Outbreak-Related Hep A Infections on the Rise

The epidemiology of hepatitis A infections may be experiencing a recent dramatic shift from common-source infections to outbreaks, a researcher said here.

A steadily increasing trend of outbreak-associated infections from 2012-2016 shot up dramatically, when a combination of 2017 data found that 43% of hepatitis A infections were outbreak-associated infections, reported Monique Foster, MD, of the CDC in Atlanta.

In a late-breaking presentation, she noted how previously, large community outbreaks of hepatitis A were associated with asymptomatic children, who would then pass the virus onto adults who would then infect other adults. But that has changed with the CDC recommendation that all children receive the hepatitis A vaccine.

Foster added that a large population of adults — who are more likely to experience severe disease and adverse outcomes — are not immune to hepatitis A virus, and that uptake of the vaccine among high-risk adults, such as travelers, men who have sex with men, and persons who use drugs, has been low, she said.

“There is no universal recommendation for hepatitis A vaccination in adults. The outbreaks in the last 2 years highlighted that vulnerable populations can be better protected,” she said in a presentation at the ID Week, with joint sponsorship by the Infectious Diseases Society of America (IDSA), the Pediatric Infectious Diseases Society (PIDS), the Society for Healthcare Epidemiology of America (SHEA), and the HIV Medicine Association (HIVMA).

Recently, the CDC Advisory Committee on Immunization Practices (ACIP) recommendedthe use of hepatitis A vaccine in outbreaks, and the FDA recently approved a new formulation of hepatitis A immunoglobulin, which is recommended for certain populations as post-exposure prophylaxis.

Given the recent outbreaks, which Foster characterized as having “high hospitalization and case mortality rates,” researchers sought to examine if the epidemiology of the disease has changed by looking at two 5 year time-periods — 2007-2011 and 2012-2016, as reported to the National Notifiable Diseases Surveillance System (NNDSS).

The 2017 data was a combination of NNDSS data and “cases reported directly to the CDC hepatitis outbreak response team during 2017,” and excluded data from four states that were reporting directly to the latter, to avoid double-counting.

When examining the two 5-year time periods only, the total number of reported hepatitis A infections declined (10,619 in 2007-2011 vs 8,419 in 2012-2016), although there was a statistically significant increase in the median age of these cases (36 to 42, respectively). There was no difference between the sexes, with about half of cases among men. Examining race, cases were 53% to 59% white, though the number of “unknown” race decreased in the most recent time period (28% to 19%, respectively).

In these time periods, the number of infections associated with outbreaks climbed from 5% to 8%, respectively, with a dramatic increase in median age (28 to 41). Of outbreak-associated infections where clinical data was reported, hospitalizations rose from 39% to 58%.

However, these results shifted dramatically when factoring in preliminary 2017 data. Last year, there were 3,421 reported hepatitis A infections, with a median age of 40. Two-thirds of 2017 cases were men, and over two-thirds were white.

Moreover, the portion of outbreak-associated infections climbed to 43% of total infections based on preliminary 2017 data. Of these infections where clinical data were reported, 99% were hospitalized, and the death rate jumped from 0.7% in 2012-2016 to 4%.

The authors concluded that previously hepatitis A outbreaks were “infrequent and typically associated with a common source,” outbreak-linked cases, hospitalizations and deaths were on the rise. However, Foster cautioned that “clinical outcomes are difficult to interpret from NNDSS alone.”

Foster and co-authors disclosed no relevant relationships with industry.

LAST UPDATED 10.08.2018

• Primary Source

  IDWeek

  Source Reference: Foster M, et al “Changing epidemiology of hepatitis A virus infections — United States, 2011-2017” IDWeek 2018; Abstract LB10.

https://www.medpagetoday.com/meetingcoverage/idweek/75554

CAR T-Cell Therapy Cost-Effective in Pediatric Leukemia

Despite its $475,000 per-patient price tag, the survival gains and cost per life-year gained with tisagenlecleucel (Kymriah) in pediatric B-cell acute lymphoblastic leukemia (ALL) were both in line with commonly accepted thresholds, a cost-effectiveness analysis found.

