Sunday, November 24, 2013

HCV Drug Olysio (simeprevir) - The New Kid On The Block

HCV Drug Olysio (simeprevir) - The New Kid On The Block

Hello everyone,
It sure is another cold weekend here in Michigan, hope it's warmer in your part of the world.

Today, as I sat cuddled in my warm chair, gazing out the window, I found myself watching the birds on our backyard feeder. One seed at a time, slowly they ate their afternoon meal. This arduous task ensures their survival, and will continue day in and day out, season after season.

The same can be said of hepatitis C patients, waiting day after day, year after year for new therapies to be approved. In some cases, the drugs are needed for patients to remain healthy, and yes, for others, they are needed for survival.

The HCV standard-of-care treatment in 2001 was the combination of pegylated interferon and ribavirin. Unfortunately this treatment only cured around 50% of individuals with genotype 1, which is the most prevalent HCV genotype in the US and Europe.  The HCV community waited ten years before a new drug was available, finally, in 2011 the first direct-acting antivirals (DAAs) boceprevir and telaprevir received FDA approval.

Two years later, and some 48 hours ago, the FDA approved Olysio (simeprevir), a new drug to treat HCV.

On this special occasion, and for the newly diagnosed, I thought a few links for reference purposes and a bit of information on simeprevir may be helpful.

Check back often, as new updates are available links and information will be provided below;

December 5-3 Updates
Simeprevir (Olysio): J & J Patient Access Programs

Video - Dr. Joseph Galati talks about HCV drug OLYSIO (simeprevir)

Olysio (simeprevir) - Resistant Variant (Q80K) 
Although, simeprevir appears to be slightly more effective than the standard of care, curing 80 percent of treatment-naïve patients, and easier to take, there are some drawbacks. Before starting simeprevir patients with HCV genotype 1a need to be screened for a genetic mutation called Q80K polymorphism.

November 26th updates: An article written by Marc Iskowitz on the cost of OLYSIO and an educational video from Janssen

OLYSIO (Simeprevir) Cost?
Janssen has priced Olysio at a wholesale acquisition price of $22,120 per bottle of 28 capsules (150 mg capsules), which is an approximately one-month supply. That's roughly $66,360 for a three-month course.
Read more here...

Hepatitis C Drug OLYSIO™ (simeprevir)

The Basics

OLYSIO (Simeprevir) - The New Kid On The Block

Simeprevir is used to treat HCV genotype 1 infected subjects with compensated liver disease (including cirrhosis) in combination with peginterferon and ribavirin. Simeprevir has yet to be studied in patients who have previously failed therapy with a treatment regimen that includes other HCV protease inhibitors.

Before starting simeprevir patients with HCV genotype 1a should be screened for a genetic mutation called Q80K polymorphism. Alternative therapy should be considered for people with the mutation according to Prescribing Information.

Like Simeprevir, both boceprevir and telaprevir are protease inhibitors approved to treat HCV genotype 1 patients in combination with peginterferon and ribavirin.

Simeprevir and telaprevir are used for 12 weeks, boceprevir is used from 24 to 44 weeks.

Peginterferon and ribavirin are used with these drugs, from 24 to 48 weeks.

Simeprevir Duration of Treatment

The recommended duration of treatment with OLYSIO is 12 weeks in combination with peginterferon alfa and ribavirin. In all patients, treatment with OLYSIO should be initiated in combination with peginterferon alfa and ribavirin and should be administered for 12 weeks.

All treatment - naïve and prior relapser patients , including those with cirrhosis , should receive an additional 12 weeks of peginterferon alfa and ribavirin after completing 12 weeks of treatment with OLYSIO , peginterferon alfa and ribavirin (total treatment duration of 24 weeks)

All prior non - responder patients (including partial and null - responder s), including those with cirrhosis, should receive an additional 36 weeks of peginterferon alfa and ribavirin after completing 12 weeks of treatment with OLYSIO, peginterferon alfa and ribavirin (total treatment duration of 48 weeks)

The good news? Simeprevir is taken only once daily (capsule of 150 mg taken orally) with food.

*The type of food does not affect exposure to simeprevir. The capsule should be swallowed as a whole. 

Boceprevir and telaprevir are both taken three times a day with a meal or snack, telaprevir should be taken with a snack that contains protein (cheese, peanut butter, eggs). Although, in some patients telaprevir can be taken twice daily.

Lesson Learned

Telaprevir and boceprevir have significantly increased the ability to cure HCV, but both PIs have their own side effects, including those from interferon.

An important lesson we learned from these drugs may serve as a reminder for future DDAs, that is, once telaprevir and boceprevir were used in larger groups of patients, or in "real-life" settings - outside clinical trials, new response rates and adverse effects began to emerge.

