Competing In The Rare Disease Space

By Cindy Dubin, contributing editor

There are approximately 7,000 different types of rare diseases and disorders affecting an estimated 350 million people worldwide. Because these diseases are so diverse and complex, there are inherent gaps that exist in patient treatment. The Rare Disease Impact Report illustrates that it takes an average of seven years for a patient with a rare disease in the United States to receive a proper diagnosis. On the journey to diagnosis, a patient typically visits up to eight different physicians and receives two to three misdiagnoses.

CSL Behring began carving out its niche in the rare disease space about 25 years ago, focusing on plasma-derived proteins (PDPs). PDPs are used to treat rare and serious diseases that include coagulation disorders such as hemophilia and immune deficiencies, Alpha-1 antitrypsin deficiency, hereditary angioedema (HAE), and hemolytic disease in newborns.

At that time, CSL was the lone fish in a small pond. Today, the global provider of plasmaderived and recombinant factor products is up against a handful of competitors in a space estimated to be worth more than $15 billion annually. As previously reported by Life Science Leader magazine (see September 2009 issue, “Lessons Learned From PDP Market Success”), industry experts expect the size of the market to continue to steadily grow and potentially exceed $32 billion per year by 2016.

“In the rare disease arena, there is generally a lower cost of development and the promise of patent protection, so it becomes evident that a company can realize a certain degree of profitability under the right circumstances,” says Russell Basser, senior VP of global clinical research and development at CSL Behring. “This tends to attract more companies to the space.”

Consider the hemophilia sector. Basser explains that there was a flurry of recombinant factor development and launches after the contamination issues in the late 1980s with several recombinants hitting the market. Yet, prior to that, little or no technological progress had been made for 25 years. But, in the last five or six years, he says, competition has picked up, and the market is now worth about $10 billion.

A similar story is unfolding in the HAE space. According to Basser, CSL held the title of being the only company in the world to offer a product to treat HAE, and things remained that way for 15 years. According to the Orphan Druganaut Blog, there are now a handful of similarly licensed products for HAE, a space valued at about $113.8 million in 2011 and expected to reach $385 million in 2019.

“It’s interesting how the rare disease space is becoming so crowded,” reflects Basser. “We all have to be that much smarter about how we do business, and it puts more pressure on drug development as we are a few players vying for the same patients and skilled personnel.”

Embrace the Space
With a feeding frenzy under way in the rare disease drug-development sector, staying ahead of the competition requires a focused commitment. “Considering we are now surrounded by competitors in HAE, we have had to strengthen our focus even more,” says Basser.

To remain focused, CSL Behring has formed close relationships with patient advocacy groups. These organizations educate patients and family members about a given rare disease: how to seek a diagnosis, and how to gain access to treatment. Some groups are diseasespecific while others are umbrella organizations, such as the European Organization for Rare Diseases (EURODIS) and the National Organization for Rare Disorders (NORD). CSL works with both types of organizations to ensure patients have access to appropriate therapies. “The secondary gain becomes obvious in that we have the therapies the patients need, and we want them to use them,” explains Basser.

Engaging with patient groups also helps ensure that diseases don’t go underappreciated or misdiagnosed, he says. “We understand that having one of these diseases can be isolating, but a misdiagnosis can lead to death. We are working with the groups to improve the rates of accurate diagnosis and the proper choice of treatments.”

CSL also uses social media to spread its message about treating rare diseases. Basser explains that tapping into online groups enables the company to provide education about treatments as well as information regarding what trials are occurring in a patient’s region. The goal is to empower the patients. CSL has also set up specific Web pages and YouTube videos to do the same.

“Engaging with patient advocacy groups isn’t unique, but I think we do it as well as anyone who competes in our disease areas,” says Basser. “We give support to patients beyond getting them to use our product. It’s about embracing the entire opportunity. That’s why we’ve been successful.”

Enlist Patients
Patient advocacy groups are also playing a larger role in designing clinical trials. These groups help to make sure the drugs are valuable for the patients from a regulatory and medical perspective as well as from a patient perspective. The challenge with rare diseases is that only a small number of individuals are available to participate in a clinical study. In order for a disease to be qualified in the U.S. as “rare,” the afflicted patient pool needs to be fewer than 200,000 individuals. So, a patient advocacy group can really help recruit patients.

