Forbes.com: Why A Change In A Bristol-Myers Hepatitis C Trial Has Big Implications

Posted 6/29/12 on Forbes.com . Commentary on the implications of BMS restricting enrollment in COMMAND-3 to subjects with genotype 1b, which makes up only 25% of the genotype 1 patients here in the US. Also see http://www.viralmatters.blogspot.com/2012/06/presidio-pharmaceuticals-completes.html on a tx-naive patient having baseline resistance to PPI-668, Presidio's NS5A inhibitor.

Why A Change In A Bristol-Myers Hepatitis C Trial Has Big Implications

Is a promising new class of drugs for treating hepatitis C going to be limited because patients with the most common genotype of the virus are likely to develop resistance to the medications? This is the possibility raised by a Wall Street analyst after learning that Bristol-Myers Squibb has altered the protocol for a clinical trial for its daclatasvir antiviral, which is believed to be the most potent in the forthcoming NS5a class of hepatitis c treatments.

According to ClinicalTrials.gov, the drugmaker changed the protocol to its COMMAND-3 trial, which compares its drug in combination with interferon and ribavirin to Incivek, a protease inhibitor sold by Vertex Pharmaceuticals, along with interferon and ribavarin. What was the change? Bristol-Myers restricted future enrollment to patients who have only genotype 1b HCV, rather than all genotype 1 patients (see this and this).

“This effectively eliminates from the trial the most common HCV genotype in the US – 75 percent of HCV is genotype 1 in the US, 80 percent of genotype 1 is genotype 1a,” Sanford Bernstein analyst Tim Anderson wrote in a recent investor note. “This change, some three months after the study started enrollment, suggests that some form of virologic failure has emerged in the patients with these genotypes… The NS5a class, as a whole, might be limited by the propensity to rapidly develop virological resistance, and by significant differences in potency from one viral genotype to another.”

He adds that the change in the protocol has “major strategic and tactical implications” for the hot and fast-growing hepatitis C market. How so? Several drugmakers are developing NS5a treatments and the possibility that these drugs generate resistance to the virus may prompt changes in how different types of medications are combined and, consequently, alter various corporate strategies for drug development, alliances and dealmaking.

Take Gilead Sciences. The drugmaker is developing an NS5a, which has the code name of GS5885, as well as another that is a nucleotide inhibitor, or nuke, which Gilead calls GS7977 and believes could be the cornerstone of the first all-oral regimen for hepatitis C. Gilead, you may recall, acquired GS7977 last fall as part of its $11 billion acquisition of Pharmasset, a bet that has transformed the investor view of the drugmaker (back story).

Two months ago, results of a study that combined daclatasvir with GS7977 suppressed hepatitis C in most patients four weeks after completing treatment, raising hopes about the prospects for a therapy that does not involve an injectable medication. But further collaboration between the two drugmakers appeared uncertain, because Gilead indicated a preference for developing its own NS5a drug with GS7977 (look here).

However, as Anderson notes, the Gilead NS5a drug is less potent than daclatasvir, which “increases the risk for Gilead of sticking with GS5885. On the Bristol side, their ‘go-it-alone’ strategy may be developing a hole, increasing the urgency of incorporating daclatasvir into an all-oral combination with a potent resistance-fighting nuke such as GS7977. This collaboration appears to have become more important to both parties,” he writes.

Both drugmakers declined comment on this topic, although late last month, Bristol-Myers ceo Lamberto Andreotti renewed a call for Gilead to jointly develop their hepatitis C medications. And Bristol-Myers has not responded to questions about the change in the trial protocol.

Looking ahead, Anderson sees greater potential for combination therapy that relies on three drugs, instead of two, including GS7977 from Gilead, since the response to NS5a drugs suggests there can be limitations to at least one of the agents that drug developers would want to use in a one-two punch. And he believes Gilead’s prospects for creating one “super-regimen” for all subtypes with GS7977 and GS5885 alone, or even with ribavirin, have fallen.

As for other drugmakers, the questions concerning the NS5a drugs may result in slightly extended utility for Incivek as well as Victrelis, another protease inhibitor that is sold by Merck. This also suggests additional jockeying surrounding the NS5a drugs being developed by Achillion Pharmaceuticals and Idenix Pharmaceuticals, since larger drugmakers may decide to adjust their strategies and portfolios in response to the changing dynamics of this class of treatments.

