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Jan 08, 2008 - 4 comments

ALINIA INFO ARTICLE FOLLOWED BY QUESTIONS ASKED TO  HR at medhelp.
A (lifetime grant) hepatitis researcher vetted by MedHelp.com   He is the cofounder and inventor of NGI's SuperQuant and UltraQual PCR methodology. NGI has the most sensitive PCR technology in the world.

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Interim Data Show Nitazoxanide (Alinia) Improves Anti-HCV Activity When Added to Pegylated Interferon plus Ribavirin

The addition of the experimental anti-HCV drug nitazoxanide (Alinia) may significantly increase sustained response rates when added to pegylated interferon plus ribavirin, according to data presented at the recent 58th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2007) in Boston (November 2-6, 2007).

Nitazoxanide, produced by Romark Laboratories, is already approved as a treatment for diarrhea caused by Giardia or Cryptosporidium. Its anti-HCV activity was discovered by chance when it was noted that patients receiving the drug to treat parasitic infections also experienced improvement in their hepatitis C.

Egyptian researchers studied 120 chronic hepatitis C patients with HCV genotype 4, which is the predominant type in Egypt but uncommon in the U.S. and Europe. Most clinical trials group genotypes 1 and 4 together as "hard to treat," but some studies have indicated that genotype 4 responds better than genotype 1 to interferon-based therapy. Most study participants were treatment-naive, but 24 were prior non-responders to interferon-based therapy.

Participants were randomly assigned to receive one of 3 regimens:

• Standard therapy with 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus 1000-1200 weight-based ribavirin for 48 weeks;

• Nitazoxanide monotherapy (500 mg twice daily) for 12 weeks, then nitazoxanide plus pegylated interferon for an additional 36 weeks;

• Nitazoxanide monotherapy for 12 weeks, then triple-therapy with nitazoxanide plus pegylated interferon plus ribavirin for 36 additional weeks.


Results

• Interim results 12 weeks after completion of treatment (known as SVR-12) showed that 79% of treatment-naive patients in the nitazoxanide triple-therapy group achieved undetectable HCV RNA compared with 43% in the standard therapy arm.

• Among treatment-naive patients, rapid virological response, early virological response, and end-of-treatment response rates were lowest in the standard therapy arm, intermediate in the nitazoxanide/pegylated interferon arm, and highest in the triple-therapy arm.

• Among treatment-experienced subjects, all rates were higher in the nitazoxanide/pegylated interferon arm than in the triple-therapy arm (no such patients were included in the standard therapy arm).

• Adverse events were similar across the 3 treatment groups, except for an expected significantly lower incidence of anemia in the group that did not receive ribavirin.


Evaluation for standard 24 week post-treatment SVR is ongoing. Romark has commenced a U.S. study of nitazoxanide for chronic hepatitis C. However, since the drug is already approved for another indication, physicians may choose to prescribe it "off label" for patients with HCV.

Below is an excerpt of a press release from Romark announcing the findings:

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
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AASLD CONFERANCE NOTES:  By 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 viral RNA..

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.
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Would you recommend Alinia as an adjunct to SOC?

I could not  recommend Alinia at this time as it is not fully FDA approved for this indication. HAVING SAID THAT, there are indications that it is possibly, at this moment, the most meaningful addition to the available SOC options, for those  patients whose doctors feel they should treat NOW.

Three lines of thought are important:

1. Do we have reason to believe that the reports and results from the Egyption study, as reported at the AASLD are truthful and therefore meaningful, at least within the Genotyoe 4 context?
The answer is yes, see my previous detailed report re the actual presentation at the AASLD, who spoke, who did the study, how were the methods to ensure patient compliance.

One further aspect that is not typically fully understood by many, is that the  90% 12wk SVR rate achieved was an intention to treat - ITT- analysis. This means that all the failures that constitute in toto the missing 10% INCLUDE the failures that are not related to the inherent capacity of this regimen to work when properly administered. Thus, for example, a deadly accident after EOT preventing a likely SVR patient to bre counted as such made this patient a "nonSVR" statistic.Similarly, all the ones who skipped Riba pills and failed therefore are failures in this ITT count, while they could have been SVRs, if taken their meds properly. The conclusion from this aspect is, that whoever does everything properly, will have a better than ITT chance for SVR.

