Scientists at Merck Weigh In on Work Done and Work Yet to Do
by Chael Needle
We know the drugs on the pharmacy shelves. We hear of the discoveries. We watch the pipeline. Unless we are lucky enough to travel to AIDS conferences, or sit down with some academic journals for some light reading, we rarely get a chance to hear from the creative forces behind the science that supports our health.
Here’s our chance.
Three scientists. Three sets of insights and inspirations. All three have made significant contributions to AIDS drug discovery, research and development. All three are still seeking answers and posing questions. All three have contributed to and continue to evolve the scientific lifeblood of Merck & Co., Inc., particularly in the field of HIV/AIDS.
Meet Randi Y. Leavitt, MD, PhD, Executive Director, Clinical Research, Infectious Diseases, Merck & Co., Inc. After a long stint at NIAID, Dr. Leavitt joined Merck in 1993 and has since worked on clinical studies of Crixivan, Isentress, and HIV vaccine development.
Meet Daria Hazuda, PhD, Vice-President and Therapeutic Area Head, Infectious Disease, Merck Research Labs. Trained as a biochemist, Dr. Hazuda has focused much of her energies on HIV and HCV antiviral research. Leading to the development of a new class of drugs, and first-in-class Isentress, her work on integrase inhibition earned her the Prix Galien prize in 2008. Dr. Hazuda’s lab first identified HIV-1 integrase inhibitors, established their mechanism of action, showed anti-HIV efficacy in vivo, and reported on basic mechanisms of resistance.
Meet Sandi Lehrman, MD, Global Director for Scientific Affairs (GDSA) for Antivirals in the Office of the Chief Medical Officer at Merck. Joining the company in 2007, she provides scientific input into the Global Infectious Diseases Franchise strategy, focusing on Merck’s portfolio of HIV and HIV/HCV co-infection treatments. Her previous work included a tenure as Director of the Therapeutic Research Program in the NIH’s Division of AIDS, providing strategic leadership and direction to a staff responsible for clinical trials focused on the development of treatment of HIV/AIDS, associated co-infections, complications, and co-morbidities.
These brief introductions barely do justice to the breadth and acuity of their work, but hopefully the following Q&A will help you understand just a little bit better some of the people behind the pipeline.
A&U: What inspires you to commit (and recommit year in, year out) to improving the health of others, particularly when it comes to HIV/AIDS?
Randi Y. Leavitt: As an infectious disease physician, I saw the impact of HIV/AIDS from early on in the epidemic. There was little we could do except treat the complications, but nothing really made a big difference. I was very lucky to join Merck when Crixivan was entering clinical trials. It was an amazing experience when we realized the impact of the drug on the disease and epidemic, and saw patients improving and planning to live. Similarly, I feel very lucky to have also worked on Isentress, which proved to be another incredible drug that positively impacted HIV-infected patients. I also had the opportunity to work on the HIV vaccine trials at Merck and everyone involved was very disappointed that the vaccines that looked promising in animal models did not prevent disease in patients.
Sandi Lehrman: I began working on HIV/AIDS in 1983 as part of the team at Wellcome that discovered and developed AZT. Over the three decades I have worked in the field I have seen survival of individuals with HIV infection go from six months to sixty years. Although HIV has been transformed into a chronic manageable disease there is still much work to be done. Our past successes motivate us to work toward a future that will provide research and medical insights that continually improve our knowledge of this infection with the goal of even better patient outcomes.
As we learn more about the pathology/biology of HIV infection and its role in driving cardiovascular and other complications we have recognized that this knowledge is also important in understanding the possible factors impacting these diseases in the uninfected population. These broader lessons learned are also important motivators. The science is fascinating and ever-evolving.
Daria Hazuda: Knowing that you have the opportunity to contribute to something that has the potential to have a significant impact in the lives of others is a tremendous inspiration for me. Having been a part of the team that developed Isentress and meeting HIV patients who are alive in part because of something that I helped to create is among the most amazing and rewarding of experiences. But having seen what can be accomplished, this experience also helps me focus and remain committed to HIV, knowing that there is still so much more to do.
The media often trumpets news of an “HIV cure,” and many in the general public are arguably left with an impression that a functional (or even sterilizing) cure is right around the corner. Yet, solid research advances have been made toward realizing a functional cure. Could a “functional cure” be imagined as a relatively stable 1,000-piece jigsaw puzzle, and, if so, how much would you say we’ve completed of it? Or is the puzzle too changeable that it’s hard to tell where we are?
RL: For me, I would have to say the latter. The field has made incredible progress and we are all hopeful that a cure will be defined, but it is clear that the disease is very complicated. Although I am hopeful, it is hard to figure out how close to a cure we might be. What is clear is that the field is moving forward and I am optimistic.
DH: I think we are still at the stage of defining whether the puzzle is 100, 1,000 or 10,000 pieces, or even if it is one puzzle or many that will have to be solved. Drug discovery research is always an iterative process and, until you begin, it is often difficult to define the issues and complexity of the challenge. HIV cure research is no different; we have hypotheses and need to develop the tools and methods required to better understand the issues.
