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Non-Small Cell Lung Cancer: EGFR Mutations and Targeted Therapies

For the next several weeks, Real World Health Care will take a brief hiatus as we re-publish some of our most popular interviews on oncology-related topics.

The editors of Real World Health Care, along with our sponsor, the HealthWell Foundation, understand that cancer takes a huge toll on patients, their families and loved ones. About 1.6 million new cases of cancer were diagnosed in the United States last year, and nearly 600,000 people died from the disease.

Real World Health Care is pleased to shine a spotlight again on the researchers, clinicians and organizations dedicated to the future of cancer care. We also are proud of the work being done by the HealthWell Foundation, which provides a financial lifeline to underinsured Americans through grants for cancer patients across a variety of funds, such as multiple myeloma, bone metastases, and chronic myeloid leukemia for Medicare patients, to help them afford the medical treatments they so desperately need.

Continuing our series on non-small cell lung cancer, this week Real World Health Care speaks with Lecia V. Sequist, MD, MPH, Associate Professor of Medicine at Harvard Medical School and the Mary B. Soltonstall endowed chair in oncology at Massachusetts General Hospital. Dr. Sequist’s research focuses on studying novel targets and targeted agents for lung cancer treatment, particularly those that target the epidermal growth factor receptor (EGFR) and in detecting and studying the significance of tumor cells circulating in the bloodstream.

Real World Health Care: Tell us about what you do at Massachusetts General Hospital, especially in relation to research and treatment of non-small cell lung cancer.

Lecia V. Sequist, MD, MPH, Harvard Medical School

Lecia Sequist: I’m a medical oncologist with a busy practice, seeing and treating patients with lung cancer. I also conduct clinical and translational research on new drugs, looking at the molecular aspects of tumors and biopsies as patients go through various forms of treatment. My focus is on personalizing treatment for each patient.

RWHC: Can you share some highlights of your recent research in non-small cell lung cancer?

LS: Most of my recent research has revolved around EGFR mutations. One of the biggest advances in lung cancer in recent years is that we’ve come to understand lung cancer is not one disease. It’s many diseases. We can now tell the difference between one cancer and another by looking at the tumor genetics. These are not the genes we inherit from our parents, rather they are genes that reside only in cancer cells. These genes are at the core of what causes cancer. By identifying these genes in a lung cancer patient’s tumor, we can be more successful with treatments that target those genes and the proteins they produce.

EGFR mutations were first discovered here at Mass General, right around the time I started in oncology. It was a very exciting time, and ushered in a new era of personalized treatment for cancer. Since those early days, we’ve done a tremendous amount of research with patients who have the EGFR mutation, and we’ve found treatments that work better than standard chemotherapy.

RWHC: What are some of the biggest challenges you face as a researcher studying non-small cell lung cancer?

LS: I think of the challenges in two categories: scientific and societal. From the scientific point of view, we can’t currently identify mutations in every lung cancer, though we’re constantly working to uncover more of them. The group of lung cancer patients who have no identifiable mutation, or who have a mutation with no matching drug therapies at this time, are effectively left out of the “molecular revolution.” For those groups, the challenge is to find alternative approaches. Luckily some of the newer immunotherapies may work particularly well in such patients. Then down the road, we know that targeted therapies eventually “wear off,” in the sense that cancer cells get smart and find ways to work around the roadblocks we put in their path. For example, we saw this with the first generation of tyrosine kinase inhibitors (TKIs) developed to target EGFR mutations. Most patients initially responded, but subsequently developed a resistance after about a year, because they developed a second mutation that prevents the TKIs from binding to the cancer cells. Last year, a new EGFR drug was FDA approved that is able to effectively target this second mutation. Now we’re racing trying to learn how the cancers may get around the newer drug and also looking at strategies to prevent resistance.

