July 1, 2020 PAP-Q2-20-RT-002
A: Penicillin has had a significant impact on society and the pharmaceutical industry. As the first true antibiotic, it ushered in advances in therapeutic medicine. Before penicillin, there were no effective treatments for infections caused by bacteria, including cholera, tuberculosis, pneumonia, and typhoid fever. Without penicillin, the majority of today’s population may not be alive, as ancestors would have likely succumbed to infections and died. Its impact on society is truly remarkable. Another drug that has had a tremendous impact on society and the pharmaceutical industry is insulin, which is used to treat type 1 and type 2 diabetes. Insulin dramatically changed and saved the lives of those suffering with diabetes and ultimately opened the door for other forms of hormone replacement therapies. Before the discovery of insulin, the only treatment for those suffering from diabetes was a near-starvation diet so their bodies could process the sugars they needed. Since the discovery of insulin was ultimately the result of collaboration between a team of researchers and medical professionals, it is a shining example of what can be accomplished when industry and academic researchers work together.
A: Improvements in quality of life have largely come about through small, incremental advances in scientific understanding, translated into products and policies over many decades. Each advance has offered some improvement or mitigation against significant risks to health, most frequently infectious diseases. However, occasionally a step-change in welfare has occurred due to single events.
One such event was the introduction of antiseptics in the 19th century. Carbolic acid (a phenolic) was first employed in 1867 by Joseph Lister, surgeon at the Royal Infirmary in Glasgow, Scotland, to clean his instruments and as an antibacterial spray during operations. Disinfection with carbolic acid meant that surgery was no longer associated with extremely high rates of mortality (25–50%) due to postoperative gangrene and enabled the subsequent development of myriad, routine surgical procedures.
Bizarrely enough, another product derived from coal tars, but in this instance an antibiotic (from dye derivatives), has given us a second methodology to chemically intervene in potentially life-threatening situations. Although penicillin is seen as the gateway discovery for antibiotics, I would like to suggest that the sulfonamides (the sulfa drugs) offered an earlier glimpse of the potential of small molecules and paved the way for the antibiotic revolution in medicine. The earliest mass formulated and manufactured sulfonamide, Prontosil, was developed in the laboratories of Bayer AG and gave rise to the modern big pharma phenomenon. First prescribed in 1935, they are still used today for some streptococcal infections.
Finally, I would like to nominate the most widely prescribed, wholly curative, directly acting antiviral for hepatitis C — sofosbuvir. Building on the successes of HIV research in identifying drugs to interrupt viral replication, the direct-acting antiviral agents have offered a remarkable glimpse into the future of antivirals where our understanding of pathways may be translated directly into powerful therapeutic interventions.
A: I would select three distinct types of therapies:
1. The groundbreaking work from Louis Pasteur and his assistant Emile Roux to create modern vaccine science through their work on rabies in 1885. Since that time, vaccines have become part of daily life and led to an amazing increase in life expectancy. Today, measles represents one of the best and most secure vaccine platforms, with more than 3 billion inoculations since introduction with no systemic side effects. This resulted in saving hundreds of millions of children’s lives across the globe. In the fight against COVID-19, the Institut Pasteur is designing vaccines based on the measle platform via a recombinant approach.
2. The discovery of the first mass-produced antibiotic — penicillin — in 1928 by the British scientist Alexander Fleming. Mass production and wide usage of the drug was achieved during the second world war. Labeled the “wonder drug,” penicillin single-handedly changed the way we live and improved life expectancy. If we were to assess its impact in combination with all modern antibiotic derivation thereof, this class of drugs saves billions of lives a year, making antibiotics a foundation of our modern civilization. Today, COVID-19 has raised awareness of the real risks caused by pandemics. Nothing would be more devastating than a pandemic caused by a contagious antibiotic-resistant microbe. Such a pandemic would have devastating effects, far dwarfing the serious impact we are currently seeing from COVID-19. Awareness around antibioticresistant microbes has increased over the past three years, but now has reached an inflection point. I expect to see substantial government funding in this field in the coming years.