2. The fact that Nitazoxanide also has effectivness against HBV and rotavirus, combined with the undisputable DDW 2006  reported ( #1821 and # 1852) in vitro results against HCV  ( genotype not mentioned in abstract) and HBV  lends meaningful support to the putative assumption that it will be effective against other genotypes as well.

3. All the Egyption trial date will have been scrutinized by the FDA before an IND necessary to begin the US trial using NTZ and SOC was successfully processed ( A planned trial needs to be as such  approved before start for basis and design and toxicity issues etc).

While the NTZ monotherapy ( 12wk"lead in")  VL reduction results were meager, just barely better than  ribavirin on its own (riba monotherapy)  in earlier trials, it seems to have, similar to riba, but with a somewhat different, synergistic mechanism, the capacity to enhance the IFN dependent immune clearance mechanisms. In the Egypt trial, all participants stayed on the NTZ for the full duration - 48wks.

With respect to the effect of food administration the public domain FDA files from the Alinia registration trials state that the Cmax of NTZ was slghtly higher (2%) , the Tmax was significantly delayed and the elimination half life was slightly longer following administration of NTZ with food. Overall bioavailibility of tizoxanide was 48% higher when administered with a high fat, high caloric meal.

Best to space riba and NTZ apart to avoid theoretical resorption/bioavailibility  competition.

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The importance of reliable VL info on Alinia, particular after 4 and 8 weeks cannot be overstated. If it works well initially in most patients, but later rebounds, we know that it is early resistance. But then it might still be a godsend in Combos and just what many many need at this point in the historical development of HCV treatment (New drugs still only future hope, Alinia waiting at the pharmacy, with very little sides.)  The test to use if extreme sensitive UND status is desired, is the Labcorp test called HCV NGI ultraqual LC#140609. It has the same >2 iU cutoff, but is only a qual test. pos or neg. But that is really all you need at 4, 8, and EOT.  It is of course cheaper than the NGI quantasure. This test is identical with the NGI ultraqual, it is just started with a NGI HCV Superquant and continued with Ultraqual, if below 40 IU, the limit of the NGI Superquant. You can trust me on these issues, since i am actually the inventor of all these NGI tests. But to be clear there is absolutely NFI of mine in these tests.

Labcorp will only perform  the more sensitive test if you do specify it  EXACTLY by name and labcorp number, otherwise it will default to their quantasure. The regular "quantasure" is easier to perform and likely has  a slightly higher profit margin, so it is the preferred test, from the companys point of view. I guess we have to understand these views as well, but you can get the better test, if you specify EXACTLY.  I have given these numbers and explanations several times here, but everything gets diluted and forgotten.   (HCV NGI ultraqual LC#140609).


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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 at the 2007 AASLD?

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.
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.).

I was told, that not a single EOT neg patient in the NTZ group actually available for testing was found pos at post treatment 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.

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.

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.
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How can I get a script?
You can order  through an online pharmacy in Mexico w/o script. The drug you'd be getting in Mexico is called Daxon and it's a brand named drug, licensed by Romark  by Ziegfried Rhein....it's perfectly good and a quarter of the price of the drug offered here...(Romark is of course an American company out of Florida). If you google "Daxon in Mexico" you will likely find websites representing pharmacies there.

or:

Call Romark and ask for the patient assistance application which is one page.  Fill out two or three financial questions (income and number of household members) then forward it to your doctor who will complete his/her section and fax it to Romark.  Romark sends drugs to doctor  who forwards them to you.  Took about 2 weeks.

Tell your doctor  you need one vial of 60 tablets (500 mg. twice daily) per month.  If I remember correctly. Romark will only send a six month supply and then requires re-application for more.
This is the info for Romark Patient Assistance Program - Alinia
3000 Bayport Drive Su 200
Tampa, Fl 33607

Phone 813-282-8544    Fax 813-282-9055
If you call the number at Romark  813-282-8544  and ask to speak to Dr. Shane Jackson.  He is extremely nice and helpful.  He has additional information that he can send your Doctor if anyone from the office will  request it.  He isn't allowed to give it out to an individual and he can't call the Doctor's office unless they call him first.

