HR et al. Alinia lowdown from AASLD?

Any comments or info on Alinia as a adjunct to SOC?

[Forseegood]

hate to talk for anybody else, but it can get tricky when a person, who is not exactly a layperson, by any means, but isn't your personal physician either, gets into recommendations    of certain unproven protocols, etc., on a public forum. Even diagnosing from a distance, lol... I'm sure you can understand a person's trepidation on this. (Trying to make this as general as possible, not doing a very good job of it though.) Hopefully, some general comments will be forthcoming though, from anybody with any info. That's just my take.

[gauf]

I get it. lol

[Forseegood]

this is the info for Romark Patient Assistance Program - Alinia
3000 Bayport Drive Su 200
Tampa, Fl 33607

Phone [phone]    Fax [phone]

[TravelMom]

There is some real hope for Alinia...here is some info:

Romark Initiates Clinical Trial of Alinia for
Chronic Hepatitis C in the United States

International Clinical Data to be Presented at the 58th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)

TAMPA, Fla., Aug. 15 -- PRNewswire -- Romark Laboratories announced that it has initiated a phase II clinical trial of Alinia (nitazoxanide) for treating chronic hepatitis C in the United States.

The clinical trial is designed to evaluate the effectiveness and safety of Alinia tablets administered in combination with Pegasys (peginterferon alfa-2a) and Copegus (ribavirin) in 60 patients with chronic hepatitis C genotype 1 who have failed to respond to standard therapy (peginterferon and ribavirin). Pegasys and Copegus are being provided under a collaborative agreement between Romark and F. Hoffmann-La Roche Ltd.

"We are excited to be participating in this clinical trial," said David Nelson, MD, Associate Professor of Medicine, Medical Director of Liver Transplantation, and Chief of the Hepatobiliary Disease Section at the University of Florida. "There is a critical need for new therapies for patients with hepatitis C, particularly those who have already failed existing therapies."

The company also announced that interim data from an international clinical trial in patients with chronic hepatitis C will be communicated at the 58th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in early November 2007.

"Initiation of the U.S. study and communication of our international data represent important milestones for our development program," said Jean-Francois Rossignol, MD, PhD, Chairman and Chief Science Officer of Romark who invented nitazoxanide and is leading its clinical development.

"We are enthusiastic about the results to be presented at the upcoming AASLD meeting and the opportunity to develop an important new treatment for patients suffering from chronic hepatitis C."

The company's STEALTH C (Studies to Evaluate Alinia for Treatment of Hepatitis C) development program is being directed in collaboration with the Division of Gastroenterology and Hepatology at Stanford University School of Medicine by Emmet B. Keeffe, MD, Jeffrey S. Glenn, MD, PhD, and Dr. Rossignol, who is also a Stanford affiliate.

Nitazoxanide is the first of a new class of small molecule drugs called the thiazolides that target cell signaling pathways used in viral replication. Data related to the in vitro activity of nitazoxanide against virus replication in hepatitis C virus (HCV) replicons was presented earlier this year at the 20th International Conference on Antiviral Research.

Stephen A. Harrison, MD, Chief of Hepatology at Brooke Army Medical Center in Fort Sam Houston, Texas, said, "The potential for use of nitazoxanide in the treatment of chronic hepatitis C is exciting. To better optimize treatment outcomes for patients, we need new antiviral drugs that can be used safely and effectively in combination with existing drugs or with other new drugs in development."

STEALTH C Clinical Development Program

The US and international clinical trials described above comprise part of the company's STEALTH C (Studies to Evaluate Alinia for Treatment of Hepatitis C) clinical development program, a series of clinical trials designed to evaluate the safety and efficacy of Alinia tablets in combination with peginterferon or peginterferon and ribavirin in patients with chronic hepatitis C.

The STEALTH C-1 trial, conducted in Egypt in interferon-experienced and naive patients with chronic hepatitis C genotype 4, is a phase II randomized controlled trial evaluating the effectiveness and safety of three treatment regimens: (i) Alinia administered 500 mg twice daily for 12 weeks followed by Alinia-Pegasys combination therapy for 36 weeks, (ii) Alinia 12 weeks followed by Alinia-Pegasys-Copegus combination therapy for 36 weeks and (iii) Pegasys- Copegus combination therapy for 48 weeks (standard of care). The study randomized 120 patients. Patients enrolled in this trial have reached the end of treatment and are undergoing follow-up for sustained virologic response. Data from the STEALTH C-1 clinical trial is expected to provide important efficacy and safety data that will guide the continuing development of nitazoxanide for treating chronic hepatitis C. Interim data from this trial will be presented at the 58th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in early November 2007.