Using conservative assumptions of survival in these patients, the incremental cost-effectiveness ratio for the chimeric antigen receptor (CAR) T-cell therapy would be between $37,000 and $78,000 per quality-adjusted life year (QALY) gained, reported Melanie Whittington, PhD, of the University of Colorado Anschutz Medical Campus in Aurora, and colleagues.

By extrapolating trial results of tisagenlecleucel, the researchers estimated that about four in 10 pediatric patients who initiated the CAR T-cell therapy could be considered long-term survivors compared with about one in 10 treated with the comparator, clofarabine.

“With the evidence available at this time, tisagenlecleucel seems to be priced in alignment with benefits observed over a patient lifetime horizon,” the authors wrote in JAMA Pediatrics, while noting that considerable uncertainty of the drug’s long-term benefit remains due to the limited available evidence.

Tisagenlecleucel was the first FDA-approved gene therapy, indicated for use in pediatric patients with relapsed or refractory B-cell ALL. The one-time cost of the treatment is the most expensive in cancer care.

The findings from Whittington’s group are similar to those from a recent report in the Journal of Clinical Oncology, which concluded that the treatment represented “reasonable value” if the long-term effectiveness holds up and enough patients are able to remain in remission without a need for transplantation.

In May, tisagenlecleucel received an expanded indication from the FDA for treating adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) whose disease progressed on two or more systemic therapies. But last month, Britain’s cost watchdog NICE recommended against use of the agent in adults with DLBCL.

For the current analysis, Whittington’s group created a decision analytic model to adapt trial evidence of tisagenlecleucel to a lifetime horizon for these pediatric patients. The model included data from three trials: B2202, B2205J, and B2101J (with 18.6 months being the longest trial duration).

At 5 years, the model estimated that 40% of patients who started tisagenlecleucel would still be alive and responding to treatment. Given this, the discounted cost of tisagenlecleucel was $667,000 with more than a decade (10.34 years) of discounted life-years gained and 9.28 QALYs gained.

In comparison, only 10.8% of patients receiving clofarabine were estimated to be long-term survivors. Clofarabine had a total discounted cost of $337,000, butwith only 2.43 discounted life-years gained and 2.10 QALYs gained. This equated to an approximately $46,000 difference per QALY gained for tisagenlecleucel compared with clofarabine.

Whittington’s group also conducted several scenario analyses that adjusted for more conservative assumptions about long-term relapse and survival. In the first scenario the discount rate was adjusted from 3.0% to 1.5%. This change increased life years and QALYs, resulting in a more favorable cost-effectiveness ratio of $37,000 per QALY gained. In another scenario they adjusted their model to start at treatment infusion instead of leukapheresis. This increased the incremental cost-effectiveness ratio to $50,000 per QALY as compared with $45,871.

Despite attempting to adjust for some of the unknowns about tisagenlecleucel, Whittington and colleagues wrote that the value of tisagenlecleucel must be reassessed once data with longer follow-up time is available.

In an editorial that accompanied the study, Lisa Prosser, PhD, of the University of Michigan, reiterated the study authors’ concerns about their ability to assess long-term clinical utility and cost-effectiveness in a rare pediatric condition.

“Extrapolating benefits beyond the trial time-frame can be especially difficult for rare pediatric interventions, because this often requires assumptions for treatment effectiveness across the lifespan based on only 1 to 2 years of trial data,” Prosser pointed out. “In this case, the effectiveness of tisagenlecleucel is based on pooled data from three trials that included fewer than 200 patients combined, with a median follow-up time shorter than 2 years.”

However, she acknowledged that the researchers’ use of several scenario analyses helped address many of the issues inherent to this type of study.