3. Aspirin, a simple-to-manufacture and cheap drug with so many benefits that one could qualify it as a sort of “miracle drug.” The drug was originally developed and marketed by Bayer in 1899, and amazingly Bayer still generates more than $600 million in sales of aspirin today, making it by far the most resilient drug of all!
A: Throughout history, many drugs have proven to be critical in promoting the survival of the species. Attempting to distill the vast number of seminal discoveries into a few that have had the most impact on society and the pharmaceutical industry is a daunting task. Beginning in the early 1800s, the discovery of a number of key medicines has improved our lives and extended our lifespans; each one has been so important. Determining which ones are most important depends on the factors used to judge them, such as the scale of the drug’s use and the benefit to society in terms of pure volume of patients helped.
The lowly aspirin might fall into this category, as it is a staple in just about every medicine cabinet in the world. Another consideration would be those developed to treat life-threatening conditions or previously untreatable conditions. Before the discovery of insulin, type 1 diabetes, as we now call it, was a death sentence. Before the discovery of chlorpromazine, psychiatric disorders were treated with lithium, electroshock therapy, and radical surgery.
Another argument could be made for those initial medicines that paved the way for an entire class of treatments. Fleming’s discovery of penicillin marked the beginning of the development of antibacterial therapy, and mustard gas started the search for cancer chemotherapeutic agents. It is the inherent toxicity of these treatments that resulted in the pursuit of immune therapies that are effective with limited side effects. My vote for two drugs with significant impact on society would go to morphine and the smallpox vaccine.
A: Over the last century, several groundbreaking inventions in drug discovery have contributed to a remarkable increase in life expectancy. Against this backdrop, it is difficult to identify three drugs having had the greatest impact on society. I’ve identified three that changed the course of medicine.
Insulin: The discovery of insulin revolutionized both the therapy and prognosis of diabetes. This is one of the most studied diseases in the history of medicine, dating back to Egyptian medical texts in 1552 BC. Ever since the isolation of insulin from pancreas tissue in 1923, numerous efforts were made to produce fully synthetic insulin, from rDNA human insulin in 1978 to various insulin analogs in 1996, aimed at optimizing the insulin absorption, distribution, metabolism, and elimination. The dream someday is for a needle-free delivery of insulin by oral route.
Penicillin: The accidental discovery in 1928 of penicillin, an antibiotic drug, changed the history of medicine. Penicillin has become the most widely used antibiotic in the world. It is impossible to imagine what the world would be like without penicillin and the progress we made subsequently in the management of infectious diseases with the currently available antimicrobialdrugs. This discovery of penicillin led to the synthesis of over 40+ drug molecules with varying antimicrobial activity against different types of pathogenic bacteria.
Trastuzumab: Trastuzumab, approved in 1998, derives from basic molecular biology and animal tumor virology focusing on receptor-mediated monoclonal antibody drug therapy. It is a humanized IgG1 kappa monoclonal antibody that selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor 2 protein, HER2. More than 250,000 U.S. women are diagnosed each year with invasive breast cancer, 20% of whom have tumors with HER2 mutations. Based on a published report in 2014, 85% of these women (with HER2) are expected to survive for at least 10 years with treatment with trastuzumab. In addition, the success of monoclonal antibody therapy has revolutionized the discovery programs with more selective drug therapies, exemplified by more than 45 FDA-approved drug products based on monoclonal antibodies.
A: The fight is still ongoing, with developments just starting in many applications. We can just point out the wide variety of technologies behind the development of the COVID-19 vaccines. Platforms based on DNA, RNA, recombinant proteins, and viral vectors, to mention a few, have been successful in the development of vaccines around certain diseases and less successful around others. Every virus is different, making the vaccine strategy and technology that needs to be adopted unique. It is too early to identify the one, two, or three drug molecules that will have the greatest impact.
