Introduction
It is easy to lose sight of the patient with all the distractions in the pharmaceutical industry—including meetings, committees, policies, inspections, career paths, timelines, and budgets. However, focusing on the patient is not only a noble goal, but an excellent business strategy. My career in health care started late in the last century as an after-school job in a retail pharmacy. Much to my dismay, the pharmacy did not sell candy bars, magazines, soda, or hair care products. It was a professional pharmacy located in a small medical center at the foot of a major university campus. The medical center was founded by a savvy and flamboyant general practitioner. The center contained the offices of several specialists, a blood chemistry lab, and a radiology lab in addition to the general practice. The latest and greatest new medicines were detailed by company sales representatives, and professors visited regularly to discuss medicine, chemistry, pharmacy, and biology. The pharmacy became the hub for discussions about case studies and treatment with vital impact to their patients. The pharmacy provided patients with everything from adhesive bandages and witch hazel to complex medical devices and cutting-edge new medicines. The pharmacy could compound products not commercially available to meet the specific needs of the patients, and this was particularly important for pediatric, geriatric, and hospitalized patients.
My roles and responsibilities grew with time. Initially I was a maintenance engineer in charge of vacuuming, replacing light bulbs, and shoveling the walkway in the winter. I added logistics and supply chain to my responsibilities by signing for incoming packages, verifying the contents, and unpacking and shelving the myriad of products. The cold-chain was also my responsibility, and I promptly put the insulin products into the freezer (bovine and porcine) and the β-lactams into the refrigerator. Drug delivery meant driving in an old Rambler American to bring prescriptions to patients who couldn’t travel. The most memorable part of the job was meeting patients and watching their recovery with a snapshot of the progress every 30 days. Although much has changed, including my transition into the pharmaceutical industry, focusing on patients is still the most important aspect of health care, and the team of dedicated professionals is just as critical.
Building Safe and Efficacious New Drugs
The team approach is more important than ever to the discovery and development of new therapies. Dedicated teams of biologists, chemists, statisticians, medical doctors, toxicologists, engineers, and pharmaceutical professionals must find new targets, develop model compounds, validate the targets, and refine the molecules to engineer in safety and pharmacokinetics. Ultimately, the goal is to bring these molecules to patients in convenient products that deliver precise doses of life-saving medicine time after time. The team passes the lead from one expert to another as the molecules progress toward commercialization. The team takes calculated risks, responds quickly to data, and is persistent in the face of setbacks, while doing so without arrogance or cavalier abandon. These teams work tirelessly not only in their own laboratories, but in collaboration with academic experts, CMOs/CROs, government health authorities, patient advocacy groups, venture capitalists, and industrial partners. The collaborations must cross international boarders and cultural divides. They must recognize both tried and true experience as well as groundbreaking new ideas. The tool box used by teams to meet patient needs has improved greatly since the last century. Some of the advances used to bring new therapies to patients are highlighted here.
Biotechnology, Monoclonal Antibodies, and Antibody Drug Conjugates
The biotechnology industry is now ~40 years old and has led a revolution in medicine. Before genetic engineering, biologic drugs were isolated from animal tissues and included simple animal proteins such as insulin and growth hormone. Variability of purity and potency was high, and the supply chain was difficult to control, with limited availability. Human proteins were generally out of the question with the exception of IGgs as prophylactic therapies from previously exposed donors and certain blood factors useful in treating hemophilia.
The therapeutic protein revolution began with human insulin, human growth hormone, and human tissue plasminogen activator. These proteins were produced by engineering cell lines such as E. coli bacteria and Chinese hamster ovary (CHO) cells. Engineering involved using bacterial plasmids to vector copies of DNA needed to code for therapeutic protein into the host cell’s genetic code. The cell line was propagated and grown to express these proteins (upstream process) which were purified (downstream process) and formulated. The number of therapeutic proteins increased rapidly.
The introduction of genetically engineered monoclonal antibodies opened up a seemingly limitless number of antigen targets, and the new technologies produce “human” monoclonal antibodies (Mabs) with much safer immunogenicity profiles. Some of the Mab targets where highly efficacious therapies have been developed include VEGF (cancer and macular degradation), Her2 (breast cancer), and IL6 (rheumatoid arthritis). Where more knockdown power is needed to kill cancer cells, high-potency small-molecule drugs can be chemically linked (conjugated) to a Mab to produce an antibody drug conjugate (ADC). These ADCs are a near-perfect delivery system that target only cells with high antigen level for certain destruction by the highly potent oncology drugs. In this type of therapy, healthy cells are spared the toxicity of these high-potency drugs. These ADC products are now making their way to patients both in clinical development and as commercial products.
