EASL - Beyond protease inhibitors hep C pipeline filling up

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With the development of hepatitis C protease inhibitors boceprevir and telaprevir all but concluded, specialists in treating the liver disease now are looking beyond the two first-in-class drugs (see tables below). Research is focusing on a combination of molecules or even a single agent that can reduce the burden of treatment, combat a wider spectrum of virus genotypes, dodge viral resistance and succeed in more patients, particularly those who have not seen relief with existing therapies.

A top priority among experts gathered at the EASL International Liver Congress is developing an interferon-free regimen, to eliminate the flu-like symptoms and other side effects common with the immunostimulant, a goal that seems tantalysingly just out of reach for patients and physicians. “The real success will probably be in five or six years when we’re able to combine different oral agents, different small molecules with different modes of action and maybe get rid of interferon,” says Antonio Craxi, professor of gastroenterology and internal medicine at the University of Palermo.

Viral breakthrough

For now, viral breakthrough has haunted therapies that have attempted trial arms without peginterferon-alfa and ribavirin, the antiviral that makes up the other half of the current standard of care. For example, viral breakthrough forced Vertex Pharmaceuticals to cancel an arm of its phase II trial of telaprevir and VX-222 that did not include a background standard of care therapy. The trial continues in the quadruple-therapy arm, with positive interim results presented at the conference.

Dr Craxi, coordinator of an EASL group that wrote new guidelines for hep C management, says he does not believe interferon can be successfully removed from therapy until 2020. That is because to accomplish the same thing as interferon, a replacement treatment must achieve a 5-log reduction – or be 0.0001% of baseline viral load – within a week of treatment initiation.

So for all their tolerability issues, interferons are actually very effective at clearing the virus from the body. More potent drugs may exist, Prof Craxi says, but “we will probably still have to wait two or three years to have them in large clinical-based experiments.”

Long shadow

While protease inhibitors cast a long shadow over the late-stage landscape, polymerase inhibitors are now a significant chunk of the phase II pipeline (see table). At EASL, data was presented in various forms from polymerase inhibitors from VX-222 and Pharmasset’s PSI-7977 and PSI-352938, to name just three.

Biggest classes of direct-acting hepatitis C R&D projects 
Hepatitis C protease inhibitor 43
Hepatitis C polymerase inhibitor    37
Hepatitis C vaccine 16
Nucleoside analogue 13
Hepatitis C NS5a and/or NS4b inhibitors    17
miR-122 antisense 6
Cyclophilin inhibitor 6
Anti-PD-1 MAb 4
Serine palmitoyl transferase inhibitor 3
Hepatitis C entry inhibitor 3
Others/Unclassified 130
Total direct-acting hepatitis C R&D projects 278

The question for polymerase inhibitors and other emerging classes, such as Bristol-Myers Squibb’s NS5a inhibitor BMS-650032, is whether they will present a sufficient barrier to viral breakthrough in the absence of a background of standard of care. This challenge was clearly demonstrated by Vertex’s alteration of the phase II combination trial of VX-222 and telaprevir.

“If you take two direct antivirals only and then those have a low antiviral activity and a low barrier to resistance this is clearly insufficient. You get high rates of viral breakthrough and you cannot eradicate the virus,” says Christoph Sarrazin, a medical professor at J.W. Goethe-University Hospital in Germany. “If you have two direct antivirals that have high antiviral activity but low barrier to resistance, then it might be possible (to fight) some (virus) subtypes. We have seen that proof of principle.

“If you take two direct antivirals with medium to high antiviral activity and a high barrier to resistance, the game is still open,” Prof Sarrazin says.

Another danger is that reliance on the same or similar mechanisms of action runs a greater risk of side effects, notes Prof Craxi.

“Many of the new drugs use similar intercellular pathways. What you get in the end is toxicity due to accumulation of these drugs,” he says. “This is something we’ve already seen in the HIV field and something where if we are not careful enough we will see in the (hepatitis C) field.”

Building hopes

Pharmasset has a hope of showing it can be done. A 14-day trial testing various combinations of its two nucleotide analogue polymerase inhibitors in 30 patients has yielded results equalling or exceeding a 5-log reduction. The results were sufficient enough to announce a larger phase II trial to begin mid-year of “multiple hundreds,” in part to build a larger safety data base for ‘938, says Richard Smith, vice president of investor relations.

