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三、发展历程
Detailed Information
Nitazoxanide is a nitrothiazole benzamide, developed by Romark for the treatment of a broad spectrum of parasitic and bacterial infections, and as an anthelmintic (Company communication, Romark, Jan 1996). It inhibits an essential bacterial enzyme, pyruvate synthase, disrupting bacterial metabolism (BioVenture View Daily Online, 14 Nov 2002, B00778598). It does not interact with warfarin (Press release, Romark, 8 Dec 2005). It targets the maturation and intracellular transport of the viral haemagglutinin protein (HA) (Press release, Romark, 1 Feb 2010).
Marketing
It is launched in Mexico (1996) (by Columbia) and most Latin American countries as Daxon and Colufase, a 3-day treatment for a wide range of protozoan and helminth infections (Direct communication, Romark, 4 Jun 1999; Press release, Romark, 2 Jul 2001; Company Web Page, Romark, 11 Jun 2002). It is launched in the US (2003) as Alinia oral suspension for the treatment of Cryptosporidium parvum and Giardia lamblia-associated diarrhoea in children, aged 12mth-11yr (Press release, Romark, 2 Dec 2002; Scrip Daily Online, 19 Mar 2003, S00793616). Approval was extended to include patients aged >12yr. A tablet formulation is also approved in the US for the treatment of G lamblia-associated diarrhoea in patients aged >12yr (Press release, Romark, 22 Jul 2004; Company Web Page, Romark, 8 Dec 2005). It was filed for registration in the EU via the centralized procedure (Direct communication, Romark, 4 Jun 1999). It had US FDA allowance for compassionate use in AIDS patients with cryptosporidiosis (Press release, Unimed, Feb 1996). However, the FDA voted against approving nitazoxanide for cryptosporidial diarrhoea (CD) in AIDS patients (Scrip, 1998, 2334, 21). Unimed (Solvay (now Abbott)) decided not to continue seeking its approval for this indication (Scrip, 1998, 2338/9, 14). It has an expanded orphan drug designation for use in all immunocompromised patients with cryptosporidiosis (Scrip, 1997, 2202, 19). It has US orphan drug status for the treatment of intestinal giardiasis (FDA Orange Book, Suppl 3, Mar 2002) and intestinal amoebiasis (FDA Orange Book, Suppl 9, Sep 2002). Romark plans to seek US fast-track designation for chronic hepatitis-C virus (HCV) (Press release, Romark, 10 Jan 2006). Chugai has exclusive rights in Japan for development, manufacture and distribution (Press release, Chugai, 18 Feb 2009). It was licensed to Unimed for Australia, Canada, New Zealand and the US, where Unimed had development and marketing rights to po and iv formulations for cryptosporidiosis, and marketing rights to po formulations in all indications (Company communication, Unimed, Oct 1995; Ann Rep, Unimed, 1997). However, Unimed transferred rights to Romark (Scrip, 1998, 2392, 12). Unimed sublicensed it to BioChem Pharma (now Shire) for Canada, but this was discontinued (Direct communication, BioChem Pharma, 4 May 2000).
Clinical
Phase III
In a Phase III trial in Mexico for the eradication of C parvum, 23/23 patients were cured, but 5 patients required large doses for >1mth (3rd Int Cong Drug Ther HIV Infection (Birmingham), 1996, Abs P93; Scrip, 1996, 2092, 22). In a Phase III trial in Egypt in 100 adults and children with CD, 80% were well 1wk after initiating the 3 day nitazoxanide treatment cf 41% of the placebo group, and the duration of diarrhoea and oocyst shedding was reduced (Press release, Romark, 2 Jul 2001). In clinical studies in 1500 patients, it showed a broad spectrum of antiparasitic activity. As an anthelmintic, it was effective against intestinal nematodes and cestodes, as well as the liver trematode Fasciola hepatica (Company communication, Romark, Jan 1996). In a Phase III trial in Egypt in children <5yr infected with rotavirus, nitazoxanide reduced the duration of severe dehydrating rotavirus diarrhoea and gastroenteritis by 2 days after 3 days of treatment. No AEs were reported (Company Web Page, Romark, 5 Sep 2006). It was in a Phase II/III trial for cryptosporidiosis in AIDS patients, conducted by the US AIDS Clinical Trials Group (ACTG); however, the trial was shut down due to poor patient enrollment (Scrip, 1998, 2334, 21). In 22 patients with AIDS-related CD, interim results showed that nitazoxanide 500, 1000, 1500 or 2000mg/day po x4wk gave reductions in bowel movement frequency (BMF) in 33, 100, 67 and 67% of patients, respectively, and 41% of patients had a parasitological improvement (36th ICAAC (New Orleans), 1996, Abs LM50). In 50 HIV-negative malnourished children aged <3yr with CD given nitazoxanide suspension 100mg bid x3 days, there were no deaths, cf 18% on placebo. In 50 HIV-positive children with CD on the same dose there was no response to a 3-day treatment, but 87% clinically responded after a 2nd treatment cycle. It was in studies to evaluate longer treatments in children with AIDS (Press release, Romark, 2 Nov 2002). In adults, nitazoxanide tablets and suspension were 83-100% effective in treating diarrhoea and related symptoms. AEs were not significantly different to placebo and included abdominal pain, diarrhoea, headache and nausea (6.7, 4.3, 3.1 and 3.1%, respectively) (Press release, Romark, 22 Jul 2004). In a randomized, double-blind trial in 142 hospitalized adults with CDAD, nitazoxanide 500mg bid x10 days gave a lower recurrence rate of 12.5% cf 28.6% on metronidazole 250mg qid x10 days and cf 25% on nitazoxanide 500mg x bid x7 days. The difference was not significant (Press release, Romark, 21 Nov 2005). Phase III trials in combination with peginterferon with or without ribavirin are expected in 2010 (Press release, Romark, 1 Feb 2010).
