significant progress toward developing an effective and affordable treatment for TB, a disease that every year kills more than 1.4 million people and is the primary cause of death among people with AIDS. Released on Monday during a presentation at the International AIDS Conference (IAC), the results of the Phase II trial in South Africa offer hope for a treatment breakthrough amid the growing and dangerous epidemic of drug-resistant forms of TB that, in some cases, are becoming untreatable. Image courtesy of the TB Alliance. In a story by the Associated Press, science writer Lauran Neergaard reports, “Scientists are hot on the trail of a new tuberculosis treatment that a small study suggests might one day offer an alternative to battle this deadly lung disease, even if it’s resistant to today’s two main drugs.” Asked to comment on the new study, IAC Co-Chair Dr. Diane Havlir of the University of California,San Francisco told the Associated Press, “We are cautiously optimistic that we are at the dawn of a new era for TB drugs." In The Guardian, Sarah Boseley quotes TB Alliance CEO Dr. Mel Spigelman, who calls the implications of the findings “huge.” "People with drug-susceptible and [some forms of] drug-resistant TB could be cured in as little as four months or even shorter,” Spigelman tells Boseley. “In the case of multi-drug-resistant TB, we could be reducing their treatment by one to two years or more. The regimen also promises to be in the order of 90 percent cheaper than the current [multi-drug resistant] treatment regimen. There is potential for a dramatically shorter, simpler, cheaper, and more effective regimen all at the same time.’” Also quoted in The Guardian, principal investigator Dr. Andreas Diacon of Stellenbosch University in South Africa says he speaks as a clinician and researcher. "Treating drug-sensitive and drug-resistant TB with the same regimen can simplify the delivery of TB treatment worldwide. The results of this study give healthcare providers on the front lines of the TB epidemic hopes for better, faster tools needed to stop this disease." Spigelman notes in Amy Maxmen’s article in Nature that the Lancet study also validates a new model for speeding development of such treatments. “After a new drug reaches the market, the traditional route is to work from the standard of care and substitute one drug for another. But if you do it in an incremental way, that will give you incrementally better results,” Spigelman says. “Our goal is to shorten the path to getting a new, cohesive regimen out there in one fell swoop.” Mario Raviglione, director of the Stop TB Department at the World Health Organization, says testing multiple new TB drug candidates simultaneously has already proven to be a major advance. "Because of testing drugs in combination, we have already saved several years in the research process to find new, effective regimens to treat TB," according to Raviglione. "The results look strongly promising from this early trial. If further testing holds up these results and the regimen is affordable in poor countries, it is huge progress. We could shorten drug regimens substantially for everyone, regardless of whether the form of TB is sensitive or multi-drug resistant. That would be a dramatic step forward." “If full clinical trials confirm its promise, the therapy could prove a boon for HIV-infected people,” writes Maxmen in Nature. “TB, which is common in its latent form in many parts of the developing world, often becomes active in those who are HIV-positive because of their weakened immune systems.” Unlike some existing therapies, Maxmen continues, the “new combination does not seem to interact adversely with drugs for HIV.” To illustrate the situation on the ground, where both diseases wreak havoc, Maxmen quotes John Farley, deputy director of the antimicrobial product division at the US Food and Drug Administration who once worked with HIV patients in West Africa: “…there were times when our HIV patients would die of drug-resistant TB before we could even get them their antiretroviral therapy,” says Farley in Maxmen’s story.