However, such a variety of approaches increases the probability of having good candidates in the battle against COVID-19. From our side, Cytiva is ensuring that we can support all different vaccine approaches with our technology, knowledge, and biomanufacturing platforms to provide production capacity with speed, at a time when fast response is essential.
A: Since its discovery in 1928, penicillin has saved millions of lives around the world and is still the most widely used antibiotic globally. The discovery has allowed health professionals to treat formerly lifethreatening illnesses, such as bacterial pneumococcal pneumonia, meningitis, syphilis, and gonorrhea.
On a broader note, it has been stated that vaccinations have made the greatest contribution to improved global health of any human intervention besides the introduction of clean water and sanitation. Since the introduction of vaccines, two major infections — smallpox and rinderpest — have been eradicated, polio has almost been eradicated, and measles is well on the way to eradication. Before the introduction of vaccinations, deaths from smallpox and measles were massive, with a large portion of the population dying from smallpox during an epidemic. The COVID-19 pandemic, which the world is currently experiencing and has led to millions of infections and tens of thousands of deaths worldwide, unfortunately emphasizes the personal, social, and economic consequences of not having a suitable vaccine during a pandemic.
A: Platform technologies that allow for the therapeutic delivery and actuation of genetic therapy will continue to transform medicine, with the greatest impact yet to be seen. The “power of the platform,” as it has been called, allows for development of a singular technology to be leveraged in order to treat a smorgasbord of diseases. By far, and for different reasons, the two most promising among these are Cas9 and mRNA therapeutics.
In seven short years, Cas9 has revolutionized genetic research and captured the attention of the public at large with its lofty ambitions. The ability to quickly and efficiently target pieces of DNA for editing utilizing the same ribonucleoprotein construct is an example of platform therapeutics (the same chemical material capable of targeting a variety of indications via small changes to sequence). In the coming years, we will see the clinical readouts from the first Cas9 trials, as well as initiations of a host of new trials. Furthermore, we will see how, once initial clinical proof of concept is established, the “power of the platform” will enable these technologies to be rapidly expanded to new and emerging therapeutic areas. The ability to fix underlying genetic mutations will continue to expand, and, with it, investor confidence in new and emerging technology that builds upon Cas9’s editing ability to correct for issues, such as off-target editing and low efficiencies. This positive feedback loop will prove to be transformative.
The second revolutionary movement in the development of therapeutics is mRNA as a gene delivery vehicle (otherwise known as mRNA therapeutics). While initially pioneered by companies such as BioNTech (and later by Moderna), this field will rapidly move the needle for therapeutic gene delivery. When an underlying genetic disorder results in a lack of protein activity, a new, correct gene must replace it. In some diseases, this gene replacement can be a transient process that only needs a short amount of gene expression to correct the mistake. mRNA presents the most advantageous method to create a single molecule substance (ribonucleic acid, sometimes encapsulated in a delivery system) that can effectively deliver a corrected gene to the cells. Efficient transgene delivery systems such as viruses are incredibly expensive to manufacture due to the need for large bioreactors and create acquired immune responses against their viral capsid proteins. Synthetic nucleic acids, such as mRNA, can be cheaply produced in enzymatic reactions that are low cost and highly scalable, allowing for rapid and cheap synthesis. Further, mRNA is translated into protein in the cytoplasm rather than the nucleus, creating a massive advantage in delivery over synthetic DNA, where DNA has to reach the target cell’s nucleus, which is highly guarded by the nuclear membrane. Taken together, the advantages of mRNA make it the most highly suited vector for transient therapeutic gene delivery. The continued clinical development of these molecules will demonstrate that this revolutionary turn in genetic medicine will create a host of new therapies that can treat diseases currently unreachable by modern therapeutics, leading to a breakthrough potential as yet unimaginable.
