A Lifesaving Drug’s Race To America

Accelerating A Pivotal Rare Disease Trial By Empowering CRAs

This Atlantic Research Group rare disease white paper is available for download as a PDF.

For nearly three decades, people born with the rare disease hereditary angioedema, or HAE, on either side of the Atlantic were fated to very different lives. A potentially life-saving medication, Cinryze, was approved only in Europe. This left families in the U.S. with few treatment options.

“Everyone in the HAE community knew it was out there,” says Lyle Camblos, president and co-founder of Atlantic Research Group (ARG), the contract research organization (CRO) that brought Cinryze to the United States in 2008.

“Many of the wealthier patients and their families would go to Europe, buy it and import it.”

Patients went to such great lengths because HAE causes such misery. It’s a hereditary disease, affecting entire families. A genetic defect results in insufficient or dysfunctional C1 esterase inhibitor, a protein involved in blood coagulation and immune system regulation.

Without adequate levels of this protein, a biochemical cascade causes fluid to leak from capillaries into surrounding tissues. The result is severe swelling in various parts of the body—face, hands, feet, and airway.

Before treatment was approved, up to 30% of people with airway swelling died of asphyxiation. Swelling also can occur in the gastrointestinal tract, causing extreme abdominal pain, nausea and vomiting.

Patients sometimes undergo unnecessary surgery because the reason for abdominal symptoms is not apparent.

“These patients can’t hold a regular job; they end up having not much money,” Camblos says. “They have kids; their kids have HAE. It’s terrible to watch your kids go through this.”

“This was a dreaded disease and there was no treatment available for it in the U.S.,” adds Jason Bablak, a former vice president of Lev Pharmaceuticals, Inc., a small biotech which developed Cinryze for clinical use in the U.S.

History Of Cinryze

The drug’s mechanism is straightforward. It’s a plasma-derived C1 esterase inhibitor that replaces what’s missing in the body. But bringing the drug to market was anything but straightforward. There were two events that complicated bringing Cinryze to the United States. The first was the HIV/AIDs epidemic in the 1980s and ‘90s. At that time, there was a concern for viral pathogen transmission in plasma-based products. When those fears died down, interest in developing a C1 esterase inhibitor renewed among pharmaceutical companies.

“Investors became a lot more comfortable putting money into plasma derivatives and people were more comfortable taking them,” Camblos says.

The second major complication occurred in the early 2000s. At that time, Baxter International acquired a small European company that produced a C1 esterase inhibitor, and subsequently launched a U.S. clinical trial. However, Baxter discontinued the trial because the inhibitor failed to meet its primary endpointThe U.S. Hereditary Angioedema Association (HAEA) became concerned when Baxter discontinued its U.S. trial and planned to stop supplying the patients with medication through a compassionate use program.

“It’s bad enough for patients who never had treatment for this disease,” Bablak says. “But for patients who had the treatment and then had it taken away, it was devastating.”

At the time, Bablak had yet to join Lev Pharmaceuticals. He was a leader at a patient advocacy group, the Immune Deficiency Foundation, which partnered with the HAEA, Baxter, and the FDA tried to devise a way for patients to import the drug on their own from Europe. As the plan slowly progressed, Bablak was approached by Lev’s future founder about a faster way to help patients: starting new U.S. clinical trials to develop a C1 esterase inhibitor. Bablak became Lev’s first employee in 2003.

It took about two years to acquire the rights to the European product from Sanquin, revise Baxter’s original protocol, prepare the Investigational New Drug application, file it with the FDA, and begin setting up clinical sites.

By 2005, Lev’s Cinryze trials began. The small company aimed to move faster than the stalled or slow-moving efforts of larger companies. It funded its efforts by attracting investment with the FDA’s orphan drug program, which grants seven years of market exclusivity to any company producing drugs for rare diseases.

For Camblos and others at ARG who worked on the Cinryze trials, the goal of picking up the tempo meant that “nimble” became the watchword.