How do antiretrovirals, like raltegravir (Isentress); next-generation candidates like Merck’s MK-1439; HIV-preventive approaches like microbicidal candidates; or novel agents that activate HIV reservoirs fit into this puzzle?
RL: I think every new advance and option is a step toward better control of the disease. Better-tolerated drugs, once-a-day drugs, and fixed-dose combinations have all had an important impact on making the disease easier to control. It is very clear that patients are more compliant with these better-tolerated, easier-to-use drugs. Effective microbicides would also be important in controlling the epidemic and providing additional options in preventing acquisition of HIV.
SL: If we are to continually improve the outcomes for those infected, prevent new infections, and ultimately cure those infected, the research community must be open to pursuit of new molecules for established modes of therapy and new approaches for prevention and cure. There are no magic bullets for any disease. For infectious diseases we must always think on a continuum of prevention, treatment, and cure. The changing nature of the infecting virus and the immune response to the infection requires that we not become complacent.
DH: To address the global HIV epidemic requires a comprehensive approach including treatment, prevention and eradication. Improving therapy with new agents such as MK-1439, exploring different prevention approaches, including vaccine and microbicides, as well as research on eradication are all pieces of the puzzle that are needed to make progress towards the ultimate goal of global eradication.
What role can individuals living with HIV take in the research (or any other) aspect of working toward the end of AIDS?
RL: Willingness to participate in clinical trials is really important. We really appreciate the participation of patients in trials. Without these trials, we cannot understand whether new drugs have the potential to impact patients. Additionally, encouraging others to participate in trials, get tested and take their HIV medications as prescribed can make a difference. Enthusiastic support of fundraising events is also important in raising community awareness. I think the HIV-infected and at-risk communities have been very supportive of the community and involved in drug development, and this support has had a major impact. Community outreach to maintain awareness of the disease is really important. It is important that people, particularly teenagers, understand that everyone is at risk and also understand that HIV/AIDS is a serious disease. I worry that people think since there are drugs to control HIV that it is not a big deal.
DH: The HIV community has always played an important role in the progress of HIV research; HIV patient advocates have been key in increasing public awareness, providing forums for education and support, partnering with the government and pharmaceutical companies to facilitate drug development and supporting the need to make HIV research a priority for government and other funding agencies. In the current economic environment, these activities are as important today as in the past. We have made such great strides with therapy that the same sense of urgency is no longer apparent, but, given the enormity of the issues that still remain, we must continue to work together to make progress.
From the beginning of AIDS research, Merck has been a generative environment for HIV-related research advances. In 1984, Merck launched a comprehensive AIDS research program. In 1988, its research team was the first to show that HIV replication could be interrupted by inhibiting the protease enzyme; and then its team was the first to determine the 3-D structure of protease. In 1996, Crixivan (indinavir) was approved as one of the first protease inhibitors. In 2007, Isentress (raltegravir) hit the shelves. Next-generation NNRTI candidate MK-1439 is now in Phase II. Sincerely, what do you believe accounts for such a productive track record? What are the special ingredients—the values or best practices—beyond attracting top researchers?
RL: I think Merck has incredibly bright and committed basic researchers developing new drugs. The company has committed its resources toward drug discovery and development.
SL: I came to Merck after working at Wellcome and also serving as the head of the Therapeutic Research Program for the Division of AIDS at NIAID. Merck is committed to advancing the best science to enable continually improving outcomes for patients. The integrase program, with which I have been highly involved, is an example of commitment to new molecules and mechanisms that make a difference in HIV. This began with the first non-nucleoside reverse transcriptase inhibitor (NNRTI), efavirenz, and progressed to the first protease inhibitor, Crixivan. The ongoing “cure” work at Merck, in collaboration with many academic investigators, is an additional example of Merck leading the field. In my entire career I have been privileged to be part of the teams leading the field. In coming to Merck I felt that I would have continued opportunity to advance science.
DH: I am biased, but I believe Merck HIV research has some of the best scientists in the world. We are all driven by a passion to make a difference and commitment to a mission that we believe supersedes us as individual scientists. HIV provides a compelling mission that is a deeply and personally unifying force. It is that common mission and the ability to work collectively as one team utilizing the strengths and skills of each individual to tackle the most difficult and sometimes seemingly insurmountable challenges that makes us successful and also makes it both fun and a privilege to come to work every day. We are not afraid to take on these challenges or learn from failure because we believe in the mission and trust each other, and we all love what we do.
Is there anything you would like to add that we haven’t covered?
DH: Drug discovery is incredibly challenging, fraught with failure and disappointment and many people who work in drug discovery research never participate in a project that makes a drug. I have been very fortunate to have been a part of the team that discovered Isentress and I wish everyone could experience the amazing feeling it is to know that the work you do has had a significant impact in the lives of patients.
Chael Needle is Managing Editor of A&U.