FDA Approves Mavyret (glecaprevir and pibrentasvir) as First Treatment for All Genotypes of Hepatitis C in Pediatric Patients

The U.S. Food and Drug Administration today approved Mavyret (telaprevir and pibrentasvir) tablets to treat all six genotypes of hepatitis C virus (HCV) in children ages 12 to 17. Mavyret was previously approved to treat HCV in adults in 2017.

   Pibrentasvir

                                  Glecaprevir

“Direct-acting antiviral drugs reduce the amount of HCV in the body by preventing the virus from multiplying, and in most cases, they cure HCV infection,” said Jeffrey Murray, M.D., M.P.H., deputy director of the Division of Antiviral Products in the FDA’s Center for Drug Evaluation and Research. “Today’s approval represents another treatment option for children and adolescents with HCV infection, but for the first time, in all genotypes of HCV.”

HCV is a viral disease that causes inflammation of the liver that can lead to diminished liver function or liver failure. According to the U.S. Centers for Disease Control and Prevention, an estimated 2.7 to 3.9 million people in the U.S. have chronic HCV, and children born to HCV-positive mothers are at risk for HCV infection. It is estimated that there are 23,000 to 46,000 children in the U.S. with HCV infection.

With today’s approval, dosing information is provided for Mavyret for the treatment of adult or pediatric patients 12 years and older, or weighing at least 99 pounds, who are infected with any of six identified HCV genotypes either without cirrhosis or with compensated cirrhosis.

The safety and efficacy of Mavyret in pediatric patients was evaluated during clinical trials of 47 patients with genotype 1, 2, 3 or 4 HCV infection without cirrhosis or with mild cirrhosis. Results of the trials demonstrated that 100 percent of patients who received Mavyret for eight or 16 weeks had no virus detected in the blood 12 weeks after finishing treatment, suggesting that patients’ infection had been cured. In pediatric patients with cirrhosis, history of a kidney and/or liver transplant, or genotype 5 or 6 HCV infection, the safety and efficacy of Mavyret are supported by previous studies observed in glecaprevir and pibrentasvir in adults. The adverse reactions observed were consistent with those observed in clinical studies of Mavyret in adults.

Treatment duration with Mavyret differs depending on treatment history, viral genotype and cirrhosis status. The most common adverse reactions in patients taking Mavyret were headache and fatigue. Mavyret is not recommended in patients with moderate cirrhosis and contraindicated in patients with severe cirrhosis. It is also contraindicated in patients taking the drugs atazanavir and rifampin.

Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected adult patients who were undergoing or had completed treatment with HCV direct-acting antivirals, and who were not receiving HBV antiviral therapy. HBV reactivation in patients treated with direct-acting antiviral medicines can result in serious liver problems or death in some patients. Health care professionals should screen all patients for evidence of current or prior HBV infection before starting treatment with Mavyret.

https://www.drugbank.ca/drugs/DB13879

https://pubchem.ncbi.nlm.nih.gov/compound/Glecaprevir#section=Structures

https://en.wikipedia.org/wiki/Pibrentasvir

https://pubchem.ncbi.nlm.nih.gov/compound/Pibrentasvir

FDA Approves Mavyret (glecaprevir and pibrentasvir) as First Treatment for All Genotypes of Hepatitis C in Pediatric Patients

Allergy drug inhibits hepatitis C in mice

Chlorcyclizine (Di-Paralene,  Mantadil, Pruresidine, Trihistan) is a first-generation antihistamine of the phenylpiperazine class marketed in the United States and certain other countries. It is used primarily to treat allergy symptoms such as rhinitis,urticaria, and pruritus, and may also be used as an antiemetic. In addition to its antihistamine effects, chlorcyclizine also has some anticholinergic, antiserotonergic, and local anesthetic properties. It also has been studied as a potential treatment forhepatitis C.