This started with what became an atypically complicated process for preparing the medicine needed for the trials. The FDA required that plasma used in the trials be obtained in the U.S., not in Europe.

However, setting up a facility in the U.S. to isolate the C1 esterase inhibitor from plasma would trigger many months of preclinical studies, an expensive process that the European manufacturer of Cinryze had already undergone. Therefore, Lev took the unusual step of shipping plasma from the U.S., to the Amsterdam-based Sanquin, who then shipped the purified plasma components back across the Atlantic.

“That allowed us to move quickly into a phase 3 study instead of starting off in the earlier phases,” Bablak says.
But the manufacturing process was complex and took time. “From the point of plasma collection to manufacture of the final product was between four and six months,” Bablak recalls.

Moreover, because Sanquin didn’t produce large amounts, the product often was in short supply during the trials. At the same time, ARG personnel had to ensure that the trial’s clinical sites remained adequately stocked.
“It became a real logistics nightmare,” Bablak says.

The CRO Challenge: Too Small & Too Large

When it came time to choose a CRO, Lev selected a very small company with a special interest in HAE.
“They knew a lot about the disease state,” says Bablak. “We thought it made sense.”

In theory, it did. But the company wasn’t doing well in managing the clinical sites, so Lev decided to find a different partner.

When the new, North Carolina-based CRO came on board, Lyle Camblos was a clinical research associate (CRA) there. He became the head CRA for the Cinryze trials and supervised the other CRAs working with the trial sites. The new CRO managed clinical sites and analyzed statistics.

But the relationship was still a mismatch.

“This second company was a large CRO, but we were a tiny company,” Bablak says. “Our study was in the tens of patients, not hundreds or thousands.”

Standard practice for a large CRO testing drugs for more common illnesses is to recruit physicians and patients From a number of large medical centers and enroll thousands of study participants.

Small trials for rare disease treatments require a much different approach: locating specialized physicians who perhaps treat only one or two patients with that illness.

“It’s not like you can just go to every major city in the country and fill out your study that way,” Bablak says.

CRA turnover became a major problem, too. “It was 100 percent,” Bablak recalls. “It got to the point where we weren’t getting anything done because we kept training people but they never got out into the field.”

Lev found itself in need of a new strategy. “We just weren’t getting the kind of attention we needed,” Bablak notes.

By that time however, databases had been built and patients were being treated. “Moving the data was going to be problematic,” Bablak says. “What we really needed was someone to focus on our clinical sites.”

So Lev made a split decision. Camblos and a colleague were ready to move on and form their own CRO. They asked Lev to hire them for the Cinryze trials.

“Individually, Camblos’s team was the bright spot of the whole study,” says Bablak. Lev brought the pair on to handle the clinical sites, while keeping the current CRO to analyze data.

The newly formed Atlantic Research Group gave Lev the personal attention needed for the Cinryze trials.

“They never said no,” Bablak recalls. “It was always, let’s do whatever we need to do to solve the problem.”

Throughout the trials, the CRA turnover rate with ARG was zero.

Heads Down

The initial Cinryze trial was planned as a small study with six sites. But locating small numbers of patients who were scattered throughout the country proved to be a major challenge.

“It was going to take years to enroll,” Camblos says. “If the other pharmas realized we were recruiting and restarted their own efforts, the thin patient population would be split between trials and all efforts could stall or slow to a crawl.”

The strategy: move with speed and stealth, so the larger companies would fall too far behind to catch up. “That’s exactly what happened,” Camblos recalls.

The relationship that Bablak formed earlier with the HAEA proved invaluable in finding patients. “The patients would contact Lev directly through the HAEA,” Camblos explains. “Then Lev would tell us that they had a patient in a certain city.”

Cooperation blossomed. “ARG was instrumental in working with the HAEA to figure out where the potential sites were and then do the initial visits to see whether these sites actually could do the study,” Bablak recalls. Sometimes that meant coaxing physicians who weren’t sure they were up to the task.

