From The Editor | January 12, 2021

A Clinical Setback Leads To A Transformation And A New Trial

Ed Miseta

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

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Someone once told me that you can tell a lot about a person by the way they handle adversity. Anyone can hold their head up when everything is going well. But the real test of a person’s character comes when they are faced with bad news and must perform under difficult conditions. 

Pharnext is a small pharma company which faced adversity and was able to overcome it. The setback occurred in 2019 when data produced from a Phase 3 trial was rejected by the FDA. 

“The company carried out a Phase 3 study in Charcot-Marie-Tooth, which is a debilitating and genetic neurological disorder,” says David Horn Solomon, CEO Of Pharnext. “The treatment targeted a gene called PMP 22, and the company was conducting a high dose/low dose study. The treatment had to be kept refrigerated and then warmed prior to administration. As a result of the warming and cooling, some crystals were found in bottles of the high dose medicine. Unfortunately, that was the dose that showed effectiveness in the study. When the data was reviewed by the FDA, the regulator felt there was missing and uninterpretable data.”

Solomon notes this was a manufacturing problem, not a failure of the trial execution or the trial design. The company faced a manufacturing issue that resulted in issues with the data generated. Although the trial was not a failure, another study would have to be conducted.

A Change In Leadership

Solomon had experience in late-stage trials, manufacturing, and taking drug products through to FDA approval. For that reason, the board of directors brought him in to get the company back on track. Solomon knew the problem was manufacturing related. He also knew the problem only existed in the high-dose treatment. The high-dose treatment was double the potency of the low-dose treatment. Therefore, he felt the problem could be eliminated by simply administering the low-dose treatment twice.

David Horn Solomon, CEO, Pharnext
David Horn Solomon, CEO, Pharnext
“The low-dose treatment administered five milliliters per day to patients,” says Solomon. “By administering that to patients twice a day, they would receive 10 milliliters of product, which is the same as the high-dose treatment in the previous trial. It sounds like a simple solution, but the concentration of the medicine in the low-dose treatment showed no manufacturing issues in 25 batches produced over a two-year period.”

Pharnext then wrote a proposal for a new study and submitted it to the FDA. It would use the same endpoint as the prior study. The regulator gave its blessing to the new plan which has since led to a Special Protocol Assessment (SPA) filing. The first patient is expected to be dosed in early 2021. 

“I believe we are back on track,” says Solomon. “No one wants to repeat a Phase 3 trial. However, we learned some important lessons from the earlier trial. That trial was promising and produced positive data, but the crystals presented a problem for the FDA. We corrected the mistakes and expect a positive outcome from this new effort. We transformed the company, and we brought in a new management team and six new board members. I think we're in a very good place.”

A Partnership With FDA

Although the prior trial did not result in an FDA approval, Solomon notes there are two important lessons the company learned from it. The first is how to work with the FDA. Solomon notes the relationship his company had with the FDA was critical to bringing the new trial to patients. He believes trials function best when there is ample interaction with the FDA, and he views the regulator as a partner in clinical studies.

“We were able to interact with the FDA iteratively and almost in real time,” says Solomon. “They are the key regulator to set standards of what is required in terms of safety, tolerability, and efficacy of the medicine. We prepared a very complete briefing book of our intentions, describing every feature of our study and the risks involved. The FDA wrote back and provided great feedback. I consider them real partners and they are also the best advocates for patients.”

Charcot-Marie-Tooth is a rare disease, and there is currently no treatment option for patients. So, Solomon believes FDA is not just a partner for sponsor companies, but for patients and patient groups as well. The agency will ensure safe and well tolerated medicines are approved to help patients with the disease. Pharnext is working with both the FDA and patient groups to move the new trial forward.

The first trial also helped Pharnext learn how to find the patients needed for its trial. Patient groups were aware of the first trial as well as the safety, tolerability, and promising efficacy results it generated. Pharnext worked closely with the patient advocacy organizations and the physicians who treat the patients. Doing so enabled them to identify 26,000 potential study participants for a trial that only required 375 patients. It took about a year to complete recruitment for the first trial and recruitment for the new trial could be done in even less time.

A Scale Makes A Good Endpoint

I speak to many executives working on rare diseases who bemoan the clinical difficulties caused by the lack of a natural history for the disease. That was not the case for the clinical team at Pharnext. Solomon notes the natural history of the disease is well mapped and understood. Sadly, most patients have an unstoppable decline in physical function that often ends with being confined to a wheelchair.

For patients with Charcot-Marie-Tooth, the Overall Neuropathy Limitation Scale (OLNS) is used to measure arm and leg function. A change in score using the scale was used as the primary trial endpoint, as it is understood by patients and approved by the FDA. A zero on that scale is normal while a 12 on the scale means a patient is wheelchair bound. Changes in a patient’s abilities are measured and recorded.

“For example, we check to see if a patient can hold a key in their hand, put it in a lock, and turn it,” says Solomon. “We want to see if they can they open the latch and pull the door open. That may sound trivial, but patients with this disease might not be able to feel the key, hold it, or put it in a lock. Failure to complete these tasks will cause their point score to rise. Our hope is to stabilize the score of a patient, which is what we were able to show in the earlier study. Keeping that score from rising provides a great clinical benefit to patients.”

Finally, Pharnext did have concerns about how COVID might impact the trial. The OLNS is normally measured by a neurologist or a nurse practitioner in a hospital or clinic. However, the pandemic could make it difficult for patients to visit those venues.

As a result, Pharnext has developed mechanisms for the scores to be recorded remotely. This will be done with video and apps provided to patients and caretakers. “We are currently working with the FDA to get those approved for use,” says Solomon. “That is a unique feature of our trial and will be the first time the OLNS is conducted virtually. The test will be patient administered with guidance from a physician. It’s an exciting advancement that will allow us to conduct the study in a COVID environment.”