Advances continued in the race for ever-better, oral, direct-acting hepatitis C virus (HCV) therapies with the approval Friday of Abbvie Inc.'s Viekira Pak to treat patients with chronic genotype 1 (GT1) infection, partnered with Enanta Pharmaceuticals Inc.

Three new drugs in Viekira – ombitasvir (an NS5A inhibitor), paritaprevir (an NS3/4A protease inhibitor) and dasabuvir (a non-nucleoside NS5B palm polymerase inhibitor) in a single pill – work synergistically, and previously approved ritonavir, co-packaged as part of the regimen, boosts blood levels of paritaprevir.

Having more choices for patients is "absolutely" what it's all about, said Fred Poordad, an investigator in the Viekira trials. "With almost anything in life, more options are better than fewer options," he told BioWorld Today. "We look forward to more options. The three approved regimens will have their day for a limited period of time. They're all going to be replaced by next-generation – this is not the be-all, end-all. R&D continues, and we look forward to the day when we figure out how to treat patients in even shorter durations with 100 percent efficacy." For the moment, though, "this [approval] is wonderful news for the patients," he said.

The approval triggers a $75 million milestone payment from Abbie to Enanta, shares of which (NASDAQ:ENTA) closed Monday at $51.32, up $4.70. Approval is pending in Europe. Watertown, Mass.-based Enanta and Abbott in December 2006 entered their deal for NS3 and NS3/4A protease inhibitors and HCV protease inhibitor-containing drug combinations. Officials at Enanta could not be reached. Abbvie's stock (NYSE:ABBV) ended at $66.97 down 74 cents. (See BioWorld Today, Dec. 11, 2013.)

More good news for Abbvie, of North Chicago, and Enanta came as Express Scripts Holding Co., the biggest pharmacy benefit manager (PBM) in the U.S., made known its plan to take up Viekira and drop from its list Gilead Sciences Inc.'s Sovaldi (sofosbuvir), the blockbuster nucleotide analogue inhibitor of NS5B approved in late 2013 for GT1 HCV. Also disappearing from Express' roster is Harvoni, Gilead's HCV therapy that combines a dose of Sovaldi with ledipasvir, the direct-acting macrocyclic antiviral agent and NS5A inhibitor, as well as Olysio (simeprevir), the NS3/4A protease inhibitor from Johnson & Johnson, of New Brunswick, N.J.

Gilead's stock (NASDAQ:GILD) ended Monday at $92.90, down $15.55, or 14.3 percent, in a sell-off that Wells Fargo analyst Brian Abrahams viewed as overdone. He deemed the Viekira label "even less competitive than originally anticipated, with limitations on the addressable market, burden for clinicians on monitoring/screening and dosing burden for patients." Harvoni "should clearly be preferred" by doctors and patients alike, Abrahams wrote in a research report.

"About 75 percent of the 3.2 million U.S. HCV patients are GT1, for a relevant latent population of 2.4 million, of which we estimate 250,000 coming onto treatment annually [between] 2015 and 2019," Abrahams went on. "Express Scripts administers pharmacy benefits for 25 million Americans (about 10 percent of the U.S. insured population), suggesting immediate impact is limited to that 10 percent of the U.S. HCV population (and perhaps less since Express will have carve-outs for [Viekira]-ineligible patients)."

What about other PBMs? Abrahams sees the fallout from Express as "limited. Recall that Express was one of the most outspoken and vocal critics of Gilead this year, and had openly signaled its intention to contest Gilead using competitive regimens," he wrote. "We believe other payers will consider the totality of data supporting Harvoni's advantages, which we believe make real-world SVRs more likely, and would provide Gilead more ample opportunity to negotiate on price than Express did."

'LEVEL PLAYING FIELD'

Sharing the HCV spotlight with clinical news was New Haven, Conn.-based Achillion Pharmaceuticals Inc., which popped the lid off positive interim results from a pair of studies that support short duration HCV therapy with a regimen that includes its NS5A and nucleotide inhibitors ACH-3102 and ACH-3422. Investors particularly liked the phase II "proxy" experiment testing ACH-3102 with Sovaldi in treatment-naïve GT1 HCV patients. Achillion gained 100 percent sustained virologic response rate four weeks after treatment (SVR4) in the ongoing, 18-patient, six-week trial, which administers 50 mg of ACH-3102 and 400 mg of Sovaldi. The main goal of the trial is to determine SVR12.