This has not gone unnoticed by CSL. The company has teamed up with several advocacy groups, including the Alpha-1 Foundation, a not-for-profit Florida corporation cofounded by John Walsh in 1995, for individuals diagnosed with Alpha-1 antitrypsin deficiency, also known as genetic COPD. When someone is diagnosed with Alpha-1, that person is automatically asked to enroll in the Alpha-1 research registry and connected with a clinical resource center doing trials and studies. In fact, the Alpha-1 Foundation was the result of a seven-year Alpha-1 progression study being conducted by the NIH.

“Those of us who participated in that study realized the value of participating in clinical research,” explains Walsh, who is also president and CEO of the foundation, we can recruit for a Phase 3 pivotal study within 6 to 10 weeks. That’s why we have been able to get companies like CSL Behring to focus on developing therapies for Alpha-1.”

One of those therapies is Zemaira, an Alpha-1 proteinase inhibitor developed about 10 years ago by CSL Behring. This augmentation therapy replaces the missing protein in people who have Alpha-1 deficiency. CSL asked the Alpha-1 Foundation to participate in the design of the clinical trial protocols and to be involved with FDA discussions in getting the Zemaira trial design approved.

“Having a patient advocacy group at the table brings a completely new perspective that the FDA wouldn’t have otherwise,” says Walsh. “We actually challenged a reviewer on the number of bronchoscopies that would be given and the number of patients to whom it would be given. And the FDA backed off. The importance of being at the table with the sponsor of a drug trial adds tremendous value because the FDA gets a completely different perspective on the potential impact of the clinical protocol.”

Zemaira was ultimately approved by the FDA as an injectable therapy for patients suffering from Alpha-1 and is among a handful of such therapies.

“It is critically important for individuals afflicted with rare diseases to be involved with clinical research,” says Walsh. “Without the patients, the research won’t get done. As a whole, I think the pharmaceutical industry is realizing the importance of getting patients involved with clinical studies.”

In fact, the FDA is promoting opportunities for patient advocacy earlier in the policymaking process than has been the case historically. The FDA Safety and Innovation Act (enacted in mid-2012) mandates the involvement of patient representatives in roles beyond those of the advisory committees. Draft procedures for patient involvement were made public in September.

Both Walsh and Basser agree that the mandate will be embraced by patients and will accelerate therapies. “In the future, we will need to think more about how we engage patients in the design of a trial program,” says Basser.

Educate the Trial Sites
Just as patients are essential to the success of a clinical trial, so too are the investigator sites. Basser explains that it is important that the sites are engaged and that a coordinated effort be made to ensure the investigators really understand the complicated protocols. “As our success and portfolio have grown over the years, we have had to learn to engage the sites in a much more intimate way.”

This, he adds, is necessary because every patient counts in studies in rare disease. “We have many studies where we expect each site to recruit only one or two patients. This has a number of implications. For starters, we need to work closely with our study investigators to ensure they identify every potentially eligible patient in their clinics. We must also cast a wide net for patients and often work with investigators who have a lot of expertise in the particular rare disease but limited experience in clinical trials. Finally, there is a very steep learning curve for the site teams as the first patient they treat might be the only one.”

So, CSL has learned to stay close to the study coordinators and investigators to get patients into the trials and make sure the quality of the data is adequate. For example, when investigators sign up for a trial, they must learn and understand the process and the protocol, but ultimately, the sponsor has a responsibility to ensure the trial is conducted according to good clinical practice guidelines and that the data is accurate. That’s especially important considering the sponsor wants to use that data when getting approval from a federal regulatory agency.

Basser explains that if investigators are going to sign up for a trial, it’s up to them to learn and understand all aspects of the trial, “But in the end, we’re the ones who have the most in the game. If they don’t follow the protocol appropriately, we get data that we can’t use. Then, the product might not get licensed. It’s our responsibility to ensure investigators are trained adequately.”