Published on Feb 21, 2014
Steven Flamm, MD, medical director of the liver transplant program for Northwestern Medicine discusses the hepatitis C drug pipeline.
Topics include Sovaldi (sofosbuvir), interferon free regimes, pricing, possible U.S. managed care restrictions with regard to Canadian coverage.
Less than three years ago, the FDA approved two new breakthrough drugs for treating chronic hepatitis C (HCV)—Victrelis (boceprevir) and Incivek (telaprevir)—the first protease inhibitors approved for HCV. Although their introductions caught the attention of the marketplace, their successors are arriving quickly.
Late last year, the FDA approved two new HCV drugs, Solvadi (sofosbuvir), a polymerase inhibitor to treat genotypes 1 through 4, manufactured by Gilead Sciences, and Olysio (simeprevir), a protease inhibitor from Janssen Therapeutics targeting genotype 1.
Costing $1,000 a day, 400 mg of sofosbuvir is taken with either ribavirin alone, or with ribavirin and interferon, orally, once a day for 12 to 24 weeks, depending on the genotype. Simeprevir at 150 mg, also an oral, once-a-day drug, is recommended for 12 weeks in combination with ribavirin and interferon, followed by another 24 weeks of ribavirin and interferon. Its cost is $790 a day.
The Centers for Disease Control and Prevention (CDC) estimates that 3.2 million persons are chronically infected with HCV. Approximately 75% to 85% of people infected with the HCV virus will develop chronic infection.
Successful treatment is measured by a sustained virologic response (SVR), which signifies an undetectable viral load/serum HCV RNA (ribonucleic acid—the virus’ genetic material) after the designated period of treatment.
As with any new specialty drugs, insurers, pharmacy benefit managers and physicians must weigh the value of the new products, balancing cost, efficacy, effectiveness and ease of use.
Managed Healthcare Executive recently convened three key thought leaders to discuss the impact of simeprevir and sofosbuvir and whether they will stand the test of time.
Mary Dorholt leads Express Script’s specialty clinical strategy and protocol development, creating clinical guidelines for patient care and physician interaction. She is also responsible for driving organizational research around specialty medications and Express Scripts’ experience. Prior to her current role, she was responsible for provision of specialty strategic guidance to employer, government and labor organizations. She holds a doctor of pharmacy degree from the University of Minnesota College of Pharmacy in Minneapolis and B.S. degrees in mathematics and biology.
Karla Thornton, MD, MPH, is a professor in the Division of Infectious Diseases at the University of New Mexico School of Medicine in Albuquerque. She also serves as the associate director of Project ECHO (Extension for Community Healthcare Outcomes). Using her clinical expertise in the treatment of hepatitis C and HIV, she facilitates teleECHO clinics through which she trains other clinicians on comprehensive care. In 2009, Dr. Thornton started an education project that trains New Mexico state prisoners to be peer educators in hepatitis C, other infectious diseases and addiction.
John Poniatowski joined CIGNA in 1994, and currently serves as clinical program director, specialty pharmacy for CIGNA Pharmacy Management. He is responsible for establishing and executing utilization management and health management strategies related to the use of specialty pharmaceuticals. Programs focus on the integration of medication therapy with CIGNA’s medical, health and wellness programs to improve health outcomes and lower overall healthcare costs. Poniatowski received his bachelor of pharmacy degree from Northeastern University and his M.S. degree from Saint John’s University. He completed an American Society of Health-System Pharmacists’ hospital pharmacy residency at Mercy Hospital in Rockville Centre, N.Y.
MHE: Why has there been an increase in cases of hepatitis C?
Thornton: There actually is not an increase in the incidence of new infections, but what’s happening is that we’re identifying more people who are chronically infected with hepatitis C. The actual incidence of hepatitis C has decreased dramatically over the last 20-plus years. In the 1980s, incidence was about 200,000 cases per year compared to an estimated 17,000 cases in 2010.
About a year ago, the CDC and the U.S. Preventive Services Task Force came out with guidelines to actually screen more people. They recommend that anyone born between 1945 and 1965 get a blood test for hepatitis C. The recommendation is important because we haven’t been very good at screening in the past.
Dorholt: Sometimes there’s a perception of increasing new infections because there’s been this warehousing phenomenon going on where patients who don’t necessarily need to be treated—those who are not showing overt signs of disease or are not deteriorating—are being held back [from treatment] while physicians wait for the newer, more efficacious and perhaps easier-to-use medications to treat those patients that they know are infected.
MHE: As for warehousing patients to wait for a newer treatment, is that a problem?
Thornton: I don’t think I would characterize it as a problem. These folks that have the virus are not always becoming sicker, so there is time to wait for perhaps a more successful opportunity for treatment.
