Tony Hagen is senior managing editor for The Center for Biosimilars®.
Oral biologics would offer many advantages over injectable drugs, and some companies believe they are on the cusp of making this happen.
The holy grail of an oral biologic has inspired many pharmaceutical companies to enter the race. Among biosimilar makers, the most recent of these was Celltrion, which partnered with Intract Pharma to incorporate its pill technology into an infliximab treatment that would avoid the need for injections.
There are various companies like Intract that have worked to circumvent the powerful digestive and body protection systems in the digestive system so that medicine can be delivered through the lower intestine, where if successful, the therapeutic effect may be more direct and more effective.
The Incheon, Republic of Korea–based Celltrion contends that its oral formulation of infliximab would be the first of its kind. But before that, Celltrion and Intract, a United Kingdom–based company, have to prove that the technology works.
Intract’s pill technology uses a shell covered with a coating that resists breakdown as it passes through the large and small intestines, only releasing the medication in the colon. The company is licensing the product to interested parties. Within the spectrum of inflammatory bowel disease (IBD), Intract is moving forward with oral infliximab formulations that would treat ulcerative colitis and Crohn disease.
Intract anticipates a phase 1b trial in ulcerative colitis to initiate in the second half of 2021 and a phase 2 trial for the Crohn disease pill formulation in the first half of 2022. Whereas injectible versions of infliximab need to be refrigerated, Intract Pharma says its oral version would be stable and storable at room temperature, making it possible for patients to self-administer from their homes.
“We anticipate that the oral infliximab product, which we will co-develop with Celltrion Group, will have an improved safety profile and will offer a less expensive biotherapeutic treatment for IBD,” said Bill Lindsay, CEO of Intract. "We are hopeful that the product will address a large proportion of the IBD market, potentially replacing steroid and immune-suppressive drugs in addition to capturing a large share of the biologics market."
Multiple technologies are under development for the oral delivery of biologics. A review by the Pharmaceutical Journal in January described the formidable obstacles to this achievement. As large and complex molecules, biologics are “extremely sensitive to the physical and chemical conditions of the gastrointestinal environment,” which is why they have been restricted to delivery via injection so far, the article explained.
However, the growing market for biologics and the perceived value of oral biologics have given impetus to the development of oral formulations. In the case of insulin, delivery through the digestive system would most closely resemble the natural provision of insulin secreted via the pancreas. It would also obviate the need for needles and bring down the overall costs of care.
Various methods for making oral biologics work include pills are embedded with medicine-containing microneedles that become exposed as the pills are digested. These embed themselves in the lining of the intestine and enable the drug to penetrate the mucosal and epithelial walls. Alternative methods under study include attaching the biotherapeutic to a molecule enabled with a receptor that grants it passage through the intestinal epithelium. These transport-enabling molecules include peptides and proteins.
Rani Therapeutics, based in San Jose, California, has a micro-needle approach that it has touted as a way for biosimilar companies to diversify their products from originator biologics and achieve market share gains. In January 2020 the company announced positive results from a phase 1 study of an oral version of octreotide, a biologic used for the treatment of acromegaly and neuroendocrine tumors. The technology was evaluated in a group of 58 healthy volunteers and Rani Therapeutics reported that bioavailability of octreotide was greater than 70%.
Entera Bio is an example of a company that is developing a conjugate molecule–based technology. The company’s oral delivery vehicle works via use of a carrier molecule or “synthetic absorption enhancer,” to enable the walls of the intestine to absorb biologic drugs, along with protease inhibitors that resist the enzymatic degradation process within the digestive system. “Oral drug delivery provides significantly more flexibility, both in size of dose and number of doses per day, than injectable drugs, which are frequently administered by preset injection pen and only once per day,” the company stated.
In 2018, Amgen and Entera Bio began a collaboration to develop orally administered versions of biologic drugs. In June Entera Bio reported positive interim results from an ongoing phase 2 clinical trial of an oral parathyroid hormone (EB613) for the treatment of osteoporosis. The company reported a 1.44% increase in bone mineral density in the lumbar spine in the 1.5 mg treatment arm versus a mean decrease of 0.71% in the placebo arm. Entera Bio added that results suggested higher dosages will increase efficacy.
The partnership with Amgen involves the development of an undisclosed, early stage biologic for the treatment of inflammatory disease, among other illnesses. “This collaboration is an important validation of our platform technology. Importantly, the first program included in this agreement is very different from the [oral parathyroid hormone] in Entera’s pipeline, highlighting the broad applicability of our technology,” the company stated.