FDA Approves Pretomanid for Highly Drug-Resistant Forms of Tuberculosis

In continuation of my update on Pretomanid

 Pretomanid, a novel compound developed by the non-profit organization TB Alliance, was approved by the U.S. Food & Drug Administration (FDA) today for treating some of the most drug-resistant forms of tuberculosis (TB).1 The new drug was approved under the Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD pathway) as part of a three-drug, six-month, all-oral regimen for the treatment of people with extensively drug-resistant TB (XDR-TB) or multidrug-resistant TB (MDR-TB) who are treatment-intolerant or non-responsive (collectively “highly drug-resistant TB”).1,2

The LPAD pathway was established by FDA as a tool to encourage further development of antibacterial and antifungal drugs to treat serious, life-threatening infections that affect a limited population of patients with unmet needs. 

“FDA approval of this treatment represents a victory for the people suffering from these highly drug-resistant forms of the world’s deadliest infectious disease,” said Mel Spigelman, MD, president and CEO of TB Alliance. “The associated novel regimen will hopefully provide a shorter, more easily manageable and highly efficacious treatment for those in need.”

The three-drug regimen consisting of bedaquiline, pretomanid and linezolid – collectively referred to as the BPaL regimen – was studied in the pivotal Nix-TB trial across three sites in South Africa. The trial enrolled 109 people with XDR-TB as well as treatment-intolerant or non-responsive MDR-TB.2

Nix-TB data have demonstrated a successful outcome in 95 of the first 107 patients after six months of treatment with BPaL and six months of post-treatment follow-up.2 For two patients, treatment was extended to nine months. The new drug application contains data on 1,168 people who have received pretomanid in 19 clinical trials that have evaluated the drug’s safety and efficacy.2 Pretomanid has been clinically studied in 14 countries.

TB, in all forms, must be treated with a combination of drugs; the most drug-sensitive forms of TB require six months of treatment using four anti-TB drugs.3 Treatment of XDR-TB or treatment-intolerant/non-responsive MDR-TB has historically been lengthy and complex; most XDR-TB patients currently take a combination of as many as eight antibiotics, some involving daily injections, for 18 months or longer.3,4 Prior to recent introduction of new drugs for drug-resistant TB, the World Health Organization (WHO) has reported estimates for treatment success rates of XDR-TB therapy at approximately 34 percent and about 55 percent for MDR-TB therapy.4

“Until very recently, people infected with highly drug-resistant TB had poor treatment options and a poor prognosis,” said Dr. Francesca Conradie, principal investigator of the Nix-TB trial. “This new regimen provides hope with 9 out of 10 patients achieving culture negative status at 6 months post-treatment  with this short, all-oral regimen."

Pretomanid is a new chemical entity and a member of a class of compounds known as nitroimidazooxazines. TB Alliance acquired the developmental rights to the compound in 2002. It has been developed as an oral tablet formulation for the treatment of TB in combination with bedaquiline and linezolid, two other anti-TB agents, and is now indicated for use in a limited and specific population of patients.1 Adverse reactions reported during the Nix-TB trial of the BPaL regimen include hepatotoxicity, myelosuppression, as well as peripheral and optic neuropathy.1 Please see additional safety information in the Important Safety Information below.

Pretomanid is only the third new anti-TB drug approved for use by FDA in more than 40 years, as well as the first to be developed and registered by a not-for-profit organization.5,6 Pretomanid was granted Priority Review, Qualified Infectious Disease Product, and Orphan Drug status. As a product development partnership, TB Alliance has collaborated with and received significant support from numerous governments, academia, philanthropic institutions, the private sector, civil society organizations and other partners over the course of pretomanid’s development.

Pretomanid is expected to be available in the United States by the end of this year. In addition to the U.S. FDA, TB Alliance has submitted pretomanid as part of the BPaL regimen for review by the European Medicines Agency and has provided data to the World Health Organization for consideration of inclusion in treatment guidelines for highly drug-resistant TB.

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

FDA Approves Rinvoq (upadacitinib), an Oral JAK Inhibitor for the Treatment of Moderate to Severe Rheumatoid Arthritis

In continuation of my update on Rinvoq (upadacitinib)

AbbVie (NYSE: ABBV), a research-based global biopharmaceutical company, today announced that the U.S. Food and Drug Administration (FDA) has approved Rinvoq (upadacitinib), a 15 mg, once-daily oral Janus kinase (JAK) inhibitor, for the treatment of adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to methotrexate (MTX-IR).1 Rinvoq is expected to be available in the U.S. in late August 2019.

The FDA approval of Rinvoq is supported by data from the SELECT program, one of the largest registrational Phase 3 programs in RA with approximately 4,400 patients evaluated across all treatment arms in five studies.2-6 The studies include assessments of efficacy, safety and tolerability across a variety of RA patients, including those who failed or were intolerant to biologic disease-modifying anti-rheumatic drugs and who were naïve or inadequate responders to methotrexate. Rinvoq is not indicated for methotrexate-naïve patients.

