A Multiple Arm, Multiple Stage, Phase 2, OL, Randomized, Controlled Trial to Evaluate 4 Treatment Regimens of SQ109, Increased Doses of Rifampicin, and Moxifloxacin in Adults With Newly Diagnosed, Smear-positive Pulmonary Tuberculosis

This study is a multiple-arm, multiple-stage (MAMS), phase 2, open label, randomized, controlled clinical trial that will compare the efficacy and safety of four experimental four drug regimens with a standard control regimen in patients with smear positive, pulmonary tuberculosis (TB). Patients will be randomly allocated to the control or one of the four experimental regimens in the ratio 2:1:1:1:1. Experimental regimens will be given for 12 weeks. Thereafter, participants in the experimental arms will receive continuation phase treatment for 14 weeks containing standard-dose rifampicin and isoniazid. All participants will receive 25 mg of vitamin B6 (pyridoxine) with every dose of INH to prevent INH-related neuropathy. Interim analyses will be conducted during the trial for efficacy, with the aim of identifying experimental arms that perform below a pre-specified efficacy threshold; these arms will then be stopped from further recruitment.
Following the first scheduled interim analysis on March 3rd, the Trial Steering Committee (TSC) followed a recommendation of the independent data monitoring committee (IDMC) and has stopped the enrolment into two of the arms in the MAMS-TB trial: HRZQ and HR20ZQ, based on these arms not meeting the pre-specified gain in efficacy over control. Importantly, there was no safety concern that prompted stopping recruitment to these arms. They recommended that recruitment to arm 2 (HRZQ) and 3 (HR20ZQ) be terminated as there was insufficient evidence that these regimens could shorten treatment. Importantly, there was no evidence that either arm was inferior to standard treatment (the control arm) with regards to efficacy. There was, however, sufficient evidence that the other intervention arms HR35ZE and HR20ZM could shorten treatment to continue enrolling patients.

Start Date01 Apr 2013

Sponsor / Collaborator

Ludwig-Maximilians-Universität München

[+4]

PACTR201205000383208 / Unknown statusPhase 2IIT

A multiple arm, multiple stage (MAMS), phase 2, open label, randomized, controlled clinical trial to evaluate four treatment regimens including SQ109, two increased doses of rifampicin, and moxifloxacin in adult subjects with newly diagnosed, smear¿positive pulmonary tuberculosis

Start Date11 Jan 2013

Sponsor / Collaborator-

NCT01252108 / WithdrawnPhase 2

Phase 2A Open-label Study to Evaluate Safety, Tolerability, and Antimicrobial Activity of Single, Daily Doses of SQ109 in Urea Breath Test Positive Volunteers

Helicobacter pylori infection of the gastric epithelium is the most common bacterial infection worldwide. Its global prevalence is estimated at 50%, though the burden falls disproportionately on the developing world, where the prevalence in some areas is 80%. H. pylori infection is generally acquired during childhood, and without specific antibiotic treatment can persist for life. The infection is generally clinically asymptomatic during childhood, and even in adulthood 80-90% of infected individuals will remain asymptomatic (although they may transmit the bacteria).
SQ109 is a new, small molecule antibiotic with characteristics that make it particularly attractive to evaluate against H. pylori. In brief, SQ109 is orally bioavailable, acid-stable, has in vitro activity against H. pylori and achieves high intracellular concentration (which may be important to effect bacterial eradication).
Based on the antimicrobial activity and clinical safety, SQ109 will be evaluated in this clinical trial to assess safety and antimicrobial activity in adults infected with H. pylori. Data from this study will help determine whether larger safety and efficacy studies in individuals with H. pylori-associated duodenal ulcer disease are warranted.

Start Date01 Mar 2012

Sponsor / Collaborator

Sequella, Inc.

100 Clinical Results associated with SQ-109

100 Translational Medicine associated with SQ-109

100 Patents (Medical) associated with SQ-109

102

Literatures (Medical) associated with SQ-109

01 Nov 2024·ARCHIV DER PHARMAZIE

Repurposing antiparasitic N,N′‐aliphatic diamine derivatives as promising antimycobacterial agents

Article

Author: Morbidoni, Héctor R. ; Carlucci, Renzo ; Giovannuzzi, Simone ; Supuran, Claudiu T. ; Tekwani, Babu L. ; Recio‐Balsells, Alejandro I. ; Labadie, Guillermo R. ; Carta, Fabrizio

Abstract:

