Category Archives: C. diff. Research & Development

Pharmacy OneSource Discusses Artificial Intelligence With Three Wolters Kluwer Experts Developing AI Tools Managing CDIs

Hospitals around the world continue to struggle with preventing and managing Clostridioides difficile (C. diff) infections. They are seeking better ways to predict which patients are at risk for C. diff infections (CDIs) sooner, and to improve prevention and treatment. 

 We ( Pharmacy One Source) sat down with three Wolters Kluwer experts—who have been working on developing, testing and integrating artificial intelligence (AI) tools into Sentri7—to discuss why AI is such an important advance for managing CDIs.  

  • Matt Weissenbach, DrPH, CPH, CIC, is the Director of Clinical Operations, Clinical Surveillance  
  • Steve Mok, PharmD, BCPS, BCIDP, is the Pharmacy Clinical Program Manager and Fellowship Director, Clinical Surveillance 
  • John Langton, PhD, is the Director of Applied Data Science, Wolters Kluwer, Health 

What’s at risk when hospitals do not give their full attention to reducing C. diff infections? 

Matt: C. diff is an opportunistic infection, often healthcare-associated, that is debilitating for patients because it can cause symptoms that range from diarrhea to life-threatening inflammation of the colon. It’s a very hardy bacterium that is spore-forming and is very difficult to remove from the environment, dramatically increasing the risk of transmission.

C. diff is also somewhat difficult to treat because it tends to recur over time. And as hospitals know all too well, patients that do become infected experience sub-optimal outcomes. In the U.S. alone, there are about a half-million C. diff infections each year, responsible for about 29,000 deaths. To make things worse, C. diff infection increases the length of stay and treatment costs. In fact, the CDC estimates that C. diff is responsible for $4.8 billion in costs each year. Financial penalties are also in play because C. diff is monitored within hospital pay-for-performance programs. Those organizations that are not proactively focusing on preventing C. diff will typically find themselves among the poorest performers, and their bottom lines will suffer due to penalties. That’s why so much work goes into controlling and preventing CDIs.

Steve: From a pharmacy and antimicrobial stewardship perspectiveC. diff is concerning because treatment options are limited to three antibiotics, and here is also the high risk of recurrence that Matt referencedEven if we successfully treat the infection, the C. diff bacteria hangs around in the gut or the patient’s surroundings, waiting for the next flora disturbance, and we have to go back to the same three antibiotics. In the past 6-8 years, some people have gotten so desperate to address recurring infections that they’ve opted for a fecal microbiota transplantationThat has shown some promise, but the treatment is not without risk, especially for acquiring other types of infections.  

Why did Wolters Kluwer choose AI technology to address this challenge?  

Matt: We saw an opportunity to leverage AI, identify at-risk patients sooner, and allow clinicians the opportunity to address modifiable risk factors and proactively prevent C. diff infection using known, evidence-based prevention strategies. We know our hospital and health system clients are incredibly concerned with how C. diff tends to increase mortality risk, length of stay, and introduce potential for financial penalties and pressures. Our customers already rely on Sentri7 as a trusted clinical surveillance platform, and this enabled us to provide extended value across members of the care team while addressing this worrisome infection.

What are some of the identifiers of those highrisk patients? 

Steve: Well, there’s a consensus, for example, that some antibiotics, like fluoroquinolones, predispose patients to C. diff infections. If we identify those patients, the physician and pharmacist can assess whether they need that particular antibiotic and then change it, if possible, to lower-risk antibiotics. Another example is the proton pump inhibitor. It is also highly associated with C. diff infection. Again here, with more information, pharmacists can have a meaningful conversation with prescribers to do a better-informed risk-benefit analysis. We see AI as an opportunity to introduce many other risk factors and dimensions to the risk-benefit analysis so providers can make more informed clinical decisions.

John: I agree that the clinical concerns were the most important drivers behind our effort, and I would add, from that perspective, that early identification also enables you to isolate patients more promptly. We’ve statistically shown that when CDI happens in a hospital, it typically occurs in clusters. That is, as soon as the first patient contracts a C. diff infection, usually a number of other people in the same hospital area contract it as well. So if you can detect C. diff earlier, or even predict, you can not only begin treatment, but you can also isolate patients to try to prevent the spread and implement other necessary protocols. With early action, you can keep the infection to one person rather than five.  

