Alinia undergoing trials for Hep C

[alagirl]

Of course, I am hopeful that my hep c will clear with regular combo therapy.  However, I recently came into contact with a girl from Romark whose mother has Hep C.  Romark is trials both with Alinia in conjunction with interferon alone, as a monotherapy by itself, and as an adjunct to the the combo therapy.  Alinia is an already on the books drug FDA approved for treatment of giardia, which I believe is a parasitic intestinal disorder.  Which means that until the FDA approves it. treatment of Hep C outside the studies would, I suppose, be off-label.  I am posting this info for those who relapsed after first tx to see if anyone else has heard about this tx/drug.

http://www.romark.com/news/08152007.aspx

http://www.prnewswire.com/cgi-bin/stories.pl?ACCT=104&STORY=/www/story/01-10-2006/0004246208&EDATE=

[CockSparrow]

Alinia has been discussed here a few times.
Some think why bother there are better drugs around the corner.
Me I like the sound of it. Has something to do with the fact that its anti HCV qualities were found accidently.
You are right about Alinia being used to treat Giiardia and other intestinal parasites. Its found in the water supply btw.

I dont like what I here about the trials of it though. Mono anything doesnt work. The virus has a habit of building resistance to any single drug.

As you are still in the Acute stage your chance of SVR is excellent with the current drugs.
CS

[Forseegood]

well said.

alagirl: thanks for posting this!

[alagirl]

sorry, didn't know it had been posted before.  I saw that it was being mono tested, but the good thing is they are now testing it with the combo therapy for those refractory to tx.  Now obviously I also think my chances are excellent for clearence with combo alone due to being acute and low viral load.  However, I had posted this for those who aren't in my shoes and ALSO just because I am looking down the road for myself just in case.

I was also thinking that since God knows how long it takes FDA to pass these things since this drug is already approved for one use, it is also worth mentioning that this drug is approved for another purpose.  My mind wanders way ahead and I think of crazy things like, I could get my doc to give it to me for one thing and use it for another, just stupid stuff I know.

But, I don't like mono-therapy anything either.  I am in absolutel agreement with you there.  The girl my best friend ran into is a neat girl though my best friend's online college class in one of her courses.  They were just all sharing one Unique thing about themselves and this girl - first name Grace - I won't for her confidentiality say her last name was saying she was excited about the new trial they are doing with the combo therapy plus her own company's Alinia because her own mother has entrenched Hep C that is refractory to the combo tx alone and since her mom is a family member of someone working for romark (her own company) I don't believe she was able to get her into her company's trials (Grace works for Romark).  I have since spoken with her via email (as soon as my best friend found out about the research she got my permission to put us together, and I of course said yes [of course she emailed her, she didn't like post it in the class or anything]).

Anyway, very nice girl for a pharmaceutical company person, I guess I was expecting somebody really cold or something but she really believes in their work or seems too.  I wanted to know if anyone else had heard about this drug and if anyone was in this study here but I didn't know it had been posted about before.  I guess I can search archives on this site?  Duh?  Sorry lol

I think I have read just about every study on hep C that has been published in the past 10 years that I can find online but I had not heard of this particular drug prior to talking with her.  It's a pretty interesting subject just from an academic standpoint, even if I weren't now an acute patient myself.  I pretty much address any health issue in this manner (yeah.  that's right, I'm a control freak lol ;)~ I know, I know - It just helps me FEEL in control the more knowledge I have even though I am not really IN any more control, you know?)

[debnevada]

I did know that there had been discussion about it before but this kind of new insight always spurs interest from the group here again.  And great discussion.

Good post, thanks for doing it...

deb

[TnHepGuy_]

I think the Alinia research certainly looks promising. And it will be interesting to see the results of the STEALTH C-1 trail (though it is comprised striclty of geno 4's). The US Phase II (STEALTH C-2) is of geno 1 non-responders to current SOC - a tough group to re-tx, so the results from this will be very interesting (and skewed downwards, most likely, when compared to a tx-naive group). Perhaps they will a a tx-naive arm in any Phase III.

Also interesting is that they will start the patients off on 4 weeks of mono-Alinia, before moving on to full triple-tx. This, too, could very well skew the results downward given that hitting the virus up-front with all three at once would seem - in practicality - to be have the most potent approach.


TnHepGuy

[willing]

yeah, I'm also in the alinia fan club. Any drug that's already cleared  FDA hurdles, has minimal sides/toxicity and interferes with the HCV replication cycle looks interesting regardless of its monotherapy eradication potential.