The hepatitis C virus (HCV) causes liver inflammation and often leads to serious complications such as cirrhosis. Early diagnosis and treatment of HCV can prevent liver damage. Drugs are available to treat HCV, but costs can reach tens of thousands of dollars.

"Although hepatitis C is curable, there is an unmet need for effective and affordable medication," said lead author T. Jake Liang, M.D., senior investigator at NIH's National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). "CCZ is a promising candidate for part of a treatment regimen for this potentially life-threatening disease."

Conducted at the NIH campus in Bethesda, Maryland, the study found that CCZ blocked the early stage of HCV infection likely by impairing the ability of the virus to enter human liver cells grafted in the mice. The outcome was similar to that of commonly used antiviral drugs but without those drugs' toxic side effects.

"Using an innovative high-throughput screening process, we identified CCZ as a potent inhibitor of hepatitis C," said Anton Simeonov, Ph.D., acting scientific director of NIH's National Center for Advancing Translational Sciences (NCATS), which collaborated in the study. "Identifying already approved drugs from the NCATS Pharmaceutical Collection may offer a faster route to potential discovery of treatments for all diseases."

The researchers will next study how the drug affects people. CCZ is currently used for the treatment of allergies, not for HCV. "People should not take CCZ to treat their hepatitis C until it has been demonstrated that CCZ can be used safely and effectively for that purpose," cautions Liang.

Ref : http://stm.sciencemag.org/content/7/282/282ra49

Allergy drug inhibits hepatitis C in mice  

Added benefit of daclatasvir drug not proven for chronic hepatitis C infection

In continuation of my update on daclatasvir 

The drug daclatasvir (trade name Daklinza) has been available since August 2014 for the treatment of adults with chronic hepatitis C (CHC) infection. The German Institute for Quality and Efficiency in Health Care (IQWiG) examined in a dossier assessment whether this new drug offers an added benefit over the appropriate comparator therapy.

The drug manufacturer presented data for patients without cirrhosis of the liver who are infected with hepatitis C virus (HCV) genotype 1, and for patients with HCV genotype 4. However, these data are unsuitable in various aspects to prove an added benefit.

The manufacturer dossier contained no data at all for three further patient groups with HCV genotype 1 infection (pretreated patients, untreated patients with cirrhosis of the liver, and patients with HIV coinfection) as well as for patients with HCV genotype 3 (with compensated cirrhosis and/or treatment-experienced).

Added benefit of daclatasvir drug not proven for chronic hepatitis C infection

New treatment regimen for hepatitis C in transplant patients produces promising results

The investigational three-drug regimen, which produced hepatitis C cure rates of 97 percent, is an oral interferon-free therapy. Previously, the typical treatment for hepatitis C after a liver transplant was an interferon-based therapy, usually given for 48 weeks. It had a much lower response rate, had a risk of organ rejection and was poorly tolerated because of the immunosuppressants required to prevent rejection. The new oral regimen -- ABT-450, ombitasvir and dasabuvir (with or without ribavirin) -- produces significantly fewer side effects and is prescribed for 24 weeks.

New treatment regimen for hepatitis C in transplant patients produces promising results

Harvoni Approved for Chronic Hepatitis C

In continuation of my update on  ledipasvir and sofosbuvir (Harvoni-combination pill) 

Harvoni, a daily pill that treats the most common form of hepatitis C, was approved by the U.S. Food and Drug Administration on Friday.

It's the first combination pill (ledipasvir and sofosbuvir) approved to treat the chronic infection, and the first medication that doesn't require that the antiviral drugs interferon or ribavirin be taken at the same time, the FDA said in a news release.

Both drugs in the combination pill interfere with the hepatitis C virus' ability to multiply. One of the drugs, sofosbuvir (Sovaldi) was approved in December 2013, while ledipasvir is a new antiviral, the agency said.

"With the development and approval of new treatments for hepatitis C virus, we are changing the treatment paradigm for Americans living with the disease," Dr. Edward Cox, director of the Office of Antimicrobial Products in the FDA's Center for Drug Evaluation and Research, said in the news release. "Until last year, the only available treatments for hepatitis C virus required administration with interferon and ribavirin. Now, patients and health care professionals have multiple treatment options, including a combination pill to help simplify treatment regimens."