Presidio Pharmaceuticals completes Phase 1b proof-of-concept trial with HCV NS5A inhibitor PPI-668...

Posted 6/26/12 on Market Watch.com.  San Francisco's Presidio Pharmaceuticals successfully completed it's Phase 1 Proof-of-Concept trial for it's (perhaps pan-genotypic) HCV NS5A inhibitor, PPI-668. The data was convincing enough for the company to slot PPI-668 for Phase II trials, although in what combination remains a mystery. One patient in the highest dose group (240mg) was found to be fully resistant to PPI-668 at baseline - a little worrisome given that these were treatment-naive genotype 1 subjects. This may or may not provide insight into why BMS narrowed enrollment to it's COMMAND-3 trial with daclatasvir to genotype 1b subjects. 


SAN FRANCISCO, Jun 26, 2012 (BUSINESS WIRE) -- Presidio Pharmaceuticals, Inc. announced today successful completion of Phase 1b clinical testing of its lead HCV NS5A inhibitor in patients with HCV genotype-1 infection, with positive efficacy and safety observations supporting advancement of PPI-668 to Phase 2 combination studies.

The randomized, blinded Phase 1b trial of PPI-668 involved sequential cohorts of treatment-naive HCV genotype-1 patients who received oral doses of PPI-668 of 40, 80, 160 or 240 mg, once daily for three consecutive days. Within each 10-patient cohort, patients were randomized 8:2 to PPI-668 or placebo.

In all of the Phase 1b dose cohorts, PPI-668 was well tolerated with no serious or severe adverse events, no premature treatment discontinuations and no apparent pattern of treatment-related clinical side effects or laboratory abnormalities.

The Phase 1 clinical results indicate that PPI-668 had a favorable pharmacokinetic (PK) profile that included rapid achievement of high (micromolar) plasma levels, prolonged maintenance of potentially effective levels between doses, and achievement of steady-state pharmacokinetics after the first dose.

The Phase 1b efficacy observations indicated consistently rapid, marked reductions in patients' serum viral load (HCV RNA levels), that were dose-related. Patients' HCV RNA reductions typically exceeded 3 log10 IU/ml (99.9%) by Day 2. During the 3-day treatment period, mean maximal HCV RNA reductions for the 4 dosing groups were:

-- 3.2 log10 IU/mL in the 40 mg dose group

-- 3.5 log10 IU/mL in the 80 mg dose group

-- 3.5 log10 IU/mL in the 160 mg dose group

-- 3.7 log10 IU/mL in the 240 mg dose group

There was only one minimal-responder in the trial. A patient in the 240 mg dose group was found to be fully resistant at baseline with 100% of this patient's pre-treatment HCV RNA containing 3 genetically linked NS5A resistance mutations. This patient was excluded from the efficacy analysis of the 240 mg cohort, since he was pre-resistant and could not contribute to dose-response inferences.

Five other patients with detectable resistance mutations at baseline, including those harboring the relatively common L31M variant, responded well to PPI-668 treatment, with multi-log HCV RNA reductions.

A protocol amendment has been completed to explore the pan-genotypic clinical efficacy of PPI-668 in HCV genotype-2a/3a patients. Recruitment is currently underway for this added cohort.

"The rapid 3.5 to 3.7 log10 HCV RNA reductions observed with PPI-668 at the three higher dose levels and the encouraging safety profile support advancement of PPI-668 to Phase 2 combination studies with other promising HCV antiviral agents," said Nathaniel A. Brown, M.D., Presidio's Chief Medical Officer. "The PK profile of PPI-668 appears to be a major factor in its efficacy profile, with rapid achievement of potentially effective plasma levels and with inter-dose plasma concentrations exceeding those needed to inhibit both wild-type HCV and many naturally-occurring HCV variants."

Detailed results of the completed trial are expected to be presented at a scientific meeting in the fall of 2012.

About Hepatitis C

Chronic hepatitis C is a progressive inflammatory liver disease caused by chronic infection with the hepatitis C virus (HCV). Approximately 170 to 200 million persons have chronic HCV infection worldwide, resulting in more than 350,000 deaths annually.

The current standard treatment for patients with hepatitis C genotype-1 infection in the United States and several other countries is combined administration of pegylated-interferon-alfa, ribavirin, and an HCV protease inhibitor. This treatment is characterized by incomplete efficacy and severe side effects in some patients.