Poniatowski: When Incivek and Victrelis came to market in mid-2011, they were obviously seen as improvements over the prior two drug combinations, so we saw an increase of people coming in to be treated. That continued through 2011 into late 2012, and then started tapering off by 2013 for the reason that Mary stated: It’s not always urgent to treat these folks, and clinicians knew that there were better drugs coming around the corner.
MHE: Before the introduction of Incivek and Victrelis, what was the situation for HCV drugs? And what can sofosbuvir and simeprevir do that their predecessors cannot?
Thornton: The prior treatment before May of 2011 was injected pegolated interferon and oral ribavirin for all genotypes.
The success rate with that particular regimen was about 50% in genotype 1 patients, which is the predominant genotype in the United States, and higher in genotype 2 and 3 patients—up to 70%. All genotypes required interferon—that is a very difficult drug to take. It has a lot of toxicity; people can’t tolerate it. And the duration of therapy at that time for genotype 1 patients was a minimum of 48 weeks.
Telaprevir and boceprevir increased the cure rate in genotype 1 to about 70%, compared to about 50% with interferon and ribavirin alone. They also introduced what was called response-guided therapy, meaning the duration of therapy will depend on a patient’s actual response to the medication. If someone had a good initial response to therapy, they might just need six months of therapy versus 48 weeks. The new therapies had the potential to increase the cure rate and shorten the duration.
Simeprevir is an improvement over its immediate predecessors because it’s one pill, once a day. It has fewer side effects and drug interactions and has a very similar cure rate to that of telaprevir and boceprevir. Unfortunately, you still have to take interferon and ribavirin, and it’s a response-guided therapy just like the other ones are. Therefore, people would also have to continue on interferon with simeprevir.
Sofosbuvir is a brand new class of drugs called a polymerase inhibitor. For genotype 1, it’s given in combination with pegolated interferon and ribavirin, but it’s only for 12 weeks. It shortens the duration for using interferon, and the cure rate for 12 weeks is about 90% in patients who have not previously been treated. For the other genotypes, that particular drug is given just in combination with ribavirin. And again, there is a much higher cure rate than what we were seeing in the past with interferon-based regimens.
Dorholt: I think it also is fair to say that the direction of new drug development in this area continues to move toward the shorter, all-oral regimen that can be used in the majority of hepatitis C patients in the United States. That really eliminates the historically used pegolated interferons and ribavirin. We’re not necessarily there for genotype 1, which is the most predominant type of hepatitis C in the United States, but these drugs are getting us much, much closer, and there is a lot in the pipeline that will help us move the needle as well.
Poniatowski: As each generation of HCV medications comes to market, they bring different advances, hopefully all driving towards the fact that the patient will be more likely to take the drug as intended, and for the full duration. The result is not just achieving better effectiveness, but fewer side effects with less likelihood of stopping the drug.
MHE: Are sofosbuvir and simeprevir considered to be cures?
Thornton: Yes. Any drug that gets rid of the hepatitis C virus, and there’s no virus six months after therapy, is considered a cure.
Dorholt: All of the approved agents, even the interferons and ribavirins have been cures; they just differ in the number of patients that are successfully cured. For patients who achieve SVR, the incidence of them actually relapsing is very low at 1% to 2%. For the older two drugs, the SVR is around 40%, while it is in the range of 80% to even 90% with the new medications.
MHE: Since simeprevir requires interferon, won’t the problem with side effects and longer treatment times with that drug still exist?
Thornton: That’s true, because with simeprevir as a response-guided therapy, somebody could still end up getting an entire year of interferon therapy. Recently, guidelines for treatment of chronic hepatitis C from the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) came out, and they do not recommend simeprevir as first line therapy for genotype 1 because of the risk of having to prescribe that much interferon. However, when simpeprevir is used in combination with sofosbuvir, it’s only 12 weeks of interferon, and there is a very high cure rate.
Poniatowski: There is at least one interferon-free regimen in genotype 1 that is FDA-approved for the population that’s considered interferon-ineligible.
Thornton: FDA labeling says that for interferon intolerant, or unwilling individuals, the second-line therapy would be a combination of sofosbuvir and ribavirin for 24 weeks. You don’t get as good of a cure rate, but it is an option for people who really need therapy and can’t wait for newer therapies, nor can they take interferon.
**Hi folks, as mentioned, the AASLD/IDSA launched an up-to-date guidance for the treatment of hepatitis C. The new guidelines will have a complex
algorithm for practitioners around the country to follow and see whats
the right treatment, for the right patients, for the right about of
time. Information includes both newly FDA approved drugs sofosbuvir and
simeprevir, as well as off-label use for specific HCV combinations.
Click here to begin reading.....
MHE: Let’s discuss the new guidelines and their implications.
Thornton: The guidelines are the result of a joint effort by the two associations (AASLD and IDSA), and this is the first time this has ever happened. It is exciting for us in the field to have guidelines that are going to be kept up-to-date and are user-friendly. In the past, they were always behind if a new drug came out. At least in my practice, they reflect exactly what we’re doing.
