Biologics: The Third Age of Pharmaceutical Development
Some of these complex creations can be derived from elementary sources.
By Whitney Hauser, OD
The history of pharmaceuticals dates back to the ancient world when humans sought the basics: food, water, shelter, and herbs to manage ailments. The Ebers Papyrus, dating to approximately 1550 BC, lists some 800 prescriptions outlined in hieroglyphics. Physicians in India compiled an anthology of Ayurvedic medications developed from plants, herbs, and essential oils around 900 BC. Like modern man, ancient man was in search of relief from pain.1
Modern drug development can be divided into three periods. The first period, in the 19th century, was one of accidental discovery of medications by chemists. The second, in the early 20th century, introduced antibiotics. The proliferation of drugs was driven in part by advances in drug design and in part by manufacturing techniques. We are in the midst of the third stage, which is led by the evolution of biopharmaceuticals, or biologics.2
Biologics are medical products that are created from biologic origins. They are either created completely from biologic sources or partially synthesized from them.3 By contrast, traditional pharmaceuticals are derived from small molecule petrochemicals combined in specific orders. Chemically derived pharmaceuticals can be analyzed to determine their components. Biologics, however, are macromolecules engineered within a living system such as a plant or animal cell and are so complex that some of their building blocks may remain unknown.4
In fact, biopharmaceuticals are not necessarily one molecule, but rather a combination of different ones. The proportion of each molecule is crucial to achieve the activity outcome desired. They are often derived from proteins but can originate from carbohydrates, peptides, lipids, nucleic acids, cells walls, or complete cells.5 Typically, a sequence of DNA is selected and modified, creating recombinant DNA, then reinserted into a cell for expression.
While biologics have garnered attention in the media recently, they are hardly a new phenomenon. Insulin, human growth hormone, and erythropoietin stimulating agents all fall into the category of biologics and have been widely used for decades. Innovative biologics may offer therapeutic benefits for diseases such as anemia, hemophilia, cystic fibrosis, hepatitis, and diabetes. They may also represent predictive indicators for Parkinson disease and can have nondrug uses such as immune suppression for use in transplantation and growth stimulation for tissue development.5
METICULOUS PRODUCTION, HIGH PRICE TAGS
The manufacturing process is crucial for biologics. The delicate living components of this drug class require meticulous processing, storage, and testing. The key building blocks of biologics are often macroproteins that are remodeled from a primary protein. The products are inconstant and may have differences in glycosylation or folding patterns. Contamination is a chief concern in the production process. Due to the multifarious nature of the components, the impurity profile is specific to each production. Biologic drugs are not homogeneous in nature, but rather must be characterized and function as a molecular group. Exceptional production quality is required. Forty to 50 tests are performed in the manufacturing of chemically derived drugs, whereas biologics require more than 250.6
Biologic drugs come with a hefty price tag. Formulations may cost upward of $50,000 for 1 year of administration. Unfortunately, no generics are available for these medications. In fact, the term generic can be applied only to conventionally manufactured small-molecule drugs. The term used with biosimilar medications are drugs with relatively similar structure and may offer an equivalent treatment option to their biologic brethren. Biosimilars are being researched around the world, however, none are currently available in the United States for consumer use.7
INFLAMMATION IN DED
Dry eye disease (DED) affects more than 9 million Americans and is among the most common reasons that patients seek care from eye care providers. DED may result in a decrease in the quantity and quality of vision. These changes are often accompanied by a decline in activities of daily living, work productivity, and quality of life. An estimated $55 billion is spent on DED care annually in the United States. The socioeconomic burden is both direct (eg, the costs of medications and examinations) and indirect (eg, absenteeism and decreased productivity).8,9
DED is a multifactorial condition that varies in presentation and whose pathogenic origins are not completely understood. Medications, hormonal changes, environmental conditions, systemic disease, and eyelid mechanics can each play a role individually or in concert. In addition to these triggers, DED is associated with remarkable overexpression of inflammatory cytokines, including interleukin 1 (IL-1). Topical and oral medications have been successfully used to modulate the presence of inflammation, but not without potential deleterious effects. Reduction of IL-1 and elevation of IL-1 receptor antagonist (IL-1RA) on the ocular surface reduce inflammation. Topical IL-1RA treatment has been successful in animal models of corneal transplant and trauma, DED, and allergic conjunctivitis.8
Inflammation secondary to DED is also mediated by lymphocytic activity. Stimulation of the lacrimal gland initiated by dryness triggers the production of cytokines, which leads to activation of T-cells, which in turn secrete more inflammatory cytokines and cause further T-cell activation.10 Patients with and without Sjögren syndrome have been shown to manifest similar conjunctival inflammation and associated infiltration.11 The impaired function of the lacrimal gland produces inadequate tear composition, which leads to diminished comfort and inflammation.
