alfa is produced using CHO cells.24
CHO cells are used to make nearly 70% of recombinant protein therapeutics today. The first product manufactured using CHO cells was a plasminogen activator called Activase® (r‐tPA) in 1987. Rationale for the popularity of CHO cells in biopharmaceutical endeavors include accommodating complex protein folding and post‐translational modifications (shaping a protein after it has been made to a desirable structure), adaptive ability to study G‐protein coupled receptors in a stable environment, and structural characteristics related to cytoskeletal and microtubule structure, adhesion, and motility. Furthermore, there are logistical benefits to using CHO for protein synthesis; the cells can grow to very high densities in bioreactors, which benefits scalability and CHO cells have been found not to replicate human viruses such as HIV, influenza, polio, herpes, or measles.26
3.4 What Does the Future Hold?
3.4.1 Gene Therapy
How genes are identified, isolated, modified, and produced on a large scale using bacteria or CHO cells to generate the desired protein, whether it be, insulin, mAbs, TNF‐inhibitors, or others has been described in this chapter so far. Following the production of the therapeutic protein in a manufacturing facility, it is purified through a complex process, and formulated into a form that makes it stable for storage and shipment to the pharmacy, hospital, or clinic where it will be delivered or administered. Finally, the therapeutic protein (biopharmaceutical) is administered by an injection either by a medical professional or by the patient.
The latest breakthroughs in biotechnology research and development (R&D) have been in gene therapies. The initial stages of gene therapy development still require identifying a target gene that is clinically important. There are various ways that gene therapy can be used therapeutically. For example, a patient may be missing a gene that codes for a life‐sustaining enzyme, in which case the goal is to introduce that missing gene into the patient, or a patient may have a defective gene that requires modification to restore its normal function. What is unique to gene therapy versus the majority of biological medicines to date is that with gene therapy, the gene is introduced into the patient and the patient makes the protein; the protein is not produced in bacteria or in CHO cells, but rather in the patient.
Like the plasmid vectors described previously for manufacturing biologic drugs like insulin, gene therapies typically require a vector to be successfully administered to a human patient. Viral vectors are the most commonly used vectors in gene therapy representing nearly 70% of clinical trials.27 Viruses make good vectors due to their natural ability to infect cells. For clinical use, the viruses are modified to avoid causing disease when given to patients. Some viruses, such as retrovirus can incorporate the genetic material into a human cell and chromosome, whereas adenoviruses introduce their DNA into the cell, but the DNA does not get integrated into the chromosome. There exists a broad spectrum of viral vectors for delivering gene therapies and their choice can be influenced by factors such as how much expression is desired and for how long.27
3.4.2 Personalized Medicine
Gene therapies are another milestone in the progression from one‐size‐fits‐all medicine to personalized medicine. Much of this progress has been made in oncology where molecular diagnostics are part of the drug development process and predictive biomarkers are used to guide treatment. By 2018, there were 21 different drugs that had been approved alongside companion diagnostics by the USFDA with testing requirements as part of their labeled approval. Of the drugs with required companion diagnostic tests, nearly half are for treatments of non‐small cell lung cancers (NSCLC).28
In 2004, epidermal growth factor receptor (EGFR) mutations were identified to have predictive potential. In subsequent years, ALK and ROS mutations would also be identified to further direct cancer treatment based on the types of mutations present in the lung tumors.29 A decade later, Opdivo® (nivolumab) and Keytruda® (pembrolizumab) were the first programmed death 1 (PD‐1) and programed death‐ligand 1 (PD‐L1) inhibitors approved. PD‐1 is a checkpoint protein found on T cells and these drugs cause the patient's immune system to attack cancer. Both these drugs are IgG humanized, mAbs that work by binding to the PD‐1 receptor and blocking its interaction with PD‐L1 and PD‐L2 ligands; blocking PD‐1 activity has resulted in decreased tumor growth in clinical trials. There are multiple drugs currently marketed for inhibiting the PD‐1 system, and most have companion diagnostics that look for PD‐L1 ligand expression to direct use. Additionally, patients with certain cancers are tested for other tumor mutations, which may indicate that a different drug should be tried first before a PD‐1 inhibitor. For example, the FDA‐labeled indication as a single agent for metastatic NSCLC for Keytruda® includes the following:
KEYTRUDA®, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD‐L1 (TPS ≥ 1%) as determined by an FDA‐approved test, with disease progression on or after platinum‐containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA‐approved therapy for these aberrations prior to receiving KEYTRUDA®.30
As this labeling indicates, patients are directed to use an FDA‐approved test to determine their PD‐L1 expression. If they have EGFR or ALK mutations, they are to try other targeted therapies first (e.g. drugs to treat EGFR or ALK mutations) before using Keytruda®, which targets PD‐L1. These types of treatment pathways are becoming synonymous with precision medicine and the impact to the healthcare system is significant. Reimbursement groups welcome the ability to better predict that the medicines being paid for will work, and clinicians and patients welcome the potential for improved health outcomes based on more specific science. Precision medicine, however, will not progress into the future without challenges. The remainder of this chapter will focus on clinical and market‐related challenges with biologic drugs in precision medicine.
3.5 Global Biologics Market
According to the USFDA, biologic products are the fastest growing class of therapeutic products in the United States and make up an increasing and substantial share of health care costs.31 In the past five years, there has been an increase in drug approvals and spending on new drugs globally. The types of drugs being approved are also changing. New drug approvals continue to trend toward biologic, orphan, and oncology products32:
Oncology will make up 30% of new drug approvals.
Orphan drugs could represent 45% of new drug approvals.
Orphan disease is a term used to describe rare diseases. The definitions vary by country, with some using prevalence rates and others basing the definition on the number of affected individuals. The United States defines a disease as rare when it affects fewer than 200 000 individuals. Europe defines a rare disease as one that affects fewer than 5 individuals per 10 000, whereas Taiwan's definition is fewer than 1 in 10 000. Brazil is in line with the World Health Organization's definition where a disease is considered rare when it affects less than 65 per 100 000 individuals. There are an estimated 5000–8000 rare diseases identified globally, and while individually they are rare, collectively they may impact 6–8% of the population.33
As the number of orphan drugs being approved continues to increase, and the use of biomarkers and precision medicine‐driven principles continue to gain traction, it is expected that the number of patients treated per new drug will go down, and the price per treatment will go up. Theoretically, a drug that costs $1 million per treatment and treats one person with a rare disease would generate the same return as a drug that costs $1 and treats one million people with a more common disease.
