Monday, June 30, 2014

Genotype 1 HCV–Infected Cirrhotic Patients: Still Hard to Treat?

Posted Today: HCV therapies for genotype 1: A final good-bye to interferon

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Genotype 1 HCV–Infected Cirrhotic Patients: Still Hard to Treat?
Mark S. Sulkowski, MD - 6/27/2014
More from this author

After years of telling our patients that better HCV treatments are coming soon, we finally have access to potent, safe, oral direct-acting antivirals (DAAs) in our clinics and we expect more oral DAA regimens to be approved over the next 18 months. As clinicians, the ability to offer the opportunity for HCV cure to our patients with the greatest medical need—those with cirrhosis—is truly great news.

Patients with HCV-related cirrhosis have the greatest risk for the development of hepatic decompensation, hepatocellular carcinoma (HCC), and the need for transplantation. They are also at the greatest risk for liver-related death in the absence of liver transplantation. At the same time, we are increasingly confident that we can decrease the risk of these life-threatening outcomes in patients with compensated cirrhosis if their underlying HCV infection is cured, appropriate lifestyle modifications are adopted (eg, cessation of alcohol and reduction of caloric intake coupled with more exercise in obese patients), and medical interventions are provided (eg, serial liver imaging studies for HCC and endoscopic surveillance and/or treatment of esophageal varices). But the bottom line is this: Patients with compensated HCV-related cirrhosis need to be cured of their chronic HCV infection with some degree of urgency.

Poor Cure Rates, High Adverse Events With Previous Therapies
So, let’s set aside the decompensated patients and those with HCC for now and focus on compensated cirrhosis. In my practice, these patients tend to be older adults infected with HCV genotype 1 or 3 and are previous nonresponders to peginterferon/ribavirin or one of the first-generation protease inhibitors. Many are poor candidates for interferon-based treatments, as this drug simply does not work well for cirrhotics; this was demonstrated as far back as the IDEAL study evaluating peginterferon alfa-2a vs alfa-2b both with ribavirin (once an important question—my, how times have changed in the world of HCV therapeutics!). With peginterferon alfa plus ribavirin, the cure rate for genotype 1 HCV–infected patients with F3/F4 fibrosis or cirrhosis was low (24% with peginterferon alfa-2a and 21% to 30% with peginterferon alfa-2b across two dosing arm), and approximately one half that seen in patients with minimal fibrosis (44%). In later studies that added one of the first-generation HCV protease inhibitors to peginterferon/ribavirin, rates of HCV cure in cirrhotic patients with genotype 1 infection were higher, in the low 60% range, but not as high as those reported in patients without cirrhosis (approximately 80%).

However, when we drill down further to the most “difficult-to-treat” patients—those with genotype 1 infection, cirrhosis, and previous null response to peginterferon/ribavirin—the cure rate with telaprevir plus peginterferon/ribavirin was an abysmal 15%. Comparable data on boceprevir use in this population are limited. Two of 4 previous null responders with F3/F4 fibrosis who received boceprevir plus peginterferon/ribavirin in the PROVIDE study achieved SVR. To make matters worse, we commonly saw significant adverse effects in these patients, including anemia and infections, not to mention liver failure in some. Good riddance to that—boceprevir and telaprevir earned a “not recommended” designation in the 2014 AASLD/IDSA guidance, and I agree they should no longer be used in settings where the newer DAAs are now available.

The Current Era of HCV Therapies
Late 2013 saw the launch of the current era of HCV treatment with sofosbuvir, the first of a brand new class of antivirals, nucleotide analogue NS5B polymerase inhibitors, and simeprevir, a vastly improved HCV NS3/4A protease inhibitor with once-daily dosing and no discernible risk of anemia. After a couple years of administering epoetin alfa and blood transfusions to our boceprevir- and telaprevir-treated patients, I am grateful for that particular attribute. My clinic has been bustling with patients wanting treatment and, not surprisingly, many are treatment-experienced cirrhotic patients.

I would like to describe one such patient, a 55-year-old black man with genotype 1b HCV compensated cirrhosis (MELD score: 10) and previous null response to peginterferon/ribavirin (his HCV RNA level actually went up at Week 12 of peginterferon/ribavirin treatment). He is healthy otherwise and anxious to take treatment, even willing to take interferon if required.

Is an interferon-based regimen his best option? In the phase III NEUTRINO study, the SVR rate in treatment-naive, genotype 1 HCV–infected cirrhotic patients treated with sofosbuvir plus peginterferon/ribavirin was approximately 80%, a good response rate compared with the past regimens. Once again, noncirrhotic patients did better: In this group, more than 90% were cured. The NEUTRINO regimen was not tested in cirrhotic previous null responders like our case patient, but an FDA analysis estimated the likely SVR rate in such patients to be approximately 70%. A few years ago, if I could have gotten my hands on an HCV regimen that could cure 70% of black cirrhotic, null responders, I would have prescribed the regimen in a heartbeat. But, today, there are treatment regimens with a higher likelihood of success available for patients like this one, including the “off-label” combination of sofosbuvir plus simeprevir.

The Coming Wave of All-Oral DAA Therapy
The data are crystal clear: For previous null responders with cirrhosis and perhaps for treatment-naive cirrhotic patients too, the best chance for a potentially life-saving HCV cure is an oral combination regimen of potent DAAs. By the end of 2014, we expect the FDA approval of the first agents in a new class of HCV DAAs called NS5A inhibitors. These agents will be an important part of 2 potent, interferon-free, all-oral regimens: the once-daily, single tablet, fixed-dose combination of sofosbuvir/ledipasvir and a 3-drug regimen that includes a fixed-dose combination of a ritonavir-boosted HCV protease inhibitor (ABT-450) plus ombitasvir (an NS5A inhibitor) administered with dasabuvir (a nonnucleoside polymerase inhibitor). The New England Journal of Medicine has published results from a series of historic phase III studies, also presented at the 2014 EASL annual meeting, in which HCV cure rates were between 82% and 100% across treated and untreated genotype 1 HCV–infected cirrhotic patients receiving these novel regimens with or without ribavirin.

Some fine-tuning of therapy may still be needed in this group of patients. In the phase III ION-1 study of sofosbuvir/ledipasvir in untreated patients, there appeared to be some drop off in response rate among cirrhotic patients who did not receive additional ribavirin compared with those who did (94% vs 100%, respectively). In the phase III ION-2 study of the same regimen in previously treated patients, cirrhotic individuals appeared to benefit more from the 24-week regimens than from 12 weeks of therapy (100% vs 82% to 86%, respectively). And in the phase III TURQUOISE-II study of the 3-drug regimen plus ribavirin in cirrhotic patients, previous null responders with genotype 1a infection also appeared to do better with 24 weeks of therapy compared with 12 weeks (93% vs 80%, respectively). Overall, however, the development of these therapies remains a remarkable achievement, and we are really looking forward to these regimens as they will permanently transform how we think about this important disease.

What About Cirrhotic Patients Who Cannot Delay Therapy?
What about my patient? To recap, he’s a 55-year-old black cirrhotic null responder with HCV genotype 1b infection. Should I wait for these future treatment options in his case? After all, we have been waiting for new therapies since he first failed peginterferon/ribavirin in 2006. This is a long time to wait for treatment that can yield an HCV cure, while hoping that HCC is not found on the next liver ultrasound.