"Despite the availability of multiple treatment options with varying mechanisms of action, many patients still do not achieve clinical remission or low disease activity—the primary treatment goals for rheumatoid arthritis," said Roy M. Fleischmann, M.D., primary investigator for SELECT-COMPARE and clinical professor at the University of Texas Southwestern Medical Center at Dallas. "With this FDA approval, Rinvoq has the potential to help additional people living with RA achieve remission who have not yet reached this goal."

Across the SELECT Phase 3 studies, Rinvoq met all primary and ranked secondary endpoints. The primary endpoints include:

• In SELECT-EARLY, 52 percent of MTX-naïve patients treated with Rinvoq 15 mg achieved ACR50 vs 28 percent treated with MTX at week 121
• In SELECT-MONOTHERAPY, 68 percent of MTX-IR patients treated with Rinvoq 15 mg achieved ACR20 vs 41 percent treated with continued MTX at week 141
• In SELECT-COMPARE, 71 percent of MTX-IR patients treated with Rinvoq 15 mg plus MTX achieved ACR20 vs 36 percent treated with placebo plus MTX at week 121
• In SELECT-NEXT, 64 percent of csDMARD-IR patients treated with Rinvoq 15 mg plus csDMARDs achieved ACR20 vs 36 percent treated with placebo plus csDMARDs at week 121
• In SELECT-BEYOND, 65 percent of biologic-IR patients treated with Rinvoq 15 mg plus csDMARDs achieved ACR20 vs 28 percent treated with placebo plus csDMARDs at week 121

"The discovery and development of Rinvoq is indicative of AbbVie's long-standing commitment to advancing the science for people living with immune-mediated conditions," said Michael Severino, M.D., vice chairman and president, AbbVie. "Today's FDA approval marks an important milestone in our pursuit to deliver innovative medicines that advance care for people living with rheumatoid arthritis."

Clinical Remission

Patients taking Rinvoq achieved clinical remission, a state characterized by almost no disease activity and symptoms, even without methotrexate.2-3,6 Approximately 30 percent of patients treated with Rinvoq achieved clinical remission (as assessed by DAS28-CRP<2.6) at week 12 in SELECT-COMPARE and week 14 in SELECT-MONOTHERAPY compared to six percent with placebo plus methotrexate and eight percent with methotrexate, respectively.1 In SELECT-EARLY, 36 percent of patients treated with Rinvoq achieved clinical remission (as assessed by DAS28-CRP<2.6) at week 12 compared to 14 percent with methotrexate.1 

Durable remission rates were observed up to week 26. Forty-eight percent of patients treated with Rinvoq alone in SELECT-EARLY and 41 percent of patients treated with Rinvoq plus methotrexate in SELECT-COMPARE achieved clinical remission at weeks 24 and 26, compared to nine percent with placebo plus methotrexate and 18 percent with methotrexate, respectively.1 Analysis at weeks 24 and 26 were not controlled for multiple comparisons.3,10

Radiographic Inhibition

Rinvoq significantly inhibited radiographic progression as measured by the change in modified total Sharp score (mTSS) from baseline compared to methotrexate in SELECT-EARLY (0.14 vs 0.67) and Rinvoq plus methotrexate compared to placebo plus methotrexate in SELECT-COMPARE (0.15 vs 0.78) through weeks 24 and 26, respectively.1 

Safety

The most common side effects associated with Rinvoq include upper respiratory tract infections (common cold, sinus infections), nausea, cough and pyrexia.1 Patients treated with Rinvoq are at increased risk for developing serious infections that may lead to hospitalization or death. These infections include tuberculosis (TB), invasive fungal, bacterial, viral, and other infections due to opportunistic pathogens. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.1 Lymphoma and other malignancies have been observed in Rinvoq-treated patients.1 Thrombosis, including deep vein thrombosis, pulmonary embolism, and arterial thrombosis, have occurred in patients treated with JAK inhibitors used to treat inflammatory conditions.1 Patients treated with RINVOQ also may be at risk for other serious adverse reactions, including gastrointestinal perforations, neutropenia, lymphopenia, anemia, lipid elevations, liver enzyme elevations, and embryo-fetal toxicity.1 

Ease of Use and Access

Designed to help accommodate the physical limitations of people living with RA, the packaging for Rinvoq includes a bottle cap with a wide, easy-to-grip texture and an embedded tool that punctures the foil liner to simplify medication access. This packaging design was awarded the Arthritis Foundation Ease of Use Commendation.

"Rheumatoid arthritis can have a debilitating impact on the lives of those with the chronic disease, including making it difficult to perform everyday tasks," said Cindy McDaniel, senior vice president, consumer health, Arthritis Foundation. "The Arthritis Foundation is committed to recognizing innovation that can help patients living with rheumatoid arthritis and we are proud to recognize AbbVie with our Ease of Use Commendation for the packaging design of Rinvoq."

AbbVie continues to work closely with key stakeholders to support patient access to Rinvoq, including offering a patient support program and a co-pay card that may reduce out-of-pocket costs to $5 per month for eligible, commercially-insured patients. For those with limited or no health insurance, AbbVie offers myAbbVie Assist, a patient assistance program that provides Rinvoq to qualifying patients.