A: There are two classes of drugs that I believe have had the greatest impact on society: pain medications and antibiotics. Before pain medications — morphine being one of the first — surgery wards were full of patients screaming in pain before, during, and after surgeries. That pain effect takes a huge toll on the mental and physical well-being of patients and their families. Today, doctors’ offices and hospitals are places of care and comfort instead of torture suites. Before the effective use of antibiotics, even simple common issues caused loss of limb and loss of life. A case of strep throat at one point was a death sentence; now it is commonly and easily cured.
The pharmaceutical industry was most impacted by the safety issues associated with thalidomide. Although the drug industry was a couple of centuries old, it was at this point in the 1960s that the harm from poorly documented and poorly understood pharmaceuticals was known. Soon after, the safety regulations and agencies to enforce regulations were created to protect patients.
A: In my view, the three drug types that have had the greatest impact on society are beta-lactam antibiotics, monoclonal antibodies, and beta-agonists, either for asthma or for cardiovascular disease.
A: The all-time most impactful drugs on society are those that caused massive shifts in society’s structure. Penicillin opened an era where we heavily impacted life expectancy by beating back infectious diseases and shifted the age structure and hierarchy of societies. Estradiol/progestin as contraceptive treatment completely changed society for the better by providing women much greater control over life choices and has had broad-reaching, positive impacts around the globe. The most impactful drugs on the industry have been those that caused paradigm shifts. Humulin, at the forefront of recombinant DNA biotech drugs, ushered us into an era that required us to rename all other programs as “small molecules.” Herceptin and other drugs led the way in the current era of personalized medicine. More generally, the use of antibodies as drug therapies has had a lasting impact on our thinking and pipelines.
A: Societal impact of pharmaceutical products can be measured based on lives saved or suffering mitigated. At the same time, pharmaceutical companies must also generate revenues to allow future R&D and to satisfy financial stakeholders. The discovery of new molecules can also change paradigms of development and manufacturing that have implications for other companies. There are several small and large molecules that stand out as particularly influential on society and on the pharmaceutical industry.
Small Molecules: A few small molecules have had tremendous success saving lives and reducing suffering over the last 100+ years. First, if penicillin had not been identified as a frontline antibiotic in 1942, about 75% of people today would not be here due to their ancestors succumbing to infections of various sorts. In 1899, aspirin (acetyl salicylic acid) was one of the first compounds used routinely for pain relief and to reduce fever or inflammation, and it is sometimes used to treat or prevent heart attacks, strokes, and chest pain (angina). More recently, in 1995 saquinavir was introduced as the first HIV protease inhibitor that prevented progression from HIV to AIDS and eventually led the way for follow-on compounds and the “cocktail” mixture of protease inhibitors to treat HIV.
Large Molecules: On the large molecule side, the history is shorter but no less impressive. The first TNF-α antibody, infliximab, was approved in 1998 for the treatment of Crohn’s disease. The first fully human anti-TNF antibody, adalimumab, was approved for the treatment of rheumatoid arthritis a few years later. A plethora of follow-on indications for various inflammatory conditions followed. The introduction of these large molecules represents a remarkable addition to the armamentarium available to physicians and their patients, because it put targets previously considered “undruggable” with small molecules squarely in the crosshairs. Suddenly, a specific step of the inflammatory pathway could be targeted with laser-like precision rather than the general approach of corticosteroids and immunosuppressive antimetabolites. Antibody-based advances in other therapeutic areas, especially oncology, followed rapidly.
A: Drugs developed to treat previous viral epidemics are being used off label with the potential to treat different disease aspects of patients with COVID-19.
These include: (1) chloroquine and hydroxychloroquine, two antimalarials developed in the 1940s–1950s and widely used for over forty years; (2) Remdesivir, developed by Gilead, which inhibits the RNA polymerase of the Ebola virus; and (3) the combination lopinavir and ritonavir (Kaletra) developed by AbbVie, used since 2000 as an AIDS treatment, which was tested in 2018 on the coronavirus MERS-CoV.