Small-Molecule Design and Drug Delivery
Discovering new small-molecule drugs had traditionally relied on molecules found in nature, library screening, and serendipity. Characterization of cell membrane receptors and signaling proteins followed by modeling are now the first steps in translational medicine. In translational medicine, the impact of gene mutations in disease can be followed through to the changes in expressed protein, and drugs can be built with high affinity for these mutant proteins. Attacking protein active sites in multiple ways and attacking allosteric sites can lead to a range of new drugs. For oncology, having multiple points of attack can help to continue treating the disease as cells try to escape from first-line therapies. The advances in research biology and protein crystallography combined with powerful new modeling techniques have given medicinal chemists a way to build activity, selectivity, and safety into their new small-molecule drugs. By using these models, drug–protein interactions are optimized and a series of unique structural motifs can rapidly be conceived. Often a tool compound or a biological substrate can be used as a starting place. The model can be refined as more compounds are synthesized and studied. Models can be used to minimize toxicity, optimize pharmacokinetics, and dial blood–brain permeability in or out. Developability criteria such as solubility, logP, molecular weight, polarity, and stability are now routinely considered during the design of new drugs.
The ability to bring this wide range of new drugs to patients has advanced significantly in the last several years. Administering high doses of oral medicine multiple times per day is no longer well accepted to patients due to the xenobiotic burden, difficulty in compliance, and pulsatile pharmacokinetic profiles. Improving bioavailable and fixing poor pharmacokinetic profiles is now commonplace in the pharmaceutical industry. Characterizing drug substance using the Biopharmaceutical Classification System (BCS) to understand solubility and permeability was a major step forward to make drug delivery more systematic. Pharmaceutical technologies such as spray-dried amorphous dispersions, hot-melt extrusion, creative use of functional excipients, and liquid-filled capsules are making poorly bioavailable drugs more bioavailable. Tailoring pharmacokinetic profiles is now commonplace, with ultra-fast drug delivery products such as orally disintegrable tablets and longacting products such as bilayer tablets, osmotic pump products, and sophisticated time-release coating systems. The improved pharmacokinetic profiles minimize side effects by lowering Cmax while maximizing efficacy by keeping blood levels above critical therapeutic levels. These approaches have been of major benefit to patients, especially for CNS, oncology, HIV, and antifungal therapies.
Personalized Medicine
Diagnosing disease has always relied on skilled medical practitioners and examinations. The medical community has collectively refined and taught this skill over many years. Physicians strive to prescribe the best medicine available for their patients. Diagnostic tools available to the practitioner have advanced rapidly from simple X-rays and blood chemistry to include sophisticated tests for genetic mutations, biomarkers, and soft tissue imaging. Diseases that present with similar symptoms can have very different etiology. Better diagnostics help physicians treat disease more appropriately with less medicine switching. The physician can prescribe therapies personalized for a specific patient with great benefit. For example, prescribing a Her2-specific Mab for Her2 overexpressing positive breast cancer patients is extremely beneficial. Prescribing the same Her2-specific Mab for Her2 negative patients is not beneficial and exposes these patients to unnecessary risks in addition to potential delays in treatment with more appropriate therapies. Development of new drugs is now often accompanied by development of biomarkers during the preclinical phase, clinical phase, and commercialization. Not only does this lead to more statistically significant clinical trials, but physicians can create highly personalized therapies for their patients. Personalized medicine is widely practiced in oncology where gene mutations and pathways are well elucidated. The concept is rapidly expanding to other areas such as rheumatology and neurology.
Author Biography
Dr. Larry Wigman is an Analytical Chemist by training with his doctorate from Duke University, under the direction of the late Charles Lochmuller. Larry has held various positions including: Senior Research Scientist at Pfizer, Manager at Mylan, Associate Director at Sanofi, Principal Consultant at Regulitics LLC, and, most recently Senior Scientific Manager of the Small Molecule Analytical Chemistry and Quality Control Group at Genentech.