GSK receives marketing authorisation from the European Commission for additional Revolade (eltrombopag) indication as treatment for chronic hepatitis C-associated thrombocytopenia

GSK receives marketing authorisation from the European Commission for additional Revolade (eltrombopag) indication as the first approved treatment for chronic hepatitis C-associated thrombocytopenia

Revolade is approved for additional indication of hepatitis C

GlaxoSmithKline plc announced today that the European Commission has granted an additional indication for Revolade™ (eltrombopag) as a treatment for low platelet counts (thrombocytopenia) in adult patients with chronic hepatitis C infection, where the degree of thrombocytopenia is the main factor preventing the initiation or limiting the ability to maintain optimal interferon (IFN)-based therapy.1

Thrombocytopenia (platelet count ≤150Gi/L) can occur in people with chronic hepatitis C infection as a consequence of liver damage.2 It is also a common side effect of peginterferon (pIFN)-based therapy.3,4

25 percent of patients with chronic hepatitis C have thrombocytopenia5 and up to nine percent of patients are severely thrombocytopenic (platelet count <50Gi/L).6

Thrombocytopenia may prevent the initiation5 and maintenance of pIFN-based treatment, thereby reducing a patient's chances of achieving a sustained virologic response (SVR)*7 - the primary goal of hepatitis C treatment.

"Until now, prescribers were without an option for treating low platelet counts in patients with chronic hepatitis C infection" said Paolo Paoletti, President, GlaxoSmithKline Oncology. "Today's announcement is important as it means that healthcare professionals can now use Revolade to help patients start and stay on interferon therapy which will facilitate achieving the best outcome for these individuals - that being a sustained virologic response."

The ENABLE clinical trials

The marketing authorisation granted to eltrombopag is based on results from ENABLE-1 and -2 (Eltrombopag to INitiate and Maintain Interferon Antiviral Treatment to Benefit Subjects with Hepatitis C related Liver DiseasE), two Phase III global, multicentre, two-part studies (n=1,520), that comprised an open-label pre-antiviral treatment phase and a randomised, double-blind, placebo-controlled antiviral treatment phase. Eighty percent of the patients had bridging fibrosis or cirrhosis.1,8 ENABLE-1 utilised peginterferon alfa-2a plus ribavirin for antiviral treatment and ENABLE-2 utilised peginterferon alfa-2b plus ribavirin.1

Efficacy:

Phase III clinical studies demonstrated that eltrombopag may achieve and maintain target platelet counts in chronic hepatitis C patients with associated thrombocytopenia.8,9

* where the hepatitis C virus remains undetectable for six months - following completion of antiviral therapy

Eltrombopag enabled 95 percent of patients with chronic hepatitis C-associated thrombocytopenia to achieve platelet counts sufficient for initiation of pIFN-based therapy.1,8-10

§ Eltrombopag enabled more patients to maintain pIFN-based therapy without dose reduction compared to placebo (45 percent vs 27 percent).1

§ Eltrombopag enabled approximately one in five patients who, because of thrombocytopenia, were previously ineligible or poor candidates for pIFN-based therapy to achieve SVR.1,8,9

Safety:

The Phase III clinical studies showed an increased risk of adverse events, including potentially fatal hepatic decompensation and thromboembolic events, in thrombocytopenic hepatitis C patients with advanced chronic liver disease, as defined by low albumin levels ≤ 35 g/L or MELD (model for end-stage liver disease) score ≥ 10, when treated with eltrombopag in combination with IFN-based therapy.1

§ Eltrombopag may cause hepatotoxicity. Eltrombopag in combination with IFN and ribavirin, in patients with chronic hepatitis C infection, may increase the risk of hepatic decompensation.1

§ An increase in platelet counts with eltrombopag may heighten the risk of thrombotic/thromboembolic complications.1

§ Serious adverse events were more common in patients treated with eltrombopag.11,12

http://www.firstwordpharma.com/node/1141300?tsid=28&region_id=3#axzz2foy6e2JF

A New Tool for HCV Patients With Low Platelet Counts

A New Tool for HCV Patients With Low Platelet Counts

Although the use of a platelet-boosting agent will assist certain subsets of patients who cannot wait for the approval of direct-acting antivirals, we can envision that the need for such a strategy will steadily wane over time.

Raymond T. Chung, MD - 1/7/2013 More from this author

*Free registration required.

The US Food and Drug Administration recently approved an additional indication for eltrombopag for the treatment of thrombocytopenia in patients with chronic hepatitis C to enable the initiation and maintenance of interferon-based therapy. This will come as welcome news for those patients sidelined from treatment because of the relative or absolute contraindication of low platelet counts, which are aggravated by the marrow suppressive effects of interferon.

