AASLD preview – Novel hep C combo therapies emerge as US launches awaited

As dawn is breaking over the post-interferon era in hepatitis C treatment, the hazy landscape of oral antiviral treatment is beginning to take shape. The AASLD meeting in Washington, DC, beginning November 1, most importantly will reveal how effective the two new agents closest to the market, Gilead Sciences’ sofosbuvir and Johnson & Johnson’s simeprevir, work in combination.

No single agent so far has proven adequate at attacking hep C without triggering viral resistance, so specialists have long assumed that drug cocktails relying on different mechanisms of action will be necessary to defeat the disease (EASL Preview – Hep C combination therapies to take centre stage, March 16, 2011). A simeprevir-sofosbuvir combination might fit that bill. And with US approval decisions on both hep C drugs due in the next six weeks, strong viral cure data at AASLD could have specialists prescribing the two together almost straight out of the box.

Support expected

By the time liver specialists convene in DC, they will already have a clear idea of how the regulators feel about the two drugs. A two-day FDA advisory committee meeting later this week will see medical experts reviewing and voting on the compounds’ safety and efficacy (Event – Hep C advances await panel votes, October 7, 2013).

Simeprevir, a hepatitis C NS3/4A protease inhibitor licensed to J&J by Swedish firm Medivir, has gotten a bit of a head start as it has achieved Japanese approval under the name Sovriad. That approval is with the mainstay backbone treatment of interferon and ribavirin in genotype 1 patients, the same as its FDA application.

Likewise, sofosbuvir’s FDA application is in combination with both commonly used agents in genotypes 1, 4, 5, and 6, and with ribavirin alone in genotypes 2 and 3. The flu-like effects of interferon are a major barrier to treatment for many chronically infected patients, and ribavirin carries with it haematological, cardiovascular and central nervous system risks. Thus, eliminating one or both will be a major step forward for hep C treatment.

The phase II Cosmos study of the simeprevir-sofosbuvir combination gives some tantalising hope. According to the abstract submitted to the AASLD meeting, four weeks after the end of a 12-week treatment regimen, more than 90% of a cohort of cirrhotic or advanced liver fibrosis patients had undetectable levels of genotype 1 hep C virus. This finding came regardless of whether ribavirin was included in their regimen and whether they had responded to previous treatment.

Cosmos will be presented at the late-breaking abstracts session, so it is possible that investigators will disclose analysis 12 weeks after the end of treatment, as well as data from patients with no liver disease or less progression.

The big prize for Gilead will be in a year or so when its fixed dose, once-daily pill combining sofosbuvir, a hepatitis C nucleoside NS5B polymerase inhibitor, with NS5A inhibitor ledipasvir, reports pivotal data. However, the study with simeprevir suggests that group is more open than it was 18 months ago when it walked away from a collaboration to test the $11bn drug sofosbuvir with Bristol-Myers Squibb’s daclatasvir (EASL - Gilead-BMS score all-oral hep C win but will pairing last?, April 19, 2012). With J&J it has an established relationship – after all, the two were happy to combine HIV drugs Truvada and Edurant to create Complera.

Pipeline hopes

This is not to say the only news on sofosbuvir will be from the J&J collaboration. Two other Gilead studies, the phase III Lonestar-2 study of sofo plus interferon and ribavirin in previously treated patients and a trial in post-transplant patients will feature as late breakers.

Also in that session will be data from the all-oral combination Bristol-Myers Squibb was left with when Gilead backed away – daclatasvir, asunaprevir and BMS-791325. The New York group will disclose data from expanded patient cohorts that include cirrhotic patients – four week results indicate viral cure rates of above 80% for those cirrhotic patients, and investigators will detail data 12 weeks following the end of treatment at the AASLD meeting.

Outside the late-breakers, other companies will have a chance to showcase their data. AbbVie will disclose phase II data from a combination of ABT-450 and ABT-267. This is intended to support its three-drug combo of ABT-450, ABT-267 and ABT-333. ‘450 and ‘267 together achieved an 87% cure rate four weeks following the end of treatment in the phase II Pearl-I trial, boding well for the three drug grouping in ongoing phase III trials.

Boehringer Ingelheim will disclose some of its first data from treatment with faldaprevir and deleobuvir in combination with Presidio Pharmaceuticals’ PPI-668, the subject of a non-exclusive partnership announced earlier this year (Boehringer hep C venture a mild balm for Presidio investors, March 13, 2013). And Merck will disclose some of the early data from its combination of MK-5172 and MK-8742.

Outside of the realm of drug development, an assessment of the size of the potential commercial market will be revealed in the late-breaker session. A screening programme found that one out of every eight “baby boom” age patients presenting at emergency departments was positive for chronic hepatitis C infection.

Thus, there may be much to play for yet for the companies trailing Gilead and J&J.

Featured AASLD presentations
Trial Treatments Companies Setting ID
Cosmos sofosbuvir/simeprevir Gilead Sciences/Johnson & Johnson/Medivir Genotype 1 previously untreated or null responders NCT01466790
Lonestar-2 sofosbuvir/ribavirin/interferon Gilead Sciences  Genotype 2 or 3 patients with cirrhosis NCT01687257
- sofosbuvir/ribavirin  Gilead Sciences Recurrent infection post-transplant NCT01687270
- daclatasvir/asunaprevir/BMS-791325 Bristol-Myers Squibb Genotype 1 previously untreated patients NCT01455090
Pearl-I ABT-450/ABT-267 AbbVie Genotype 1 and 4 patients NCT01685203
C-Worthy MK-5172/MK-8742/Ribavirin Merck & Co Genotype 1 NCT01717326
- faldaprevir/deleobuvir/PPI-668/ribavirin Boehringer Ingelheim/Presidio Pharmaceuticals Genotype 1 NCT01859962

To contact the writer of this story email Jonathan Gardner in London at jonathang@epvantage.com or follow @JonEPVantage on Twitter

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