There is a continuing need for all oral, more consistently effective and better tolerated antiviral combinations for HCV infection, regardless of HCV genotype, patient genetic factors, or disease stage.

About Presidio

Presidio Pharmaceuticals, Inc. is a San Francisco-based clinical stage specialty pharmaceutical company focused on the discovery and development of novel oral antiviral therapeutics. For more information, please visit our website at: www.presidiopharma.com

SOURCE: Presidio Pharmaceuticals, Inc.

Journal of Clinical Virology - "Analysis of long-term persistence of resistance mutations within the hepatitis C virus NS3 protease after treatment with telaprevir or boceprevir"

Lovingly pinched from the great NATAP.com - coverage of a study appearing in the 'Journal of Virology' looking at long-term resistance in patients who experienced viral break-through or relapse in the early phase trials of Telaprevir and Boceprevir.  The authors follow 28 patients (14 each for Telaprevir and Boceprevir resistance) a median of 4.2 years post-therapy.  Resistant variants of varying levels were discovered in 2/14 subjects exposed to Telaprevir and 4/14 exposed to Boceprevir. Surprisingly, the dominant quasispecies uncovered during sequencing done at end-of-treatment didn't always match the quasispecies sequencing done at follow-up - whether this was due to the highly replicative nature of the HCV virus, re-infection or some other phenomena, I'm not sure.  


HCV resistance doesn't get a lot of press time, but it's really a critically important issue - most importantly because no one understands it all that well. The jury is still out on re-treatment (and who'd want to do THAT again??).  Sequential therapy with custom-tailored regimens that lack cross-resistance looks to be the logical answer to treatment failures on first generation treatments like Telaprevir and Boceprevir. It looks like we'll have a broad array of potent compounds within differing classes with differing resistance profiles to choose from in the long run, which is fantastic news. In the short-term, it's an issue however.  The patients currently waiting for effective 2nd-line sequential therapy, unless they are enrolled in a clinical trial, may have to wait awhile until other options come to the market. 


There aren't any easy answers until researchers really understand HCV resistance and all it's implications. The best treatment options, in my very humble opinion, would be treatments that don't run the risk of resistance.  Virtually ignored by the press and investors alike was pegylated interferon lambda which garnered impressive results without running the risk of viral resistance. Another contender with a decidedly lower opportunity for resistance are cycophilin inhibitors, which have been regulated as the ugly step-sister of Direct Acting Antivirals drug classes.  It might be time to take a longer, more holistic view on HCV resistance and take a second look at compounds that have the potential to cure patients with less chance of incurring resistance issues that might become more complicated as time goes on. 

Analysis of long-term persistence of resistance mutations within the hepatitis C virus NS3 protease after treatment with telaprevir or boceprevir

 Journal of Clinical Virology 52 (2011) 321- 327

Simone Sussera , Johannes Vermehrena , Nicole Forestiera , Martin Walter Welkera , Natalia Grigorianb, Caterina Fuller a, Dany Pernera, Stefan Zeuzema, Christoph Sarrazina, a Klinikum der Goethe Universitαt, Medizinische Klinik 1, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany
b Universitαtsklinikum Homburg, Klinik fur Innere Medizin 2, Kirrberger Str., Homburg/Saar, Germany

Abstract


Background

Telaprevir and boceprevir are highly selective hepatitis C virus (HCV) NS3/4A proteaseinhibitors in phase 3 development. Viral breakthrough during mono- and triple-therapies with PEG-interferon and ribavirin and relapse is associated with resistance.

Objectives

Potential persistence of resistance mutations during long-term follow-up should be analyzed.

Study design

Clonal sequence analysis of the NS3-protease gene was performed at long-term follow-up in HCV genotyp-1 infected patients who received telaprevir or boceprevir within phase-1b studies for comparison with resistant variants present directly after the end-of-treatment.

Results

After a median follow-up of 4.2 years in 28 of 82 patients HCV-RNA was still detectable. Resistance variants were detected in two of 14 telaprevir- and in four of 14 boceprevir-treated patients. For telaprevir patients two low-level (V36M, V36A) and one high-level (A156T) mutation associated with resistance were detected at low frequencies (4-9% of the clones). In five boceprevir-treated patients four low level mutations (V36A, T54A/S, V55A) were observed at low frequencies (1-10%) while in one patient additionally a combined variant (T54S + R155K) was detected at 94%. Presence of resistant variants at long-term follow-up was not predictable by variants detected at the end-of-treatment. In one patient a V55A variant which was dominant already at baseline was still detectable at long-term follow-up.

