Thursday, October 19, 2017

The Liver Meeting® 2017 - AASLD Liver Meeting Covers a Lot of Ground

AASLD Liver Meeting Covers a Lot of Ground
by Michael Smith Michael Smith
North American Correspondent, MedPage Today

October 19, 2017
New science could 'potentially change the field'

WASHINGTON -- The annual Liver Meeting always draws a crowd, largely because there's pretty much something for everyone with an interest in hepatology.

"We don't have a specific theme because we have to cover every aspect of liver development," according to Anna Lok, MD, of the University of Michigan in Ann Arbor, president of the American Association for Liver Diseases, which sponsors the meeting.

There remains a great deal of interest in HCV, evidenced by dozens of posters and oral presentations on new therapeutics, as well as on other aspects of the disease.  Indeed, organizers are planning a special session on the path to elimination of viral hepatitis, featuring a talk by U.S. Surgeon General Jerome Adams, MD. Adams will discuss the opioid crisis and the related epidemics of HIV and HCV.

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Wednesday, October 18, 2017

Healio Rheumatology - Hepatitis C and the Rheumatologist

Healio Rheumatology

Hepatitis C and the Rheumatologist: Our Role in the Quest for Global Eradication of HCV
Healio Rheumatology, October 2017
Leonard H. Calabrese, DO
I am pleased to have Healio Rheumatology focus this issue’s Cover Story on the intersection of viral hepatitis and rheumatology, as this is a subject both near to my heart as well as one of great importance to many patients. Our esteemed sources enlighten us on many aspects of the impact of viral hepatitis and rheumatic diseases from not only from the perspective of these viruses as etiologies for many rheumatic syndromes, but also, and far more important, from a prevalence perspective – the impact of chronic viral hepatitis, both hepatitis B and C, as comorbidities.

Educating Rheumatologists on Hepatic Associations With Rheumatic Diseases
Healio Rheumatology, October 2017
Historic advances have been occurring in hepatitis C therapy during the last decade. This once difficult-to-treat chronic infection is essentially curable with direct-acting antiviral therapies. For hepatitis B, a wave of biologic therapies is changing the landscape and offering hepatologists, gastroenterologists and infectious diseases clinicians a host of options to manage patients.

Fibromyalgia: Few New Treatments, But Understanding Continues to Grow
Healio Rheumatology, October 2017
Efforts to better understand and treat fibromyalgia are ongoing and multifaceted, with an increased emphasis on both drug and non-drug treatments during the past 20…

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HCV Advocate - Extrahepatic Manifestations of Hepatitis C
Oct 5 - Diabetes

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Rheumatologic manifestations of hepatitis C virus - is included in this collection of articles.

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Categorized article directory on the extrahepatic manifestations of hepatitis C.

Fatty liver disease fastest-growing reason for transplants in young U.S. adults

Fatty liver disease fastest-growing reason for transplants in young U.S. adults
Last Updated: 2017-10-17
By Carolyn Crist

(Reuters Health) - Nonalcoholic fatty liver disease and its more aggressive form, nonalcoholic steatohepatitis, have become the fastest-growing reasons for liver transplants in young Americans, according to a recent study.

Typically, older adults experience the slow progression of fatty liver disease that is not related to alcohol but can lead ultimately to liver cirrhosis. Due to increasing childhood obesity, hypertension and diabetes, however, more young adults are reaching end-stage liver disease early in life, researchers say.

"I see kids at ages 7 and 8 with this problem, and one of my youngest patients developed cirrhosis at 13," said senior study author Dr. Naim Alkhouri, who directs the metabolic program at the Texas Liver Institute in San Antonio, Texas.

"In Texas in particular, nonalcoholic steatohepatitis is the No. 1 indicator for transplants in adults," he told Reuters Health in a phone interview. "It now affects 1 in 3 adults and 1 in 10 children."

Alkhouri and colleagues analyzed nationwide data from the United Network for Organ Sharing on liver transplants in young adults between 2002 and 2012 to examine the reasons they needed a transplant.