In previous studies, we demonstrated the potent activity of a library of 25 N,N′‐disubstituted diamines (NNDDA) toward Trypanosomatid and Apicomplexa parasites. Considering the structure similarity between this collection and SQ109, an antituberculosis compound, and its compelling antiparasitic properties, we aimed to repurpose this library for tuberculosis treatment. We assayed this collection against Mycobacterium tuberculosis H37Rv and M. avium, obtaining several compounds with MIC values below 10 µM. The most active analogs were also evaluated against M. smegmatis, a non‐pathogenic species, and the non‐tuberculosis mycobacteria M. abscessus, M. kansasii, and M. fortuitum. 3c stands out as the lead mycobacterial compound of the collection, with potent activity against M. tuberculosis (minimal inhibitory concentration [MIC] = 3.4 µM) and moderate activity against M. smegmatis, M. kansasii, and M. fortuitum (all with MIC values of 26.8 µM). To unravel the mechanism of action, we employed the web‐based platform Polypharmacology Browser 2 (PPB2), obtaining carbonic anhydrases as potential drug targets. Nevertheless, none of the compounds displayed experimental inhibition. In summary, our study confirms the validity of the repurposing approach and underscores the antimycobacterial potential of NNDDA compounds, especially the analog 3c, setting a stepping stone for further studies.

16 Oct 2024·mBio

Allosteric coupling of substrate binding and proton translocation in MmpL3 transporter from Mycobacterium tuberculosis

Article

Author: Yang, Lixinhao ; Li, Wei ; Babii, Svitlana ; Gumbart, James C. ; Grzegorzewicz, Anna E. ; Zgurskaya, Helen I. ; Jackson, Mary

ABSTRACT:

Infections caused by Mycobacterium spp. are very challenging to treat, and multidrug-resistant strains rapidly spread in human populations. Major contributing factors include the unique physiological features of these bacteria, drug efflux, and the low permeability barrier of their outer membrane. Here, we focus on MmpL3 from Mycobacterium tuberculosis , an essential inner membrane transporter of the resistance–nodulation–division superfamily required for the translocation of mycolic acids in the form of trehalose monomycolates (TMM) from the cytoplasm or plasma membrane to the periplasm or outer membrane. The MmpL3-dependent transport of TMM is essential for the growth of M. tuberculosis in vitro , inside macrophages, and in M. tuberculosis- infected mice. MmpL3 is also a validated target for several recently identified anti-mycobacterial agents. In this study, we reconstituted the lipid transport activity of the purified MmpL3 using a two-lipid vesicle system and established the ability of MmpL3 to actively extract phospholipids from the outer leaflet of a lipid bilayer. In contrast, we found that MmpL3 lacks the ability to translocate the same phospholipid substrate across the plasma membrane indicating that it is not an energy-dependent flippase. The lipid extraction activity was modulated by substitutions in critical charged and polar residues of the periplasmic substrate-binding pocket of MmpL3, coupled to the proton transfer activity of MmpL3 and inhibited by a small molecule inhibitor SQ109. Based on the results, we propose a mechanism of allosteric coupling wherein substrate translocation by MmpL3 is coupled to the energy provided by the downhill transfer of protons. The reconstituted activities will facilitate understanding the mechanism of MmpL3-dependent transport of lipids and the discovery of new therapeutic options for Mycobacterium spp. infections.

IMPORTANCE:

MmpL3 from Mycobacterium tuberculosis is an essential transporter involved in the assembly of the mycobacterial outer membrane. It is also an important target in undergoing efforts to discover new anti-tuberculosis drugs effective against multidrug-resistant strains spreading in human populations. The recent breakthrough structural studies uncovered features of MmpL3 that suggested a possible lipid transport mechanism. In this study, we reconstituted and characterized the lipid transport activity of MmpL3 and demonstrated that this activity is blocked by MmpL3 inhibitors and substrate mimics. We further uncovered the mechanism of how the binding of a substrate in the periplasmic domain is communicated to the transmembrane proton relay of MmpL3. The uncovered mechanism and the developed assays provide new opportunities for mechanistic analyses of MmpL3 function and its inhibition.

13 Sep 2024·ACS Infectious Diseases

The Tuberculosis Drug Candidate SQ109 and Its Analogs Have Multistage Activity against Plasmodium falciparum

Article

Author: Chibale, Kelly ; Oldfield, Eric ; Koekemoer, Lizette L. ; van der Watt, Mariette E. ; Vazquez, Santiago ; Birkholtz, Lyn-Marie ; Ko, Jihee ; Birkholtz, Lyn-Marié ; van der Watt, Mariëtte E ; Tshabalala, Sizwe ; Onajole, Oluseye K. ; Erlank, Erica ; Malwal, Satish R. ; Watson, Savannah J ; Mazurek, Ben ; Watson, Savannah J. ; van der Watt, Mariëtte E. ; Kolocouris, Antonios ; Perez-Lozano, Pilar ; Adewole, Feyisola ; Singh, Davinder ; Njoroge, Mathew ; Sadowska, Katie ; Theron, Anjo ; Stampolaki, Marianna ; Naude, Mariska ; Reader, Janette ; Turcu, Andreea L.

