Repurposing Medications: Reimagining Treatment Options

Last month around the Chinese New Year holiday, a prominent Chinese scientist from Guangzhou Medical University made an announcement that stirred controversy both domestically and internationally while also highlighting a route to combat ailments that global academia and pharmaceutical industries have been attracted to for years. The scientist revealed that his team had been injecting patients with a malaria-causing parasite in order to cure a range of cancers – with two patients seeming to have no cancer cells remaining at the site of tumor and five additional patients having no disease progression out of ten total patients receiving this malarial therapy for at least a year. Although this type of treatment has been attempted in the past in an attempt to combat HIV in the 1990s, the Centers for Disease Control (CDC) and other health governing bodies determined that there was insufficient pre-clinical data to justify human trials during this time period. The controversy revolving around this announcement encompasses the aforementioned determination by CDC, the release of trial results before being published in a peer-reviewed journal, and, most importantly, the possibility of creating a malaria public health emergency for a country due to eradicate the communicable disease by 2020. Although the scientist who underwent this study clearly abdicated internationally conferred health principles, this avenue of repurposing – repositioning, re-profiling, re-tasking, etc – medications and therapy is becoming more appealing to those invested in novel treatment options for both established and emerging diseases.

Throughout the development lifecycle of new chemical entity (NCE), the process for regulatory approval could span over ten to fifteen years with an associated cost of over 2 billion dollars. This has led to an average of only 20 to 30 NCEs being approved by the Food & Drug Administration (FDA) each year. However, through repurposing medications, the development span can be cut to five to eight years at approximately 60% of the total NCE cost – in addition to higher approval rates from regulatory agencies. This repurposing process, as shown by the statistics, is enormously appealing for pharmaceutical companies/investors, but also provides targeted therapy for patient’s disease states at a theoretically lower price than an NCE. Even for rare genetic diseases, repurposing has become common due to only 400 medications being on the market to treat over 7000 genetic conditions. Repurposing is accomplished through the theory of translational research which takes a look at basic scientific discoveries and determining how a medication can be made to match this discovery – for example, examining the molecular pathway of diabetes and then matching it with a chemical entity that has an effect within the pathway like glucagon-like peptide 1 (GLP-1). The known chemical entities are commonly stored in giant databases within academia and the industry. Through big-data analytics, advanced modeling, and high throughput screening techniques, these chemical entities can then be extracted from the databases and determined if it has a possible role in a certain molecular pathway.

This method of establishing novel treatment options ought to be utilized more frequently and effectively, though there are medications over the years that have undergone this type of approval. The following are examples of already approved medications and others undergoing clinical trials:

Approved Repurposed Medications:

  1. Thalidomide, which was originally developed as a racemic mixture of enantiomers for the treatment of morning sickness but found to be teratogenic due to the effect of the (S)-isomer, was later successfully developed by Celgene as a single (R)-isomer product for the treatment of leprosy and multiple myeloma.
  2. Viagra (Pfizer’s sildenafil) was a drug that initially failed as an angina treatment in clinical studies; however, during these trials, its effect on erectile dysfunction was noted and then later approved for this indication.
  3. Celebrex, commonly used in osteoarthritis, works by inhibiting COX-2 receptors. Recently it has been shown that for patients that previously had colon cancer, taking this agent can reduce the risk of additional polyp formation without negative gastrointestinal effects associated with existing treatments.
  4. All-trans retinoic acid (ATRA), which is an acne medication, when combined with traditional chemotherapy, results in complete remission of acute promyelocytic leukemia in 90% of treated patients.
  5. Tamoxifen, a hormone therapy medication, treats metastatic breast cancers, or those that have spread to other parts of the body, in both women and men, and it was originally approved in 1977. Thirty years later, researchers discovered that it also helps people with bipolar disorder by blocking the enzyme PKC, which goes into overdrive during the manic phase of the disorder.
  6. Raloxifene was initially developed to treat osteoporosis, but has since been shown to reduce the risk of invasive breast cancer in postmenopausal women in 2007.
  7. Zidovudine (AZT) was initially developed to treat various types of cancer, but was determined to be ineffective. However, it was repurposed into the first approved HIV/AIDs medications in 1987 and has had a tremendous impact on the progression of the autoimmune disorder.

