The outlook for the future of hepatitis C virus (HCV) treatment seemed to split into two distinct camps at the 2018 International Liver Congress (ILC), the annual meeting of the European Association for the Study of the Liver (EASL), held this month in Paris.

On one hand, some participants viewed additional efforts to develop HCV therapies as almost superfluous, advocating that – in light of effective commercial therapies and limited drug discovery and development resources – new endeavors in the field should focus on preventive measures, such as vaccines. Others, however, decried the continuing unmet need, citing estimates that more than 95 percent of individuals with HCV have no access to treatment four years after the introduction of Gilead Sciences Inc.’s Harvoni (sofosbuvir/ledipasvir), the first oral therapy for people with genotype 1 HCV to eliminate the need for interferon and ribavirin. (See BioWorld Today, Oct. 13, 2014.)

Despite the “concept of elimination,” more than 300 million individuals, or nine of 10 living with HCV, also remain unaware of their condition, according to Michael Ninburg, president of the World Hepatitis Alliance. And some speakers at the ILC criticized alleged discrimination in the health care industry or, at a minimum, lack of sensitivity against certain HCV patient populations, complicating efforts to eliminate the disease.

Certainly, the 2018 ILC meeting featured plenty of bright spots related to HCV, including the publication of updated clinical practice guidelines from EASL in the Journal of Hepatology that won widespread praise from attendees. Tilman Sauerbruch, professor emeritus at the University of Bonn and head of the department of gastroenterology and endocrinology at the University of Göttingen, who chaired the ILC’s first general session and opening ceremony, referenced the guidelines as, perhaps, the “penultimate” recommendations on HCV treatment.

The 2018 standards focused on detailed screening mechanisms for various populations, assessment of liver disease severity before and after corrective measures and widespread adoption of curative therapies.

“All patients with HCV infection must be considered for therapy, including treatment-naïve patients and individuals who failed to achieve SVR [sustained virologic response] after prior treatment,” the 2018 recommendations stated. “Treatment should be considered without delay in patients with significant fibrosis or cirrhosis (METAVIR score F2, F3 or F4), including compensated (Child-Pugh A) and decompensated (Child-Pugh B or C) cirrhosis, in patients with clinically significant extra-hepatic manifestations (e.g. symptomatic vasculitis associated with HCV-related mixed cryoglobulinemia, HCV immune complex-related nephropathy and non-Hodgkin B-cell lymphoma), in patients with HCV recurrence after liver transplantation, in patients at risk of a rapid evolution of liver disease because of concurrent comorbidities (non-liver solid organ or stem cell transplant recipients, HBV co-infection, diabetes) and in individuals at risk of transmitting HCV.”

Future EASL conferences, Sauerbruch suggested, may concentrate less on viruses and more on other culprits of liver disease, such as alcohol and poor nutrition, while also examining the interaction between disease states and organ systems.

Real-world data show Mavyret, sofosbuvir regimens hitting mark

Research presented at the ILC showed just how far the HCV field has come. Real-world studies conducted in Italy and Germany confirmed the effectiveness and safety of Abbvie Inc.’s Mavyret (glecaprevir/pibrentasvir, or G/P), approved last year to treat chronic HCV, showing viral suppression rates like those observed in clinical trials. (See BioWorld, Aug. 7, 2017.)

The Italian study, presented by researcher Roberta D’Ambrosio from the University of Milan, reported findings from an interim analysis of the outcomes of 723 consecutively treated patients within the Lombardy Navigator-II Network, with G/P administered according to label. Of those with available data, 99.7 percent achieved SVR4 (346/347). HCV RNA was reported to be undetectable in 74 percent of patients at week four and in 98 percent of patients at end of treatment across the cohort. The prevalence of treatment-related adverse events (AEs) was low and mainly mild in severity. Only three patients discontinued G/P treatment prematurely.