[Hepatitis Researcher]

Abstract 178 of the AASLD contains the results of a 48wk SOC vs 48wk Alinia plus 36wk SOC study. End of Treatment results are given as %  10Iu PCR negativity. 50 vs 93.  120 pt.Geno4. No added sides from Alinia. Results are quite astounding.

[Hepatitis Researcher]

Abstract 178 of the AASLD contains the results of a 48wk SOC vs 48wk Alinia plus 36wk SOC study. End of Treatment results are given as %  10Iu PCR negativity. 50 vs 93.  120 pt.Geno4. No added sides from Alinia. Results are quite astounding.

[mremeet]

Well hot damn!! I've heard about alinia, but only dribs and drabs in the background. I never had any idea it may have the kind of potential suggested in the references above. And really good to hear from you HR, thanks for the update! Man, Jeffrey Boger must be poopin' his pants right about now if this thing is what it looks like it might be. Got to keep an eye on vertex stock, I suspect this won't be good for it. If this doesn't turn out to be some kind of false alarm, it's history in the making!

Travelmom and dointime??? Take a gander at this stuff!!!

[jmjm530]

Good to see you contributing again. Do you have a link to the study, or to the AASLD abstracts?

I'm assuming that "90%" was a SVR rate from 48 weeks of Alinia followed by 36 weeks of SOC? Did they have a 24 week SOC group?

We need all the help we can get, but in weighing one treatment against another (of course they may end up combined) where I come out is that the least amount of time exposure to interferon the better. The thing that appears to stand out about Teleprevir is that it appears to work with only 24 weeks of SOC, and according to something recently posted here -- even less exposure to interferon (down to 12 weeks) may be possible for those with a very rapid viral response.

All the best,

-- Jim

[Forseegood]

also, in case anybody is wondering and I think this info is useful, don't think he put it in his post, HR told me that it really doesn't matter what genotype you are, the Alinia works in a different way then SOC...

[Forseegood]

unless he's going to contribute again, which would be great, he told me that this was sent out to docs, whatever, and that it isn't widely published as of yet...and I think, don't quote me, it was the inverse, with the  Alinia starting after SOC...hopefully, he'll come back on to answer you more thoroughly...

[jmjm530]

It makes more sense that they would have started with Alinia, but also of interest is whether these are SVR results and whether less than 36 weeks of SOC was tested in conjunction with Alinia and if so, what were the results. Hopefully HR will contribute cause I don't have as much time to research things out myself these days.

-- Jim

[Hepatitis Researcher]

3arms : Randomized. First arm SOC 48wks. Second arm 12 wk Alinia mono then ADDED 36wks of Alinia +Peg2a. Third arm 12 wk Alinia mono then ADDED SOC (peg+riba) plus Alinia  for 36wks. Results are End of Treatment response (EOT), defined as PCR negativity immediately after EOT. No SVR data available yet.
No link possible, you have to be subsribed to hepatology, this might change in a few days.

[Forseegood]

youre making me look like a ninny here! lol...or more then usual anyway, glad YOU posted!!!

[jmjm530]

Thanks. But what's confusing is what appears to be 50% EOT negativity for SOC per your previous post. 50% is the approx SVR rate for SOC, and I would imagine that the negative EOT negativity rate would be closer to 80% for SOC with 30% then relapsing after the treatment drugs are stopped.

-- Jim

[jmjm530]

For those interested, you can purchase 24-hour access to the article in question for $25 here: http://tinyurl.com/3x4q7m

[Hepatitis Researcher]

Yes, you might expect a higher EOT from SOC. I just quoted the facts as displayed in the abstract. There will be a presentation of this trial on Tue, Nov 6 in the Hynes Auditorium at 11:15.The auditorium will have questions like this to the presenter.

[willing]

thanks for pointing this out. It does indeed look  a very  promising addition to the tool bag. The center where I see a liver specialist is one of the recruiting centers  for the US study and I asked about participation but was turned down as a relapser rather than  a non-responder.  Given my interest in combo tx I have to ask  why at this point wouldn't that study not  also  include a vx+soc+ntz branch?.