“We know that nucleotides have a high barrier to resistance,” Mr Smith says. “We’ve never seen any resistant breakthroughs on treatment probably because of the mechanism of action. We know that both of them are safe

“We’re one of the only companies now that has a shot of achieving (sustained viral response) with an oral combination,” he says.

Excitement has been building around the New Jersey group’s chances. Shares have nearly tripled over the past six months, and were trading 2% higher in early trading this morning at $84.15, a record high.

Patient expectations

Excitement also surrounds alisporivir, also known as Debio-025, the Novartis-partnered cyclophilin inhibitor that blocks proteins that are necessary for the replication of the virus in the body. Unlike many of drugs in development - or indeed, the two protease inhibitors nearing the maket – alisporivir has shown activity in combating genotypes 2, 3 and 4. of the disease, as well as the most common genotype 1. Most current candidates are effective only against genotype 1.

With such pipeline activity, Prof Craxi views the protease inhibitors as perhaps “stop gap drugs,” no matter the billion-dollar forecasts being built for them.

The table below shows some of the most promising phase II candidates which are not protease inhibitors - none of these alternative therapeutic classes have yet made it into phase III trials.

Many patients are waiting for a more effective and less arduous treatment regimen. Despite the interest and the growing number of candidates, a packed mid-stage pipeline needs to translate into an equally full late-stage pipeline for hopes to be realised.

Selected phase II direct-acting hepatitis C treatments, excluding protease inhibitors
Product Generic Name Pharmacological Class Company First Introduction
Taribavirin taribavirin Nucleoside analogue Kadmon Pharmaceuticals 2013
RG7128 - Hepatitis C polymerase inhibitor Pharmasset  2014
BMS-790052 - Hepatitis C NS5a inhibitor Bristol-Myers Squibb 2014
Bavituximab bavituximab Anti-PS MAb Peregrine Pharmaceuticals 2014
Debio-025 alisporivir  Cyclophilin inhibitor Novartis 2014
PF-4136309 - CCR2 antagonist Pfizer 2014
ANA598 - Hepatitis C polymerase inhibitor Anadys Pharmaceuticals 2014
TG 4040 hepatitis C vaccine Hepatitis C vaccine Transgene 2015
ABT-333 - Hepatitis C polymerase inhibitor Abbott Laboratories 2015
PSI-7977 - Hepatitis C polymerase inhibitor Pharmasset 2016
BMS-791325 - Hepatitis C polymerase inhibitor Bristol-Myers Squibb 2016
PF-868554 filibuvir Hepatitis C polymerase inhibitor Pfizer 2016
ABT-072 - Hepatitis C polymerase inhibitor Abbott Laboratories 2016
VX-222 - Hepatitis C polymerase inhibitor Vertex Pharmaceuticals -
NIM811 - Cyclophilin inhibitor Novartis -
PSI-7851 - Hepatitis C polymerase inhibitor Pharmasset -
GS 9190 tegobuvir Hepatitis C polymerase inhibitor Gilead Sciences -
CTS-1027 - Matrix metalloprotease (MMP) inhibitor Conatus Pharmaceuticals -
SPC3649 miravirsen miR-122 antisense Santaris Pharma (GSK has option) -
SCY-635 - Cyclophilin inhibitor Scynexis -
ITX5061 - Hepatitis C entry inhibitor iTherX Pharmaceuticals -
NOV-205 glutathione & inosine Glutathione-S-Transferase activator Novelos Therapeutics -
IC41 hepatitis C vaccine Hepatitis C vaccine Intercell -
ChronVac-C hepatitis C vaccine Hepatitis C vaccine ChronTech Pharma -
MitoQ mitoquinone mesylate Hepatoprotectant Antipodean Pharmaceuticals -
PHN121 herbal extract Hepatitis C agent PhytoHealth -
ABT-267 - Hepatitis C agent Abbott Laboratories -
PF-3,491,390 (IDN-6556) emricasan Caspase inhibitor Conatus Pharmaceuticals -
Pictovir mifepristone Glucocorticoid receptor antagonist Inovio Pharmaceuticals -
CF102 cl-ib-meca Adenosine A3 receptor agonist Can-Fite BioPharma -
CT-011 - Anti-PD-1 MAb Teva Pharmaceutical Industries -
Source: EvaluatePharma

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