Matt: Clinical policies and protocols for environmental cleaning recognize that routine disinfectants are often not sporicidal. If the bacteria are on a bedrail, glove, telephone, etc., it may be transmitted to other patients or providers and may contribute to the clustering effect. At a high level, I view AI-enabled technologies for C. diff—and, ultimately, for other HAIs—as a way to bridge the prevention aspects of public health with the diagnosis and treatment components of clinical medicine. With CDI, we aim to address things earlier in the care process by looking upstream at hospitalized patients to determine if they’re at risk of developing CDI. Then, clinicians may reassess their choices of antimicrobial therapy or other medications that could increase that risk. That’s what I mean by bringing the prevention aspect to clinical medicine. We can create proactive workflows that target the prevention of adverse events.

How does our AI model help this process of identifying patients and instigating proactive prevention? 

John: The simplest way to put it is that AI deals with more than the binary risk indicators assessment that humans commonly perform in their heads. The reality is that we can only look at a small set of variables and how they might factor with the other. Thus, systems that merely assess binary risk indicators are brittle because they are so limited in terms of the complexity of situations they can address. In contrast, the power of AI is its ability to consider many different interaction effects. Working with our clinicians, we incorporate a tremendous number of inputs: lab results, white blood cell count, bilirubin, neutrophils, vital signs, medicine administration, concentrations and durations of meds, duration in hospital, demographics about the patients and demographics on a hospital—to name a few. The AI model can look at hundreds of these things – and the hundreds of correlations among them. To give just one simple example: We know older people are more at risk, and if they are on a particular broad-spectrum antibiotic, there can be a multiplicative effect – that is, the effect is greater than simply adding each of the factors independently. Now expand that to looking at hundreds of things. We’ve trained all of the statistics and variables and have shown that we can be incredibly precise. When you compare them head-to-head, machine learning and AI crush current risk assessment systems.

But given the complexity you’re describing, how can clinicians feel comfortable that this tool is delivering reliable decision support? 

John: A few different things should ease those concerns. First, working with bedside providers in a clinical setting, we’ve shown we can identify a higher percentage of C. diff cases, predict them significantly sooner, and therefore, empower clinicians to respond both more quickly and more effectively.

In addition, one of the features of this model is that it provides a visual picture of its output that explains why it made the predictions it did: what features it identified as most important and why they put the patient at greater risk. For example, it might note it is predicting a CDI in a hospitalized older adult who has a high white blood cell count and fever lasting two days. This information allows physicians to examine the output and decide if the logic makes sense. If there are other considerations rooted in the provider’s clinical experience, he or she can always disregard the tool’s assessments and recommendations.

Finally, and maybe most importantly, there is the time component—the ability to track when all of these factors occur and understand how they figure into the various interaction effects. Time is complicated. Many algorithms become popular because they are easy to use and deploy, in part because they treat each feature independently and don’t perceive an order between input features. But the order of things matters. Knowing when there was an increase or decrease in the white blood cell count, for example, is critical to making accurate predictions.

Other AI tools are emerging. How is this tool different?  

Steve: Well, the time element is pretty rare, if not unique, and it is essential for accuracy. Then there’s the data. The power and reliability of AI tools depend on having the right data and lots of it. A recent survey commissioned by Wolters Kluwer—Mending Healthcare in America 2020—found that nearly 90 percent of hospital executives feel they need more comprehensive patient data to deliver better care, and attribute incorrect or poor quality data as a cause of increased costs. Clinical data is a strength of Wolters Kluwer, as is our ability to integrate a tool like this into an established clinical surveillance solution like Sentri7—one that has a familiar workflow for users. Sentri7 monitors over 500,000 patients at any given time, as well as processing 4 billion lab orders and 677 million drug orders each year. That amount of information dramatically increases the predictive power of the tool.

John: My team at Wolters Kluwer employs rigorous data science approaches, including cross-validation, in which we hold out some data, so that we can do multiple evaluations of the holdout data versus the AI-trained data. We have also completed extensive analysis to understand how different demographic factors, such as age, contribute to predictions to control for bias.  Last of all, and maybe the most important difference, is the way we have always combined data science expertise and clinical expertise at Wolters Kluwer. While building the model, clinicians strongly influenced the feature engineeringthat is the way we determined how to transpose raw data from the electronic medical record in a way that gives the AI algorithm traction to learn from the data and statistics. Clinical expertise is critical both at that point and, of course, in the validation process.  

Steve: Another difference is that the tool offers evidence-based, customizable recommendations on how to treat these high-risk patients. This customizable risk score threshold enables each facility to decide at which point they want to act. We always give our hospital partners the control to fine-tune the alerts for their specific settings.

Any final thoughts? 