From a societal standpoint, one of our biggest challenges in the lung cancer research community is the stigma that still exists around lung cancer. In the United States, we were fortunate to have had a very successful public health campaign around the dangers of smoking over the last generation. Those dangers are important to understand, but one of the unexpected consequences of this was to popularize the opinion that lung cancer is a self-inflicted disease and therefore patients carry some degree of blame. Not only does this end up negatively affecting individual patients, it also cuts into research funding. The fact is, some smokers get lung cancer while others don’t. And more importantly, many lung cancer patients have never smoked. No one deserves lung cancer and research must push forward to stop this, the deadliest of all cancers.

RWHC: What are some of the biggest challenges you face as a clinician treating patients with non-small cell lung cancer?

LS: There are promising treatments being studied in clinical trials, but many patients don’t have access to those treatments because the trials are concentrated in academic centers. Even if patients have geographic access to research studies, clinical trials have fairly high thresholds for eligibility, so if a patient has other medical conditions — which many lung cancer patients have — or if their cancer has certain characteristics, they won’t be eligible for the trial. We need to keep pressure on the pharmaceutical industry to include broader groups of patients in trials so all patients can get access to promising new treatments.

RWHC: What do you think are some of the biggest opportunities for advancement in how we research non-small cell lung cancer and treat people with the disease?

LS: Immunotherapy has really changed the paradigm for non-small cell lung cancer. Years of failed vaccine studies led us to believe that it wasn’t possible to affect the human immune system in meaningful ways against lung cancer. Now that we’ve hit upon a different way to activate the immune system, new discoveries are tumbling out the door every day. Unlike past treatments, immunotherapy has true promise for long-term disease control. There are already three FDA-approved lung cancer immune therapy treatments over the last year and likely many more to come. I think someday we’ll look back on this time and say that this is when the needle really started to move.

RWHC: Why did you get into this field of research? What continues to inspire you?

LS: I was initially drawn to studying lung cancer when I was in training by the doctors who were mentoring me and the patients I met. At the time, there weren’t many treatments available for non-small cell lung cancer, so there was a lot of room for improvement. This was attractive to me as a clinician and a researcher and it has remained a vibrant and ever-changing field. I enjoy being involved in the exponentially increasing number of treatments available and how these new treatments can bring hope to patients. It has ended up being an intellectually stimulating and extremely fulfilling career and I continue to be inspired by the patients I meet every day.

Non-Small Cell Lung Cancer: EGFR Mutations and Targeted Therapies

Continuing our series on non-small cell lung cancer, this week Real World Health Care speaks with Lecia V. Sequist, MD, MPH, Associate Professor of Medicine at Harvard Medical School and the Mary B. Soltonstall endowed chair in oncology at Massachusetts General Hospital. Dr. Sequist’s research focuses on studying novel targets and targeted agents for lung cancer treatment, particularly those that target the epidermal growth factor receptor (EGFR) and in detecting and studying the significance of tumor cells circulating in the bloodstream.

Real World Health Care: Tell us about what you do at Massachusetts General Hospital, especially in relation to research and treatment of non-small cell lung cancer.

Lecia V. Sequist, MD, MPH, Harvard Medical School

Lecia V. Sequist, MD, MPH, Harvard Medical School

Lecia Sequist: I’m a medical oncologist with a busy practice, seeing and treating patients with lung cancer. I also conduct clinical and translational research on new drugs, looking at the molecular aspects of tumors and biopsies as patients go through various forms of treatment. My focus is on personalizing treatment for each patient.

RWHC: Can you share some highlights of your recent research in non-small cell lung cancer?

LS: Most of my recent research has revolved around EGFR mutations. One of the biggest advances in lung cancer in recent years is that we’ve come to understand lung cancer is not one disease. It’s many diseases. We can now tell the difference between one cancer and another by looking at the tumor genetics. These are not the genes we inherit from our parents, rather they are genes that reside only in cancer cells. These genes are at the core of what causes cancer. By identifying these genes in a lung cancer patient’s tumor, we can be more successful with treatments that target those genes and the proteins they produce.

