HCV Drugs - Alan Franciscus

OCTOBER 2015
Vol. 18, Issue 10

HCV DRUGS
—Alan Franciscus, Editor-in-Chief

In this month’s column, I will discuss the recently released data from Achillion, and I will touch on various issues related to current treatment—drug-drug interactions, medical providers and insurance companies, and those who are still the most difficult to treat.
  
Achillion1
On September 17, 2015, Achillion announced the second part of their Phase 2 study (the PROXY study) of odalasvir (ACH-3102) and sofosbuvir to treat genotype 1.  The cure rates were 100% (6 of 6 patients). Earlier, Achillion had announced a 100% cure rate for 12 patients treated for eight weeks, and a 100% cure rate for 12 patients treated for six weeks.  Although there was a small number of patients in the PROXY study, this is encouraging data.
 
The study used Gilead’s drug—sofosbuvir—as the proxy drug.  A proxy drug is used as a placeholder while another drug is being developed and tested by a pharmaceutical company—in this case Achillion.  Also noteworthy, Achillion and Janssen are collaborating to develop and commercialize HCV drugs worldwide.  Janssen has many drugs in development to treat hepatitis C.  As well, Gilead, AbbVie, and Merck have drugs in the pipeline.  Merck’s new combination of two drugs is expected to be approved by the Food and Drug Administration (FDA) in early 2017.  

Medical Providers
Patients are not the only ones who are having a difficult time with the insurance restrictions.  Medical providers who have to tell their patients are also upset.  Many providers have to spend a lot of time submitting paperwork over and over trying to get their patients’ medications approved.  It takes up an inordinate amount of the medical provider and office staff’s time—many times only to be told that the insurance claim was denied.  As you can imagine it breaks their hearts to tell a patient “there is a cure, but I cannot give you it because insurance will not cover it.”  

Insurance
There are other issues that are difficult for patients, medical and service providers.  Access to the new medications can be very difficult depending on your insurance carrier.  Many people are being denied access to these life-saving HCV medications unless they have more serious disease progression.  Shame on the insurance companies that are not covering HCV medications!  It doesn’t help that the price of the drugs are so expensive.

The Current State of HCV Therapy
We have certainly come a long way compared to the interferon days.  Additionally, many populations—HIV/HCV coinfection, Latinos, compensated cirrhosis, healthy liver-transplanted—and other groups had very low cure rates.

The current state of HCV treatment is nothing short of amazing.  Current therapy cures up to 90% to 100% of people with HCV genotype 1, 2, and 4.  The medications also have lower side effects and shorter treatment duration.

The improvements in cure rates are impressive especially in certain populations with hepatitis C. In the September 2015 “Mid-Month Edition” of the HCV Advocate newsletter I wrote about 3 different clinical trials using 3 different combinations of direct-acting antivirals to treat HCV in people coinfected with HIV.  The patient populations in these studies included many of the patient characteristics previously considered the most difficult to treat—people with HIV, genotype 1a, cirrhosis, Black patients, previously treated patients—all who had not achieved a cure.  The cure rate in the three trials ranged from 96% to 98%.  Another population that has had dramatic improvements is liver transplanted patients (with moderate liver function and compensated cirrhosis).  The cure rates were 96% - 98%.  
 
Drug-Drug Interactions
A very important issue with the new direct antiviral medications is the potential for drug-drug interactions (DDIs). This is more of an issue for people of the Baby Boomer generation who may take additional medications for blood pressure, diabetes, cholesterol, etc.  People who are infected with HIV/HCV are also at risk for DDIs.  There is also a risk of DDIs with common over-the-counter medications and herbs. This is why it is so important to tell your medical provider(s) about anything you are taking.

Still Difficult to Treat2
A caveat:  Even though we need better therapies and strategies to treat the most difficult to treat patients listed here, the DAA therapies are still vast improvements from the older therapies in the people and groups below.

People with genotype 3 with cirrhosis and who have not been cured with a previous course of treatment are an unmet medical need.  Current treatments only yield cure rates in the 60 percentile. There is an option of adding pegylated interferon. I wrote about this before and advised people to think about this but I did not get a very positive reaction.

People with decompensated cirrhosis are at risk for severe disease progression, but unfortunately, current treatment does not work as well. Similarly, people with end-stage kidney disease or people who are on dialysis also have a large unmet medical need.  Note:  Merck’s new combination looks very promising for this group of patients.  People who do not respond to a previous course of therapy are another difficult group to treat, but treatment strategies are slowly evolving.

