Imara attempts to spin weak data into an 'encouraging' result

 Imara unveiled data from two subgroups of a Phase IIa trial for its lead compound Wednesday, aiming to conjure up a positive light despite challenges tied to the Covid-19 pandemic. But investors weren’t buying it and sent the company’s shares into a tailspin.

The experimental drug, dubbed IMR-687, is being evaluated for sickle cell disease as both a monotherapy and in combination with hydroxyurea. In the monotherapy subgroup, Imara reported IMR-687 showed no meaningful changes in F-cells, fetal hemoglobin (HbF) levels or Hb levels from baseline after 24 weeks.

Additionally, in the combo subgroup, the candidate demonstrated numerical increases in F-cells and HbF levels from baseline, but Hb levels did not meaningfully change. But Imara was unable to measure the difference against a placebo in both groups, as patients in those arms could not be evaluated due “in part” to missed study visits, the company said.

Ultimately, only one placebo patient in the combination group had appropriate biomarker data after the 24-week period, and p-values were not reported. Imara attempted to spin those less-than-stellar results into a win in a release, but investors saw through the effort immediately.

“I am encouraged by the incremental data from this readout, especially in light of the COVID-19 pandemic challenges,” lead investigator Biree Andemariam said in a statement. “This includes a favorable safety profile of IMR-687, lower rate of VOCs/SCPCs and VOC-related hospitalizations in the Population A1 monotherapy arm and improvements in several biomarker results across both the monotherapy and combination groups.”

Imara $IMRA shares were down 33% in early trading Wednesday.

The results make up part of a 93-patient Phase IIa trial, studying four different dose levels across the monotherapy and combination regimens. Wednesday’s monotherapy data come from a regimen of a once-daily dose of 100 mg through 4 weeks, which escalates to 200 mg through an additional 20 weeks.

In the combination group, patients took a 50 mg dose once a day on top of standard of care HU, with escalation after 4 weeks to 100 mg for the remaining 20 weeks. There were 18 total individuals in this monotherapy cohort and 14 in the combo portion.

Imara can still hang its hat on interim data from the other subgroups in the study, which showed the higher dose of the monotherapy had statistically significant increases in F-cells, as well as a dose-dependent increase in HbF levels in adults. There was also a mean increase from baseline of 1.7% in HbF percentage in the 100 mg / 200 mg dose group through week 24, a figure that SVB Leerink analyst Joseph Schwartz had deemed promising.

Ahead of Wednesday’s data, Schwartz had been hoping to see a further rise in this specific data point, regardless of whether or not it reached the 3% level the FDA set as the threshold for the Phase IIb study that launched in August. But the overall percent change in monotherapy reported Wednesday was -1.1%, even though Imara noted an absolute, dose-dependent increase in HbF of 1.3% when patients escalated from 100 mg to 200 mg.

Schwartz wrote Wednesday that he does not believe the data is a good indicator of the upcoming Phase IIb results, and still believes the 3% figure is achievable. He also noted that the doses being used in that study are much higher — up to 400 mg — than those in Phase IIa, with signs pointing to longer and higher doses resulting in better efficacy.

IMR-687 was one of a group of small molecule PDE9 inhibitors that Imara had licensed from Lundbeck. The theory is that blocking PDE9 increases cyclic GMP levels, which is associated with reactivation of fetal hemoglobin and thus restore some functionality impaired in blood disorders. Imara went public in March following a $75.2 million IPO raise.

https://endpts.com/imara-attempts-to-spin-weak-data-into-an-encouraging-result-but-investors-arent-having-it/

Why New York’s COVID-19 vaccine rollout stalled and how to fix it

 If you live in Florida or Texas, and you’re 65 or older, you can get in line for a COVID-19 vaccine at a mall, stadium or drive-thru center. You may have to wait hours, but being in line is better than being in the dark. That’s where most New Yorkers find themselves: desperate to get vaccinated, with no way to sign up. It may be months before they can. Other states are failing, too.

The first vaccines were shipped to the states Dec. 13, but most are sitting on shelves unused, while some 2,600 people a day die from the novel coronavirus nationwide. State and local officials, including Gov. Cuomo and Mayor de Blasio, are showing a depraved indifference to life as they play politics over who gets vaccine priority.

