About 3 percent of the world’s population has been infected with the hepatitis C virus (HCV) and more than 170 million chronic carriers are at risk of developing serious related diseases such as liver cirrhosis and liver cancer, the World Health Organization estimates. It is not surprising then that the global market for new HCV medicines is poised for dramatic growth. It is predicted that this growth will be driven primarily by the launch of premium-priced therapies that will increase the size of the drug-treated population, mainly as a result of the re-treatment of patients who did not respond on prior therapies.

In the first part of this series we described how a variety of therapeutic approaches involving NS5B polymerase inhibitors, NS3 protease inhibitors or NS5A inhibitors has swelled the HCV drug pipeline with close to 80 oral HCV drugs currently in development. (See BioWorld Insight, Feb. 3, 2014.)

Some of these products are in the late-stage trials and, near term, all eyes will certainly be on Gilead Sciences Inc. and Abbvie Inc. which will be vying for market share with their HCV drug combination treatments.

At the end of January, for example, Abbvie reported the completion of its phase III program and released results from four additional studies designed to assess the company’s investigational all-oral, interferon-free therapy with and without ribavirin (RBV) in patients with chronic genotype 1 (GT1) HCV infection.

COMBO REGIMENS

The results from the PEARL-II, PEARL-III, PEARL-IV and TURQUOISE-II studies were the remaining studies in six phase III registrational studies using Watertown, Mass.-based Enanta Pharmaceuticals Inc.’s lead protease inhibitor ABT-450. The compound is part of Abbvie’s investigational three direct-acting antiviral regimen consisting of boosted protease inhibitor ABT-450/ritonavir, NS5A inhibitor ABT-267, and non-nucleoside polymerase inhibitor ABT-333. The studies were conducted with and without ribavirin. The combination of the three different mechanisms of action in the regimen interrupts the HCV replication process with the goal of optimizing SVR rates across different patient populations. Results from the studies demonstrated high sustained virologic response rates (>90 percent) 12 weeks post-treatment (SVR12) and tolerability in the GT1 patients and low rates of discontinuation due to adverse events.

Jefferies & Co. analyst Tom Tarrant said, “We are encouraged by these strong results and expect the regimen to be competitive to current therapies in clinic. Abbvie has breakthrough therapy status for its HCV program, which will likely expedite approval in our view.”

Gilead also is developing an all-oral regimen for genotype 1. The company said it plans to submit a new drug application to the FDA for the combo for approval this quarter.

In December Gilead reported topline results from three phase III trials (ION-1, ION-2 and ION-3) evaluating the investigational once-daily fixed-dose combination of the nucleotide analog polymerase inhibitor sofosbuvir (SOF) 400 mg and the NS5A inhibitor ledipasvir (LDV) 90 mg, with and without ribavirin (RBV), for the treatment of genotype 1 chronic hepatitis C virus (HCV) infection.

Sustained viral response at 12 weeks after treatment stopped (SVR12, or cure) reached 95 percent to 98 percent among treatment-naïve patients with the 12-week regimen, a rate that held even among hard-to-treat people with cirrhosis. Among treatment-experienced patients given the same regimen, the SVR12 was 94 percent to 96 percent, which jumped to 99 percent when patients took the drug for 24 weeks. (See BioWorld Today, Dec. 19, 2013.)

If all goes well both combo treatments will be available this year and could capture a significant share of the estimated $12 billion market.

Investors have certainly rewarded Abbvie’s partner in the HCV program, Enanta, with the company’s stock (NASDAQ:ENTA) jumping 27 percent in value since the beginning of December.

COSTLY MISSTEPS

Missteps in this space can be costly, however. Back in October last year, Achillion Pharmaceuticals Inc.’s stock dropped more than 58 percent following news that the FDA had refused to lift the clinical hold imposed on its HCV candidate sovaprevir because of elevated liver enzymes.

Although its stock price has not recovered its lost value to date, the company is not giving up on HCV. In an update on its plans for 2014, Milind Deshpande, president and CEO, said, “We believe that we have the broad portfolio of HCV compounds necessary to succeed in achieving our primary goal of developing commercially competitive short duration therapies for the treatment of HCV that are once-daily and ribavirin-free.”

With $150 million in the bank Achillion is well placed to execute its plans to prepare a complete response package on sovaprevir, its NS3/4A protease inhibitor, still on clinical hold and said it anticipates a response from the FDA by mid-year.

Its pipeline also includes ACH-3422, a uridine nucleotide inhibitor of NS5B polymerase, and ACH-3102, its phase II, pan-genotypic, second-generation NS5A inhibitor. The company plans to initiate a pilot phase II study evaluating the combination of ACH-3102 with sofosbuvir in treatment-nïve HCV patients over treatment durations of eight weeks or less. The study aims to optimize the use of ACH-3102 in nucleotide-based regimens and to expedite the development of the combination of ACH-3102 and ACH-3422.

While Achillion still believes it can compete in this highly competitive space, other companies could be having second thoughts about the risks and rewards of their current HCV candidate drug programs.

Given the competition, Vertex Pharmaceuticals Inc. is one company that may be re-thinking its game plan. Deutsche Bank analyst Robyn Karnauskas wrote that the company is “at crossroads with VX-135,” its HCV nucleotide analogue, which targets the NS5B polymerase, noting that the company and partner Bristol Myers Squibb Co. “are thinking hard about going forward with the ’135/dac combo.” Eliminating the program would save $45 million to $50 million, estimates Karnauskas.

It is clear that Gilead and Abbvie have set the bar extremely high for other companies attempting to bring innovative new HCV treatments to the market. Like Vertex, those companies with products in early and mid-stage development might be wondering if their R&D investments will ever be rewarded.