AASLD preview – The cocktail hour approaches for interferon-free regimens

Analysis

A year ago, Abbott Laboratories was seemingly nowhere in the chase for the first all-oral interferon-free hepatitis C regimen. Today, the Illinois group is well and truly a competitor to Gilead Sciences.

Following release of abstracts from the upcoming American Association for the Study of Liver Disease meeting, investors judged Abbott the big winner based on phase IIb data for its five-drug cocktail, buoying shares to a record high on Monday. Gilead’s $11bn sofosbuvir remains the compound to beat, but Abbott’s combination may give it a run.

Tightening race

The interferon-free stakes is looking increasingly like a three-horse race, with Bristol-Myers Squibb the third entrant. A falling out with Gilead and a clinical stumble this summer slowed Bristol-Myers’ momentum, although it too is presenting positive data for its wholly-owned three-drug combination based on the NS5A inhibitor daclatasvir (Bristol-Myers setback another blow to hep C field, August 24, 2012).

The share performance of all three companies is of course affected by external factors: Abbott’s by the upcoming spinning out of its pharmaceutical operations into AbbVie; Gilead’s by sky-high expectations for sofosbuvir, formerly known as GS-7977; and Bristol-Myers by a series of pipeline successes.

Sofosbuvir’s net present value of $21.4bn accounts for 41% of Gilead’s market capitalisation, rivalling the value of its entire HIV franchise even with the approval of the four-drug regimen Stribild, so there seems to be little room for shares to move further upward. In the case of Abbott and Bristol-Myers Squibb, there would appear to be a little more leeway; certainly on Monday, the day the AASLD late-breaking abstracts were released, Abbott climbed 4% to $72.05 and Bristol-Myers 3% to $33.93, whilst Gilead declined 1% to $67.32.

Impressive numbers

Late-breaking trial data to be presented at the AASLD meeting in Boston next month will flesh out some of the details of these emerging combinations.

The Abbott combo successfully suppressed the virus in nearly all treatment-naïve and previously non-responding patients 12 weeks after completing a 12 week course. The combination consisted of ritonavir-boosted ABT-450 – a protease inhibitor like the marketed hep C drugs – as well as the NS5A inhibitor ABT-267, the NS5B inhibitor ABT-333, and ribavirin. 

Bristol-Myers’ daclatasvir in conjuntion with the protease inhibitor asunaprevir and NS5B inhibitor BMS-791325 showed similarly impressive numbers.

Amongst the data to be presented on Gilead’s candidates are results of a trial assessing sofosbuvir combined with its NS5A inhibitor GS-5885 12 weeks after completion of treatment in patients with the difficult-to-treat genotype 1 of the virus, and an NIH trial of sofosbuvir with ribavirin in advanced patients with liver fibrosis.

At this point, all of these combinations are achieving near-complete viral suppression, and if these data are confirmed in phase III trials issues such as tolerability and side effect profiles will play a large role in the choices made by patients and doctors. ISI Group analyst Mark Schoenebaum flagged up Abbott’s use of the HIV antiviral ritonavir, known as Norvir, to boost its cocktail, as the drug has nausea and diarrhoea as significant side effects.

Moving ahead

Until the introduction of the protease inhibitors Incivek and Victrelis in 2011, the only treatment option for chronic infections was a combination of interferon and ribavirin. However, the flu-like symptoms and other side effects of interferon are arduous; many patients have delayed treatment in the hope of drugs with a better side effect profile, and thus first-mover advantage will be critical in this space (Signs are growing that the hep C ship is sailing, August 1, 2012).

Gilead has thrown down the gauntlet by initiating phase III recruitment first for a trial of sofosbuvir, an NS5B polymerase inhibitor also known as GS-7977, along with GS-65885 and hep C mainstay ribavirin. Abbott has announced a plan for a phase III trial of its cocktail, but recruitment has not yet begun.

Bristol-Myers has put daclatasvir into two phase III trials already, but in combination with interferon and ribavirin – that regiment will likely be used as an efficacy yardstick but not as a commercial product. The clinical hold placed on the former Inhibitex candidate BMS-986094, an NS5B, was not a fatal blow, but definitely was a disappointment; it was fortunate that the group had a replacement compound in the form of BMS-791325.

With pivotal trial results emerging in coming months and years, the shape of the post-interferon hepatitis C world will become clearer. With some estimates putting the incidence at three million patients in the US there is probably room for more than one product.

As with HIV, such issues as tolerability, side effects and drug interactions will play an increasing role in individual patients’ choices in a cocktail, and thus the variety of treatments reaching pivotal stage research is a reason for optimism. But unlike HIV, the hepatitis C drugs offer a cure rather than a chronic treatment – so drugmakers who are not in the game by 2016 are likely to miss out.

Selected AASLD presentations
Company Product Trial name Trial ID
Abbott Laboratories ABT-450, ABT-333, ABT-267 Aviator NCT01464827
Gilead Sciences GS-7977, GS-5885 Electron NCT01260350
Bristol Myers Squibb daclatasvir - NCT01455090
Vertex Pharmaceuticals VX-222
ALS-2200
Zenith
-
NCT01080222
NCT01590407
Medivir TMC435 Pillar
Aspire
NCT00882908
NCT00980330

To contact the writer of this story email Jonathan Gardner in London at jonathang@epvantage.com

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