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Notes:
The bioavailibility of NTZ increases 116% when taken with food.
Nitazoxanide is rapidly converted to Tizoxanide, the active compound. Nitazoxanide is never detected in the blood stream or the urine or feces of human subjects.
Tizoxqanide: Its Tmax is 1.5 hours, after 12 hours the remaining plama level is under 10%. .
Its plasma half live is 1.4 hours in the fasted and 1.6 hours in the fed state.
It is converted in the liver to its glucuronide derivative that allows for rather rapid excretion mainly in the urine.
No presaturation is therefore required or useful.  
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ADDENDUM: HR comment

"....a combo treatment cocktail needs to be given in combo from the start and ideally the virus has never seen any of the drugs before.

Thus any of the official helper drugs or the Alinia or perhaps the oxymatrine should NEVER be used without the IFN/riba combo, started simultaneously and should never be used before in mono form.  

Rapid supression of the adaptive evolutionary power of HCV must be the guiding concept to combat HCV. The mutants that eventually stage the HCV combeback when treaters relapse after a full year of therapy with even "UND" for 6 month are PROBABLY CREATED WITHIN THE FIRST DAYS AFTER THE IFN/RIBA WAS STARTED, in tiny amounts. If you cut -by using additional replication reducing drugs("helpers") - the adaptive power by a factor of 100 or 1000, then these early mutants probably never come to live.

HCV is an incredible sophisticated huge molecular machine that has a million times a million! offspring and mutants per day. There is nothing trivial about that and we must use all levels of sophistication to combat it. No mistakes are forgiven.

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"........Predosing the Alinia before SOC has been done by Romark in its Egypt studies more as a result of happenstance than intentional design....
As a principal stance, Simulstart is the proper concept for antiviral cocktails,.exceptions are possible, and Alinia might be one of them, since resistance is likely to develop slowly., if ever.

BTW also mentioned here before, if someones VL is already very low or UND, adding the Alinia holds no risk of Alinia resistance and future use is NOT precluded/hampered. On the contrary, it might add a DECIDING  level of protection against relapse - this is a good theory at this point in time nothing more, but if you consider the benefit/risk equation it is something to consider.............."
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Addendum 7/08



Researchers say drug suppresses HCV

By Geoff Drushel

  
Body:  
A drug already on the market in the U.S. could be used to greatly increase the success rate of standard interferon treatment in hepatitis B and C patients, should further testing and evaluation lead to government approval. Currently, clinical trials with the drug nitazoxanide, sold under the brand name Alinia, are under way here and researchers are hopeful that it will continue to show the type of remarkable success it has shown in previous trials, including a large one conducted in Egypt between 2005 and 2007. In that trial, patients given the drug along with interferon/ribavirin treatment (standard of care) showed a success rate nearly double over those who received standard interferon/ribavirin treatment alone.

Initially developed to combat diarrhea caused by the emerging parasite Cryptosporidium parvum, the drug, one of a promising new class of antiviral drugs known as thiazolides, was found to have strong antiviral properties that significantly impacted the hepatitis viruses. Trial participants in the Egypt study achieved a sustained virologic response (SVR) of almost 80 percent in those given the drug while on interferon treatment compared to an about 43 percent SVR rate in those who did not take it. Significantly, the patients – all genotype 4 – treated with nitazoxanide also experienced no relapse and no more side effects than patients who received the standard of care. Genotype 4 is to Egypt what genotype 1 is to the U.S.

The drug’s manufacturer, Romark Pharmaceuticals, a biopharmaceutical company headquartered in Tampa, Fla., is continuing to test the drug in phase II clinical trials here in the U.S., and its discoverer believes it ultimately will win approval from the Federal Drug Administration (FDA) for treatment of hepatitis and other similar viruses. Nitazoxanide could be available to patients as early as 2010 to 2011, according to its inventor, Jean-Francois Rossignol, M.D., who co-founded Romark in 1993 and serves as director of the company’s Institute for Medical Research.

“It’s quite a discovery, actually. It’s an interferon-like product, so that’s quite a breakthrough in that (area), and that’s why it’s making quite a lot of noise right now at EASL (European Association for the Study of the Liver) in Milan (see “Treatment Takes Center Stage at EASL Meeting,” p. 10),” says Dr. Rossignol, a 64-year-old, Sorbonne-trained synthetic medicinal chemist and physician who invented thiazolides while attending medical school. “And that’s why AASLD (American Association for the Study of Liver Diseases) took it for the fall meeting.” Thiazolides are a class of small molecule drugs that target cell signaling pathways used in viral replication.