In addition, Prosser said that based on this analysis, tisagenlecleucel meets the threshold for cost-effectiveness despite being approved by the FDA with an orphan drug status.

“Using modeling to understand the tradeoffs between clinical outcomes and economic value for treatments for rare pediatric conditions provides insights for decision-making,” Prosser said. “This analysis demonstrates that costly interventions can be cost-effective if the clinical utility is high, which underscores the importance of using an economic evaluation framework, such as cost-effectiveness analysis.”

The study was funded by the Institute for Clinical and Economic Review, which receives funding from a number of organizations as well as insurance companies, and its annual summit includes support from pharmaceutical companies that include Novartis, the maker of tisagenlecleucel (Kymriah).

Whittington disclosed no relationship with industry. Several co-authors are employees of the Institute for Clinical and Economic Review.

Prosser reported no conflicts of interest.

• Primary Source

  JAMA Pediatrics

  Source Reference: Whittington MD, et al “Long-term survival and value of chimeric antigen receptor T-cell therapy for pediatric patients with relapsed or refractory leukemia” JAMA Pediatr 2018; DOI:10.1001/jamapediatrics/2018.2530.

• Secondary Source

  JAMA Pediatrics

  Source Reference: Prosser LA “Defining the value of treatments of rare pediatric conditions” JAMA Pediatr 2018; DOI:10.1001/jamapediatrics.2018.3343.

https://www.medpagetoday.com/hematologyoncology/leukemia/75557

Viking Presents at American Thyroid Association

VK2809 Treatment Leads to Rapid Reduction in Steatosis, Inflammation and Liver Size in Mouse Model of Glycogen Storage Disease Type Ia (GSD Ia)   

Viking Therapeutics, Inc. (“Viking”) (NASDAQ: VKTX), a clinical-stage biopharmaceutical company focused on the development of novel therapies for metabolic and endocrine disorders, today announced the presentation of positive data from a study of VK2809 in an in vivo model of glycogen storage disease type Ia (GSD Ia) at the 88^thAnnual Meeting of the American Thyroid Association (ATA) in Washington, D.C.  The results demonstrated that treatment with VK2809 led to an overall improvement in liver health highlighted by restoration of autophagy, reduction in steatosis, and improvements in inflammation and liver size.  The study investigators concluded that these histological improvements are potentially relevant to non-alcoholic fatty liver disease (NAFLD), including non-alcoholic steatohepatitis (NASH), due to certain similarities between those conditions and GSD Ia.

Study results were summarized in an oral presentation titled, “Liver-selective Thyromimetic, VK2809, Reduces Hepatosteatosis in Mouse Model of the Glycogen Storage Disease GSD Ia,” by professor Paul Yen, M.D., head of the Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore.  GSD Ia is a rare genetic disease that results in excess accumulation of glycogen and lipids in liver tissue.  This study utilized the glucose-6-phosphatase (G6PC) knockout mouse model, which is intended to replicate the impairment of this enzyme’s activity in patients with GSD Ia.  G6PC knockouts develop enlarged livers due to elevated fat content.

The results demonstrated decreases in steatosis, liver mass, and triglyceride concentration in VK2809-treated cohorts compared with vehicle controls.  Significant improvements in LC3B-II protein density, an important mediator of fat disposal, as well as reduced levels of p62 protein, were also observed.  These data suggest that, in addition to stimulation of beta-oxidation via increased PGC1-alpha and CPT1-alpha expression, restoration of autophagy may be contributing to the reduction of fat content in this setting.

Importantly, this study also demonstrated indications of reduced inflammatory signalling following treatment with VK2809.  The expression of inflammatory markers such as tumor necrosis factor alpha (TNF alpha) and interleukin 6 (IL-6) were normalized or reduced in the livers of VK2809-treated cohorts compared with vehicle controls, suggesting an overall reduction in inflammation.  These data may be of interest for other indications in which inflammation plays a role in disease progression and severity.

