U.S. employers look to prioritize well-being of remote workers- Mercer survey

 Several U.S. companies are looking to prioritize employee well-being by offering perks such as home delivery of meals and subsidized furniture to meet the rigors of working from home, a survey showed on Wednesday.

One of five employers have such plans for next year, according to early results from a national survey of 1,502 respondents that was conducted by employee benefits consultant Mercer between June and September.

With a majority of people working remotely due to the COVID-19 pandemic, employers are looking for at-home alternatives for offerings such as subsidized healthy food choices in cafeterias or onsite gyms, the survey of employer-sponsored health plans found.

Large companies such as Twitter and PwC have said they would allow some U.S. employees to work from home and live anywhere, and some others have delayed reopening offices.

The well-being measures such as virtual cooking, exercise, yoga classes and apps for relaxation can cost between $1 and $3 a month per employee, said Beth Umland, director of research for health and benefits at Mercer and Elissa Rosenbaum, principal in Mercer’s health business.

One of four employers were emphasizing virtual care strategies for workers living away from urban areas, the survey showed. Last year, at the height of the pandemic when people stayed indoors, the use of telehealth services from companies such as Teladoc Health Inc jumped.

Seventy six percent of survey respondents with 500 or more employees said addressing issues related to employees’ mental and emotional health will be a top priority over the next 3-5 years, compared with just 44% that considered it a priority in Mercer’s 2019 survey.

Roughly one-third of the respondents provide employees with a virtual behavioral healthcare option, often through specialized programs from companies such as video-based therapy services provider Ginger, and 21% said they were considering the option.

https://www.reuters.com/article/usa-remote-work/u-s-employers-look-to-prioritize-well-being-of-remote-workers-survey-idUSL4N2R225B

Could Pfizer’s Inlyta have a role in Alzheimer’s disease?

 Pfizer’s tyrosine kinase inhibitor Inlyta is already a cornerstone of treatment for some forms of cancer, but could have potential as a therapy for Alzheimer’s disease as well, according to scientists in Canada.

The team – from the University of British Columbia – are particularly excited about their findings because the drug could represent an entirely new therapeutic approach for Alzheimer’s dementia to the current strategies of targeting beta amyloid and tau proteins in the brain.

Inlyta (axitinib) is used in cancer because it prevents the formation of new blood vessels that support the growth of tumours, allowing them to be effectively starved from within.

The Canadian researchers think this mechanism could also have a role in Alzheimer’s, as people with the disease show signs of abnormal blood vessel formation or ‘hypervascularity’ in their brains.

The work is still at the animal testing stage – and there’s a long history of promising therapies for Alzheimer’s failing when they get to the clinical testing stage – but warrants further study given the dearth of effective therapies for the disease.

In their studies, published in The Lancet, mice with Alzheimer’s that were treated with Inlyta not only exhibited a reduction in blood vessel formation and biomarkers related to the disease, but also performed better in tests designed to measure learning and memory than control animals.

The scientists – led by Professor Wilf Jefferies – speculate that in Alzheimer’s patients proliferation of blood vessels in the brain compromises the blood brain barrier, a defense against pathogens and other harmful factors.

“The vast majority of clinical trials have either directly or indirectly targeted beta-amyloid or tau,” said Jefferies.

Notwithstanding the approval of Biogen and Eisai’s amyloid-targeting Aduhelm (aducanumab) – based on controversial trial results – there has been very little success in clinical trials of drugs against these targets.

“A great deal of effort appears to have been directed toward the wrong targets for reversing Alzheimer’s disease,” according to Jefferies.

“The therapeutic approach we discovered has an opportunity to revise the clinical treatment of Alzheimer’s patients, which I think is absolutely needed at this point for the field to advance.”

While they acknowledge that Inlyta will need to be tested in clinical trials, the fact that the drug is already approved for cancer means it could be brought through development for Alzheimer’s at an accelerated rate.

https://pharmaphorum.com/news/could-pfizers-inlyta-have-a-role-in-alzheimers-disease/

Future of Corticosteroids in DMD Therapy?