One expert applauded Harvoni's approval.

"This is a giant step forward for people with [hepatitis C]. One pill, once daily, no interferon, no ribavirin and 94 to 99 percent cure! It moves the risk-benefit ratio needle way over toward benefit," said Dr. Douglas Dieterich, a professor of medicine in the division of liver diseases at The Mount Sinai Hospital in New York City.

However, price has been an issue with some of the new treatments for hepatitis C. For example, Sovaldi alone costs $1,000 a day and not all insurance companies cover the cost of treatment, experts have noted. Harvoni will cost $1,125 a pill, the Associated Press reported Friday.

Hepatitis C causes inflammation of the liver, which could spark other problems including diminished liver function (cirrhosis), scarring, liver cancer or liver failure. Most infected people aren't aware that they carry the virus until liver damage has occurred, the agency said.

Some 3.2 million Americans are believed to be infected with hepatitis C, the FDA said.

Harvoni was evaluated in three clinical studies involving more than 1,500 people who either hadn't been treated previously or hadn't responded to prior treatment. The most common side effects were fatigue and headache.

Harvoni Approved for Chronic Hepatitis C  

Investigational oral regimen for hepatitis C shows promise

In a study of an all-oral drug regimen, a majority of volunteers with liver damage due to hepatitis C virus (HCV) infection were cured following a six-month course of therapy that combined an experimental drug, sofosbuvir, with the licensed antiviral drug ribavirin. The results showed that the regimen was highly effective in clearing the virus and well tolerated in a group of patients who historically have had unfavorable prognoses.

Investigational oral regimen for hepatitis C shows promise

New Drug Combo for Hepatitis C Shows Promise...

A new cocktail of two investigational drugs appears to have successfully cleared the hepatitis C virus in people who don't respond to standard treatment. What's more, the approach seems to work without the need for injections with interferon alpha, an onerous medication that causes serious side effects in many patients.

"We saw a sustained virologic response -- the virus was undetectable in the patients -- during treatment and remained undetectable after the drugs were stopped," said study author Dr. Anna Lok, director of clinical hepatology at the University of Michigan Medical School in Ann Arbor.

The study had two arms:  a group of 10 patients received four medications, including the two investigational drugs, the antivirals daclatasvir (see right structure)  and asunaprevir (see left structure-courtesy: ChemSpider), along with the standard treatment combination of interferon and ribavirin. The other arm of the study included 11 patients who received only the two investigational drugs. Both groups underwent treatment for 24 weeks.

The 10 patients on the four-drug regimen experienced a sustained virologic response with undetectable virus at the end of treatment and again at 12 weeks beyond their treatment, the researchers reported. In the two-drug group, four of the 11 patients also had undetectable levels of the hepatitis C virus in their blood 12 weeks after treatment ended.

"The four-drug arm was very impressive. These patients had not shown a response before and now we get a 90 to 100 percent rate of sustained response," said Lok....

Ref : http://www.nejm.org/doi/full/10.1056/NEJMoa1104430

Telaprevir drug shows promise in curing hepatitis C infection

In continuation of my update on Telaprevir...............

Telaprevir drug shows promise in curing hepatitis C infection

Will new drugs (p7 inhibitors) block hepatitis C virus in its tracks?

Will new drugs block hepatitis C virus in its tracks?

New drugs (Victrelis and Incivek ) encouraging for African Americans with hepatitis C

Current standard of treatment of interferon and ribavirun has only been effective in curing 38 to 40 percent of patients with chronic hepatitis C genotype 1. In clinical trials, Victrelis and Incivek, when working in concert with interferon and ribavirun, cured 65 to 75 percent of people with chronic disease and Victrelis-alone doubled the previous cure rate among African Americans......