Re-Treatment
For someone who has relapsed, coming up with a plan to prescribe the right combination of drugs to optimize the chances of re-treatment success is more difficult with the development of RAVs (see a brief overview of RAVs in this issue).

There have been many advances in hepatitis C treatment in a short period of time. Hopefully, many of the treatment issues listed above will be quickly resolved.  In the meantime, we all have to advocate for ourselves and others with hepatitis C and remember to thank those medical providers who are providing such wonderful care.

References:
1 Company Press Release
2 Difficult-to-cure populations with chronic hepatitis c: Vanishing in the direct-acting antiviral era?
Norah Terrault M.D. Hepatology Volume 62, Issue 1, pages 4–7, July 2015

The True Cost of an Expensive Medication

It was supposed to be a miracle, but now it’s what keeps Laura Bush, a nurse-practitioner near Albuquerque, awake at night.

There’s a drug called Sovaldi that works astonishingly well to cure people with the liver disease Hepatitis C. The rub? It costs $1,000 per day for all 12 weeks of treatment.

Bush’s clinic, First Choice Community Healthcare, is a federally qualified health center in the rural town of Los Lunas, New Mexico, which means she sees a disproportionate number of patients who are uninsured, underinsured, and on Medicaid, the government insurance program for the poor. In other words, they can’t afford Sovaldi.

Read more....

HCV Drugs: AbbVie, BMS, Merck —Alan Franciscus, Editor-in-Chief

AbbVie:

TECHNIVIE:
On July 24, The Food and Drug Administration (FDA) approved the first interferon-free combination therapy to treat HCV genotype 4. The combination called TECHNIVIE (ombitasvir, paritaprevir and ritonavir) is taken with ribavirin and for 12 weeks.  There was a total of 135 patients in the study—91 received TECHNIVIE with ribavirin and 41 received TECHNIVIE without ribavirin.  None of the trial participants had cirrhosis.  In the group that received TECHNIVIE with ribavirin there was a 100% cure rate; in the group that did not receive ribavirin there was a 91% cure rate.  Since the study did not include people with cirrhosis the FDA did not approve TECHNIVIE for the treatment of genotype 4 with cirrhosis.  AbbVie has indicated that there are on-going studies of genotype 4 cirrhotic patients and they will pursue an indication for cirrhotic patients on the TECHNIVIE product label. 

Genotype 4 is uncommon in this country—the estimated prevalence is between 1.3% to 2.3%.  There are some higher populations in areas around New York City, Los Angeles and Southern California estimated between 2 to 3%.   Genotype 4 is the fourth most common genotype worldwide.  It also accounts for 90% (6,030,000) of the hepatitis C population in Egypt.  The remaining HCV population is genotype 1.  The total HCV population of Egypt is 6.7 million. 

Source:  FDA Press Release (The total HCV population of Egypt is 6.7 million.

Be sure to check out our fact sheet on hepatitis C in Egypt: http://hcvadvocate.org/hepatitis/factsheets_pdf/HCAW_Egypt.pdf  

New Combo:
A new phase 2 study of ombitasvir, paritaprevir and ritonavir—once-a-day  combination of AbbVie drugs to treat 181 genotype 1b patients for a treatment period of 12 weeks ( without cirrhosis) or 24 weeks (with cirrhosis).   The cure rates among the groups are listed below:

• No-cirrhosis group: 95.2% cure rate among people who had never been treated (treatment naïve (42 patients); 90% cure rate among people who had been previously treated (treatment experienced  (40 patients))
• Cirrhosis group: 97.9% cure rate among treatment naïve (47 patients);  96.2% cure rate in the treatment-experienced group (52 patients)

The most common side effects were headache, lack of energy, itching, and diarrhea. There was one treatment discontinuation due to treatment-related side effects.

This combination without interferon or ribavirin in a once-a-day pill for people with HCV genotype 1b would be a welcome addition to the landscape of hepatitis C treatment. 

Source: Efficacy and Safety of Ombitasvir, Paritaprevir, and Ritonavir in an Open-label Study of Patients With Genotype 1b Chronic Hepatitis C Virus, With and Without Cirrhosis—Erica Lawtz– et al. http://dx.doi.org/10.1053/j.gastro.2015.07.001

Bristol-Myers Squibb
On July 24, 2015, the FDA approved BMS’s Daklinza (daclatasvir) in combination with Gilead’s sofosbuvir to treat HCV genotype 3.  In the phase 3 studies of patients who were treated with Daklinza and sofosobuvir for 12 weeks the cure rates broken down by cirrhosis and prior treatment response are listed below:

• Without Cirrhosis:  Treatment naïve—98%;
  Treatment experienced—92%
• With Cirrhosis:  Treatment naïve—58%;
  Treatment experienced—69%

The most common side effects were fatigue and headache.

