From The Editor | June 19, 2018

What Would Convince You To Delay Your Trial For 12 Months?

Ed Miseta

By Ed Miseta, Chief Editor, Clinical Leader
Follow Me On Twitter @EdClinical

What Would Convince You To Delay Your Trial For 12 Months?

AdAlta Ltd, a biotechnology company headquartered in Victoria, Australia, is seeking a treatment for idiopathic pulmonary fibrosis (IPF), which loosely translated means unexplained scarring of the lungs. Samantha Cobb, CEO of AdAlta, notes the damage is the result of inflammation and the buildup of a protein called collagen. The condition causes the lungs to stiffen, making patients unable to breathe.

“Although the cause of IPF is unknown, researchers have found there are risk factors, including smoking, environmental exposure, viral infections, and pollution,” says Cobb. “The disease impacts 300,000 people worldwide and about one-third of those patients reside in the U.S. Approximately 40,000 IPF patients die every year. The disease is characterized by a progressive and irreversible decline in lung function. If someone is diagnosed with the disease, they typically live another two to three years.”

There are currently two drugs available to treat patients: pirfenidone (Roche/Genentech) and nintedanib (Boehringer Ingelheim). But, Cobb notes both treatments have side effects and are only effective in 30 percent of patients. With the rapid decline in the health of patients, there is a real unmet need for a safe and effective treatment.

Following A New Path

AdAlta’s approach takes a completely different route than the two existing treatments. AdAlta’s i-body molecule binds to a drug target known as CXCR4. As a first-in-class drug, it has received Orphan Drug status from the FDA. AdAlta has been able to show, via animal models, a reduction of collagen in the lung. But as AdAlta was about to start its Phase 1 trial with its lead candidate AD-114, it was faced with a difficult decision.

An improved version in development at the company was found to have superior qualities. The company had also been receiving feedback from pharmaceutical companies and investors that although AD-114 was an impressive molecule, its short half-life was not ideal.

The new molecule, AD-214, produced data that was so compelling, AdAlta decided to delay its Phase 1 trial for 12 months so as to switch its focus. AD-214 was improved via redesign, which was found to extend the product’s half-life and potency.

 “We have a photo that we use in presentations that shows a lung looking almost normal after being treated with AD-214,” says Cobb. “Additionally, a researcher at Cedar Sinai in LA has tested human tissue from IPF patients in a test tube. He found that our drug had an effect on the diseased tissue but demonstrated no effect on normal tissue. AdAlta’s compound was able to inhibit cells from producing collagen and also inhibited their movement. Pirfenidone demonstrated no effect in these assays, and nintedanib affected both normal and diseased cell types.”

A Patient-Centric Decision

A lot of discussions surrounded the decision to delay the Phase 1 trial until the first half of 2020. There are costs involved in doing so, and the delay could also cost a company the opportunity to be first to market with a new treatment. Still, one of the overriding factors that convinced the company to wait another year was the impact on patients.

“With the original drug, patients would have been looking at daily subcutaneous injections,” says Cobb.  “With the new drug, we’re looking at less-frequent dosing, possibly just once per week. This is due to the enhanced potency and longer half-life. The less-frequent injections are a huge benefit to patients and means AD-214 could be effective in treating other fibrotic conditions, such as fibrosis of the liver, kidney, and eyes.”

Although Cobb wants the treatment to be attractive to patients, she also wants it to be attractive to pharma companies that AdAlta could potentially partner with. She notes that while this postponement could be painful for the company in the short run, the longer-term outcome will be a superior drug candidate for AdAlta, its partners, and patients.

Trial Delay Requires Board Approval

Cobb did have to go to her board of directors to get approval to delay the trial. She gives a lot of credit for the decision to her board members who recognized that this was the right decision to make, especially for patients. She mentions two of those directors by name, who were familiar with IPF and the company’s technology. 

“Our board has two directors who are based in the U.S.,” she says. “One of them is Robert Peach, the CSO and co-founder of Receptos, a company purchased by Celgene in 2015. He has over 25 years of experience in drug discovery and development. He also spent time at BMS, where he helped develop a drug that is similar format to AD-214. Knowing antibody based drugs as well as he does, Peach was very supportive of the pathway forward.”

John Chiplin is another U.S.-based board member. Chiplin is managing director at Newstar Ventures, has served as CEO at Polynoma LLC and Arana Therapeutics, and has extensive experience with antibodies.

“When I went to the board for approval, what resulted was a long and in-depth discussion on the moral, scientific, and commercial implications of our decision,” says Cobb. “When we finished discussing the situation, there was no doubt in any of our minds that we were making the right decision.”

Scientists Help Make The Decision

Another group that helped with the decision was AdAlta’s scientific advisory board. Two scientists on the board have experience with Novartis. Brian Richardson is a disease area manager at Novartis and John Westwick served as global head of respiratory diseases before starting his own consulting firm. Westwick has developed 13 drugs in the respiratory disease space, four of which have already been granted regulatory approval.

“John and Brian were very supportive of our decision,” notes Cobb. “Another scientific advisory board member, Steve Felstead, is a physician who served as head of clinical research for Pfizer in the U.K. He has been very instrumental in helping us design our Phase 1 and Phase 2 studies. He strongly supported our decision to not subject patients to a daily treatment when there was a weekly alternative in our pipeline. We certainly did not want to put patients through a rigorous clinical trial only to have them come back to take part in another one because we neglected to get it right the first time.” 

AdAlta’s scientific advisory board has been in place for a few years. It was started when investors recommended Cobb start getting advice from individuals who had experience conducting clinical trials. Several private U.S. investors recommended potential members to Cobb, who then connected with them to have conversations about the board and member responsibilities. Cobb notes she speaks to the board frequently.

“I recommend everyone have this type of board in place,” says Cobb. “It’s nice to get advice from experts who are internationally recognized and have a proven track record. These individuals have brought a number of drugs to market and have many more under development.”

Getting members on both boards was not always an easy endeavor. Cobb recalls reaching out to one individual who was located in the U.S. He liked the technology, but was busy with other projects and initially declined her offer. Cobb did not give up, and went back to him on multiple occasions. “I simply kept harassing him until he agreed to join,” she states. “He has since become one of my best board members.”

Connections Cobb has made over the years were instrumental in building both boards. Some board members connected her with individuals who were a good fit. Others were introduced to her by someone else in her professional network who simply said, “Would you be able to help these guys out?” Cobb notes no one on either board came about via a cold call.

Find The Right Patients

The Phase 1 trial in 2019 will be conducted in Australia, where Cobb notes study start-up time can be as short as six to eight weeks. Subsequent Phase 2 and Phase 3 trials will be conducted worldwide. Cobb expects the U.S. will be a key market for attracting patients.

As noted earlier, approximately 300,000 patients worldwide are impacted by IPF. Afflicted individuals will generally visit their IPF clinic. In Australia, there is even an IPF register for patients. AdAlta has already been getting emails from patients wanting to know when the treatment might become available.

“Patients registering can also indicate their interest in participating in clinical trials, which helps with patient recruitment,” adds Cobb. “In the U.S. there is an IPF lung group called the Pulmonary Fibrosis Foundation (PFF). That group is in the process of setting up a similar register. We are already interacting with the group and keeping in touch with them.”