In Falmouth, Cape Cod, Massachusetts, Camblos met with a physician whose patient was referred through the HAEA.
“He was on the fence, as he had never before done clinical research. We had to convince him he could do the study,” Camblos says. “I talked him through the process and showed him what we could do and how we could help him,” Camblos adds. “We made it as easy as possible for him.” The physician’s wife, who was his nurse and ran his office, acted as the study coordinator.

“It was gratifying to see a doctor who cared so much about his patient — whom he had seen for nearly 20 years — that he would go to all these lengths to get access to this drug,” Camblos says.

Intensive training at clinical sites is one example of how ARG established positive relationships that helped them enroll patients and outpace the competition. Another was offering patientfriendly features, such as open label access to the product until it was approved or halted by the FDA.

Yet another was having confident, experienced CRAs who effectively navigated the ins and outs of clinical trials.
“The CRAs are our liaison to the clinical sites,” says Bablak. “It’s more than just monitoring.”

Effective, empowered CRAs have to answer questions, troubleshoot issues by phone, establish face-to-face relationships with study coordinators and help learn to persuade patients into the sponsor’s trial.

“With [Camblos], they really were an extension of us,” Bablak adds.

“They were really handson,” recalls Julie Tucker, a study coordinator at a clinical site in Texas.

Because patients in the Cinryze trials received repeated intravenous doses, accessing their veins could become difficult.

“It was necessary for the site to have many different sizes and types of IV supplies for us to be able to treat them. ARG delivered in making sure we had them in bulk and on time.”

In fact, after 24 years of working with the same physician-researcher, Tucker changed careers and signed on with ARG as a CRA.

“That’s the biggest compliment I can give them,” she says. “ARG is where I wanted to be.”

With strategies like these, the numbers of clinical sites and patients grew quickly.

“We ended up having about 75 sites for a study of 73 patients,” Camblos notes. “Several sites had no patients and many sites had only one patient.”

By the time the competition realized how far along ARG was, enough patients were enrolled for the trial data to achieve statistical significance.

“We were just waiting out the results,” Camblos says.

Road Trips

It goes without saying that monitoring clinical sites requires travel. The Cinryze trials, however, took CRA travel to a whole new level. In part, it was because many patients have acute attacks and so product availability and site visits had to accommodate some very unpredictable patient events.

“I would find out at 4 p.m. on Monday that I needed to be somewhere by noon on Tuesday,” Camblos recalls. “We made that happen.”

In one extreme case, while attending a conference in Miami, Camblos learned he had to quickly get to a trial site in Spokane, Washington.

“I had to fly the longest continental flight there is—Miami to Seattle,” he says. Then he drove four and a half hours to Spokane. “It was 12 years ago, and I still remember it,” he adds.

Timing was critical. Missing even one product delivery or patient attack could throw a study off by months.
“At the time we were all so nervous about time that we didn’t consider losing a month to anything,” Camblos says.

Because the product was shipped from the Netherlands, it sometimes got hung up with U.S. Customs. Delays of even a day or two posed logistical problems because schedules were planned out to the day. Furthermore, the product can’t just be picked up and dropped off, like a FedEx package. The product is temperature-sensitive and has to be checked in and out at each site. Documentation is critical.

“Once we had to get product just from a site in Manhattan to one on Long Island,” Camblos recalls. Standard courier wouldn’t do — a single vial costs $3,500; one box represents $40,000. Such transports were handled directly by CRAs.

The Finish Line

Bablak’s work in HAE encompassed six years, including his time at the IDF. When it became apparent that Cinryze was headed for FDA approval—primary endpoints had been met and an FDA advisory committee gave its unanimous endorsement—he felt almost overwhelmed.Camblos shared the same experience.

“When you work on something for years, it becomes part of who you are for a while. It’s all you live and breathe,” he says. “It just means that much more when you’re done and when it’s successful, it’s even that much greater.”