For instance  Dr. Arpita Sheth presented a poster at the Interscience Conference which found 30% of veterans taking direct-acting antivirals boceprevir and telaprevir in "real-life" settings, discontinued treatment by week 24, despite high rates of early response. The study included a greater proportion of cirrhotic patients, then compared to clinical trials. Anemia was  increased by 15%  - over what has been reported elsewhere. The study appears in the 2013 August issue of Clinical Gastroenterology and Hepatology

Food For Thought

In an editorial, in which both simeprevir and sofosbuvir were the topic, researchers wrote; Time will tell if these first second wave DAA agents will prove to be safe and effective when used in large numbers of real life chronic HCV infected patients. The article was published in the November, December issue of Annals Of Hepatology.

Simeprevir Side Effects

Common side effects reported in clinical trials were rash, itching, and nausea, some patients experienced serious photosensitivity reactions which required a trip to the hospital.

The FDA’s advisory panel determined simeprevir was much easier to take than the first generation protease inhibitors (PIs) telaprevir and boceprevir. With SVR rates of 79%-80% in phase III studies and an impressive risk profile the drug was unanimously supported by the panel and approved by the FDA.

In the above mentioned editorial researchers agreed, both simeprevir and sofosbuvir, had a better safety profile and comparable, if not higher, efficacy then telaprevir and boceprevir. However,

In an article written by Elizabeth Mechcatie, the side effects reported in the simeprevir phase III trials included;
In phase III studies fatigue, headache, and influenza like illness, associated with PR, were the most common adverse events. The only deaths reported were in three patients treated with simeprevir after they stopped taking the drug, but were not considered related to the drug. During the first 12 weeks of treatment, dyspnea was also higher among those on simeprevir (12% vs. 8%), but so far, the cause has not been determined, according to the FDA reviewer. Hyperbilirubinemia was also higher among those on simeprevir (49% vs. 26%), mostly grade 1 and 2 abnormalities.

In the first 12 weeks in the phase III studies, rashes (including photosensitivity) were reported in 28% of those on simeprevir, vs. 20% of those on PR only. Pruritus was also more common among those on simeprevir (22% vs. 15%); 1% of patients discontinued treatment because of a rash.

Download the FDA review package for simeprevir and Johnson & Johnson document released Oct 23.

Drug-drug interactions

The complexity of managing drug–drug interactions is another similarity shared by the PIs. A study in the December 2013 issue of Alimentary Pharmacology & Therapeutics, investigating drug–drug interactions in patients using telaprevir and boceprevir reported;  Drug–drug interactions between a PI and drugs newly prescribed during anti-viral therapy were considerable in 42% of the patients.

Other medications used while treating with telaprevir and boceprevir can interfere with the way DDAs are metabolized. The drug–drug interactions can either increase drug concentrations which may cause toxicity and lead to side effects, or decrease drug concentrations leading to a loss of efficacy, and, if the PIs are affected, this may lead to treatment failure due to emergence of viral resistance and subsequently a virological breakthrough.

An excerpt from the study;
The next wave of DAAs including the protease inhibitors faldaprevir and simeprevir as well as the NS5B nucleotide inhibitor sofosbuvir may be available in early 2014 and more will follow in the upcoming years. 
Risk for DDIs differ between the various future DAA classes. The nucleotide NS5B inhibitor sofosbuvir does not seem to be involved in significant DDIs.[24, 25] In contrast, DDIs have to be considered for several nonnucleotide NS5B inhibitors.[15] DDIs may also play a role for some NS5A inhibitors. Daclatasvir is substrate and inhibitor of P-glycoprotein and substrate of CYP3A4. However, pharmacokinetic data suggest that risk for significant DDIs is far lower compared with using protease inhibitors.[15]  
Soon-available PIs faldaprevir and simeprevir are also both inhibitors and substrates of CYP3A4 and it has already been shown that drug levels are altered in the presence of other strong inhibitors or inducers of CYP3A4.[15] Taken together, it can be assumed that the challenge of DDIs will certainly accompany HCV therapy in upcoming years, in particular, as combination treatments with several DAAs will most likely be necessary to finally achieve an efficient interferon-free anti-viral treatment.[6, 26]
Continue to the full text @ Alimentary Pharmacology & Therapeutics

Simeprevir has a list of medications that can cause drug–drug interactions as well, those medications along with patient and prescribing information, can be found online at

Let this be an important reminder folks, to ensure a safe, successful treatment plan, provide a complete health history to your healthcare provider and include a list of all medications, vitamins, or herbs you are taking before and during HCV therapy. Going forward, treating with new agents, the importance of preparing for treatment can not be underestimated, communicating with your physician or treatment nurse is key to a promising outcome.