During those years, there were a total of 5,157 transplants in people ages 18 to 40, of whom 23% were obese, the researchers found. The top reason for transplant, accounting for 25%, was autoimmune/cholestatic liver disease, which includes conditions such as bile duct infections, immune system-related hepatitis, hereditary bile duct problems and drug-related liver damage.

About 18% of transplants were for acute liver failure, and other important causes were hepatitis C and B as well as liver cancers. Nonalcoholic steatohepatitis, also called NASH, accounted for just 3.3% of transplants across the entire study period, but it was the fastest-growing reason for transplant.

The number of liver transplants performed for NASH increased from 0.53% in 2002 to 4.46% in 2012, a nine-fold jump, the study team reports in Journal of Clinical Gastroenterology, online September 28.

Survival rates were similar among NASH and non-NASH liver recipients, but graft survival was lower and re-transplantation rates were higher in NASH recipients, the researchers note.

"Following the childhood obesity explosion in the '80s and '90s, we're seeing young adults with old bodies," Alkhouri said. "Although they're 30, their organs are sick."

Fatty liver disease and NASH can often go unrecognized and untreated in young adults since pediatricians and primary care doctors don't look for signs of the disease in younger people, the study authors write.

New studies are investigating ways to treat fatty liver disease early in life and prevent it from reoccurring after transplantation, Alkhouri said. Although the Federal Drug Administration doesn't currently approve medication for NASH, phase 3 clinical trials underway now could lead to approved medication in a few years, he added.

"The other looming question is about fatty liver disease developing into liver cancer," said Dr. Robert Wong of Highland Hospital in Oakland, California, and University of California, San Francisco, who wasn't involved in the study.

"In medical school, we're taught that cirrhosis is a prerequisite for cancer, but we're seeing more reports that fatty liver can develop into cancer with little cirrhosis," he told Reuters Health by phone. "If our only indicator to screen for cancer is to look for cirrhosis, that's scary. We're not going to look for it or find it."

Liver specialists still don't know why fatty liver disease and NASH develop so rapidly, Wong added. Factors could include differences in metabolism, demographics and lifestyle, which researchers are still trying to pinpoint so they can better diagnose patients in the future.

"The best treatment is still prevention," Wong said. "If we can ID it early and then focus on blood pressure, diabetes, weight loss and a healthy lifestyle, we can better help patients with fatty liver disease."

J Clin Gastroenterol 2017.

Percutaneous treatment of hepatocellular carcinoma: state of the art and innovations

Journal of Hepatology
Article in Press
Percutaneous treatment of hepatocellular carcinoma: state of the art and innovations
Jean-Charles Nault, Olivier Sutter, Pierre Nahon, Nathalie Ganne-Carrié


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Percutaneous treatment of hepatocellular carcinoma (HCC) encompasses a vast range of techniques, including monopolar radiofrequency ablation (RFA), multibipolar RFA, microwave ablation, cryoablation and irreversible electroporation. RFA is considered to be one of the main curative treatments for HCC of less than 5 cm developing on cirrhosis, together with surgical resection and liver transplantation. However, controversies exist concerning the respective roles of ablation and liver resection for HCC of less than 3 to 5 cm on cirrhosis. In line with the therapeutic algorithm of early HCC, percutaneous ablation could also be used as a bridge to liver transplantation or in a sequence of upfront percutaneous treatment, followed by transplantation if tumor relapses. Moreover, several innovations in ablation methods may help to efficiently treat early HCC initially considered as “non-ablatable”, and might, in some cases, extend ablation criteria beyond early HCC in order to treat the largest number of patients using a curative approach.