Victrelis (Boceprevir)             

                                                                                                                                                                                                                                      Incivek (Telaprevir)


News Release Archives > New drugs encouraging for African Americans with hepatitis C

Merck receives FDA approval for Victrelis to treat chronic hepatitis C

In continuation of my update on Victrelis (Boceprevir)

Merck receives FDA approval for Victrelis to treat chronic hepatitis C

New Anti-Viral Drug Shows Promise for Dramatic Improvement in Hepatitis C Treatment

Research team, led by Paul Kwo, M.D., of Indiana University School of Medicine, reported that adding the drug boceprevir, nearly doubled the treatment's effectiveness when given for 48 weeks in one treatment arm of the study. We knew that, Boceprevir (see structure) is a protease inhibitor being studied as a treatment for hepatitis C. It was being developed by Schering-Plough and has since been absorbed into the Merck's new pipeline since its acquired Schering in 2009. As of 2008, it is in phase II clinical trials (SPRINT-1 trial). Researchers claim that, adding a direct acting anti-viral drug to the standard treatment regimen for hepatitis C significantly increases the cure rate in the most difficult to treat patients.

Researchers claim that, the drug boceprevir increased the cure rate to as high as 75 percent in those who received 48 weeks of the three-drug combination therapy, compared to 38 percent of those in the control group, who received the standard two-drug treatment (peginterferon alfa-2b plus ribavirin)   for 48 weeks, said Dr. Kwo, associate professor of medicine at the IU School of Medicine. The two-year phase 2 trial was conducted at 67 sites with 520 patients in the US, Canada and Europe.

In the boceprevir study, known as the SPRINT-1 trial, researchers tested several different options to evaluate the effectiveness of the combination therapy.

"Both 28- and 48-week boceprevir regimens significantly increased sustained virologic response rates  which is the best definition of a cure we have  compared to the 48 week control," said Dr. Kwo. "The 48-week treatment arm with 4 weeks of peg interferon lead-in and 44 weeks of peg interferon, ribavirin, and boceprevir led to the largest improvement over the control group ever reported. That's very impressive." 

Researchers conclude that, best results were reported for the 103 patients who were treated for four weeks with the standard two drug regiment, followed by 44 weeks of the three-drug regimen including boceprevir: 75 percent of these patients tested negative for evidence of the virus six months after the end of treatment.

As per the lead researcher, Dr. Kwo, based on this phase 2 study, it appears that if this drug receives final approval approximately two-thirds of patients will be able to be treated successfully with 28 weeks of treatment and one-third will need 48 weeks of treatment, though this will require confirmation from the phase 3 trials, from which preliminary results were recently released.

Ref  : http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2810%2960934-8/fulltext

SPC3649 ( LNA- locked nucleic acid) - a new hope for hepatitis C.....

When  I was working with Innovasynth Technologies, Khopoli, I had an opportunity to do literature survey about  Lock Nucleic Acids (LNAs) and Peptide Nucleic Acids (PNAs) (we were supposed to work on the preparation of  some of the LNAs & PNAs for US based companies). In my opinion though these class of compounds (including oligonucleotides) are  still emerging,  I think in the days to come there will be more and more drugs from oligonucleotides, Locked Nucleic Acids (LNAs) and Peptide Nucleic Acids, (PNAs) class of compounds.

LNAs : A locked nucleic acid (LNA) (see the right side general structure), is a modified RNA nucleotide. Ribose moiety of an LNA nucleotide is modified with an extra bridge

connecting the 2' oxygen and 4' carbon. The bridge "locks" the ribose  in the 3'-endo (North) conformation, which is often found in the A-form of DNA or RNA. LNA nucleotides can be mixed with DNA or RNA bases in the oligonucleotide whenever desired. This locking  significantly increases the thermal stability (mp) of oligonucleotide.