 Boys with Duchenne muscular dystrophy (DMD) got the same benefit from 30 months of treatment with a novel type of corticosteroid as would be expected with conventional versions, a researcher reported, but without most of the adverse effects typically seen with such agents.

In 23 boys receiving the investigational drug vamorolone, mean trajectories of muscle function as measured by time to stand and time to run or walk 10 meters were the same as in a historical cohort (n=75) of boys receiving conventional steroids including prednisone and deflazacort (Emflaza), according to Stefan Jackowski, PhD, of the Ottawa Pediatric Bone Health Research Group in Ontario.

Yet while the historical cohort showed the classical negative effects on stature and bone structure with long-term conventional steroid therapy, these did not occur in the patients treated with vamorolone, Jackowski told attendees at the American Society for Bone and Mineral Research's annual meeting, held online and in San Diego.

The only adverse effect still seen with vamorolone was weight gain, with predicted trajectories the same as those documented in the control cohort.

Corticosteroids remain the mainstay of DMD therapy, even after the approval of putatively disease-modifying drugs such as eteplirsen (Exondys 51), which haven't conclusively shown clinical benefits. As Jackowski explained, steroids keep DMD kids walking longer, decrease their risk of scoliosis, and allow most to live at least into their 20s. But "harsh side effects limit their use," he noted. Years of steroid therapy lead to growth inhibition and weakened bone structure, with patients increasingly susceptible to fractures.

Vamorolone is designed to be a "dissociative steroid" -- a term invented by its developers to describe their goal of separating the desired clinical effects from the undesired. The chemical structure of vamorolone is nearly identical to that of prednisolone (the active form of prednisone) but with one modification altering its contact site with steroid receptors. In doing so, the molecule retains the anti-inflammatory activity expected from steroids while dropping the "positive transcriptional activity" driving the adverse effects, Jackowski said.

The commercial developer, Maryland-based ReveraGen BioPharma, has sponsored two open-label, dose-finding trials with vamorolone in boys with DMD who had not previously received steroids. Of the total 48 enrolled in these studies, 23 received at least 2 mg/kg/day for 30 months, and this was the group on which Jackowski focused his presentation.

For comparison, he and colleagues obtained data on 75 boys from a prospective registry of DMD patients, treated with steroids for at least 6 months (mean 24 months). These 75 were matched to the 23 treated with vamorolone by baseline age after they'd been in treatment for 6 months. All patients in both groups were able to walk at baseline.

Mean age in the two groups was similar at about 6. By the time they'd been on treatment 6 months, those receiving vamorolone were somewhat bigger for their age than the control cohort, by both height and weight, but were very similar in functional performance.

As expected, vamorolone was not a cure. Muscle function showed an overall downward trend over the full 30 months of treatment, at rates similar to patients in the conventionally treated cohort.

Where the groups did differ substantially was in predicted height trajectories. Those receiving vamorolone at 2 mg/kg/day or higher showed them catching up a bit with their healthy peers, whereas growth virtually stopped in those on long-term conventional steroids.

After 3 years, 10% of the vamorolone cohort had experienced vertebral fractures (identified on imaging in central analyses) compared with 20% of patients in a different historical cohort receiving daily prednisone. Structural analyses of bone age showed that it was only minimally delayed, "which in the setting of improved growth on vamorolone compared with traditional [steroids] is anticipated to benefit adult height," Jackowski said.

He also addressed vamorolone's safety. One of the dosage groups in the phase II studies was 6 mg/kg/day, and one-quarter of this group had the dosage reduced because of new-onset weight gain. Five boys in all suffered clinical fractures, two of which were in the spine. Two serious treatment-emergent events were recorded -- one case each of pneumonia and myoglobinuria -- but these were considered unrelated to vamorolone.

Perhaps the most important question surrounding vamorolone didn't come up in Jackowski's presentation. If this drug genuinely does "dissociate" the benefits from the adverse effects, could it be used in many rheumatologic and other conditions for which steroids are often prescribed, or would be if not for the side effects?

ReveraGen says yes, for sure. The company currently has a phase I/II trial underway in pediatric ulcerative colitis, and its website confirms that it sees potential in asthma, rheumatoid arthritis, multiple sclerosis, and several less common disorders.

