•Multi-omics reveals markers of CDI in pediatric IBD patients
•Identification of metabolites reveals distinctive features for IBD and CDI
•Isocaproyltaurine is made by C. difficile and associates with active IBD
•Identifies biomarkers potentially useful for distinguishing disease processes
Children with inflammatory bowel diseases (IBD) are particularly vulnerable to infection with Clostridioides difficile (CDI). IBD and IBD + CDI have overlapping symptoms but respond to distinctive treatments, highlighting the need for diagnostic biomarkers. Here, we studied pediatric patients with IBD and IBD + CDI, comparing longitudinal data on the gut microbiome, metabolome, and other measures. The microbiome is dysbiotic and heterogeneous in both disease states, but the metabolome reveals disease-specific patterns. The IBD group shows increased concentrations of markers of inflammation and tissue damage compared with healthy controls, and metabolic changes associate with susceptibility to CDI. In IBD + CDI, we detect both metabolites associated with inflammation/tissue damage and fermentation products produced by C. difficile. The most discriminating metabolite found is isocaproyltaurine, a covalent conjugate of a distinctive C. difficile fermentation product (isocaproate) and an amino acid associated with tissue damage (taurine), which may be useful as a joint marker of the two disease processes.
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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 ofClostridioides (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.
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.
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).
Cubist Pharmaceuticals, Inc. today announced it will present new data from a phase 1 safety and pharmacokinetic study of fidaxomicin in children with Clostridium difficile-associated diarrhea (CDAD) at IDWeek 2014, being held October 8-12 in Philadelphia.
These new data will be featured as a late-breaking oral presentation (LB-8, session #186) Saturday, October 11, 2014, at 10:30 a.m. EDT, given by Pam Sears, Vice President, Clinical Sciences, Cubist.
The presentation will provide early insight into the safety, pharmacokinetic profile and efficacy of fidaxomicin in children who have CDAD.
“Children, especially those who have serious underlying medical conditions, are susceptible to Clostridium difficile-associated diarrhea, which can be very serious,” said Steven Gilman, Ph.D., Executive Vice President of Research and Development and Chief Scientific Officer of Cubist Pharmaceuticals. “These first data of fidaxomicin in children are important because they offer the first insights into a patient population that is typically excluded from Phase 3 clinical trials.”
This study of fidaxomicin enrolled 38 patients whose ages ranged from 11 months to 17 years, most of whom had complex underlying medical issues, including cancer (23.7%) and/or gastrointestinal disorders (78.9%). Adverse events observed in greater than two subjects included fever, vomiting, upper abdominal pain and C-difficile colitis.
At least one adverse event was reported in 73.7% of patients. The majority of adverse events were categorized as mild (44.7%) or moderate (21.1%). Nine severe adverse events were observed during the course of the study and were not considered related to fidaxomicin. The pharmacokinetic profile seen in this study is similar to the profile shown in an adult population. Although not powered to assess efficacy, the clinical response observed in the study was 92.1%. The infections recurred in 28.6% of patients, all but one of whom had a history of recurrent CDAD.
“This study supports the further evaluation of fidaxomicin in children with C. difficile-associated diarrhea,” said Pam Sears. “As CDAD is most often observed in adults, there is much less information known about the pediatric presentation of the disease, and we are excited to present the results of our first study on the treatment of CDAD in children. We hope the results presented at IDWeek 2014 encourage ongoing dialogue and exchange on this important topic.”
In addition to this study, Cubist’s other presentations at IDWeek 2014 will feature the company’s portfolio of antibiotics for serious infections caused by multidrug-resistant bacteria. Data highlighted will offer insights into Cubist’s commitment to identifying treatments for drug-resistant Gram-positive and Gram-negative bacteria that cause serious infections.
Fidaxomicin is not currently approved for use in pediatric patients. Fidaxomicin is marketed in the U.S. as DIFICID® for the treatment of adult CDAD.
Indication and Important Safety Information
DIFICD Indication and Usage
DIFICID® (fidaxomicin) is indicated in adults (≥18 years of age) for treatment of Clostridium difficile-associated diarrhea (CDAD)
To reduce the development of drug-resistant bacteria, DIFICID should be used only to treat infections that are proven or strongly suspected to be caused by Clostridium difficile
DIFICD Important Safety Information
DIFICID should not be used for systemic infections.
Acute hypersensitivity reactions (angioedema, dyspnea, pruritus, and rash) have been reported. In the event of a severe reaction, discontinue DIFICID
Development of drug-resistant bacteria: 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 the development of drug resistant bacteria
Adverse Reactions: The most common adverse reactions are nausea (11%), vomiting (7%), abdominal pain (6%), gastrointestinal hemorrhage (4%), anemia (2%), and neutropenia (2%)
About Cubist’s Commitment to Antibiotic R&D
Cubist has a growing commitment to global public health through its leadership in the discovery, development and commercialization of novel antibiotics to treat serious and potentially life-threatening infections caused by a broad range of increasingly drug-resistant bacteria. The Company hopes to deliver at least four new antibiotics in support of the Infectious Diseases Society of America (IDSA) goal of 10 new antibiotics by 2020. Cubist expects to invest approximately $400M USD in 2014 on antibacterial R&D and approximately 75% of its employee base is focused on the research, development, commercialization and support of antibiotics.