Toward repositioning the antitubercular clinical candidate SQ109 as an antimalarial, analogs were investigated for structure-activity relationships for activity against asexual blood stages of the human malaria parasite Plasmodium falciparum pathogenic forms, as well as transmissible, sexual stage gametocytes. We show that equipotent activity (IC₅₀) in the 100-300 nM range could be attained for both asexual and sexual stages, with the activity of most compounds retained against a multidrug-resistant strain. The multistage activity profile relies on high lipophilicity ascribed to the adamantane headgroup, and antiplasmodial activity is critically dependent on the diamine linker. Frontrunner compounds showed conserved activity against genetically diverse southern African clinical isolates. We additionally validated that this series could block transmission to mosquitoes, marking these compounds as novel chemotypes with multistage antiplasmodial activity.

News (Medical) associated with SQ-109

29 Oct 2008

·www.biospace.com

Sequella, Inc. Presents Data on Synergy Between Investigational New TB Drugs SQ109 and TMC207

Study results to be presented at 2008 ICAAC/IDSA Joint Meeting ROCKVILLE, Md., Oct. 28 /PRNewswire/ -- Sequella, Inc., a clinical-stage biopharmaceutical company focused on commercializing products to treat infectious diseases of epidemic potential, announces the successful demonstration of synergistic activities and improvement of minimal inhibitory concentration (MIC) resulting from in vitro combination studies of Sequella lead TB drug candidate, SQ109, and Tibotec's lead TB drug candidate, TMC207. Both drug candidates are currently undergoing human clinical studies. Results from these studies were presented on October 28th at the Interscience Conference on Anti-Microbial Agents and Chemotherapeutics (ICAAC) and Infectious Disease Society of America (IDSA) joint meeting in Washington, DC. The collaboration between Sequella and Tibotec was designed to investigate in vitro interactions of SQ109 for synergistic, additive, or antagonistic activity in the presence of TMC207, using a number of clinical and laboratory strains of both drug sensitive and drug resistant M. tuberculosis (MTB). In vitro interactions investigated included synergy studies, rate of killing, post antibiotic effect and intracellular activity against MTB in macrophages. There were no antagonistic activities observed in any combination studies. SQ109 and TMC207 in combination were either synergistic or additive with the various MTB strains and showed increased rate of killing, enhanced post antibiotic effect and intracellular killing activity. Results showed that the SQ109 and TMC207 drug combination was extraordinary potent, with greater than 90% kill of MTB as early as 1 day after drug combination exposure. Dr. Carol Nacy, CEO of Sequella said, "We are very pleased to be collaborating with Tibotec, a world renowned product development organization, and we look forward to our continuing partnership to examine these important drug synergies in animal models of TB." The next step of the collaboration will be to complete a series of in vivo studies in animal models of TB, currently underway. About SQ109 The company's lead drug candidate, SQ109, completing Phase I clinical trials, is a new diamine antibiotic that could replace one or more of the current first-line anti-tuberculosis drugs to simplify or shorten therapy. SQ109 was granted U.S. FDA Fast Track and FDA/EMEA Orphan Drug Designation in 2007. About Sequella Sequella is a clinical stage biopharmaceutical company focused on commercializing improved treatments for infectious diseases of epidemic potential. The company leverages its global influence, R&D platforms and infectious disease expertise to proactively address emerging health threats. Through focused execution, clear commercialization pathways, and strategic partnerships, Sequella intends to commercialize a broad product portfolio designed to treat global health threats with significant market opportunity. Forward-Looking Statement This press release contains forward-looking statements that are subject to risks and uncertainties, and includes statements that are not historical facts. Actual results could differ significantly from results discussed. Sequella disclaims any intent or obligation to update forward-looking statements, except as required by law. CONTACT: Alicia Moran, +1-410-991-7027, for Sequella, Inc. Web site:

CollaborateSmall molecular drugAntibodyOrphan DrugFast Track

100 Deals associated with SQ-109

External Link

KEGG	Wiki	ATC	Drug Bank
-	SQ-109	-	DB05186

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Pulmonary Tuberculosis	Phase 3	RU	Infectex LLC	29 Aug 2022
Helicobacter pylori infection	Phase 2	-	Sequella, Inc.	01 Mar 2012
Tuberculosis	Phase 1	US	Sequella, Inc.	01 Sep 2006

Clinical Result

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01785186 (CTgov)	Phase 2	Pulmonary Tuberculosis	365	pyridoxine+Ethambutol+Rifampicin+Isoniazid+Pyrazinamide (Arm 1 (R35))	jfykasgsce(uozgxokgay) = hkvmuvvmvw pzbnxycifw (siantqaqdm, bvrylrgclk - kgyiisdyck) View more	-	20 Sep 2017
				pyridoxine+SQ109+Rifampicin+Isoniazid+Pyrazinamide (HRZQ)	jfykasgsce(uozgxokgay) = wqxpsboiqo pzbnxycifw (siantqaqdm, wnwrxnrtjq - hkgignrfmm) View more

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