The public should demand that these officials open up mass vaccination centers and get lifesaving shots into our arms.

De Blasio is boasting that 1 million Gothamites will be vaccinated by the end of January. But as of Monday, only a handful of sites have been opened — for health workers only.

The mayor says he plans to send an e-mail to city employees asking them to volunteer to administer the vaccines. De Blasio should be asking Cuomo to call in the ­National Guard to set up and operate vaccination sites. West Virginia, Ohio and Maryland are already using the guard and turning armories into vaccine clinics. Hizzoner should be treating vaccination like a D-Day invasion in the war against the virus.

That’s how the city responded to the challenge of smallpox in 1947. With no warning, smallpox — a deadly disease thought to have been eradicated — was brought to New York by a sick traveler. All it takes to spread smallpox is a cough, sneeze or touch, just like COVID-19. Back then, the city Department of Health swung into action and vaccinated more than 6 million residents in one month. First come, first served. And it worked. Only two New Yorkers died.

Compare that to the thousands expected to die in the coming months because they couldn’t get the vaccine.

De Blasio says the city would be moving faster if the state loosens regulations on who can receive the vaccine. He has got a point. Right now, the state is limiting the vaccine to health workers and long-term-care residents, and next in line will be “essential workers” — mostly from unions — and people over 75. That means seniors ages 65 to 74 and adults with critical health problems will wait several months.

The Cuomo administration is adamant about that schedule, even though two-thirds of vaccines are unused.

That’s a mistake. States doling out vaccines in tiny increments are letting people die needlessly and delaying herd immunity, when enough people are vaccinated to stop the virus.

The invasion of a new, more contagious strain of COVID is another reason to vaccinate widely, advises former FDA Commissioner Scott Gottlieb. It’s likely to become the dominant strain, increasing everyone’s risk. It has now been identified in New York. Gottlieb advises “moving more quickly into a general vaccination program” for people 65 and up.

Will Cuomo listen? He has shown a callous lack of interest. When the Centers for Disease Control and Prevention requested a vaccine rollout plan, New York sent in 86 pages of blather: no specifics on where the shots would be given or who would administer them when hospital staff are ­already stretched. Yet we have known for months the vaccines were coming.

Of course, when the Buffalo Bills made the playoffs, Cuomo jumped into action, charging the state to produce a precision plan to open the stadium at limited ­capacity. Meanwhile, next Saturday, when the Bills play, another 150 New Yorkers will likely die from COVID-19.

New Yorkers should be in open revolt and screaming bloody murder about the vaccination delay. Because that’s what it is.

Betsy McCaughey is a former lieutenant governor of New York.

https://nypost.com/2021/01/05/a-2/

Alzheimer's Blood Tests: Big Breakthroughs in 2020

 The search for a blood test to diagnose Alzheimer's disease has been a long one, and researchers moved closer this year than ever before. In May, MedPage Today reported on an investigational blood assay for tau phosphorylated at threonine 181 (p-tau181). Here's a review of what's happened since then.

Plasma phosphorylated tau (p-tau) assays for Alzheimer's disease continued to take center stage with big breakthroughs this year, but it was an amyloid test that was first on the market.

In October, C₂N Diagnostics, a company based on the work of Randall Bateman, MD, and David Holtzman, MD, of Washington University in St. Louis, announced the launch of PrecivityAD, the first widely available blood test to help clinicians diagnose Alzheimer's.

The test uses mass spectrometry to look at the ratio of two amyloid-beta isoforms -- Aβ42 and Aβ40 -- and the presence of apolipoprotein E (APOE)-specific peptides that reflect a patient's APOE genotype. The results form a score that indicates the probability of being amyloid-positive on PET imaging.

The score correctly identified amyloid status (determined by PET scans) in 86% of 686 older adults with cognitive impairment or dementia, with an area under the receiver operating curve (AUC) of 0.88, the company said.

PrecivityAD is not a stand-alone diagnostic tool. It was introduced as a laboratory developed test (LDT) regulated under the CMS Clinical Laboratory Improvement Amendments (CLIA) program and received FDA breakthrough designation, but is not FDA-approved, though that's in the works, C₂N CEO Joel Braunstein told MedPage Today. "It's important to recognize that the two pathways -- LDT through CLIA pathway vs FDA pathway -- are not mutually exclusive and instead can be seen as rather complementary," he said.

