FDA Approves Talicia (omeprazole magnesium, amoxicillin and rifabutin) for the Treatment of H. pylori Infection in Adults

In continuation of my update on omeprazole and amoxicillin   

RedHill Biopharma Ltd. (Nasdaq: RDHL) (Tel-Aviv Stock Exchange: RDHL) (“RedHill” or the “Company”), a specialty biopharmaceutical company primarily focused on the development and commercialization of proprietary drugs for the treatment of gastrointestinal diseases,  announced that the U.S. Food and Drug Administration (FDA) has approved Talicia (omeprazole magnesium, amoxicillin and rifabutin) delayed-release capsules 10 mg1/250 mg/12.5 mg for the treatment of Helicobacter pylori (H. pylori) infection in adults. RedHill expects to launch Talicia1 in the U.S. in the first quarter of 2020 with its dedicated sales force.

Talicia is the only rifabutin-based therapy approved for the treatment of H. pylori infection and is designed to address the high resistance of H. pylori bacteria to current clarithromycin-based standard-of-care therapies. It is estimated that H. pylori resistance to clarithromycin more than doubled between 2009-2013.

Professor David Y. Graham, MD, MACG, Professor of Medicine, Molecular Virology and Microbiology at Baylor College of Medicine, Houston and Lead Investigator of the Talicia Phase 3 studies, said: “Talicia offers patients a much-needed new treatment option for H. pylori with an excellent safety and efficacy profile that is not compromised by clarithromycin or metronidazole resistance. The clinical studies for Talicia demonstrated high efficacy in eradication of H. pylori. Studies with Talicia found zero resistance to rifabutin and showed 17% resistance to clarithromycin, a current standard-of-care macrolide antibiotic, consistent with current data showing that clarithromycin-containing therapies fail in approximately 25-40% of cases.”

Colin W. Howden, MD, AGAF, FACG, Hyman Professor of Medicine & Chief of the Division of Gastroenterology, University of Tennessee Health Science Center, added: “H. pylori is a major cause of peptic ulcer and gastritis. It is also carcinogenic and is the leading cause of gastric cancer. Treatment of H. pylori infection has become increasingly difficult due to growing bacterial resistance and the lack of advances in treatment options over the past decade. Talicia offers a new effective treatment option to overcome bacterial resistance and provide optimal efficacy and I believe it could become a recommended first-line standard-of-care treatment for H. pylori infection.”

“The FDA’s approval of Talicia demonstrates our unwavering dedication to patients suffering from gastrointestinal diseases. We thank the patients, researchers and clinical staff who participated in the studies of Talicia and the RedHill team and vendors for this important milestone achieved by their commitment and hard work,” said Dror Ben-Asher, Chief Executive Officer of RedHill Biopharma. “We are working to expand our sales force to approximately 140 representatives who will promote Talicia, Aemcolo and other gastrointestinal-focused products in our basket.”

Allergan Announces FDA Approval of Avycaz (ceftazidime and avibactam) for Pediatric Patients

Allergan plc (NYSE: AGN) announced that the U.S. Food and Drug Administration (FDA) has approved the company's supplemental New Drug Application (sNDA) for Avycaz (ceftazidime and avibactam), expanding the label to include pediatric patients 3 months and older for the treatment of complicated intra-abdominal infections (cIAI) in combination with metronidazole and complicated urinary tract infections (cUTI). This is the first FDA approval of a pediatric indication for cUTI and cIAI in more than a decade.

      

"Difficult-to-treat gram-negative pathogens pose a significant health risk, particularly to the vulnerable and sensitive pediatric patient population with few options for treatment," said David Nicholson, Chief Research & Development Officer at Allergan.  "As resistance rises among the gram-negative pathogens that cause these serious infections, the expanded label for Avycaz provides a safe and effective treatment option now for pediatric patients with cIAI and cUTI. These expanded indications in pediatric patients with infections, including infants and those at a particularly young age, address an unmet need among this vulnerable population and  underscore Allergan's efforts in anti-infective research."

The label expansion was approved based on results from two active-controlled clinical studies evaluating Avycaz in children or infants with cIAI or cUTI, as well as a single-dose pharmacokinetic study. In the cIAI study, the safety and efficacy of Avycaz (in combination with metronidazole) was compared with meropenem. In the cUTI study, Avycaz was compared with cefepime.

Across the trials, 128 pediatric patients 3 months to less than 18 years of age were treated with Avycaz. Overall, the findings from the pediatric studies were similar to the previous determination of safety for Avycaz for the treatment of adult patients with cIAI or cUTI, and no new safety concerns were identified in pediatric patients.