Expectation for Limited Use

The availability of expanded therapeutic options is always good news. However, I suspect the uptake of this thrombopoietin receptor agonist will likely be limited for several reasons related to clinical population and timing:

• Clinical need: The clinical need among patients with HCV would appear to be restricted primarily to those patients with cirrhosis and portal hypertension who have very low platelet counts.
• Tolerability of HCV therapy: The ability of such patients to be safely treated with peginterferon, ribavirin, and, in the case of genotype 1–infected persons, telaprevir or boceprevir will also be constrained by concerns about the risk of more serious adverse events, including anemia, and even hepatic decompensation described in several reports from Europe and the United States. Indeed, one of the largest such studies, the CUPIC study, found that an important risk factor for decompensation was platelet count < 100,000. Conversely, eltrombopag provides a new tool that may boost platelet counts and theoretically reduce this risk of decompensation.
• Safety concerns: There was a small but finite excess occurrence of portal vein thrombosis described in study participants receiving eltrombopag, along with hepatic decompensation. There exists the concern, then, that adding this profile onto a cirrhotic population, in conjunction with interferon-based treatment, raises the stakes for adverse outcomes. Real vigilance will need to be practiced in this group of patients who start eltrombopag.
• The interferon-free future: Finally, and perhaps most importantly, help in the form of other agents (direct-acting antivirals [DAAs]) is rapidly on the way, and we can envision success in the form of SVR being accomplished with interferon-sparing regimens in patients with cirrhosis. Evidence that this will be possible has come from the SOUND-C2 trial, which found comparable SVR rates between patients with and without cirrhosis using an all-oral 2 DAAs plus ribavirin regimen.

Although the use of a platelet-boosting agent will assist certain subsets of patients who cannot wait for the approval of DAAs, it seems to me that the need for such a strategy will steadily wane over time.

Your Thoughts
What are your expectations? Do you envision using eltrombopag in your practice? If so, for which patients? In your opinion, what are the greatest advantages and disadvantages?

Topics: HCV - Treatment, Fibrosis and Cirrhosis - Treatment

 

Source- http://www.clinicaloptions.com/Hepatitis.aspx  

 

EASL- Eltrombopag Increases Platelet Counts During HCV Treatment in Patients With Thrombocytopenia

By Chris Berrie

BARCELONA, Spain -- April 25, 2012 -- Eltrombopag increases and maintains platelet counts throughout treatment with pegylated interferon (PEG IFN) alfa-2b and ribavirin (RBV) among patients with thrombocytopenia and chronic hepatitis C virus (HCV) who would otherwise be ineligible for antiviral therapy.

In addition, eltrombopag was associated with clinically meaningful improvement in sustained virological response (SVR), researchers said here April 20 at the 47th Annual Meeting of the European Association for the Study of the Liver (EASL).

However, there was an increased incidence of thromboembolic complications with eltrombopag treatment, which requires further analysis, according to Geoffrey Dusheiko, MD, Royal Free Hospital, London, United Kingdom, and colleagues.

Thrombocytopenia limits the ability of many patients with cirrhosis and HCV to initiate and maintain PEG-IFN alfa-2b/RBV therapy. PEG IFN alfa-2b is not recommended for patients with platelets <100 Gi/L.

In the first part of the study, patients with HCV and platelets <75 Gi/Lreceived eltrombopag 25 mg (increased to 50, 75, or 100 mg daily until platelets reached ≥100 Gi/L). For the second part of the study, patients eligible for PEG-IFN alfa-2b/RBV were randomised to receive eltrombopag (n =506) or placebo (n = 253).

Treatment was administered for 24 weeks or 48 weeks according to genotype. The primary endpoint was SVR.

Compared with placebo, eltrombopag was associated with improved SVR (19% vs13%; P =.0202), fewer antiviral dose reductions (P=.0001), improved early virological response (62% vs 41%; P <.0001),and end-of-treatment response (38% vs 23%; P <.0001).

Patients with the lowest platelet counts at baseline and the highest viral load at screening showed the greatest benefits of eltrombopag treatment.

Serious adverse events occurred more often in the eltrombopag group than in the placebo group (20% vs 15%). More deaths occurred in the eltrombopag group (4% vs 2%).

Treatment with eltrombopag appeared to be associated with increased thromboembolic events (4% vs <1%), including portal vein thrombosis (2% vs 0%),and events suggestive of progressive liver disease (13% vs 6%).

We had higher rates of thromboembolic events and transient hepatobiliary events in the eltrombopag arm, and this would require evaluation in this group of patients in need of treatment,ö concluded Dr. Dusheiko.