EGFR mutations were first discovered here at Mass General, right around the time I started in oncology. It was a very exciting time, and ushered in a new era of personalized treatment for cancer. Since those early days, we’ve done a tremendous amount of research with patients who have the EGFR mutation, and we’ve found treatments that work better than standard chemotherapy.

RWHC: What are some of the biggest challenges you face as a researcher studying non-small cell lung cancer?

LS: I think of the challenges in two categories: scientific and societal. From the scientific point of view, we can’t currently identify mutations in every lung cancer, though we’re constantly working to uncover more of them. The group of lung cancer patients who have no identifiable mutation, or who have a mutation with no matching drug therapies at this time, are effectively left out of the “molecular revolution.” For those groups, the challenge is to find alternative approaches. Luckily some of the newer immunotherapies may work particularly well in such patients. Then down the road, we know that targeted therapies eventually “wear off,” in the sense that cancer cells get smart and find ways to work around the roadblocks we put in their path. For example, we saw this with the first generation of tyrosine kinase inhibitors (TKIs) developed to target EGFR mutations. Most patients initially responded, but subsequently developed a resistance after about a year, because they developed a second mutation that prevents the TKIs from binding to the cancer cells. Last year, a new EGFR drug was FDA approved that is able to effectively target this second mutation. Now we’re racing trying to learn how the cancers may get around the newer drug and also looking at strategies to prevent resistance.

From a societal standpoint, one of our biggest challenges in the lung cancer research community is the stigma that still exists around lung cancer. In the United States, we were fortunate to have had a very successful public health campaign around the dangers of smoking over the last generation. Those dangers are important to understand, but one of the unexpected consequences of this was to popularize the opinion that lung cancer is a self-inflicted disease and therefore patients carry some degree of blame. Not only does this end up negatively affecting individual patients, it also cuts into research funding. The fact is, some smokers get lung cancer while others don’t. And more importantly, many lung cancer patients have never smoked. No one deserves lung cancer and research must push forward to stop this, the deadliest of all cancers.

RWHC: What are some of the biggest challenges you face as a clinician treating patients with non-small cell lung cancer?

LS: There are promising treatments being studied in clinical trials, but many patients don’t have access to those treatments because the trials are concentrated in academic centers. Even if patients have geographic access to research studies, clinical trials have fairly high thresholds for eligibility, so if a patient has other medical conditions — which many lung cancer patients have — or if their cancer has certain characteristics, they won’t be eligible for the trial. We need to keep pressure on the pharmaceutical industry to include broader groups of patients in trials so all patients can get access to promising new treatments.

RWHC: What do you think are some of the biggest opportunities for advancement in how we research non-small cell lung cancer and treat people with the disease?

LS: Immunotherapy has really changed the paradigm for non-small cell lung cancer. Years of failed vaccine studies led us to believe that it wasn’t possible to affect the human immune system in meaningful ways against lung cancer. Now that we’ve hit upon a different way to activate the immune system, new discoveries are tumbling out the door every day. Unlike past treatments, immunotherapy has true promise for long-term disease control. There are already three FDA-approved lung cancer immune therapy treatments over the last year and likely many more to come. I think someday we’ll look back on this time and say that this is when the needle really started to move.

RWHC: Why did you get into this field of research? What continues to inspire you?

LS: I was initially drawn to studying lung cancer when I was in training by the doctors who were mentoring me and the patients I met. At the time, there weren’t many treatments available for non-small cell lung cancer, so there was a lot of room for improvement. This was attractive to me as a clinician and a researcher and it has remained a vibrant and ever-changing field. I enjoy being involved in the exponentially increasing number of treatments available and how these new treatments can bring hope to patients. It has ended up being an intellectually stimulating and extremely fulfilling career and I continue to be inspired by the patients I meet every day.

Lung Cancer Alliance Moves Research Forward Through Innovative Partnerships

This week, Real World Health Care speaks with Jennifer King, Ph.D., Director of Science and Research for the Lung Cancer Alliance. The Lung Cancer Alliance is the leading and highest rated nonprofit organization dedicated to fighting lung cancer in the nation. Since 1995, it has played a critical role in every major advance — changing how people support, talk about, detect and treat the disease — and turning those impacted into survivors. Its mission is saving lives and advancing research by empowering those living with and at risk for lung cancer.