In the phase I trial with ACH-3422, treatment-naïve GT1 HCV patients were randomized to escalating doses of 50 mg, 150 mg and 300 mg for seven days, plus 500 mg and 700 mg ACH-3422 for 14 days of monotherapy. All doses proved well tolerated with no discontinuations due to adverse events. The 700-mg ACH-3422 cohort showed an "impressive" mean maximum viral load reduction of 4.8 log IU/ml with three of six patients at undetectable levels of HCV RNA (< 10 IU/mL), said Piper Jaffray analyst Edward Tenthoff. "We view this as validating data that Achillion has a safe and potent nucleotide inhibitor," he wrote in a research report.

Achillion's stock (NASDAQ:ACHN) closed Monday at $15.49, up $1.28.

Market watchers also took note of new guidelines from the American Association for the Study of Liver Diseases (AASLD), disclosed late Friday. The advice did not surprise J.P. Morgan analyst Cory Kasimov, who said the AASLD judged by its guidelines that Harvoni and Viekira show "similar efficacy" in treatment-naïve and experienced GT1 patients.

On the Gilead question, though, Leerink Swann analyst Howard Liang seemed to agree with Abrahams, saying the AASLD guidelines combined with the label on Viekira "appear to position [Abbvie/Enanta's drug] as somewhat more inferior to Gilead's Harvoni than originally expected."

Liang cited the label's contraindication for Viekira in patients on certain other drugs including oral contraceptives as well as those with severe hepatic impairment. Viekira also is not recommended in patients with decompensated cirrhosis or moderate hepatic impairment. Liver enzyme monitoring is required in the first four weeks of treatment, too.

Poordad, however, said the HCV arena has "three very competitive" therapies. "There are no regimens that are approved for decompensated cirrhosis. That's a very level playing field. In terms of drug-drug interactions, all of the regimens have some interactions, and it's a matter of clinicians knowing how to handle those and how to work with their resources at hand, whether it's a pharmacist or multiple websites" designed for doctors to check for potential problems.

"It can certainly make oral contraceptives less effective," he said. "We learned long ago that when patients are being treated for HCV, we need to always have them use two different methods of birth control concurrently. That's nothing new here."

As for the liver enzymes, "I don't see that as a big deal at all," Poordad said. "We routinely monitor liver enzymes in the first four weeks, regardless of regimen. Your clinician is going to be monitoring blood tests – none of these therapies is dumbed down to the point where you can just give them to the patient and forget about the patient."

'MAKE THE FIRST TIME COUNT'

Liang wrote in a research note that the "labeling language on duration in more difficult-to-treat patients is vague, although the guideline recommends 24 weeks of treatment for all GT1a cirrhotic patients. We expect the payer enforcement of label or guideline duration (which in turn determines price per patient), as well as [the] negotiated volume discount, to determine the market-share split."

By Liang's math, the dueling companies' price discount of 12 percent for 12 weeks of treatment ($83,319 for Viekira vs. $94,500 for Harvoni) is "small compared to the price difference due to duration difference and potentially volume discounts in the form of rebates," and Harvoni, if doctors follow the FDA's labeling, could have an advantage of eight weeks compared with 12 weeks in an easier-to-treat population (treatment-naive, lower viral load, nearly half of GT1), which leads to a discount of 24 percent based on the list price or $20,000 in difference in price per patient. Under the guidelines, "Harvoni has a duration advantage of 12 vs. 24 weeks in [the] more difficult-to-treat population (GT1a cirrhotics, roughly 20 percent of GT1 patients by our estimate), providing a discount of 43 percent using the list price, or a very substantial $72,000 difference in price per patient."

Poordad said "most patient types with either regimen, whether it's Viekira or Harvoni, are indicated for 12 weeks." He acknowledged that "the label for Harvoni is for 12 weeks with a consideration of eight weeks in a certain subset of patients. Both regimens have a 24-week arm for certain patient types. With Harvoni, the previously failed patient who is cirrhotic needs 24 weeks. With Viekira, you need 24 weeks in the GT1a population [that] has cirrhosis, and there's consideration to shorten to 12 weeks if they meet certain criteria." In practice, Poordad said, "most clinicians I work with are always going down the side of getting the highest cure rate for the patient," since "we don't know if there's going to be an opportunity to treat them again, for lots of different reasons. So make the first time count – if you go for the highest cure rate, you're doing what's right for the patients."

Physicians will make their own decisions, based on individual patients' needs, regarding which drugs to try. "I must say that all of these regimens are incredibly well tolerated," Poordad said. "I have not noticed any difference. Patients feel good on all the regimens, so at the end of the day, everyone is happy. It's really amazing, when you talk to the patients, how well they feel, even before you know they're cured, just [by] getting that viral count down to undetectable. If there ever was any question in anyone's mind that HCV is a bad thing to have, this answers it. Our big challenge is finding all the HCV patients in this country, identifying them, and then linking them with care."