Conclusions

In the majority of patients after short-term treatment with telaprevir or boceprevir wild-type NS3-protease isolates are detectable by clonal sequencing at long-term follow-up. Detectable resistance mutations in single patients are not predictable by initial frequencies of variants.

Clinical Care Options: "Importance of Pharmacokinetics and Adherence to Avoid Emergence of Resistant HCV Variants"

A new CCO module is available here, focusing on the importance of PK and compliance to regimens in an effort to stem HCV resistance. The parallels between HCV antivirals and the evolution of HIV antiretrovirals are becoming numerous. Pharmacokinetics, pharmacogenetics and pharmacodynamics will all increase in importance as HCV drug development marketplace continues to move forward and potentially become as competitive as the HIV marketplace was back in the mid-90's and 2000's.

APASL: Alisporivir Resistance/CC/TT Gt Phase 2b Study...

Lovingly swiped from the great NATAP.org newsletter - a report from intrepid advocate/reporter Jules Levin from the Asian Pacific Association for the Study of the Liver conference on Alisporivir (formerly known as DEBIO-025) resistance analysis from the ESSENTIAL study.  Alisporivir is a Cyclophilin Inhibitor under development by Novartis. I thought that this was an interesting poster, as viral resistance to the DAAs is somewhat uncharted territory/conveniently overlooked depending on your particular position. A solid knowledge base regarding HCV resistance will be essential to HCV drug developers in regards to successfully sequencing therapy to achieve and SVR in patients that have failed previous therapy.  Cyclophilin Inhibitors, long the unsexy underdog in HCV drug developmen,t may have an important role in possible interferon-free combinations. With Alisporivir's polymerase and protease inhibitor brethren,   genotypic resistance is the primary driver to viral resistance, thus breakthrough and relapse.  With the Cyclophilin Inhibitor class, it appears that a combination of suboptimal drug exposure, frequent PEG/RBV dose reduction or host factors seem to be the reason for the rare breakthrough seen in this particular study. This harkens back to HIV Antiretroviral 101 - drug exposure and adherence - and not just to Alisporivir, but to PEG/RBG as well  - is critical. This thinking should be applied to the current paradigm of DAA therapy with Boceprevir and Telaprevir as well to ensure successful outcomes.  

Subject: NATAP/APASL: Alisporivir Resistance/CC/TT Gt Phase 2b Study

Alisporivir, a Host-targeting Antiviral, in Combination with Peg-IFNα2a and Ribavirin Results in Superior SVR and No Viral Breakthrough in HCV Genotype 1 Treatment-naïve Patients of IL28B CC Genotype: Results from the Phase IIb ESSENTIAL Study

- see attached full poster report

Reported by Jules Levin

22nd Conference of the Asian Pacific Association for the Study of the Liver • February 16-19, 2012 • Taipei, Taiwan

Bin Li,1 Joke Snoeck,2 Yanhua Tang,1 Christopher T. Jones,1 Weibin Bao,3 Jing Yu,1 Yali Li,1 Anne-Mieke Vandamme,2 Gregoire Vuagniaux,4 Kai Lin1

1Novartis Institutes for BioMedical Research, Inc, Cambridge MA, USA; 2Rega Institute and KU Leuven, Leuven, Belgium; 3Novartis Pharmaceuticals, East Hanover NJ, USA; 4Debiopharm SA, Lausanne, Switzerland

SUMMARY

• Alisporivir (ALV)/Peg-IFN2α/RBV treatment achieved 100% SVR in patients of IL28B CC genotype in the RGT and ALV/48wks arms

• Nearly 70% of patients of CC genotype cleared virus within 4 wks of treatment and qualified for shortened therapy

• No VB was observed in any patient of CC genotype while on full dose of ALV treatment

• The rare occurrence of VB (patients of CT or TT genotype) was associated with frequent Peg/RBV dose adjustment or treatment stoppage, as well as suboptimal drug exposure

• Previously reported D320E (NS5A domain II) mutation emerged at the time of breakthrough in one patient (1/215), although phenotypic analysis revealed only ~3-fold change in susceptibility to ALV for clinical isolates harboring D320E