Real World Health Care: How does the Lung Cancer Alliance fund, or acquire funding, for the research it supports?

Jennifer King, Lung Cancer Alliance

Jennifer King, Lung Cancer Alliance

Jennifer King: Our funding for all our programmatic work, including our research platform, comes from a variety of sources. The majority is through individuals, private family foundations and corporate partnerships. On the research side of things, we also apply for grant funding, including through federal agencies like the National Cancer Institute.

RWHC: How does the LCA determine which research it supports, either through funding or through its advocacy work?

JK: Our research vision consists of six core areas: screening implementation, biomarker research, patient-powered research, enhancing clinical trial participation, survivorship, and increasing research capital. If a project or initiative fits in one of these six buckets, we will consider it for our portfolio. We don’t make direct grants; we work with researchers and other organizations to move projects forward through innovative partnerships.

RWHC: What is the LCA currently doing to promote and/or fund research into non-small cell lung cancer? What are your priorities in this area?

JK: We have funded a young investigator in partnership with the Conquer Cancer Foundation. Her work is currently focused on immunotherapy research for people with late stage NSCLC. We are also launching a clinical trials initiative to navigate more patients through the clinical trials process and enhance clinical research. There are so many emerging therapies in this area that more clinical research is necessary to understand what the right treatments are at the right time for individual patients.

RWHC: What are the biggest challenges in NSCLC research and how is the LCA working to overcome them?

JK: A big challenge is the lack of research capital. We fund young investigators, as I mentioned, to support more people studying lung cancer. We also work with Congress to ensure the continued funding of the Lung Cancer Research Program with the Congressionally Directed Medical Research Program at the Department of Defense. To date, $102 million has been allocated for lung cancer research through this program.

RWHC: What would you say have been the most important advances in NSCLC treatment over the past 10 years?

JK: Without a doubt, the two biggest advances have been targeted therapies and immunotherapies. Targeted therapies attack a specific mutation in the cancer cells. This typically causes fewer side effects than standard chemo and truly personalizes the treatment plans for each person diagnosed. Immunotherapies use a patient’s own immune system to fight his or her cancer. There have been a number of new drugs in both fields that are offering more hope to patients, but a lot of questions remain about how to best use the new therapies.

RWHC: What do you think will be the next biggest advances in NSCLC treatment in the near future?

JK: We are on the horizon of understanding how to combine different types of NSCLC treatments and for whom. There are trials using immunotherapies and targeted therapies with each other, as well as with chemo, radiation, and surgery. A huge number of questions remain about how to use these drugs, for whom, and together or in what sequence. Understanding how the new agents do and don’t work together and being able to personalize the treatments for each individual cancer will lead to major changes in how we care for NSCLC patients. There are also exciting new advances in fields like nanotechnology and health information technology that may someday have a broad impact on cancer care.

RWHC: Why did you get into this field in the first place? What continues to inspire you about it?

JK: I have always been interested in the science of how disease works and how we can potentially use that knowledge to help patients. This started back in high school when I did a biology project on gene therapy. I’m a former cancer researcher, but I joined Lung Cancer Alliance in early 2015 because I was excited about seeing how the science was impacting the patients themselves.

It’s been such an inspirational 18 months. We had six new drugs approved in 2015 for lung cancer, and there’s many more on the way. The science is constantly changing as we keep learning, which keeps the work interesting. Now, I get to talk with patients, respond to questions and understand the issues that matter most to people living with lung cancer. It’s a constant inspiration to keep pushing for new and innovative research studies that will help patients and their families.

Alzheimer’s Association Outlines Research Priorities & Treatment Horizons

This week, Real World Health Care brings you a conversation with Maria Carrillo, PhD, Alzheimer’s Association Chief Scientific Officer. Formed in 1980, the Alzheimer’s Association advances research to end Alzheimer’s and dementia while enhancing care for those living with the disease.

