There are currently no cures or treatments directly targeting Berger’s disease. The rare illness, which affects about 130,000 people in the U.S. annually, is the product of an overactive immune system that pollutes and inflames the liver, damaging the organ for years until it can no longer function.
Several well-known pharmaceutical companies, including Astellas and Anthera, have worked on pushing candidates for the disease and its symptoms through the clinic. But in order to get trials underway, the companies had to recruit enough patients.
Enrollment is challenging across nearly all clinical trials. But for the rare disease variety, it’s often akin to finding a needle in a haystack — or in some cases a field of haystacks, if the illness is particularly uncommon. Though sponsors have over the years crafted electronic tools to resolve geographical barriers and reimbursement programs to alleviate financial burdens on patients, many of the studies’ inherent complications have yet to be fully remedied.
For Berger’s disease, Astellas successfully pulled together sufficient participation for a mid-stage trial of its drug, though total enrollment reached just 40. Anthera, meanwhile, gathered only 57 of the 200 it sought to recruit in a Phase 2/3 study, which forced the company to downgrade the trial to Phase 2.
In the most extreme cases, though, recruitment woes can squelch trials before they start or sap investor faith in a candidate. XOMA Corp. and Applied Genetic Technologies, for example, saw their stocks plummet when (in addition to poor quarterly earnings) they announced slow enrollment was stymieing the completion of studies for their respective eye disease treatments.
It's not just tiny biotechs having trouble, either. Big players have also gotten stuck: Johnson & Johnson recently scrapped an investigation of Darzalex (daratumumab) in mantle cell lymphoma because it couldn't lock down enough participants.
Understanding the disease
Before researchers consider a patient for a clinical trial, they first need to determine whether he or she actually has the disease under investigation. It’s a fairly straightforward answer for prevalent ailments such as diabetes or hepatitis, which have recognizable side effects and are easily identified via screenings or tests.
Fortunately, the characteristic blood found in the urine of patients with Berger’s disease is a helpful tip off for physicians. Other rare conditions are stealthier.
Take acid sphingomyelinase deficiency, or ASMD, a genetic disorder that leads to the build up of a protein called sphingomyelin in the body. People with ASMD can display a debilitating and sometimes fatal breakdown of the nervous system during infancy, or they can grow to adulthood without ever showing a symptom. What’s more, illnesses such as galactosemia, Gaucher disease and Wolman disease cause similar side effects, according to the National Organization for Rare Disorders (NORD), which may impair a proper diagnosis.
Olipudase alfa is one treatment aimed at helping patients with ASMD. The breakthrough designated Sanofi medication is currently in a Phase 2/3 pivotal trial with an estimated enrollment of 36 patients. It is also one of a handful of rare disease candidates, including drugs for Fabry disease, Pompe disease and hemophilia, in the French pharma’s pipeline.
"There's an epidemiological driver that means that just mere identification of patients can be a challenge," Rand Sutherland, head of rare diseases development at Sanofi, said in an interview. "That obviously has an impact then on how broadly geographically one might need to set up operations to identify patients."
Broadening a trial’s footprint involves increasing the number of sites where investigators administer treatment, or expanding into new regions that are home to an untapped population. Partnering with patient-focused organizations like advocacy groups, which keep tabs on potential good fits for clinical studies, also helps facilitate enrollment. Still, having clinicians who understand a rare disease well enough to properly diagnose it — a resource often concentrated at universities or specialized research centers — can be a limiting factor as well.
"Our training is really based off pattern recognition," said Erika Augustine, an associate director of the University of Rochester’s Center for Human Experimental Therapeutics. "And so, when it comes to rare disease, you haven't had that experience of multiple patients with the same thing to rely on that pattern recognition that you're used to."
Looking to remedy that problem, sponsors and regulatory officials are investing time and money into becoming more knowledgeable about rare disease natural histories, which look into factors such as a condition’s geographic range or how it differs in various sub-populations. The Food and Drug Administration, for example, recently announced it would give up to five grants in 2017 for natural history studies. The grants will be worth roughly $2 million all together.
Getting patients there
If identifying possible participants for a trial is the first hurdle in the race to enrollment, the next is getting them to sign on. Stakeholders have found that given the often lacking information or years of buildup before a diagnosis is given, rare disease patients and their families are, on average, exceedingly educated about the condition by the time a drugmaker takes its treatment into human testing.
"When it comes to research, they are able to apply that same kind of medical and scientific savvy that they've already developed to considering trials, to considering interventions," Augustine said. "But it's not as simple as ‘I have a rare disease, and my options are limited, so of course I'll want to be a part of this trial.’ Families really want to consider ... well, what is this intervention? What does it do? What do we know about it?"
Families must also consider the financial and time commitments required by clinical observations.
Pharmaceutical developers have made efforts to minimize those drawbacks. According to Sutherland, Sanofi has employed remote sensory equipment such as actigraphs, which monitor movement, and video streaming through services like Skype to reduce patients’ need to visit far away sites.
When those devices aren’t adequate, the company generally pays back patients and caregivers for travel expenses.
So does Alexion Pharmaceuticals. The New Haven, Conn.-based rare disease drugmaker works with institutional review boards at treatment locations to get reimbursement programs approved, then partners with third-party vendors to institute them.
"It would be folly to not consider that when we're doing clinical studies," Alexion’s head of R&D Martin Mackay said in an interview. "It's clear that sometimes it's better for a clinical study to be conducted in a center where they're just very familiar with the disease and how we're doing the study … and some of our patients do travel to these centers.”
Making it all worth it
Despite the immense preparation needed to enroll and conduct orphan drugs trials, many don’t have standardized endpoints set by regulatory officials. In fact, both Sutherland and Mackay said their companies developed a good chunk of endpoint decisions for certain trials in-house and then worked with governing agencies to make them a reality.
Alexion’s Strensiq (asfotase alfa), for instance, gained approval in October 2015 as a treatment for perinatal, infantile and juvenile-onset hypophosphatasia, a disease that NORD cites as occurring in 1 out of every 100,000 births in Canada.
"We had to literally come up with our own endpoints, and then gain agreement with the regulators that these were the right ones that would show the transformative nature of the therapy," Mackay said of the therapy.
Tapping patients and patient groups has become an essential part of such efforts, as they can provide insight on whether a drug has a promising risk-benefit profile or a developer grasps which quality of life improvements are most desired. While incorporating their voices doesn’t guarantee patients will participate in the trials, drugmakers have found it at least fosters a more trusting relationship.
"We worked very closely with patient associations and advocacy groups to try to incorporate their perspectives into our work, not just in R&D but really across the board. And I think those relationships have helped us as organization when we then go to do clinical trials," Sutherland said, adding that Sanofi takes "a very ethical approach and doesn't want to be perceived as trying to leverage these relationships purely for the purpose of doing our clinical trials."