Anyway, it also looks  like progress has also been made in determining the mechanism of ntz's anti-viral action. It seems surprising that the non-naive results are so different from the naive given that blocking viral protein synthesis is presumably independent of ifn resistance. The 50% SOC/EOT does looks a bit strange - I wonder is that just reflects the fact that these are ITT numbers and the completion stats are not given.  The abstract and data below , hopefully with just enough mods to avoid copyright infringement:

Nitazoxanide (NTZ), a thiazolide anti-infective agent approved in the United States for treating emerging intracellular protozoan infections, blocks viral protein synthesis at a cellular level by selectively inhibiting dephosphorylation of eukaryotic initiation factor 2α (eIF2α). A randomized controlled clinical trial was conducted to evaluate the efficacy and safety of NTZ added to peginterferon α-2a (PegIFN) plus ribavirin (RBV) or PegIFN without RBV in treating chronic hepatitis C genotype 4.

Methods. 120 patients with chronic hepatitis C genotype 4 were enrolled in the trial at two centers in Egypt. Liver biopsy was obtained from each patient before enrollment. Patients were sequentially randomized to one of three treatment groups: (a) PegIFN-RBV for 48 weeks (standard of care),
(b) NTZ monotherapy for 12 weeks followed by NTZ-PegIFN for 36 weeks, and
(c) NTZ monotherapy for 12 weeks followed by NTZ-PegIFN-RBV for 36 weeks.

Eleven interferon-experienced patients were allowed to be enrolled in each of the two NTZ groups. NTZ was administered one 500 mg tablet twice daily with food; RBV was administered 1000 mg (weight <75kgs), or 1200 mg (≥75 kgs) daily in divided doses; and PegIFN was injected by clinical investigators once weekly (180 μg). Evaluations performed every 4 weeks during treatment included physical examination, standard laboratory hematologic and chemistry tests and determination of HCV viral load by RT-PCR. The primary endpoint of the study is SVR (HCV RNA <10 IU/mL 24 weeks following end of treatment). Secondary endpoints include RVR (HCV RNA <10 IU/mL after 4 weeks of combination therapy), EVR (≥2 log10 drop in HCV RNA after 12 weeks of combination therapy) and ETR (HCV RNA <10 IU/mL at end of treatment). Analysis is intent to treat.

Results. Baseline viral loads, BMI, fibrosis, age, sex and other demographic and disease-related characteristics were similar across the three groups. RVR, EVR and ETR rates are presented in the table below. Adverse events were similar across the three treatment groups except that the rate of anemia was significantly reduced
in the group that did not receive RBV. Conclusions. The addition of NTZ to PegIFN or PegIFN-RBV improved RVR, EVR and ETR rates compared with PegIFN-RBV therapy without increase in adverse events. Patients are being followed to evaluate SVR rates. Further trials are being conducted in the United States in patients with genotype 1.

Data:   RVR-EVR-ETR (% in paren)
naive :
soc            14/40(35) 26/40(65) 20/40(50)
ntz+peg        18/29(62) 22/29(76) 20/29(69)
ntz+soc+rbv    21/29(72) 26/29(90) 27/29(93!!!!!!!)

exp:
ntz+peg         5/11(45)  5/11(45) 5/11(45)
ntz+peg+rbv     3/11(27)  4/11(36) 4/11(36)

[GoofyDad]

On the question of EOT UND of 50% - Geno 4 is an interesting bug, and apparently less responsive to SOC that GT 1 (www.hivandhepatitis.com/hep_c/news/2007/071007_b.html):

However, SVR rates were higher in patients infected in Egypt, compared with those infected in France or Africa (54.9%, 40.3%, and 32.4%, respectively; P < 0.05).

• In a multivariate analysis, the 2 factors independently associated with SVR were infection in Egypt and absence of severe fibrosis.

Conclusion

In conclusion, the authors wrote, "the distribution of HCV-4 subtypes varies with the geographical origin of transmission and affects the SVR following antiviral treatment."

[jmjm530]

This suggests that genotype 4 is *more* responsive to treatment than genotype 1.
http://tinyurl.com/2xjbty Specificiallly 77 per cent EOT response and 68 per cent SVR with SOC. That puts it closer to genotype 2 in terms of response although apparently genotype 4 is understudied.

It will be interesting to see full-text on the study in question as to patient population, ribavirin dosage as well as compliance rates, etc. While I have no knowledge, I'm guessing the trial was held out of the country due to the low numbers of genotype 4's in this country.