But its lack of FDA approval means groups like the Alzheimer's Association have not endorsed the test. "Without FDA review, health care providers lack the agency's guidance for how to use it when making decisions about a person's health or treatment," Alzheimer's Association chief science officer Maria Carrillo, PhD, told MedPage Today. "The FDA has had no say about what the test should measure, what are healthy and unhealthy levels, or how to ensure accuracy and predictability."

The test costs $1,250 and is not covered by private insurance providers, Medicare, or Medicaid, but patients who qualify based on income can pay between $25 and $400, Braunstein said. In contrast, amyloid PET scans, which also aren't covered by third-party payers, can cost about $4,000, though costs vary widely.

P-tau217: 'a real game changer'

In May, plasma p-tau181 was heralded as "an important advance that could transform the diagnosis of Alzheimer's disease," in an editorial by Mayo Clinic's Clifford Jack, Jr., MD. But in July, two papers presented at the Alzheimer's Association International Conference (AAIC) suggested another phosphorylated isoform might produce even better results.

Plasma p-tau217 discriminated Alzheimer's from other neurodegenerative diseases with significantly higher accuracy than plasma p-tau181, neurofilament light chain, or MRI biomarkers in several cohorts, said Oskar Hansson, MD, PhD, of Skåne University Hospital in Sweden, at the AAIC.

And while both p-tau217 and p-tau181 could predict the presence of amyloid plaques on PET scans, p-tau217 amyloid measures were superior, Bateman and Nicolas Barthélemy, PhD, also of Washington University, reported at the meeting. In a discovery cohort of 36 people, p-tau217 and p-tau181 were highly specific for amyloid plaque pathology (AUC 0.99 and 0.98, respectively). In a validation cohort of 92 people, p-tau217 was still specific to amyloid status (AUC 0.92), but p-tau181 measures were less specific (AUC 0.75).

A p-tau217 blood test could be "a real game changer," said Howard Fillit, MD, of the Alzheimer's Drug Discovery Foundation in New York City, who wasn't involved with either study. "It's almost like the first steps that blood tests for cholesterol in heart disease took back in the 1950s and '60s," he told MedPage Today.

Another analysis by Hansson's group, this one published in November, showed p-tau217 levels were increased in people who had abnormal amyloid-PET but normal tau-PET in the entorhinal cortex, an early region of neurofibrillary tangle formation.

"Our results are congruent with the idea that amyloid pathology increases phosphorylation and secretion of tau in neurons, which might be an important step in the development of widespread neurofibrillary tangle pathology in Alzheimer's disease," Hansson told MedPage Today.

The findings add to the growing evidence that plasma tau, especially p-tau217, may be used one day to detect and treat Alzheimer's disease, he noted.

"A blood-based biomarker like plasma p-tau217, detecting early Alzheimer's pathology, can be used to identify subjects suitable for clinical trials that evaluate disease-modifying therapies during the pre-symptomatic stages of the disease," Hansson said. "Such markers can also be used as pharmacodynamic markers, indicating whether a new treatment has an effect on Alzheimer's pathology in the brain."

https://www.medpagetoday.com/neurology/alzheimersdisease/90553

Can Second COVID Vaccine Dose Be Delayed?

 As COVID-19 vaccine administration lags behind early projections and a new, more infectious variant circulates, many experts are calling for a change in plans. By extending the time between the two doses, or halving the dose, more people can be inoculated sooner without sacrificing broad efficacy, they argue.

Others, however, including FDA leadership, advocate staying the current course. The evidence for efficacy of single doses isn't strong enough to delay the second dose, they say, and public health officials should focus on speeding up the distribution and administration processes instead.

"Suggesting changes to the FDA-authorized dosing or schedules of these vaccines is premature and not rooted solidly in the available evidence," according to a statement released by FDA's Stephen Hahn, MD, and Peter Marks, MD, PhD, on Monday. "Without appropriate data supporting such changes in vaccine administration, we run a significant risk of placing public health at risk."