I opted to treat him in accordance with the AASLD/IDSA HCV guidance recommendation for genotype 1 patients with previous nonresponse to therapy. I prescribed a 12-week course of sofosbuvir and simeprevir, a potent once-daily regimen. Is this his best option? The final results of the phase II COSMOS study that evaluated this regimen were hard to beat for cirrhotic patients with genotype 1b HCV : All genotype 1b patients were cured, as were most cirrhotic null responders.

The response rates in this study for patients with genotype 1a infection were also quite good, although a number of patients with this subgenotype receiving the 12-week regimens did experience viral relapse, whereas those treated for 24 weeks did well: SVR rates in the 12-week arms were between 88% to 100% across arms vs 100% in both treatment arms for the 24-week regimens. Use of ribavirin did not appear to make a difference to SVR rates, but this is not definitive. I know that some of my colleagues are adding ribavirin to the regimen for patients with genotype 1a infection who are receiving sofosbuvir plus simeprevir, on the basis that other studies have demonstrated some benefit from this approach. While I understand the limitations of the COSMOS study—it is a small phase 2 trial—currently, it is the best option for HCV cure for this cirrhotic patient who has been waiting a long time for treatment. Achieving HCV cure will dramatically reduce the likelihood that he will develop HCC or liver failure and need a liver transplant, complications of HCV that are both expensive and, for at least 15,000 Americans each year, deadly.

Your Thoughts
I am interested to hear about your own current practice for treating cirrhotic patients. In light of the new data on all-oral regimens for genotype 1 HCV, what is your management approach? Please use the comments section below to provide your insights.

Topics: HCV - Treatment
Of Interest @ CCO
My Approach to Identifying Treatment Candidates and Maintaining Patients on Long-term HBV Therapy
Highlights From EASL 2014 
Antiretroviral Therapy Update 2014

Common Herbal Supplement Can Cause Dangerous Interactions with Prescription Drugs

Good morning folks, over at Newswise, researchers at Wake Forest Baptist Medical Center reported ‘natural’ treatments like St. John’s wort can interact with other medications reducing effectiveness and cause treatment failure.

On a side note, according to SOVALDI's packet insert, found here,  St. John’s wort also has the potential to interact with our newly approved HCV drug SOVALDI:
Drugs that are potent P-gp inducers in the intestine (e.g., rifampin or St. John's wort) may decrease sofosbuvir plasma concentration leading to reduced therapeutic effect of SOVALDI and thus should not be used with SOVALDI 


Common Herbal Supplement Can Cause Dangerous Interactions with Prescription Drugs

Newswise — WINSTON-SALEM, N.C. – June 30, 2014 – St. John’s wort, the leading complementary and alternative treatment for depression in the United States, can be dangerous when taken with many commonly prescribed drugs, according to a study by researchers at Wake Forest Baptist Medical Center.

The researchers reported that the herbal supplement can reduce the concentration of numerous drugs in the body, including oral contraceptive, blood thinners, cancer chemotherapy and blood pressure medications, resulting in impaired effectiveness and treatment failure.

“Patients may have a false sense of safety with so-called ‘natural’ treatments like St. John’s wort,” said Sarah Taylor, M.D., assistant professor of dermatology at Wake Forest Baptist and lead author of the study. “And it is crucial for physicians to know the dangers of ‘natural’ treatments and to communicate the risks to patients effectively.”

The study is published in the current online issue of The Journal of Alternative and Complementary Medicine.

To determine how often S. John’s wort (SJW) was being prescribed or taken with other medications, the team conducted a retrospective analysis of nationally representative data collected by the National Ambulatory Medical Care Survey from 1993 to 2010. The research team found the use of SJW in potentially harmful combinations in 28 percent of the cases reviewed.

Possible drug interactions can include serotonin syndrome, a potentially fatal condition that causes high levels of the chemical serotonin to accumulate in your body, heart disease due to impaired efficacy of blood pressure medications or unplanned pregnancy due to contraceptive failure, Taylor said.

Limitations of the study are that only medications recorded by the physician were analyzed. However, she said the rate of SJW interactions may actually be underestimated because the database did not include patients who were using SJW but did not tell their doctor.

“Labeling requirements for helpful supplements such as St. John’s wort need to provide appropriate cautions and risk information,” Taylor said, adding that France has banned the use of St. John’s wort products and several other countries, including Japan, the United Kingdom, and Canada, are in the process of including drug-herb interaction warnings on St. John’s wort products.

“Doctors also need to be trained to always ask if the patient is taking any supplements, vitamins, minerals or herbs, especially before prescribing any of the common drugs that might interact with St. John’s wort.”

Co-authors are Steven Feldman, M.D., and Scott Davis, M.A., of Wake Forest Baptist.
Funding was provided by the Center for Dermatology Research at Wake Forest Baptist.

Related:Linking Herbal Supplements with Liver Injury

HCV therapies for genotype 1: A final good-bye to interferon

Clinical Liver Disease
Special Issue: Vascular Disorders
Volume 3, Issue 6, pages 137–140, June 2014

New all-oral HCV therapies for genotype 1: A final good-bye to interferon

Watch a video presentation of this article, here
Watch the interview with the author here or below

New all-oral HCV therapies for genotype 1: A final good-bye to interferon 

Proof-of-Concept Studies of Interferon-free Regimens
With more than 30 direct-acting antiviral agents (DAAs) in clinical trials, the hepatitis C community (scientists, physicians, patients) expect that the right combinations of DAAs will emerge, permitting treatment of hepatitis C virus (HCV) genotype 1 with interferon (IFN)-free regimens. In 2012, the first report of sustained virologic response (SVR) with an IFN-free regimen in patients with genotype 1 was published. In this study, 4 of 11 (36%; 2 of 9 with genotype 1a, 2 of 2 with genotype 1b) noncirrhotic null responders to pegylated IFN (PEG-IFN) and ribavirin (RBV) achieved SVR after a 24-week course of asunaprevir, a protease inhibitor, and daclatasvir, a NS5A inhibitor.[1] Whereas the number of patients studied was small and the SVR rate was low in patients with genotype 1a, these data provided proof of concept that SVR can be achieved without IFN or RBV in patients with HCV genotype 1. These data have encouraged the evaluation of many other IFN-free regimens.

IFN-free Regimens Expected to Be Approved in 2014/2015

In late 2013, two new DAAs for genotype 1 were approved by the US Food and Drug Administration (FDA): simeprevir, a protease inhibitor, and sofosbuvir, a nucleotide polymerase inhibitor. Both drugs are to be used with PEG-IFN and RBV. Although sofosbuvir was also approved to be used with RBV (without PEG-IFN) for IFN-ineligible patients, the SVR rate of the 2-drug regimen is substantially lower than the 3-drug regimen: 68% to 76% versus 89%.[2-4] Many experts have advocated the off-label combination of simeprevir and sofosbuvir based on data from a phase 2 study, and this approach is endorsed by the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America HCV guidelines.[5] However, only 167 patients were included in that study, and the cost of this off-label combination is substantially higher than the approved regimens.
Two IFN-free regimens for HCV genotype 1 are expected to be approved by the FDA in late 2014. Phase 3 trials of both regimens have been completed and results published.

