A5409/RAD-TB is an adaptive Phase 2 randomized, controlled, open-label, dose-ranging, platform protocol to evaluate the safety and efficacy of multidrug regimens for the treatment of adults with drug-susceptible pulmonary tuberculosis (TB).
A5409 hypothesizes that novel regimens for the treatment of pulmonary tuberculosis will result in superior early efficacy, as determined by longitudinal mycobacteria growth indicator tube (MGIT) liquid culture time to positivity (TTP) measurements over the first 6 weeks of treatment, and will have acceptable safety and tolerability over 8 weeks of treatment relative to standard of care [(SOC) isoniazid/rifampicin/pyrazinamide/ethambutol (HRZE)].
The study will run for 52 weeks, inclusive of 26 weeks of TB treatment comprised of 8 weeks of experimental or SOC treatment (based on treatment arm assignment) followed by 18 weeks of SOC treatment with 45 participants in each experimental treatment arm and at least 90 participants in the SOC arm.

Start Date10 Jan 2025

Sponsor / Collaborator

National Institute of Allergy & Infectious Diseases

[+1]

NCT06253715 / Not yet recruitingPhase 3IIT

Shortened Regimen for Drug-susceptible TB in Children

While drug-susceptible tuberculosis (TB) disease in children currently requires four to six months of treatment, most children may be able to be cured with a shorter treatment of more powerful drugs. Shorter treatment may be easier for children to tolerate and finish as well as ease caregiver strain from managing treatment side effects and supporting children over many months. The primary objective of this study is to evaluate if a 2-month regimen (including isoniazid (H), rifapentine (P), pyrazinamide (Z) and moxifloxacin (M)) is as safe and effective as a 4- to 6-month regimen (isoniazid, rifampicin (R), pyrazinamide, ethambutol (E)) in curing drug-susceptible TB disease in children under 10 years old. The study is also evaluating the safety of the HPZM in children with and without HIV.

Start Date27 Nov 2024

Sponsor / Collaborator

The Johns Hopkins University

100 Clinical Results associated with Isoniazid

100 Translational Medicine associated with Isoniazid

100 Patents (Medical) associated with Isoniazid

20,072

Literatures (Medical) associated with Isoniazid

01 Feb 2025·Infectious disorders drug targets

Vigilance Needed in Treating a Child with Disseminated TB: A Case Report

Author: Keshari Kar, Bikram ; Gaikwad, Nitin Rewaram ; Chouhan, Dushyant ; Velmurugan, Hemasri ; Thangaraju, Pugazhenthan ; Neelambaram, Krishnapriya ; Gurunthalingam, Meenalotchini Prakash

Background::

Tuberculosis is still one of the biggest causes of infection-related death around the world. Disseminated tuberculosis is a potentially fatal disease caused by the haematogenous spread of Mycobacterium tuberculosis. First-line anti-tuberculosis drugs in-clude isoniazid, rifampicin, pyrazinamide, and ethambutol. The first three drugs are known to cause hepatotoxicity.

Case Presentation::

We have, herein, reported a case of Drug-induced Liver Injury (DILI) due to anti-tuberculosis therapy in a one-year-old male child with disseminated tuberculosis. He was started on a fixed-dose combination of Anti-tuberculosis Therapy (ATT; isoniazid 50 mg, rifampicin 75 mg, and pyrazinamide 150 mg) and pyridoxine 10 mg orally. Initially, liver pa-rameters were normal, but later on with the course of the treatment, there was a rapid rise in liver enzymes, suggesting liver injury.

Discussion::

The association between liver injury and anti-tuberculosis therapy has been con-firmed by applying various causality association scales. It is obvious that proper treatment of disseminated tuberculosis can avoid the development of drug-resistant strains that can be harm-ful, worsening the prognosis as there are fewer therapeutic alternatives available. At the same time, there is a need to monitor the patient with ATT-induced DILI.

Conclusion::

The diagnosis of tuberculosis in children is difficult because of the mild, nonspe-cific clinical presentation, which usually reflects the implicated underlying organ. In addition to prompt diagnosis and treatment of disseminated TB, careful monitoring is equally important.

01 Jan 2025·JOURNAL OF MOLECULAR GRAPHICS & MODELLING

Molecular dynamics simulations, essential dynamics and MMPBSA to evaluate natural compounds as potential inhibitors for AccD6, a key drug target in the fatty acid biosynthesis pathway in Mycobacterium tuberculosis

Article

Author: Singha, Chandra Jyoti ; Krishna, Ramadas

Antibiotic resistance in Mycobacterium tuberculosis, the primary causative agent of the tuberculosis disease is an ever growing threat especially in developing and underdeveloped countries. Isoniazid is a commonly used first line anti-tuberculosis drug used during the first phase of tuberculosis treatment. However, due to its improper use, many strains of Mycobacterium tuberculosis have acquired resistance to the drug. Advancements in next generation sequencing technologies, such as transcriptomics have paved way for identifying alternative drug targets based on the differential expression pattern of genes. Therefore, this study makes use of RNA-Seq data of Mycobacterium tuberculosis isolates treated with different concentrations of isoniazid to identify genes that can be proposed as drug targets. From the differential expression analysis, it was observed that four genes were significantly upregulated under all the conditions. Among the four genes, accD6 was selected as the drug target for virtual screening and molecular dynamics studies, because of its role in fatty acid elongation and contribution to the synthesis of mycolic acids. The protein-protein interaction network and gene ontology based functional enrichment studies show an enrichment in fatty acid biosynthesis related pathways. Furthermore, virtual screening studies successfully screened the top three natural inhibitor molecules with satisfactory ADME properties and a better glide score than the reference compound, NCI-172033. The trajectory analysis, essential dynamics studies and MMPBSA analysis, concluded that among the hit molecules, NPC41982, a thiazole derivative showed the most promising results and can be considered as a potential drug candidate.