Funding for this study was provided by GlaxoSmithKline.
[Presentation title: Results of ENABLE 2, a Phase 3, Placebo-Controlled, Multicenter Study of Eltrombopag, Peginterferon Alfa-2b, and Ribavirin Treatment in Patients With Hepatitis C and Thrombocytopenia. Abstract 060]

Source: DGNews

What are Platelets?

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Platelets, along with red cells and plasma, form a major proportion of both human and animal blood. Microscopically, they look like little thorned or spiky ovals, and they can only be viewed microscopically, as the average size is about four hundred thousandths of an inch (1 to 3.5 um).
Platelets are actually fragments of the cells in bone marrow, called megakaryocytes. Stimulated by the hormone thrombopoietin, platelets break off the megakaryocytes and enter the blood stream, where they circulate for about 10 days before ending their short lives in the spleen.

Normal Results
150,000 to 400,000 platelets per microliter (mcL)
Note: Normal value ranges may vary slightly among different laboratories. Talk to your doctor about the meaning of your specific test results.

According to some studies, almost 95% of healthy people have platelet values within this range. Even though a platelet count which is above or below this range is considered abnormal, some people with small variations are found to be perfectly healthy

Specifically, platelets provide the necessary hormones and proteins for coagulation. Collagen is released when the lining of a blood vessel is damaged. The platelet recognizes collagen and begins to work on coagulating the blood by forming a kind of stopper, so further damage to the blood vessel is prevented.

Bleeding in the skin may be the first sign that the platelet count is low. Often, many tiny red dots appear in the skin on the lower legs. People may bruise easily. Slight injuries sometimes cause small scattered bruises. The gums may bleed, and blood may appear in the stool or urine. Bleeding due to injuries may be hard to stop. Bleeding worsens as the platelet count decreases. When the count is below 20,000, bleeding in the digestive tract or brain may occur even when there is no injury. This bleeding may be life threatening.

A level which is below 50,000 or above 1,000,000 is considered as critical. In short, drastic variations in the normal platelet count can be considered as serious conditions, which have to be addressed as soon as possible. While these variations can be indications of diseases, serious health problems may also arise from such variations. As such, any variation in platelet count should be brought to the notice of a medical professional immediately.

A higher than normal count of platelets, known as thrombocytosis, can cause serious health risks. Too much clotting of the blood can lead to formation of blood clots that can cause stroke. Conversely, lower than normal counts can lead to extensive bleeding.

However, in some cases, inducing a lower platelet count is desirable, for instance if a person has susceptibility to strokes or has had extensive heart repair. Platelet counts can be lowered by a daily intake of aspirin or other clot reducing drugs. Additionally, when a patient has an intravenous drip (IV), heparin is used to keep the IV from clotting so fluids can be either taken from or added to the body.

While disease or a genetic disorder can cause a lower number of platelets, other times, they are depleted because of a specific treatment or surgery. Burn victims, organ transplant patients, marrow transplant patients, those undergoing chemotherapy, and those who have undergone heart surgery often require not only blood transfusions but platelet transfusions as well.

An infection of the hepatitis C virus and cirrhosis is another cause of low platelets. Most are familiar with the blood's ability to coagulate should one receive a cut or bruise. When the liver slows or stops producing the proteins needed for blood clotting, a person will bruise or bleed easily. Normally, blood from the intestines and spleen is carried to the liver through the portal vein. But cirrhosis slows the normal flow of blood, which increases the pressure in the portal vein. This condition is called portal hypertension. If your spleen enlarges due to cirrhosis of the liver or portal hypertension occurs, the spleen frequently holds white blood cells and platelets, reducing the numbers of these cells in the blood. A low platelet count may be the first evidence that a person has developed cirrhosis.

Spleen Geography 101:

A part of the lymphatic system, the dark purplish spleen lies in the upper left abdomen protected by the lower ribs. (Our unscientific, people-on-the-street survey suggests wide gaps in anatomy knowledge.

"Where is the spleen?" was met with, "Uh, it's somewhere in the main part of the body--not in the extremities.")

My, What a Fine Looking Spleen:

Size and weight can vary greatly, but in healthy adults the spleen is often about 5 inches long by 3 inches wide and 1 1/2 inches thick. A typical spleen weighs in at about 6 ounces in a healthy adult. But when it becomes enlarged--from malaria or other diseases--it can weigh a hefty 4 pounds or so.

They're Not Just for Venting:

Not that you've noticed, but the spleen is a busy little part. Its main tasks are to remove worn-out and damaged red blood cells and platelets and to help the body fight off infection.It filters foreign substances from the blood and produces white blood cells called lymphocytes, which help boost immunity.