LNA nucleotides are used to increase the sensitivity and specificity of expression in DNA microarrays, FISH probes, real-time PCR probes and other molecular biology techniques based on oligonucleotides. For the in situ detection of miRNA the use of LNA is currently the only efficient method. A triplet of LNA nucleotides surrounding a single-base mismatch site maximizes LNA probe specificity unless the probe contains the  G-T mismatch. We have already seen some antisense drugs (oligonucleotides from Geron & Isis) and some are into clinical trials.

Now its interesting to see that Santaris Pharma   is currently advancing LNA based compounds within infectious diseases, metabolic disorders, oncology, inflammatory and rare genetic disorders.

Santaris Pharama, has developed a LNA,  SPC3649 - which captures a small RNA molecule in the liver, called microRNA122, that is required for HCV replication.

As per the claim by the company, SPC3649 works by altering the environment in the host liver cell to inhibit viral replication rather than inhibiting the virus itself. This subtle difference (in comparison  with other therapies) may have significant implications, as it may reduce the risk of the virus becoming resistant to therapy – a major concern with current therapies.

As per the claim by Dr. Robert Lanford,  (who has collaboration with Santaris Pharma), that in a preclinical study  SPC3649 successfully inhibited miR-122, a liver-expressed microRNA important for Hepatitis C viral replication. By inhibiting miR-122, SPC3649 dramatically reduced Hepatitis C virus in the liver and in the bloodstream in chimpanzees chronically infected with the Hepatitis C virus. Four HCV chronically infected chimpanzees were treated weekly with 5 or 1 mg/kg of SPC3649 for 12 weeks followed by a treatment free period of 17 weeks. The two animals that received the 5 mg/kg dose had a significant decline in viral levels in the blood and liver of approximately 2.5 orders of magnitude or approximately 350 fold. Hope the new therapy could potentially replace interferon (interferon and ribavirin is  approved by FDA for hepatitis C and this treatment is very toxic, requires 48 weeks with 50% success) in future cocktails, since it provides a high barrier to resistance. This antiviral could be used alone to treat disease progression and there are indications that it can convert interferon non-responders to responders, so that non-responders to the current therapy could be treated with the combination of this drug with interferon.   More....

Those interested  can see the video demo with the link

New class of drugs for hepatitis C .....

Eiger BioPharmaceuticals, Inc., has come up with a novel class of compounds as HCV Inhibitors. The  research validates a domain, termed 4BAH2, within the non-structural protein (NS4B) of the HCV genome, as essential for HCV replication and describes the development of a high-throughput screen leading to the identification of small molecule inhibitors of 4BAH2.

 Interestingly, the researchers claims that 4BAH2 is the second new domain within NS4B now proven necessary and essential for HCV replication, and which has been shown to be susceptible to pharmacologic inhibition.  Eiger is developing small molecule inhibitors of both NS4B-RNA binding and small molecule inhibitors of NS4B-AH2, each of which has significant activity alone and significant synergy when combined. The researchers have tried the following two compounds (a pyrazolopyrimidine derivative and an amiloride derivative see the below structures). Mechanistic studies reveal that the inhibitors target 4BAH2 function by preventing either 4BAH2 oligomerization or 4BAH2 membrane association. 4BAH2 inhibitors represent an additional class of compounds with potential to effectively treat HCV.

The researchers  claims that like AIDS and tuberculosis, future effective therapy for HCV is expected to require a cocktail of several independent classes of drugs, each designed against a different viral target.

Eiger is focused on the discovery and development of new antiviral agents  against novel targets for the treatment of hepatitis virus infections. Eiger's pipeline includes repurposed clinical stage therapeutic agents as well as preclinical NCEs from discovery that exhibit antiviral activity against Hepatitis C, Hepatitis D, and other viruses.

Ref : http://stm.sciencemag.org/content/2/15/15ra6.abstract

Quercetin blocks Hepatitis C infection....

The conventional treatments for hepatitis C are interferon and ribavirin, which can cause major side effects and aren't effective in all patients. But something interesting and unique has been achieved  by UCLA researchers.