The primary objectives of the studies were to evaluate the safety and tolerability of Avycaz, and they were not powered for a statistical analysis of efficacy. The descriptive efficacy analyses in the pediatric studies were consistent with data from studies in adults with cIAI and cUTI. In the pediatric cIAI study, the clinical cure rate at the test-of-cure (TOC) visit in the intent-to-treat (ITT) population was 91.8% (56/61) in the Avycaz plus metronidazole group and 95.5% (21/22) in the meropenem group. Clinical cure rates for the predominant pathogens, Escherichia coli and Pseudomonas aeruginosa, were 90.5% and 85.7%, respectively for patients treated with Avycaz plus metronidazole, and 92.3% and 88.9%, respectively, for patients treated with meropenem. In the pediatric cUTI study, the combined favorable clinical and microbiological response rate at TOC in the microbiological-ITT population was 72.2% (39/54) in the Avycaz group and 60.9% (14/23) in the cefepime group. The microbiologic response rate for E.coli, the most common uropathogen identified in the study, was 79.6% for patients treated with Avycaz and 59.1% for patients treated with cefepime.

Avycaz was first approved by the FDA in February 2015 for the treatment of cUTI including pyelonephritis, and cIAI in combination with metronidazole, caused by designated susceptible bacteria including certain Enterobacteriaceae and P. aeruginosa, for patients 18 years of age and older. Avycaz was subsequently approved for the treatment of adults with hospital-acquired pneumonia / ventilator-associated pneumonia (HABP/VABP) caused by designated susceptible bacteria in February 2018.

About Avycaz (ceftazidime and avibactam)

Avycaz is a fixed-dose combination antibacterial indicated for the treatment of cIAI (in combination with metronidazole), and cUTI caused by designated susceptible Gram-negative microorganisms in patients 3 months or older. Avycaz is also indicated for the treatment  of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) in adults. Avycaz consists of a combination of avibactam and ceftazidime.

Avibactam is a first-in-class non-beta-lactam beta-lactamase inhibitor which protects ceftazidime against degradation by certain beta-lactamases. Avibactam does not decrease the activity of ceftazidime against ceftazidime-susceptible organisms. Ceftazadime is a third-generation cephalosporin with a well-established efficacy and safety profile.

Avycaz has demonstrated in vitro activity against Enterobacteriaceae in the presence of some beta-lactamases and extended-spectrum beta-lactamases (ESBLs) of the following groups: TEM, SHV, CTX-M, Klebsiella pneumoniae carbapenemase (KPCs), AmpC and certain oxacillinases (OXA). Avycaz also demonstrated in vitro activity against P. aeruginosa in the presence of some AmpC beta-lactamases, and certain strains lacking outer membrane porin (OprD). Avycaz is not active against bacteria that produce metallo-beta lactamases and may not have activity against Gram-negative bacteria that overexpress efflux pumps or have porin mutations.

Ceftazidime and avibactam is being jointly developed with Pfizer. Allergan holds the rights to commercialize ceftazidime and avibactam in North America under the brand name Avycaz, while Pfizer holds the rights to commercialize the combination in the rest of the world under the brand 

Ref : https://www.drugbank.ca/drugs/DB00438

https://en.wikipedia.org/wiki/Ceftazidime

https://en.wikipedia.org/wiki/Avibactam

https://pubchem.ncbi.nlm.nih.gov/compound/Avibactam#section=2D-Structure

Treatment reduces risk of recurrence of C. difficile infection

In continuation of my update on metronidazole  &  vancomycin

Among patients with Clostridium difficile infection (CDI) who recovered following standard treatment with the antibiotics metronidazole or vancomycin, oral administration of spores of a strain of C difficilethat does not produce toxins colonized the gastrointestinal tract and significantly reduced CDI recurrence, according to a study in the May 5 issue of JAMA.

C difficile is the cause of one of the most common and deadly health care-associated infections, linked to 29,000 U.S. deaths each year. Rates of CDI remain at unprecedented high levels in U.S. hospitals. Clinical infection also has a recurrence rate of 25 percent to 30 percent among affected patients. Not all strains of C difficile produce toxins. Nontoxigenic C difficile strains that lack the genes for toxin production are also found in the hospital environment and can colonize hospitalized patients, although patients are usually asymptomatic. Gastrointestinal colonization by these nontoxigenic C difficilestrains (in both humans and hamsters) has shown promising results as a potential way to prevent CDI, according to background information in the article.