Matt: I would reiterate that having this on a trusted clinical surveillance platform already embraced and used by hundreds of hospitals and health systems extends the value of that solution to clinical teams that are hungry for a more progressive and forward-thinking approach to their problems. C. diff is a prime example of that. What I find especially exciting is that we provide transparency to clinicians and hospitals in terms of their patients’ risk and empower them to consider the next steps that are relevant to their circumstances. For example, hospitals can implement a pre-authorization protocol for a certain class of antimicrobials or protocols that avoid inappropriate CDI testing in combination with laxative use, a combination that can artificially inflate CDI rates. Lastly, it’s not a black-box approach, and that’s very, very important for making sure clinicians feel that they can embrace this, interpret it, and use it to its fullest potential within the confines of their facility.

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Biologists Develop Models to Aid Development of Novel Therapies to Fight Clostridioides difficile (C. diff.) Pathogen

The Clostridium difficile pathogen takes its name from the French word for “difficult.” A bacterium that is known to cause symptoms ranging from diarrhea to life-threatening colon damage,

 

 

 

C. difficile is part of a growing epidemic of concern for the elderly and patients on antibiotics.

Outbreaks of C. difficile-infected cases have progressively increased in Western countries, with 29,000 reported deaths per year in the United States alone.

Now, biologists at the University of California San Diego are drawing parallels from newly developed models of the common fruit fly to help lay the foundation for novel therapies to fight the pathogen’s spread. Their report is published in the journal iScience.

C. difficile infections pose a serious risk to hospitalized patients,” said Ethan Bier, a distinguished professor in the Division of Biological Sciences and science director of the UC San Diego unit of the Tata Institute for Genetics and Society (TIGS). “This research opens a new avenue for understanding how this pathogen gains an advantage over other beneficial bacteria in the human microbiome through its production of toxic factors. Such knowledge could aid in devising strategies to contain this pathogen and reduce the great suffering it causes.”

As with most bacterial pathogens, C. difficile secretes toxins that enter host cells, disrupt key signaling pathways and weaken the host’s normal defense mechanisms. The most potent strains of C. difficile unleash a two-component toxin that triggers a string of complex cellular responses, culminating in the formation of long membrane protrusions that allow the bacteria to attach more effectively to host cells.

UC San Diego scientists in Bier’s lab-created strains of fruit flies that are capable of expressing the active component of this toxin, known as “CDTa.” The strains allowed them to study the elaborate mechanisms underlying CDTa toxicity in a live model system focused on the gut, which is key since the digestive system of these small flies is surprisingly similar to that of humans.

“The fly gut provides a rapid and surprisingly accurate model for the human intestine, which is the site of infection by C. difficile,” said Bier. “The vast array of sophisticated genetic tools in flies can identify new mechanisms for how toxic factors produced by bacteria disrupt cellular processes and molecular pathways. Such discoveries, once validated in a mammalian system or human cells, can lead to novel treatments for preventing or reducing the severity of C. difficile infections.”

The fruit fly model gave the researchers a clear path to examine genetic interactions disrupted at the hands of CDTa. They ultimately found that the toxin induces a collapse of networks that are essential for nutrient absorption. As a result, the model flies’ body weight, fecal output and overall lifespan were severely reduced, mimicking symptoms in human C. difficile-infected patients.

In addition to Bier, study coauthors include first-author Ruth Schwartz, Annabel Guichard, Nathalie Franc, and Sitara Roy.

The National Institutes of Health (R01 AI110713) funded the research.


Story Source:

Materials provided by the University of California – San Diego. Original written by Mario Aguilera. Note: Content may be edited for style and length.


Journal Reference:

  1. Ruth Schwartz, Annabel Guichard, Nathalie C. Franc, Sitara Roy, Ethan Bier. A Drosophila Model for Clostridium difficile Toxin CDT Reveals Interactions with Multiple Effector Pathways. iScience, 2020; 100865 DOI: 10.1016/j.isci.2020.100865

Transgenic fruit flies help scientists trace the cascade of symptoms caused by toxic infection

Date: February 7, 2020

Source: University of California – San Diego
Summary: Clostridium difficile, a bacterium is known to cause symptoms from diarrhea to life-threatening colon damage, is part of a growing epidemic for the elderly and hospitalized patients. Biologists have now developed models of the common fruit fly to help develop novel therapies to fight the pathogen

Researchers Report Bezlotoxumab Treatment Reduced C. diff. Recurrence in Cancer Patients

Abstract

Background

The incidence of Clostridioides difficile infection (CDI) is reportedly higher and the cure rate lower in individuals with cancer versus those without cancer. An exploratory post-hoc analysis of the MODIFY I/II trials (NCT01241552/NCT01513239) investigated how bezlotoxumab affected the rate of CDI-related outcomes in participants with cancer.