31 Dec 2024·Annals of medicine

Tuberculosis (TB) treatment challenges in TB-diabetes comorbid patients: a systematic review and meta-analysis

Review

Author: Almalki, Mesfer Safar ; Najjar, Muath Fahmi ; Firash, Shuruq Zuhair ; Alturkistani, Samar Adel ; Alzahrani, Oseid Mohammed ; Saleem, Zikria ; Abuhussain, Safa Almarzooky ; Hussain, Rabia ; Rehman, Anees Ur ; Rasool, Muhammad Fawad ; Muqaddas, Tuba ; Khattak, Mahnoor ; Elsabaa, Hossameldeen Mahmoud Ali ; Haseeb, Abdul ; Bahauddin, Ammar Abdulraheem

BACKGROUND:

The Directly Observed Treatment-Short Course (DOTS) Programme was implemented by WHO and includes a combination of four anti-tuberculosis (TB) drugs (isoniazid, pyrazinamide, ethambutol and rifampicin) for a period of six months to eradicate the TB infection completely. Diabetes mellitus (DM) is recognized as one of a strong contributor of TB according to World Health Organization (WHO). The presence of diabetes mellitus type 2 (DM type 2) makes TB treatment complicated. Thus, the objective of the current meta-analysis was to identify and quantify the impact of type 2 DM on treatment outcomes of TB patients treated under the DOTS Programme.

METHODS:

This meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Through a systematic review of relevant literature, we focused on studies investigating treatment outcomes including extended treatment duration and recurrence for individuals with both TB and DM undergoing DOTS therapy. The extracted information included study designs, sample sizes, patient characteristics and reported treatment results.

RESULTS:

In 44 studies from different parts of the world, the pooled HR for the impact of DM on extended treatment duration and reoccurrence were HR 0.72, 95% CI 0.56-0.83, p < .01 and HR 0.93, 95% CI 0.70-1.04, p = .08, respectively. The pooled HR for impact of DM on composite TB treatment outcomes was calculated as 0.76 (95% CI 0.60-0.87), p < .01 with an effect size of 41.18. The heterogeneity observed among the included studies was moderate (I² = 55.79%).

CONCLUSIONS:

A negative impact of DM was found on recurrence and extended treatment duration in TB patients treated with DOTS therapy. DM type 2 is responsible for the TB treatment prolongation and TB recurrence rates. By implementing effective management strategies and advancing research, the challenges can be mitigated, arising due to the complex interaction between DM and TB.

News (Medical) associated with Isoniazid

14 Nov 2024

·www.globenewswire.com

ACTG Presents Two Studies Providing Insights Into TB Treatment at Union Conference on Lung Health