As for the DMD indication, the company said it successfully completed a pivotal study (full results not published yet; topline data were announced in June), and U.S. marketing approval will be sought early next year.

Disclosures

The study was funded by ReveraGen BioPharma.

Most investigators reported relationships with this company and others.

Primary Source

American Society for Bone and Mineral Research

Source Reference: Jackowski S, et al "Vamorolone, a first-in-class dissociative steroid, is associated with improved muscle strength and favourable bone and growth plate profiles in young boys with ambulatory Duchenne muscular dystrophy" ASBMR 2021; Abstract LB-1113.

https://www.medpagetoday.com/meetingcoverage/asbmr/94862

Israeli Data Favor Higher Estimates of Post-Vax Myocarditis

 The incidence of myocarditis after receipt of the Pfizer-BioNTech COVID-19 mRNA vaccine was several times higher in two reports from Israel compared with some estimates, but remained low through the late spring of this year.

For patients in Israel's largest healthcare system, Clalit Health Services, the estimate of myocarditis was 2.13 cases per 100,000 vaccinated persons, reaching as high as 10.69 cases per 100,000 in men and boys ages 16 to 29.

A separate study using Israel's government database, capturing active and passive periods of surveillance for myocarditis, supported the higher risk in young men. In this report, males of all ages had myocarditis occur at 0.64 cases per 100,000 persons after the first dose and 3.83 cases per 100,000 after the second dose -- with the incidence increasing to 1.34 and 15.07 per 100,000 after the first and second doses, respectively, for teenage boys ages 16 to 19.

Both papers were published online in the New England Journal of Medicine.

Differences in methodology -- how myocarditis cases were counted and how far out from mRNA vaccination they would have to be to be considered post-vaccination cases -- may account for the different estimates between the two studies.

These differences may also explain why these latest myocarditis estimates greatly exceed those from the CDC and a California health system. Notably, they are relatively closer to estimates in a controversial preprint study that had suggested post-vaccination myocarditis rates of 162 per million (16.2 per 100,000) in boys ages 12 to 15 and 94 per million (9.4 per 100,000) in boys ages 16 to 17 based on Vaccine Adverse Event Reporting System (VAERS) data.

In line with prior observations, the Israeli studies showed that the risk of post-vaccination myocarditis was greatest within a week after the second vaccine dose. Although cases were largely mild, there were deaths in these two reports.

Nevertheless, the latest data do not negate the previous finding that myocarditis is more common after SARS-CoV-2 infection than after vaccination.

Myocarditis in a Large Health System

The first Israeli study of the Clalit health system used electronic health record (EHR) data and cardiologist adjudication of these records.

Investigators counted 54 myocarditis cases within 42 days of receipt of a first dose of the Pfizer mRNA vaccine from Dec. 20, 2020 through May 24, 2021. The incidence of such inflammation varied according to age and sex.

• Overall population: 2.13 cases per 100,000 persons
• Men and boys: 4.12 per 100,000
• Women and girls: 0.23 per 100,000
• Young people ages 16 to 29: 5.49 per 100,000
• Men and boys ages 16 to 29: 10.69 per 100,000
• Individuals age 30 or older: 1.13 per 100,000

Of the 54 myocarditis cases, 41 were deemed mild and 12 were of intermediate severity. One person suffered cardiogenic shock that led to extracorporeal membrane oxygenation, according to a group led by Guy Witberg, MD, of Rabin Medical Center, Beilinson Hospital in Petah Tikva.

Follow-up lasted a median 83 days after myocarditis onset, during which one person with pre-existing cardiac disease died from an unspecified cause the day after discharge, and another with a history of pericarditis was readmitted to the hospital three times for recurrence (with no further myocardial involvement after the index hospitalization).

Witberg's group counted more than 2.5 million Clalit patients who had received at least one dose of the Pfizer vaccine during the study period.

For cases identified from EHRs with enough data to satisfy CDC diagnostic criteria for myocarditis, cardiologists were brought in for adjudication. No biopsy was required for diagnosis.

