Molecules that Changed Medicine

The Next-Generation Feature: Molecules

Since its earliest beginnings, the pharmaceutical industry has had a tremendous impact on society. From the discovery of early pain medications, anesthetics, and antibiotics to the latest cell and gene therapies, novel drugs have saved countless lives and dramatically improved the quality of life for both patients and caregivers. The current pharma pipeline suggests that innovation remains high, and the pharma industry will continue to achieve medical miracles.

Revolutionizing Medicine

Some of the earliest drug discoveries helped establish the possibilities of modern medicine. Morphine, first marketed commercially by Merck in 1827, was the first drug to block pain.¹ Despite the problems associated with addiction, morphine allowed millions of people to live pain-free for the first time.² It also served as the basis for the development of the field of pain management and the discovery of many other drugs, including some that are still available today.³

Ether, while a known substance for over 300 years, was first used in the medical field in 1846 as the first anesthetic, allowing patients to be unconscious during surgery.² Like morphine, it also served as the foundation for the development of more modern anesthetics.¹

Aspirin, originally as acetylsalicylic acid, was first marketed as a pain medication by Bayer in 1899.³ At the time, it was the first drug known to treat simple pain — an analgesic — without the addiction concerns of morphine.² Today, aspirin is used for considerably more than just pain relief, including reducing inflammation that can cause heart disease and even some cancers.¹

Early 20th Century Advances: Modernizing Medicine

Two incredibly important drugs discovered in the early 20th century — insulin and penicillin — have had a tremendous impact on society and the pharmaceutical industry.

With the introduction of insulin in 1922, diabetic patients no longer had to adhere to a near-starvation diet, which most often did not prevent death.¹ The first insulin was extracted from a cow pancreas. Its use, it should be noted, was made possible by the development of diagnostic tests to determine blood sugar levels in small blood samples.³ Interestingly, as a hormone, insulin served as the first hormone-replacement therapy.²

Penicillin, discovered by accident in 1928, became the first commercial antibiotic in 1942. With the development of this drug, it became possible to treat many bacterial diseases. It is estimated that penicillin has saved more than 80 million lives. It’s possible that without its discovery and use, the world population would be reduced by 75% because so many individuals of earlier generations would have died from infections.¹ The knowledge gained in isolating and purifying penicillin also led to the discovery of many other antibiotics in the 1940s and 1950s, including streptomycin, chloramphenicol, erythromycin, vancomycin, and others — many of which are still prescribed.³

One historian also points to the syphilis drug, salvarsan, as being a crucially important molecule in the history of the pharma industry.² It was the first drug developed to treat a specific disease, and it was the first chemotherapy — a drug that is efficacious but harmful, curing the disease before killing the patient.

Mid-Century Miracles

The first cancer drug approved by the U.S. FDA reached the market in 1949.⁴ Mechlorethamine, originally developed in the 1920s and 1930s as a mustard gas agent for use in World War I, was by the 1940s recognized to be an effective treatment for patients with lymphomas.

The first medicines to treat psychiatric illnesses also appeared in the 1950s. The first was chlorpromazine, also known as Thorazine, in 1951. This first official antipsychotic drug changed the way physicians approached psychiatry — what some call the “psychopharmacological revolution.”¹ Other drugs followed, including haloperidol (Haldol), which was discovered in 1958 and was the first drug effective for the treatment of schizophrenia without sedative properties (unlike lithium, which was the only option up to that point).²

The first oral contraceptives also reached the market during this time. Although hormones were first proposed to be effective as a means of contraception in the 1920s, their potential use was highly controversial.⁴ In the United States, it was even illegal to discuss (let alone research) contraception under the Comstock Law, which equated the topic with pornography.³ It was not until 1960 that the FDA approved the first birth control pill.⁴ Even with its availability, it wasn’t until the 1980s that family planning became accepted and the use of the birth control pill became much more common.³

Heart disease patients gained access to the first approved medication for conditions such as atrial fibrillation, atrial flutter, and heart failure with the marketing of digoxin (Lanoxin) in 1954.² The drug was first isolated from the foxglove plant in the late 1700s and has since been placed on the World Health Organization’s (WHO’s) List of Essential Medicines. Furosemide (Lasix), the first loop diuretic, was approved 10 years later for the treatment of hypertension and heart failure.