Real World Health Care: According to your literature, more than 5 million Americans suffer from Alzheimer’s disease. What do the majority of these patients most need in terms of treatments: treatments to address the symptoms of the disease, or treatments to stop or slow the progression of the disease? Why?

Maria Carrillo, Alzheimer's Association

Maria Carrillo, Alzheimer’s Association

Maria Carillo: What people need most is hope – hope that comes from significant progress in Alzheimer’s research that they can understand and that benefits their day to day life. Thanks to the amazing work of thousands of Alzheimer’s Association advocates, and many dedicated legislators, we have in place a U.S. National Plan to Address Alzheimer’s Disease. The Plan calls for real progress in treating and preventing Alzheimer’s disease by 2025. An expert workgroup convened by the Alzheimer’s Association recommended a federal investment of $2 billion per year for 10 years to make this achievement a real possibility. We are making strides toward that level of commitment – we’re over half way there – but we still have a way to go.

To more directly answer your question, both symptomatic and preventive therapies have a lot of value. People with Alzheimer’s, and those at high risk of getting it in the near-term, need something to help them now. Greatly reducing or eliminating dementia symptoms and/or pushing back the onset of dementia by ten, or even five, years, will act as something like prevention for the great majority of people – they will live most if not all of their lives free from debilitating symptoms.

Finally, we all look forward to the development of proven ways to reduce risk and prevent Alzheimer’s disease and other dementias – for the millions of lives saved, the billions of dollars saved, and the enormous suffering eliminated.

RWHC: What are some of the most promising areas of treatment research that the Alzheimer’s Association is funding?

MC: The Alzheimer’s Association is the largest private, nonprofit funder of Alzheimer’s research, awarding more than $350 million to more than 2,300 projects. Our goals are to (1) advance our understanding of Alzheimer’s, (2) help identify new treatments, (3) improve care, and (4) further our knowledge of brain health and Alzheimer’s prevention.

The Alzheimer’s Association has provided essential startup funding to, and/or funding to expand the scope of, three major Alzheimer’s disease prevention trials currently underway – the A4 Trial, DIAN TU, and API APOE4.

The Alzheimer’s Association grants program has funded – and continues to fund – some of the most important research threads in Alzheimer’s science. These topics and ideas move the field forward by contributing to knowledge about Alzheimer’s, refining research questions, and yielding clues to causes and treatments. Examples include:

  • Sex, gender and vulnerability to Alzheimer’s and other dementias
  • Commonalities between cancer and Alzheimer’s
  • Effects of oxidative stress and inflammation in Alzheimer’s
  • Vascular contributions to Alzheimer’s
  • Protein misfolding and Alzheimer’s
  • Tau toxicity in Alzheimer’s
  • Biomarkers for Alzheimer’s
  • Development of new scales for Alzheimer’s, including pain and clinical meaningfulness
  • Vaccines/Immunotherapies for Alzheimer’s
  • Insulin and insulin-degrading enzyme in Alzheimer’s
  • Down syndrome and Alzheimer’s
  • Patient ability to consent in Alzheimer’s
  • Differences in Alzheimer’s in minority communities
  • Blood pressure control and Alzheimer’s

RWHC: What are some of the biggest challenges or obstacles that Alzheimer’s researchers are facing in terms of developing new treatments? What can or should be done to overcome those challenges or obstacles, and how is the Alzheimer’s Association helping to overcome them?

MC: The two biggest issues/obstacles are insufficient funding for Alzheimer’s research and the need for more participants for clinical studies.

The Alzheimer’s Association and its nationwide constituency is the leading advocate for increased research funding at the federal level, and also the leading nonprofit funder of Alzheimer’s research. That said, many more voices need to be heard – every day and through every vehicle – to ensure that the federal government understands exactly how high a priority this issue is, and allocates the needed funds.

Recruiting and retaining clinical trial participants is now the greatest obstacle, other than funding, to developing new and better treatments for Alzheimer’s disease. Before any drug or therapy can be used in medical practice, it must be rigorously tested to certify that it is safe and effective.