The ION-1, 2, and 3 trials compared sofosbuvir plus ledipasvir, an NS5A inhibitor coformulated as a single pill, with or without RBV, for 8 to 24 weeks (Table 1) (Fig. 1). In the ION-1 trial in treatment naive patients (16% with cirrhosis), SVR rates after 12 weeks of therapy were 97% and 98% in the groups with or without RBV, respectively[7]; results in the 24-week treatment groups were 99% and 98% with and without ribavirin respectively.[7] In the ION-3 trial, the possibility of shortening the duration of treatment to 8 weeks was tested in treatment naive patients with no to moderate fibrosis (Metavir F0-F2); SVR rates after 8 weeks of therapy were 93% and 94% in the groups with or without RBV, respectively, and 95% after 12 weeks of treatment without RBV.[6] In the ION-2 trial in treatment-experienced patients (20% with cirrhosis), SVR rates after 12 weeks of therapy were 96% and 94% in the groups with or without RBV, respectively, and 99% in patients who received 24 weeks of treatment, with or without RBV.[8] Anemia was reported in 0.5% of patients in the RBV-free groups compared to 9.2% in the RBV-containing groups. Fewer than 1% of patients in the ION studies discontinued treatment due to treatment-related adverse events.

Figure 1. SVR12 rates in ION-I, ION-II, and ION-III trials of sofosbuvir and ledipasvir with or without ribavirin in treatment naive and treatment-experienced patients with HCV genotype 1.

The AbbVie regimen consisted of fixed-dose combination of ABT-450 (a protease inhibitor) with ritonavir boost coformulated with ombitasvir (ABT-267, an NS5A inhibitor) plus dasabuvir (ABT-333, a non-nucleoside polymerase inhibitor) with or without RBV for 12 or 24 weeks (Table 2).[9-12] SAPPHIRE-I, PEARL-III, and PEARL-IV included treatment naive, noncirrhotic patients; and SAPPHIRE-II and PEARL-II included treatment-experienced, noncirrhotic patients, whereas TURQUOISE-II included both treatment naive and treatment-experienced patients with compensated cirrhosis. In SAPPHIRE-I, all patients received 12 weeks treatment with RBV, and SVR rates were 95% for subtype 1a and 98% for subtype 1b (Fig. 2a).[11] In PEARL-III and PEARL-IV, all patients received 12 weeks treatment with or without RBV; SVR rates for PEARL-III (subtype 1b) were 99% in both groups; and for PEARL-IV (subtype 1a) rates were 97% and 90% in the groups with and without RBV, respectively (Fig. 2a). In SAPPHIRE-II, 49% of the patients were null responders to PEG-IFN and RBV. All patients received 12 weeks treatment with RBV, and SVR rates were 96% for subtype 1a and 97% for subtype 1b (Fig. 2b).[12] In PEARL-II, all patients had subtype 1b, and SVR rates were 97% and 100% in the groups with and without RBV, respectively (Fig. 2b).

In TURQUOISE-II, all patients had cirrhosis and all received RBV. SVR rates were 92% and 96% for the groups that received 12 and 24 weeks treatment, respectively (Fig. 2c).[9] Only 2% of the patients in either treatment group in TURQUOISE-II discontinued treatment because of adverse events. 

Table 2. SVR Rates to Phase 3 Trials of IFN-free AbbVie Regimens in Patients with HCV Genotype 1(see references [9-12])

Figure 2. SVR12 rates in phase 3 trials of AbbVie regimens of ABT-450/ritonavir, Ombitasvir (ABT-267) and Dasabuvir (ABT-333) with or without ribavirin in patients with HCV genotype 1.[9-12] (A) Treatment naive noncirrhotic patients: SAPPHIRE-I (subtype 1a and 1b), PEARL-IV (subtype 1a), and PEARL-III (subtype 1a). (B) Treatment-experienced, noncirrhotic patients: SAPPHIRE-II (subtype 1a and 1b) and PEARL-II (subtype 1b). (C) Treatment naive and treatment-experienced patients with cirrhosis (subtype 1a and 1b). 

Other IFN-free Regimens in the Pipeline
There are several other IFN-free regimens in the pipeline. The furthest along involves a combination of asunaprevir, daclatasvir, and BMS-791325 a nonnucleoside polymerase inhibitor. In a phase 2b trial of 166 treatment naive patients including 9% with cirrhosis, SVR rates were 92% and 92% in the groups that received low-dose or high-dose BMS-791325.[13] Phase 3 trial of this regimen is ongoing. Combination of daclatasvir and asunaprevir without BMS-791325 is also pursued in Japan, where nearly all patients with HCV genotype 1 have subtype 1b. As discussed earlier, this combination has low efficacy for subtype 1a. Another regimen involves a combination of a second-generation protease inhibitor MK-5172 and a second-generation NS5A inhibitor MK-8742.[14] Preliminary data showed SVR rates of 96% to 100% with or without RBV.

Are We Ready to Say Good-bye to Interferon for HCV Genotype 1?
Data from the studies presented above show that a 12-week course of IFN-free, all-oral combination of 2 or 3 DAAs can result in a more than 90% SVR rates in most patients with genotype 1 infection, including those with subtype 1a, treatment-experienced patients, and patients with cirrhosis. Some of these regimens would also be RBV-free. Phase 3 trials of two of the IFN-free regimens have been completed and qualify for expedited review by the FDA; thus, it is expected that they will be available in late 2014 or early 2015. This is tremendous news for patients and HCV providers because the wait is finally over for most, if not all, patients with genotype 1 infection.

  • 1
    Lok AS, Gardiner DF, Lawitz E, Martorell C, Everson GT, Ghalib R, Reindollar R, et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. N Engl J Med 2012;366:216-224.
  • 2
    Osinusi A, Meissner EG, Lee YJ, Bon D, Heytens L, Nelson A, et al. Sofosbuvir and ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a randomized clinical trial. JAMA 2013;310:804-811.
  • 3
    Sulkowski M, Rodriguez-Torres M, Lalezari JP, Fessel WJ, Mounzer K, Shuhart MC, et al. All-oral therapy with sofosbuvir plus ribavirin for the treatment of HCV genotype 1, 2, and 3 infection in patients co-infected with HIV (PHOTON-1). Hepatology 2013;58(suppl 1):313A.
  • 4
    Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med 2013;368:1878-1887.
  • 5
    AASLD, IDSA. Recommendations for testing, managing, and treating hepatitis C. Last accessed May 10, 2014.
  • 6
    Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med 2014;370:18791888.
  • 7
    Afdhal N, Zeuzem S, Kwo P, Chojkier M, Gitlin N, Puoti M, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. N Engl J Med 2014;370:18891898.
  • 8
    Afdhal N, Reddy KR, Nelson DR, Lawitz E, Gordon SC, Schiff E, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. N Engl J Med 2014;370:14831493.
  • 9
    Poordad F, Hezode C, Trinh R, Kowdley KV, Zeuzem S, Agarwal K, et al. ABT-0000/r-Ombitasvir and Dasabuvir with Ribavirin for Hepatitis C with Cirrhosis. N Engl J Med 2014;370:19731982.
  • 10
    Ferenci P, Bernstein D, Lalezari J, Cohen D, Luo Y, Cooper C, et al. ABT-0000/r-Ombitasvir and Dasabuvir with or without Ribavirin for HCV. N Engl J Med 2014;370:19831992.
  • 11
    Feld JJ, Kowdley KV, Coakley E, Sigal S, Nelson DR, Crawford D, et al. Treatment of HCV with ABT-0000/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med 2014;370:15941603.
  • 12
    Zeuzem S, Jacobson IM, Baykal T, Marinho RT, Poordad F, Bourlière M, et al. Retreatment of HCV with ABT-0000/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med 2014;370:16041614.
  • 13
    Everson GT, Sims KD, Thuluvath PJ, Lawitz E, Hassanein T, Rodriguez-Torres M, et al. Phase 2b study of the interferon-free and ribavirin-free combination of daclatasvir, asunaprevir, and BMS-791325 for 12 weeks in treatment-naïve patients with chronic HCV genotype 1 infection. Hepatology 2013;58(suppl):1377A.
  • 14
    Lawitz E, Vierling JM, Murillo A, Kugelmas M, Gerstoft J, Winkle P, et al. High efficacy and safety of the all-oral combination regimen, MK-5172/MK-8742 ± RBV for 12 weeks in HCV genotype 1 infected patients: the C-WORTHY study. Hepatology 2013;58(suppl 1):244A.

