Kristi Rosa

Baloxavir marboxil has been shown to significantly cut the time to improvement of flu symptoms compared with placebo in patients deemed to be at high risk of serious complications from influenza. The treatment was also found to be well-tolerated with no new safety signals observed.

Results from the phase 3 CAPSTONE-2 study were presented by Michael G. Ison, MD, MS, FIDSA, a professor at Northwestern University Feinberg School of Medicine, in a 

Discovered by Shionogi & Co., Ltd., and further developed and commercialized by Roche Group, baloxavir marboxil is a first-in-class, investigational medicine to be taken by mouth via a single dose, with a novel mechanism of action.

“I think the most important feature of baloxavir is that it’s a new class of antiviral medications for influenza,” Dr. Ison told 

 in an exclusive interview. “The currently approved medications that are available to us are the m2 inhibitors that inhibit the m2 ion channel and the neuraminidase inhibitors that inhibit the neuraminidase. Baloxavir affects the flow rates in the PA segment, and therefore, is active against viruses that may be resistant to either the neuraminidase or the m2 ion channel.”

For the phase 3, multicenter, randomized, double-blind trial, investigators set out to evaluate how safe and effective baloxavir marboxil would be in comparison with oseltamivir or placebo in individuals 12 years of age or older with high risk of complications from the flu. These individuals included those 65 years of age or older or those with conditions such as asthma, chronic lung disease, morbid obesity, or heart disease.

The investigators enrolled 2184 participants in the trial and randomized (1:1:1) them to receive either a single, oral dose of 40 mg or 80 mg of baloxavir marboxil (in accordance with body weight), placebo, or oseltamivir 75 mg, twice daily for the duration of 5 days.

Of the 2184 participants, 1163 were confirmed to be infected with influenza via the use of reverse transcription polymerase chain reaction (RT-PCR) testing. Of those with confirmed influenza infections, 47.9% had subtype A/H3N2, 6.9% had A/H1N1, and 41.6% had subtype B.

Dr. Ison added that the most common risk factors observed in participants were asthma or chronic lung disease (39.2%), being 65 years of age or older (27.4%), endocrine disorders (32.8%), metabolic disorders (13.5%), heart disease (12.7%), and morbid obesity (10.6%).

The investigators found that baloxavir marboxil significantly reduced the time to improvement of flu symptoms in patients with high risk of serious complications compared with placebo (median time of 73.2 hours vs 102.3 hours, p<.0001). Specifically, when it came to patients with influenza type A/H3N2, the investigative treatment demonstrated efficacy of reducing time to improvement of flu symptoms compared with placebo (median time of 75.4 hours vs 100.4 hours, p<.05); it was also effective in those with influenza B compared to placebo (median time of 74.6 hours vs 100.6 hours; p<.05).

In the overall patient population, those who received baloxavir marboxil demonstrated a shorter time to improvement of flu symptoms compared with oseltamivir, with a median time to improvement of 73.2 hours versus 81.0 hours, respectively, p=.8347).

The investigators highlight that when looking specifically at a subset of patients with influenza B—a subgroup for which some antiviral treatments only show limited efficacy&mdash;baloxavir marboxil was found to be “significantly efficacious” compared with oseltamivir in cutting time to improvement of flu symptoms (median time of 74.6 hours vs 101.6 hours, p<.05).

The virologic clearance was faster in the patients who received baloxavir marboxil compared with oseltamivir and placebo (viral shedding; median time of 48.0 hours, 96.0, 96.0, p<.0001, respectively). The investigative treatment was also found to cut the use of antibiotics and incidence of flu complications (3.4% and 2.8%, respectively) in comparison with placebo (7.5% and 10.4%; p=.01, p<.05).

“The patients tolerated the medicine very well,” Dr. Ison said, adding that there was a lower overall incidence of adverse events in those who received baloxavir marboxil (25.1%), compared with placebo or oseltamivir (29.7% and 28%, respectively).

In our interview, Dr. Ison discussed the important takeaways from the study (

“Most importantly, it will bring a therapy that only requires a single dose, so, patients will be able to take a pill and will be done taking the medication for the treatment for influenza,” he concluded. “And after taking it, they will be at reduced risk for complications, including those requiring antibiotics or other complications of influenza.”

Articles

The phase 3 CAPSTONE-2 trial shows treatment with baloxavir marboxil significantly reduced the time to improvement of flu symptoms compared with placebo.

Baloxavir Marboxil Significantly Reduces Time to Improvement of Flu Complications

The US Centers for Disease Control and Prevention (CDC) has expressed concern over an increase in the number of cases reported across the United States of a rare, polio-like illness.