The STEALTH C-2 trial is a randomized double-blind placebo-controlled trial conducted in the United States in 60 patients with chronic hepatitis C genotype 1 who have previously failed to respond to peginterferon and ribavirin combination therapy. This trial is designed to evaluate the effectiveness and safety of Alinia administered 500 mg twice daily for 4 weeks followed by Alinia-Pegasys-Copegus combination therapy for 48 weeks compared to placebo for 4 weeks followed by placebo-Pegasys-Copegus combination therapy for 48 weeks (standard of care).

About Hepatitis C

Hepatitis C is a liver disease caused by the hepatitis C virus (HCV), a virus spread through direct contact with the blood of infected people. Chronic HCV infection may cause liver cirrhosis or hepatocellular carcinoma. An estimated 3.2 million people in the U.S. are chronically infected by hepatitis C virus. Globally, an estimated 170 million people are chronically infected, with three to four million persons newly infected each year, according to the World Health Organization.

About Romark Laboratories

Romark Laboratories, L.C. (http://www.romark.com) is a biotechnology company committed to the discovery and development of innovative new small molecules for treating infectious diseases, cancers, and autoimmune diseases.

About Alinia

Alinia (nitazoxanide) is indicated in the United States for treatment of diarrhea caused by Cryptosporidium parvum or Giardia lamblia in patients 1 year of age and older. Alinia has not been shown to be superior to placebo for the treatment of diarrhea caused by Cryptosporidium parvum in HIV-infected or immunodeficient patients. The most common adverse events reported by patients receiving Alinia have been abdominal pain, diarrhea, headache, and nausea. In controlled trials, the frequency of these events has been similar to patients receiving a placebo.


08/28/07

[drofi]

I am a little bit disappointed. There was such a hype here about Alinia, now the presentation from Boston is over, some critical questions are open, and there are no comments from skilled congress visitors (e.g. HR) at all. Ok, perhaps we just have to be a little more patient. I really would appreciate some comments about the discussions with Romark and their answers to critical questions. There is no need for an individualised treatment advice for any person here.
Are there any data or comments about Alinia and different genotypes? What did Romarck say about the treated population and about differences in SVR rates compared to other geno 4 studies? Are there any interim data from geno 1 studies etc?
Thank you very much in advance.

Regards, drofi

[drofi]

sorry, the mail should be addressed to Hepatitis Researcher and all, of course

[copyman]

hey Fore, hope you dont take this wrong but i do not think HR needs someone to speak for him.  you seem to do this often. there should be no problem with him commenting and his feelings about new drugs, etc. and if there is he will tell us that. before he left for the meeting he said he would report back.  after all he is a doctor and knows what he can say and not say on a forum. there are many here that value his opinion and are looking forward to what he has to say about the meeting. i will be posting a thread to him in the next few days if he does not post by then.

[Forseegood]

no offense taken, he asks me to say some things now and then, if you don't believe me, you can ask him. Hopefully he will comment, but he's extremely busy as well...Hope youre well....

[copyman]

sorry i forgot that you have met him and know him way more then most of us do. maybe you could asked him to post his thoughts on the new drugs. this would be a great help not only to me but many here. thanks

[Forseegood]

no worries, prob seems kinda strange I'm sure...it's just that he's so busy, he's not home all the time, but I'd like it if he could post - he just doesn't want to be in some type of position where it looks like he's recommending anything, etc, you know how it is...if I find out anything, I'll post as well...

[Hepatitis Researcher]

This was as usual a huge conference with incredible bizarre and frustrating features: Hundreds of important posters that nobody has time to visit and study in any detail, with no atttendance even at the two hours officially foreseen for poster viewing. The posters are much better than the abstracts, of course, and details matter.
The long term ( three years)! maintenance IFN treatment and the results of the various retreatment protocal trials for previous nonresponders for SOC were, frankly, very disappointing.

As for the much expected Alinia presentation that was presented right after Jacobsons presentation of the week 24 treatment naive Telaprevir/SOC combo presentation:

1. I was primed by a one hour prior discussion of the results by a trusted insider scientist/friend with regard to details of how to view/interpret  the data.

2. The data were presented by Dr. Elfert from Tanta University. His English was fair, but he was somewhat nervous and not very informative when questioned by the audience in regard to the important strange feature of the less than historically data based performance of the SOC group.In other words, SOC was doing worse than expected by historical comparison for Genotype 4. The answer given was, that the data are the data. I personally found it strange that in the comparison UND%curves a a function of time, the SOC group was having apparantly increasing breakthrough towards the end of the 48 weeks, while the NTZ arms were holding their UNDs, in particular the triple arm with Ribavirin.