Methods

Participants received a single infusion of bezlotoxumab (10 mg/kg) or placebo during anti-CDI antibacterial treatment. A post-hoc analysis of CDI-related outcomes was conducted in subgroups of MODIFY I/II participants with and without cancer.

Results

Of 1,554 participants in the modified intent-to-treat (mITT) population, 382 (24.6%) were diagnosed with cancer (bezlotoxumab 190, placebo 192). Of participants without cancer, 591 and 581 received bezlotoxumab and placebo, respectively. In the placebo group, initial clinical cure (ICC) was achieved by fewer cancer participants versus participants without cancer (71.9% versus 83.1%; absolute difference [95% CI]: -11.3% [-18.6, -4.5]), however, CDI recurrence (rCDI) rates were similar in cancer (30.4%) and non-cancer (34.0%) participants. In participants with cancer, bezlotoxumab treatment had no effect on ICC rate compared with placebo (76.8% versus 71.9%), but resulted in a statistically significant reduction in rCDI versus placebo (17.8% versus 30.4%; absolute difference [95% CI]: 12.6% [-22.5, -2.7]).

Conclusions

In this post-hoc analysis of participants with cancer enrolled in MODIFY I/II, the rate of rCDI in bezlotoxumab-treated participants was lower than in placebo-treated participants. Additional studies are needed to confirm these results.

Open Forum Infectious Diseases, ofaa038, https://doi.org/10.1093/ofid/ofaa038
Published:
31 January 2020

 

To access the article in its entirety please click on the following link:

https://academic.oup.com/ofid/advance-article/doi/10.1093/ofid/ofaa038/5718256

DEINOVE Announced Enrollment of First Patient in Phase II Trial Testing DNV3837 in Clostridioides difficile infections

On January 27, 2020, DEINOVE announced the inclusion of the first patient in the Phase II trial testing DNV3837.

 

  • The Phase II clinical trial aims to evaluate the efficacy, safety, and pharmacokinetics of DNV3837 in patients with Clostridioides difficile gastrointestinal infection (CDI).
  • The trial will be conducted mainly in 15 centers in the United States, in two successive stages:
    • a cohort of 10 patients with moderate to severe CDI treated with DNV3837,
    • a randomized cohort study testing DNV3837 against the standard of care in 30 patients with severe CDI.
  • The final results of this trial are expected by the end of 2020.
  • DEINOVE is the only French player to conduct a clinical trial with an antibiotic.
  • On 17 January, the WHO warned about the extreme lack of new antibiotics and the threat posed by antibiotic resistance.

DEINOVE (Euronext Growth Paris: ALDEI), a French biotech company that uses a disruptive approach to develop innovative antibiotics and bio-based active ingredients for cosmetics, announced the inclusion of the first patient in the Phase II trial testing DNV3837.

DNV3837 targets the treatment of Clostridioides difficile infections (CDI), a disease classified as a priority by the WHO and one of the global leading causes of healthcare-related infections*.

DNV3837 is an intravenous antibiotic that, when converted to its active form DNV3681, crosses the gastrointestinal barrier and accumulates in the intestinal lumen, allowing it to precisely target the infection site. DNV3837 has demonstrated a promising efficacy profile and acceptable tolerance in Phase I trials (on healthy volunteers). It has also demonstrated its ability to eliminate Clostridioides bacteria without affecting the gut microbiota. It has been granted Fast Track status and QIDP designation**.

The Phase II trial aims to evaluate the efficacy of DNV3837 in pathological conditions (through monitoring of symptoms, stool analysis, etc.), as well as to consolidate the safety and pharmacokinetic data of the antibiotic candidate.

This trial is concentrated in the United States. It will take place in two stages:

  • In the first phase, involving 5 centers, a cohort of 10 patients with moderate to severe CDI will be treated with DNV3837. At the end of this phase, the DSMB*** will review the interim results.
  • The second phase will involve 30 patients with severe CDI and will be carried out in 15 investigation centers. This will be an open-label randomized trial testing DNV3837 (in 2/3 of patients) against an approved standard of care**** (1/3 of patients) for comparison purposes.

The results of this clinical trial should be available by the end of 2020.

 “The start of this Phase II clinical trial is a significant step forward for DEINOVE and a great hope for patients. We are very proud to provide a potential solution to this unmet medical need and, to this end, work with the best American specialists in this area. The investigation centers are very committed to conducting this trial which, in the event of positive results, will be an important milestone towards the registration of DNV3837,” said Dr. Georges Gaudriault, Scientific Director of DEINOVE.