LOS ANGELES, Nov. 14, 2024 (GLOBE NEWSWIRE) -- ACTG, a global clinical trials network focused on HIV and other infectious diseases, announced two oral presentations on tuberculosis (TB) therapy that took place at The Union Conference on Lung Health 2024, in Bali, Indonesia. The oral presentation “Six Months is a Lot of Time to Lie:” Disclosure and Treatment Preferences Among Participants in a Tuberculosis Therapeutic Trial was presented by Faith Mugodhi, M.Sc., H.S.W., University of Zimbabwe-Clinical Trials Research Centre (UZ-CTRC). The oral presentation High Prevalence of Fluoroquinolone Resistance and katG Mutations in Adult Index Patients in a Multinational MDR-TB Prevention Trial was presented by Soyeon Kim, Sc.D., IMPAACT Senior Statistician, Frontier Science Foundation. “ACTG is honored to share these important findings with the many global stakeholders who are gathered in Indonesia at the Union Conference,” said ACTG Chair Judith Currier, M.D., M.Sc., University of California, Los Angeles. “TB is one of ACTG’s key research priorities, as the disease remains a leading killer worldwide. The knowledge gained from the research presented today has the potential to inform our approach to TB treatment and ultimately improve the experiences of people with TB.” “Six Months is a Lot of Time to Lie:” Disclosure and Treatment Preferences Among Participants in a Tuberculosis Therapeutic Trial was a sub-study that investigated experiences around disclosure and treatment preferences among participants in ACTG 5362. Also known as CLO-FAST, this multi-center treatment-shortening trial for drug-susceptible TB randomized individuals to receive either a three-month regimen containing clofazimine (which can be associated with skin hyperpigmentation) or the six-month standard of care. The sub-study consisted of exploratory, qualitative in-depth interviews with 23 participants undergoing treatment in CLO-FAST from India, Malawi, and Zimbabwe. This presentation reported that all sub-study participants with TB had voluntarily disclosed their TB status to at least one other person. Nearly half of participants (43.5 percent) feared inadvertent disclosure of their status due to their treatment and attendance at the TB clinic; 80 percent (n=8) of these were taking clofazimine. One in five participants reported experiencing stigma or discrimination as a result of inadvertent disclosure, including being treated badly by their families or communities. Today’s presentation also found that participants had different preferences around the kind of treatment they received. Two-thirds (n=15) of participants reported that they would prefer the shortened regimen even if one of the medications led to a change in their skin color, while one-third (n=8) reported a preference for the longer regimen. That preference was associated with anticipation of stigma and beliefs that a longer regimen is more potent against TB. These data suggest that anticipated stigma and pre-existing beliefs may be important in understanding treatment preferences. High Prevalence of Fluoroquinolone Resistance and katG Mutations in Adult Index Patients in a Multinational MDR-TB Prevention Trial is an analysis from the PHOENIx study, an ongoing clinical trial evaluating the efficacy and safety of preventive treatment for multi-drug resistant TB (MDR-TB) with delamanid compared to isoniazid, conducted jointly by the ACTG and IMPAACT (International Maternal Pediatric Adolescent AIDS Clinical Trials) networks. (IMPAACT is a global collaboration of investigators, institutions, community representatives, and other partners, with a mission to improve health outcomes for infants, children, and adolescents as well as pregnant and postpartum people who are impacted by or living with HIV by evaluating novel treatments and interventions for HIV and its complications for tuberculosis and other related complications, through the conduct of high-quality clinical trials.) Knowledge of drug susceptibility in people with active TB is important for the provision of both efficacious treatment for their TB disease and TB preventive treatment for their contacts. This presentation sought to describe drug resistance patterns in adults with MDR-TB whose household members were approached to participate in PHOENIx. Between June 2019 and October 2023, 1,353 adults with documented MDR-TB were enrolled from 28 sites and 13 countries in Africa, Asia, and Central and South America. Among those for whom isoniazid mutation data were available, 73 percent (n=783 of 1078) had high-level resistance (katG mutations). Among the 699 participants who had fluoroquinolone drug-susceptibility testing available, 20 percent (n=139) had fluoroquinolone resistance. These results suggest that it is important to have non-fluoroquinolone options for TB preventive treatment. They also support the relevance of the PHOENIx trial’s evaluation of delamanid vs. isoniazid for TB preventive treatment in high-risk household contacts of adults with MDR-TB. Primary results of the clinical trial are anticipated in 2027. CLO-FAST is led by John Metcalfe, M.D., Ph.D., M.P.H., University of California San Francisco; Samuel Pierre, M.D., Les Centres Gheskio, Haiti; and Kimberly Scarsi, Pharm.D., M.S., University of Nebraska Medical Center and study drugs were supplied by the Global Drug Facility. PHOENIx is jointly conducted by ACTG and IMPAACT and led by Gavin Churchyard M.B.Ch.B., M.Med., Ph.D., The Aurum Institute NPC; Amita Gupta, M.D., M.H.S., Johns Hopkins University; Anneke Hesseling, M.B.Ch.B., M.Sc., Ph.D., Desmond Tutu TB Centre - Stellenbosch University; and Susan Swindells, M.B.B.S., University of Colorado. Delamanid is supplied for PHOENIx by Otsuka Pharmaceutical Company, Ltd. ACTG is led by Dr. Currier and Joseph J. Eron, M.D., University of North Carolina (ACTG Vice-Chair). The studies are sponsored by the National Institute of Health’s (NIH) National Institute of Allergy and Infectious Diseases (NIAID, which also funds ACTG) under award numbers UM1 AI068636, UM1 AI107716, and UM1 AI068634. IMPAACT is also funded by NIAID with support and co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Mental Health (NIMH). About ACTGACTG is the world’s largest and longest running clinical trials network focused on HIV and other infectious diseases and the people living with them. It is funded by NIAID and collaborating NIH Institutes. Founded in 1987, ACTG conducts research to improve the management of HIV and its comorbidities; develop a cure for HIV; and innovate treatments for tuberculosis, hepatitis B, and emerging infectious diseases. It comprises thousands of dedicated researchers, staff, and community members who are pursuing research into novel treatments and cures for infectious diseases at hundreds of locations across four continents, with the ultimate goal of advancing science that meaningfully impacts the lives of the people we serve. Disclaimer: This content is solely the responsibility of ACTG and does not necessarily represent the official views of the NIH. Media Contact:Jenna Conley, ACTGjenna@conleycommunications.net

Clinical StudyClinical Result

17 Oct 2024

·pipelinereview.com

U.S. FDA Approves VYALEV™ (foscarbidopa and foslevodopa) for Adults Living with Advanced Parkinson's Disease