Benadryl, the first antihistamine, was approved in 1946, though it did not become available over-the-counter until the 1980s.⁵ The anticoagulant coumadin (Warfarin) was first approved in 1954. It is, like digoxin, considered an essential medicine by WHO.

Notable Molecules from the 1950s–1980s

Several more important new classes of drugs were developed in the 1950s through the 1980s.² Prednisone in 1955 became the first corticosteroid approved for medical use in the United States. L-dopa was first approved by the FDA in 1970 and had a tremendous impact on the lives of people suffering from Parkinson’s disease. The immunosuppressant cyclosporin received FDA approval in 1983, enabling successful transplants. In 1987, lovastatin was the first statin approved in the United States for lowering cholesterol.

Albuterol (salbutamol) was first approved in the United States in the 1980s for the treatment of asthma and has saved countless lives.⁵ In 1987, Prozac became the first approved selective serotonin reuptake inhibitor for the treatment of depression and helped change the way society looks at depression and mental illness in general. The first modern epinephrine auto injector was also approved in the United States in 1987.

1990s Advances

The 1990s witnessed the approval of many well-known drugs that continue to be used today. A number of these drugs have had important, positive impacts on the patients suffering from the diseases or disorders they treat. Patients recovering from surgery have benefited from ondansetron (Zofran), which prevents nausea, since it was first approved in 1991.⁵ Also approved in 1991, zolpidem (Ambien) is a sedative that has helped millions of people maintain sleep. Lipitor, approved in 1996, represented a new class of statins used to lower lipid levels and prevent cardiovascular disease.

Viagra, the first medication approved to treat erectile dysfunction, received an FDA nod in 1998. While some might not believe it belongs in a discussion of the top drug molecules, others argue that sexual intimacy is essential to good quality of life.²

The first protease inhibitors for the treatment of patients with acquired immunodeficiency syndrome (AIDS) were approved in the 1990s. When used with other AIDS therapies, these new drugs allowed doctors to keep virus infections to levels low enough to prevent the development of AIDS.¹

First-in-Class Advances in the 21st Century

The speed at which novel drugs have been developed has accelerated in the 21st century, in part due to the increased understanding of biological processes and access to new genetic data, and because of the implementation of accelerated review pathways by the FDA and other regulatory agencies.

It still takes a long time to turn the idea of a drug into an approved product, however. A study conducted in 2014 of 113 first-in-class drugs approved by the FDA from 1999 to 2013 found that it took 20–25 years on average from the first disclosure of a drug concept (target, pathway, or chemotype) up to FDA approval.⁶ Nearly 70% (45 small molecule and 33 biologic drugs) were discovered through target-based approaches. Of the remaining 33, 25 were discovered using a chemocentric approach based on compounds with known pharmacology, and eight were identified using phenotypic screening. Those discovered using targeted approaches had shorted timelines to approval (median 20 years) than those with non-target-based origins (25 years).

A separate study of 645 novel drugs and therapeutic biologics regulated by the FDA Center for Drug Evaluation and Research (CDER) and approved by the FDA during 1987–2011 found that 32% were first-in-class products, 22% were advance-in-class drugs (not first-in-class but considered to offer significant advances over existing drugs), and 46% were addition-to-class medicines (offer additional options for patients, but typically with similar efficacy and safety as existing products).⁷

Overall, the researchers noted that the rate of development of first-in-class drugs has remained steady.⁷ However, they argued that, given the increasing cost and complexity of drug development, greater levels of innovation would likely be needed going forward, and this innovation should be fostered both within the pharmaceutical industry and through government initiatives.