This announcement echoes warnings issued by the WHO about the lack of antibiotics renewal.

Dr. Tedros Adhanom Ghebreyesus, Director-General of WHO, declared last January 17 « Never has the threat of antimicrobial resistance been more immediate and the need for solutions more urgent ».

https://www.who.int/news-room/detail/17-01-2020-lack-of-new-antibiotics-threatens-global-efforts-to-contain-drug-resistant-infections

 

* Source: CDC (US Centers for Disease Control and Prevention)

** ‘Fast Track’ status facilitates the development of the molecule through a faster and more flexible regulatory review of the application. The QIDP designation gives the drug exclusive access to the market for an additional five-year period. These designations are granted by the FDA to drugs under development that meet critical and unmet therapeutic needs.

*** DSMB – Data Safety Monitoring Board: a group of independent experts tasked to review the data generated during the trial and make recommendations on patient safety as well as trial relevance and validity.

**** Standard treatments approved in the United States for the treatment of CDIs include vancomycin, fidaxomicin and metronidazole (all three antibiotics). The choice will be at the discretion of the clinicians. 

Rebiotix, a Ferring Company, Completes Enrollment for First-Ever, Pivotal Phase 3 Clinical Trial RBX2660

Rebiotix, a Ferring Company, completes enrollment for first-ever, pivotal Phase 3 Clinical Trial of Microbiota -based RBX2660

Enrollment completion for the first Phase 3 clinical trial in microbiome industry

 The largest randomized, double-blinded study, with over 300 patients enrolled aimed to demonstrate the potential benefit of RBX2660 in reducing rates of recurrent Clostridioides difficile (C. diff) infection

 Rebiotix intends to use the results from the Phase 3 trial to serve as the basis for licensure application to the US Food and Drug Admin (FDA)

 Saint-Prex, Switzerland – On February 4, 2020

Rebiotix, a Ferring company, announced today that it has completed enrollment of the pivotal Phase 3 clinical trial for RBX2660, an investigational therapy aimed at breaking the cycle of recurrent Clostridioides difficile (C. diff) infection, which is responsible for the deaths of thousands of people in the US alone. The Centers for Disease Control and Prevention (CDC) has classified C. diff as an urgent public health threat, with limited options for treatment.

 

RBX2660 was developed under Rebiotix’s investigational microbiota-based MRT™ drug platform with the goal of delivering standardized, stabilized formulations to meet unmet medical needs. Conducted in the US and Canada, this is the first Phase 3 trial of its kind to be completed using a broad consortia microbiota-based formulation.

 

“Rebiotix was founded to harness the power of the human microbiome to treat debilitating diseases,” said Lee Jones, Rebiotix Founder, and CEO. “Microbiota-based therapies have shown tremendous potential as an innovative, non-antibiotic therapy, starting with C. diff. The completion of enrollment of this trial is a critical next step in making microbiota-based products accessible to patients – we are excited about this important milestone and look forward to sharing results later this year.”

 

The Phase 3 trial builds on the company’s extensive history with the formulation, including several hundred participants previously enrolled in multiple Phase 2 clinical trials. The robust data collected over the course of the company’s multi-year clinical development program will be eventually presented to the US FDA as part of a Biological License Application (BLA).

 

Ferring Pharmaceuticals, also with a rich and vast history of microbiome research of its own, led the industry by becoming the first major pharmaceutical company to acquire a microbiome therapeutics company in April 2018. Headquartered in Saint-Prex, Switzerland, Ferring is expected to have the first regulatory approved microbiota-based therapeutic in the world through the potential approval of the RBX2660 in the US.

 

About Clostridioides difficile Infection

Clostridioides difficile (also known as C. diff) is a bacterium that causes diarrhea and colitis (inflammation of the colon). C. diff, impacts nearly a half a million people each year in the United States; of those impacted, up to one in five patients will experience a recurrent episode.1 In 2019, the U.S. Centers for Disease Control listed C. diff as an urgent threat to public health.2

 

About RBX2660

RBX2660 is currently in Phase 3 clinical development for the reduction of recurrent Clostridioides difficile (C. diff) infection. RBX2660 has been granted Fast Track, Orphan, and Breakthrough Therapy Status designations from the US FDA. For more information about the RBX2660 Phase 3 study, visit http://www.clinicaltrials.gov (NCT03244644).