Key Points
  1. Classical monopolar RFA appears to provide the same long-term results as surgical resection in cases of HCC of less than 2-3 cm developing on cirrhosis
  2. Morbi-mortality of percutaneous ablation of HCC on cirrhosis is low
  3. While local recurrence may be efficiently controlled by additional percutaneous approaches, long-term results are impaired by a high rate of distant tumor recurrence
  4. Up to 30 % of small HCC were classically considered as « non-ablatable » due to « high-risk location » or « at-risk patients », but several techniques are now available to efficiently and safely treat these patients
  5. Percutaneous ablation could be used as a bridge to transplantation, or via a sequence of « ablation first » followed by salvage liver transplantation if the tumor recurs
  6. Several new methods of percutaneous ablation (multi-bipolar No-touch RFA, microwave, irreversible electroporation, cryoablation, etc.) seek to increase the safety and efficacy of these treatments and to extend their indications into the algorithm of HCC treatment
  7. Ablation therapies combined with transarterial chemo-embolization may improve sustained local control of tumors of over 3 cm in diameter compared to monopolar RFA
Survival of patients with hepatocellular carcinoma (HCC) is poor, with 5-year overal survival of around 10 to 15 %, mainly explained by diagnosis of the tumor at an advanced stage inaccessible to curative treatment [1]. Ultimately, application of a curative treatment at an early stage is the cornerstone to improving overall survival of cirrhotic patients with HCC [2]. To achieve this goal, the first step is to identify the “at-risk population”, mainly cirrhotic patients for whom HCC screening will be cost-effective. The second step is to perform a well-conducted screening program using ultrasonography every 6 months in cirrhotic patients [3]. Screening aims to identify HCC falling within Milan criteria that will be treated by a curative approach [4]. The final step consists of using curative treatment for all small HCC detected by screening. Each of these steps has defects in its application to real-life cases that need to be improved. In the field of therapeutics, three major types of curative treatment exist in HCC: liver resection, liver transplantation and percutaneous ablation. Each has its limitations that may be partially overcome in order to curatively treat the highest number of patients and avoid premature use of palliative treatment for small HCC [[5], [6]]. However, the term of “curative” treatment for resection or ablation of HCC in cirrhotic patients is discussed because the patients are still exposed to de novo carcinogenesis on cirrhosis. Percutaneous ablation includes a vast range of techniques that have changed over the 20 last years, enabling treatment of an increasing number of patients, with improved efficacy in local control [7]. Moreover, extension of the criteria for borderline HCC treatment using advanced percutaneous techniques, or combinations with endo-arterial approaches, have also been proposed in order to augment the size and number of treatable tumors [8]. In this review, we summarize the different types of percutaneous treatment, discuss their role within the perspective of the therapeutic algorithm of early HCC, and describe innovations in the field that seek to increase efficacy and extend the boundaries of indications for ablation.

Full Text Article -

Tuesday, October 17, 2017

Watch - Debrief from EASL-AASLD joint meeting on Alcohol related Liver Disease

Debrief from EASL-AASLD joint meeting on Alcohol related Liver Disease, the conference was held on September 30, 2017 - October 01, 2017 in London.  

Alcohol related liver disease remains the most important cause of liver disease morbidity and mortality in Europe and North America and is therefore relevant to all hepatologists. 

Published on Oct 12, 2017

The changing HCV treatment cascade

Pharmacology Consult
The changing HCV treatment cascade
Infectious Disease News, October 2017
Jocelyn Mason, PharmD; Kimberly D. Boeser, PharmD, MPH, BCPS, AQ-ID
The rapid development of DAA combinations provides simplified regimens, shorter durations, improved efficacy and greater tolerability, unlike the previous interferon and ribavirin cornerstone regimens. Although the IDSA/AASLD guidelines provide the map to managing HCV, they do not identify the ideal interferon-free regimen to begin with, nor have they given a clear path to treating genotype 3 and those with decompensated cirrhosis. This ever-changing field will require collaboration among health care providers, including those specializing in infectious diseases, hepatology and gastroenterology, as well as pharmacists, to optimize treatment strategies. As the landscape of HCV continues to update with new literature and new medications, this subspecialty continues to be dynamic.
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Monday, October 16, 2017

CDC Considers Expanding Hepatitis C Testing

Coverage from the International Conference on Viral Hepatitis (ICVH) 2017

CDC Considers Expanding Hepatitis C Testing
Laird Harrison
October 16, 2017
CHICAGO — In response to an increase in the incidence of hepatitis C infections, which tripled from 2010 to 2015, the Centers for Disease Control and Prevention (CDC) and the US Preventive Services Task Force (USPSTF) are considering augmenting their recommendations for screening.