Highlights from the Last Decade

In 2015, the CDER approved 45 novel drugs, significantly up from the average of 28 approved from 2006–2014.8 Sixteen (36%) of the 45 were first-in-class, 21 (~47%) targeted rare diseases, 27 (60%) were designated in one or more expedited categories, 39 (87%) were approved on the first cycle of review, and 29 (64%) were approved in the United States before receiving approval in another country.

CDER approved 22 novel drugs in 2016, more in line with the average from the first half of the decade.9 Eight (36%) were first-in-class, nine (41%) targeted rare diseases, 16 (73%) were designated in one or more expedited categories, all but one were approved on the first review cycle, and 19 (86%) were approved first in the United States.

In 2017, new drugs to treat infectious diseases, neurological disorders, various cancers, and many other chronic conditions were approved by FDA.10 The number of approvals rose dramatically over the year to 47, more than doubling 2016’s total. Once again, one-third (17) of the approvals were for first-in-class medicines, and 18 (39%) targeted rare diseases.

The FDA approved 59 new drugs in 2018 — a new agency record — targeting infectious diseases; neurological disorders; heart, lung, and circulatory diseases; women’s health issues; cancer and blood disorders; and many other conditions.¹¹ First-in-class drugs accounted for 32% (19) of the approvals, while 58% (34) targeted rare diseases, and 75% (59) were designated in one or more expedited categories.

The high rate of approvals was maintained in 2019, with the FDA giving the nod to 48 drugs treating neurological and psychiatric disorders; infectious diseases; heart, lung, circulatory and endocrine diseases; autoimmune conditions; women’s and men’s specific health issues; cancers and blood disorders; and numerous other conditions.¹² Several biosimilars were also approved. This year, a higher percentage (44%) of the approvals were for first-in-class drugs. The same percentage of drugs were approved for rare diseases, while 60% (29) were approved under expedited designations, 90% (43) after the first review cycle, and 69% (33) were approved first in the United States.

With so many first-in-class drugs being developed and approved each year, it is impossible to highlight all that have been improving patient lives even in the first two decades of the 21st century. Choosing drugs to spotlight from the last 10 years alone is difficult, though the following are worth mentioning:^13,14

• Monoclonal antibody denosumab (Prolia), approved by the FDA in 2010 for the treatment of osteoporosis in men and women; 
  
  
• Monoclonal antibody tofacitinib (Xeljanz), a Janus kinase (JAK) inhibitor, approved by the FDA in 2012 (and tofacitinib citrate in 2016) for the treatment of rheumatoid arthritis;
  
  
• Sodium–glucose cotransporter 2 inhibitor canagliflozin (Invokana), approved by the FDA in 2014 for treatment of patients with type 2 diabetes;
  
  
• PD-1/PD-L1 checkpoint immune inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) for the treatment of metastatic melanoma; 
  
  
• Monoclonal antibody dupilumab (Dupixent), an inhibitor of interleukin (IL)-4 and IL-3 signaling and cytokine-reduced responses, approved by the FDA in 2017 for the treatment of eczema (atopic dermatitis);
  
  
• Calcitonin gene–related peptide receptor agonist erenumab-aooe (Aimovig), approved as a new migraine treatment by the FDA in 2018; 
  
  
• Lofexidine (Lucemyra), the first non-opioid drug that dampens the withdrawal effects when detoxing from opioids, approved by the FDA in 2018; and
  
  
• Lefamulin (Xenleta), a new antibiotic that inhibits bacterial protein synthesis, approved by the FDA in 2019 for the treatment of community-acquired pneumonia.

Modern Molecules for Personalized Medicine 

The last two decades have also witnessed the strong emergence of personalized medicine. Cell and gene therapies and cancer immunotherapies designed to target specific populations with a particular genetic makeup have received approval. Autologous cell therapies produced by modifying and then growing cells isolated from patient samples — namely chimeric antigen receptor (CAR)-T cell therapies — represent the most extreme example. 