To address the growing need for clinical trial participants, the Alzheimer’s Association launched Alzheimer’s Association TrialMatch – a free clinical studies matching service. More than 100,000 individuals have registered to search for Alzheimer’s clinical trials using TrialMatch.

Alzheimer’s Association TrialMatch provides users with comprehensive clinical trial information and a customized list of studies they may seek to enroll in. TrialMatch is open to everyone, including people with Alzheimer’s or other dementias, their caregivers, family members, and anyone who wants to get involved in the fight against Alzheimer’s.

There are several other registries also working to identify and marshal individuals for Alzheimer’s disease research. The primary need is for increased awareness that these services exist, and that participating in Alzheimer’s research is one of the greatest gifts that one can give to current and future generations.

RWHC: Is a preventative or curative treatment on the horizon? Do you think this is a disease that can ultimately be prevented before it starts or cured after it starts?

MC: Similar to the way we address heart disease, the preferred strategy for Alzheimer’s would include:

  • Early detection methods that identify those most at risk. Preferably these would be simple, inexpensive and non-invasive, such as a blood test.
  • Effective methods to track the biological course of the disease, and the impact of drugs and other interventions.
  • Preventive and risk reduction strategies – lifestyle and pharmacological – that can be engaged in by everyone throughout life.
  • Multiple effective treatments – that address the disease in multiple ways – for those who, despite the points above, suffer from dementia symptoms.

The Alzheimer’s Association believes that all these things are possible in the relative near-term with the appropriate investment in research.

We have made great strides in treating and preventing many diseases – even major killers such as cancer, heart disease, and HIV/AIDS – when we have made the issue a high priority and made the resources available for research. Now is the time to do the same for Alzheimer’s disease.

RWHC: What sort of initiatives or activities can we expect to see from the Alzheimer’s Association over the next few years?

MC: We still do not completely understand the causes of Alzheimer’s disease, and many questions remain about exactly how it progresses. The Alzheimer’s Association plans to redouble its efforts to support and spotlight in the basic science of the disease, for example at the Alzheimer’s Association International Conference. Increasing our knowledge in these areas should uncover multiple opportunities for therapeutic targets.

At the same time, the Association is deeply involved in clinical trials aiming to prevent Alzheimer’s disease. In addition to the funding initiatives mentioned earlier, we collaborate with Fidelity Biosciences Research Initiative (FBRI) and the principal investigators of all the major prevention studies in the Collaboration for Alzheimer’s Prevention (CAP) seeking to facilitate the sharing of information, resources and expertise that may speed the discovery of new preventive treatments. CAP was first convened in 2011 to help researchers learn from and support each other’s work; share data; harmonize data gathering and trial outcomes to allow for comparability across studies; and hold open, informal dialogue with regulators.

Inflammation is a factor that contributes to the cause and progression of many diseases and conditions. This is emerging as a significant area now in Alzheimer’s research. The Alzheimer’s Association’s Part the Cloud initiative, for example, is making the development of new therapies in this area a target of multi-million dollars in research funding.

Newly launched is Alzheimer’s Combination Therapy Opportunities (ACTO), which aims to provide pilot funding to explore combination therapy opportunities in Alzheimer’s disease. This program will support a biomarker-based clinical trial testing of repurposed drug combinations through Phase II proof of concept.

The Alzheimer’s Association also continues to prioritize issues such as the impact of sex/gender, race/ethnicity, education, and socioeconomic status on the development and progression of Alzheimer’s and other dementias.

 

National Institute on Aging Outlines Alzheimer’s Priorities

As part of our series on Alzheimer’s Disease, Real World Health Care spoke with Creighton Phelps, Ph.D., acting director, Division of Neuroscience, National Institute on Aging, National Institutes of Health. Dr. Phelps discusses the challenges facing AD researchers and how the NIA is working to overcome them.

Real World Health Care: In terms of comparative effectiveness research for Alzheimer’s disease, where is the NIA focusing its efforts and why?