“It is exciting, and we are looking for seeing a great development in not only hepatitis C and B, particularly hepatitis C because of its national priority, but also other viruses down the road,” he says. “And we intend to absolutely pursue registration of the drug very aggressively. But we need to test the drug fully to make sure we have something and have it well recognized by the peer review process, which is why AASLD and EASL are important because these are two – Europe and the U.S. – pretty good, credible peer review processes.”

Romark currently is conducting a U.S. phase II trial with nitazoxanide plus standard of care in patients with hepatitis C genotype 1 who were previously treated with interferon, so called nonresponders. The company also plans to initiate a phase II trial in treatment naive (see “Remaining Naive – or Not,” p. 14) patients this year. “It’s undergoing clinical trials in the U.S., and we should have the communication of the U.S. trials by the fall at AASLD in San Francisco. So we will know the complete story at that point in time – its complete potential,” he says. “What we know right now is that you add the drug to the standard of care, and what you end up with is a pretty high cure rate – SVR in the 80 percent-plus range, which obviously is quite interesting.”
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12/08 update:  http://www.medhelp.org/posts/show/711437


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3/9/09 update

Phase 1 OPTIMA Trial Finds Controlled-release Nitazoxanide Improves Response to Pegylated Interferon plus Ribavirin

Researchers are studying a variety of approaches to improve response to interferon-based therapy for hepatitis C virus (HCV) infection. One agent under study, nitazoxanide, is a thiazolide anti-infective with activity against a variety of protozoa, bacteria, and viruses; it is currently FDA-approved for the treatment of Cryptosporidium and Giardia (under the brand name Alinia).

In laboratory studies, nitazoxanide and its active metabolite, tizoxanide, potently inhibited HCV replication. In the STEALTH-C1 trial, genotype 4 chronic hepatitis C patients who received nitazoxanide prior to pegylated interferon, with or without ribavirin, responded more rapidly and had a higher sustained virological response (SVR) rate than those receiving standard therapy.

At the 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) this past October, Romark Laboratories researchers presented promising data on nitazoxanide in combination with pegylated interferon/ribavirin in patients with other HCV genotypes, and combined with directly targeted "STAT-C" agents in vitro.

Last week Romark announced new data on a controlled release formulation of nitazoxanide that may enable less frequent administration. Below is an edited excerpt of a press release from the company describing the study and its findings.

Romark Announces Presentation of New Data for Controlled Release Nitazoxanide in Chronic Hepatitis C

Studies presented at the 19th Conference of the Asian Pacific Association for the Study of the Liver (APASL) Demonstrated Favorable Pharmacokinetics and Significant Reduction in Viral Load
Tampa, Fla. -- February 17, 2009 -- Romark Laboratories, a privately held biopharmaceutical company, today announced results from international Phase I and II clinical trials evaluating a controlled release version of nitazoxanide in the treatment of chronic hepatitis C virus (HCV) infection. In the phase II study in treatment-naive patients infected with HCV genotype 4, 82% (n=17) and 100% (n=16) of patients receiving low and high doses of controlled release nitazoxanide, respectively, experienced undetectable serum HCV RNA (<12 IU/mL) after 12 weeks of combination therapy with peginterferon and ribavirin.

The data, part of Romark's OPTIMA HCN (OPTImizing MAnagement of Hepatitis C with Nitazoxanide) development program, were presented this weekend in an oral presentation at the 19th Conference of the Asian Pacific Association for the Study of the Liver (APASL) in Hong Kong. The presentation titled "Controlled Release Tablet Improves Pharmacokinetics, Viral Kinetics and Tolerability of Nitazoxanide for Treatment of Chronic Hepatitis C," abstract FP052, was given by Emmet B. Keeffe, MD of the Romark Institute for Medical Research, Tampa, FL.

"We continue to be encouraged by the results of the ongoing nitazoxanide clinical development program," said Jean-Francois Rossignol, MD, Director of the Romark Institute for Medical Research and discoverer of nitazoxanide. "These data show that controlled release nitazoxanide exhibits favorable pharmacokinetics and tolerability, and -- in combination with the standard of care therapy -- robust antiviral activity in a small number of patients with HCV genotype 4. We look forward to reporting interim data from our U.S. studies evaluating the standard nitazoxanide tablet in patients with chronic hepatitis C genotype 1 later this year."