The release of the complete set of human genetic information to the public by the Human Genome Project in 2000 set the stage for new approaches to drug discovery and development.¹⁵ Rapid advances in digital technologies, such as artificial intelligence, machine learning, and natural language processing, are making it possible to accelerate the application of this new knowledge. New diagnostic tests allow the identification of specific genetic mutations and their correlations with diseases. 

Novel drugs, from gene and cell therapies to antibody–drug conjugates and other next-generation antibody-based treatments, are now developed to target patient populations with very specific genetic mutations and/or oncogenes, enabling more targeted treatment of cancer and other challenging diseases. Some companies have even developed digital tools for analyzing patient samples and suggesting tailored drug cocktails that, based on previous patient responses, should provide the best results for each individual. 

The first-ever approval for a gene therapy was granted by the Chinese Food and Drug Administration in 2003 for gendi-cine, a skin cancer treatment. This drug has not yet been approved in the United States, but the FDA has approved several others, including Emlygic (melanoma), Luxturna (a rare form of inherited blindness), and Zolgensma (spinal muscular atrophy). 

Kymriah (B cell lymphoblastic leukemia) and Yescarta (B cell lymphoma) were the first two CAR-T cell therapies approved in the United States (2017). Strimevelis is the first gene-modified stem cell therapy, but is only approved in the EU. It is designed to treat the rare disease severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID). 

Zalmoxis is a somatic cell therapy product containing genetically modified T cells designed to help restore a patient’s immune system after they have received a hematopoietic stem cell transplant as a treatment for blood cancer. Zynteglo is an autologous therapy using CS34+ cells encoding the ß^A-T87Q- globin gene for transfusion-dependent ß-thalassemia with conditional marketing authorization in Europe.

Oncorine for the treatment of patients with late-stage refractory nasopharyngeal cancer was approved in China in 2005, making it the first oncolytic viral therapy approved by any regulatory agency.

The FDA is processing approximately 800 cell-based or directly administered gene therapy INDs and expects to receive more than 200 gene and gene-modified cell therapy INDs per year beginning by 2020.¹⁷ As a result, the agency predicts that it will approve 10–20 cell and gene therapy products per year.

Recent and Future Top Sellers

So which of the drugs developed in the last couple of decades have had the most commercial success, and which might be at the top of the sales heap through this decade?

The top sellers between 2000 and 2011 were led by Lipitor (atorvastatin) at just over $121 billion and Plavix (clopidogrel) at nearly $75 billion.¹⁸ Rounding out the top ten were Advair (fluticasone/salmeterol), Zyprexa (olanzapine), Enbrel (etanercept), Nexium (esomeprazole), Singulair (montelukast), Seroquel (quetiapine fumarate), Lovenox (enoxaparin), and Humira (adalimumab), all with sales between $30 and $60 billion.

Many of these drugs also fall on the list of top-selling drugs of all time (from launch to 2018).¹⁹ Lipitor is on the top of that list as well at nearly $165 billion, followed by Humira ($137 billion), Rituxan (rituximab, $112 billion), Enbrel ($108 billion), and Epogen (epoetin alfa, $104 billion). 

In one analysis of sales going forward, total sales of Humira are projected to surpass those of Lipitor and Enbrel to move into third place ahead of Enbrel. Revlimid (lenalidomide) will take the fifth spot, followed by Epogen, Herceptin (trastuzumab), Avastin (bevacizumab), and Advair. In another evaluation looking at annual sales only, in 2025 Keytruda (pembrolizumab) was projected to hold the top spot, followed by Eliquis (apixaban), Revlimid, Opdivo (nivolumab), Imbruvica (ibrutinib), Humira, Biktarvy (bictegravir, emtricitabine and tenofovir alafenamide), Ibrance (palbociclib), Stelara (ustekinumab), and Trulicity (dulaglutide).

