Abbott Laboratories releases data on PILOT & CO-PILOT studies...

The EASL madness begins! An article posted today on Wall Street Journal.com below on Abbott's (or soon-to-be spin-off AbbVie) PILOT and CO-PILOT studies looking at protease inhibitor ABT-450 and polymerase inhibitors ABT-072 and ABT-333.  These studies are remarkable for a couple of reasons in my view:

• Interferon-free regimens, at least for certain populations, is really a reality.
• An SVR12 of at least 90% (in the tx-naive, no complications populations) is the new 75% of last year.
• The majority of large pharma companies now in the HCV marketplace is astounding. Competition will be fierce.
• The prospects of a Novir-boosted HCV PI is questionable, especially with 4 severe adverse events attached to it. 
• The drug to really, really beat is Ribavirin. Don't say I didn't tell you so. 

This EASL is going to be a big one for HCV drug development - stay tuned!

Abbott Drugs Suppress Hepatitis C Virus In 2 Studies

--Abbott is testing several experimental hepatitis C drugs

--More than 90% of patients with no prior treatment in one study had suppressed virus 12 weeks after treatment

--Abbott is targeting launch of hepatitis C regimen in 2015

(Adds details of a Bristol-Myers study in final paragraph; updates stock prices.)


   By Peter Loftus
   Of DOW JONES NEWSWIRES

Experimental drugs from Abbott Laboratories (ABT) suppressed the hepatitis C virus in most patients in two small, midstage studies.

The results unveiled Wednesday could reinforce Abbott's position as a key player in an industry race to bring the next generation of drugs to what is expected to be a multibillion-dollar market for hepatitis C therapies. The drugs' safety and efficacy, however, need to be confirmed in additional studies.

"The Abbott data are clearly impressive from an efficacy perspective," said ISI Group analyst Mark Schoenebaum.

Abbott shares rose 36 cents, or 0.6%, to $61.50 in recent trading, and earlier set a 52-week high of $62.57.

Abbott has said it could begin selling a new hepatitis C regimen in 2015, and sales could eventually exceed $2 billion annually. The drugs would be sold by the pharmaceutical business that Abbott plans to split off into an independent company later this year, to be named AbbVie.

Summaries of the Abbott studies and studies of other liver-disease drugs were posted online Wednesday by the European Association for the Study of the Liver, or EASL, in advance of its annual scientific meeting in Barcelona in mid-April. Some EASL study results won't be released until the conference begins in two weeks, including data for key drugs from Gilead Sciences Inc. (GILD) and Bristol-Myers Squibb Co. (BMY).

Gilead, Bristol-Myers, Vertex Pharmaceuticals Inc. (VRTX) and Merck & Co. (MRK) are among several companies developing hepatitis C drugs to tap a market that research firm Decision Resources predicts will hit $16 billion in 2015, up from just $1.7 billion in 2010.

Hepatitis C is a viral disease that attacks the liver, and is believed to afflict about 180 million world-wide, with more than 4 million in the U.S., according to the National Institute of Allergy and Infectious Diseases. At-risk groups include people who had blood transfusions before 1992, when a screening test for the virus was developed.

Abbott is developing several potential hepatitis C drugs. One of them, ABT-450, is a so-called protease inhibitor, which is the same class of drugs as two that went on sale last year, Merck's Victrelis and Vertex's Incivek, which is marketed outside the U.S. by Johnson & Johnson (JNJ) as Incivo.

The protease inhibitors advanced treatment of hepatitis C, but there is still room for improvement because current treatments require an injectable drug, interferon, that can be difficult for patients to tolerate. Abbott and other companies want to develop all-oral regimens that eliminate the need for interferon.

In addition, Abbott is developing two polymerase inhibitors, ABT-072 and ABT-333, which have different mechanisms of action than the protease inhibitors.

The two studies released Wednesday each focused on ABT-450. One, titled "Co-Pilot," involved 50 patients who were given the following: one of two different dose levels of ABT-450, combined in the same pill with Abbott's Norvir boosting agent; ABT-333; and an existing drug called ribavirin that is part of the current standard of care for hepatitis C. The regimen amounted to several pills taken daily.