NORTH CHICAGO, IL, USA I October 17, 2024 I AbbVie (NYSE: ABBV ) today announced that the U.S. Food and Drug Administration (FDA) has approved VYALEV™ (foscarbidopa and foslevodopa) as the first and only subcutaneous 24-hour infusion of levodopa-based therapy for the treatment of motor fluctuations in adults with advanced Parkinson’s disease (PD). “For too long, the Parkinson’s community has had limited treatment options for advanced disease. Due to the progressive nature of the disease, oral medications are eventually no longer as effective at motor symptom control and surgical treatment may be required,” said Robert A. Hauser, M.D., MBA, Professor of Neurology and Director of the Parkinson’s and Movement Disorder Center at the University of South Florida. “This new, non-surgical regimen provides continuous delivery of levodopa morning, day and night.” The approval was supported by the pivotal Phase 3, 12-week study evaluating the efficacy of continuous subcutaneous infusion of VYALEV in adult patients with advanced PD compared to oral immediate-release carbidopa/levodopa (CD/LD IR) 1 , along with a 52-week, open-label study which evaluated the long-term safety and efficacy of VYALEV. 2 Findings from the pivotal study showed patients receiving VYALEV demonstrated superior improvement in motor fluctuations, with increased “on” time without troublesome dyskinesia and decreased “off” time, compared with oral CD/LD IR. 1 “On” time refers to the periods of time when patients are experiencing optimal motor symptom control while “off” time is when symptoms return. 3,4 The majority of adverse reactions (ARs) with VYALEV were non-serious and mild or moderate in severity. The most frequent ARs (greater than or equal to 10 percent and greater than CD/LD IR incidence) were infusion site events, hallucinations, and dyskinesia. 1,2 “People living with advanced Parkinson’s disease experience daily challenges as a result of uncertainty in managing motor fluctuations, especially as their disease progresses,” said Roopal Thakkar, M.D., executive vice president, research & development, and chief scientific officer, AbbVie. “We are proud to bring this innovation to patients who may benefit from motor symptom control through continuous 24-hour administration of VYALEV.” PD is a progressive and chronic movement disorder resulting in tremor, muscle rigidity, slowness of movement and difficulty with balance resulting from the loss of dopamine-producing brain cells. 5 Timing for a patient’s access to VYALEV is dependent on their individual insurance plan. Coverage for Medicare patients is expected in the second half of 2025. To learn more about this treatment, people should speak with their prescribing healthcare provider. About Parkinson’s Disease More than 10 million people worldwide are living with Parkinson’s disease (PD) 6 , a progressive and chronic neurological disorder characterized by tremor, muscle rigidity, slowness of movement, and difficulty with balance. 5 The motor symptoms of Parkinson’s disease begin when approximately 60-80 percent of the dopamine-producing cells in the brain are lost and symptoms continue to worsen slowly over the course of time. 7 While there is no known cure for the disease, there are treatments available to help reduce symptoms. 7 As PD progresses, patients experience complications, including motor and non-motor fluctuations and dyskinesia. Patients report switching from an “on” state (when symptoms are generally well controlled) to an “off” state, during which symptoms such as tremor and stiffness may reappear and patients have more difficulty moving. 4 Patients with advanced PD may also experience dyskinesia (involuntary movements) which can significantly hinder daily activities. 4 Neuronal degeneration and fluctuating plasma levodopa levels are responsible for the onset of these motor complications, with 50 percent of patients reporting them two to five years after diagnosis and approximately 80-100 percent of patients presenting with them after 10 years. 8 About the Phase 3 M15-736 Study 1 The Phase 3 randomized, double-blind, double-dummy, active-controlled study compared the efficacy, safety and tolerability of VYALEV to oral CD/LD IR in patients with advanced PD. Participants were provided with a home diary (the PD Diary) to assess their motor state during the day. The primary endpoint of good “on” time (defined as “on” time without dyskinesia plus “on” time with non-troublesome dyskinesia), was collected and averaged over three consecutive days and normalized to a typical 16-hour waking period. Baseline values are defined as the average of normalized good “on” time collected over the three PD Diary days before randomization. Approximately 130 adult participants with advanced PD were enrolled in the study across 80 sites in the U.S. and Australia. Participants were randomized 1:1 to receive either the VYALEV solution as a continuous delivery under the skin (subcutaneous) plus oral placebo capsules for CD/LD or oral capsules containing CD/LD IR plus continuous subcutaneous delivery of placebo solution for VYALEV. The treatment duration was 12 weeks. The increase in “on” time without troublesome dyskinesia at week 12 was 2.72 hours for VYALEV versus 0.97 hours for oral CD/LD IR (p=0.0083). Improvements in “on” time were observed as early as the first week and persisted throughout the 12 weeks. More information on the study can be found on www.clinicaltrials.gov (NCT04380142) and in The Lancet Neurology ( https://doi.org/10.1016/S1474-4422(22)00400-8 ). About VYALEV™ VYALEV (foscarbidopa and foslevodopa) is a solution of carbidopa and levodopa prodrugs for 24-hour continuous subcutaneous infusion for the treatment of motor fluctuations in adults with advanced PD. VYALEV, also known as PRODUODOPA ® , has been approved in 35 countries and over 4,200 patients worldwide have started treatment. AbbVie continues to work with regulatory authorities around the world to bring VYALEV to people living with advanced Parkinson’s disease. IMPORTANT SAFETY INFORMATION What is the most important safety information I should know about VYALEV TM (foscarbidopa/foslevodopa)? Do not take VYALEV if you currently take or have recently taken (within the last 14 days) a medication for depression called a nonselective monoamine oxidase (MAO) inhibitor. Ask your healthcare provider or pharmacist if you are not sure if you take an MAO inhibitor. Tell your healthcare provider about all your medical conditions and the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. When used together, VYALEV and certain other medicines, including medications for high blood pressure, MAO inhibitors, antipsychotics, metoclopramide, and isoniazid, may affect each other and cause serious side effects. VYALEV may cause other serious side effects. Talk to your healthcare provider before starting VYALEV and while on VYALEV if you have had or have any of the following: Do not stop using VYALEV or change your dose unless you are told to do so by your healthcare provider. Tell your healthcare provider if you develop withdrawal symptoms, such as fever, confusion, or severe muscle stiffness. These are not all the possible side effects of VYALEV. For more information, ask your healthcare provider or pharmacist. VYALEV (foscarbidopa and foslevodopa) injection for subcutaneous use is available in a 120 mg foscarbidopa and 2,400 mg foslevodopa per 10 mL (12 mg foscarbidopa and 240 mg foslevodopa per mL) solution. Please see the full Prescribing Information , including Medication Guide , for additional information about VYALEV. Talk to your healthcare provider if you have questions. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. If you are having difficulty paying for your medicine, AbbVie may be able to help. Visit AbbVie.com/PatientAccessSupport to learn more. About AbbVie in Neuroscience At AbbVie, our commitment to preserving personhood of people around the world living with neurological and psychiatric disorders is unwavering. With more than three decades of experience in neuroscience, we are providing meaningful treatment options today and advancing innovation for the future. AbbVie’s Neuroscience portfolio consists of approved treatments in neurological conditions, including migraine, movement disorders, and psychiatric disorders, along with a robust pipeline of transformative therapies. We have made a strong investment in research and are committed to building a deeper understanding of neurological and psychiatric disorders. Every challenge makes us more determined and drives us to discover and deliver advancements for those impacted by these conditions, their care partners, and clinicians. For more information, visit www.abbvie.com . About AbbVie AbbVie’s mission is to discover and deliver innovative medicines and solutions that solve serious health issues today and address the medical challenges of tomorrow. We strive to have a remarkable impact on people’s lives across several key therapeutic areas – immunology, oncology, neuroscience, and eye care – and products and services in our Allergan Aesthetics portfolio. For more information about AbbVie, please visit us at www.abbvie.com . Follow @AbbVie on X (formally Twitter), Facebook , Instagram , YouTube, and LinkedIn References 1 Soileau, M., et al. Safety and efficacy of continuous subcutaneous foslevodopa-foscarbidopa in patients with advanced Parkinson’s disease: a randomised, double-blind, active-controlled, phase 3 trial. Lancet Neurol. 2022 Dec;21(12):P1099-1109. 2 Aldred, J., et al. Continuous Subcutaneous Foslevodopa/Foscarbidopa in Parkinson’s Disease: Safety and Efficacy Results From a 12-Month, Single-Arm, Open-Label, Phase 3 Study. Neurol Ther. 2023 Dec;12(6):1937-1958. 3 “Motor fluctuations.” Parkinson’s Foundation. Available at: https://www.parkinson.org/library/fact-sheets/motor-fluctuations#:~:text=As%20levodopa%20begins%20to%20lose,are%20at%20their%20highest%20point . Accessed October 16, 2024. 4 “Off” Time in Parkinson’s Disease.” The Michael J. Fox Foundation for Parkinson’s Research . Available at: https://www.michaeljfox.org/time-parkinsons-disease . Accessed October 16, 2024. 5 “About Parkinson’s: Parkinson’s 101.” The Michael J. Fox Foundation for Parkinson’s Research . Available at: https://www.michaeljfox.org/understanding-parkinsons/i-have-got-what.php#q2 . Accessed October 16, 2024. 6 “Statistics.” Parkinson’s Foundation . Available at: https://www.parkinson.org/understanding-parkinsons/statistics#:~:text=Nearly%2090%2C000%20people%20in%20the,worldwide%20are%20living%20with%20PD . Accessed October 16, 2024. 7 “Parkinson’s Disease: Hope Through Research.” National Institute of Neurological Disorders and Stroke . Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Hope-Through-Research/Parkinsons-Disease-Hope-Through-Research#:~:text=Loss%20of%20dopamine%20results%20in,by%20the%20time%20symptoms%20appear . Accessed October 16, 2024. 8 Freitas, ME., et al. Motor Complications of Dopaminergic Medications in Parkinson’s Disease. Semin Neurol. 2017;37(2):147-157. SOURCE: AbbVie