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

https://www.drugbank.ca/drugs/DB15091

TB Medicine Pretomanid Enters Regulatory Review Process in the United States

 TB Alliance’s new drug application (NDA) for the novel tuberculosis (TB) drug candidate pretomanid has been accepted for review by the United States Food and Drug Administration (FDA). The application is for the use of pretomanid as part of a new regimen, in combination with bedaquiline and linezolid, for the treatment of extensively drug-resistant (XDR) TB, treatment intolerant multidrug-resistant (MDR) TB, and treatment non-responsive MDR-TB.

The NDA for pretomanid has been granted Priority Review by FDA. The Prescription Drug User Fee Act (PDUFA) action date for an FDA decision is in third quarter 2019.

TB Alliance will work with manufacturing partners to ensure that pretomanid, if approved for use in the BPaL regimen, will be accessible to those who need it.

About Pretomanid and the BPaL Regimen

Pretomanid is a new chemical entity and a member of a class of compounds known as nitroimidazooxazines. It has been studied in 20 clinical trials alone or in combination with other anti-TB drugs. Since TB Alliance began development of pretomanid in 2002, it has been administered in a clinical trial setting to more than 1,200 people in 14 countries.

The BPaL regimen (comprised of bedaquiline, pretomanid and linezolid) was first studied clinically in the Phase 3 Nix-TB trial. Nix-TB participants with XDR-TB and treatment intolerant or nonresponsive MDR-TB were enrolled for treatment with the BPaL regimen for six months, extendable to nine months, with the intent to cure. Nix-TB is an open label, single arm trial. According to a modified intention-to-treat analysis of interim results on the first 75 participants presented at the 2018 Union World Conference on Lung Health, 89% of the trial participants had a favorable outcome with their clinical infection resolved and sputum cultures negative for TB after six months of treatment and six months of post-treatment follow-up.

https://www.tballiance.org/portfolio/compound/pretomanid

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

https://www.drugbank.ca/drugs/DB05154

TB Medicine Pretomanid Enters Regulatory Review Process in the United States

Ancient Chinese medicine for malaria could potentially aid in treatment of tuberculosis

In continuation of my update on Artemisinin

A centuries-old herbal medicine, discovered by Chinese scientists and used to effectively treat malaria, has been found to potentially aid in the treatment of tuberculosis and may slow the evolution of drug resistance.

In a promising study led by Robert Abramovitch, a Michigan State University microbiologist and TB expert, the ancient remedy artemisinin stopped the ability of TB-causing bacteria, known as Mycobacterium tuberculosis, to become dormant. This stage of the disease often makes the use of antibiotics ineffective.

The study is published in the journal Nature Chemical Biology.

"When TB bacteria are dormant, they become highly tolerant to antibiotics," Abramovitch said, an assistant professor in the College of Veterinary Medicine. "Blocking dormancy makes the TB bacteria more sensitive to these drugs and could shorten treatment times."

One-third of the world's population is infected with TB and the disease killed 1.8 million people in 2015, according to the Centers for Disease Control and Prevention.

Mycobacterium tuberculosis, or Mtb, needs oxygen to thrive in the body. The immune system starves this bacterium of oxygen to control the infection. Abramovitch and his team found that artemisinin attacks a molecule called heme, which is found in the Mtb oxygen sensor. By disrupting this sensor and essentially turning it off, the artemisinin stopped the disease's ability to sense how much oxygen it was getting.

"When the Mtb is starved of oxygen, it goes into a dormant state, which protects it from the stress of low-oxygen environments," Abramovitch said. "If Mtb can't sense low oxygen, then it can't become dormant and will die."

Abramovitch indicated that dormant TB can remain inactive for decades in the body. But if the immune system weakens at some point, it can wake back up and spread. Whether it wakes up or stays 'asleep' though, he said TB can take up to six months to treat and is one of the main reasons the disease is so difficult to control.

"Patients often don't stick to the treatment regimen because of the length of time it takes to cure the disease," he said. "Incomplete therapy plays an important role in the evolution and spread of multi-drug resistant TB strains."

He said the research could be key to shortening the course of therapy because it can clear out the dormant, hard-to-kill bacteria. This could lead to improving patient outcomes and slowing the evolution of drug-resistant TB.

After screening 540,000 different compounds, Abramovitch also found five other possible chemical inhibitors that target the Mtb oxygen sensor in various ways and could be effective in treatment as well.

"Two billion people worldwide are infected with Mtb," Abramovitch said. "TB is a global problem that requires new tools to slow its spread and overcome drug resistance. This new method of targeting dormant bacteria is exciting because it shows us a new way to kill it."

Ref : http://www.nature.com/nchembio/journal/vaop/ncurrent/full/nchembio.2259.html

Scientists identify new agent to combat tuberculosis

(Griselimycin)

Above pic: The protein forms a homodimeric ring (shown as blue cartoon & surface representation). Each polypetide chain binds one molecule of griselimycin (red). The optimized compound cyclohexylgriselimycin contains an additional cyclohexane moiety (yellow, shown only for the ligand in the foreground).