Poniatowski: I was impressed and surprised by the timing because practice-based guidelines don’t typically react that quickly to changes in the marketplace. I was struck by the fact that the earlier two new improved drugs are not recommended. The other thing that’s interesting is that the guidelines recommend a combination of simeprevir and sofosbuvir, which is not yet approved by the FDA. It’s precedent setting so that when the next drugs arrive, we can expect guidelines to be just as timely.
Thornton: The combination has been shown—at least in Phase II clinical trials—to be extremely effective for even people who are the most difficult to treat, who have cirrhosis and have previously failed therapy. In the clinical practice, we are desperately trying to get that combination for the patients who are interferon-ineligible.
Dorholt: This is kind of groundbreaking in terms of how quickly they have encompassed the new drugs into the guidelines and even incorporated some things that are not necessarily FDA approved, that are a little bit off-label but have evidence.
MHE: Is the FDA working on approval of the combination of simeprevir and sofosbuvir?
Poniatowski: It’s a tough question about which to speculate because it really comes down to the pharmaceutical manufacturers’ strategies—two different companies deciding whether or not they want to actually pursue that type of label and indication. Not only has the combination been incorporated into the guidelines, but there also are ongoing studies, so you know the requirement for FDA approval is certainly not a necessity for practitioners to use the drugs in such a way. The lack of approval is not the only consideration for payers in determining whether it would be appropriate to cover that combination.
The coverage question at Cigna is based on the evidence in terms of published studies, and we really consider the specific characteristics of each patient case and hold periodic conversations between our medical director and the physician.
Thornton: The many different permutations and combinations of drugs and durations of therapy for hepatitis C must come into play when decisions are being made about what types of therapy to recommend and which courses of therapy are most appropriate.
MHE: How are patients going to be able to afford these new drugs?
Dorholt: At Accredo, we never want to see cost be a barrier to patients who need a medication. If patients express any level of concern about costs or payment while we’re working with them, we connect them to our reimbursement specialists, who can find appropriate financial assistance, including a patient assistance program or resources available from a foundation.
We also work with our payer clients to help them make cost share choices to manage costs, while also not deterring patient access because costs are so excessive. From our research and understanding of patient behavior, we know that there’s a tipping point where that can occur, and so benefits also have to be created using that perspective.
Poniatowski: Due to our holistic approach to patients, Cigna Specialty Pharmacy Services also informs customers about programs and resources available to them, including financial assistance programs for the costly specialty medications.
MHE: Is there a way for physicians to determine who is going to benefit most from these new drugs?
Dorholt: Because of the complexity of the drugs and the nuances of patients, I think there are many elements that play into the individual selection process. Efficacy, for example, is a major factor. You also have to think about the viral genotypes and their subsets because that will influence which drug you pick and which is more successful.
Other things that need to be considered are: previous treatment history and the response to that treatment, because there is some cross resistance between some of these products; the severity of the disease and whether the patient already has cirrhosis; a patient’s other diseases that might influence drug choices; whether medications for those other conditions have an effect; and if a patient has HIV.
In addition, you have to look at patient dynamics: What is that patient’s ability to handle a really complicated regimen with complicated side effects?
Poniatowski: A combination of what a person’s disease looks like, what drugs are on the market and their pros and cons, and what is on the horizon is necessary in making that decision about treating now or waiting.
MHE: What kinds of disease management programs prove to be most effective in targeting non-adherence and eliminating the virus?
Poniatowski: At Cigna, we approach disease management programs by looking at patients holistically, not just paying attention to their hep C because they may have comorbid conditions. Instead, we consider their care across the whole spectrum of their disease.
Cigna Specialty Pharmacy Services creates teams of pharmacists, certified pharmacist technicians, registered nurses and call center personnel whose training focuses on a particular chronic condition such as hepatitis C. They continually monitor adherence, side effects and drug interactions and reach out to the treating doctor when adjustments are needed.
Dorholt: Any effective program in our portfolio has to include a multifaceted approach to support the patient, including direct education, clinical outreach, ongoing adherence messaging and reminders, and technology-based tools to create a sense of community or patient connection.
Express Script’s specialty unit, Accredo, offers patients with hepatitis C one-on-one counseling by pharmacists with expertise specifically in managing hepatitis C. Nurses and pharmacists make follow up calls to these patients depending on their specific situations.
Thornton: Our most important offering is Project ECHO, providing 24 service centers of excellence around the state of New Mexico that treat hepatitis C.
Hepatitis C treatment is actually embedded in patients’ primary care settings, which offer a team-based approach. Along with a clinician, there is always a community health worker, a medical assistant or someone with similar capabilities. The key is having very close follow-up with providers and the hepatitis C team in clinics where patients are treated. When we studied the effectiveness of treatment through the project, we had really phenomenal responses and adherence rates because people were being treated within their own home base and in their own primary care setting.
Article Source