Cubist Pharmaceuticals, Inc. is a global biopharmaceutical company focused on the research, development, and commercialization of pharmaceutical products that address significant unmet medical needs in the acute care environment. Cubist is headquartered in Lexington, Massachusetts, with a central international office located in Zurich, Switzerland. Additional information can be found at Cubist’s web site at www.cubist.com. Also, connect with Cubist on Twitter @cubistbiopharma and @cubistcareers, LinkedIn, or YouTube.
About IDWeek 2014TM
IDWeek 2014TM is an annual meeting of the Infectious Diseases Society of America (IDSA), the Society for Healthcare Epidemiology of America (SHEA), the HIV Medicine Association (HIVMA) and the Pediatric Infectious Diseases Society (PIDS). With the theme “Advancing Science, Improving Care,” IDWeek features the latest science and bench-to-bedside approaches in prevention, diagnosis, treatment, and epidemiology of infectious diseases, including HIV, across the lifespan. IDWeek 2014 takes place October 8-12 at the Pennsylvania Convention Center in Philadelphia, Pennsylvania. The full name of the meeting is IDWeek 2014TM.For more information, visit www.idweek.org.
Forward Looking Statements
This press release contains forward-looking statements. Any statements contained herein which do not describe historical facts, including but not limited to, statements regarding: our intention to present data at IDWeek 2014 from a phase 1 study of fidaxomicin in children with CDAD, including our view that this study supports further evaluation of fidaxomicin in children with CDAD; our intention to present at IDWeek 2014 regarding our other antibiotics; our commitment to identifying treatments for drug-resistant bacteria that cause serious infections, including our commitment to global public health in this area; the level of our financial and personnel commitments towards antibiotic research, development and commercialization; our aspirations to achieve a portion of the IDSA goal of 10 new antibiotics by 2020; and the therapeutic potential of our products, are forward-looking statements which involve risks and uncertainties that could cause actual results to differ materially from those discussed in such forward-looking statements. Such risks and uncertainties include, among others: the fact that drug development involves a high degree of risk and a high rate of failure and success in early stage clinical trials does not mean that later stage trials will be successful; regulatory developments in the U.S. and other countries; the strength of, and our ability to successfully obtain, maintain and enforce intellectual property protecting our products; the fact that drug discovery and development is complex, time consuming, expensive and fraught with a high risk of failure; we are dependent on our ability to successfully work with, and the performance of, our third party clinical research organizations that we significantly rely on to help us conduct clinical trials; the timing and feasibility of any new clinical trials is dependent on our ability to successfully work with regulatory authorities, including the FDA on the design of the trials, among other things; technical difficulties or excessive costs relating to the manufacture or supply of our products, including our dependence on and the performance of our third party contract manufacturers that manufacture and supply our products on our behalf and those additional factors discussed in our most recent annual report on Form 10-K and subsequent quarterly reports on Form 10-Q filed with the Securities and Exchange Commission and available at http://www.sec.gov
We caution investors not to place considerable reliance on the forward-looking statements contained in this press release. These forward-looking statements speak only as of the date of this press release, and we undertake no obligation to update or revise any of these statements.
After nine months of hospital and doctor visits, a young boy received an unusual, life-saving stool transplant from his brother.
Doctors diagnosed 3-year-old Michael Ham with Clostridium difficile (C. diff), an intestinal tract infection resulting from the use of antibiotics
“Initially, we went to the hospital for dehydration in February,” (2014) said Michael’s mom, Rachel Donegan Ham.
“He stayed there for eight days because he couldn’t stop throwing up and having diarrhea.”
Doctors took a chance giving Michael another antibiotic. It worked for a few weeks, then he relapsed and began wasting away.
Four months of constant doctor visits finally turned into a diagnosis.
Antibiotics kill both the bad and good bacteria in intestines. In some cases they cause the bad bacteria, C. diff, to multiply and cause life-altering and sometimes deadly infections.
Dr. Sujal Rangwalla, a pediatric gastroenterologist at Seton Dell Children’s Hospital, (Texas) suggested an experimental treatment only performed on two patients at that facility. He recommended Michael have a fecal transplant.
“We take a stool specimen from a sibling or family member and place it in the patient to see if it helps regenerate their normal florum,” Rangwalla said.
So on Aug. 7, Michael and his older brother Bryan arrived at Dell Children’s in hopes of a miracle.
He was improving a few days after the transplant. Within weeks, doctors declared him cured.
“So many doctors want the proof before they do the treatment, and he listened to his heart and it saved Michael,” Rachel Ham said.
Hospital records show C. diff is linked to more than * 30,000 deaths a year in the United States. It sickens more than half a million Americans a year, mostly older people.
About 500 people around the world have undergone fecal transplants, and doctors say this antibiotic-resistant bacteria is evidence of a bigger problem.
Tips to fight antibiotic resistance include avoiding taking antibiotics unless necessary. Anyone who is prescribed an antibiotic should take the full dosage.
People should also limit the amount of antibiotic soap and hand sanitizer used in their households.
Rachel Ham reigns as the C Diff Foundation’s Pediatric Support Team Leader working in cooperation with Tiffani Eberflus, Chairperson of the Pediatric Support, Research and Development Committee. The Foundation sincerely applauds their efforts and participation in both their support of the Foundation and their diligent strides in raising C. difficile awareness/prevention/treatments worldwide.