Repurposed Medications Undergoing Clinical Trials:

  1. The lipid soluble simvastatin is currently undergoing a trial in the UK to assess the efficacy of reducing the progression of Parkinson’s disease. The statin drug class is thought to prevent this ailment through its pleiotropic effects including reducing inflammation, reducing oxidative stress, reducing the formation of sticky bundles of alpha-synuclein, and increasing the production of neurotrophic factors. The results are expected to be released in 2020.
  2. Purdue University received a grant from the National Institutes of Health (NIH) to discover the effectiveness of Ebselen, a chemical entity, against methicillin-resistant Staphylococcus aureus (MRSA), and auranofin, which is FDA-approved for the treatment of unresponsive rheumatoid arthritis, against Clostridium difficile.
  3. Metformin, a first line agent for many diabetics, has been shown to reduce the risk of breast cancer in diabetes patients and is being investigated as a treatment for cancer in many different clinical trials

Although this is certainly not an exhaustible list of the impacts repurposing has had on healthcare, the majority of this repurposing stems from serendipitous observations rather than targeted interventions. Through these unanticipated occurrences, a range of disease states can now be more effectively treated ranging from communicable diseases like HIV/AIDS to mental health ailments including bipolar disorder and Parkinson’s disease to non-communicable diseases. As the rising cost of healthcare continues to devastate humanity and lead to health inequalities, heads of governments, pharmaceutical industries, academia, and nonprofits need to commit themselves into investing their time and resources into this repurposing method. The targeted repurposing interventions are more vital and should be devoted to in order to expand options for health disorders rather than the unexpected observed effects. The financial and health outcomes will lead to novel treatment options accessible to a majority of the world which will allow health care professionals to properly accompany their patients through their disease state.

It’s National Public Health Week!

From the National Public Health Week Website: http://www.nphw.org/

We hope you’ll take advantage of all National Public Health Week 2019 has to offer as we celebrate public health and highlight key issues. During these seven days of inspiring events, conversations and celebrations nationwide, don’t miss:

  • Our annual Twitter chat, a conversation with public health leaders from around the country. Mark your calendar for April 3, and don’t forget to RSVP.
  • The NPHW Forum on April 1 featuring grassroots organizers sharing how they’ve activated their communities to improve health right where they live. You can register to attend in person or watch the event via webcast.
  • NPHW’s Student Day discussion on April 4, when public health professionals will share tips on how to break into the field. You can join us in D.C. or watch the webcast to ask questions about getting that first job out of school.
  • Our Shareables page featuring images you can post on social media and NPHW logos to help you spread the word about NPHW 2019.
  • NPHW events in your community, from fundraising fitness walks to health fairs to educational workshops. You can search by state on our Events page.

Our fact sheets are available year-round on the NPHW website so we can keep the momentum and learning going. Learn more about this year’s daily themes and how you can be part of the movement for science, action and health.

Why do we celebrate National Public Health Week? APHA Executive Director Georges Benjamin explains that perfectly in his NPHW 2019 Welcome Letter.

Kaiser Family Foundation releases budget summary analyzing global health-related funding in FY20 budget request

KFF released a budget summary analyzing global health-related funding contained in the FY20 budget request. The analysis includes a table that compares U.S. global health funding in the FY20 request to the FY19 request and enacted levels. It will be updated as more information becomes available.

https://http://www.kff.org/news-summary/white-house-releases-fy20-budget-request/

Looking Ahead: Global Health Threats in 2019

The past year felt turbulent across many facets of life- global health included. Between threats to health from climate change, infectious disease outbreaks, the opioid crisis, threats to healthcare in war zones, and the ever-present health risks of noncommunicable diseases, global health resources are stretched thin. The coming year promises to be just as challenging.

Many global health organizations, such as the World Health Organization and IntraHealth, release reports on health risks to look out for at the start of each year. Between these lists, there is significant overlap, suggesting that the problems in global health are not a matter of lack of data or direction, but poor prioritization and lack of resources. Pollution and climate change rank high on almost all such lists; the WHO reports that 90% of people breathe polluted air on a daily basis. As a result, the WHO considers air pollution the greatest environmental threat to health for 2019- a significant step considering the threats of water pollution and other environmental contaminants. As with most global health issues, the world’s poorest people are hit the hardest. Nearly nine in ten of global deaths due to inhaled pollutants are in low- and middle-income countries (LMIC), due to entirely preventable causes like poor regulation of transport emissions and using gas-powered cookstoves in homes.