As per the claim by the lead researcher Samuel French Assistant Professor, Pathology of UCLA, they have  identified major two cellular proteins (HSPs, heat shock proteins 40 and 70) that play an important role in hepatitis C infection, and they say the finding may point to new and less toxic treatments for the disease, which can lead to cirrhosis and liver cancer. The researchers also found that Quercetin,  blocks the synthesis of two heat shock proteins 40 and 70proteins  and significantly inhibited viral infection in tissue culture.

 

Quercetin (see the structure) :  

Is a plant-derived flavonoid, specifically a flavonol, used as a nutritional supplement. Laboratory studies show it may have anti-inflammatory and antioxidant properties,  and it is being investigated for a wide range of potential health benefits.Interestingly American cancer society, says that while quercetin has been promoted as being effective against a wide variety of diseases, including cancer, There is current early-stage clinical research on quercetin addressing safety and efficacy against sarcoidosis, asthma and glucose absorption in obesity and diabetes. Food riches in Quercetin includes, capers, lovage, apples, tea (Camellia sinensis), onion, especially red onion (higher concentrations of quercetin occur in the outermost rings), red grapes, citrus fruit, tomato, broccoli and other leafy green vegetables, cherries and berries.

Significant claims by the researchers are ;

a. quercetin targets cellular proteins rather than viral proteins, there is less likelihood of developing viral

    resistance (cellular proteins cannot change like viral proteins can);

b. quercetin may allow for the dissection of the viral life cycle and has potential therapeutic use to reduce
    virus  production with low associated toxicity.

Hope the researcher will have positive results from the phase 1 clinical trial.....

Ref :http://www.cancer.ucla.edu/Index.aspx?page=644&recordid=312

Positive Phase 2 results of Telaprevir...

I did mention about telaprevir (structure) in my earlier blog, and following other developments for hepatitis C (blogs). Now Vertex Pharmaceuticals has announced the results of Phase 2.

The results are really encouraging and as per the claim by the company "more than 80 percent of hepatitis C patients in each arm of the Phase 2 Study C208 achieved a sustained viral response (SVR) with a telaprevir-based regimen according to results of an intent-to-treat (ITT) analysis".

Across the four arms, SVR rates were 82 and 83 percent in patients treated with the every 12 hour telaprevir-based regimen (PEGINTRON and PEGASYS, respectively) and 81 and 85 percent in patients treated with the every 8 hour regimen (PEGINTRON and PEGASYS, respectively). For the majority of patients, these SVR rates were obtained with a 24-week telaprevir-based regimen.

Ref : http://investors.vrtx.com/releasedetail.cfm?ReleaseID=420611

Patients with chronic hepatitis C can benefit by drinking coffee

Patients with chronic hepatitis C and advanced liver disease who drink three or more cups of coffee per day have a 53% lower risk of liver disease progression than non-coffee drinkers according to a new study. The study found that patients with hepatitis C-related bridging fibrosis or cirrhosis who did not respond to standard disease treatment benefited from increased coffee intake. An effect on liver disease was not observed in patients who drank black or green tea.

Read......

Patients with chronic hepatitis C can benefit by drinking coffee

Current Hepatitis C Treatments................

Current Hepatitis C Treatments Work Equally Well, Researchers Report

Shared via AddThis

Genetic Hint For Ridding The Body Of Hepatitis C

Genetic Hint For Ridding The Body Of Hepatitis C

Shared via AddThis

Survey Concludes Telaprevir a Winner for HCV Genotype 1 | Hepatitis Central News, Updates and Commentary

I did mention in my earlier blog about this drug and one person did (Dawn - Blog Name) mention she was happy about the info. I am sure the following update will help her. All the best...(Dawn, U can mail me at dr.umesh1969@gmail.com-if u find this info useful). I am happy something I did blog and that helped a needy & this encourages me to do spend more time with my blog.....

Survey Concludes Telaprevir a Winner for HCV Genotype 1 | Hepatitis Central News, Updates and Commentary

Shared via AddThis