"We really have to work together to see how we can expand testing in the future to move along with the changes in epidemiological trends," said John Ward, MD, from the division of viral hepatitis at the CDC.

After decades of decline, the incidence of the disease is rising, particularly in indigenous American and non-Hispanic white people, Dr Ward reported here at the International Conference on Viral Hepatitis 2017.

The highest incidence is in nonurban areas — particularly in states in the Appalachian, Midwestern, and New England regions — in people 20 to 29 years of age, followed by people 30 to 39 years of age....
Link -

From Medscape Gastroenterology

Short-term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting anti-viral treatment

Alimentary Pharmacology & Therapeutics Early View, Version of Record online: 16 OCT 2017

Short-term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting anti-viral treatment
E. Ogawa, N. Furusyo, H. Nomura, K. Dohmen, N. Higashi, K. Takahashi, A. Kawano, K. Azuma, T. Satoh, M. Nakamuta, T. Koyanagi, M. Kato, S. Shimoda, E. Kajiwara, J. Hayashi, The Kyushu University Liver Disease Study (KULDS) Group

First published: 16 October 2017
With the development of direct-acting anti-virals (DAAs), almost all patients with chronic hepatitis C virus (HCV) infection can achieve sustained viral response (SVR).

To evaluate the short-term risk of HCC among patients with SVR by DAAs, including those with cirrhosis or previous HCC.

This large-scale, multicentre cohort study included 1,675 consecutive patients who achieved SVR by treatment with interferon-free sofosbuvir-based regimens, divided into groups with (n = 152) or without previous HCC (n = 1,523). The Kaplan-Meier method and Cox proportional hazard analysis were used to calculate the cumulative HCC incidence and related factors of HCC.

During the follow-up period (median: 17 months), 46 (2.7%) patients developed HCC. The 1-year cumulative rates of de novo HCC were 0.4% and 4.9% for the noncirrhosis and cirrhosis groups respectively (log-rank test: P < 0.001). For cirrhotic patients, serum α-fetoprotein level at the end of treatment (EOT-AFP) was the strongest predictor of de novo HCC. The 1-year cumulative de novo HCC rates were 1.4% and 13.1% in the EOT-AFP < 9.0 ng/mL and ≥ 9.0 ng/mL groups (cut-off value) respectively (log-rank test: P < 0.001). The 1-year cumulative rates of HCC recurrence were 6.5% and 23.1% for the noncirrhosis and cirrhosis groups respectively (log-rank test: P = 0.023). For cirrhotic patients, previous HCC characteristics were significantly associated with HCC recurrence. In contrast, sex, age and metabolic features did not influence de novo HCC or recurrence.

For cirrhotic patients after elimination of HCV, serum EOT-AFP level and previous HCC characteristics would be useful markers for predicting de novo HCC or recurrence.

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This large-scale, multicentre cohort study provides a great amount of data regarding the frequency of and demographic factors related to the development of HCC by SVR patients following interferon-free SOF-based treatment for 12 weeks. As would be expected, the cumulative incidence of HCC was significantly higher for cirrhotic patients than for noncirrhotic patients, irrespective of a past history of HCC. It is worth noting that the serum EOT-AFP level was the strongest predictor of de novo HCC for cirrhotic patients in the short-term after the initiation of DAA. The risk of early de novo HCC or recurrence for patients with chronic HCV treated with DAAs has received considerable attention in recent years. A better understanding of HCC development by patients treated with DAAs who achieve SVR is necessary to provide better care in real-life practice. Advantages of this study include that we divided the patents into groups based on cirrhosis status and focused on longitudinal biochemical parameters, such as serum albumin, ALT and AFP levels, which allowed us to better evaluate the risk of HCC development by SVR patients during and after interferon-free treatment with DAAs.

