Digestive Disease Week(DDW) is one of the world’s largest conferences, covering a wide array of basic and clinical research topics in the fields of Inflammatory Bowel Diseases (IBD), cancer, and liver diseases. At this conference, several companies showcased their GI products, technology, and services for these fields. While there was a lot covered at the conference, below is my summary of the data presented druing the DDW 2018 conference.
The principal topic discussed at Digestive Disease Week was IBD. Inflammatory Bowel Disease (IBD) is a collective term used to describe disorders that include chronic inflammation of the digestive tract caused by defective immune signaling. The primary IBD disorders are ulcerative colitis and Crohn’s disease. Ulcerative colitis (UC) causes an inflammation in the inner lining of the colon, while Crohns disease (CD) causes inflammation of the lining of the digestive tract.
In most cases, surface injuries or impaired cells within the gut allow bacteria to infiltrate and trigger an immune response leading to the activation and release of pro-inflammatory cytokines, resulting in further damage and significant complications typical of IBD. There are different classes of drugs that treat IBD, such as aminosalicylates, corticosteroids, immunomodulators, antibiotics, and biologics (e.g., antibodies). From the list, biologics are the best suited for use in treatment to induce and maintain remission of mild to severe IBD.
For nearly 20 years, biologics have become a cornerstone in the treatment of IBD by revolutionizing the therapeutic approach. Currently, IBD affects millions of people worldwide, with an estimated global drug market of $8.5bn in 2016, expanding to $9.5bn in 2020. In 2016 biologic therapeutics account for 68% ($5.8bn) of the global IBD market. Biologic products can significantly reduce inflammation by targeting specific cytokines that play a critical role in causing the inflammation.
Antibodies comprise the majority of biologics used to treat IBD and are classified into two categories by their target. The first-class of antibodies specifically target tumor necrosis factor alpha (TNF-alpha) and such products commercially available include adalimumab, certolizumab pegol, golimumab, infliximab. The second class of antibodies include natalizumab and vedolizumab, which target and block integrins.
Taking biologic therapeutics can significantly reduce the risk of developing complications related to IBD given their specificity and longer half-life. Therefore, it’s not surprising that several posters and oral presentations given during Digestive Disease Week related to IBD treatment using biologic therapeutic products.
Over the past years, the patents of some of the multi-billion-dollar global blockbuster biologics have expired, and several companies have invested in developing biosimilars for IBD treatment. A Biosimilar is a biologic product which is approved by demonstrating that it is highly similar (not exactly the same) to an FDA approved biologic therapeutic known as the originator. Biosimilar products are expected to have no clinically meaningful difference when compared with the originator regarding its safety and efficacy.
As of Digestive Disease Week, the FDA approved eleven biosimilars, five of which are for the treatment of IBD including: Inflectra (infliximab-dyyb), Renflexis (infliximab-abda), IXIFI™ (INFLIXIMAB-QBTX), AMJEVITA (adalimumab-atto) and CyltezoTM (adalimumab-adbm). These recent approvals and the development of biosimilars were discussed a lot at the conference, especially in regards to the significance of analytical characterization in developing a biosimilar.
Unlike small molecule drugs in which structurally identical copies can be produced, developing a biosimilar is far more complex and challenging. Biologics are inherently a mixture of different posttranslational modifications (PTMs) such as glycosylation, deamidation, oxidation, and phosphorylation. Even minor changes in the manufacturing process can result in altered protein stability and PTMs which ultimately affect the quality attribute of the products. For instance, a change in glycan composition due to a change in the manufacturing process or a specific cell-line clone can alter the pharmacokinetic/pharmacodynamic profile, efficacy, and trigger immunogenicity.
The cell-line and manufacturing process for biosimilars was also highlighted during these discussions at DDW. Because the originator’s process is proprietary information and not accessible for the biosimilar sponsor, they must develop a new cell-line clone and consistent manufacturing process using only quality attributes of the originator as a reference. Also, the manufacturer has to develop an acceptable range of product variation and set a tight control over the critical quality attributes of the product. Overall, due to the complex nature of developing biosimilars, the cost and time invested is much higher than developing a generic small molecule.
However, one of the major advantages of developing a biosimilar compared to a new biologic product is a reduced clinical package can be achieved if a higher degree of similarity is demonstrated in pre-clinical studies. In some cases, a biosimilar can be approved for the indications that were not evaluated during clinical trials. This concept is called indication extrapolation, and can eliminate or reduce the need to conduct a clinical trial for other indications of the reference product.
It was clear at Digestive Disease Week that the future for biosimilars is bright. The looming expiration of patents, less costly bioreactors, improved production yield, and regulatory initiatives will continue to be key factors in driving the future of biosimilar development.
Current IBD treatments administer antibodies through injection/IV. However, this method can potentially alter the immune system and consequently reduce the patient’s ability to fight infection or worsen the existing infection. Plus, this injection/IV method has other side effects including allergy response, and in some cases, resistance to treatment.
At the conference, antibody therapies that provide a localized and direct effect to the influenced site without systemic exposure were presented as an alternative form of treatment for IBD. Designed to target specific reactive cytokines (e.g., TNF-Alpha) and pro-inflammatory bacterial agents in the gut, this type of treatment is highly desirable. One example presented at Digestive Disease Week was a product from an Israeli company called Protalix.. The company presented data for a clinical phase product code-named OPRX-106, an oral TNF receptor-Fc fusion protein for the treatment of IBD that is made in plant cells rather than using traditional methods of biologic manufacting with mammalian cells. The benefit of this product would be the convenience of oral delivery and the potential for improved safety due to less systemic exposure to the drug. Logically, a reduced systemic exposure of biologic therapy would do less harm to the patient’s immune system. Positive results from phase II clinical trial of OPRX-106 for the treatment of ulcerative colitis were presented at DDW.
Overall, the oral administration of antibodies for IBD is expected to minimize systemic exposure and alteration of the immune system, reduce the risk of allergic response, and increase patient convenience and compliance. However, the oral administration of antibodies is changing due to the presence of proteolytic enzymes in the gastrointestinal tract that degrade and compromise the activity. Also dosing can be increased with oral delivery, suggesting that a more advanced biologic manufacturing technology would be required for affordable therapy.
To address the proteolytic degradation of biologics, a novel formulation and delivery approach should be developed. Ventria Bioscience is currently working on developing biologic products for the treatment of IBD to address the unmet needs of patients by using a novel scientific approach and cutting-edge technologies including the use of recombinant proteins from colostrum to modulate the immune system through orally delivered biologics. New approaches to biologic manufacturing are needed in order to expand the therapeutic benefit to global health markets. Currently, many approaches are underway, including the use of large-scale manufacturing like ExpressTec.
This year DDW was full of exciting innovations for patients, physicians and the gastrointestinal health community. We were glad to participate.
Solomon Okbazghi, Ph.D is a formulation scientist at Ventria Bioscience Inc.
Ventria Bioscience Inc. is a biopharmaceutical company with a product pipeline targeting unmet medical needs. Ventria Bioscience’s proprietary ExpressTec biomanufacturing technology enables the development of new, safe and effective biologic products to treat gastrointestinal, autoimmune and infectious disease.
For more information, visit www.Ventria.com.