Acute flaccid myelitis, an extremely rare condition that affects the nervous system—specifically the spinal cord&mdash;and causes weakness in the arms or legs.

From August 2014 to September 2018, a total of 386 cases of acute flaccid myelitis have been confirmed throughout the country, with 62 cases reported in 22 states for 2018 alone, Nancy Messonnier, MD, the director at the CDC’s National Center for Immunization and Respiratory Diseases, said in a telebriefing held earlier this week.

Although the CDC has not been able to pinpoint the cause for the majority of these cases, they have launched an active investigation to find more answers.

Many of the patients are presenting with symptoms similar to those of poliovirus, non-polio enteroviruses, adenoviruses, and West Nile virus. The sudden onset of weakness leads patients to seek medical care, and patients are then assessed by neurologists, infectious disease doctors, and pediatricians.

Milder cases of the disease might not be reported; however, Dr. Messonnier explained that the CDC is likely receiving information pertaining to the majority of cases. Their efforts to promote awareness of the issue is working to encourage those who might be infected with the illness to seek medical care. The CDC does not believe that the growing awareness of the rare disease is contributing to the increase in cases.

, officials tested all suspected cases for poliovirus—all came back negative. Furthermore, although enteroviruses are capable of causing neurological illnesses such as meningitis, and acute flaccid myelitis, the investigators state that instances of this happening are few and far between.

Specimens collected from those affected were tested for a wide array of pathogens that can potentially cause acute flaccid myelitis. To date, none of the pathogens have been consistently detected in any of the patients’ spinal fluid, which would provide a strong indication of the cause of the condition because acute flaccid myelitis affects the spinal cord. 

An influx of acute flaccid myelitis cases reported in 2014 coincided with a large national outbreak of enterovirus D68 associated with severe respiratory illness, according to the CDC. However, officials did not identify EV-D68 in every patient confirmed to have acute flaccid myelitis.

Officials will continue to explore other viruses, environmental toxins, and other avenues, in order to identify the cause of these cases, Dr. Messonnier said.

The CDC is also working on verifying clinical information reported to them by health departments and testing specimens collected from suspected cases. Other efforts are dedicated to gaining a better understanding of the disease and its potential causes, providing new information to providers, health departments, policymakers, and the public, and further exploring the potential association of the rare condition with possible causes as well as risk factors.

To do this, officials will be working with experts to review MRI scans taken from people over the last 10 years to identify how many cases of acute flaccid myelitis occurred previous to 2014. The CDC also aims to update treatment and management guidance for the disease and to work with academic centers across the country to conduct active surveillance for the condition as well as respiratory viruses.

 will provide updates on the investigation as more information becomes available.

From August 2014 to September 2018, the CDC received information on a total of 386 confirmed US cases of a polio-like illness occurring mostly among children.

CDC Investigating Increase in Polio-like Illness Reported Throughout the United States

In most healthy individuals, the immune system is able to prevent cytomegalovirus (CMV) from causing illness but those who are immunocompromised are not so lucky; these individuals are prone to suffer from more serious symptoms that often affect the eyes, liver, esophagus, stomach, and intestines. Furthermore, congenital CMV infection can result in severe, and sometimes permanent, neurological injury in newborns.

To date, there are no approved vaccines available to protect against the virus, but progress toward this goal has been made in recent clinical trials.

Just last week, promising findings from a first-in-human phase 1 trial evaluating VBI Vaccine’s vaccine candidate, VBI-1501A, were presented at 

, by Soren Gantt, MD, PhD, MPH, associate professor with the division of Infectious Disease in the department of pediatrics at the University British Columbia Faculty of Medicine, BC Children’s Hospital.

“Neutralizing antibodies (nAb) to the CMV envelope glycoprotein B (gB) in natural infection are thought to confer protection, and there was a recombinant gB/MF59 vaccine that was shown to be partially protective against infection and disease,” Dr. Gantt said, “but higher, longer-lived gB nAb titers are needed for a more effective vaccine.”

Enter VBI Vaccine’s candidate, VBI-1501A, an enveloped virus-like particle vaccine (VLP), designed via VBI’s 

. eVLPS, according to VBI, are a new, innovative class of synthetic vaccines that are developed to closely mimic the structure of viruses.

The idea is that because the vaccines are designed to be structurally similar to viruses found in nature, vaccination with a target protein expressed in an eVLP should have the potential to impart greater immunity than vaccination with the same recombinant target protein by itself.