In a 2019 report, the IQVIA Institute identified the classes of most prescribed drugs to be those that treat nervous system disorders, bacterial infections, diabetes, respiratory diseases, ulcers, thyroid conditions, dermatologic issues, and attention deficit hyperactivity disorder.²¹ The fastest-growing classes included antihypertensives (angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, diuretics, and angiotensin receptor blockers), pain medications, mental health treatments, and lipid regulators.

Candidates Continue to Create Excitement

Access to new genetic information has only begun to open up the possibilities for innovative new medicines operating via previously unknown mechanisms of action. In addition to a rapid increase in approvals of new cell and gene therapies, other novel medicines, including RNA- and DNA-based therapies and treatments — both molecules and live therapeutics — derived from our increasing knowledge of the microbiome will provide novel methods for attacking a whole host of diseases.

In mid-2019, EvaluatePharma identified several pipeline candidates with the potential to become blockbuster medicines by 2024.²² Some have already received FDA approval. They include Vertex Pharmaceutical’s triple-combination drug comprising VX-445 (elexacaftor) with tezacaftor and ivacaftor for the treatment of cystic fibrosis, AbbVie’s upadacitinib for the treatment of rheumatoid arthritis, Daiichi Sankyo’s ADC DS-8201 (trastuzumab deruxtecan) for the treatment of HER+ breast cancer, Celgene’s (now part of Bristol-Myers Squibb, BMS) CAR-T therapy Liso-cel for the treatment of non-Hodgkin lymphoma, and Lilly’s diabetes drug LY3298176. 

Med Ad News, meanwhile, identified the top 10 companies that have pipelines with the most potential to be AbbVie, Alexion, Argenx, Bluebird Bio, Bristol-Myers Squibb/Celgene, FibroGen, Gilead, GlaxoSmithKline (GSK), Novartis, and Vertex Pharmaceuticals.²³ Interestingly, five of those ten companies are EvalautePharma’s top five candidates. In addition to its RA drug, AbbVie has promising endometriosis, cancer, and immunology drugs in development, as well as the possibility of extending the applications of some of its marketed drugs. Alexion is an expert in complement inhibitors and is developing candidates targeting hematology, nephrology, neurology, and metabolic disorders. 

Argenx develops antibody-based drugs designed for greater efficacy and longer duration of effect, including one autoimmune asset in clinical phase, two potential oncology medicines in the clinic, and several product leads undergoing preclinical development. Bluebird Bio develops gene therapies and T cell–based immunotherapies. The combination of Celgene and BMS has created a company with an extensive pipeline, including six phase III candidates in immunology and inflammation and hematology.

FibroGen develops first-in-class medicines for treating chronic and life-threatening or debilitating conditions, including anemia in chronic kidney disease (CKD), anemia in myelodysplastic syndromes (MDS), idiopathic pulmonary fibrosis (IPF), pancreatic cancer, and Duchenne muscular dystrophy (DMD). Gilead Sciences, with blockbuster therapies for hepatitis C and HIV and one of the first CAR-T cell therapies approved by the FDA, is expanding its focus from HIV, oncology, and hepatitis to also include inflammatory diseases and nonalcoholic steatohepatitis (NASH).

GSK recently expanded its oncology pipeline with the acquisition of Tesaro and is also developing novel HIV treatments. Novartis, according to the company, has 26 potential blockbusters in confirmatory development; 13 projects in clinical development across cell, gene, and radioligand therapies; and 60 major filings planned from 2019 to 2021 tackling diseases such as multiple sclerosis, neovascular age-related macular degeneration, and lung and other cancers. It also has one of the largest CAR-T cell development programs addressing multiple indications. In addition to developing medicines to treat cystic fibrosis, Vertex is also developing an autologous gene-edited hematopoietic stem cell therapy or the treatment of ß-thalassemia and sickle cell disease, small-molecule drugs for the treatment of the genetic disorder alpha-1 antitrypsin (AAT), and other precision medicines.