Physicians implanted livers into rats after four days

Physicians implanted livers into rats after four days

US scientists are currently working on a way to prolong the preservation of organs for transplantations. Using a combination of various methods, the researchers successfully transplanted rat livers preserved for four days.

The physicians from Massachusetts General Hospital in Boston described the method with which they preserved the organs in "Nature Medicine". After removal from donor animals, the livers were attached to a machine perfusion system where they were first loaded with the glucose derivative 3-OMG and then flushed with a combination of the currently used protective solution and polyethylene glycol (PEG) while being cooled to 4 degrees Celsius (40 degrees Fahrenheit). Then they were submerged into the combined solutions and stored at minus 6 degrees Celsius (21 degrees Fahrenheit) for 72 or 96 hours.

Subsequently, the temperature was increased to 4 degrees and the organs were then again attached to a machine and flushed with the combination of the two solutions for three hours at room temperature before being transplanted.

All the rats that had received organs supercooled for 72 hours were still alive after three months. Of the animals that had received organs cooled for 96 hours, 58 per cent survived. However, tests carried out before surgery were able to predict which organs would still be good enough. "Even among the livers preserved for four days, if we had only used those in which oxygen uptake, bile production and the flow of perfusion solution were good, we would have achieved 100 per cent survival", emphasised co-senior author Martin Yarmush.

Much work still needs to be done before this technology can be applied to humans, said the researchers. However, with the possibility of extending the preservation time, organs can now be transported over considerably longer distances, which, in turn, may counteract the global shortage of organs.

Press Release: 

NIH-funded researchers extend liver preservation for transplantation

Researchers have developed a new supercooling technique to increase the amount of time human organs could remain viable outside the body. This study was conducted in rats, and if it succeeds in humans, it would enable a world-wide allocation of donor organs, saving more lives.

The research is supported by National Institute of Biomedical Imaging and Bioengineering (NIBIB) and the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), both parts of the National Institutes of Health.

The liver is perfused with a solution in this pump system before and after supercooling preservation. The blue color is caused by antifreeze that surrounds the components of the system to regulate the temperature. Source: Wally Reeves, Korkut Uygun, Maish Yarmush, Harvard University

The first human whole organ transplant 60 years ago — a living kidney transplant — changed the landscape of the medical world. Since then, transplants of skin, kidneys, hearts, lungs, corneas, and livers have become commonplace but due to a shortage of donor organs, more than 120,000 patients are still on waitlists for organ transplantation in the United States alone.

Current technology can preserve livers outside the body for a maximum of 24 hours using a combination of cold temperatures and a chemical solution developed by scientists at the University of Wisconsin-Madison in 1983. The solution helps keep the liver tissue from dying while in transit to the recipient site. This has helped increase the number of successful liver transplants — but extending even further the time a liver can survive outside the body would provide many benefits. It would allow for more time to prepare the patient and ease logistics at the donor hospital site, reduce the urgency of rushing the organ to its destination, and expand the donation area to allow for transcontinental and intercontinental transplantations — thus increasing the chances of patients finding better matches while simultaneously significantly reducing costs.

The difficulty with long-term preservation of human organs stems mostly from the extensive tissue damage that occurs when organs are cryopreserved, frozen at temperatures of -320.8 degrees Fahrenheit. While successful for single cells and simple tissues, the problem is exacerbated with whole organs because of the multiple cell types and other structures that react differently to cold. To combat these problems, Martin Yarmush, M.D., Ph.D., and Korkut Uygun, Ph.D., investigators in the Center for Engineering in Medicine at Massachusetts General Hospital (MGH), Boston, have developed a four-step preservation technique that has tripled the amount of time that rat livers can be stored before transplantation.

In the June 19 online issue of Nature Medicine, the researchers describe their process. The first step is to employ the use of machine perfusion — a way of delivering oxygen and nutrients to capillaries in biological tissues while outside the body — to supercool the liver tissue without causing irreversible damage to the cells. In order to accomplish this, the MGH team added 3-OMG (3-O-methyl-D-glucose), a non-toxic, modified glucose compound, to the solution being delivered to the liver. The 3-OMG is taken up and because it cannot be metabolized by cells, accumulates in the hepatocytes (liver cells), acting as a protectant against the cold. The team also modified the solution by adding PEG-35kD (polyethylene glycol) to specifically protect cell membranes. Ethylene glycol is the active ingredient in anti-freeze, and it works by lowering the freezing point of a solution.

The livers were then slowly cooled below the freezing point, to 21 degrees Fahrenheit, without inducing freezing — thereby supercooling the organ for preservation. After storing the organs for several days, the researchers again used machine perfusion to rewarm the organ, while also delivering oxygen and other nutrients to prepare the organ for transplantation.

 A supercooled rat liver sits in the preservation solution in the machine perfusion system. Source: Wally Reeves, Korkut Uygun, Maish Yarmush, Harvard University

Using this new technique, the researchers were able to store the supercooled rat livers for three days (72 hours) and four days (96 hours) at 21 degrees Fahrenheit. All the rats who had supercooled livers stored for three days survived three months, but none of the rats who had transplants using current methods did. The survival rate for animals receiving livers stored for four days was 58 percent. When testing to see if all the steps in their method were essential, the researchers found that if they eliminated the supplemental components PEG-35kD or 3-OMG, none of the rats survived for even a week. If they did not use machine perfusion or supercooling, death occurred within an hour of transplantation.

“The next step will be to conduct similar studies in larger animals,” said Rosemarie Hunziker, Ph.D., program director of Tissue Engineering and Regenerative Medicine at NIBIB. “It is exciting to see such an achievement in small animals, by recombining and optimizing existing technology. The main point here is that using all of these approaches at once was what led to success. Halfway measures did not do. Such a tour de force reflects this team’s very deep understanding of the complex processes at work here, and how they relate simultaneously to each other.”

The process must go through extensive testing and refinement before it could be considered for use in humans. But the technique’s achievement in being the first method to have a successful survival rate after the livers had been stored for three days and possible potential for four-day storage has broad implications for the future of liver transplantation.

