For most patients, taking a pill rather than receiving medicine intravenously makes their life much simpler and less painful. Oral delivery of a medicine will also make it easier for those patients to continue to take their medications and remain engaged with clinical trials. Oramed Pharmaceuticals hopes to make oral delivery of medicines a reality for all patients. The company is focused on taking many treatments that have only been available via intravenous injections and making them available to patients via oral dosage.
“There are many attractive advantages to oral drug delivery,” says Josh Hexter, COO of Oramed. “Most people know there will be increased comfort and compliance by the patient. But in addition to that, oral drug delivery creates a reduced risk of infection, simpler applications in pediatric medicine, and greater cost effectiveness. These factors have positioned it to be the most popular and preferred route of drug administration.”
Historically, it has been difficult to administer many drugs via oral dosage. The problem often revolves around proteins. Proteins are the basis of cell structures and perform many essential tasks within the body. In diseases and conditions involving protein deficiency or inactivity, modern medical care relies heavily on protein-based drugs that mimic the actions of the body’s natural proteins.
“When properly absorbed within, and distributed throughout the body, these drugs can restore or maintain normal body functions,” says Hexter. “The problem is that the integrity and potency of orally ingested proteins become jeopardized by harsh acids and proteolytic enzymes within the gut. Additionally, there is the physical barrier posed by the wall of the small intestine, which blunts the translocation of large particles. As a result, most protein-based pharmaceuticals cannot be taken as a pill and are typically provided in injectable forms, which can be delivered directly to the bloodstream.”
Not An Easy Task
Oramed has developed a Protein Oral Delivery (POD) technology designed to protect orally-delivered proteins from enzymes in the gastrointestinal tract while also enhancing their absorption across the intestinal wall. By preventing protein-drug breakdown in the gastrointestinal tract as well as promoting its absorption beyond the small intestine, the POD technology brings oral protein-drug delivery significantly closer to a reality.
“We are calling this the Holy Grail of treatments for diabetic patients,” notes Hexter. “Oral delivery of insulin solves many problems. It’s potentially a safer and more efficacious way of providing insulin. This enables us to address the problem of diabetes directly by giving the body the insulin it requires, and doing it in a safe and easy manner.”
This type of delivery method has eluded the medical community. Insulin was first discovered in the early 1920s. Until today, the problem of passing it through the digestive system has thwarted researchers. A solution was needed that would protect the insulin in its journey through the digestive tract, but also kept it in a format that remained viable and able to be absorbed by the intestine. If Oramed’s POD technology is a success, those problems may be a thing of the past.
With the prevalence of diabetes around the world, patient recruitment has not been an issue for Oramed. In fact, considering the ease of taking an oral dose compared to an injection, many patients welcomed the opportunity to take part in the studies.
“We have been very successful at getting patients, and you can’t always assume you will be, even with a large patient population,” states Hexter. “We are currently running a Phase 2b study with 240 patients and the recruitment process is proceeding at a rapid rate. The oral delivery system makes receiving the medicine very easy on the patient, and that was certainly a contributing factor. Recruitment for our prior Phase 2 study was equally successful.”
Find The Right CRO
Oramed does not take all of the credit for the quick recruitment process. Hexter notes that any sponsor company, from a small firm like Oramed to a large pharma company like Pfizer, will be more successful when they are able to tether their products and technology to the right CRO.
Hexter has thus far had success with the company’s CRO partner, Integrium Clinical Research. He credits the program manager with keeping their studies on track. He notes the team is also pounding the pavement to make sure all sites are recruiting successfully. If a site is not meeting its recruitment goals, Integrium moves quickly to bring in another.
Integrium Clinical Research is a small- to mid-sized CRO. Oramed’s current diabetes study covers multiple sites, but Hexter notes Oramed has also conducted single site studies with Integrium. Dr. Joel Neutel, principal and director of research for Integrium, runs a site and has a strong focus in diabetes and metabolic diseases. Hexter believes knowledgeable specialists like Neutel are instrumental to the successful conduct of a trial.
The relationship between Oramed and Integrium began with small, single-site, Phase 2a studies. When it came time to perform the larger Phase 2b studies, the company opted to stay with the same partner. “I felt a certain amount of risk in running our Phase 2b trial with Integrium as opposed to going with a larger CRO that was a one-stop, full-service shop,” says Hexter. “But our past experiences gave us the confidence we needed to move forward.”
One of the biggest complaints about CROs that Hexter hears from peers is personnel turnover. He notes you often start off with one program manager, but a few months into the contract you suddenly find yourself working with someone new. That is a concern for Hexter as well, as he believes continuity in the program manager position helps to keep a study from going off the rails.
“Communication is so important between the pharma company and the CRO,” says Hexter. “I find it easy to talk to top management of Integrium if and when an issue arises. We are able to quickly drill down, identify the problem, and get it resolved. With any study, there will come a time where you run into problems. That cannot be avoided. But the quicker you can get those issues resolved, the quicker you can complete the study and start analyzing the results. You should know that the people running your study believe in your drug and are not just going through the motions. When they believe they are an integral part of your team, and not just working a 9-to-5 job, that is when you know you are working with the right team.”
Challenges in Manufacturing Scale-Up
Oramed is now conducting its largest study to date. Advancing from a small study to a 240-person Phase 2b trial also meant there would be issues with scaling-up the manufacturing process. Many chemists will tell you that whether you perform a manufacturing process one time or 100 times, there should be no difference in the material produced. Still, anyone who has had to scale-up a drug manufacturing process will tell you with a larger process, issues will arise.
“Thankfully, we have not run into any major problems,” says Hexter. “But anytime you do something in a larger scale, there are risks you have to be aware of. We use two CMOs that are located overseas, one in Switzerland and one in France. We had to make sure the CMOs were running enough batches. The product also had to be sent to a drug depot in the U.S. for randomization, bottling, and labeling. This is not a simple process and it required a lot of logistics planning. It also helped us understand the importance of having good people to run these processes.”
Hexter mentions one learning experience for the company. Oramed toyed with the idea of having the material produced by a CMO in the U.S., since that is where the study would be conducted. It seemed producing the study material here could cut down on the logistical challenges involved in moving the material from overseas facilities. Unfortunately, the process did not go according to plan.
“We ran some technical batches with them and were not happy with the results,” states Hexter. “The yields were small and production problems seemed to keep arising. In the end we opted to leave the manufacturing with the overseas CMOs. The lesson we learned was to stay with the partner that has performed well for you in the past.”
Hexter adds that the FDA and other regulators want to see redundancy in your manufacturing processes. For that reason, Oramed continues to work with CMOs and drug depots in the U.S. to ensure the company will have that redundancy as it continues to move into larger scale studies.