Sustained Virologic Response - SVR 

The results from three phase III studies used to determine the FDA approval of simeprevir were QUEST-1 and QUEST-2, made up of treatment-naïve patients. In PROMISE patients relapsed after prior interferon-based treatment – as well as data from the Phase 2b ASPIRE study in prior non-responder patients.

In the two studies deemed QUEST-1 and QUEST-2, of 785 treatment-naive patients, 80 percent of those treated with simeprevir achieved sustained virologic response 12 weeks after the end of treatment, called SVR12, compared with 50 percent in the placebo groups.

In the third study called PROMISE of 393 prior-relapsers, 79 percent in the simeprevir group achieved SVR12 compared with 37 percent of patients in the placebo group.

Results from ASPIRE led to sustained virologic response 24 weeks after the end of treatment (SVR24) in 65 percent of prior partial-responder patients and 53 percent of prior-null responder patients compared with 9 percent and 19 percent of prior partial- and null-responder patients in the placebo groups, respectively.

OLYSIO Website
Simeprevir (Olysio): J & J Patient Access Programs
Prescribing Information
Patient Information
Important Safety Information

With great anticipation we patiently await for the approval of sofosbuvir, a nucleotide analog NS5B polymerase inhibitor. The FDA approval is expected to be announced in early December. Sofosbuvir will be used only with ribavirin, for treating adult HCV genotypes 2 and 3. However, in HCV genotype 1 and 4 treatment-naive patients, sofosbuvir will be used in combination with pegylated interferon and ribavirin. 

Off Label Use - Simeprevir and Sofosbuvir

Paul Sax, Editor-in-Chief at NEJM Journal Watch wrote an article this past summer; Both Simeprevir and Sofosbuvir Likely Approved by 2014 - Clinical/Ethical/Pharmacoeconomic Dilemmas Loom on the possibility of combining simeprevir and sofosbuvir with or without ribavirin, to create an off label interferon-free regimen;
The interim results of the COSMOS study, presented at CROI this year, showed a >90% cure rate in 80 prior null responders (no cirrhosis) who received simeprevir and sofosbuvir together for 12 or 24 weeks, with and without ribavirin. There was no interferon in this study. (The full slide set of the presentation is on NATAP.)
So if these two drugs are both approved as expected, one could easily make the case that the best treatment for HCV genotype 1 — in terms of efficacy, safety, tolerability, pretty much everything except drug-drug interactions and cost — will be the COSMOS regimen of simeprevir and sofosbuvir, with or without ribavirin. And emphatically without interferon.
And that, my dear friends, is off-label use.

Continue reading...

I hate to be redundant, but once again, in the editorial discussing simeprevir and sofosbuvir, I noticed the mention of off label use combining simeprevir and sofosbuvir;


As soon as simeprevir and sofosbuvir become commercially available, it is possible that some people will entertain the possibility of combining both agents with our without RBV, to create an off label IFN free regimen. In this regard, it is important to review the results of the COSMOS study.23 This Phase 2 exploratory trial enrolled two cohorts of HCV genotype 1 null responders:one with fibrosis stage Metavir F0-F2 and the other with F3-F4. Both cohorts were randomized to receive simeprevir plus sofosbuvir with or without RBV for 12 vs. 24 weeks of fixed therapy duration.

Preliminary results are so far available only for the12 week arm of the first cohort, with less significant liver fibrosis. Among 27 patients that received simeprevir plus sofosbuvir with RBV, the rate of undetectable HCV RNA 8 weeks after the end of therapy (SVR-8) was 96%. Similarly, among 14patients treated with simeprevir plus sofosbuvir without RBV, SVR-8 was 93%. Overall, 24 patients already reached 12 weeks of follow-up after the end of therapy and all maintain undetectable HCV RNA(SVR-12). Eight patients reached week 24 follow up after the end of therapy and also remain HCV RNA undetectable (SVR-24). Only 2% of patients had to interrupt prematurely the trial for adverse events.These results are surely preliminary, however the message they send out is powerful: in some areas of the world we may start to see the first IFN free regimens already being used to treat chronic HCV patients in routine clinical practice as early as 2014. 

Continue reading...

Once sofosbuvir is FDA approved I assume we will be reading more on off label use, as is often the case, the patient is the last to know.

Other then simeprevir and sofosbuvir, there are many additional potent agents in the clinical pipeline. AbbVie reported this month an interferon-free combination of three drugs plus ribavirin achieved a sustained virologic response (SVR12) in 96 percent of previously untreated genotype 1 patients.

I am determined to remain optimistic that in the future, interferon-free regimens will provide safe and effective therapy in all different HCV infected patient populations.

Stay healthy and positive.

1 comment:

  1. Thank you, need all the new info I can get. great blog