According to recent reports from Europe,[14, 15] SVR patients with previous HCC have high risk of HCC recurrence in the short-term, which has been hypothesised to be because the rapid HCV load decline brings about a misbalance of HCV-stimulated immune control that allows tumour clones to emerge.[23] On the other hand, multicentre studies that included different study designs, baseline characteristics and treatment options for prior HCC do not support this finding.[16, 24, 25] In this study, the overall 1-year cumulative HCC recurrence rate was 16.5%, with a lower annual recurrence rate after resection or percutaneous ablation.[26] However, the 1-year cumulative HCC recurrence rate was 23.1% when limited to cirrhotic patients. Previously, we reported on HCC recurrence after treatment with pegylated-interferon alpha plus RBV, finding a 1-year cumulative HCC recurrence rate of 22.2%,[27] with no significant difference between treatment with interferon and DAAs. We were not able to provide a new perspective because of differences in the age-composition of the treatment option groups (interferon median age, 57: interferon-free DAA median age, 66), which made it difficult to analyse the data with propensity-score matching. Moreover, selection bias was an important consideration because of the fact that DAAs allow patients who in the past would never qualify for interferon therapy to be treated. A prospective cohort in comparison with untreated patients showed no evidence of an increased risk of early HCC recurrence in DAA treatment.[16] Although it is conceivable that the anti-viral treatment options are not associated with the HCC recurrence seen in our study, further studies will be necessary to better elucidate the relation.

The strength of this study is the evaluation of the risk factors for the development of HCC. In this era of interferon-based treatment, including combination therapy with DAA, the risk of HCC development for SVR patients is modulated by host factors such as older age, abnormalities of glucose metabolism such as diabetes mellitus and insulin resistance, metabolic features, high serum AFP level and the severity of fibrosis.[28-31] Interestingly, in the DAA-only treatment of this study, neither age nor metabolic features were significantly associated with de novo HCC and recurrence; the long-term risk factors for HCC should be elucidated in future study. Instead, the serum EOT-AFP level was the most important predictor of de novo HCC for cirrhotic patients. Although the AFP level of almost all patients improves during DAA treatment, the longitudinal AFP level may play a role in early de novo HCC. In the group with previous HCC, cirrhotic patients were significantly more prone to experience HCC recurrence, but the AFP levels at baseline and EOT were not significant factors. This finding was similar to a previous report by Conti et al. that reported that liver stiffness by transient elastography was associated with HCC recurrence.[15] In fact, among our 21 patients who had HCC recurrence after DAA treatment, 15 (71.4%) had decreased AFP <10 ng/mL at EOT. The expression of several biochemical markers has been used to predict poor prognosis of HCC recurrence. On the other hand, characteristics of previous HCC, such as a short time from previous HCC treatment to initiation of DAA, within 1 year, and noncurative HCC treatment procedures, were significantly associated with early HCC recurrence, despite our exclusion of the patients with potential HCC at the time of screening, as stated in the Methods section. Therefore, close HCC screening should be required for all patients with previous HCC, during and after viral clearance.

In contrast to patients with advanced fibrosis or cirrhosis, the risk of HCC development is very low for patients with no/mild fibrosis who achieved SVR. Thus, most HCV guidelines have little mention of HCC surveillance for these patients, except for those with other liver disease, such as from alcohol consumption, non-alcoholic fatty liver disease/steatohepatitis, or metabolic disease including obesity (body mass index >25 kg/m2) and/or diabetes. In our study, among the 903 patients with no/mild fibrosis and no history of HCC who achieved SVR, 565 (62.6%) fit these criteria and none developed de novo HCC during the short-term follow-up period.

