Gilead has filed the first interferon-free hepatitis C virus regimen for approval in the United States, but drug developers are making strides with better combinations.
Gilead submitted sofosbuvir for approval in the United States in April, hoping to usher in a new era of hepatitis C virus (HCV) treatment. After years of developing direct-acting antivirals (DAAs), suprisingly quick progress with interferon (IFN)-free combinations means a first all-oral approval is at last near.
Noted Update* June 7 2013
Gilead Announces U.S. FDA Priority Review Designation for Sofosbuvir for the Treatment of Hepatitis C
Patients with HCV have long been put off by up to 48-week treatment programmes and the harsh side effects of IFN. Although the 2011 approval of two DAAs — Vertex’s telaprevir and Merck’s boceprevir — provided better response rates, the burden of treatment has remained too high for many. “A lot of physicians right now are backing off prescribing these protease inhibitors,” says Nathaniel Brown, Chief Medical Officer of Presidio Pharmaceuticals, one of the many players in the HCV space. “They’ve seen the rapid progress in second- and third-generation oral medicines that look more effective and safer.”
Sofosbuvir will be the first of these next-generation agents to be put through its regulatory paces. For now, Gilead is only requesting all-oral use of the drug, in combination with ribavirin, in patients infected with HCV genotypes 2 and 3. The company is also requesting approval in HCV genotype 1 — the most prevalent form of the virus in the United States and Europe — and in genotypes 4–6, but it would be used with ribavirin and pegylated (PEG)-IFN in these settings. An approval for genotypes 2 and 3 would be a first step towards entry into what Gilead hopes is a US$20 billion-plus all-oral HCV market.
Over 40 other DAAs are in the pipeline, jostling for position in a growing number of combinations with different aims. “We think of the whole development programme in three ways,” says Norbert Bischofberger, Chief Scientific Officer at Gilead. “The first is to simplify what we currently have, the second is an all-oral therapy for genotype 1, and the third is a pan-genotypic approach.”
Most of the up-and-coming DAAs act on three key viral targets in the HCV replication cycle: the NS3/4A protease, the NS5B polymerase and the NS5A protein (Table 1).
Table 1: Selected HCV inhibitors in late-stage development
|Drug name||Lead companies||Phase|
NS3/4A protease inhibitors
|Asunaprevir (BMS-650032)||Bristol-Myers Squibb||III|
|Faldaprevir (BI-201335)||Boehringer Ingelheim||III|
|Danoprevir*||Roche (from InterMune)||IIb|
|MK-5172||Merck & Co.||II|
Nucleoside/nucleotide NS5B polymerase inhibitors
|Sofosbuvir (GS-7977/PSI-7977; uridine nucleotide prodrug)||Gilead (from Pharmasset)||NDA|
|Mericitabine (RG-7128/RO-5024048; cytidine nucleoside prodrug)||Roche||IIb|
|VX-135 (ALS-2200; uridine nucleotide prodrug)||Vertex (licensed from Alios)||II|
Non-nucleoside NS5B polymerase inhibitors
|Daclatasvir (BMS-790052)||Bristol-Myers Squibb||III|
|MK-8742||Merck & Co.||II|
HCV, hepatitis C virus; NDA, new drug application. *Requires boosting with ritonavir. Sources: Cortellis database (Thomson Reuters) and company websites.
A second class of agents inhibits the NS5B polymerase, an RNA-dependent polymerase. Nucleoside and nucleotide inhibitors of NS5B polymerase act at the catalytic site. As the catalytic site is conserved across genotypes, these tend to have broad activity. And because mutations in the catalytic region are highly detrimental to protein function and viral survival, these inhibitors offer high barriers to resistance. Gilead’s sofosbuvir, which it snapped up through an $11.2 billion purchase of Pharmasset, is in the lead in this space.
Other nucleoside and nucleotide NS5B inhibitors in development include Roche’s mericitabine and Vertex’s VX-135, which are both in Phase II trials. BMS’s ill-fated BMS-986094 (previously known as INX-189) also belongs to this class. BMS acquired BMS-986094 through the $2.5 billion purchase of Inhibitex in 2011, but terminated development months later after a trial participant died from heart failure. Some attribute this cardiotoxicity to the guanosine-based chemical structure of BMS-986094 (sofosbuvir, by contrast, is a uridine analogue). As yet, there is no evidence that this toxicity is a class effect.
Non-nucleoside NS5B inhibitors act on various allosteric sites to induce conformational changes in the polymerase. These agents include AbbVie’s ABT-333 and Boehringer Ingelheim’s BI-207127.
They offer lower genetic barriers to resistance than the nucleoside and nucleotide analogues, partly because mutations that occur in these regions are less detrimental to polymerase function.
NS5A inhibitors, meanwhile, act on the most recently discovered crucial component of the HCV life cycle. NS5A’s role is unclear, but it is involved in modulating the host immune response, HCV pathogenicity and replication (Nature 465, 96–100; 2010). BMS pioneered this new class of inhibitors, which are highly potent and could offer broad genotype coverage. BMS’s Phase III candidate daclatasvir is the most advanced, followed by AbbVie’s ABT-267 and Gilead’s ledipasvir.
Mix and match
With these candidates in hand, the quest is on to achieve the three main aims of HCV drug development. Sofosbuvir, which is given once daily, ticks the box for simplifying the current regimen. Phase III trials showed that a cure could be achieved in up to a quarter of the time taken with conventional regimens (N. Engl. J. Med. 368, 1878–1887; 2013). “It’s a seismic shift,” says John Tucker, an analyst at BioMedTracker, USA. “We are going from a treatment regimen that takes 24–48 weeks and that has an awful side effect profile — that’s almost like going through chemotherapy — to new regimens that are down to 12 weeks.”