“The longer we are able to store donated organs, the better the chance the patient will find the best match possible, with both doctors and patients fully prepared for surgery,” said Hunziker. “This is a critically important step in advancing the practice of organ storage for transplantation.”Among the researchers contributing to this project are Tim Berendsen, M.D., who performed the transplants, and Bote Bruinsma, an M.D., PhD. student at University of Amsterdam conducting his graduate studies with Drs. Yarmush and Uygun. The team was comprised of 10 engineers, scientists and surgeons at the Center for Engineering in Medicine at the Massachusetts General Hospital/Harvard Medical School, Boston.

This work was supported by NIH’s National Institute of Biomedical Imaging and Bioengineering and the National Institute of Diabetes and Digestive and Kidney Disease under award numbers R01EB008678, R01DK096075, R00DK080942, R00DK088962; the authors also gratefully acknowledge Shriners Hospitals for Children.

NIBIB’s mission is to improve health by leading the development and accelerating the application of biomedical technologies. The Institute is committed to integrating the physical and engineering sciences with the life sciences to advance basic research and medical care. NIBIB supports emerging technology research and development within its internal laboratories and through grants, collaborations, and training. More information is available at the NIBIB website:

The NIDDK, a component of the NIH, conducts and supports research on diabetes and other endocrine and metabolic diseases; digestive diseases, nutrition and obesity; and kidney, urologic and hematologic diseases. Spanning the full spectrum of medicine and afflicting people of all ages and ethnic groups, these diseases encompass some of the most common, severe and disabling conditions affecting Americans. For more information about the NIDDK and its programs, see

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit

Saturday, June 28, 2014

Future Therapies for HCV: The Importance of New Treatment Paradigms and Interferon-free Regimens

Future Therapies for CHC: The Importance of New Treatment Paradigms and Interferon-free Regimens

Good afternoon folks, its time to catch up on what you missed with another edition of Weekend Reading.

Today we have a documentary exploring the high cost of HCV treatment in the UK (BAD BLOOD), a bit of news, and a must watch learning activity released last month by ViralEd. The latter; Improving the Care Patients with Chronic Hepatitis C Online Program will focus on guidelines, diagnosis, and new all oral treatments for hepatitis C.  Although the CME is for healthcare professionals, the patient will benefit greatly by viewing all three narrated presentations. The activity is easy on the ears, and even easier to follow, especially because the CME is presented in a video and slide format. However, if the program is consuming too much of your Saturday, and the family is waiting in the wings for some weekend action, skip to the last presentation - you won't be disappointed.

Each teaching module is hosted by a different CHC specialist; Mark Sulkowski, MD., Professor of Medicine, and Medical Director of Viral Hepatitis Center, Johns Hopkins University School of Medicine, will host 1) Current Guidelines for the Diagnosis and Management of Patients with HCV Infection; K. Rajender Reddy, MD., Professor of Medicine, University of Pennsylvania, presents 2) Overcoming Host and Viral Barriers to Successful Hepatitis C Therapy; and finally Nezam H. Afdhal, MD., Professor of Medicine, Harvard School of Medicine, and Chief of Hepatology, Director of Liver Center, Beth Israel Deaconess Medical Center, will end with 3) Future Therapies for CHC: The Importance of New Treatment Paradigms and Interferon-free Regimens.

After viewing each module a link is provided for anyone interested in receiving a CME credit. Finally, a menu offering all three modules will once again appear allowing us to continue. 

Just like any CME a quick free registration is required, click here to register. Enter your name, email address, and degree. If you are not a physician or nurse, type in My Degree, it worked for me.

Topic Highlights

Patient Case
Baby Boomers
Revised Screening
Who Should Be Tested
Staging Disease
Morbidity and Mortality Predictions
Cure and Outcome
FDA Approved Drugs

Patient Case 
Undiagnosed HCV
Evolution Of HCV Treatment
Drug To Drug Interactions
Side Effects
Current Treatments
Regimens (Genotype)
SVR - Cirrhosis
 Treating Patients With Advanced Liver Disease
Sofosbuvir - Decompensated Liver Disease

HCV - Past, Present, and Future
Patient Case
Ledipasvir  - Sofosbuvir
And MORE.......

Begin here 



Published on Jun 26, 2014 

A documentary exploring the treatment of Hepatitis C in the UK


New From Healio  

NICE seeks information from Gilead regarding cost-effectiveness of Sovaldi 

 The National Institute for Health and Care Excellence in the UK is requesting Gilead Sciences to provide more information on sofosbuvir to determine if it is cost effective to treat hepatitis C virus, according to a press release.

The antiviral oral drug sofosbuvir (Sovaldi) currently has marketing authorization in the UK for use in combination with other drugs for treating hepatitis C virus (HCV).
The National Institute for Health and Care Excellence (NICE) request is included in draft guidance on the drug, which is available for public consultation. Comments on the draft will be accepted until July 4, according to the release.

In the draft, the NICE committee does not recommend sofosbuvir within its marketing authorization for treating chronic HCV in adults. It also requests further analyses from Gilead for sofosbuvir in combination with ribavirin, with or without pegylated interferon-alfa vs. peginterferon-alfa and ribavirin in patients with HCV genotypes 1 and 3, regarding revised analyses to cost-effectiveness for patients with and without cirrhosis, HIV coinfection, along with patients’ treatment history. Sensitivity analyses that address any incremental cost-effectiveness ratios also are sought, the release said.

“Poor diagnosis rates, combined with a high number of new infections annually means that chronic hepatitis C presents a major public health challenge,” Carole Longson, PhD, director of the NICE Centre for Health Technology Evaluation, said in the release. “The available evidence shows that sofosbuvir is an effective treatment for chronic hepatitis C in certain patients. However, evidence is lacking for some subgroups of patients with chronic hepatitis C, and there are also substantial uncertainties in the evidence base presented by the manufacturer. The committee has therefore requested further information from the manufacturer before it can decide whether sofosbuvir is a cost-effective use of [National Health Service] resources.”

According to the release, approximately 160,000 people are infected with HCV in England, and a majority have genotypes 1 (46%) and 3 (43%).

 Heads Up In Canada 

SOVALDI (sofosbuvir) WEBINAR July 3, noon (PST) with Dr. Alnoor Ramji

HepCBC is co-hosting a Webinar with the Pacific Hepatitis C Network on July 3rd at noon Pacific time. Dr. Alnoor Ramji will present the most accurate and most current information about SOVALDI (sofosbuvir), and will be available to answer your questions. Registration information will be available at this website soon. Stay tuned!

HepCBC is asking everyone’s help in approving all the new hepatitis drugs for coverage by BC PharmaCare. Between now and July 10th, you can contribute your voice to HepCBC’s Patient Group SOVALDI (sofosbuvir) submission:

You can also find the forms for individual patient and caregiver submissions at Deadline for these submissions is midnight, July 11th.

In Today's News

Health insurer Anthem Blue Cross and Blue Shield asks state for 12.5% rate hike

By SUSAN HAIGH Associated Press

Michael Bears, Anthem's vice president of actuary, spelled out a number of reasons for the proposed rate increase. The list included higher costs for medical services and pharmaceuticals, especially drugs for treating Hepatitis C, and fees levied by the federal government as part of the Affordable Care Act. 