Six patients (0.4%) died during the follow-up period, including 3 from liver-related complications. It must be emphasised that only 1 of the patients without previous HCC died of liver-related complications. In this regard, the benefits of treatment with DAAs before the development of HCC include a decreased risk of death, reduced need for liver transplantation and less development of HCC over the long term. These benefits apply to patients with previous HCC because all patients, with or without a history of HCC, have short-term restoration of the liver functional reserve. Continued follow-up will be necessary to determine the potential long-term benefits related to the development of HCC and mortality.

The limitations of our study include factors related to its observational, real-life design, including potential physician prescribing bias and incomplete patient records. However, over 99% of the data for all items, except for EOT-AFP level (91.3%) and IL28B genotype (77.8%), were available in this study, and there were only 3 patients lost to follow-up. Taken together, our analysis was done from highly precise data that gives important insights into the risk of HCC development in a diverse patient population managed in clinical practice. Another limitation is the lack of data on decompensated cirrhosis patients because they are not covered by public insurance in Japan, which may have contributed to the relatively low rate of HCC incidence. An advantage is that many elderly patients were included in this study because the age of HCV-infected patients is increasing in Japan. Our findings will be useful for HCV management in other countries, with a similar trend forecast in Europe and the USA.[32]

In conclusion, our data showed no evidence of an increased risk of de novo HCC or recurrence by patients treated with interferon-free SOF-based regimens. However, cirrhosis was strongly associated with the short-term development of HCC after HCV eradication. Moreover, our findings underscore the fact that the serum EOT-AFP level is a useful marker for predicting de novo HCC for cirrhotic patients and that close HCC surveillance should be required for patients with a past history of HCC, especially for patients treated with noncurative procedures. Going forward, further studies will be required to elucidate the risk of HCC development over the long-term.

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Early View
(Online Version of Record published before inclusion in an issue)

Merck targets high-risk military veterans for hepatitis C lessons

In case you missed it

“Despite their increased risk for chronic hepatitis C virus infection, too many veterans remain undiagnosed,” said Thomas F. Nealon III, chief executive officer of the American Liver Foundation. “We are proud to work with Merck on this important initiative, which we believe will help many veterans better understand their risk, as well as their options for getting tested and linked to care.” Link -

Of Interest
Investment Commentary
Merck targets high-risk military veterans for hepatitis C lessons
by Carly Helfand |
Oct 16, 2017 9:15am
Veterans are three times more likely to have hepatitis C than the general population—and Merck & Co. wants to make sure they know that.

The pharma giant, which makes the hep C-fighting therapy Zepatier, has partnered up with the American Liver Foundation, which will join educational events in Boston, Philadelphia, Phoenix and San Diego to speak with veterans about their risk factors, dole out tips and resources for living with hep C, and provide info about testing and treatment.

The awareness push comes as Merck has been focusing on veterans as a market for Zepatier, which was third to the next-gen hep C market after Gilead Sciences, with its megablockbuster meds, and AbbVie's Viekira Pak. In May of last year, executives at rival AbbVie told investors the New Jersey drugmaker had introduced steeper-than-expected discounts for the U.S. Department of Veterans Affairs, snapping up a good portion of AbbVie’s market share in that segment.
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Exelixis’ Phase 3 CELESTIAL Trial of Cabozantinib Meets Primary Endpoint of Overall Survival in Patients with Advanced Hepatocellular Carcinoma

October is Liver Cancer Awareness Month
Learn more about liver cancer: Visit the American Liver Foundation and Liver Cancer Connect
Video - Hepatitis and Liver Cancer | Did You Know?