Dr. Creighton Phelps

Dr. Creighton Phelps

Creighton Phelps: Currently, because we do not have treatments to delay or prevent Alzheimer’s, comparative effectiveness research is not really an option. That said, Alzheimer’s disease is a complicated disorder and we are funding research into genetic, behavioral, and environmental factors that may all play a role in disease onset and progression. As a result, not one, but many interventions may be needed. For this reason, we can’t leave any stone unturned. NIA is funding drug-discovery projects, trials using pharmacological interventions, preventative lifestyle interventions, and caregiving interventions.

RWHC: What are some of the biggest challenges researchers and industry face in developing AD therapies?

CP: Clinical trials focused on finding a prevention or cure are imperative to Alzheimer’s disease and related dementias research. But a big challenge is that it is often difficult to recruit participants into trials. We need participants with cognitive impairments, as well as those without; we need ethnic minorities; we need people age 65 and older, and also younger adults. This point of comparison helps us to determine which changes in the brain are specifically related to Alzheimer’s disease and which can be attributed to aging. Increased participation in clinical trials will really hasten our search for effective therapies. Additionally, participants with dementia need a study partner to assist the participants during the trial, which adds another level of burden for families and loved ones. But without the generous participation of clinical trials volunteers, we won’t find a cure for Alzheimer’s.

RWHC: How is the NIA helping to overcome these challenges?

CP: NIA is working hard to overcome these and other challenges, and we are grateful that both public and private organizations, and the general public, also place a high priority on dementia research.

Congress just boosted federal funding for Alzheimer’s disease and related dementias research by $350 million dollars. It is anticipated that this increased budget will accelerate investigator-initiated discovery after years of smaller budget increases. The budget increase will enable new, highly collaborative initiatives.

In 2011, President Obama signed into law the National Alzheimer’s Project Act. This called for the creation and maintenance of an integrated National Plan to overcome Alzheimer’s, with the ultimate goal being to find a prevention or cure by year 2025. As mandated in the National Plan, NIA hosted Alzheimer’s Disease Summits in 2012 and 2015, bringing experts from pharma, academia, and advocacy groups together to advance the research agenda. NIA also worked with the National Institute of Neurological Disorders and Stroke to hold two Alzheimer’s Disease-Related Dementias Summits in 2013 and 2016 to examine the issues central to the other dementias that sometimes overlap with Alzheimer’s.

This spirit of collaboration can also be seen in the groundbreaking Accelerating Medicines Partnership (AMP). AMP is a bold new venture among the NIH, 10 biopharmaceutical companies, and several nonprofit organizations that aims to transform the current model for developing new diagnostics and treatments for chronic diseases. AMP-AD, which applies this innovative model to Alzheimer’s disease, will enable the rapid sharing of large biomedical datasets that may lead to speedier discovery of therapeutic targets.

RWHC: Can you please provide an overview of some of the more promising therapeutic targets (particularly those moving out of the lab and into human studies) on which the NIA is focused? Where you can, please explain why those have become a priority.

CP: NIA is funding, often in collaboration with others, prevention trials testing drugs that may clear amyloid protein—a hallmark of the disease—in cognitively normal volunteers at high risk for developing the disease due to genetics or who show abnormal amyloid levels in their brains, as visualized by PET Scans. The hope is that by treating the disorder earlier in the disease process that we may delay or even prevent the disease.

RWHC: Where does the NIA see the greatest need for research into Alzheimer’s disease: diagnosis, symptom management, stopping/slowing the progression of the disease, or prevention of AD? Why?

CP: Currently, about 5.2 million Americans age 65 and older are living with Alzheimer’s disease; many thousands more are diagnosed with related disorders, such as Lewy body or frontotemporal dementia. An even greater number are in the pre-symptomatic stages, sometimes called Mild Cognitive Impairment (MCI) or prodromal disease. These numbers are expected to more than double by 2050 unless we find one or more treatments. Alzheimer’s and other forms of dementia are expected to cost the United States $236 billion this year. Of course, the ultimate goal is to treat and prevent the disease. But these staggering statistics reveal that any discoveries—whether in diagnosis, symptom management, stopping/slowing disease progression, or preventing the disease—could help the millions currently afflicted.