Phase 3Clinical ResultDrug Approval

16 Oct 2024

·www.globenewswire.com

Bioversys Announces Last Patient Last Visit in BV100 Phase 2 Clinical Trial in Ventilator Associated Bacterial Pneumonia (VABP) and Provides a Business Update

BV100 Phase 2 preliminary results suggest BV100 is generally safe and well tolerated and showed strong initial signs of efficacy in VABP patientsStrategic investment from GIBF and launch of BV100 clinical program in ChinaSecond lead asset, alpibectir Phase 2a trial completed in April showing human proof of concept in tuberculosis BASEL, Switzerland, Oct. 16, 2024 (GLOBE NEWSWIRE) -- BioVersys AG, a multi-asset, clinical stage biopharmaceutical company focusing on research and development of novel antibacterial products for serious life-threatening infections caused by multi-drug resistant ("MDR") bacteria, announced today the completion of the last patient's last visit in the Phase 2 clinical trial with its lead asset BV100, the company's novel formulation of rifabutin suitable for intravenous administration. The Phase 2 multicenter, open label, randomized, active controlled study evaluated the pharmacokinetics, efficacy and safety of BV100 in adult patients with ventilator associated bacterial pneumonia (VABP) suspected or confirmed to be due to Carbapenem Resistant Acinetobacter baumannii (CRAB). Preliminary analysis of the data shows that the primary endpoint was met. BV100 is generally safe and well tolerated, met the expected pharmacokinetic targets and showed strong signs of efficacy in VABP patients with confirmed CRAB infection. In Part A of the study, the 14- and 28-day all-cause mortality (ACM) for BV100 was 12.5% and 25% respectively compared to the best available therapy control arm with 40% and 60% ACM respectively in patients with carbapenem resistant Acinetobacter infections. Similar trends in the test of cure and microbiological endpoints were seen. Full top line results from the trial are expected in early 2025 once analysis of the data has been finalized. BV100 is based on the newly identified mode of action for the active uptake of rifabutin into Acinetobacter baumannii-calcoaceticus complex and is being developed for hospital infections caused by Acinetobacter baumannii, including CRAB strains. There is a serious lack of effective and safe treatment options for CRAB infections and mortality rates in hospitals can be as high as 50%. CRAB has been designated a priority pathogen by the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC). Due to the high unmet need and based on the current carbapenem resistance rates in Acinetobacter baumannii, we estimate in excess of 1 million hospital treated patients across the United States, Europe, the Middle East and China that could benefit from BV100. BioVersys is committed to advancing the clinical development of BV100 in a global Phase 3 registration trial, which it expects to initiate in the second half of 2025. To date, BV100 has been administered to over 230 subjects, at doses of up to 900 mg and over periods of up to 14 days in Phase 1 and 2 clinical trials and was considered generally safe and well tolerated. The strong clinical data package comprising the first in human studies, the Phase 2 in VABP patients, two drug-drug interaction studies, studies in renally and hepatic impaired patients and a bronchoalveolar study provides the foundation for progressing BV100 into the final clinical Phase. Dr. Glenn E. Dale, Chief Development Officer of BioVersys: "We are making great progress with our clinical evaluation of BV100, and we are very pleased to have met this latest milestone with the final visit of our last patient in the Phase 2 trial, with BV100 demonstrating strong signs of efficacy. We are now looking forward to finalizing the data ahead of our planned readout early next year, which we expect will build on the promising safety profile that BV100 demonstrated in Phase 1 and provide a further basis for our planned Phase 3 study." Prof. David Paterson: "BV100 could bring a much-needed solution for patients with an unmet need due to carbapenem resistant infections caused by Acinetobacter. Its safety profile and ease of use in an ICU setting, together with the strong signs of efficacy seen in the Phase 2 trial, make BV100 a compelling treatment option to be tested in a pivotal Phase 3 trial of VABP patients with confirmed CRAB infection.” In addition to the progress of BV100, the company's second clinical asset, alpibectir a first in class molecule for tuberculosis which is developed in partnership with GSK, completed a Phase 2a clinical trial earlier this year. Alpibectir delivered a proof of concept in patients and was also shown to be generally safe and well tolerated. Alpibectir will continue to be developed in close partnership with GSK. In May 2024, BioVersys announced the expansion of the strategic collaboration with GSK and the extension of the Series C round by CHF 14.7 million. This was complemented by the strategic investment of the investment firm Guangzhou Sino-Israel Bio-Industry Investment Fund 2 LLP (GIBF) of US$ 6 mio (approximately CHF 5.17 mio) announced in September 2024. This investment provides a strategic partnership to extend our development of BV100 to China as well as adding additional flexibility to our cash position. BV100 Phase 1 study in China is expected to start in 1H 2025 as part of our preparation for a global Phase 3 registration study. Dr. Marc Gitzinger, Chief Executive Officer and founder of BioVersys: "BioVersys has made significant progress during 2024 on multiple fronts. Our lead asset BV100 holds a lot of promise towards treating patients with very severe, drug-resistant bacterial infections, with limited or no treatment options. We are now looking forward to engaging with regulatory authorities to expedite the Phase 3 development of our lead asset in order to make this drug available as soon as possible to patients in need. Besides our clinical assets, BV100 