According to figures of the World Health Organization, some 8.7 million people contracted tuberculosis in 2012 and this disease is fatal for approximately 1.3 million people throughout the world each year. One of the main problems is that the tuberculosis pathogens have become resistant to the antibiotics used to fight them. Scientists from the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) in Saarbrücken, the Helmholtz Centre for Infection Research (HZI) in Braunschweig and the German Center for Infection Research (DZIF) joined forces with scientists from Sanofi, a global health care company, and identified a new agent, which might potentially remedy these problems. The scientists just described this agent and its unique mechanism of action in the highly renowned scientific journal Science.

Mycobacterium tuberculosis is the main cause of tuberculosis. The treatment for drug-susceptible tuberculosis consists of the daily administration of multiple drugs for a minimum of six months. Lack of adherence to this regimen can result in treatment failure and the emergence of drug resistance. "Complexity and duration of the treatment are true issues and the main reasons for the development of resistant pathogens," says Prof Rolf Müller, who is the Executive Director and head of the Microbial Natural Substances department of the HIPS, an institution jointly sponsored by the HZI and Saarland University.

Consequently, there is an urgent need for new medications and therapeutic approaches to both fight the resistant pathogens, as well as to shorten the duration for the treatment of drug-susceptible organisms. Based on earlier reports, Müller, in collaboration with Prof Jacques Grosset from the Johns Hopkins University School of Medicine in Baltimore, and his colleagues from the HZI and Sanofi scientists, initially focused on the natural substance called griselimycin. The potential of this natural substance, was discovered in the 1960s. However, due to the success of other tuberculosis medications and its low efficacy in an infection model, the substance was not developed any further at the time.

"We resumed the work on this agent and optimised it such that it shows excellent activity in the infection model - even against multi-resistant tuberculosis pathogens," says Müller. In the course of their work, the scientists discovered that cyclohexylgriselimycin, a variant of griselimycin, is particularly effective against Mycobacterium tuberculosis, both in cells and in the animal model. Importantly, cyclohexylgriselimycin was effective when administered orally, which is key in tuberculosis treatment, non-orally available drugs are extremely burdensome to administer daily during the many months of treatment. Moreover, combining this substance with current TB antibiotics increases the efficacy compared to the antibiotic cocktail that is usually administered.

Scientists identify new agent to combat tuberculosis

Combination of bedaquiline and verapamil reduces side effects, improves outcomes for TB patients

In continuation of my update on Bedaquiline

While an effective treatment is available for combating multidrug-resistant tuberculosis, it carries serious side effects for patients. New research conducted at the Center for Tuberculosis Research at the Johns Hopkins University School of Medicine shows that lower doses of the toxic drug bedaquiline — given together with verapamil, a medication that's used to treat various heart conditions — can lead to the same antibacterial effects as higher toxic doses of bedaquiline. The combination of the two drugs could potentially shorten treatment time, reduce the side effects of bedaquiline and improve patient outcomes for those suffering from TB.

The study will be published in the January 2014 issue of Antimicrobial Agents and Chemotherapy. The lead author is William Bishai, M.D., Ph.D., co-director of the Center for Tuberculosis Research.

"Using a mouse model of tuberculosis, we have shown lower doses of bedaquiline together with verapamil have the same antibacterial effect as the higher toxic doses," says Shashank Gupta, Ph.D., a research fellow at Johns Hopkins. "A lower dose of bedaquiline will cause no or less severe side effects."

Two years ago, bedaquiline became the first drug in the last four decades to be approved by the U.S. Food and Drug Administration for the treatment of multidrug-resistant TB. The drug works by inhibiting an enzyme used by Mycobacterium tuberculosis to replicate and spread throughout the body. While it can be a lifesaving therapy against one of the world's deadliest diseases, bedaquiline can also cause serious side effects in the heart and liver. Therefore, strategies to reduce the dose of bedaquiline while retaining its antibacterial activity would provide significant benefits to patients.

"Shortening treatment regimens and reducing the required doses may be a promising strategy to reduce the incidence of bedaquiline-related adverse effects and thereby improve multidrug-resistant TB treatment outcomes," says Gupta.