• Clinical data demonstrated virus harboring D320E was susceptible to ALV when exposed to sufficient drug level

• Unlike DAAs, VB in ALV triple therapy was not primarily driven by genotypic resistance; a combination o f suboptimal drug exposure, host factors and low-level of genotypic resistance may all contribute to VB

• Consistent with in vitro cross-resistance data, patients with preexisting resistance mutations to DAAs remained susceptible to ALV triple therapy, supporting combining ALV with DAA in IFN-free combination to treat HCV 

“No difference observed between GT1a and 1b: 1/43 GT1a and 5/172 GT1b patients had VB while on full dose of ALV”

New CCO Module: Update of HCV Resistance from AASLD 2011

New Clinical Care Options CME Module now online: Update on HCV Resistance from AASLD 2011
Christoph Sarrazin, MD, reviews new data on resistance to direct-acting antiviral agents from the 2011 American Association for the Study of Liver Diseases conference. (Registration required)

Topics covered include:

New data on resistance to boceprevir and telaprevir
New data on resistance to second-wave and second-generation HCV protease inhibitors
Key findings on resistance to daclatasvir, an NS5A inhibitor
Current understanding of resistance to PSI-7977, a nucleotide polymerase inhibitor
New data on resistance to oral combination HCV therapies

Clinical Care Options presents "Resistance in Hepatitis C"

A new CCO CME is online, this one taking a looks at Hepatitis C resistance in the era of the Direct Acting Anitivirals. Faculty includes Stephane Zeuzem MD, Stephane Chevaliez Pharm.D, Ph.D and Paul Pockros MD. Registration to CCO required.

Click here for the CME module

Sexual transmission of HCV virus more prevalent than previously thought....

(From the LA Times 'Booster Shots' blog, July 21, 2011. This type of thing isn't usually fare for the purposes of this group but I think it is significant in a couple of different ways - first, sexual transmission of the HCV virus is still inefficient, but it happens more than we previously though. Second, this opens up the possibility that transmission of fit drug resistant variants of the virus may be possible which is of major concern, especially in the HIV/HCV co-infected population where the progression of the disease is much more rapid. Currently, there is no sequential therapy for HCV and not likely to be until late 2013. - Chris)


By Thomas H. Maugh II, Los Angeles Times/For the Booster Shots blog
July 21, 2011, 11:12 a.m.

The hepatitis C virus, normally thought to be transmitted exclusively through blood — such as by sharing of needles among intravenous drug abusers — can also be transmitted through sexual activity, principally through anal sex among gay men, a growing body of evidence suggests. The most recent evidence was reported Thursday by New York City researchers who documented an outbreak of the virus, commonly known as HCV, among gay men.

Hepatitis C, which can cause severe liver disease and even death if left untreated, affects an estimated 3.2 million Americans. Many infected people show no symptoms, but others have severe disease that can require liver transplants. The infection can be cured in most people with a combination of the drugs pegylated interferon alpha and ribavirin, plus a recently approved drug called Incivek, but treatment is most successful when started early in the course of the disease.

Dr. Daniel Fierer, an infectious diseases expert at the Mount Sinai School of Medicine, and his colleagues first observed two cases of HCV that they believed to be caused by sexual transmission in late 2005. They requested referrals of similar patients. The team reported Thursday in the Centers for Disease Control and Prevention's Morbidity and Mortality Weekly Report that they found a total of 74 cases. All the men reported having receptive anal sex and none had any other risk factors for HCV, such as intravenous drug abuse. When the team compared the infected men to other gay men who were not infected with the virus, they found that those who became infected were 23 times more likely to have had unprotected gay sex and 29 times more likely to have had anal sex while using crystal methamphetamine. Moreover, genetic analysis showed that there were five separate clusters of the virus, indicating that the virus was getting transmitted through groups of interconnected men.

"While hepatitis C is not sexually transmitted among stable heterosexual couples, this is clearly not the case among HIV-infected [men having sex with men] in New York City," Fierer said in a statement. Such men, "and to some extent their healthcare providers, are generally not aware that having unprotected receptive sex can result in HCV infection .... Our study suggests that HIV-infected [gay men] should take steps to protect themselves and others by using condoms and by avoiding crystal methamphetamine."

Diana Sylvestre article on the possibilities of HCV resistance in underserved populations with the new DAA agents....