As companies develop new treatments and vaccines and repurpose older drug products to fight COVID- 19, the importance of excipients used, either in (bio)processing or formulation, cannot be forgotten. Excipients play a critical role in the pharmaceutical supply chain and development of new treatments and vaccines to fight COVID-19.
A: Historically, penicillin is one of the most important drug molecules ever discovered, which triggered mass attention on antibiotics. Antibiotics have since continued to revolutionize medicine by making some of the most infectious bacterial diseases like tuberculosis treatable. Another molecule to mention of significant merit is a synthetic insulin for treating diabetes. While it is not a cure, treating patients with synthetic insulin injections allows for the survival of millions as well as providing them with a good quality of life.
As a result of a better scientific understanding of how diseases progress and spread, we are increasingly able to tackle the root cause of the problem by deciphering the human genome. The pharmaceutical industry is facing the following challenge: to gain a deep and scientifically founded understanding of biochemical processes in the human body and resulting diseases, followed by specifically engineered medications based on novel modes of action.
A: The first would be Humira, as one of the earlier humanized monoclonal antibody drugs. In 2019, it was the world’s number one selling medication. This medication has multiple indications and paved the way for an antibody medicine to be highly effective in numerous conditions of unmet medical need. Additionally, providing this therapy in different delivery forms is critical as it becomes easier for certain types of patients to self-administer. Another is certainly Keytruda, which has been revolutionary as an immunotherapy drug extending life for certain cancer patients. Chemotherapy has a place in cancer treatment, but some of the drugs like Keytruda working as an immunotherapy have fewer side effects and clearly extend the life of specific cancer patients. Gene therapy and immunotherapy are revolutionizing drug development, and this all started with the sequencing of the human genome.
A: The process of drug development takes time and resources and is filled with uncertainty about whether it will work, how safe and effective it will be (if it works), and how long before something better comes along. Three inspiring drug development stories, among many that have stood out for me over the past three decades as an infectious disease expert, include the following.
Antiretroviral protease inhibitors for HIV, which prevent viral replication, are a prime example of what the pharma industry, academia, and government can do together to turn a deadly infection threat into a chronic, manageable condition. It is my hope that we can replicate that collaborative approach to curb the COVID-19 pandemic.
Anti-TNF monoclonal antibodies have changed the lives of millions of patients with many different untreatable conditions by blocking TNF signaling to reduce inflammation and suppress autoimmunity. This has paved the way for immuno-oncology. As one of the first widely used monoclonal antibodies, anti- TNF therapies mark a significant shift in the field away from small molecule inhibitors to biologics capable of a level of precision previously thought impossible. Anti-TNF therapies have some of the broadest potential uses of any monoclonal antibody and are currently used to treat rheumatoid arthritis, skin diseases, gastrointestinal disorders, and cancer.
Selective serotonin reuptake inhibitors (SSRIs) have changed the way we treat depression and anxiety by increasing the levels of serotonin in the brain. Prior to the development of this class of pharmaceuticals, treatments for depression were greatly restricted due to the overwhelming adverse side effects. SSRIs, which were some of the first drugs developed through rational drug design, have provided a safer alternative to the previous treatments and have proven largely successful in treating mood disorders. The development of SSRIs has also helped to root mood disorders in biology and, in doing so, has eroded the social stigma commonly associated with mental illness.
This list does not encompass the remarkable advancement in other therapies, such as vaccines, antimicrobials, antipsychotics, antihypertensives, and others, but provides compelling examples of the power of collaboration with modern medicine to improve the lives of people around the globe.
Andrew Bulpin is Executive Vice President of Process Solutions for the life science business of Merck KGaA, Darmstadt, Germany, and is based in Bedford, MA. He joined the organization in 2006 as Vice President of Upstream Processing and later assumed leadership of the Services and Solutions business. He has also served as Global Head of Sales for Pharmaceutical Chemical Solutions.
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