The 54 people determined to have post-vaccination myocarditis had a median age of 27 years, and 94% were men. Two of them had contracted COVID-19 before vaccination.

A diagnosis of myocarditis occurred after the second mRNA vaccine dose in 69% of cases, with a median 21 days between the two doses.

Witberg and colleagues cautioned that the short follow-up in their report prevented them from drawing conclusions about the long-term prognosis of people with post-vaccination myocarditis. Furthermore, they couldn't count cases from out-of-network hospitals where patients may have received care for myocarditis.

More Cases in a Government Database

In a separate study using a longer follow-up period, the Israeli government reported 136 definitive or probable cases of myocarditis across the country within 21 days after the first Pfizer dose and 30 days after the second dose.

Researchers led by Sharon Alroy-Preis, MD, MPH, of the Israeli Ministry of Health, calculated the incidence of myocarditis between the two mRNA vaccine doses.

• All men and boys: 0.64 cases per 100,000 persons after the first dose vs 3.83 per 100,000 persons after the second dose
• Males ages 16 to 19: 1.34 vs 15.07 per 100,000 persons
• Males ages 20 to 24: 1.91 vs 10.86 per 100,000 persons
• Males ages 25 to 29: 1.22 vs 6.99 per 100,000 persons
• Males ages 30 to 39: 0.41 vs 3.69 per 100,000 persons
• All women and girls: 0.07 vs 0.46 per 100,000 persons

Compared with historical data from 2017 to 2019, myocarditis was more than five times as likely after mRNA vaccination in the overall population. Compared with people who remained unvaccinated during the study period (from Dec. 20, 2020, to May 31, 2021), fully vaccinated individuals had about double the risk at 30 days after the second dose.

"The incidence of myocarditis declined as the number of newly vaccinated persons decreased over time. This finding was suggestive of a possible causal relationship between two doses of the vaccine and the risk of myocarditis," wrote Alroy-Preis and colleagues.

People who had post-vaccination myocarditis had mild symptoms in 95% of cases. One person with fulminant myocarditis, a 22-year-old presenting with high elevated troponin T, died within 24 hours of receiving a myocarditis diagnosis.

Israel's Ministry of Health had initiated active surveillance of post-vaccination myocarditis in February, requesting that all hospitals report cases of myocarditis going back to as early as December 2020.

"Since persons with suspected myocarditis are almost always hospitalized in Israel, such surveillance data should approximate all cases of myocarditis during the period of active surveillance," the study authors noted.

They opted to use the Brighton Collaboration criteria in the diagnosis of myocarditis among the 9.2 million Israeli residents vaccinated with at least one dose during the surveillance period.

Of the 136 cases of myocarditis, 95 were accompanied by sex and age data; 91% were male, and 76% were under the age of 30. Patients presented after the first vaccine dose in 19 cases and after the second dose in 117.

Like Witberg's group, Alroy-Preis and colleagues acknowledged that they did not validate myocarditis cases with biopsies. Their study design also left room for ascertainment bias and confounding.

Disclosures

Witberg's study was supported by a collaboration between Harvard Medical School and Clalit Research Institute.

Witberg and Alroy-Preis reported no disclosures.

Primary Source

New England Journal of Medicine

Source Reference: Witberg G, et al "Myocarditis after Covid-19 vaccination in a large health care organization" N Engl J Med 2021; DOI: 10.1056/NEJMoa2110737.

Secondary Source

New England Journal of Medicine

Source Reference: Mevorach D, et al "Myocarditis after BNT162b2 mRNA vaccine against Covid-19 in Israel" N Engl J Med 2021; DOI: 10.1056/NEJMoa2109730.

https://www.medpagetoday.com/infectiousdisease/covid19vaccine/94892

Bharat Biotech submits data on COVID-19 drug clinical trial in children

 Indian drugmaker Bharat Biotech said on Wednesday data on clinical trials for its COVID-19 vaccine, Covaxin, conducted on children aged 2 to 18 has been submitted to the country’s drug regulator.

https://kfgo.com/2021/10/06/indias-bharat-biotech-submits-data-on-covid-19-drug-clinical-trial-in-children/

Moderna Wants Fed Court Help to Avoid Covid Vaccine Patent Suits

 Moderna Inc. subsidiary ModernaTX will ask the Federal Circuit at oral arguments Thursday to invalidate two patents it says could make its Covid-19 vaccine vulnerable to infringement suits.