 

About Rebiotix

Rebiotix Inc., part of the Ferring Pharmaceuticals Group, is a late-stage clinical microbiome company focused on harnessing the power of the human microbiome to revolutionize the treatment of challenging diseases. Rebiotix has a diverse pipeline of investigational drug products built on its pioneering microbiota-based MRT™ drug platform. The platform consists of investigational drug technologies designed to potentially rehabilitate the human microbiome by delivering a broad consortium of live microbes into a patient’s intestinal tract. For more information on Rebiotix and its pipeline of human microbiome-directed therapies for diverse disease states, visit http://www.rebiotix.com.

 

About Ferring Pharmaceuticals

Ferring Pharmaceuticals is a research-driven, specialty biopharmaceutical group committed to helping people around the world build families and live better lives. Headquartered in Saint-Prex, Switzerland, Ferring is a leader in reproductive medicine and maternal health, and in specialty areas within gastroenterology and urology. Founded in 1950, privately-owned Ferring now employs approximately 6,500 people worldwide, has its own operating subsidiaries in nearly 60 countries and markets its products in 110 countries.

 

References:

1Centers for Disease Control and Prevention. What Is C. Diff?,17 Dec. 2018. Available at: https://www.cdc.gov/cdiff/what-is.html.

2Centers for Disease Control and Prevention. Biggest Threats and Data, 14 Nov. 2019. Available at: https://www.cdc.gov/drugresistance/biggest-threats.html.

 

Source:  Rebiotix, Press Release

http://www.rebiotix.com

Research Provides a Promising Starting Point for Scientists Developing Medications That Can Resolve C. diff. Infections

A newly published paper in PNAS details a research breakthrough that provides a promising starting point for scientists to create drugs that can cure C. diff — a virulent infection associated with health care facilities that cause severe diarrhea, nausea, internal bleeding, and potentially death. The bacteria affect roughly half a million Americans and cause nearly 15,000 deaths in the U.S. annually.

Overuse of antibiotics has increased the risk of patients in health care facilities acquiring C. diff and made some strains of the bacteria particularly hard to treat. But newly discovered information about a type of toxin released by the most dangerous strains of C. diff is providing researchers with a map to develop drugs that can block the toxin and prevent the bacteria from entering human cells.

NSF-funded researchers at CUNY, Merck and the University of Maryland used a combination of tools — cryogenic electron microscopy, X-ray crystallography, nuclear magnetic resonance spectroscopy, and small-angle X-ray scattering — to observe and identify the C. diff toxin’s structure and mode of action.

The scientists believe that it is a binary toxin (it needs two components to function) that might employ a method similar to that used by anthrax to enter cells. Using this information as their starting point, the researchers sought to characterize how the C. diff toxin is different from anthrax.

The researchers observed two similar but distinct forms of the C. diff toxin — one where they saw a pore-forming channel and one where the channel was invisible. That observation gave them clues about how to stop the channel from forming and bacteria from entering the cell.

According to Robin McCarley, a program director in NSF’s Division of Chemistry, “NSF funds this type of research because it allows a fundamental understanding of the behavior, at the molecular level, of a highly complex biological system with broad impacts on society.”

 

 

 

 

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FDA Approves Merck’s DIFICID® (fidaxomicin) to Treat Clostridioides difficile (C. diff. ) in Children Aged Six Months and Older

Merck (NYSE: MRK), known as MSD outside the United States and Canada, announced on January 27, 2020, that the U.S. Food and Drug Administration (FDA) has approved a New Drug Application (NDA) for DIFICID® (fidaxomicin) for oral suspension, and a supplemental New Drug Application (sNDA) for DIFICID tablets for the treatment of Clostridioides (formerly Clostridium) difficile-associated diarrhea (CDAD) in children aged six months and older.1

 

DIFICID is a macrolide antibacterial medicine indicated in adults and pediatric patients aged 6 months and older for the treatment of CDAD.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of DIFICID and other antibacterial drugs, DIFICID should be used only to treat infections that are proven or strongly suspected to be caused by Clostridioides difficile (C. difficile).

DIFICID is contraindicated in patients who have known hypersensitivity to fidaxomicin or any other ingredient in DIFICID. DIFICID should only be used for the treatment of CDAD. DIFICID is not expected to be effective for the treatment of other types of infections due to minimal systemic absorption of fidaxomicin.

C. difficile is an important cause of health care- and community-associated diarrheal illness in children and sustained cure is difficult to achieve in some patients. The fidaxomicin pediatric trial was the first randomized controlled trial of C. difficile infection treatment in children,” said Dr. Larry K. Kociolek, Associate Medical Director of Infection Prevention and Control at Ann & Robert H. Lurie Children’s Hospital of Chicago. “I am very excited to have a new C. difficile infection treatment option for my pediatric patients.”