In the Phase I study, OPTIMA HCN-1, a total of 12 healthy adult volunteers were enrolled to evaluate pharmacokinetics following oral administration of nitazoxanide at 675 mg or 1,350 mg twice daily with food for seven days. This was a randomized, double blind crossover study. The 675 mg and 1,350 mg twice daily doses of controlled release nitazoxanide produced trough plasma concentrations of tizoxanide, the active metabolite of nitazoxanide, that were approximately 3 x and 12 x the trough concentrations observed in historical studies using a standard nitazoxanide 500 mg tablet. Controlled release nitazoxanide showed favorable safety and tolerability throughout the course of the study, with mild to moderate adverse events (primarily GI-related) reported.

In a subsequent Phase II study, OPTIMA HCN-2, a total of 41 treatment-naive patients with chronic hepatitis C genotype 4 were randomized to receive nitazoxanide at 675 mg (n=17), nitazoxanide at 1,350 mg (n=16) or placebo (n=8) twice daily for four weeks followed by the same regimen plus standard of care with peginterferon alfa-2a (Pegasys; 180 micrograms once per week) and ribavirin (Copegus; 1,000 or 1,200 mg daily according to body weight) for 36 weeks (48 weeks for the placebo arm).

Interim virologic response rates are as follows: for the low and high-dose nitazoxanide arms, rapid virologic response (RVR, HCV RNA < 12 IU/mL after 4 weeks of combination therapy) 59% and 63% respectively, compared with 50% for the placebo group; complete early virologic response (cEVR, HCV RNA < 12 IU/mL after 12 weeks of combination therapy) 82% and 100%, respectively, compared with 63% for the placebo group; early virologic response (EVR, greater than or equal to 2 log10 decline in HCV RNA after 12 weeks of combination therapy) 88% and 100%, respectively, compared with 63% for placebo. In this study, a dose-related decline in serum HCV RNA was observed beginning on day 4 of combination therapy and was maintained through week 16.

Controlled release nitazoxanide was also shown to be well-tolerated without serious adverse events or drug discontinuations secondary to adverse events in these patients with chronic hepatitis C.

"These studies further demonstrate our commitment to optimizing treatment of chronic hepatitis C using nitazoxanide as an integral part of anti-hepatitis C therapy," added Dr. Rossignol. "We are excited about the development of controlled release nitazoxanide and plan to study once daily dosing in future trials."

About Nitazoxanide and Hepatitis C

Nitazoxanide, the first of a new class of broad spectrum antiviral drugs known as the thiazolides, is undergoing worldwide development as a treatment of chronic hepatitis C. Nitazoxanide is a potent inhibitor of hepatitis C virus (HCV) replication in HCV genotype 1-derived replicon cell lines, and in vitro studies have shown that it does not induce mutations in the virus that confer resistance. In phase II clinical trials, the addition of nitazoxanide to peginterferon alfa-2a with or without ribavirin significantly increased sustained virologic response rates in patients with chronic hepatitis C infected with HCV genotype 4. Phase II clinical trials of the standard nitazoxanide (Alinia) tablet are ongoing in the United States in patients with HCV genotype 1.

For more information, see www.romark.com.

2/27/09

Source
Romark Laboratories. Romark Announces Presentation of New Data for Controlled Release Nitazoxanide in Chronic Hepatitis C. Press release. February 17, 2009.



http://www.hivandhepatitis.com/hep_c/news/2009/022709_a.html



Contributors: HR, 4CGood, Kittyface, Gauf, St.George, Evangelin, JmJm.

Comments
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Avatar universal
by orleans, Jan 09, 2008
Thanks, jerry

233616 tn?1312790796
by merryBe, Jan 09, 2008
yes, thanks for putting this somewhere we can find it!!  

I want your doctor!!! Mine gives this drug the brush off.

233616 tn?1312790796
by merryBe, Dec 08, 2008
update: my doc finally saw the light, I've been on Alinia for 8-9 months now.

475555 tn?1469307939
by mike716, Nov 29, 2009
Good stuff! I'm collecting everything I can on Alinia, and trying to find a hep MD down here in Argentina who will go along with trying it. Your posts on it are invaluable. Thanks again.

Mike

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