The FDA press release noted that the response rates were reduced for HCV genotype 3 patients with cirrhosis.  It should also be noted that the treatment duration is only 12 weeks as opposed to 24 weeks with the current standard of care—Sovaldi plus ribavirin.  Still there is an unmet medical need for people with HCV genotype 3 with cirrhosis. 

Source:  FDA press release. 

Merck
On July 28, 2015, Merck announced that the FDA had accepted their New Drug Application for grazoprevir/elbasvir for the treatment of HCV genotype 1, 4 and 6 infection.  Merck has been granted Breakthrough Therapy designation for grazoprevir/elbasvir for the treatment of patients with HCV genotype 1 with end stage kidney disease who are on hemodialysis, and also for those patients with HCV genotype 4.

The cure rates for grazoprevir/elbasvir (one-pill/once-a-day) are impressive:  genotype 1 up to 100%; genotype 4 up to 100% and up to 80% for genotype 6.

Merck stated that they expected a notification for drug approval from the FDA by January 28, 2016.

Source:  Company press release

http://hcvadvocate.org/news/newsLetter/2015/advocate0815_mid.html#1

HCV Drugs, by Alan Franciscus, Editor-in-Chief

This month’s edition of HCV Drugs will be short due to the upcoming European Association for the Study of the Liver (EASL) conference.  Join us for extensive coverage on www.hcvadvocate.org for the latest news and the next edition of the HCV Advocate newsletter.   There is, however, important news included in this issue:  Merck is granted Breakthrough Therapy designation; phase 2 study results of AbbVie’s combo to treat genotype 4; and, lastly not really drug-related, a new study that is being sponsored by the National Institutes of Health (NIH) that may finally help expand care and treatment to other medical providers. 

Merck
Just when we thought that the Food and Drug Administration (FDA) had rescinded Breakthrough Therapy designation for all HCV therapies – we were wrong—they have given it to Merck’s combination of grazoprevir plus elbasvir for the treatment of people with HCV genotype 1 who have end-stage renal (kidney) disease on hemodialysis and for people with HCV genotype 4.  The designation will allow for expedited review and approval. 

Comment:  These two groups are definitely in need of expedited review!  This is very good news for people living with hepatitis C.  Merck has this combination of medications in multiple studies. 

Source:  Company press release

AbbVie
Results from a small phase 2 trial was recently published in The Lancet.  The trial included 86 HCV genotype 4 patients who had never been treated (treatment naïve) as well as those who had been treated previously (treatment-experienced).  The patients were treated with ombitasvir (once-daily), paritaprevir/ritonavir—with and without ribavirin (twice daily) for 12 weeks. 

Forty-nine patients who had previously received treatment (treatment-experienced) received the AbbVie combination treatment plus ribavirin for 12 weeks. 

In the treatment-naïve group the cure rate was 100% in the group that received ribavirin and 91% in the group that did not receive ribavirin.  In the treatment-experienced group the cure rate was 100%.

Comment: More good news for patients—although genotype 4 is uncommon in the United States it is estimated that about 13% of the global population (mostly in Egypt) is infected with genotype 4.  However, when I conduct training workshops it always surprises me that there is usually one or more persons with genotype 4!

Source:  Hézode C et al. Ombitasvir plus paritaprevir plus ritonavir with or without ribavirin in treatment-naive and treatment-experienced patients with genotype 4 chronic hepatitis C virus infection (PEARL-I): A randomised, open-label trial. Lancet 2015 Mar 30; [e-pub].

NIH
The NIH and the city of Washington, D. C., with support from the NIH Office of AIDS Research has launched a study that will include 600 patients with HCV or HIV/HCV coinfection.  Of the patients enrolled, 350 will continue with their current specialist, and 250 will be assigned to a primary care doctor, physician, physician assistant or nurse practitioner for treatment.  The treatment will be Harvoni for two to six months. 

Comments:  There has always been a lack of medical providers to manage and treat people with hepatitis C.  This is increasingly becoming a problem due to the increased awareness, testing and treatments that are easier to tolerate and more effective.   Hopefully, this will show that more medical providers can safely and effectively manage and treat people with hepatitis C. 