Combination of bedaquiline and verapamil reduces side effects, improves outcomes for TB patients

Final Phase 1 data of zoptarelin doxorubicin Phase 1/2 trial published in Clinical Cancer Research

Aeterna Zentaris Inc. (NASDAQ: AEZS, TSX: AEZ) (the "Company")  announced that an article on final data for the Phase 1 portion of the ongoing Phase 1/2 trial in prostate cancer with zoptarelin doxorubicin (formerly AEZS-108), a hybrid molecule composed of a synthetic peptide carrier and a well-known chemotherapy agent, doxorubicin, has been published in the December issue of Clinical Cancer Research. The article outlines data previously disclosed in June 2013 at the American Society of Clinical Oncology's ("ASCO") Annual Meeting, which demonstrated the compound's safety profile and promising anti-tumor activity in heavily pre‑treated men with castration- and taxane-resistant prostate cancer. These results led to the current investigator-driven Phase 2 portion in this same indication under the supervision of lead investigator, Jacek Pinski, MD, PhD, of the USC Norris Comprehensive Cancer Center. Titled, "Phase I, Dose-Escalation Study of the Targeted Cytotoxic LHRH Analog AEZS-108 in Patients with Castration- and Taxane-Resistant Prostate Cancer", Liu SV, Tsao-Wei DD, Xiong S, Groshen S, Dorff TB, Quinn DI, Tai YC, Engel J, Hawes D, Schally AV, Pinski J., the article is available at this link: Clin Cancer Res.

Final Phase 1 data of zoptarelin doxorubicin Phase 1/2 trial published in Clinical Cancer Research

Diabetes drug can boost efficacy of TB medication without causing drug resistance

In continuation of my update on Metformin

A more effective treatment for tuberculosis (TB) could soon be available as scientists have discovered that Metformin (MET), a drug for treating diabetes, can also be used to boost the efficacy of TB medication without inducing drug resistance.

This discovery was made by a team of international scientists led by the Singapore Immunology Network (SIgN), a research institute under the Agency for Science, Technology and Research (A*STAR), Singapore.

TB is an air-borne infectious disease caused by a bacterium called Mycobacterium tuberculosis (Mtb), which often infects the lungs. Even though drugs are available to treat the disease, TB continues to be a major threat to public health, killing close to 1.5 million people every year .

Conventional drugs used to treat TB usually adopt a pathogen-targeted strategy which attacks and kills bacteria directly. This approach has caused Mtb strains to acquire drug resistance, making existing treatments become increasingly ineffective and resulting in a pressing need to design new therapeutic strategies for the disease.

MET as an adjunct treatment for TB

The team of scientists led by SIgN began searching for drugs that could control Mtb replication indirectly. They screened FDA-approved drugs and identified MET, an old anti-diabetic drug that could defend Mtb invasion without targeting the bacteria directly. Instead, MET targets the host cells to trigger the production of a chemical which then damages Mtb and stops its replication. Such indirect, host-targeted approach is less likely to engender drug resistance. The team also discovered that MET improves the efficacy of conventional anti-TB drugs when used in combination with them.

The scientists then validated the findings with patient data provided by the Tuberculosis Clinical Unit at the Tan Tock Seng Hospital, and consequently verified that the use of MET is indeed associated with improved TB control and decreased disease severity. This anti-diabetic drug is therefore a promising adjunctive therapy that could enhance the effectiveness of existing TB treatments. As it is a drug that is currently in use, another benefit of using MET as an adjunct treatment for TB is that it is likely to shorten the time required for clinical trials.

Diabetes drug can boost efficacy of TB medication without causing drug resistance

Multitarget TB drug could treat other diseases, evade resistance -- ScienceDaily

A drug under clinical trials to treat tuberculosis could be the basis for a class  of broad-spectrum drugs that act against various bacteria, fungal infections and parasites, yet evade resistance, according to a study. The team determined the different ways the drug SQ109 attacks the tuberculosis bacterium, how the drug can be tweaked to target other pathogens from yeast to malaria  and how targeting multiple pathways reduces the probability of pathogens becoming resistant.

Led by U. of I. chemistry professor Eric Oldfield, the team determined the different ways the drug SQ109 attacks the tuberculosis bacterium, how the drug  can be tweaked to target other pathogens from yeast to malaria -- and how targeting multiple pathways reduces the probability of pathogens becoming resistant. SQ109 is made by Sequella Inc., a pharmaceutical company. 

"Drug resistance is a major public health threat," Oldfield said. "We have to make new antibiotics, and we have to find ways to get around the resistance problem. And one way to do that is with multitarget drugs. Resistance in many cases arises because there's a specific mutation in the target protein so the drug will no longer bind. Thus, one possible route to attacking the drug resistance problem will be to devise drugs that don't have just one target, but
two or three targets."

Oldfield read published reports about SQ109 and realized that the drug would likely be multifunctional because it had chemical features similar to those found in other systems he had investigated. The original developers had identified one key action against tuberculosis -- blocking a protein involved in building the cell wall of the bacterium -- but conceded that the drug could have other actions within the cell as well since it was found to kill other bacteria and
fungi that lacked the target protein. Oldfield believed he could identify those actions  and perhaps improve upon SQ109. 

"I was reading Science magazine one day and saw this molecule, SQ109, and I thought, that looks a bit like molecules we've been studying that have multiple targets," Oldfield said. "Given its chemical structure, we thought that some of the enzymes that we study as cancer and antiparasitic drug targets also could be SQ109 targets. We hoped that we could make some analogs that would be more potent against tuberculosis, and maybe even against parasites.