According to Dr. Gantt, his team was pleased to see that an antigenic domain (AD) of gB—AD-2&mdash;was recognized on VBI-1501; this domain is increasingly recognized to have a functional importance when it comes to CMV.

In the first-in-humans dose-ranging, controlled, observer-blinded phase 1 trial, the investigators set out to study the safety and immunogenicity of an eVLP expressing the ectodomain of gB fused to transmembrane and cytoplasmic domains of the vesicular stomatitis virus G protein (gB-G), according to the 

A total of 125 healthy CMV-negative participants between 18 and 40 years of age were enrolled in the trial, which was conducted at 3 Canadian Immunization Research Network (CIRN) sites in Canada—Vancouver, Montreal, and Halifax.

Participants were randomized to 1 of 5 treatment groups. The first group received .5 μg VBI-1501A + alum; the second received 1.0 μg VBI-1501A; the third were given 2.0 μg VBI-1501A; the fourth received 1.0 μg VBI-1501 (unadjuvanted); and the fifth group received placebo. Each participant received 3 intramuscular doses of the CMV eVLP vaccine or placebo on days 0, 56, and 168, according to Dr. Gantt.

Outcome measures for the trial were solicited and unsolicited adverse events (AEs) and serious AEs. Specifically, local and systemic AEs 7 days following each injection, any AEs 28 days following each injection and SAEs through day 336 of the trial or early withdrawal, and any laboratory abnormality at the following days: 28, 56, 84, 168, 196, 280, or 336.

Secondary outcome measures pertained to immunogenicity; specifically, gB binding antibody titers and avidity assessment, as well as nAB to CMV infection of fibroblast and epithelial cells, study authors write.

Dr. Gantt reported that the most common AEs reported were headache, infections, and fatigue. However, the vaccine was not found to be associated with any clinically significant AEs compared with the placebo group. Further, there were no significant differences observed in abnormal laboratory results compared with those who received placebo.

He added that the events reported ranged from mild to moderate in severity and none of the events resulted in withdrawal from the trial. SAEs, according to Dr. Gantt, were “relatively infrequent” and did not seem to be associated with dose.

After doses 2 and 3, a dose-dependent boosting of nAB titers was noted, with the highest titers in the third treatment group, who received the highest dose of the vaccine. Dr. Gantt said that fibroblast cell nAb were observed in 100% of subjects who received the 2.0 μg dose of the vaccine, while epithelial cell nAb was noted in 31%.

“Epithelial cell nAb was correlated with higher geometric mean gB binding titers,” the authors write, “and there was a correlation between fibroblast and epithelial cell nAb titers.”

Overall, Dr. Gantt and his team concluded that VBI-1501A was safe and well-tolerated at all the doses tested in the phase 1 trial, and that the vaccine is immunogenic.

“We saw gB binding titers induced at all dose levels, with clear evidence of dose-dependent boosting,” he said. “There was good neutralizing activity in fibroblasts in 100% of subjects at highest dose with titers comparable to CMV-positive controls. And there was modest epithelial cell neutralizing activity that correlated with higher gB binding titers.”

The next steps for the vaccine are currently under discussion. 

 will provide the public with updates as more information becomes available.

S. Gantt, VBI Vaccines: Investigator, No direct financial benefit—company provided institutional support for clinical trial; C. Quach, VBI Vaccines: Investigator, No direct financial benefit&mdash;company provided institutional support for clinical trial; D. E. Anderson, VBI Vaccines: Employee and Shareholder, Salary; F. Diaz-Mitoma, VBI Vaccines: Consultant and Shareholder, Salary; J. Langley, VBI Vaccines: Investigator, No direct financial benefit&mdash;company provided institutional support for clinical trial.

An eVLP cytomegalovirus (CMV) vaccine was found to be safe and immunogenic at very low doses in healthy seronegative adults.

Cytomegalovirus Vaccine Candidate Found to Be Safe & Immunogenic in First-in-Humans Trial

Patients with HIV-1 who switched over to a once-daily, single-tablet regimen of darunavir 200 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg (D/C/F/TAF), marketed as SYMTUZA, had maintained high virologic suppression rates with no resistance development at 96 weeks.

New 96-week data from the pivotal phase 3 EMERALD trial were presented by Joseph Eron, Jr. MD, professor of medicine from the University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, North Carolina, at 

, held this year in San Francisco, California.

 demonstrate that SYMTUZA can offer clinically appropriate people living with HIV a single-tablet option that may help them maintain high rates of virologic suppression over time,” Dr. Eron said in a recent statement.