The Patent Trial and Appeals Board upheld parts of Arbutus Biopharma Corp.'s U.S. Patent Nos. 9,364,435 and 8,058,069, on drug-delivery technology. Arbutus argues Moderna has no standing to appeal those decisions because Moderna hasn’t suffered any injury related to the patents.

Moderna will tell the U.S. Court of Appeals for the Federal Circuit that there is a substantial risk that Arbutus will sue, accusing various Moderna products of infringing the patents.

Moderna’s future is tied to the Covid vaccine. The company reported $60.2 million in revenue in 2019, a figure that jumped to $803.4 million last year thanks to federal grant dollars. The Cambridge, Mass.-based company has projected about $20 billion in sales this year, almost all of it from the Covid vaccine.

Warminster, Pa.-based Arbutus is “heavily favored” to win the appeals, which could lead to an infringement suit against Moderna, Jefferies analysts Kelechi Chikere and Michael Yee said in a note to clients. The “most likely outcome” is some sort of agreement that would bring in royalties in the “low single digits,” they said. Still, the analysts maintained their “hold” rating on Arbutus shares because it’s so hard to determine timing.

“A case of this nature could take years to litigate through various courts,” they said.

Lipid Nanoparticles

The patents cover lipid nanoparticles—tiny balls of fat that protect genetic material as it travels through the body to enter specific cells to deliver drugs. Messenger RNA, the genetic material at the heart of the Covid vaccines, needs the lipid nanoparticles as a protective shell.

Royalties from nerve-function drug Onpattro—the first Food and Drug Administration-approved medicine that used Arbtutus’ technology—form the only source of revenue for Arbutus, which reported just $6.9 million in licensing fees last year.

Investors are speculating that the Arbutus patents, directed to a more stable lipid nanoparticle, will entitle the company to royalties from the mRNA-based vaccines by Moderna and Pfizer Inc. Moderna has a license to the Arbutus patents, but it’s limited to the areas of a respiratory virus known as RSV, Influenza A, and the mosquito-transmitted viruses Chikungunya and Zika.

Arbutus continues to receive patents on its lipid nanoparticle technology, including one approved last month that analysts say closely hews to the technology used by Moderna.

Moderna preemptively challenged three Arbutus patents on the technology at the PTAB, with mixed results. The board invalidated U.S. Patent No. 9,404,127, upheld all of the ‘069 patent, and upheld some claims of the ‘435 patent but invalidated others.

Moderna appealed, challenging the board’s findings that it didn’t show parts of the patents were obvious and anticipated.

Moderna contends the patents are for ideas already covered by other patents, with only trivial differences in an effort to extend Arbutus’ patent protection. Arbutus said its inventions overcame technical difficulties in improving the effectiveness of the drug delivery while limiting toxicity.

Competitor Standing?

But the Federal Circuit may not reach the merits of the board’s decisions if it accepts Arbutus’ standing arguments. A line of Federal Circuit opinions holds that petitioners who lose at the board don’t have standing to appeal unless they can show they are being actively sued for infringement or that such a suit is imminent.

Moderna argues there is a real risk that Arbutus will assert the patents against its Covid-19 vaccine. “Arbutus has long proclaimed that its patent estate covers virtually all lipid particle delivery systems,” it said in its opening brief in one of the appeals.

“Furthermore, this risk of being accused of infringement and the uncertainty created by Arbutus’s aggressive stance regarding the scope of its patents is already harming Moderna in the eyes of its investors,” Moderna said. It said its stock price fell 10% in one day when the board’s decision in one of these cases was issued, even though there was no actual infringement suit.

Arbutus counters in its response brief that the relevant inquiry is whether Moderna showed there was a substantial risk of an infringement lawsuit when it appealed in September 2020, before the vaccine had even received FDA emergency use authorization.