The study tested safety and tolerability of a 12-week regimen of the drugs in people with the most common form of hepatitis C, known as genotype 1. Patients in the study either hadn't previously received any treatment or didn't respond to prior treatment.

In the treatment-naive patient groups, more than 90% had a sustained virologic response 12 weeks after the end of treatment, a measure known as SVR12. Sustained virologic response is roughly equivalent to being virus-free or having nearly undetectable viral levels.

In the patients who didn't respond to prior treatment, 47% achieved SVR12 in the Abbott-funded study.

The second, smaller study--called "Pilot"--combined ABT-450 boosted by Norvir, ribavirin, and ABT-072. All 11 patients had received no prior therapy. This group of patients had a subtype of the virus that generally responds well to an interferon-based regimen and thus considered among the easier forms to treat.

Ten of the 11 patients achieved a sustained virologic response 24 weeks after stopping treatment, for an SVR24 rate of 91%. One patient relapsed.

"We're showing a sustained, post-treatment response from 12 to 24 weeks out" from the end of treatment, said Scott Brun, divisional vice president of infectious disease development at Abbott.

In both studies, the most common adverse events included headache, fatigue and nausea, and most were mild. In the larger "Co-Pilot" study, four patients had severe adverse events including fatigue and vomiting. There were no deaths in either study.

Abbott is conducting larger mid-stage studies testing various combinations of the three experimental drugs used in the smaller studies, Brun said. Abbott hopes to move some combination of the drugs into late-stage testing next year.

Abbott has developed ABT-450 in collaboration with Enanta Pharmaceuticals.

Shares of some of Abbott's rivals in the hepatitis C field declined Wednesday. Idenix Pharmaceuticals Inc. (IDIX) dropped 14% to $8.77; Gilead was off 1.85% at $47.21; Vertex was down 2.5% at $40.73, and Bristol-Myers was down 0.6% at $33.66.

A summary of a Bristol-Myers study posted Wednesday by EASL showed that a regimen of the drugs daclatasvir and asunaprevir helped 90.5% of hepatitis C patients who hadn't responded well to prior therapy achieve sustained virologic response 12 weeks post-treatment. Some 64% of patients who were ineligible for interferon-containing regimens or who discontinued prior therapy for intolerance achieved SVR 12 with the Bristol regimen.

-By Peter Loftus, Dow Jones Newswires; 215-982-5581; peter.loftus@dowjones.com

New Journal article: Forthcoming challenges in the management of STAT-C therapy

New article "Forthcoming challenges in the management of STAT-C therapy" published online in Digestive and Liver Diseases(full article available in PDF format as well). This is the first article I've seen addressing the importance pharmacokinetics in STAT-C therapy and applies some of what we've learned from HIV antiretroviral therapy. Definitely worth a read - Cmin/IC50 ratios DO matter!!

Forthcoming challenges in the management of STAT-C therapy

Raffaele Bruno, Serena Cima, Laura Maiocchi, Paolo Sacchi

Received 22 July 2010; accepted 9 September 2010. published online 27 October 2010.
Corrected Proof

Abstract

Agents that specifically target the replication cycle of the virus [specifically targeted antiviral therapies for hepatitis C (STAT-Cs)] by directly inhibiting the NS3/4A serine protease, the NS5B polymerase and NS5A are currently in clinical development. The need to achieve serum drug concentrations able to suppress viral replication is a key factor for a successful antiviral therapy and the prevention of resistance. Thus pharmacokinetics parameters became important issues for drugs used in the therapy of hepatitis C. The ratio of Cmin/IC50 (inhibitory quotient or IQ) can provide a surrogate measure of a drug's ability to suppress HCV replication, by taking into account the relationship between plasma drug levels and viral susceptibility to the drug. Ritonavir boosting may be a useful strategy to improve pharmacokinetic parameters. Characterising resistance to STAT-Cs in clinical trials is essential for the management of a drug regimen to reduce the development of resistance and thereby maximise SVR rate. The lesson of HIV therapy, provide a compelling case for the exploration of combinations of direct-acting antiviral agents.