Hartford - Consumers and advocates urged state insurance regulators on Friday to deny a 12.5 percent rate increase proposed by Anthem Blue Cross and Blue Shield, Connecticut's largest health insurer.

The proposed rate increase for individual plans, beginning
Jan. 1, would affect nearly 66,200 policyholders, including some who recently purchased their policies through the state's health insurance exchange, Access Health CT.

"Anthem is only one insurer asking for a rate increase, but it is an insurer that enjoys a large share of the Connecticut market," Jill Zorn, senior program officer for the Universal Health Care Foundation of Connecticut, told the Department of Insurance hearing officer reviewing the rate request. "We urge you to sharpen your pencils and carefully review all input in this rate review hearing, most especially the comments of policyholders who could not be here today."

Zorn said the state owes it to the state's policyholders "not to just rubber stamp Anthem's request to raise premiums."

Anthem was the only established Connecticut insurance company that offered both individual and small group health care plans in the state's health insurance exchange during the recent open enrollment period. It is providing coverage to the bulk of the customers who signed up for private coverage on the exchange.

With its rate increase proposal, Anthem contends it is attempting to strike a balance between being competitive price-wise and remaining solvent and financially stable.

Michael Bears, Anthem's vice president of actuary, spelled out a number of reasons for the proposed rate increase. The list included higher costs for medical services and pharmaceuticals, especially drugs for treating Hepatitis C, and fees levied by the federal government as part of the Affordable Care Act.

The hearing officer, Paul Lombardo, asked Bears to provide the agency with additional information to justify the proposed rate increase. A final decision on Anthem's rate filing will be made within 30 days after the record of Friday's proceeding is closed. The decision will be posted on the Department of Insurance website.

Besides concerns about the size of the proposed rate increase, some members of the public brought up issues with Anthem's handling of its policies sold on the state's health insurance exchange.

Arvind Shaw, CEO of the Generations Family Health Center in Willimantic, said Anthem has been slow in reimbursing for services. He said his agency is owed about $43,000 but has been paid about $290 to date. Additionally, Shaw said some of his clients' prescription drug claims were erroneously denied.

"I am very concerned for the safety and care of these patients," Shaw said.

Bloggers Corner

Hepatitis C and Vultures 
Lucinda Porter RN 

 Take action and support the Viral Hepatitis Testing Act. Fortify your liver with good food, sleep, exercise, and humor. Don’t drink. If you can’t stop, get help. Get support..
Continue reading...   

Healthy You

Liver Health News and Research
A collection of  latest research, news and health tips about viral hepatitis and liver health.

Enjoy the program, and this lovely weekend.

Always Tina

Friday, June 27, 2014

Hepatitis C-Gilead Submits NDA to Japan for Sofosbuvir

Gilead Submits New Drug Application to Japan's Pharmaceutical and Medical Devices Agency for Sofosbuvir for Chronic Hepatitis C

-- If Approved, Sofosbuvir Would Be the First All-Oral Treatment Regimen for Patients in Japan with Genotype 2 HCV --

FOSTER CITY, Calif.--(BUSINESS WIRE)--Jun. 27, 2014-- Gilead Sciences, Inc. (Nasdaq:GILD) today announced that the company has submitted a New Drug Application (NDA) to Japan's Pharmaceutical and Medical Devices Agency (PMDA) for approval of sofosbuvir, a once-daily nucleotide analog polymerase inhibitor for the treatment of chronic hepatitis C virus (HCV) infection. The data in the NDA support the use of sofosbuvir with ribavirin (RBV) for 12 weeks in patients with genotype 2 HCV infection. If approved, sofosbuvir would form the basis of the first all-oral, interferon-free treatment regimen for genotype 2 patients in Japan.

Primarily due to HCV, Japan has one of the highest rates of liver cancer of any industrialized country. Of the more than one million people chronically infected with HCV, 20-30 percent have the genotype 2 strain of the virus. Currently approved therapies in Japan for genotype 2 HCV infection involve 24-48 weeks of injections with pegylated interferon, which may not be suitable for certain patients.

"There is an urgent need in Japan for new HCV treatment options that are more effective, well-tolerated and simpler for patients," said Norbert Bischofberger, PhD, Gilead's Executive Vice President of Research and Development and Chief Scientific Officer. "Based on Phase 3 studies, we believe that sofosbuvir has the potential to provide high cure rates among genotype 2 patients in just 12 weeks of interferon-free therapy. We look forward to working with the PMDA as the agency reviews our application."

The NDA is based primarily on data from a Phase 3 clinical trial conducted in Japan (Study GS-US-334-0118) among 153 treatment-naïve and treatment-experienced genotype 2 patients. In the study, 97 percent (n=148/153) of genotype 2 HCV-infected patients receiving 12 weeks of an all-oral regimen of sofosbuvir plus RBV 600-1,000 mg/day achieved a sustained virologic response 12 weeks after completing therapy (SVR12). Patients who achieve SVR12 are considered cured of HCV infection. The NDA is also supported by SVR12 results from four international Phase 3 studies (FISSION, FUSION, POSITRON and VALENCE), which included genotype 2 HCV patients.

Sofosbuvir represents Gilead's first drug application in Japan, and if approved, would be the first product to be launched and marketed by Gilead in the country. The company established operations in Japan in November 2012.

Gilead also has conducted a second Phase 3 clinical trial in Japan (Study GS-US-337-0113) that is evaluating a once-daily fixed-dose combination of sofosbuvir 400 mg and the NS5A inhibitor ledipasvir 90 mg, with and without RBV, for the treatment of genotype 1 HCV infected patients. Genotype 1 is the most common strain of HCV in Japan. Gilead announced SVR12 results from this study on June 15 and plans to file for approval of the ledipasvir/sofosbuvir combination in Japan in the second half of 2014.

Sofosbuvir is an investigational product in Japan and its safety and efficacy has not yet been established. The compound has been approved by regulatory authorities in the United States, European Union and Canada and is commercialized under the tradename Sovaldi®. The ledipasvir/sofosbuvir fixed-dose combination is an investigational product and its safety and efficacy has not yet been established.

EU smiles on a key cog in Bristol-Myers' hep C combo

Press Release
European Medicines Agency recommends approval of Daklinza in chronic hepatitis C
First-in-class medicine to offer new treatment option for patients
The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has recommended granting a marketing authorisation for Daklinza (daclatasvir) in combination with other medicines for the treatment of chronic (long-term) hepatitis C virus (HCV) infection in adults
Continue reading... 

Source- FierceBiotech:
EU smiles on a key cog in Bristol-Myers' hep C combo
June 27, 2014 | By

European regulators are recommending approval for Bristol-Myers Squibb's ($BMY) daclatasvir, an hepatitis C-fighting antiviral that plays a key role in the company's planned combo treatment.

A European Medicines Agency committee has handed down a positive opinion on daclatasvir, a pan-genotypic NS5A complex inhibitor designed to work in concert with other agents to treat chronic hep C. Bristol-Myers' agent is the first of its kind to win any European backing, the company said, and the drug is now likely to receive full approval in the coming months.

The drug, which will sell as Daklinza, is the cornerstone of Bristol-Myers' in-development cocktail therapy for hep C, an all-oral combination that includes the investigational asunaprevir and BMS-791325 and won the FDA's breakthrough therapy designation last year.

