When Gilead’s Sovaldi was launched in late 2013, the Centers for Disease Control and Prevention (CDC) had just published new guidelines recommending everyone born between 1945 and 1965 should be tested for hepatitis C (HCV). The guidance was based on statistics showing that 75% of all HCV-infected individuals in the US fell into that cohort.
However, within the last two and a half years, treatments from Gilead, Merck, and AbbVie have shifted the treatment landscape, offering ‘cure’ rates of over 90%. With this success, the focus has shifted beyond baby boomers towards new, untreated populations.
A recent report in the National Academies of Sciences, Engineering and Medicine highlighted this fact. “Although most existing cases of HCV infections are currently in the baby boomer population, most new infections are associated with unsafe injection drug use,” the report said. Curing infected injection drug users could do much to reduce transmission, but reaching this population presents a number of challenges.
As it works to compete with Gilead and AbbVie, Merck is looking to these untreated populations for building market share for its new drug Zepatier.
Designing more inclusive clinical trials
Dr. Eliav Barr, vice president of infectious diseases at Merck Research Laboratories, concedes that reaching injection drug users is challenging, but not impossible.
One of first step of that process is designing more inclusive clinical trials which can capture data on underserved populations.
“We decided to have studies that would encompass the breadth and depth of HCV, with many different types of HCV patients, including HIV-co-infected patients, patients with chronic kidney disease (CKD) and HCV-infected people who inject drugs and are receiving opiate agonist therapy (OAT). These people have traditionally been excluded from clinical trials,” Barr said.
Comparable efficacy rates, high levels of adherence
At this year’s International Liver Congress—European Association for the Study of Liver (EASL) in Barcelona, Dr. Barr is presenting data from the first HCV study to include injection-drug users, who were treated with Zepatier (elbasvir/grazoprevir), a once-daily combination tablet approved for treatment of HCV genoptyes 1 and 4 in adults.
The phase 3 study evaluated 301 injection-drugs receiving agonist therapy over a 12-week period. Roughly 20% of the patients were also HIV-co-infected. Ninety-five percent of patients treated with Zepatier in the target population achieved sustained virologic response after completing the 12 weeks of treatment. In addition, adherence—another concern with drug users—was high, with 97 percent of patients taking at least 95 percent of their study medication.
Greater awareness around injection-drug use
According to Dr. Barr, “Efficacy was no different in this population than in the larger treatment population, and 97% of patients were able to complete treatment. When you think about underserved or understudied HCV-infected people, you might think they represent small numbers, but in reality, they are the core of the epidemic. “
Merck is the first company to design a study incorporating large numbers of injection-drug users.
“Awareness of drug injection has increased from the explosion of heroin use—especially because of its spread to more affluent and suburban populations,” Dr. Barr.
Dr. Barr also noted that there is a significant level of built-in bias against injection-drug users. He said, “The assumption was that drug users could not adhere to an HCV-therapy treatment schedule, but they did. If a person can go to a methadone clinic, then taking one tablet a day is not so difficult.”
Leave no patient behind
In the US, 67% to 84% of the OAT population either is or has been HCV-infected, yet this population has typically been excluded from clinical trials.
“Limited research has been conducted in this group, because of perceived challenges and complexities in treating this population,” Barr explained.
“When we designed out phase 3 Zepatier trials, we wanted to bring new treatment options not only to ‘the big middle,’ but also to underserved patients. Our parallel-track approach was designed so that we would not leave any patients behind in our quest to get Zepatier registered.”
Theoretically, hepatitis C could be eradicated and become a historical medical condition, not unlike polio or the bubonic plague, since there is no animal reservoir for the virus. If the virus is eradicated in humans, it could potentially be eliminated entirely.
The new arsenal of antiviral medications for HCV, including Merck’s Zepatier and Gilead’s blockbuster treatments, can cure the disease in 94% to 99% of patients. These outcomes are not only beneficial for individual patients, but also have positive public health benefits, because they help break the cycle of transmission.
A principal challenge, however, is economic. The cost of treatment ranges from $54,000 to $168,000 (based on list prices before discounts and rebates). In response, some government and private payers have set up stringent reimbursement rules in which only the sickest patients get treatment.
Breaking the chain of transmission
However, others would argue that the idea of treating only the sickest patients is misguided, because the sickest patients are the least likely to transmit the virus. Younger, healthier HCV-infected injection-drug users are more likely to transmit the virus and perpetuate the cycle of transmission.
At face value, it would seem that payers would be willing to cover HCV treatments for OAT patients, based on the strength of Merck’s most recent data. But that’s not the case, however, according to Dr. Barr.
“Payers say that OAT patients are going to get re-infected. In response to that reality, we designed our trials to follow up on the OAT cohort. Preliminary data shows that new infection rates are only 4% per year.”
Despite that, since most injection-drug users are Medicaid eligible, the government may need to see a larger-scale analysis which takes into consideration cost-effectiveness and public health impact.
Towards that end, Merck is looking at communities which have successfully treated HCV-infected individuals as part of a larger public health initiative including psychosocial support and counseling.