3. There was precious time wasted by naive audience questions re the PCR methodology used to arrive at the viral load and undectabilty data. The method used a two step PCR, the sensitive Cobas Taqman( less than 10iU) was used only when negativity occured with the less sensitive PCR. The method was impeccable and well presented and described, all PCRs done with well defined assays.

4. There was a 12 week lead Nitazoxanide only treatment period, followed by 36 weeks of Nita plus SOC in the Alinia arms. The alledged reason ( not mentioned by the presenter, of course)  was that originally there was the hope that Alinia can do the trick by itself, but then the triple combo was added.

5. SVR data for 12 weeks post EOT were available and presented for all arms. They were about 50% for the SOC arm and over 80% for the Triple combo arm.

6. I was informed by reliable sources, that actualy not a single patient  that had had EOT UND had relapseat the 12 wk post mark.The difference between EOT UND and SVR % was reportedly due to some loss of follow up ( like one patient died in a car accident after EOT UND, probably had SVR, but could never be tested and counted.

7. The long awaited viral load curves for the Nitazoxanide only 12 weeks also were finally shown. They showed a disappointing  approx 1 log drop. This important feature was noit discussed by the presenter and not questioned at the short question phase post presentation, but I was able to discuss this apparant contradiction to the overall success with the expert.The explanation given was, that Nitazoxanide, while not very potent as a monotherapy, has a true and strong synergism with SOC, similar to the effect that Riba has on PegIFN therapy. Its mechanism of action on HCV is still not well known and is by preliminary data viewed as  inhibition of viral protein folding and ribosomal entry/translation of viralRNA..

8. The side effect profile between the NTZ arms and the SOC arms was not different, NTZ seemed to have caused no additional side effects.

9. Treatment experienced arms with NTZ/SOC were also presented. The numbers were too small to be convincing, but the triple combo was doing clearly much better. The exact definition of treatment experienced was not clear to me, i e if true SOC nonresponders were included.

10. Trials in the US are now recruting. There is a 4 week NTZ only lead in phase then combo with NTZ. There is a trial with treatment naive and one with prior failure patients. I see no good reason why NTZ is not given from the start in these combos. I was told that there are some data to justify this approach over SIMULSTART.

11. Every effort was made in Egypt to secure the reliability/adherence of the treatment protocol. As such all PegInterferon injections were actually done by the doctors weekly at both sites in Tanta and Alexandria at the university clinics. While pill containers were checked and counted , noone knows if all the pills were actually taken, Riba and/or Alinia. But that goes for Triple and SOC and can happen in Egypt, Europe or America.

[jmjm530]

Thanks for the commentary.  Makes me wish I took the time to attend.

Re #2 in the Alinia points. Does the unexpected SOC data -- and the apparent lack of a good explanation -- suggest that perhaps some of the other data might not be fully trusted? Or at least one should hold off too much optimism, until someone duplicates the results? Also, how would you say the Alinia data was received by the docs in terms of the newer drugs out. And, which if any of the new drugs, seemed to be getting the most talk?

[Hepatitis Researcher]

As far as one can tell there was hard work and honesty at play. Also do not forget, that Romark is not a publically traded stock company, so there is no gain from "massaging" temporary good news. As a matter of fact, they will have to bear all the cost of the US trials and would probably think twice to invest their money in a fruitless endevaour. If they work this together with Roche, then you can be assured that Roche will carefully investigate all procedural details of previous data. I just hope that nobody is so naive as to think they can sucessfully treat HCV with a painless NTZ monootherapy. And the Riba certainly has to be on board for a really high chance.
Most of the "docs' were fairly unfamiliar with Alinia and there was an air of mixed awe and disbelief in this gigantic hall after the presentation. I am glad I had my primer from the inside source to get a more solid feel for where this stands. Whatever the mechanisms, the lack of additional side effects will reduce the treatment discontinuations and improve what matters : The Intention To Treat outcome.

As for the most talked about drug, most are quite reserved at this point considering the bewildering dynamics of trial discontinuations and also the somewhat lower than hoped for INT SVR rates for the leading protease inhibitor.

[jmjm530]

"Trusted" was probably the wrong choice of words. Didn't mean to imply foul play, just trusted in the sense of procedural details resulting in data integrity etc, because of the unexpected SOC results and lack of explanation. But I think you've answered that as best as can be done, and hopefully some sort of partnership with a large company like Roche would push things along.

[TnHepGuy_]

Thanks greatly for your commentary and insights from the AASLD - and in particular re Alinia.


Couple of quick questions, if you don't mind:

- In regards to Alinia, was there any mention/speculation on how Alinia+SOC response in Egyptian geno 4's might translate to American geno 1's?