Many biologic drugs are complex creations, but biologics may also be derived from more elementary sources. According to one definition, a biological product can be a “virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, … applicable to the prevention, treatment, or cure of a disease or condition of human beings.”9 Blood-derived products such as autologous serum eye drops are considered a biologic preparation.9
Autologous peripheral blood serum (PBS) contains the same essential components as natural tears, in similar proportions. First described in 1975, autologous serum eye drops are produced by separating the cellular and liquid components of blood by centrifuge. The serum is combined with saline or another vehicle. The product is then filtered and sterilized to complete the preparation. The autologous tears are placed into dropper bottles coated with an ultraviolet-light protector and maybe instilled up to eight times a day.10
These tears are nutrient-rich, in contrast to artificial lubricants. Serum tears contain essential growth factor, fibronectin, transforming growth factor beta and other biologically active components that promote healing. Delayed onset of treatment with autologous serum may lead to poorer healing than prompt treatment.14 Use of autologous serum alone can help maintain the integrity of the cornea in the absence of natural tears.12 Corneal epithelial cells maintain integrity better in the presence of serum tears than in hydroxypropyl methylcellulose.13
Similar to PBS preparations, umbilical cord blood (UCB) also contains high levels of essential growth factors, fibronectin, vitamins, and other nutrients. UCB contains mesenchymal stem cells that can promote regeneration of corneal tissue. UCB may have beneficial effects in patients with severe dry eye disease, neurotrophic keratopathy, corneal trauma, and other causes of epithelial defects.15 UCB preparations contain even higher concentrations of nutrients and essential tear components than PBS. Both essential growth factor and transforming growth factor beta are found in significantly higher concentrations in UCB than PBS, although vitamin A concentration is lower.
Harvesting blood from the umbilical vein for this purpose is advantageous because a larger volume can be procured in comparison to PBS draws. Additionally, UCB derived from donor blood can benefit patients with blood dyscrasia or hematologic malignancy who would be unable to use an autologous preparation.15
RHEUMATOID ARTHRITIS DRUG PROMISING IN DED
Anakinra (Kineret; Amgen) is a recombinant IL-1RA biologic drug that has been approved by the US Food and Drug Administration for the treatment of moderate to severe rheumatoid arthritis in adults who have not responded to one or more disease-modifying antirheumatic drugs.15 It competitively inhibits the interaction of IL-alpha and IL-beta. The drug may be used alone or in concert with disease-modifying antirheumatic drugs. Off-label uses include cryopyrin-associated periodic syndromes, gout, juvenile idiopathic arthritis, adult-onset Stills disease, and periodic febrile syndromes.17
Amparo et al hypothesized that inhibition of the IL-mediated inflammatory response would decrease inflammation due to DED secondary to meibomian gland dysfunction.18 They performed a prospective, randomized clinical trial to evaluate the safety and efficacy of topical application of anakinra in patients with evaporative DED. Seventy-five participants with DED complaints and corneal or conjunctival staining were enrolled for a 12-week period. Patients were randomly assigned to receive the vehicle alone (1% carboxymethyl cellulose [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][Refresh Liquigel]; Allergan), 2.5% anakinra, or 5% anakinra at a 2:2:1 ratio. Patients were instructed to instill the drop three times daily. No use of cyclosporine or corticosteroids within 2 weeks of enrollment was allowed. However, other palliative therapies such as warm compresses, digital massage, and artificial tears were acceptable.18
Corneal fluorescein staining and patient symptoms were measured at weekly intervals. By week 6 there was a 30% decrease in staining in the 2.5% anakinra arm. The 5% and vehicle alone groups experienced 29% and 15% decreases, respectively. At 12 weeks, the 2.5% anakinra group peaked, with a 46% decrease in staining. The improvement in staining in the 5% anakinra and vehicle alone arms declined to 17% and 5%, respectively, at 12 weeks.
Patient symptoms as measured by the Ocular Surface Disease Index also showed significant improvement. Symptom relief was noted as early as week 2, and the difference in treated eyes compared with vehicle-treated eyes attained statistical significance at week 6. Patients in the 2.5% anakinra group reported a 30% decrease in symptoms, and those in the 5% anakinra group reported a 35% decrease. The group assigned to vehicle only reported a 5% decrease in symptoms.18
Additional primary and secondary endpoints were recorded throughout the study. Tear breakup time increased in all three groups but showed no notable differences between groups. Subjective improvement in meibomian gland secretion quality was noted by week 12 in all arms. No significant changes were seen in Schirmer testing results. Visual acuity improved in both the anakinra groups but decreased in the vehicle group. A statistically significant decrease in the frequency of artificial tear instillation was reported in both anakinra groups.18
Researchers are working on the development of more than 900 innovative biologic medications.19 It is to be hoped that these cutting-edge treatments will offer relief to patients with a variety of illnesses, who have not found it to date with more conventional therapies. Ideally, patients with DED will be among those who benefit. n
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13. Young AL, Cheng A, Ng H, et al. The use of autologous serum tears in persistent corneal epithelial defects. Eye. 2004;18:609-614. doi:10.1038/sj.eye.6700721.
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15. Yoon K. Use of umbilical cord serum in ophthalmology. Chonnam Med J. 2014 Dec; 50(3):82-85.
16. RheumatoidArthritis.net . http://rheumatoidarthritis.net/. Accessed April 27, 2015.
17. Position Statement. January 1, 2012. http://www.rheumatology.org . Accessed April 27, 2015.
18. Amparo F, Mohammad D, Okanobo A, et al. Topical interleukin 1 receptor antagonist for treatment of dry eye disease: a randomized clinical trial. JAMA Ophthalmol. 2013;131(6):715-723.
19. America’s Biopharmaceutical Research Companies. Medicines in Development: Biologics. 2013 report. http://www.phrma.org/sites/default/files/pdf/biologicsoverview2013.pdf. Accessed April 25, 2015.
- Clinical development consultant, TearWell Advanced Dry Eye Treatment Center
- Founder, Signal Ophthalmic Consulting
- Assistant professor at Southern College of Optometry, Memphis
- (901) 229-2137; firstname.lastname@example.org
- Financial disclosure: None acknowledged
Whitney Hauser, OD
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