Medivir gets good hep C news, but can it keep up with all-oral combos?

Medivir may have been second out of the gate with late-stage data from a next-generation hepatitis C drug, but it has got the bigger boost. Its shares were up 9% to SEK68.50 in late afternoon trading today following news that its Johnson & Johnson-partnered protease inhibitor simeprevir when combined with interferon and ribavirin cured four fifths of patients infected with the difficult-to-treat genotype 1 of the virus.

While this has clearly been taken as good news by investors, the value proposition for simeprevir is far from resolved, as four companies have entered or are planning late-stage trials with all-oral combinations of fully owned compounds that eliminate the flu-like symptoms and other side effects of the injectable interferon. Having a proven phase III drug is a big advantage for Medivir; however, it really needs to show that it can match the pace of the other all-oral combinations to sustain this latest share-price surge.

Impressive solo act

The Swedish group reported data from two trials in patients who had never been treated before and one trial in those who have relapsed after previous treatment. Of the patients in the two treatment-naïve trials, 80% and 81% had no detectable hepatitis C virus RNA in their blood when treated with simeprevir for 12 weeks along with interferon and ribavirin for up to 48 weeks, a measurement called SVR12.

In the trial of treatment-experienced patients, 79% achieved SVR12 on the same regimen. By comparison, 50% of patients receiving only interferon and ribavirin in the two treatment-naïve trials achieved SVR12, and 37% in the study in relapsers.

These are impressive results – on paper the cure rates are better than those shown by the currently marketed protease inhibitors, Vertex Pharmaceuticals’ J&J-partnered Incivek and Merck & Co’s Victrelis, in their pivotal trials. If that were the competition, Medivir’s pill, also known as TMC435, might be drawing “best in class” accolades from analysts and hepatologists.

However, clinical development in hep C seems to change almost daily, with Gilead Sciences’ $11bn sofosbuvir moving so swiftly that giants like Novartis have given up (Signs are growing that the hep C ship is sailing, August 1, 2012). Now that the protease inhibitors have improved cure rates over the preceding standard of care of interferon and ribavirin alone, researchers are now hoping they can eliminate interferon and ribavirin altogether.

Interferon in particular carries numerous side effects – flu-like symptoms are common, but neurophsychiatric, autoimmune, ischaemic and infectious disorders have earned it a black box warning – and it is therefore the main target for elimination. But ribavirin also has black box warnings for anaemia and birth defects, so eliminating it from treatment routines would be a step forward too.

Duets and trios

Enter the polymerase inhibitors of many stripes. Gilead’s sofosbuvir, also known as GS-7977, obtained through the acquisition of Pharmasset, is being paired with Gilead’s in-house GS-5885 to thwart replication of viral DNA.

Abbott Laboratories is using a pair of polymerase inhibitors and a protease inhibitor, while Bristol-Myers Squibb and Boehringer Ingelheim are combining a single polymerase inhibitor with a protease inhibitor (AASLD preview – The cocktail hour approaches for interferon-free regimens, October 17, 2012). Thus Medivir and J&J really do stand out as having only a single proven late-stage agent.

That is not to say that they are not trying to come up with workable combinations, and in fact Medivir and J&J have been almost promiscuous in signing non-exclusive alliances. All-oral phase II tests with Vertex’s VX-135 (ALS-2200) were announced just before the AASLD meeting in November, and Medivir has previously collaboarated with Bristol-Myers and Pharmasset to test it with daclatasvir and sofosbuvir.

However, as analysts from Jefferies note, “internal fixed-dose combos may prevail”. Indeed, Gilead and Bristol-Myers have made little secret about their hopes of coming up with single-pill treatments, especially after their break-up in the spring following successful combination testing of sofosbuvir and daclastasvir (EASL – Gilead-BMS score all-oral hep C win but will pairing last?, April 19, 2012).

A further partnership is with J&J on TMC647055, which has also started phase II trials. This, alone or combination with Vertex, is the most likely option, and as J&J has already collaborated with Vertex in the hep C space, the New Jersey mega-pharma could probably enable that partnership.

The question then becomes: what use is Medivir as a standalone company? However, with a market capitalisation of SEK2.16bn ($331m) Medivir might be a pricey speculative bet, even for J&J.

Some scalps have been taken in the hep C space of late, and although one cannot write an epitaph for simeprevir, it does have the disadvantage of being served neat in a bar where cocktails are the rage. Swift progression through phase II in its combination studies would reassure investors that they will not end up crying into their beer.

Study Population Trial ID
Quest-1 Treatment-naïve NCT01289782
Quest-2 Treatment-naïve NCT01290679
Promise Treatment-experienced NCT01281839

To contact the writer of this story email Jonathan Gardner in London at [email protected] or follow @JonEPVantage on Twitter

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