Phase II
It is in a US randomized double-blind placebo-controlled Phase II trial (STEALTH C-3) in 60 treatment-naive HCV-1 patients (enrollment complete) to evaluate safety and efficacy of nitazoxanide x4wk followed by standard-of-care (Copegus + Pegasys (both qv)) + nitazoxanide x48wk. After 12wk, patients on nitazoxanide 500mg bid + standard-of-care had 44% sustained virological response (SVR) compared to 32% for placebo. 41% of patients with high baseline viral load showed higher SVR12 rates. Adverse events were intermittent diarrhoea and discoloured urine. Final results are expected in May 2010 (Press releases, Romark, 18 Apr & 15 Apr 2010). In a 3-arm, randomized, controlled Phase II trial in 97 treatment-naive, chronic hepatitis C genotype 4 patients in Egypt, nitazoxanide + Pegasys with or without ribavirin increased SVR rates. The primary endpoint was SVR (serum HCV RNA <12 IU/mL 24wk). Secondary endpoints included HCV RNA <12 IU/mL at wk4 (rapid virological reponse, or RVR) at wk12 (complete early virological response, cEVR). 64% demonstrated SVR cf 38% for standard of care. Patients who recieved nitazoxanide + peginterferon alfa-2a had 54% of RVR and 61% of SVR (Press release, Romark, 2 Mar 2009). It is in an Egyptian, double-blind, placebo-controlled Phase II trial (STEALTH C-1) in 120 interferon-experienced and naive patients with chronic HCV genotype 4, to evaluate the effectiveness and safety of nitazoxanide 500mg bid x12wk followed by nitazoxanide-Pegasys combination therapy x36wk or nitazoxanide-Pegasys-Copegus combination therapy x36wk (triple regimen) vs Pegasys-Copegus combination therapy (standard of care) x48wk. Interim analysis in 20 evaluable patients showed that 50% on nitazoxanide 500mg bid po had undetectable HCV RNA in serum at wk24 cf 0% on placebo. It was well tolerated with no significant side-effects (Press releases, Romark, 10 Jan 2006 & 15 Aug & 2 Nov 2007). At wk12, 79% of naive patients who received a triple regimen showed higher sustained virological response (SVR) cf 43% on standard of care. 68% of patients treated with nitazoxanide-Pegasys showed a non-inferior SVR cf 43% on standard of care. In 12/24 treatment-experienced patients, the triple regimen had an SVR of 25% post-treatment, with the dual regimen achieving an SVR of 8% (Press release, Romark, 2 Nov 2007). Enrollment is complete in a US randomized, double-blind, placebo-controlled Phase II trial (STEALTH C-2) in 60 patients with chronic HCV genotype 1 who have failed to respond to standard therapy to evaluate the effectiveness and safety of nitazoxanide 500mg bid x4wk, followed by nitazoxanide-Pegasys-Copegus combination therapy x48wk vs Pegasys-Copegus combination therapy x48wk (Press releases, Romark, 15 Aug 2007 & 21 May 2008). It is in Phase II trials for Crohn's disease (Company pipeline, Romark, 14 Apr 2008). It is in a US randomized, double-blind, placebo-controlled Phase II trial in 440 patients with acute uncomplicated influenza including H1N1 strain, to assess nitazoxanide po 500mg bid x5 days on reduction of duration of influenza symptoms. The trial will also evaluvate the effect of treatment on parameters of severity of symptoms, complications of influenza and time to return to normal activities. Trial completion is expected in May 2010 (ClinicalTrials.gov Web Page, 2 Feb 2010, NCT01056380; Press release, Romark, 1 Feb 2010). |
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发表于 2010-7-24 18:02