However, the antiviral's greatest promise may come in combination with Sovaldi, the top-selling hep C treatment from rival Gilead Sciences ($GILD). Bristol plans to initiate a trial next month combining its three-drug therapy with the former sofosbuvir, creating an oral cocktail the company believes could notch near-100% cure rates while cutting treatment time down to as little as four weeks. Gilead's drug is approved as a 12-week regimen.

Bristol-Myers is among a cadre of drugmakers undaunted by Gilead's brisk success with Sovaldi, which analysts say could bring in more than $8 billion this year. AbbVie ($ABBV) has developed a four-drug cocktail treatment that eliminates the need for painful interferon, expected to receive U.S. and European approvals this year and hit the market just behind a similar Sovaldi-based combo from Gilead. Bristol-Myers and Merck ($MRK) are working up similar piggyback therapies that have notched sky-high cure rates in clinical trials.

Once approved, those interferon-free treatments are likely to dominate the market, but drugmakers believe the next big thing in hep C will be brevity. Aside from Bristol-Myers' work on a four-week treatment, Merck is paying $3.9 billion for Idenix Pharmaceuticals ($IDIX) to get its hands on assets that could fuel a fast cure, and Gilead is testing out an in-house combo with the same potential.

- read Bristol-Myers' statement
- here's the EMA release (PDF)

Related Articles:
Bristol-Myers toes the next hep C frontier: a four-week cure
Bristol-Myers looks to rival Gilead for the key to conquering the hep C market
Merck scoops up troubled Idenix's hep C drugs in $3.85B buyout

Thursday, June 26, 2014

Linking Herbal Supplements with Liver Injury

Linking Herbal Supplements with Liver Injury

Despite the perceived safety of herbal and dietary supplements, they can cause serious liver injury. In the July issue of Clinical Gastroenterology and Hepatology, Simona Rossi and Victor J. Navarro discuss the scope, use, and regulation of herbal and dietary supplements, as well as the diagnosis of herbal and dietary supplement-induced liver injury.

Patients take dietary supplements for many reasons, including anxiety, obesity, diabetes, rheumatoid arthritis, cancer, cardiovascular disease, and pain.

Almost a quarter of patients enrolled in a long-term hepatitis C treatment trial reported using herbal and dietary supplements.

Rossi and Navarro explain that the ease of access to these supplements allows consumers to assume that they are safe and can be used without consequences. Most patients do not divulge use of dietary supplements to health care providers.

However, in the US National Health and Nutrition Examination Survey, 52% of respondents reported using a dietary supplement, and other surveys have reported even higher use. In some Asian and African countries, up to 80% of the population use herbal supplements as their primary means of medical care.

Rossi and Navarro discuss the incidences of injury caused by different supplements in different countries. These range from 1%–2% of cases of liver injury in Spain (with antibiotics being among the most common class implicated) to Singapore, where 71% of cases of drug-related liver injury have been attributed to medicinal herbs—many adulterated with active drugs.

The authors discuss preliminary findings from the US Drug-Induced Liver Injury Network (DILIN) showing that herbal and dietary supplements are responsible for an increasing proportion of hepatotoxicity cases.

Rossi and Navarro discuss the US Dietary Supplement Health and Education Act of 1994, in which manufacturers are required to attest to a product’s safety, but give no authority to the Food and Drug Administration (FDA) to approve the supplements before marketing. Routine analysis of products’ contents by the FDA is performed on only a random basis.

They present strategies for diagnosis of herbal and dietary supplement–induced liver injury, and the process for linking a drug or dietary supplement to liver injury. Products and ingredients associated with hepatotoxicity include weight loss supplements (Hydroxycut, Herbalife/green tea, and usnic acid), joint health supplements (flavocoxid- and glucosamine-based supplements), and bodybuilding supplements.

Attributing liver injury to any specific ingredient in herbal and dietary supplements is the single greatest challenge to clinicians and researchers interested in liver injury. Rossi and Navarro explain that even detailed chemical analyses of products, which are expensive and complex, do not always identify the agents responsible for injury. The authors propose using chemical analyses to identify ingredients common to products implicated in injury; proposed culprits could then be tested in formal toxicologic analyses.

Nonetheless, Rossi and Navarro state that a better understanding of the epidemiology of supplement-induced liver injury is needed, to identify the scope of the problem and the groups most affected, as well as to develop management and prevention strategies. Without more accurate estimates of the overall use of herbal and dietary supplements and more complete reporting of adverse events, it is impossible to determine disease prevalence and incidence.


With Better Treatment For HCV, Companies Developing NAFLD and NASH Drugs

 Investment Commentary 

Galectin Therapeutics is the other major player in the NAFLD/NASH space, developing carbohydrate-based drug candidates for fibrotic liver (and cancer) conditions.  Galectin has chosen to go after a difficult population of NAFLD patients, those with NASH with advanced fibrosis.  This is an important distinction from Intercept and Galmed, as Galectin is hoping to show not only a reduction in fat accumulation as its peers are aiming to demonstrate, but also a reversal to fibrotic damage in the liver in more advanced patients.  There is a further distinction in tackling the more advanced class of patients in that there is no clear set of standards in the pathogenesis of NAFLD to determine which patients will advance to NASH, cirrhosis or related conditions, so while halting the accumulation of fat is certainly paramount, reversing the damage is unprecedented. 

Catalysts on the Horizon for Companies Developing NAFLD and NASH Drugs
Published Thursday, June 26, 2014 by Fred Zucker
Those following the developments of Intercept Pharmaceuticals (NASDAQ: ICPT), Galectin Therapeutics (NASDAQ: GALT) and Galmed Pharmaceuticals (NASDAQ: GLMD) are keenly aware of the tendency of fatty liver disease drug developers to move in unity upon news of clinical research.  The lack of viable treatments, increasing diagnosis rates and the economic burden associated with fatty livers has put a spotlight on the limited number of companies pursuing the indication, keeping investors on the lookout for news with market moving potential.

The Growing Prevalence of Fatty Liver Disease

Thirty years ago, nonalcoholic fatty liver disease (NAFLD) did not even have a medical name, as physicians and researchers presumed the buildup of fat in the liver to be essentially benign.  With the advent of drugs to better treat hepatitis C, NAFLD is now the face of liver disease in the U.S. with a library of research documenting that fat accumulation in the liver can lead to nonalcoholic steatohepatitis (NASH), cirrhosis of the liver, eventual liver failure and death.  Cases of NAFLD have doubled in the past two decades, while prevalence of other liver diseases has remained stable or even decreased, positioning NAFLD to overtake hepatitis C as the leading case of liver transplants by 2020.  Moreover, there are no approved drugs to treat any of these diseases, which are generally asymptomatic until advanced stages, resulting in the dubious distinction of being “silent” killers.  Worse yet, a liver transplant is the only viable treatment option for cirrhosis patients, but the fact that only about 6,300 liver transplants happen each year in the U.S. leaves a bleak prognosis.