“These results are exciting not only in the context of GSD Ia but also, as Dr. Yen highlighted, due to their relevance to settings like NAFLD and NASH.  The impressive reduction in steatosis observed in this model is supported by improved expression of genes important for autophagy and fat metabolism.  The normalization of inflammatory gene expression is of particular interest due to role of inflammation in the onset of hepatocyte damage, and ultimately fibrosis, in various liver diseases,” said Brian Lian, Ph.D., chief executive officer of Viking.  “We believe the GSD I data presented at ATA, combined with our recently reported Phase 2 results in NAFLD, provide compelling support for VK2809 as a best-in-class thyroid beta receptor agonist with significant therapeutic potential in NAFLD and NASH.”

The proof-of-concept study was conducted under a sponsored research agreement between Duke University and Viking Therapeutics and designed to evaluate the effects of VK2809 in Duke University’s G6PC knockout mouse model.  The G6PC knockout model is intended to replicate many of the same biochemical and physiological characteristics present in GSD Ia patients.

https://www.biospace.com/article/releases/viking-therapeutics-announces-data-from-in-vivo-study-of-vk2809-presented-at-oral-plenary-session-of-the-88th-annual-meeting-of-american-thyroid-association-ata-/

Merck & Co signs biosimilars deal for US veterans

Merck & Co has signed a deal with the US Department of Veterans Affairs (VA) for its inflammatory diseases biosimilar, Renflexis, so that veterans’ care can be improved.

Merck, which is known as Merck Sharp & Dohme (MSD) outside the US and Canada, was awarded the exclusive contract for its tumour necrosis factor (TNF) blocker biosimilar, Renflexis. It has become the only infliximab biosimilar on the VA national formulary.

The US Food and Drug Administration (FDA) approved Renflexis, manufactured by South Korea’s Samsung Bioepis, in April last year as a biosimilar to Janssen Biotech’s Remicade (infliximab). The drug has to be injected, as stomach acids would render the medicine ineffective.

Merck & Co and Samsung Bioepis have a deal covering marketing of certain biosimilars dating back to 2013, with the US pharma responsible for marketing, after development by the South Korean firm.

Patrick Magri, senior vice president, US Hospital & Specialty Business Unit, Merck, said: “We are pleased that VA has chosen to expand access to an important treatment option such as Renflexis for our veterans who have nobly served this country.”

And Dr Michael Valentino, chief consultant for pharmacy benefits management at the Department for Veterans Affairs, added: “VA recognises the value biosimilars bring to the health care system, and the award of this contract is consistent with VA’s goal of providing quality treatment options while optimising resources in the care of veterans.”

The drug is an artificial monoclonal antibody that is used to treat several inflammatory diseases including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and plaque psoriasis, ulcerative colitis and Crohn’s disease. The treatment can also be used for sarcoidosis when patients do not respond to other medications.

It was developed in mice as a mouse antibody and has been altered so that humans can use the medicine. The antibodies have identical structures and affinities to the target.

In August, the Canadian province, British Columbia, added Renflexis to its list of drugs that attract reimbursement. The biosimilar is approved in Canada to treat a range of disorders, including inflammatory bowel diseases and inflammatory arthritis.

https://pharmaphorum.com/news/merck-co-signs-biosimilars-deal-for-us-veterans/

Scientists use CRISPR to cure mice disorder in womb, STAT reports

Scientists reported today that they used CRISPR to alter the DNA of laboratory mice in the womb, eliminating a deadly liver disease before the animals had even been born, Sharon Begley of STAT reports. CRISPRing human fetuses is still years away, but the success in mice paves the way for curing genetic diseases before birth, the writer adds. Companies developing CRISPR-based therapies include Editas Medicine (EDIT), Intellia Therapeutics (NTLA), and Crispr Therapeutics (CRSP).
https://thefly.com/landingPageNews.php?id=2801091