RWHC: Besides translational and comparative effectiveness research, what other initiatives does the NIA support in relation to Alzheimer’s disease? Any highlights to share in terms of non-pharmacological intervention research?

CP:  With these additional financial resources, we are able to fund many new and exciting projects. The additional $350 million will enable: the development of new human cellular models of Alzheimer’s that may enable rapid screening of hundreds of thousands of molecules as potential therapeutic agents. It will also allow us to establish translational centers that will develop and apply cutting-edge approaches to drug discovery and development. Other upcoming projects include population studies of trends in the incidence and prevalence of dementia, the development of novel interventions to support dementia caregivers, and clinical trials of therapies in people at the highest risk of dementia.

What Happens When an Investigational Drug Cures Some Patients, but not Most?

David Sheon

David Sheon

To date, 179,158 clinical studies have been registered on ClinicalTrials.gov. Though the majority of these trials result in unsuccessful attempts to bring a drug to market, an untold number of lives have been saved or extended as a result of the successes.

But how many lives were saved by drugs that did not meet their clinical endpoint? Recently, the attention of the medical community has been drawn to “exceptional responders.” These are patients who, contrary to expectation, respond extremely well to drugs that are not found to be effective (or even safe) for use in the general patient population studied in a clinical trial.  The study doesn’t meet its endpoints, but a small number of patients thrive.

With the advent of relatively cheap and easy genetic sequencing, researchers are beginning to better understand why exceptional responders do so well on drugs that have little to no benefit for most patients.

In one case, featured recently in an article in The New York Times, a patient has been living four years with a cancer she was told was untreatable, because she responded well to an experimental drug. Of the seven people given the drug, she was the only one who responded. Sequencing her tumor’s genes, the researchers were able to determine that her response was due to the natural presence of a protein that her cancer needed in order to grow.  The experimental drug stops the production of the same protein. Doctors and researchers have been perplexed by these types of cases for years, yet have only recently been able to examine why this is occurring. Researchers at the National Cancer Institute have begun a study to “understand the molecular underpinnings of exceptional responses to treatment.”

Regardless of the science behind it, there is a very real, ethical dilemma raised by the existence of these exceptional responders. If the drug does not get approved, and especially if the company producing the drug  loses investors and goes out of business because the drug trial didn’t meet its endpoints, exceptional responders will have no way of accessing a treatment that could well save their lives just because of an anomalous genetic makeup. There is nothing in place to guarantee that these patients will be able to access their treatments, even if there are no other alternatives.

According to Wayne Pines, President of Regulatory Services and Healthcare at APCO Worldwide and former Associate Commissioner for Public Affairs at the FDA, however, this issue is not so clear-cut.

“There are a lot of factors that go into a decision as to what an individual patient should do.  Each decision has to be individual,” he said. “We must also take into account the fact that clinical trials are essential to determine if a new drug works and is safe, and there are limits to how much of an experimental product can be produced.”

All of this would seem to indicate that a blanketing policy for dealing with individual patients is not where we have to focus. The presence of the exceptional responder makes it difficult to determine a drug’s efficacy, especially when researchers cannot explain the patient’s response.

“If reasonable endpoints have not been met, then the question is whether the drug has the potential to work,” Mr. Pines said. “Again, this is a decision that has to be made on specific facts, not on the basis of a set policy. A general one size fits all answer to these kinds of questions does not work.”

Ultimately, more research must be done on these cases before making decisions about how to deal with them. With recent advances in molecular testing, hopefully the day is near when we can understand what causes a patient to respond exceptionally, and where to go from there.

What do you think? Should there be policies set in place to protect these patients? If not, how can we ensure that patients can access the drugs they need, when they need them? Let us know in the comment section.

Categories: Access to Care, General