Source:  NIH News press release

http://hcvadvocate.org/news/newsLetter/2015/advocate0515.html#3

HCV Drugs Alan Franciscus, Editor-in-Chief

BMS Files NDA with FDA
On March 12, 2015 Bristol-Myers Squibb (BMS) announced that the Food and Drug Administration (FDA) had accepted their new drug application (NDA) for the combination of daclatasvir plus sofosbuvir for the treatment of HCV genotype 3.  In BMS’s phase 3 studies of genotype 3 patients—101 treatment-naïve, 51 treatment-experienced—the cure rates were 90% and 86% respectively.  However, in people who had cirrhosis (F-4) the cure rates were 63% to 73% leaving an unmet need for these patients. 

CROI
The Conference on Retroviruses and Opportunistic Infections (CROI) 2015 held in Seattle, WA, had a wealth of information about the treatment of people with HIV and HCV coinfection.  Since the introduction of interferon-free therapy the cure rates of HCV in people who are coinfected with HIV and HCV are the same as the cure rates in people who are HCV mono-infected, and importantly the studies presented at CROI reinforce this information.  

Daclatasvir/Sofosbuvir
DL Wyles et al., presented “Daclatasvir in Combination with Sofosbuvir for HIV/HCV Coinfection:  ALLY-2 Study.” The study included patients with HCV genotype 1 (1a-139 pts; 1b-29 pts), genotype 2 (19 pts), genotype 3 (19 pts) and genotype 4 (3 pts).  There were three arms in the study—two arms with 12 weeks treatment duration and one arm with an eight-week treatment period—there were no genotype 4 patients in the eight-week treatment arm.  Most of the patients were male (83-91%);

White (56-65%); and there were 29 patients with cirrhosis in the study. 

The cure rates were 97% in genotype 1, and 100% in genotypes 2, 3, and 4 in the groups treated for 12 weeks.  In the groups treated for eight weeks, the cure rates fell to 76%.  There was no impact based on genotype or type of prior treatment response.

Comments:  These are remarkable cure rates regardless of genotype, viral load, and other factors at least in the 12-week group.  Based on this data 8 weeks of Daclatasvir plus sofosbuvir is not effective. 

An unmet medical need is treatment of people with genotype 3 with cirrhosis—this information was not available.  Additionally,  there were very few genotype 3 patients in the study to draw any conclusions.   

Given the results of Harvoni (below) the niche for this combination may be narrow.  However, it was noted that, if approved, adjusting the dosing would be easier since these drugs are dosed separately especially for some people on HIV medications.  

Harvoni
S Naggie et al., present data from “Ledipasvir/Sofosbuvir for 12 Weeks in Patients Coinfected with HCV and HIV-1:  ION-4.”  This study was a phase 3 clinical trial of Harvoni (sofosbuvir/ledipasvir) for the treatment of HCV genotype 1 and 4 in people who are coinfected with HIV and hepatitis C.  A total of 335 patients were included in the trial—75% were genotype 1a; 23% genotype 1b; 2% genotype 4. The study included 45% treatment-naïve patients, 55% treatment-experienced patients, and 20% of the patients had compensated cirrhosis.  The mean age of the patients was 52yo; 82% were male, 34% were Black.

The overall cure rate was 96%.  There was little difference in cure rates between treatment naïve and treatment experienced (95% vs. 97%) and those with and without cirrhosis (94% vs. 96%).  There was a difference in cure rates between Blacks (90%) and non-Blacks (99%).  The most common side effects were headache, fatigue and diarrhea. 

Gilead is trying to determine the difference in the cure rates between Blacks and non-Blacks.  They have ruled out drug concentration levels in the blood and the possible interaction of the HIV medications.  During the question and answer period there were a couple of interesting comments about the lower response rates in Blacks:

• Perhaps Black patients coinfected with HIV and HCV may need to be treated longer
• Previous clinical trials have had lower Black patient populations that may not have given us a true picture of treatment cure in Blacks—more Blacks are needed in clinical trials period.  In the days of pegylated interferon and ribavirin therapy the cure rates were much lower.

Gilead stated that they are planning to file a New Drug Application (NDA) with the FDA based on the phase 3 data for the treatment of HCV in people with HIV.  

Comments:  Impressive cure rates and low side effects regardless of prior treatment response or degree of liver damage.  Once we learn more about the reason for the lower response rates in Blacks we will keep our readers informed. 

Delaying Treatment = More Deaths
Everyone is trying to come to terms with the impact of treating people who are the sickest.  Lately, there have been studies showing this approach may not be cost effective.  It certainly isn’t patient centered or tied to improving the quality of life for people living with hepatitis C.  A study presented at CROI—“Impact of Deferring HCV Treatment on Liver-Related Events in HIV+ Patients, by C Zahnd et al.”—sheds some light on the long-term health risk of  delaying treatment.  