Tetraphase Presents Positive Data from Phase 3 Anti-infective Trials

XERAVA Demonstrated Efficacy in Treating Secondary Bacteremia in Patients with Complicated Intra-Abdominal Infections in Post-Hoc Analysis of Phase 3 Clinical Trials

TP-6076 Demonstrated Favorable Pharmacokinetic and Safety Profile in Phase 1 Trial, Supporting Advancement into a Bronchopulmonary Disposition Study

Tetraphase Pharmaceuticals, Inc. (NASDAQ:TTPH), a biopharmaceutical company focused on developing and commercializing novel antibiotics to treat life-threatening multidrug-resistant (MDR) infections, announced data from a pooled analysis of two Phase 3 studies of XERAVA in complicated intra-abdominal infection (cIAI) and a Phase 1 multiple-ascending dose study for its pipeline candidate TP-6076. These data were presented at the Infectious Disease Society of America’s (IDSA) Infectious Disease Week (IDWeek) 2018, held October 3-7 in San Francisco.

“The data presented at IDWeek demonstrate high clinical cure rates and microbiological eradication with XERAVA among patients with cIAI and concurrent bacteremia,” said Guy Macdonald, President and Chief Executive Officer of Tetraphase. “These data confirm the efficacy of XERAVA in a subgroup of cIAI patients who may be at higher risk for poor outcomes, and this new analysis comes at an exciting time as we make final preparations for the commercial launch of XERAVA in the coming weeks.”

Mr. Macdonald added, “We are also encouraged by the positive safety, tolerability and pharmacokinetic data from the multiple-ascending dose Phase 1 study evaluating a seven-day dosing regimen for intravenous (IV) TP-6076. We plan to advance TP-6076 to a bronchopulmonary disposition study beginning in the first quarter of 2019 to confirm appropriate therapeutic levels of TP-6076 in the lungs to treat infections caused by Acinetobacter baumannii and other MDR pathogens. In previously completed in vitrotesting, TP-6076 MIC₉₀ values were as much as 64-fold lower than those for tigecycline against MDR Gram-negative pathogens, including Acinetobacter baumannii, suggesting that TP-6076 could be a potent treatment for these difficult-to-treat bacteria. We are enthusiastic about the potential for TP-6076 and the future of this program.”

https://www.marketscreener.com/TETRAPHASE-PHARMACEUTICAL-12854471/news/Tetraphase-Pharmaceuticals-Announces-Presentation-of-Positive-Data-from-Phase-3-Trials-of-XERAVA-tra-27385174/

FDA Panel to Review of Mallinckrodt Abuse-Deterrent Oxycodone Formulation

Mallinckrodt plc (NYSE: MNK), a leading global specialty pharmaceutical company, today announced the U.S. Food and Drug Administration (FDA) has confirmed it will hold a joint meeting of its Anesthetic and Analgesic Drug Products Advisory Committee and Drug Safety and Risk Management Advisory Committee on Nov. 14, 2018.

The Committees will assess the 505(b)2 new drug application submission for MNK-812, Mallinckrodt’s abuse-deterrent formulation of immediate-release, single-entity oxycodone tablets with a proposed indication for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate. Mallinckrodt is advancing this reformulation of Roxicodone^®(oxycodone hydrochloride tablets USP) with properties designed to deter intravenous and intranasal abuse.

“We look forward to engaging with the Advisory Committees to discuss the potential benefits our new abuse-deterrent formulation technology can bring in helping to mitigate opioid abuse and misuse,” said Matt Harbaugh, Executive Vice President, Chief Financial Officer and President, Specialty Generics for Mallinckrodt.

The FDA has set a Prescription Drug User Fee Act (PDUFA) target action date of Nov. 16, 2018, to complete its review of Mallinckrodt’sproduct.

https://www.marketscreener.com/MALLINCKRODT-PLC-13450292/news/Mallinckrodt-U-S-FDA-Announces-Joint-Advisory-Committee-Review-of-Mallinckrodt-s-Abuse-Deterrent-27385237/