Exelixis’ Phase 3 CELESTIAL Trial of Cabozantinib Meets Primary Endpoint of Overall Survival in Patients with Advanced Hepatocellular Carcinoma

– Exelixis to submit a supplemental New Drug Application to the U.S. Food and Drug Administration (FDA) in the first quarter of 2018; cabozantinib previously granted orphan drug designation by FDA –

– Data to be submitted for presentation at an upcoming medical meeting –

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Oct. 16, 2017-- Exelixis, Inc. (NASDAQ:EXEL) today announced that its global phase 3 CELESTIAL trial met its primary endpoint of overall survival (OS), with cabozantinib providing a statistically significant and clinically meaningful improvement in median OS compared to placebo in patients with advanced hepatocellular carcinoma (HCC). The independent data monitoring committee for the study recommended that the trial should be stopped for efficacy following review of the second planned interim analysis. CELESTIAL is a randomized, global phase 3 trial of cabozantinib versus placebo in patients with advanced HCC who have been previously treated with sorafenib. The safety data in the study were consistent with the established profile of cabozantinib. Based on these results, Exelixis plans to submit a supplemental New Drug Application (sNDA) to the U.S. Food and Drug Administration (FDA) in the first quarter of 2018. Detailed results from CELESTIAL will be submitted for presentation at a future medical conference.

This press release features multimedia. View the full release here:

“We are excited that these positive results from the phase 3 CELESTIAL trial bring us one step closer to the potential of offering previously treated patients with this aggressive form of advanced liver cancer a much-needed new treatment option,” said Gisela Schwab, M.D., President, Product Development and Medical Affairs and Chief Medical Officer, Exelixis. “This is an important milestone for the cabozantinib development program; we are committed to studying cabozantinib in a range of tumor types as part of our mission to deliver medicines that improve treatment outcomes and give patients hope for the future.”

Exelixis will discuss the trial results with regulatory authorities and determine next steps for the trial, including offering patients currently receiving placebo the opportunity to cross over to cabozantinib.

In March 2017, the FDA granted orphan drug designation to cabozantinib for the treatment of advanced HCC. Orphan drug designation is granted to treatments for diseases that affect fewer than 200,000 people in the U.S. and provides certain incentives for medications intended for the treatment, diagnosis or prevention of rare diseases. At present, these incentives include seven years of marketing exclusivity for the orphan indication, certain federal grants, tax credits, and waiver of certain FDA fees.

About the CELESTIAL Study
CELESTIAL is a randomized, double-blind, placebo-controlled study of cabozantinib in patients with advanced HCC conducted at more than 100 sites globally in 19 countries. The trial was designed to enroll 760 patients with advanced HCC who received prior sorafenib and may have received up to two prior systemic cancer therapies for HCC and had adequate liver function. Enrollment of the trial was completed in September 2017. Patients were randomized 2:1 to receive 60 mg of cabozantinib once daily or placebo and were stratified based on etiology of the disease (hepatitis C, hepatitis B or other), geographic region (Asia versus other regions) and presence of extrahepatic spread and/or macrovascular invasion (yes or no). No cross-over was allowed between the study arms.

The primary endpoint for the trial is OS, and secondary endpoints include objective response rate and progression-free survival. Exploratory endpoints include patient-reported outcomes, biomarkers and safety.

Based on available clinical trial data from various published trials conducted in the second-line setting of advanced HCC, the CELESTIAL trial statistics for the primary endpoint of OS assumed a median OS of 8.2 months for the placebo arm. A total of 621 events provide the study with 90 percent power to detect a 32 percent increase in median OS (HR = 0.76) at the final analysis. Two interim analyses were planned and conducted at 50 percent and 75 percent of the planned 621 events.

About HCC
Liver cancer is the third-leading cause of death worldwide, and hepatocellular carcinoma (HCC) is the most common form, making up about three-fourths of the nearly 41,000 cases that will be diagnosed in 2017 in the U.S.1,2 Without treatment, patients with advanced disease usually survive less than 6 months, and it is estimated that 29,000 people will die due to liver cancer in the U.S.2,3 Worldwide, nearly 800,000 new cases are diagnosed annually, and the disease accounts for more than 700,000 deaths each year.4