Boosted HCV proteases in the STAT-C era - what can we learn from HIV?

I'm far from a pharmacologist and nowhere near being an expert in pharmacokinetics, but my rudimentary view, based on this report Jules Levin did on a session addressing ritonavir boosted HCV PIs from the 5th International Workshop on Hepatitis C Resistance and New Compounds last summer in Boston, is that we certainly could learn a thing or two taught from the lessons of boostings past. Boosting HIV protease inhibitors with a sub-therapeutic dose of ritonavir was a break through in the fight against HIV. Boosted PIs allowed for a 'PK cushion' when it came to trough levels... that is, when the PI was at its lowest concentration in the body - usually just before the next dose - it was still well above the IC50 of the virus thanks to the metabolic inhibition provided by ritonavir. This cushion prevented sub-therapeutic levels of the drug which could lead to viral resistance. As an added benefit, this also allowed for less frequent dosing and a sometimes drastic reduction in pill count - hopefully, one could argue - leading to an improvement in patient adherence. The dark side of ritonavir boosting is the remote possibility that even a sub-therapeutic dose could lead to the development of HIV resistance, tolerability is still an issue, increased trigylcerides, kidney toxicity and the fact that an essential metabolic enzyme, CYP 450, an enzyme responsible for the metabolism of many common drugs, not just HIV protease inhibitors, was effectively being inhibited as long as the patient was on therapy. Drug-drug interactions are a major problem in boosted PI HIV therapy, and will continue to be.

So all of the above might be applicable to ritonavir-boosting of HCV protease inhibitors as well… at least some of them. Telaprevir, despite what was shown in vitro, doesn’t respond to ritonavir boosting in vivo, at least for the long haul. Experts are still speculating on the exact reasons why – perhaps an inhibition/induction mechanism on the part of Telaprevir or some secondary mechanism of metabolism. The good news is that some initial data shows Telaprevir may not actually need to be boosted in a majority of patients, still showing some remarkably good mean concentration levels at trough even with q12h dosing. What still hasn’t been shown – at least to my knowledge – is the range of intra-patient variability from that mean. From the HIV PI history books, we know that there is usually a wide range of variability when it comes to pharmacokinetics dependent on a range of host factors. Even though it looks like HCV resistance might not mean a whole lot in the long run - the jury is still out – if the risk of being on the wrong end of that PK curve can be avoided, then it should certainly be a priority to do so.

Danoprevir and ABT-450, among others, are HCV protease inhibitors that appear to benefit from ritonavir boosting or even require it. In fact, Roche changed the dosing in their INFORM-2 Phase I trial of Danoprevir to include ritonavir boosting - but we need to see more data before the final judgment. Where the therapies for HIV and HCV differ, however, is that the HCV patient will only be on a boosted PI regimen for a short period of time, vs the HIV patient who is on the drug indefinitely so some of the long term metabolic effects of being on a boosted PI may be avoided. Still, drug-drug interactions are a concern as is the safety of a patient on a boosted HCV protease inhibitor with renal and/or liver insufficiency.

Could the benefits outweigh the risks in using ritonavir to boost HCV PIs? It’s definitely a tough call at this point and any judgment would be highly theoretical given the relative shortage of data in this area. As new data emerges, we’ll get a better idea of any clinical benefit or potential safety risks for the HCV patient in this brave new era of STAT-C therapy. My semi-educated gut feeling is that boosted PIs will offer some benefit with providing a “PK cushion” thus a leg-up in preventing resistance… but will that be enough to actually prevent resistance given a rapidly replicating virus that can make every conceivable combination of mutations in the course of one day? Does a boosted HCV PI plus a nuc or non-nuke backbone present enough of a barrier to prevent resistance given the variables such as intra-patient PK variability, drug interactions and adherence issues? Will interferon and ribiviran still be needed to shore-up any gaps left by STAT-C therapy? How about next generation metabolic blockers like Gilead's Cobicistat now in development? Only time - and solid empirical data - will tell.