In the randomized, active-controlled, open-label, noninferiority phase 3 trial, virologically suppressed (VL <50c/mL for ≥2 months), HIV-infected adults were randomized (2:1) to continue on boosted-protease inhibitors (bPI) plus emtricitabine/tenofovir disoproxil fumarate (F/TDF) or to switch over to D/C/F/TAF over 48 weeks. Patients could either continue on the D/C/F/TAF regimen or switch from the bPI F/TDF regimen over to D/C/F/TAF at week 52 (late switch, 44 weeks D/C/F/TAF exposure) in a single-arm extension phase of the trial, up until week 96.

The primary and secondary endpoints of the trial were the percentage of patients with virologic rebound (confirmed VL ≥50 c/mL) cumulative through week 48 and week 96, respectively, according to Dr. Eron and colleagues.

The investigators report that 1080 patients out of the total 1141 patients who were randomized and treated continued on to the extension phase of the trial; of the 1080 patients, 728 continued to receive the D/C/F/TAF regimen, while 352 switched over from bPI F/TDF to D/C/F/TAF.

Dr. Eron reported that few patients in the D/C/F/TAF treatment arm experienced virologic rebound cumulative through week 96 (3.1%, 24/763); virologic rebound occurred in 2.3% (8/352) of patients in the late switch arm. However, many of the patients who rebounded resuppressed at week 96 (14/24, D/C/F/TAF and 2/8, late switch).

A high percentage, 90.7% (602/763), of those in the D/C/F/TAF arm were suppressed at week 96. After 44 weeks of treatment, 93.8% (330/352) of patients in the late switch arm maintained virologic suppression. Virologic failure (≥50 c/mL) rates for D/C/F/TAF were 1% (9/763) at week 96 and 2% (6/352) after 44 weeks of D/C/F/TAF exposure in the late switch arm at week 96.

No darunavir, primary protease inhibitor, tenofovir, or emtricitabine resistance-associated mutations were seen post-baseline.

Overall, D/C/F/TAF was found to be well tolerated with few serious adverse events (9%, 66/763) and treatment-associated discontinuations (2%, [17/763]) observed over 96 weeks. Over 44 weeks, 6% (21/352) and 2% (7/352) in the late switch group experienced serious adverse events and treatment-associated discontinuations.

The most common adverse events in the extension period were as follows: upper respiratory tract infection (16%, 122/763), viral upper respiratory tract (13%, 98/763), diarrhea (11%, 80/763), headache (10%, 79/763), and back pain (10%, 79/763).

Investigators observed improvements in renal and bone parameters were maintained in the D/C/F/TAF arm and observed in the late switch arm (week 52 to 96), with a small change in TC/HDL-C ratio, which investigators deemed to be consistent with the known effect of switching from tenofovir disoproxil fumarate to tenofovir alafenamide based regimens.

“Switching to D/C/F/TAF maintained high virologic suppression rates (>90%) at week 96 with no resistance development, and was well-tolerated over 96 weeks with bone, renal, and lipid safety consistent with known TAF and cobicistat profiles,” the authors write.

The 96-week extension study reinforced the long-term safety, efficacy, and resistance profile of D/C/F/TAF previously demonstrated at 24 and 48 weeks in virologically suppressed adult patients with HIV-1.

“D/C/F/TAF combines the efficacy and high genetic barrier to resistance of darunavir with the safety benefits of TAF, even in patients with a history of non-DRV VF,” Dr. Eron and colleagues conclude.

J. Eron Jr., Gilead: Consultant and Grant Investigator, Consulting fee and Research grant. Janssen: Consultant, Consulting fee and Research grant; C. Orkin, AbbVie, Abbott, Boehringer Ingelheim, BMS, Gilead, GSK, Janssen, ViiV: Grant Investigator and Research Contractor, Research grant and Research support; D. Cunningham, Janssen: Investigator, Research grant. Gilead: Investigator, Research grant; F. Pulido, Janssen: Consultant, Investigator and Scientific Advisor, Consulting fee, Research support, and Speaker honorarium;  F. Post, Gilead: Consultant and Grant Investigator, Consulting fee and Grant recipient. Viiv: Grant Investigator, Grant recipient. Janssen: Consultant, Consulting fee. MSD: Consultant, Consulting fee; S. De Wit, Janssen: Investigator, Research grant;  E. Lathouwers, Janssen: Employee and Shareholder, Salary; V. Hufkens, Janssen: Employee and Shareholder, Salary;  R. Petrovic, Janssen R&D: Independent Contractor, Consulting fee; E. Van Landuyt, Janssen: Employee and Shareholder, Salary.

Long-term safety and efficacy data from the pivotal phase 3 EMERALD trial were presented at ID Week 2018.