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Investigational Drug Therapies Currently in Early-Stage Clinical Development for the Treatment of Clostridioides (Clostridium) Difficile Infection Mai-Chi N

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Investigational Drug Therapies Currently in Early-Stage Clinical Development for the Treatment of Clostridioides (Clostridium) Difficile Infection Mai-Chi N EXPERT OPINION ON INVESTIGATIONAL DRUGS https://doi.org/10.1080/13543784.2019.1581763 REVIEW Investigational drug therapies currently in early-stage clinical development for the treatment of clostridioides (clostridium) difficile infection Mai-Chi N. Trana,b, Ravina Kullarc and Ellie J. C. Goldsteind,e aDepartment of Pharmacy, Providence St. John’s Health Center, Santa Monica, CA, USA; bDepartment of Pharmacy, Clinica Juan Pablo Medical Group, Los Angeles, CA, USA; cDoctor Evidence, LLC, Santa Monica, CA, USA; dR M Alden Research Laboratory, Santa Monica, CA, USA; eDavid Geffen School of Medicine, Los Angeles, CA, USA ABSTRACT ARTICLE HISTORY Introduction: Clostridioides (Clostridium) difficile Infection (CDI) is an urgent global threat causing Received 16 August 2018 ~500,000 infections annually in the United States of America (USA) and is associated with a 36% 30- Accepted 8 February 2019 day attributable mortality rate. Despite the availability of three therapeutic agents, CDI recurrence KEYWORDS – – occurs in 20 40% of patients, with a 30 40% second recurrence rate in these patients. Consequently, ACX-362F; DS-2969b; there is a need for novel agents for treating CDI. LFF571; ribaxamase; Areas covered: We searched MEDLINE, PubMed, Embase, Web of Science, Cochrane Central Register of ridinilazole; RBX 2660; Controlled Trials, and ClinicalTrials.gov for agents in early stages of clinical development. CRS3123; MCB3681/ These drugs include ACX-362E, DS-2969b, LFF 571, RBX2660, ribaxamase, ridinilazole that have MCB3837 advanced to at least phase 2 and several other drugs in phase 1 development. Expert opinion: The challenge for these new agents is three-fold: (1) to have a novel approach such as a different target/mechanism of action; (2) be ‘significantly’ better than existing agents in regard to ‘sustained clinical response’; or (3) be priced at a reasonable cost when it comes to market or perhaps all three. Their utility can only be proven by clinical trials. 1. Introduction initial agent of choice to a secondary role often when there are Clostridioides (Clostridium) difficile Infection (CDI) is a major cause extremecostconsiderationsbecauseitwasshowntobeinferiorto of healthcare-associated diarrheal infection, an immediate and vancomycin for even mild and moderate disease with an increased urgent global healthcare threat and a reportable disease to recurrence rate. Fidaxomicin waselevatedasafirstlineoption[10]. National Health Safety Network (NHSN) [1] and is an element in Their focus was not based just on equivalence, but highlighted the the value-based purchasing initiative. The Centers for Medicare need for new drugs to prove superiority in sustained clinical and Medicaid Services (CMS) introduced Hospital Inpatient response (sustained cure/lower relapse rate), which is a major Value-Based Purchasing program, which are quality perfor- concernasevenwithfidaxomicintherecurrencerateat25days mance–based adjustments of up to 1% to Medicare reimburse- post-therapy is approximately 15% [11,12]. Consequently, there is ments for acute care hospitals [2]. As part of this value-based need for better therapeutic alternatives with improved efficacy, purchasing initiative, CMS reduces payment for patients diag- lower recurrence rates, and lower costs. Unfortunately, there have nosed with selected hospital-acquired infections such as been some recent expensive failures such as cadazolid and suro- C. difficile [3,4]. Over the past 15 years, there has been a 237% tomycin that did not reach their endpoints after phase 3 drug increase in CDI-related hospitalizations [5]. Primary (15–40%) and development. This highlights the question of how will a new secondary (15–30%) CDI recurrence is not infrequent including agent differentiate itself, what questions/endpoints need to be a 31% risk in patients >65 years old [6], 33% risk in immunocom- asked and how diagnostic criteria for CDI to establish study inclu- promised hosts and a twofold increased risk in patients with sion should be documented [13]. A number of new agents with renal disease [7]. These recurrences lead to an increased re- narrower spectra against normal microbiota, different targets admission in 28.3% of patients (75.2% vs. 46.9% CDI infected including effecting toxin secretion and inhibiting spore formation, vs. non-infected, respectively) [8]. The increased 30-day mortality new treatment paradigms and rationales are attempting to answer has risen to 36.3% vs. 25.7% (p < 0.004) [9]. CDI has added these questions and potentially improve patient outcomes (Tables approximately $4.5 billion in extra medical care costs and 1 and 2). patients have a 55% increased length of stay. In 2017, CDI became a quality indicator and hospitals can be penalized for 2. Methodology both readmissions and as a quality measure. The 2018 Infectious Diseases Society of America (IDSA) We searched MEDLINE, PubMed, Embase, Web of Science, Guidelines [7] have devalued the use of metronidazole from an Cochrane Central Register of Controlled Trials, and ClinicalTrials. CONTACT Ellie J. C. Goldstein [email protected] 2021 Santa Monica Blvd #740E, Santa Monica, CA 90404, USA © 2019 Informa UK Limited, trading as Taylor & Francis Group 2 M.