“Whatever a market fluctuation may prove, it certainly does not establish an imminent lawsuit, nor does it establish standing,” Arbutus said.

Amy Wigmore of Wilmer Cutler Pickering Hale and Dorr LLP in Washington will argue both cases for Moderna. David I. Berl of Williams & Connolly LLP in Washington will argue both cases for Arbutus.

The cases are ModernaTX, Inc. v. Arbutus Biopharma Corp., Fed. Cir., No. 20-1184, argument 10/7/21 and ModernaTX, Inc. v. Arbutus Biopharma Corp., Fed. Cir., No. 20-2329, argument 10/7/21.

https://news.bloomberglaw.com/ip-law/moderna-wants-fed-cir-help-to-avoid-covid-vaccine-patent-suits

Denali, Sanofi ALS candidate fast tracked

 Denali Therapeutics Inc. (NASDAQ: DNLI), a biopharmaceutical company developing a broad portfolio of product candidates engineered to cross the blood-brain barrier (BBB) for neurodegenerative diseases, today announced positive Phase 1 clinical results and regulatory progress for two investigational small molecule therapeutics in development for the treatment of amyotrophic lateral sclerosis (ALS) at the 2021 Annual Northeast ALS (NEALS) Meeting being held virtually, October 6-7.

Denali presented positive results from a Phase 1 study in healthy volunteers (n=95) in which safety, pharmacokinetics (PK) and pharmacodynamics (PD) of single and multiple ascending doses of DNL343 were evaluated. The results demonstrated that DNL343 was generally well tolerated for up to 14 days of dosing, with robust distribution in the central nervous system (CNS) and predictable dose-related increases in DNL343 exposure with a PK profile supporting once daily dosing. Biomarker assessments were also made as related to the cellular integrated stress response (ISR). The ISR is a biological pathway implicated in ALS and other diseases. After healthy volunteers were treated with DNL343, samples of their blood cells were subjected to stress ex vivo, and robust changes in biomarkers of the ISR were observed, confirming pathway engagement.

Denali also presented preclinical data in a mouse model of vanishing white matter (VWM) disease, a genetic and progressive disorder that causes severe neurological symptoms after exposure to certain stressors. eIF2B activity is reduced in the VMW disease model leading to chronic activation of the ISR, making this a relevant model for demonstrating target engagement and ISR modulation by DNL343. After treatment with DNL343, body weight and motor function were normalized in these mice. Furthermore, ISR gene expression and stress response protein levels were reduced in both peripheral tissues as well as the brain. A similar PK/PD relationship was observed in mice and in humans, supporting DNL343 dose selection in the ongoing Phase 1b study in participants with ALS.

The Phase 1b study (NCT05006352) is a multicenter, randomized, placebo-controlled, double-blind, 28-day study followed by an 18-month open-label extension, designed to evaluate the safety, PK and PD of DNL343 in approximately 30 participants with ALS. Dosing in this study began in the third quarter of 2021.

Denali’s partner Sanofi presented plans for a Phase 2 study of RIPK1 inhibitor SAR443820 in participants with ALS based on positive results of a Phase 1 study in healthy volunteers. In that study, robust target engagement was demonstrated at doses that were generally well tolerated. The Phase 2 study, named HIMALAYA, is a multi-center, randomized, double-blind, placebo-controlled study, followed by an open-label long-term extension, to evaluate the efficacy and safety of SAR443820 in adult participants with ALS. This Phase 2 study is expected to commence in the first quarter of 2022.

The U.S. FDA has granted Fast Track designation to SAR443820 for the treatment of ALS. Fast Track is an FDA process designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need. Fast Track designation may allow for early and frequent communication with the FDA regarding the development of SAR443820 for the treatment of ALS. This designation also enables rolling review of the marketing application.

https://www.globenewswire.com/news-release/2021/10/06/2309876/0/en/Denali-Therapeutics-Announces-Positive-Clinical-Results-and-Regulatory-Progress-for-Development-Programs-in-Amyotrophic-Lateral-Sclerosis-ALS.html