and alpibectir, we are also very happy with the progress our pre-clinical pipeline in the form of BV200 and BV500, which is also moving forward. On the business side, we have extended our collaboration with GSK and we recently announced the investment from GIBF that will enable us to extend our clinical development to China. We remain committed to bringing new treatment options for drug resistant infections to patients in dire need and take great encouragement from the headway we are making towards that goal." About BV100BV100 is a novel formulation of rifabutin suitable for intravenous administration, with a recently discovered novel mode of action showing an active uptake of rifabutin into the Gram-negative bacterial species, Acinetobacter baumannii. For the first time, the lead candidate allows for the targeting of the RNA-polymerase enzyme in Gram-negative bacteria with a human-suitable dose. BV100 is being developed for the treatment of infections caused by Acinetobacter baumannii calcoaceticus complex (ABC), including Carbapenem-Resistant ABC (CRAB) in critically important indications of ventilator associated bacterial pneumonia (VABP), hospital-acquired bacterial pneumonia (HABP) and bloodstream infections (BSI). BV100 was granted QIDP Designation by the U.S. FDA in May 2019 for use in the treatment of VABP, HABP and BSI, making BV100 eligible for priority FDA review, Fast Track designation, and a five-year extension of market exclusivity upon approval of the first QIDP indication. About Acinetobacter baumanniiAcinetobacter baumannii calcoaceticus complex (ABC) are Gram-negative bacteria found in the environment (e.g., in soil and water) and an opportunistic pathogen in humans, typically infecting critically ill and immunocompromised patients, that can result in severe pneumonia and bloodstream infections in addition to affecting other parts of the body. ABC is considered a significant worldwide threat in the healthcare setting given its ability to survive for prolonged periods on surfaces, combined with its ability to develop or acquire resistance to standard of care antibiotics, e.g. carbapenems. Carbapenem-resistance as well as multidrug-resistance (MDR) rates for ABC are among the highest recorded for any bacteria in current times (The Lancet 2022; 399: 629–55). Incidence and resistance rates for ABC are trending upwards and COVID-19 has exacerbated this significantly. BioVersys forecasts the annual number of carbapenem-resistant A. baumannii infections in hospitals to have surpassed one million globally and due to the limited treatment options, such infections come with high (up to 50%) mortality rates. About alpibectirAlpibectir is a first in class small molecule acting on a transcriptional regulator protein in Mycobacterium tuberculosis (TB). Alpibectir rejuvenates the existing drug ethionamide (Eto), by both potentiating the activity of Eto and restoring the antibacterial activity of Eto towards Eto-resistant TB. The resulting fast bactericidal effect of alpibectir/Eto at low and safe doses offers the potential to replace Isoniazid (INH) in future TB drug regimens for MDR/XDR-TB but also in TB-meningitis patients or INH-mono-resistant patients. Alpibectir is being co-developed with our long-term partner GSK and the molecule originates form a very successful public-private partnership with the Pasteur Institute Lille and the University of Lille. The program was supported by several grants from the Wellcome Trust, EU IMI joint undertaking and EDCTP. Alpibectir in combination with Eto has the orphan drug designation (ODD) and QIDP designation from the US FDA. About tuberculosis (TB) Tuberculosis (TB) is one of the leading causes of death worldwide. Its causative agent is the bacterial pathogen Mycobacterium tuberculosis (Mtb). Worldwide, an estimated 10.6 million people developed TB in 2022 and an estimated 1.30 million died from TB. The WHO estimates that there were 410’000 new cases with resistance to rifampicin – the most effective first-line drug – most of them were multi-drug resistant (MDR). MDR-TB remains a public health crisis and a health security threat. Worldwide, only 63% of MDR-TB patients are currently successfully treated.1 In the modern world of global travel, and ease with which infections spread, it is very worrying to note that two-thirds of the global total of TB cases was in eight countries: India (27%), Indonesia (10%), China (7.1%), the Philippines (7.0%), Pakistan (5.7%), Nigeria (4.5%), Bangladesh (3.6%) and the Democratic Republic of the Congo (3.0%). Furthermore, 3.3% of all new and 17% of reoccurring TB cases were MDR/RR-TB. About BioVersysBioVersys AG is a multi-asset, clinical stage biopharmaceutical company focused on identifying, developing and commercializing novel antibacterial products for serious life-threatening infections caused by multi-drug resistant (“MDR”) bacteria. Derived from the company’s two internal technology platforms (TRIC and Ansamycin Chemistry), candidates are designed and developed to overcome resistance mechanisms, block virulence production and directly affect the pathogenesis of harmful bacteria towards the identification of new treatment options in the antimicrobial and microbiome fields. This enables BioVersys to address the high unmet medical need for new treatments against life-threatening resistant bacterial infections and bacteria-exacerbated chronic inflammatory microbiome disorders. The company’s most advanced research and development programs address nosocomial infections of Acinetobacter baumannii (BV100, Phase 2), and tuberculosis (alpibectir, Phase 2a, in collaboration with GlaxoSmithKline (GSK) and a consortium of the University of Lille, France). BioVersys is located in the biotech hub of Basel, Switzerland. BioVersys contact Sylvia Mundt, Tel. +41 61 633 22 50; Mail: IR@bioversys.com www.bioversys.com https://twitter.com/Bioversyshttps://www.linkedin.com/company/bioversys-ag 1 Global Tuberculosis Report 2023 WHO