Another problem heavily featured in the forecasting reports for 2019 include health risks due to conflict. More than 1 in 5 people across the globe (22%) live in a conflict-affected environment. These are the populations least likely to meet health and development targets, like the Sustainable Development Goals. Specific conflicts are high on the radar of global health officials, especially Yemen and Syria. Both countries have experienced heavy destruction of their existing health infrastructure, brain drain of medical personnel, and tangential struggles that bode poorly for health, such as food insecurity and poor sanitation. Dogged efforts by both local and international humanitarian workers have been able to stave off many public health disasters in such environments, but as wars proliferate and donor attention drifts, only the most pressing issues can be addressed. For example, in Yemen, an unprecedented multi-wave cholera outbreakled to more than 1 million cases of cholera. Of these cases, 30% were children. An effort by many international and local NGOs to distribute vaccines to these cases likely decreased the death toll, but the existing malnutrition of the population coupled with factors like destroyed water supplies exacerbated the outbreak and accelerated the need for resources and personnel.

Risks from infectious disease are typically present throughout global health forecasts, and this coming year was no different. In fact, for the first time, the WHO considers vaccine hesitancy, which they define as the reluctance or refusal to vaccinate despite the availability of vaccines, to be a public health risk that threatens to undo decades of work eradicating diseases that, until quite recently, affected people around the world. Vaccine hesitancy is thought to be one of the factors that has led to a 30% increase in global measles cases. Outbreaks of Ebola have shown how dangerous and fast-moving an infectious disease can be, even with the health workers tasked with treating ill patients. Resurgence of polio in war-torn Syria was only dissipated through a massive vaccination effort. The growing threats from influenza, Dengue, Zika, MERS, SARS, and many other diseases have raised the alarm as to how well global public health processes are able to deal with a potentially catastrophic pandemic. Unfortunately, another global health risk identified by the WHO is antimicrobial resistance for the types of antibiotics that, for decades, have saved the lives of millions. This could cause currently treatable infections like pneumonia, gonorrhea, and salmonellosis to be as dangerous as in times before antibiotics were available. One such infection, tuberculosis, affects 10 million people per year and kills almost 20% of those afflicted. In 2017, almost 500,000 cases of tuberculosis were classified as “multi-drug resistant.”

It’s not all bad news. Overall, global health trends are moving in a generally positive direction. Global life expectancy has increased by 5 years since 2000. Every day, more people will be able to access clean water, electricity, and the internet. Global child mortality has fallen by almost 15% since 1960, while global extreme poverty has fallen to less than 10%, an almost 30% decrease from just three decades ago. Almost 90% of children receive the DTP vaccine before their first birthday. However, progress is uneven, and for many is too slow. Many experts believe that some of the long-simmering global health concerns of the past few decades may be coming to a head as 2019 begins.

For anyone concerned with global health, these risk forecasts can seem dire. Even under the best of conditions, most initiatives set to tackle these risks can at best hope to minimize, and not completely eradicate, the threats from these challenges. The MDGs and SDGs are an important first step in setting a global agenda that puts the social welfare of populations at the front and center, and such efforts must continue. Yet, policymakers cannot ignore the many countries around the world that continuously fail to meet minimum standards of health and well-being. We cannot decouple the political and economic circumstances that lead to failures in global health progress. Short-term aid packages are a necessary salve, but not a sustainable solution. Many global health advocates contend that putting health and well-being at the center of state strategic planning would cascade into positive indicators in all aspects of life, such as food security, education outcomes, economic development, and inter-state diplomacy and coordination. To ensure that we are poised to meet the known and still unknown risks that may come in the coming years, global health must be a primary consideration.

Tick, tick, tick: Reflections from this year’s annual meeting

Tick, tick, tick.

The ticking of Dr. Victor Sidel’s metronome resonated throughout the large ballroom where a reception in his honor was held during the first days of the 2018 APHA Annual Meeting in San Diego. Dr. Sidel, a formative figure in the field of public health and a past president of APHA, died earlier this year after spending his career as a physician vigorously defending the rights of the world’s most vulnerable populations. The beats of the metronome, which he used to punctuate his presentations and speeches since the 1980s, were meant to represent the social disparities inherent in global public health. One tick meant that somewhere in the world, a child was dying due to preventable illness. One tick also represented tens of thousands of dollars spent in weapons sales. Among Dr. Sidel’s published works included seminal books such as War and Public Health and Social Injustice and Public Health, both edited by his longtime collaborator Dr. Barry Levy, who spoke at the APHA reception to honor his colleague. At a prior eulogy for Dr. Sidel, Dr. Levy summed up the body of work that had driven them for decades: “Vic taught us that health, peace and social justice were not isolated concepts, but tightly woven together. I can still hear him saying there cannot be health without peace and social justice, and there cannot be peace and social justice without health.” In many ways, the 2018 APHA conference showed just how deeply these intersections between health, peace, and social justice have been woven into the fabric of the organization, starting with honoring Dr. Sidel, continuing with the breadth and diversity of panels and posters, and concluding with a number of resolutions that were adopted.