The researchers in the study used a model to predict health outcomes from the Swiss HIV Cohort Study to simulate HIV/HCV patients from the time of acute infection through chronic infection and fibrosis stages using the Metavir system for staging fibrosis/cirrhosis (F0 through F4), decompensated cirrhosis, liver cancer, and death. They assumed that 100% of patients were treated with interferon-free therapies and of these patients 90% were cured.   

The highlights of their findings included:

• If patients were treated one month or 1 year after diagnosis—3% would die from liver-related deaths
• If HCV treatment was delayed until later stages, the percentages of patients who were predicted to die dramatically increased:  Treated at F-2 a 5% death rate; treated at F-3 a 10% death rate; treated at F-4 a 25% death rate. 

Comment:  It is a known fact that people cured of hepatitis C still have liver disease progression especially in later stages of cirrhosis.  The authors of the study believe that HIV/HCV coinfection may contribute to liver disease progression even after being cured.  This study and other studies which show the benefits of early treatment should be an important part of the discussion on evaluating the cost-effectiveness of treatment.  There is also a matter of public health:  Treating HCV can stop the transmission of HCV.  

http://hcvadvocate.org/news/newsLetter/2015/advocate0415.html#3

HCV Drugs: Triple Drug Regimens, Exclusivity Deals, Merck & Gilead Updates —Alan Franciscus, Editor-in-Chief

At last year’s CROI conference, I wrote about a 6-week study of sofosbuvir, ledipasvir, and GS-9451.  This combination was tested against sofosbuvir/ledipasvir alone for 12 weeks and sofosbuvir/ledipasvir plus GS-9669 for 6 weeks.  The drugs were combined into one-pill, taken once-daily.  There were 20 patients in each arm.

The bottom line is that all 20 patients (100%) achieved a cure in the triple combination of sofosbuvir/ledipasvir and GS-9669 with 6 weeks of treatment.  The most common side effects were headache, fatigue and diarrhea. 

Comments:  This study is a small study and there is currently no information that it has yet entered into phase 3 studies.  But given the high cure rates and low side effects hopefully it will be entered into clinical trials with this combination or perhaps Gilead is researching another inhibitor to include. 

Study: Virological response after 6 week triple-drug regimens for hepatitis C: a proof-of-concept phase 2A cohort study. Authors: A Kohli et al.

Exclusivity Deals
Ever since AbbVie’s VIEKIRA PAK’s approval there have been intense negotiations between insurance companies/pharmacies and AbbVie and Gilead to determine who will be the exclusive distributors of the pharmaceutical HCV medications. These deals will help to drive down the costs of the drugs, and this will hopefully translate into more patients having access to HCV medications.  The real downside is that the decision as to which medication a patient should be prescribed is now being made by someone other than a patient and medical provider. This is very bad news for patients (see "Predictors" article).  The information below is from our blog as of the date that we have put together our newsletter.  If you have been denied treatment in the past, you may want to check the list below (or our Blog) to find out if you would now qualify for insurance coverage.  The agreements are on-going so keep checking back. 

• AbbVie: Express Scripts, AIDS Drug Assistance Programs (ADAPs)
• Gilead: Aetna, Humana, Anthem, CVS
• Both—AbbVie/Gilead:  Prime Therapeutics

Merck
In January, Merck announced that it has been prioritizing portions of its drug development operations including hepatitis C.  In this respect, the development of a two-drug single pill (grazoprevir/elbasvir) will be accelerated.  Merck hopes to apply for marketing approval in the first half of 2015.  The combination is currently in phase 3 studies.  Phase 2 studies of the two drug combination with and without ribavirin in multiple arm studies of monoinfected and HIV/HCV coinfected patient populations with and without cirrhosis resulted in cure rates from 90 to 100%.  The most common side effects were fatigue, headache and general weakness. 

Gilead
Gilead has announced that it has expanded its hepatitis C generic licensing agreements to include the investigational NS5A inhibitor GS-5816, which is being evaluated in Phase 3 clinical studies as part of a single tablet regimen that combines the compound and sofosbuvir for the treatment of all six genotypes of hepatitis C. If approved by regulatory authorities, the sofosbuvir/GS-5816 regimen would become the first pan-genotypic, all-oral single tablet regimen for HCV. A pan-genotypic therapeutic option is particularly important for developing countries, where genotype testing is often unreliable or not readily available.

http://hcvadvocate.org/news/newsLetter/2015/advocate0215.html#2