In its 2020 pipeline report, Credit Suisse identified top candidates in specific disease areas, including immunology (AstraZeneca’s anifrolumab, Boehringer Ingelheim’s spesolimab, and Corbus Pharmaceuticals’ lenabasum), neurology (Roche’s gantenerumab, Eisai/Biogen’s BAN2401, and Biogen’s gosuranemab), oncology (Roche/Assay Biopharma’s ipatasertib, Amgen’s AMG 701, and Daiichi Sankyo’s Trastuzunab deruxtecan), cardiovascular and metabolic diseases (Genfit’s elafibranor, Sanofi’s efpeglenatide, and Bayer/Merck’s vericiguat), blood disorders (CRISPR Therapeutics/Vertex Pharmaceuticals’ CTX001, UniQure’s AMT 061, and Otsuka/Akebia’s Vadadustat), and other indications (Merck’s V114 vaccine for pneumonia, Takeda’s vaccine TAK-003 for dengue, and Roche’s Balovaptan for autism).²⁴

Yet another 2020 pipeline report from OptumRx highlighted a different set of drugs, with bempedoic acid at the top of the list as representing a new class of cholesterol-lowering drugs.²⁵ Other candidates of interest identified in this report include the first oral immunotherapy drug for people with peanut allergy and obeticholic acid as the first treatment for NASH. Oncology represents the largest therapeutic class, with 44 drugs expected to receive approval. Other top drug classes included neurology, endocrine/metabolic disorders, infectious diseases, and musculoskeletal system/pain.

According to the 2020 pipeline report prepared by Pharmaceutical Executive, there are more than 3,300 cell and gene therapy clinical trials (phases II–ÌV) underway involving pluripotent stem cells (iPS), adeno-associated virus (AAV) gene therapies, and immune tolerance technology, among others that are targeting cancers, hemophilia, Huntington’s disease, sickle cell disease, amyotrophic lateral sclerosis (ALS), and other indications.²⁶ The candidates in development are designed to target a wide range of proteins. 

Many therapies are also being developed using CRISPR (clustered regularly interspaced short palindromic repeats) and other gene-editing tools that offer increased efficiency over the use of vectors for inserting genetic material.²⁶ Pharma companies active in this field include Novartis, AstraZeneca, Cancer Genetics, Genentech, Boehringer Ingelheim, Epizyme, Takeda, Locus Biosciences, Janssen, CRISPR Therapeutics, Vertex Pharmaceuticals, and several others. 

There is also a resurgence of interest in the discovery of new medications to treat and/or prevent cardiovascular disease. Hypertension, congestive heart failure, and atherosclerosis are the most researched conditions in preclinical phases by big pharma companies such as Bayer, Pfizer, Sanofi, Daiichi Sankyo, Roche, Novartis, and others, as well as specialty players such as Alnylam Pharmaceuticals.²⁶

Non-opioid pain treatment is another growing area. Companies such as Pfizer, Sanofi, Novartis, and Takeda are leading the way, but others, including Teva, Regeneron Pharmaceuticals, Nektar Therapeutics, and Heron Therapeutics, as well as many other smaller firms, are also developing candidates that show promise.²⁶ 

References

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16. “Gene Therapy Products on the Market.” Gene Therapy Net. n.d. Web. 

17. “Statement from FDA Commissioner Scott Gottlieb. M.D. and Peter Marks. M.D. Ph.D., Director of the Center for Biologics Evaluation and Research, on new policies to advance development of safe and effective cell and gene therapies.” U.S. FDA. 15 Jan. 2019. Web. 

18. Philippidis, Alex. “Top 10 Best-Selling Drugs of the 21st Century.” Gen. Eng. News. 6 Nov. 2012. Web. 

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