Many panels examining various aspects of health and social justice were available throughout the conference. The International Health Section sponsored panels on topics like global health and human rights, equity in global women’s health and maternal, neonatal, and child health, health and war in countries like Yemen, Mexico, Syria, and Gaza, and refugee health. The Peace Caucus sponsored several complementary panels on topics of war and public health, militarization of the border, and violence on indigenous women, along with a presentation from the joint Lancet- American University of Beirut Commission on Syria. The Human Rights Caucus also presented panels on sexual and reproductive rights, as well as issues of health governance and advocacy. A search through the 2018 conference program found topics like environmental justice, worker’s rights, racial disparities, the rights of the incarcerated, and many other issues of social and health justice presented throughout hundreds of panels, roundtables, and posters.

More than many other health-related organizations and associations, APHA has long served as an advocacy platform for the pressing social issues of the time, recognizing the depth of issues that influence public health. While many APHA resolutions address topics traditionally associated with clinical outcomes, like smoking, diet, and reproductive health, combing through the decades of policy statements on the APHA Database shows positions on timely and controversial issues like opposing military action in Afghanistan and Central Asia in 2002, ensuring access to health services for undocumented immigrants in 1994, and raising concerns about the health impacts of fracking in 2012. This year was no different, with a total of 12 new policy statements adopted, many directly focusing on contemporary issues of social justice such as opposing family-child separations at the US border and addressing police violence as a public health issue.

The latter topic was first brought to APHA in 2016, where a collective of authors, motivated by grassroots organizing against state violence, recognized the significance of a national public health entity taking a strong position on the issue. While the resolution passed the APHA Governing Council vote overwhelmingly in San Diego (87% to 13%), just last year it was voted down by a 30-point margin (35% to 65%). A year of collaborative work on drafting and promoting the statement resulted in this year’s triumphant victory, which was crafted to specifically point to the public health implications of the “underlying conditions of the institutions, systems, and society we live in that determine our health outcomes,” according to the End Police Violence Collective. For them, APHA recognition of this resolution “is one more tool that organizers against law enforcement violence can use to pressure their elected officials.” This success, they state, is also portending a needed shift in public health from focusing primarily on behavioral interventions to considering structural ones as well. APHA’s role as a representative of the field of public health makes its willingness to frame public health inequities as social justice issues significant. Despite the two-year trajectory of this resolution within APHA, the Collective maintains that “this work has been ongoing for generations, in communities organizing to draw attention to, intervene on, and rebuild after experiences of law enforcement violence. This statement is a product of those generations of work. It is an important step. But there is more work to be done.”

A reminder of work to be done may be seen in another resolution that came before the governing council but was not met with the same cheers and jubilation. Members from the International Health Section, including Dr. Kevin Sykes, the Chair of the Advocacy and Policy Committee for the IH Section, and well-known scholars of war and public health Leonard Rubenstein and Dr. Amy Hagopian, put forward “A Call to end to attacks on health workers and health facilities in war and armed conflict settings.” Incidentally, the latter two authors have both been recipients of the APHA Victor Sidel and Barry Levy Award for Peace, in 2011 and 2018, respectively. The statement was introduced as a latebreaker due to the accelerated pace of attacks on health workers in 2017, as detailed by a report published by Safeguarding Health in Conflict, a coalition of which APHA is a member, and received several endorsements from multiple APHA components, including from the Peace Caucus, the Occupational Health and Safety Section, and the Forum on Human Rights. However, opposition to some of the specific details of the statement, especially those regarding Israel, led to a contentious process that culminated in little floor debate on the merits of the resolution and, ultimately, the governing council voted no (25% to 75%). Dr. Hagopian echoed the sentiments of the End Police Violence Collective when discussing the importance of APHA taking a stance on issues of social justice, despite what she sees as the sometimes conservative stance of the governing council when it comes to controversial issues. “People working to make the world a better place need all the support they can get- both this sort of written, academic association support as well as political support out in the world. When they can cite the APHA, as the largest and longest stand public health organization in the country, as being on board, that carries weight.” As a result, Dr. Hagopian plans to revise the statement and resubmit it for next year’s APHA conference in Philadelphia. Upon receiving the Award for Peace at the IH Section Awards Ceremony this year, she said “It’s important to be on the right side of history, early and often. So we’ll be back another day.”

Tick, tick, tick.