A sobering article on the very real possibility of HCV resistance developing in underserved population in the June 9, 2011 issue of NATURE by O.A.S.I.S. Executive Director, Diana Sylvestre. On a personal note, I had the great honor of calling on her while I worked at Vertex. Truly one of the most remarkably compassionate human beings I have ever met. Don't let that fool you, because I also had the experience of being with her when she stared down a former patient wielding a golf club. This is one tough lady.

Published online 08 June 2011

The hepatitis C virus is endemic among injection drug users, who could harbour treatment-resistant viruses. We need to adapt to this reality, says Diana Sylvestre

Diana Sylvestre informs her patient that the hepatitis C virus has re-emerged six months after treatment.

The first antiviral agents that act directly on the hepatitis C virus (HCV) are about to hit the market. Healthcare workers have been awaiting the release of these new medications for some time, in the hope that treatment response rates would improve, even in populations of patients who are challenging to treat. But underneath the glow of anticipation lies a concern about poorly characterized risks, including the emergence of drug-resistant viral strains. The real-world impact of this risk is unclear as most of those who contract the virus do so through injection drug use and are disregarded from clinical trails.

The new protease inhibitors can elicit resistance even in patients who follow dosing regimens. But when corners are cut, risk rises. Shortening treatment, as new regimens promise to do, might reduce the burden of side effects. But the day-to-day misery will be worse with triple regimens than with the standard dual treatment, and it is important to appreciate the human tendency to reduce or skip doses of medications that make us feel ill.

Injection drug users are more complex patients: many have an unstable housing situation, unreliable transport or subject to prescription refill delays owing to insurance company bungling, which they are poorly equipped to deal with. They might be arrested and jailed during treatment. So, even though studies have shown that injection drug users have similar medication compliance rates to non-drug users4, 5, 6, external circumstances may prevent the medication fidelity that is expected and needed.

So far, modestly reduced adherence to the interferon-α and ribavirin therapy has not led to viral resistance. Taking only 80% of the prescribed interferon and ribavirin dosages for 80% of the projected duration of treatment is sufficient to achieve optimal response rates. This allows those who treat injection drug users (including me) enough latitude to be successful. We have been able to reduce the burden of HCV in those who are most at risk of transmitting it.

Unfortunately, there is no such information on new treatment regimens. It is unclear at what point reduced adherence may become a problem. The virus rapidly mutates, so the antiviral 'pressure' exerted by the medication needs to be maintained so mutant viruses are constantly destroyed. Such protease-inhibitor-resistant strains can persist for at least three years after the withdrawal of medication1, 2, 3. And the conformational changes that underpin resistance to one protease inhibitor may also confer resistance to other inhibitors of that protease — a phenomenon called class resistance. And worse: if active injection drug users become reservoirs of protease inhibitor resistance, these viral strains could predominate, requiring the kind of therapeutic arms race that we see in other infections such as HIV and Staphylococcus aureus.

Regulators should require that clinical trials consider current or former injection drug users. This is not currently being done. The US Food and Drug Administration (FDA) Guidance for Industry document encourages trial sponsors to initiate trials early in drug development for “special populations” with unmet needs: transplant patients, people co-infected with HIV and HCV, and those with decompensated, or severe, cirrhosis. The document fails to mention injection drug users. It is as though they don't exist. If diabetics or out-of-care asthmatics were at risk, the approach would be different. Instead, the FDA has turned its back on the majority population with HCV and is approving new drugs despite having almost no understanding of their potential to cause long-term harm.

Because HCV affects those on the fringes of society, large-scale treatment studies have not been representative of the face of the disease. Their doctors are not invited to enroll them in trials. Therefore, little is known about which patients are good candidates for treatment, the importance of adherence to the treatment regimen and the outcomes in the real world — this ignorance leaves addicted HCV patients subject to the vagaries of a medical system that might not welcome them. This is unacceptable from both a humanist and a public-health standpoint.

It is time that regulators, pharmaceutical companies and healthcare workers come to terms with the fact that many patients with HCV are injection drug users. These patients must be included in safety, tolerability and efficacy trials; regulatory studies should include clinics where HCV-infected drug users are seen. And study investigators should be more representative of the kinds of doctors that usually care for these patients.

The new therapies raise the possibility of eradicating hepatitis C. But that won't happen unless the key parties in this medical drama develop a more realistic approach to understanding and treating this disease.