- also, did you notice any new studies/papers related to occult hepatitis C?


David

[mremeet]

Thank you for that fantastic expert eyewitness report on the conference, we're very fortunate to have you dropping by here. It's too bad the alinia results were not reported with more clarity and under a more solid foundation. You mentioned above that the IFN was administered by the trial center so they know the participants received that part of treatment. But there's the usual ambiguity because it may not be known with real certainty if the riba and/or alinia were taken as they should have been. But were riba/alinia blood serum tests performed as a way of checking on compliance? Considering the long uptake and halflife of riba, I would think it would be difficult for anyone to effectively cheat and only take the pills just before their trial visitation; not sure if alinia has a similar dynamic. I guess it'll be wait and see for awhile, but it sounds like we still have good reason to be hopeful that alinia will pan out in some shape or form - I just wish it would start moving along at a more rapid pace (especially considering it's available in the here and now instead of the there and then). One thing's for sure, if I were contemplating treatment with SOC right now, I'd almost certainly add alinia in at least for the first few months of treatment. Even if it didn't help, sounds like it will not add to treatment misery to any meaningful extent...and if it does work, then what's not to like?

And not to beset you with a million questions (because I know you get a lot of them here) but I'm wondering if you can more fully explain your statement "As for the most talked about drug, most are quite reserved at this point considering the bewildering dynamics of trial discontinuations..."  Assuming you're talking about the same drug I think you're talking about, I'm a little confused at what trial discontinuations you're referring to(?) As far as I know telaprevir hasn't discontinued anything, so maybe you're not refrring to that one. I'm not that familiar with boceprevir's somewhat confusing test matrix, although I do recall they had some discontinued some early trials if I'm not mistaken(?) Anyway, hoping you could clarify as much as possible without stepping on any toes of course. Thanks again for the very helpful update, you are one standup doctor that's for sure.

[gauf]

Most of the "docs' were fairly unfamiliar with Alinia and there was an air of mixed awe and disbelief in this gigantic hall after the presentation.
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This certainly may explain why I can not get a doc to prescribe this to me off label. I don't blame the docs of course, but those of us with Stage 4 now might get a break once the word gets out. Hope is wonderful thing.

[jmjm530]

HR: As for the most talked about drug, most are quite reserved at this point considering the bewildering dynamics of trial discontinuations..."
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I'd also like to piggyback on Mre's statement re what I assume to be leading PI in developement at the moment. Unless I read it wrong, SVR rates are at least 60% with only 24 weeks of treatment, and that's without helper drugs and what appeared to be no strategy in place to deal with the emerging skin issues. Compare that to 40-50% SVR with 48 weeks of SOC and, at least to me, that's a signficant treatment advance.

-- Jim

[drofi]

Many thanks for your time to share your intelligent thoughts with us.
Vielen herzlichen Dank und viele Gruesse,
drofi

[Hepatitis Researcher]

considering the bewildering dynamics of trial discontinuations..."  Assuming you're talking about the same drug I think you're talking about, I'm a little confused at what trial discontinuations you're referring to(?)

I am talking about three drugs already in clinical trials, that have been fairly recently discontinued:

: Valoticitabine from Idenix ( the 2 methylcytosine-valinebound)  and HCV 796, a nonnucleoside polymerase inhibitor from Viro Pharma that the were terminated for good this summer.

Furthermore ACTILON  (CPG10101),  a potent and promising toll like receptor 9 stimulator from Coley pharma, already in human trials for HCV in combo with SOC, that elicits an enormous amount of local intratissue Interferon production and stimulates antigen presentation,  has been permanently discontinued.

[Hepatitis Researcher]

It was mentioned that there is similar sensitivity to NTZ across the Genotypes in in vitro assays. It remains to be seen how this works out in the clinic.

[Hepatitis Researcher]

t\Testing the stored sera from the study visits for riba concentrations/compliance would allow to judge if the SOC control group was more lax in their riba habits. I dont think this was done, I would assume that there is the assumption that this noncompliance burden distributes evenly between the arms. If anything the real results would be even better if the existing results contained the element of noncompliance.. What seems to matter is the reliability of the SVR12 rate and they worked hard to assure excellent testing ( dual approach, that also serves to control false negs.).

Again, I was told, that not a single EOT neg patient in the NTZ group actually available for testing was found pos at post treat wk12. Like NTZ somehow prevents relapse by having reduced the invisible residual to ultralow levels in the UND treatment phase , because it keeps working at the residual because there is no real resistance to it oppositre as this might be the case with a drug that attaches to a viral protein?