-- Jim

[geterdone]

Kind of found this instering as well. From 2005

jasper

JOHNS HOPKINS TEAM FINDS "ANCESTRAL" HEPATITIS-C VIRUS AT THE ROOT OF EVOLUTION IN ACUTE AND CHRONIC INFECTIONS
-- Scientists discover how virus evades immune system in acute and chronic infections; new vaccines may result

Researchers at Johns Hopkins have uncovered how a majority of the genetic changes in the hepatic-C virus, the most common cause of liver disease, allow it to evade the body’s immune system during infection.  Hepatitis C infection can lead to cirrhosis, cancer and even death.  In a series of experiments that describe the virus's transition from an acute to chronic infection, the Hopkins team found that one-half of the virus's changes in its genome are in sites under attack by the body's immune system.  As the virus evolves and these changes weaken the body's immune response, a second set of changes at other sites in the genome are reverting back to an "ancestral" set of amino acids.  

"We think this piecemeal exchange is helping the virus evade the body’s immune system," says study investigator and infectious disease specialist Stuart Ray, M.D., an associate professor at The Johns Hopkins University School of Medicine.  "In a newly infected person, the virus may need to adopt new mutations to escape recognition by the immune system's T cells, which fight infection, but it may need to lose the mutations that had protected it in someone else.  Despite pressure to change, the virus is always is restoring its shape."

The Hopkins findings, published in a pair of studies in the Journal of Experimental Medicine this week, are believed to be the first description of the precise genetic changes taking place in the virus during the acute phase of infection, when hepatitis C initially escapes the body's defenses and establishes itself in the body.  As the infection moves into the chronic stage, the immune response becomes weak and less effective, but until now, no one could explain exactly why.  

A second, related experiment produced similar findings when the Hopkins team partnered with researchers in Ireland to perform what is believed to be the first comparison of genetic changes across multiple genes in strains from chronically infected people to the original strain that infected them.

Ray, who served as senior investigator on the first study and led the second, believes the newly identified ancestral component of the viral genome, called a consensus sequence, could serve as the basis for development of a vaccine that is effective against both acute and chronic infections, thereby stemming the epidemic that currently afflicts more than 170 million people worldwide, including 3 million Americans.

"Hepatitis C is extremely difficult to treat if it becomes chronic," says infectious disease specialist Andrea Cox, M.D., Ph.D., an assistant professor at Hopkins who was lead author of the first study.  "While approximately 30 percent of patients have a strong enough immune response to rid themselves of the virus during the acute phase, and current treatments are 90 percent effective at treating any remaining acute infections, these treatments are only 50 percent effective against chronic infections, which otherwise persist for life and can cause death."

According to Cox, the hepatitis C virus naturally mutates, or alters its genome, very rapidly.  Its strains have two to three times more genetic variability, for example, than HIV, the virus that causes AIDS, and hepatitis C reproduces more than 100 billion times per day, 100 times faster than HIV.  Compounding the problem, the infection is asymptomatic in the acute stage, making it less likely that diagnosis will be made early, when it is easiest to treat.  

Conventional wisdom, the researchers say, was that the large numbers of mutations were simply random in the virus's ever-changing genome, but the new study suggests that Darwinian genetic selection is at play.  That is, the virus's genome changes in ways that make it more reproductively "fit" in the face of each immune system it encounters, changing what is must to evade the immune system in one host, then restoring itself when the pressure is off.  

What Ray's team found when the immune response weakens was that the virus naturally mutates toward a set of 3,000 common amino acids, what the researchers considered the virus's most preferred state.  During the acute phase, Ray says, the virus is under severe pressure from the immune response and forced to drift away from the consensus sequence, using mutations to evade the immune response.  However, the drift was reversible and, once the virus successfully evaded a particular immune cell, its amino acids reverted back to the consensus set.

[geterdone]

To assess the genetic changes in the early stages of infection, the researchers decoded, or sequenced, the virus's genome, made up of RNA, which is very similar to the more widely known DNA that makes up the genome of most organisms.  The RNA was gathered from eight newly infected patients in Baltimore, Md., all of whom were offered treatment and were participants in a larger study of infectious diseases in intravenous drug users.  The sample group was unusual, allowing analyses before and during the early stages of infection.  One patient self-recovered, while the rest proceeded to chronic infection.

Using advanced blood-sorting techniques, the Hopkins team extracted millions of immune system cells, including the system's principal fighters, called T cells, from blood samples taken between 30 days and six months after infection, when the body's initial immune response kicks in and subsequently peaks.

Immune responses were mapped using a series of more than 500 overlapping synthetic peptides, or strings of amino acids whose code was already known.  This allowed the researchers to compare changes observed in the RNA sequence to corresponding shifts in the body's immune response to the infection.  

When specifically recognized by T cells, the peptides trigger production of interferon gamma, a protein that acts as a signal to many other immune cells to respond to a new infection.  Reductions in the production of interferon gamma would indicate, the scientists say, that the immune system was weakening in its response to the virus's mutations.