The growing prevalence of NAFLD, which causes the liver to balloon with fat, is sounding alarms in the medical community.  At first, the disease was not found in children as it typically takes years and years to develop, yet today about 10 percent of youths in the U.S. are estimated to have NAFLD.  A conservative estimate is that approximately 20 percent of adults in the U.S. suffer from NAFLD, with the World Gastroenterology Organisation Global Guidelines report in 2012 estimating that NASH affects 30 percent of the population in developed countries worldwide.  Closely ties to obesity, NAFLD affects at least 50 percent of all obese adult men, with some estimates ranging up to 80 percent.  Looking directly at NASH, the U.S. Department of Health and Human Services shows that up to 5 percent of the population, about 15.7 million people, suffer from the more severe form of NAFLD.

The comorbidities that are linked to the condition, including liver cancer, heart disease and Type 2 diabetes, have limited effective therapeutic options as well, creating a vortex of illness and death with NAFLD at the epicenter. All of this explains the recent surge in investment interest in companies developing new drugs to treat any stage of a fatty liver.

Upcoming Catalysts for NASH Players

Intercept Pharma is the most widely heralded biotech pursuing a NAFLD therapy and its rise in value is nothing shy of impressive, mushrooming from an IPO price near $20 per share in October 2012 to $70 per share a year later and then going parabolic to as high as $497 per share in January.  The value driver has been Intercept’s promising drug obeticholic acid (OCA), which has shown in trials to be effecting in treating patients with NASH.  In January, a 283-patient Phase 2 trial of OCA for NASH, called the FLINT trial, was stopped one year early because it had satisfied its primary endpoints of safety and providing a significant effect on liver damage caused by NASH.

The latest good news for Intercept came in late May when the U.S. Food and Drug Administration awarded the company “Fast Track” status for OCA, a first-in-class farnesoid X receptor agonist, for treating patients suffering from primary biliary cirrhosis (PBC) who do not respond to ursodiol. Ursodiol is the only drug approved to treat PBC, a disease characterized by bile ducts in the liver being slowly destroyed, which can lead to irreversible scarring of the liver.  Note, this is not NASH, but it is promising for OCA in general as Intercept gears up to submit a New Drug Application to the FDA for the indication in mid-2015.

Those choosing to short ICPT are focused on mumblings that the company downplayed increased LDL cholesterol levels in its FLINT trial, which could raise safety concerns, as lipid abnormalities are often associated with risk of cardiovascular events.  ICPT bulls oppose this position, including Wedbush Capital, saying much ado is being made about nothing.  All patients stopped dosing in January, when the trial was halted early, and were put on a pre-specified 24-week observational phase.

This aligns Intercept for a potential sharp move in share value when final data from the trial, including the observational stage, is released. To give you an idea of the interest in that data, Intercept’s stock price dove about 7% yesterday when the company indicated at the JMP Securities Healthcare Conference that full results would likely not be released in July as previously anticipated.

Galmed, a newbie in the public domain (IPO in March), joined in the NASH race unintentionally at first, but has drawn the attention of the investment community based upon its findings.  Galmed’s experimental oral drug aramchol, a conjugate of Cholic acid and Arachidic acid, was accidentally discovered to reduce liver fat infiltration in animal models with high-fat diets during research to solubilize bile stones.  A Phase 2 study showed aramchol to be safe and effective in reducing liver fat content and improve metabolic parameters associated with NAFLD.

Galmed was hoping to initiate a 120-patient Phase 2b aramchol study late in 2013 for NASH in obese patients with insulin resistance, but the FDA recommended that the Tel Aviv, Israel-based company first run pharmacokinetic and food effect studies.  Patient screening got underway at the end of April.  The Phase 2b study, which is expected to take about 15 months, is now planned for the fourth quarter of this year.  With about $40 million in cash from raises, Galmed thinks it has enough cash to get through 2017.

Galectin Therapeutics is the other major player in the NAFLD/NASH space, developing carbohydrate-based drug candidates for fibrotic liver (and cancer) conditions.  Galectin has chosen to go after a difficult population of NAFLD patients, those with NASH with advanced fibrosis.  This is an important distinction from Intercept and Galmed, as Galectin is hoping to show not only a reduction in fat accumulation as its peers are aiming to demonstrate, but also a reversal to fibrotic damage in the liver in more advanced patients.  There is a further distinction in tackling the more advanced class of patients in that there is no clear set of standards in the pathogenesis of NAFLD to determine which patients will advance to NASH, cirrhosis or related conditions, so while halting the accumulation of fat is certainly paramount, reversing the damage is unprecedented.

In 2013, Galectin received a Fast Track designation from the FDA to expedite development of its drug GR-MD-02 for NASH patients with advanced hepatic fibrosis.

Galectin disclosed in April that it has completed enrollment in the second cohort of the trial, good news following a prior announcement that data from the first cohort showed the therapy to be safe and well tolerated.  The data further showed positive changes in pre-defined biomarkers for the trial, suggesting efficacy, although that is never a primary endpoint of early-stage clinical trials.  Dosing of GR-MD-02 for the second cohort was doubled from the first cohort, putting investors on close watch for results, which are slated for the latter part of next month.

With more than $36 million in cash on hand at the end of the first quarter, Galectin is plenty well financed to complete the Phase 1 trial of its drug, as well as other research throughout 2015.  To that point, Galectin has conducted some compelling lab studies to further support the potential of GR-MD-02, including data from a pre-clinical trial in a diabetic mouse model with NASH released on Monday.

In the study, treatment with GR-MD-02 for four weeks significantly reduced liver weight, liver-to-body weight ratio and plasma triglyceride levels in mice with induced NASH.  Blood biomarkers that are indicative of liver damage, such as aspartate aminotransferase, plasma alanine aminotransferase and plasma total bilirubin, also showed reductions back near normal levels in the treated mice.  Further, the backbone of Galectin research was supported by the study, showing a significant reduction in fibrosis of the liver. Perhaps the most important aspect of this trial is that the mice were given oral treatments, as opposed to the intravenous administration in the Phase 1 human trials. The potential market for oral delivery is distinct and additive to the potential market for IV treatments. Every disease has a target product profile and while IV administration will provide the best results in some indications, oral delivery can be more appropriate for others, such as chronic diseases and conditions. This development bears watching over the long term as Galectin advances their clinical programs.

Adding to the interest in Galectin on Monday, analysts Aegis Capital reiterated their “buy” rating on the stock.  In April, analysts at MLV & Co. put out a “buy” rating on GALT and boosted their price target from $20 to $27.

Why Pay Attention Now

Safety and tolerability are obviously imperative in studies, but the meat and potatoes of a trial is efficacy, something that investors and analysts will be trying to glean from every data set released by Galectin.  Investors know the value of a drug to treat the growing NAFLD population that has out of the blue reached epidemic proportion, and remember the multi-billion-dollar jump in valuation for Intercept on its trial news in January.  The fact that there are few companies entrenched in NASH research bolsters the interest in each upon optimistic data.

Galmed has not disclosed the date for completing its PK/food effect study, but it cannot be too far off in the distance in order to initiate the mid-stage trial of aramchol that it has planned this year.  Intercept and Galectin both have data anticipated late next month (or perhaps later in Intercept’s case), the type of data that can have market-moving potential.  The stock prices of the companies have mostly undulated in unison, including all three trading higher since Intercept’s PBC Fast Track news late in May and jumping at the opening bell Monday after Galectin released its pre-clinical data, so upcoming news in the coming weeks is likely to draw further attention to the space.