Whose Spleen Is It, Anyway?

Spleens are handled by internists, though hematologists (physicians specializing in blood and blood-producing organs) and oncologists (physicians specializing in tumors) also provide spleen care, depending on the exact problem.

Spleens Gone Bad:

So what can go wrong with the spleen?

It can get too big, sometimes producing a soreness. Besides malaria, a host of other disorders are accompanied by enlargement of the spleen. A partial list:infectious mononucleosis, chronic liver problems, rheumatoid arthritis, lupus, the early stages of AIDS. In sickle cell anemia patients, the spleen enlarges and then patients lose spleen function, says Dr. Andrew Saxon, professor of medicine and chief of the division of clinical immunology at UCLA.

Patients with Gaucher's disease (a disorder of fat metabolism) have enlarged spleens, as do people with lymphomas and people with idiopathic thrombocytopenic purpura (ITP), a systemic illness marked by low platelet counts, weakness and anemia.The spleen can also get ruptured in car accidents, falls or stabbings.If the spleen is injured seriously, or otherwise causes too much trouble, it's likely to get yanked, although in some instances it is repaired.

Spleenless Wonders:

Yes, you can live a full life without your spleen.

About 1% of the population is spleenless, estimates Dr. Lawrence May, an internist at Encino-Tarzana Medical Center.Among the spleenless is talk show host Jay Leno. In his book "Leading With My Chin" (HarperCollins, 1996), he describes his childhood trip down the banister that ended at the hospital, where he and his spleen parted company.

Spleen Understudies:

The spleen's tasks are largely taken over by other parts of the lymphatic system and the liver. Oddly, some people--no one's quite sure how many--have a spare spleen. An accessory spleen, as it's known, is not rare, Saxon says.

Spleened Versus Spleenless:"On paper, spleenless is not as good as someone who has a spleen," Saxon says, referring to overall health. "They are more susceptible to infection," he says.

Those who have lost a spleen to rupture are generally healthier than those who are spleenless due to lymphoma, for instance, Saxon notes. Folks without a spleen should take some precautions, experts concur.

Among them:

Get vaccinated against pneumonia and always alert a new doctor or dentist to your condition. When fever strikes, people without a spleen can get sicker quicker, May says.And dentists may want to take extra precautions to minimize infection risks, says Dr. Eric Sung, a dentist and program director of the UCLA hospital dentistry program.People without spleens might also want to note that fact on a medical information bracelet.

Low platelet counts can usually be traced to one of the following:

Disorders that reduce platelet production by bone marrow: Various medical problems can affect bone marrow function, such as certain cancers, leukemia, bone marrow failure syndromes such as aplastic anemia, and some viral infections (such as HIV). Heavy alcohol use may also be a factor. There's also a long list of medications that can decrease platelet production. Since the chemical signal for the bone marrow to make platelets, thrombopoietin, is made in the liver, liver failure can also reduce platelet production.

Destruction of platelets: Several medical conditions are associated with premature loss of platelets from the circulation. These include immune system disorders such as lupus, rheumatoid arthritis, and idiopathic thrombocytopenic purpura (ITP), which occurs when antibodies mistakenly attack platelets.

There are also non-immune mechanisms for platelets to get destroyed, such as accelerated clotting due to cancer, or a loose-fitting mechanical heart valve.If the low count is due to an identifiable cause, treatment of that condition will usually result in improvement in the thrombocytopenia. Should the problem be related to an adverse drug effect, low platelet counts usually improve once medication changes are made as directed by your doctor.If the cause is ITP, treatment may include the use of corticosteroids, immune globulin infusions or medications -- such as cyclophosphamide

Many people with ITP do well without bleeding for many years despite a chronically low platelet count. A new class of drugs, romiplostim (Nplate) and eltrombopag (Promacta), act like thrombopoietin to stimulate increased bone marrow production of platelets. These new drugs may be useful in patients with ITP whose condition does not respond well to other treatments.Platelet concentrates may be given to help raise platelet numbers temporarily, especially if cancer or chemotherapy is related to the low count, or to prevent bleeding if you need surgery. Routine use of platelet transfusions may be limited by the formation of antibodies that can destroy new platelets. -- David Steensma, M.D., Hematology, Mayo Clinic, Rochester, Minn.


http://www.wisegeek.com/what-are-platelets.htm http://www.livestrong.com/article/22602-conditions-cause-low-blood-platelets/ http://www.livestrong.com/article/22602-conditions-cause-low-blood-platelets / Mayo Clinic