Sofosbuvir also works without PEG-IFN (N. Engl. J. Med. 368, 1867–1877; 2013), paving the way for Gilead’s submission of the oral regimen in April.
A bigger prize will go to the drug developers who can identify all-oral cocktails for genotype 1 and with broad activity. “The holy grail for everyone is to find a very simple way to treat everybody with HCV,” says Douglas Manion, senior vice president of development and virology for BMS.
The first step towards this goal was presented in April 2011 at the European Association for the Study of the Liver (EASL) meeting in Berlin, with the report that asunaprevir plus daclatasvir could cure 36% of patients with HCV genotype 1 (N. Engl. J. Med. 366, 216–224; 2012). “This has led us to the Manhattan project going on today,” says Manion.
BMS plans to submit this combination for approval in Japan for patients with genotype 1 HCV by the end of the year. “We think we’ll be the first company in the world to file an all-oral combination for genotype 1,” says Manion.
The combination of an NS5B inhibitor and an NS5A inhibitor is also offering promise, as exemplified by a trial of sofosbuvir plus daclatasvir, run by BMS and Pharmasset (before the biotech company was acquired by Gilead). Data from this trial, presented at the American Association for the Study of Liver Diseases meeting held in Boston, USA, back in November 2012, are “still the most stunning data we have in the field of HCV therapy”, says Brown. The combination with or without ribavirin led to sustained viral responses (SVRs) of 88–100% in treatment-naive patients with HCV genotypes 1 and 2/3 after 12 or 24 weeks of treatment. Data presented at a later meeting showed that the combination was also effective after 24 weeks of treatment in patients with HCV genotype 1 who were non-responders to boceprevir or telaprevir. “The Pharmasset/Gilead ‘nuc’ is probably the most attractive partner yet for our drug,” says Manion. “With daclatasvir, it works in 12 weeks, without ribavirin, without ritonavir, in all patient populations and in all genotypes.”
Gilead is now pursuing its own once-daily, fixed-dose NS5B plus NS5A combination of sofosbuvir and ledipasvir though. In Phase II trials this combination achieved SVRs in 95% of patients with genotype 1 HCV after only 8–12 weeks of treatment, the company recently reported. Although patient groups are clamouring for the cross-company development of sofosbuvir and daclatasvir, Gilead is going ahead alone with its in-house combination. “My overall experience is that inter-company collaborations are always more cumbersome and slower,” says Bischofberger. Gilead’s sofosbuvir plus ledipasvir combination is in Phase III trials in patients with HCV genotype 1 and could be approved by mid 2015, say analysts at BioMedTracker.
Other highly effective all-oral regimens for genotype 1 HCV to look out for are built on an NS3/4A protease inhibitor, an NS5A inhibitor and a non-nucleoside NS5B inhibitor. AbbVie is testing a multi-pill combination of ABT-450 (boosted with the protease inhibitor ritonavir), ABT-267 and ABT-333, with or without ribavirin, for example, and BMS has combined asunaprevir, daclatasvir and BMS-791325. Both companies reported in the April 2013 EASL meeting in Amsterdam that their combinations achieved SVRs of >90% in Phase II trials. The US Food and Drug Administration (FDA) recently granted both of these triple DAA regimens the coveted ‘breakthrough therapy’ designations, potentially accelerating their development and review process.
Boehringer Ingelheim, another big player in the development of an IFN-free regimen, is combining the NS3/4A inhibitor faldaprevir with the non-nucleoside NS5B inhibitor BI-207127 and ribavirin. Boehringer Ingelheim initiated Phase III trials of this regimen based on Phase IIb data showing overall SVRs of up to 69% in patients with HCV genotype 1 (SVRs were 85% in patients with subtype 1b). This trial included patients with advanced liver disease, whereas AbbVie and BMS excluded these patients in their landmark combination trials, potentially accounting for the differences in SVRs. The company is now testing this combination in Phase III in patients with subtype 1b only.
Overall, the regimens in development also generally offer good tolerability, and fewer than 10% of patients drop out of trials, notes Stefan Zeuzem, Goethe University Hospital, Frankfurt, Germany, and investigator on multiple IFN-free trials. Although side effects experienced range from rash to gastrointestinal discomfort, they “are all much more tolerable than IFN”, he adds. Relapse rates have also been low so far (generally less than 10%), leading to overall high SVR rates. Zeuzem cautions that high SVRs are not achievable in all populations, such as in the elderly, in HIV-co-infected patients and in patients with liver cirrhosis.
While patients with HCV genotype 1 await more data and regulatory approval for an all-oral regimen, an off-label option may soon be on the table. Simeprevir and sofosbuvir are both likely to be approved by the end of 2013. Phase II data presented at the Conference on Retroviruses and Opportunistic Infections in March 2013 showed that when these drugs are used together, with or without ribavirin, they yield >90% SVRs in this patient population. “That’s actually going to be the first combination on the market that is not going to be approved together,” says Douglas Dieterich, Mount Sinai Hospital, New York, USA, and investigator in multiple clinical trials of IFN-free combinations.
It may not hold the all-oral monopoly for very long though. “I think this is the fastest moving therapeutic area at the moment,” says Klaus Dugi, senior vice president of medicine, Boehringer Ingelheim. “The verdict is still out as to what will be the ideal combination.” This is particularly true for the pan-genotypic regimens, says Brown. “The stage is still sparsely populated. There is no pan-genotypic regimen in advanced clinical development, and so now that’s where the emphasis is likely to turn to.”
Source: Nature Reviews Drug Discovery