“Merck is committed to developing new treatments, as well as expanding indications of existing ones, in order to provide more solutions to treat infectious diseases, particularly among children,” said Dr. Nicholas Kartsonis, senior vice president, clinical research, infectious diseases and vaccines, Merck Research Laboratories. “C. difficile infection is an urgent public health challenge. We are grateful to the health care practitioners, the patients and their families for their invaluable contributions in helping to bring this new pediatric indication and the oral suspension formulation for DIFICID to the U.S. market.”

Both applications received a priority review classification by the FDA. The investigational pediatric indication for DIFICID was granted Orphan Drug Designation in 2010.

Data Supporting the Approval of DIFICID in Pediatric Patients

The FDA’s approval of the new formulation and new indication for DIFICID was based on a Phase 3, multicenter, investigator-blind, randomized, parallel-group study (known as the SUNSHINE study, NCT02218372), in which the safety and efficacy of fidaxomicin was evaluated in pediatric patients from 6 months to less than 18 years of age (one patient was less than six months of age). This study, sponsored by Astellas Pharma Europe B.V. (with Merck & Co., Inc. as collaborator) included 148 randomized patients aged <18 years with confirmed CDI, of whom 142 received either fidaxomicin (suspension or tablets, twice daily) or vancomycin (suspension or tablets, four times daily) in a 2:1 ratio. Patients were randomized by age group, as follows: 30 patients from 6 months to <2 years; 49 patients age 2 to <6 years, 40 patients age 6 to <12 years and 29 patients age 12 to <18 years. Generally, the two treatment groups were balanced regarding demographics and other baseline characteristics. CDAD clinical response in the overall pediatric population, assessed through two days following 10 days of treatment, was similar between the fidaxomicin and vancomycin groups (77.6% vs. 70.5% with a 95% CI for the treatment difference of 7.5 [-7.4%, 23.9%]). Sustained clinical response, defined as the proportion of treated patients with confirmed clinical response and no CDAD recurrence through 30 days after the end of treatment, was higher for fidaxomicin than for vancomycin (68.4% vs. 50.0% with a 95% CI for the treatment difference of 18.4 [1.5%, 35.3%]).

The safety of DIFICID in pediatric patients 6 months to less than 18 years of age was evaluated in a Phase 2 single-arm trial in 38 patients and a Phase 3 randomized, active-controlled trial in 98 patients treated with DIFICID and 44 patients treated with vancomycin. Treatment discontinuation due to adverse reactions occurred in 7.9% (3/38) of patients in the Phase 2 trial, and in 1% (1/98) and 2.3% (1/44) of DIFICID- and vancomycin-treated patients, respectively, in the Phase 3 trial. The most common selected adverse reactions occurring in ≥5% of pediatric patients treated with DIFICID in the Phase 3 trial were pyrexia (13.3%), abdominal pain (8.2%), vomiting (7.1%), diarrhea (7.1%), constipation (5.1%), increased aminotransferases (5.1%) and rash (5.1%). One death occurred in the Phase 2 single-arm trial and three deaths occurred in the Phase 3 trial of DIFICID-treated patients. No deaths occurred in vancomycin-treated patients during the study period (40 days). All deaths occurred in patients less than 2 years of age and appeared to be related to underlying comorbidities.

About Clostridioides difficile

Clostridioides (formerly Clostridium) difficile, also known as C. difficile or C. diff, is one of the most common causes of healthcare-associated infections in U.S. hospitals.2 Recent estimates suggest C. difficile causes almost 500,000 infections annually in the United States and is associated with approximately 29,000 deaths within 30 days of initial diagnosis.3 According to the CDC’s Antibiotic Resistance Threats in the United States, 2019 (2019 AR Threats Report), C. difficile is categorized as an urgent threat and is stated as a public health threat that requires urgent and aggressive action.4

Important Safety Information about DIFICID (fidaxomicin)

DIFICID is contraindicated in patients who have known hypersensitivity to fidaxomicin or any other ingredient in DIFICID.

Acute hypersensitivity reactions, including dyspnea, rash, pruritus, and angioedema of the mouth, throat, and face have been reported with DIFICID. If a severe hypersensitivity reaction occurs, DIFICID should be discontinued and appropriate therapy should be instituted.

DIFICID is not expected to be effective for the treatment of other types of infections due to minimal systematic absorption of fidaxomicin. DIFICID has not been studied for the treatment of infections other than CDAD. DIFICID should only be used for the treatment of CDAD.

Only use DIFICID for infection proven or strongly suspected to be caused by C. difficile. Prescribing DIFICID in the absence of a proven or strongly suspected C. difficile infection is unlikely to provide benefit to the patient and increases the risk of development of drug-resistant bacteria.