More : http://pubs.acs.org/doi/abs/10.1021/jm500131s

Multitarget TB drug could treat other diseases, evade resistance

Researchers identify potential way to combat TB

Researchers have identified a potential way to manipulate the immune system to improve its ability to fight off tuberculosis (TB).

TB is a major problem for both humans and cattle and the new findings could help scientists to create better drugs to combat the disease in both.

The disease is caused by the bacterium Mycobacterium tuberculosis, which infects the lungs. The mycobacteria are able to establish persistent TB infections by taking up residence in macrophages - cells of the immune system that would normally destroy invading microorganisms.

Now, in early stage research published in the Journal of Biological Chemistry, researchers from Imperial College London and Stanford University have revealed precisely how unusual sugars on the surface of the mycobacteria that cause TB are able to latch onto the macrophages and disarm them. They now hope that scientists at Imperial and elsewhere can use this knowledge to develop small molecule drugs that latch tightly onto the same site.

These drugs could potentially fight tuberculosis in a number of ways, say the researchers. They could create a barrier to prevent the mycobacteria from attaching to the macrophages; they could transport drugs to kill the mycobacteria; or they could change how the macrophages behave, so that they destroy the mycobacteria rather than harbouring them.

Professor Kurt Drickamer, a lead author of the research from the Department of Life Sciences at Imperial College London, said: "TB is hard to fight effectively because it can hide inside the cells of the immune system that should be able to destroy it. We were surprised to find that there is an extensive interaction between the macrophage and one particular type of molecule on the surface of the mycobacteria. The nature of the interaction gives us hope that we can make simple molecules that block the ability of the mycobacteria to subvert the macrophages.

Ref : http://www.jbc.org/content/288/40/28457.abstract?sid=eeb4801e-b429-4bbf-b0cd-446229088668

"Researchers identify potential way to combat TB

Mycobacterium tuberculosis is extraordinarily sensitive to killing by a vitamin C-induced Fenton reaction : Nature Communications : Nature Publishing Group

In a striking, unexpected discovery, researchers at Albert Einstein College of Medicine of Yeshiva University have determined that vitamin C kills drug-resistant tuberculosis (TB) bacteria in laboratory culture. The finding suggests that vitamin C added to existing TB drugs could shorten TB therapy, and it highlights a new area for drug design.

Dr. Jacobs and his colleagues observed that isoniazid-resistant TB bacteria were deficient in a molecule called mycothiol. "We hypothesized that TB bacteria that can't make mycothiol might contain more cysteine, an amino acid," said Dr. Jacobs. 

"So, we predicted that if we added isoniazid and cysteine to isoniazid-sensitive M. tuberculosis in culture, the bacteria would develop resistance. Instead, we ended up killing off the culture  something totally unexpected."

The Einstein team suspected that cysteine was helping to kill TB bacteria by acting as a "reducing agent" that triggers the production of reactive oxygen species (sometimes called free radicals), which can damage DNA.

"To test this hypothesis, we repeated the experiment using isoniazid and a different reducing agent vitamin C," said Dr. Jacobs. "The combination of isoniazid and vitamin C sterilized the M. tuberculosis culture. We were then amazed to discover that vitamin C by itself not only sterilized the drug-susceptible TB, but also sterilized MDR-TB and XDR-TB strains."

To justify testing vitamin C in a clinical trial, Dr. Jacobs needed to find the molecular mechanism by which vitamin C exerted its lethal effect. More research produced the answer: Vitamin C induced what is known as a Fenton reaction, causing iron to react with other molecules to create reactive oxygen species that kill the TB bacteria.

"We don't know whether vitamin C will work in humans, but we now have a rational basis for doing a clinical trial," said Dr. Jacobs. "It also helps that we know vitamin C is inexpensive, widely available and very safe to use. At the very least, this work shows us a new mechanism that we can exploit to attack TB.".....

Ref : http://www.einstein.yu.edu/news/releases/907/study-finds-vitamin-c-can-kill-drug-resistant-tb/


Mycobacterium tuberculosis is extraordinarily sensitive to killing by a vitamin C-induced Fenton reaction : Nature Communications : Nature Publishing Group

FDA Approves Sirturo to Treat Multi-Drug Resistant Tuberculosis

In continuation of my update on bedaquiline...

Sirturo is being approved under the FDA’s accelerated approval program, which allows the agency to approve a drug to treat a serious disease based on clinical data showing that the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. This program provides patients earlier access to promising new drugs while the company conducts additional studies to confirm the drug’s clinical benefit and safe use.

The FDA also granted Sirturo fast track designation, priority review and orphan-product designation. The drug demonstrated the potential to fill an unmet medical need, has the potential to provide safe and effective treatment where no satisfactory alternative therapy exists, and is intended to treat a rare disease, respectively.

Sirturo carries a Boxed Warning alerting patients and health care professionals that the drug can affect the heart’s electrical activity (QT prolongation), which could lead to an abnormal and potentially fatal heart rhythm. The Boxed Warning also notes deaths in patients treated with Sirturo. Nine patients who received Sirturo died compared with two patients who received placebo. Five of the deaths in the Sirturo group and all of the deaths in the placebo arm seemed to be related to tuberculosis, but no consistent reason for the deaths in the remaining Sirturo-treated patients could be identified.