The ongoing German real-world study evaluated 638 patients from the German Hepatitis C-Registry (DHC-R) who received G/P treatment according to the local label. Adults with HCV genotypes 1–6, with or without compensated cirrhosis, who were either treatment-naïve or treatment-experienced were included in the interim analysis, although most were treatment-naïve without cirrhosis.

Among 49 patients with available data, 100 percent achieved SVR12 after eight weeks of treatment, excluding four patients who prematurely discontinued treatment for reasons unrelated to virological failure, according to Thomas Berg, professor at the University of Leipzig, who presented the findings. Two of the four patients stopped therapy due to AEs, but no grade 3 or higher elevations in alanine aminotransferase, or ALT, were observed.

Alessandra Mangia, a researcher at Casa Sollievo della Sofferenza Hospital in San Giovanni Rotondo, Italy, also presented interim data from Gilead’s cirrhosis registry on long-term follow-up of patients with chronic HCV infection and compensated or decompensated cirrhosis who achieved SVR following treatment with Sovaldi (sofosbuvir)-based regimens. Data showed that sofosbuvir backbone regimens are doing their job.

With a mean age (range) of 59 (26-86) years, the registry population of 1,564 patients (as of Oct. 5, 2017) was 68 percent male, and 84 percent had pretreatment Child-Pugh A scores. At a median registry follow-up of 53 weeks, 55 observed events of hepatocellular carcinoma (HCC) occurred, along with 20 liver transplants and five liver-related deaths. Overall, patients with pretreatment Child-Pugh A cirrhosis maintained their status (99 percent at registry week 96) while 67 percent and 86 percent, respectively, of those with pretreatment Child-Pugh B or C cirrhosis improved to Child-Pugh A at registry week 96. Three virologic failures occurred, including one reinfection; the others did not have baseline samples to distinguish reinfection from relapse by sequencing.

Targeting early stage HCV shows clinical, cost-effectiveness

Two presentations from Scotland suggested the impact of direct-acting antivirals (DAAs) on averting HCV-related liver disease and reducing associated clinical and economic burden. Scotland is home to an estimated 34,500 people chronically infected with HCV and regarded as a world leader in facing that problem, researcher Sharon Hutchinson from Glasgow Caledonian University reported as she described outcomes from the Hepatitis C Action Plan (2006–2011) and the Sexual Health and Blood Borne Virus Framework (2011–2020).

The Scottish HCV Clinical and Diagnosis databases, linked with the national inpatient hospital database, provided insight into the use of HCV therapy up to March 2017 and on the numbers of patients with chronic HCV diagnosis who presented and were admitted to a hospital with decompensated cirrhosis for the first time between 2000 and 2016. Among 4,800 people initiated on HCV therapy in Scotland between April 2014 and March 2017, 83 percent were treated with DAAs and 94 percent achieved SVR. That three-year scale up of therapy, compared with the three preceding years, was associated with a 29 percent and 39 percent reduction in first-time presentations for decompensated cirrhosis, respectively, among those previously diagnosed with chronic HCV and those with chronic HCV at the time of admission, Hutchinson said.

A health state transition model of the natural history of HCV, developed to forecast liver-related clinical and economic outcomes over a lifetime, showed that rates of decompensated cirrhosis, HCC, liver transplant and liver-related death – along with lifetime costs associated with complications from HCV – were predicted to be lower if treatment was initiated when disease was mild (F0–1) rather than delayed until compensated cirrhosis was present, arguing strongly for the need for early intervention.

And in the U.S., alcoholic liver disease replaced HCV infection as the leading cause of liver transplantation in patients without HCC, with nonalcoholic steatohepatitis (NASH) now ranked second as a cause of liver transplantation due to chronic liver disease, according to two independent studies that evaluated data collected by the United Network for Organ Sharing and were presented as posters at the EASL meeting.