A mutation in Genotype 3a patients may explain lack of response to standard of care treatment...

(Study in 6 genotype 3a patients from the Virology Journal which probably wouldn't garner much interest other than the fact that the authors suggests that a mutation involving the substitution of glutamine (Q) with Leucine (L) in the one of the 3 breakthrough responders in the study made the area in question identical to the same region in HCV genotype 1a - maybe one clue as to why treatment in G3 patients is tougher than G2. Because of the mutation, the HCV virus may have the same ability to evade the immune system that we see in genotype 1a patients - Chris)

Hepatitis C is a major health problem affecting more than 200 million individuals in the world. Current treatment regimen consisting of interferon alpha and ribavirin does not always succeed in eliminating the virus completely from patient's body.

One of the mechanisms by which virus evades the antiviral effect of interferon alpha involves protein kinase (PKR) eukaryotic initiation factor 2 alpha (eIF2a) phosphorylation homology domain (PePHD). This domain in genotype 1 strains is reportedly homologous to PKR and its target eIF2a.

By binding to PKR, PePHD inhibits its activity and therefore cause virus to evade antiviral activity of interferon (IFN). Many studies have correlated substitutions in this domain to the treatment response and lead to inconclusive results.

Some studies suggested that substitutions favor response while others emphasized that no correlation exists. In the present study we therefore compared sequences of PePHD domain of thirty one variants of six hepatitis C virus patients of genotype 3.

Three of our HCV 3a infected patients showed rapid virological response to interferon alpha and ribavirin combination therapy whereas the remaining three had breakthrough to the same combination therapy. It is found that PePHD domain is not entirely conserved and has substitutions in some isolates irrespective of the treatment response.

However substitution of glutamine (Q) with Leucine (L) in one of the breakthrough responders made it more identical to HCV genotype 1a. These substitutions in the breakthrough responders also tended to increase average hydrophilic activity thus making binding of PePHD to PKR and inhibition of PKR more favorable.

Author: Samia AfzalMuhammad IdreesMadiha AkranZunaira AwanBushra KhubaibMahwish AftabZareen FatimaSadaf BadarAbrar Hussain
Credits/Source: Virology Journal 2010, 7:377

Lab21 secures new patents in Hepatitis C drug resistance and fluorescent carbon-based nanoparticle technology

Diagnostics for HCV resistance seems to me to be a lucrative niche to fill with the up coming small molecules for HCV. Lab21 looks fully poised for growth with both this and other diagnostics related to personal medicine - Chris

Cambridge, UK, December 8th - Lab21 Limited, the Cambridge, UK-based specialist in personalised medicine has secured new patents in Europe and the USA relating to Hepatitis C and its SelahDOTS™ fluorescent nanoparticles, as it continues to expand its intellectual property portfolio.

The hepatitis C patent extends an existing patent, and refers to technology allowing the genotypic identification of drug resistant mutations in the 4 major global genotypes of HCV. With the imminent launch of a series of new small molecule therapies in HCV, this technology will allow accurate monitoring of when drug resistance appears in individual patients, improving patient care.

The SelahDOTS™ nanoparticles technology covers a generic approach to the development of new diagnostic and imaging reagents using carbon-based non-toxic nanoparticles. This platform technology has multiple applications in clinical diagnostics and was originally developed through a licence from Clemson University. The grant of the patent now allows Lab21 to develop a series of new product and service applications in areas such as in vivo imaging, immunodiagnostics and point-of-care biomarker analysis,

The securing of these patents builds on Lab21’s growing intellectual property portfolio as it expands its competitive proprietary position in pharmacogenetic markers, disease markers and its assay technology.

Dr Berwyn Clarke, CSO at Lab21 commented: ‘The HCV patent further strengthens our portfolio in the important HCV diagnostic area while the nanoparticle platform technology has potential to transform the ways in which particulate diagnostics are used, particularly in vivo, where particle-related toxicity has been a significant problem. Additionally we are seeing early development progress in incorporating the SelahDOTS™ technology in our own new molecular and protein based assays’

Graham Mullis, Lab21 CEO added: ‘The development of an extensive intellectual property portfolio will be an important part of Lab21’s strategy as we continue to grow. Patents such as these will ensure we are able to remain uniquely competitive and ensure we are able to provide our customers with the most advanced products and services in the markets we choose to serve.’