Dale N. Gerding, M.D., of the Edward Hines Jr. VA Hospital, Hines, Il., and Loyola University Chicago, Maywood, Il., and colleagues randomly assigned 173 adult patients who were diagnosed as having CDI (first episode or first recurrence) to receive 1 of 4 treatments: oral liquid formulation of nontoxigenic C difficile strain M3 (VP20621; NTCD-M3), 104 spores/d for 7 days (n = 43), 107 spores/d for 7 days (n = 44), 107 spores/d for 14 days (n = 42), or placebo for 14 days (n = 44). Prior to enrollment, these patients had all successfully completed treatment with metronidazole, oral vancomycin, or both at 44 study centers in the United States, Canada, and Europe.

Treatment reduces risk of recurrence of C. difficile infection 

A high-throughput drug screen for Entamoeba histolytica identifies a new lead and target

Research by a collaborative group of scientists from UC San Diego School of Medicine, UC San Francisco and Wake Forest School of Medicine has led to identification of an existing drug that is effective against Entamoeba histolytica. Using a high-throughput screen for drugs developed by the research team, they discovered that auranofin (see structure) a drug approved by the US Food and Drug Administration 25 years ago for rheumatoid arthritis -- is very effective in targeting an enzyme that protects amebae from oxygen attack (thus enhancing sensitivity of the amebae to reactive oxygen-mediated killing).

Entamoeba histolytica is a protozoan intestinal parasite that causes human amebiasis, the world's fourth leading cause of death from protozoan parasites. It is listed by the National Institutes of Health as a category B priority biodefense pathogen. Current treatment relies on metronidazole, which has adverse effects, and potential resistance to the drug is an increasing concern.

PA-824 - Aerosol: New Tool Against Tuberculosis?

We know the epidemic rates of HIV/TB coinfection as well as emerging multidrug-resistant  (MDR) and extensively drug-resistant (XDR) TB strains those are contributing to increased TB-associated deaths worldwide. 

Now PA-824 (see structure), a compound capable of being formulated into a dry powder, has not only shown promising activity against MDR (multidrug-resistant tuberculosis) and XDR (extensively drug-resistant tuberculosis, or latent TB) but has also proven safe and effective in patients coinfected with HIV and TB. Previous studies showed that PA-824 was well-tolerated in tablet form, however, side effects such as headache and stomach discomfort were reported. Aerosol delivery of PA-824 directly to the primary site of infection would limit systemic exposure and ultimately eliminate potentially bothersome side effects.

About  PA-824 :

Nitroimidazoles are widely used drugs in humans for a variety of primarily anaerobic microbial infections. Metronidazole, a 5-nitroimidazole, is an important bactericidal agent for the treatment of anaerobic infections  and shows excellent selective toxicity toward anaerobic bacterial and protozoal pathogens. This class of compounds has only recently begun to be explored for Mtb, because only anaerobic activity of metronidazole against Mtb has been reported. Bicyclic 4-nitroimidazoles such as PA-824 (a nitroimidazo-oxazine) and CGI-17341 (a nitroimidazo-oxazole) have inhibitory activity against aerobically growing and nonreplicating anaerobic Mtb. Although anaerobic conditions have not been demonstrated during TB disease in humans, various authors have suggested that an anaerobic microenvironment may contribute to a nonreplicating state that may be linked with latent disease in humans. Thus, PA-824 has been developed, in part, because it may be a promising lead for therapy against latent disease that may be linked to anaerobically persisting bacilli. The Global Alliance for TB Drug Development has recently initiated phase-I clinical trials with PA-824 

Researchers from the University of North Carolina School of Pharmacy, Chapel Hill, North Carolina; and Harvard School of Engineering and Applied Sciences, Cambridge, Massachusetts, lead by  Dr. Anthony J Hickey  have achieved this interesting finding, i.e., potential use of PA-824 dry powder aerosols in the treatment of TB.

In the study guinea pigs were used to evaluate the effects of PA-824 aerosols on TB infection. One month following infection with TB some guinea pigs received high daily aerosol treatments while others received low daily treatments for 4 weeks. Lung and spleen analysis of guinea pigs receiving the high dose of aerosol PA-284 showed less inflammation, bacterial burden and tissue damage.

"The present studies indicate the potential use of PA-824 dry powder aerosols in the treatment of TB,” say the researchers".

Ref : http://aac.asm.org/cgi/content/abstract/54/4/1436.