Seeing similarities between NASH, evolution of HCV market

The jarring contradiction of curative therapies and global unmet need makes HCV a very tough sandbox for innovation. Although Gilead will no doubt play out its market opportunity, the company has hung up its research hat in the indication, with its liver disease pipeline now focused on NASH, HBV and rare diseases such as primary biliary cirrhosis and primary sclerosing cholangitis. The company has no HCV assets in the clinic and, of more than 100 HCV agents in discovery, according to Cortellis Competitive Intelligence, none belongs to Gilead.

Recapping J.P. Morgan’s annual West Coast Biotech Forum last week, analyst Cory Kasimov observed that discussions with Gilead focused around HIV – an indication where company officials touted early launch trends for Biktarvy (bictegravir 50 mg/emtricitabine 200 mg/tenofovir alafenamide 25 mg) – along with plans for CAR T and M&A, while, “interestingly enough, there was not a single question asked on HCV,” he said.

In February, Gilead reported that fourth-quarter 2017 sales of its HCV therapies were half those of the previous year, falling to $1.5 billion from $3.2 billion in the fourth quarter of 2016. The company plans to report first-quarter 2018 data on May 1. (See BioWorld, Feb. 8, 2018.)

Several would-be contenders to the blockbuster HCV therapies from Gilead, Abbvie and Johnson & Johnson (J&J), which has Olysio (simeprevir), have stumbled in the past year, helping to ensure continued dominance by the market leaders, at least in the short term. Conatus Pharmaceuticals Inc. had a top-line miss in its phase IIb POLT-HCV-SVR trial of emricasan in individuals with post-transplant fibrosis and cirrhosis. Regulus Therapeutics Inc. halted development of its lead microRNA candidate, RG-101, an N-acetylgalactosamine-conjugated asset targeting miR-122, rather than pursuing resolution of a clinical hold placed by the FDA. Merck & Co. Inc. took a $2.9-billion write-down of its NS5B polymerase inhibitor, uprifosbuvir (MK-3682/3682B) – the crown jewel in its $3.85 billion acquisition of Idenix Pharmaceuticals Inc. – “due to recent changes to the product profile, as well as changes to pricing and marketing opportunity. (See BioWorld Today, Feb. 27, 2017, June 13, 2017, and April 6, 2018.)

Like Gilead, J&J stepped back in the field, dropping its much-ballyhooed HCV alliance with Achillion Pharmaceuticals Inc. after scrapping development of JNJ-4178, a combination of three DAAs: Achillion’s NS5A inhibitor odalasvir (also known as ACH-3102), Olysio and AL-335, an NS5B inhibitor that came to J&J by way of its buyout of South San Francisco-based Alios Biopharma Inc. for $1.75 billion. (See BioWorld Today, Oct. 1, 2014, May 20, 2015, and Sept. 12, 2017.)

In an email last week, Evercore ISI analyst Josh Schimmer examined the juxtaposition of the maturing HCV and evolving NASH markets.

“As data for various approaches to treat NASH accumulate (next up [Madrigal] biopsy data), we’re starting to see increasing similarities to how the HCV market evolved (with the obvious caveat that HCV can be cured and NASH…can’t?),” Schimmer wrote. In addition to affecting the liver, both diseases can potentially be targeted with multiple mechanisms, boast a variety of competitors pursuing diverse treatment approaches, address large patient populations that include many undiagnosed individuals and involve a spectrum of liver damage ranging from mild to severe.

In NASH, Schimmer said, “we are increasingly envisioning a treatment paradigm that mimics HCV, too, with an emphasis on combining drugs with different mechanisms and creating well-tolerated all-oral regimens. There might also be a role for induction type regimens (but as a chronic disease a role for maintenance as well).”

As the NASH field evolves, the focus, increasingly, will address safety, tolerability and oral delivery, he added. “These can sometimes take longer to fully de-risk, but for this reason, we prefer approaches where the biology is reasonably clear and validated through physiology and/or clinical experience.”

A decade ago, the same was said of HCV, where the story of innovation may now be nearly written.

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