Phase 2Fast TrackPhase 3Orphan DrugClinical Result

100 Deals associated with Isoniazid

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KEGG	Wiki	ATC	Drug Bank
D00346	Isoniazid	J04AC01	DB00951

R&D Status

Approved

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Indication	Country/Location	Organization	Date
Pulmonary Tuberculosis	JP	Alfresa Pharma Corp.	25 Feb 1986
Tuberculosis	US	Sandoz, Inc.	29 Sep 1952

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Indication	Highest Phase	Country/Location	Organization	Date
Leg Ulcer	Phase 2	DK	-	01 Apr 2008

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03510468 (CTgov)	Phase 1	-	51	Pyridoxine+Tenofovir alafenamide+Rifapentine+Isoniazid (INH)	lkgbdeelkr(hdztwkeebx) = uoxwmvbuhx pjcpufqdxk (uyfuzwcoez, pdiaqrxcqd - gobufkwpic) View more	-	25 Oct 2023
NCT03891901 (IMPACT-TB, CTgov)	Phase 2	Tuberculosis	24	Rifabutin+Imatinib+Isoniazid (Cohort 1a: Imatinib (50 mg) + Rifabutin + Isoniazid)	ajowtgadsa(kiusrkpxvf) = duvmqqssez rrzscdqiek (nnoecadrkc, rlqsoiojjk - chaofjhsqf) View more	-	28 Sep 2023
				Rifabutin+Imatinib+Isoniazid (Cohort 1b: Imatinib (100 mg) + Rifabutin + Isoniazid)	ajowtgadsa(kiusrkpxvf) = jfidwjbggi rrzscdqiek (nnoecadrkc, fgqalzuloy - hnjspbhaon) View more
NCT02256696 (CTgov)	Phase 2	Pulmonary Tuberculosis	157	PA-824+Rifampin+Isoniazid+Pyrazinamide (Arm 1)	kvydkwhzxt(wtjvkcarnj) = vfyvrbeszl gmpmcfkewt (eldxhatmcr, hbdsyncjku - ezecynwhkb) View more	-	18 Jul 2023
				PA-824+Rifabutin+Isoniazid+Pyrazinamide (Arm 2)	kvydkwhzxt(wtjvkcarnj) = utxxhdrcku gmpmcfkewt (eldxhatmcr, hzjnsrosds - rydyxhmcpx) View more
NCT02554318 (FSS, CTgov)	Not Applicable	PULMONARY TUBERCULOSIS ACTIVE	147	Fermented soybean+Ethambutol+Rifampicin+Isoniazid+Pyrazinamide (Intervention)	bdvdgkpnpu(hdvggzbtuv) = umukaxvqzh ylivftumha (yxjlsbimmn, eckhddddwm - irsuoctddk) View more	-	21 Jun 2022
				Ethambutol+Rifampicin+Isoniazid+Pyrazinamide (Control)	bdvdgkpnpu(hdvggzbtuv) = pwqrgdkcbg ylivftumha (yxjlsbimmn, ttktqwkqbz - enocqkbolb) View more
NCT02613169 (iTIPS, CTgov)	Phase 2	Tuberculosis	300	Isoniazid (Isoniazid)	nlqnrcswca(mehebkpqrg) = pgodyuxivh atseqxnlfq (clqfdamniv, cabzsiwzqk - inymttizsh) View more	-	10 Jun 2021
				INH (No Isoniazid)	nlqnrcswca(mehebkpqrg) = arpgtglxuj atseqxnlfq (clqfdamniv, gicjleefap - gfrlxikudv) View more
IAS2021	Not Applicable	HIV Infections	-	Isoniazid preventive therapy (IPT)	mfmvsupgiq(jahtdvlwtq): RR = 2.0 (95% CI, 1.7 - 2.4)	-	01 Jan 2021
				No Isoniazid preventive therapy (No IPT)
NCT00170209 \| NCT00931736 (Pubmed)	Phase 3	Tuberculosis \| Other Diseases \| HIV Infections	6,859	Rifampin	divuoqsqwz(lbosndfqbs): rate difference = 4.1 (95% CI, -6.4 to 14.7) View more	-	12 Aug 2020
				Isoniazid
NCT02613169 (Pubmed \| Clin Infect Dis)	Phase 2	Tuberculosis	300	Isoniazid	tmafhxsxvh(ubjuaaluxv) = gjzqtprfgs vievezxpea (mmtnzaksfo )	-	21 Jun 2020
				No Isoniazid	tmafhxsxvh(ubjuaaluxv) = xjsyhmhisy vievezxpea (mmtnzaksfo )
NCT01936831 (A5312, Pubmed \| Pediatrics)	Phase 2	Drug-Resistant Tuberculosis	282	Isoniazid 5 mg/kg	szeewuyuis(xeprfdjeek) = zumqdpdbjh pgjlcksqfl (xqgfmzfwrn )	-	16 Jan 2020
				Isoniazid 10 mg/kg	szeewuyuis(xeprfdjeek) = hehzxdqoov pgjlcksqfl (xqgfmzfwrn )
IAS2020	Not Applicable	HIV Infections	-	Isoniazid	zqxdvmzfjv(onrqijcdzz) = jreehjnuyk fijwhyjola (xjifgmkybq ) View more	-	01 Jan 2020

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