-C.N.TRANETAL. 3.2. DS2969b Article highlights DS-2969b (4-chloro-5-ethyl-N(3S,4R)-1-[5(2-hydroxypropan-2-yl)- ● Clostridioides (Clostridium) difficile infection (CDI) represents the most 1,3,4-thiadiazol-2-yl]-3-methyloxypiperidin-4-yl)-1H-imidazole common cause of nosocomial diarrhea worldwide. However, cur- rently approved agents for CDI therapy (metronidazole, vancomycin, -2-carboxamide 2/3 hydrate, is a novel GyrB inhibitor [27]. It and fidaxomicin) still carry a high rate of recurrence (20–40%). inhibits differently than fluoroquinolones (which binds at the ● New agents with novel mechanisms of action, narrow spectrums of enzyme–DNA interface in the cleavage–ligation active site) by activity, different targets or approaches must show superiority in relapse rates to achieve market penetration. ACX-362E, a small mole- binding to the ATP-binding site of DNA gyrase [28]. It showed cule using a new target DNA polymerase IIIC inhibition, is about to a half maximal inhibitory concentration (IC50)of20nl/mlagainst start Phase 1 trials. Early studies have suggested inhibition of DNA C. difficile. Several studies have evaluated its in vitro activity replication by ACX-362E in a mechanism that is unique to anti- C. difficile drugs. Ribaxamase (SYN-004), an orally ingested coated against C difficile.Mathuretal.foundittohaveaMIC90 of 0.06 enteric enzyme formulation, prevents microbiome disruption by µg/ml against 55 isolates, as well as a low propensity for in vitro degrading selected beta-lactam agents. resistance development [28]. Tyrrell et al. studied its activity ● RBX2260 is a commercially prepared, standardized fecal microbiota suspension packaged as a single administered enema bag. against 102 recent North American ribotyped C difficile isolates. ● Cadazolid and surotomycin were costly mistakes, failing to achieve It had an MIC50 of 0.06 μg/ml and an MIC90 of 0.125 μg/ml with final approval due to phase 3 clinical trials not meeting the primary arangeof0.03–0.125 μg/ml [29]. Using a golden Syrian hamster endpoints. Future clinical trials conducted in the pipeline agents must have consistent inclusion and testing definitions used in model with a NAP 1/027 strain, Mathur et al. suggested the high Phase 2 and Phase 3 trials as well as set considered primary and activity of DS-2969b against C. difficile,that10μg/g fecal levels secondary endpoints. would be sufficient for clearing C. difficile from the intestine [28]. This box summarizes key points contained in the article. Mathur et al. further speculated that DS2969 demonstrated promise as an oral and intravenous option for treatment of CDI. A Phase 1 placebo-controlled study of 24 healthy patient volunteers to assess the safety, tolerability, pharmacokinetics, gov for C. difficile and for agents in early stages of clinical and effects on the normal gastrointestinal microbiota of multi- development. ple daily oral ascending doses of DS-2969b in healthy subjects was recently reported [30,31]. Three sequential ascending-dose cohorts of six subjects (60 mg, 200 mg, and 400 mg for 14 days) were evaluated and 3. Investigational agents were safe and well tolerated at all doses. Nine subjects (50%) 3.1. ACX-362E reported mild events, predominantly related to the gastrointest- inal tract. Day 1 and day 14 mean plasma concentration-time ACX-362E is a novel small molecule that is using a new target, profiles found that ‘DS2969a (free form of DS-2969b) plasma DNA polymerase IIIC inhibition. DNA polymerase IIIC (pol IIIC) concentrations increased with increasing doses; however, both has been shown to be essential for replicative DNA synthesis the maximum concentration of drug in serum (Cmax) and the in aerobic, low guanine-cytosine (G-C) Gram-positive bacteria, area under the concentration-time curve (AUC) increased less than i.e. those with a low G-C ratio. Pol IIIC-specific genes of several the dose proportionally.’ While the drug is predominantly excreted such Gram-positive bacteria have been cloned and expressed in the urine (32%-54%), reasonable fecal levels were achieved [19–21], and these enzymes share a unique capacity to be on day 1 of 0.58%-1.13% and by day 14 rose to 3.21–7.89%. The inhibited by 6-anilinouracils, 2-phenylguanines (PG), and evaluation of its effect on the microbiome showed reductions in related compounds which are analogs of 2ʹ-deoxyguanosine the Clostridium coccoides and Bifidobacterium groups but little -5ʹ-triphosphate (dGTP) [22,23]. ACX-362E (formerly known as effect on Bacteroides fragilis, Clostridium leptum,andPrevotella GLS362E), a closely related dichloro-benzyl guanine inhibitor spp. suggesting a mild effect on intestinal microbiota and the of pol IIIC, emerged from an extensive discovery and synthetic protective species that maintain colonization resistance. Having effort and shows promise as a novel treatment for C. difficile just published the phase 1 data, it is unclear if the signals were diarrhea [24]. strong enough to pursue phase 2 trials.
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