Sirturo’s manufacturer, Janssen Therapeutics, will distribute the drug from a single source and will provide educational materials to help ensure the drug is used appropriately.

Sirturo’s safety and effectiveness were established in 440 patients in two Phase 2 clinical trials. Patients in the first trial were randomly assigned to be treated with Sirturo plus other drugs used to treat TB, or a placebo plus other drugs used to treat TB. All patients in the second trial, which is ongoing, received Sirturo plus other TB drugs. Both studies were designed to measure the length of time it took for a patient’s sputum to be free of M. tuberculosis (sputum culture conversion, or SCC).

FDA Approves Sirturo to Treat Multi-Drug Resistant Tuberculosis

FDA Approves Sirturo to Treat Multi-Drug Resistant Tuberculosis

In continuation of my update on Sirturo

On Dec. 28, the U.S. Food and Drug Administration approved Sirturo (bedaquiline) as part of combination therapy to treat adults with multi-drug resistant pulmonary tuberculosis (TB) when other alternatives are not available.

Bedaquiline (also known as Sirturo, TMC207 or R207910 see structure) is an diarylquinoline anti-tuberculosis drug, which was discovered by Koen Andries and his team at Janssen Pharmaceutica. It was described for the first time in 2004 at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting Late-Breaker Session, after the drug had been in development for over 7 years, and a trial of 47 patients showed that it is effective in the treatment of M. tuberculosis.

Multi-drug resistant TB occurs when M. tuberculosis becomes resistant to isonazid and rifampin, two powerful drugs most commonly used to treat TB. Sirturo is the first drug approved to treat multi-drug resistant TB and should be used in combination with other drugs used to treat TB. Sirturo works by inhibiting an enzyme needed by M. tuberculosis to replicate and spread throughout the body.

“Multi-drug resistant tuberculosis poses a serious health threat throughout the world, and Sirturo provides much-needed treatment for patients who have don’t have other therapeutic options available,” said Edward Cox, M.D., M.P.H, director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research. “However, because the drug also carries some significant risks, doctors should make sure they use it appropriately and only in patients who don’t have other treatment options.”

Sirturo is being approved under the FDA’s accelerated approval program, which allows the agency to approve a drug to treat a serious disease based on clinical data showing that the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients. This program provides patients earlier access to promising new drugs while the company conducts additional studies to confirm the drug’s clinical benefit and safe use.

The FDA also granted Sirturo fast track designation, priority review and orphan-product designation. The drug demonstrated the potential to fill an unmet medical need, has the potential to provide safe and effective treatment where no satisfactory alternative therapy exists, and is intended to treat a rare disease, respectively.

Sirturo carries a Boxed Warning alerting patients and health care professionals that the drug can affect the heart’s electrical activity (QT prolongation), which could lead to an abnormal and potentially fatal heart rhythm. The Boxed Warning also notes deaths in patients treated with Sirturo. Nine patients who received Sirturo died compared with two patients who received placebo. Five of the deaths in the Sirturo group and all of the deaths in the placebo arm seemed to be related to tuberculosis, but no consistent reason for the deaths in the remaining Sirturo-treated patients could be identified.

FDA Approves Sirturo to Treat Multi-Drug Resistant Tuberculosis

Beating Drug-Resistant TB.....

An antibiotic produced naturally by common soil bacteria kills Mycobacterium species that cause various human diseases, including tuberculosis (TB), according to a report published Monday (September 17) in EMBO Molecular Medicine. The antibiotic even kills drug-resistant strains that escape current TB treatments.

“I seldom get so tickled when I read a paper,” said William Jacobs, a microbiologist and immunologist at the Albert Einstein College of Medicine in New York, who did not participate in the research. The emergence of multidrug resistant strains of Mycobacterium tuberculosis “is a big problem,” he said. “This could be a godsend.”

Tuberculosis infections are commonly treated with a mixture of antibiotics, including one called isoniazid, which Jacobs described as “the cornerstone of TB therapy.”  Unfortunately, the most common drug-resistant strains of M. tuberculosis are isoniazid-resistant, he said.

Many researchers, including Stewart Cole, chair of the microbial pathogenesis department at the École Polytechnique Fédérale de Lausanne in Switzerland, have thus been searching for new M. tuberculosis-killing drugs. “In the past we’ve been working a lot on TB drug discovery using target-based approaches… [but] this has been spectacularly unsuccessful,” said Cole. So instead, he and his colleagues looked back over decades of academic literature searching for reports of natural compounds with M. tuberculosis-killing activity.

They found pyridomycin (see above structure). First described in the 1950s, the drug was reportedly produced by the bacteria Streptomyces pyridomyceticus and Dactylosporangium fulvum. Surprisingly, little was known about pyridomycin—perhaps, Cole suggested, because isoniazid was discovered around the same time and simply stole the limelight.