The most common adverse reactions reported in adults are nausea (11%), vomiting (7%), abdominal pain (6%), gastrointestinal hemorrhage (4%), anemia (2%) and neutropenia (2%).

The most common adverse reactions in pediatric patients are pyrexia (13.3%), abdominal pain (8.2%), vomiting (7.1%), diarrhea (7.1%), constipation (5.1%), increased aminotransferases (5.1%) and rash (5.1%).

Among patients receiving DIFICID (fidaxomicin), 33 (5.9%) withdrew from trials as a result of adverse reactions. Vomiting was the primary adverse reaction leading to discontinuation of dosing (incidence of 0.5% for both DIFICID and vancomycin patients).

The safety and effectiveness of DIFICID have not been established in pediatric patients younger than 6 months of age.

The recommended dose for adults is one 200 mg DIFICID tablet orally twice daily for 10 days, with or without food.

The recommended dose for pediatric patients weighing at least 12.5 kg and able to swallow tablets is one 200 mg DIFICID tablet administered orally twice daily for 10 days. If unable to swallow tablets, pediatric patients may be dosed with DIFICID oral suspension based on weight. DIFICID oral suspension should be administered orally twice daily for 10 days.

No dose adjustment is recommended for patients 65 years of age or older.

No dose adjustment is recommended for patients with renal impairment.

No dosage adjustments are recommended when co-administering DIFICID with substrates of P-gp or CYP enzymes.

The impact of hepatic impairment on the pharmacokinetics of DIFICID has not been evaluated; however, because DIFICID and its active metabolite (OP-1118) do not appear to undergo significant hepatic metabolism, elimination of DIFICID and OP-1118 is not expected to be significantly affected by hepatic impairment.

About Merck

For more than a century, Merck, a leading global biopharmaceutical company known as MSD outside of the United States and Canada, has been inventing for life, bringing forward medicines and vaccines for many of the world’s most challenging diseases. Through our prescription medicines, vaccines, biologic therapies, and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to health care through far-reaching policies, programs, and partnerships. Today, Merck continues to be at the forefront of research to advance the prevention and treatment of diseases that threaten people and communities around the world – including cancer, cardio-metabolic diseases, emerging animal diseases, Alzheimer’s disease and infectious diseases including HIV and Ebola. For more information, visit www.merck.com and connect with us on Twitter, Facebook, Instagram, YouTube, and LinkedIn.

Forward-Looking Statement of Merck & Co., Inc., Kenilworth, N.J., USA

This news release of Merck & Co., Inc., Kenilworth, N.J., USA (the “Company”) includes “forward-looking statements” within the meaning of the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995. These statements are based upon the current beliefs and expectations of the company’s management and are subject to significant risks and uncertainties. There can be no guarantees with respect to pipeline products that the products will receive the necessary regulatory approvals or that they will prove to be commercially successful. If underlying assumptions prove inaccurate or risks or uncertainties materialize, actual results may differ materially from those set forth in the forward-looking statements.

Risks and uncertainties include but are not limited to, general industry conditions and competition; general economic factors, including interest rate and currency exchange rate fluctuations; the impact of pharmaceutical industry regulation and health care legislation in the United States and internationally; global trends toward health care cost containment; technological advances, new products and patents attained by competitors; challenges inherent in new product development, including obtaining regulatory approval; the company’s ability to accurately predict future market conditions; manufacturing difficulties or delays; financial instability of international economies and sovereign risk; dependence on the effectiveness of the company’s patents and other protections for innovative products; and the exposure to litigation, including patent litigation, and/or regulatory actions.

The company undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise. Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s 2018 Annual Report on Form 10-K and the company’s other filings with the Securities and Exchange Commission (SEC) available at the SEC’s Internet site (www.sec.gov).

Please see U.S. Prescribing Information for DIFICID (fidaxomicin) at https://www.merck.com/product/usa/pi_circulars/d/dificid/dificid_pi.pdf, and Patient Information for DIFICID (fidaxomicin) at https://www.merck.com/product/usa/pi_circulars/d/dificid/dificid_ppi.pdf.


1 DIFICID in the US and Canada is a trademark of Cubist Pharmaceuticals LLC, an indirect wholly-owned subsidiary of Merck Sharp & Dohme Corp.

2 Lessa, Fernanda. “Burden of Clostridium difficile Infection in the United States.” The New England Journal of Medicine, vol. 372, Feb. 2015, pp.825-834.

3 Ibid.

4 “Antibiotic Resistance Threats in the United States, 2019.” U.S. Centers for Disease Control and Prevention, 2019, p. 65.

 

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