After analyzing the genetic changes in the sites, called epitopes, where the T cells specifically bind to the virus, the researchers found no changes had occurred during the one year of follow-up in the one patient who self-recovered.  However, in the remaining seven patients, there were changes in 69 percent of T-cell epitopes, showing that the virus had mutated at key locations necessary for chronic infection to proceed.

Additional analysis showed that changes in T-cell epitopes were 13 times more frequent than changes in the remaining genome of the virus.  The researchers examined the binding ability of T cells obtained early in infection to recognize 10 viral peptides known to have changed during the first six months of infection.  Eight showed severely reduced capacity to stimulate production of interferon gamma, offering confirmation that the virus was mutating to evade the immune system.  

Analysis of the viral RNA in the blood of seven patients with chronic infections revealed that eight of 16 changes in genome matched to the consensus sequence, confirming the presence of selective evolutionary pressure toward restoration of an ancestral form of the virus.  

In the second study, using blood samples collected in Cork, Ireland, the researchers compared the genetic makeup of the virus in 22 chronically infected women to the original strain that had infected them more than 20 years before.  The women were among hundreds accidentally infected in 1977 by a blood product tainted with hepatitis C, providing the researchers with unique access to the source of the infection, which came from a single donor unaware of having the illness.  

Using computer analysis techniques developed at Hopkins, the scientists mapped these changes against the genetic makeup of the women's immune response.  The researchers found that when viral mutations were clustered in epitopes specific to each woman's immune system, the changes were directed away from the consensus sequence, suggesting immune escape.  However, when mutations were clustered in epitopes that were not specific, the mutations were reversions back to the consensus sequence.

When the individual genome changes in each woman were mapped on a grid, each woman formed a unique cluster indicating individual, evolutionary selection.  However, some of the changes were shared, suggesting convergence, which would not have occurred had the virus simply mutated at random.

"Our results raise the possibility that a hepatitis-C consensus sequence could be the best practical option for a vaccine," says infectious disease specialist David Thomas, M.D., a professor of medicine at Hopkins who served as senior author of the study of Irish women.  "If we can focus vaccine development on the common genetic element in chronically infected patients, then we may be able to make a more effective vaccine."

Funding for these studies, which took place from January 2002 to January 2005, was provided by the National Institutes of Health, including the National Institute for Allergy and Infectious Disease, and the National Institute on Drug Abuse.

Other Hopkins investigators in this research were Timothy Mosbruger; Qing Mao, M.D., Ph.D.; Zhi Liu, M.D.; Xiao-Hong Wang, M.D.; Hung-Chih Yang; Xiao-Hang Wang, Ph.D., Dale Netski, Ph.D.; and Drew Pardoll, M.D.  Co-investigators in the first study also included John Sidney, Ph.D., and Alessandro Sette, Ph.D., from the La Jolla Institute for Allergy and Immunology, in San Diego, Calif.  Collaborators in the second study, conducted at Hopkins and at Cork University Hospital in Ireland, were Liam Fanning, Ph.D., and Kelizaeth Kenny-Walsh, M.D.

Hepatitis C is the leading cause of liver disease in the United States, causing an estimated 10,000 to 12,000 deaths each year.  Hepatitis C is transmitted when blood and possibly other body fluids of an infected person enter another person, primarily through injection drug use, exposures in health care settings, from an infected mother to her baby during birth, and occasionally through sexual exposure.  Symptoms of hepatitis C may not appear for years after infection, and diagnosis must be confirmed by blood tests.  However, in addition to liver inflammation and tumors, earlier signs of infection are persistent flu-like symptoms, including any combination of body aches, headaches, night sweats, loss of appetite, diarrhea, fatigue, rash, nausea and mild abdominal pain.  Current treatments for hepatitis C involve weekly injections of pegylated interferon for one year, plus twice daily doses of oral ribavirin.  While some patients recover on their own, with their immune system attacking the virus and clearing it from the body, most do not.  Scientists have not yet determined why this happens in some patients and not in others.

[Willy50]

What a great thread!!  Thanks for the information.  93% rocks!!!!  It will be interesting to see the results in 12 weeks.

It's a topic for a different thread, but given the potential for shorter and more effective treatments at just what point does it seem silly to only do SOC?

What will be the effect of partnering in several of the new compounds?  

At what point might the NTZ (Alinia) be partnered with TVR or other newer compounds?

Thanks again, this looks very promising.

Willy