Cole’s team grew cultures of D. fulvum bacteria, figured out how to isolate and purify pyridomycin, and then showed that the drug was indeed capable of killing M. tuberculosis, as well as many otherMycobacterium species, in culture.

This indiscriminate Mycobacterium-killing ability is a bonus, said Cole. “One of the problems with isoniazid is that it only works against TB,” he said. “If pyridomycin makes it into the clinic, it could have applications in leprosy or Buruli ulcer or atypical mycobacterial infections that can occur in cystic fibrosis patients.”

The team went on to identify the bactericidal target of pyridomycin—a protein called inhA, which is involved in synthesis of bacterial cell wall components. As it happens, inhA is the same protein targeted by isoniazid, but there is a difference in the two drugs’ mechanisms. While isoniazid is a pro-drug that requires activation by an intracellular enzyme called KatG before it can bind to inhA, pyridomycin binds inhA directly.

This is an important distinction, explained Valerie Mizrahi, director of the Institute of Infectious Disease and Molecular Medicine at Cape Town University, South Africa, who was not involved in the study. The overwhelming majority of drug resistance mutations in M. tuberculosis occur in the KatGgene, she explained, and such mutant strains should not be resistant to pyridomycin. Indeed, the team showed that clinical isolates of isoniazid-resistant M. tuberculosis carrying KatG mutations were killed effectively by pyridomycin. “The efficacy against drug resistant forms of M. tuberculosis is particularly encouraging,” Mizrahi said.

There is, however, much to be done before pyridomycin can be used in the clinic. “We would [need to] test that it works in animal models and that it is safe and doesn’t have any side effects,” said Cole. “That will take a couple of years.”

“It’s a long journey,” agreed Mizrahi, “but the big plus is that they don’t really need to validate inhA as a drug target because inhA is already the most well validated drug target out there… [so] it has got a good head start.”

Ref : http://onlinelibrary.wiley.com/doi/10.1002/emmm.201201689/abstract

Developing the First Novel Drug Regimen from TB Alliance...

TB Alliance’s push to test new drugs in combination has been done to produce a regimen that not only would be faster and easier for patients, but also would tackle two other challenges as a major step in stopping the spread of drug-resistant TB—the complexity and high cost of treatment. This promising regimen eliminates the use of injectables and projects to reduce the cost of MDR-TB therapy by as much as 90 percent.

The study, NC-001, or New Combination 1, was a two-week trial successfully completed at two centers in South Africa. It involved the new combination therapy called PaMZ, consisting of the novel TB drug candidate, PA-824 (see below structure left); moxifloxacin (right structure), an established antibiotic not yet approved for use in first-line TB therapy and being developed in partnership with Bayer Healthcare AG; and pyrazinamide, an existing TB drug.

“Treating drug-sensitive and drug-resistant TB with the same regimen can simplify the delivery of TB treatment worldwide,” said Andreas Diacon, MD, the trial’s principal investigator and lead author of the Lancet study. “The results of this study give healthcare providers on the front lines of the TB epidemic hope for better, faster tools needed to stop this disease.”

 (Pyrazinamide)

Newscenter | Global Alliance for TB Drug Development

New Drug, Bedaquiline to Tackle Resistant TB

Johnson & Johnson said that it is seeking U.S. approval for the first new type of medicine to fight deadly tuberculosis in more than four decades.

The experimental drug, called bedaquiline (discovered by Koen Andries, see structure), also would be the first medicine specifically for treating multi-drug-resistant tuberculosis. That's an increasingly common form in which at least two of the four primary TB drugs don't work.

Mode of action : Bedaquiline affects the proton pump for ATP synthase, which is unlike the quinolones, whose target is DNA gyrase

Tuberculosis, caused by bacterial infection of the lungs and other body areas, is the world's No. 2 killer of adults among infectious diseases.

J&J's Janssen Research & Development unit created the drug, which was tested in several hundred patients with multidrug-resistant tuberculosis in two mid-stage studies lasting for six months. Some patients were studied for about 1 1/2 years.

The company this fall is to begin late-stage testing that will compare bedaquiline to dummy pills over nine months in about 600 patients; each will also take six other drugs that are the standard treatments for tuberculosis. That study is aimed at seeing whether treatment for resistant tuberculosis can be reduced to nine months from the current 18 to 24 months recommended by the World Health Organization.

Roughly one-third of the world's population is estimated to be infected with the bacteria causing tuberculosis. It remains latent in most people for many years but can be activated by another infection or serious health problem.

TB is rare in the U.S. but kills about 1.4 million people a year worldwide, with about 150,000 of those succumbing to the increasingly common multidrug-resistant forms.

Janssen's head of infectious diseases, Dr. Wim Pays, said the company will also apply for approval of bedaquiline in other countries where TB is very common.

The disease is a serious problem in developing countries because it takes so long to cure and many patients stop taking their pills once they begin to feel better. That helps bacteria still alive in the patient to develop resistance to the medicines already taken, making future treatment much more difficult.

Ref : http://www.inpharm.com/news/173302/janssen-submits-tuberculosis-pill-fda