Both the Pfizer/BioNTech and Moderna vaccines exhibited about 95% efficacy for preventing illness in clinical trials when patients received two full doses within the companies' specified intervals -- 21 days for the Pfizer/BioNTech vaccine and 28 days for the Moderna version. Those estimates came from counting illnesses diagnosed beginning 7 days after the second dose.

But there's little data to rely on for decision-making when it comes to doling out fewer doses, or extending the interval.

In its phase I data, Pfizer reported that serum binding antibody concentrations 21 days after the first dose were comparable to or better than levels from convalescent plasma two weeks post-infection. Those levels rose far higher a week after the second dose. Neutralizing antibody levels saw "small increases" 21 days after the first dose but rose "substantially" 7 days after the second shot.

In its early data, Moderna reported that binding antibody levels "increased rapidly" after the first vaccination, and were similar to median levels from convalescent plasma specimens. But after the second dose, levels were "in the upper quartile of values in the convalescent serum specimens." For neutralizing antibodies, responses were far better after the second vaccination.

In phase III data, Pfizer reported efficacy of 52.4% within 21 days after the first dose, i.e., before the second dose. The company also reported an efficacy of 82% "after dose 1," which appeared to be for participants receiving both doses and counting all infections, including those occurring prior to the second dose.

Nevertheless, Chris Gill, MD, an infectious diseases physician at Boston University, told WBUR that efficacy may be as high as 90% with a single injection. He pointed to the roughly 2,000 participants in the Moderna trial who had only one injection, in whom efficacy appeared to be 80% to 90%.

More support for delaying the second dose came from a modeling study published this week in the Annals of Internal Medicine, which estimated that a "flexible" dosing strategy could avert an additional 23% to 29% of COVID-19 cases compared with a "fixed" strategy where doses are given 3 weeks apart. That was based on the Pfizer/BioNTech estimate of 52% efficacy with a single dose.

Given these clues, some experts have called for a change in strategy. For example, Bob Wachter, MD, of the University of California San Francisco, recently advocated delaying second doses by a few weeks or more.

"Few credible scientists have argued that a 2-month delay in dose 2 will compromise the strength/durability of the ultimate immune response. In fact, some have argued that it might enhance it," Wachter tweeted. "The possibility that immunity will wane between doses 1 and 2 ... also doesn't seem to be a major concern – particularly given the miniscule reinfection rate that we've seen from natural infection and the robust immune response seen after dose one."

But "it may make sense," Wachter added on Twitter, "to stick with the early 2nd dose to the most vulnerable (over 75, nursing home) or most exposed (frontline healthcare workers). The small drop in efficacy from the 2nd-dose-later strategy might be quite meaningful in these groups."

"Given the enhanced transmission variants on the rise, we need a modified strategy," tweeted Akiko Iwasaki, PhD, a biology professor at the Yale School of Medicine.

But even Iwasaki favors the two-dose approach in the long run, as data regarding single-dose efficacy are not robust enough. "Whether a single-dose vaccine provides protection from severe COVID is not clear due to small sample size and short follow-up duration," she tweeted.

Changing course now could also undermine public confidence in the vaccine, some experts said, which is especially important because many people, including healthcare workers, have already declined it, citing trust issues.

Some experts are calling for clinical trials of the modified vaccination proposals -- including Peter Bach, MD, of Memorial Sloan Kettering Cancer Center, who wrote in an editorial for STAT that hospitals are uniquely positioned to handle such trials, which could yield preliminary data as soon as March.

"There are two ways to resolve this question: We can debate it on social media or we can go get more data. I believe we should do the latter," Bach wrote. "Clinical studies cost money. But if we can dole out billions to companies to develop vaccines, then we should be ready to dole out millions to study how they are best used to control the pandemic."

The Infectious Diseases Society of America supports the FDA position, according to its own statement released Tuesday. Instead of deviating from the proven dosing intervals, the group said, efforts should be redoubled to "support successful vaccine administration strategies, including expanding staffing for planning and implementation, and working with healthcare providers, healthcare systems and workplaces to operate high-volume sites and ensure timely access."

Other nations have already adjusted their policies. The U.K. recently extended the Pfizer/BioNTech and AstraZeneca intervals to 12 weeks. Some patients may be permitted to mix different vaccines, despite government officials acknowledging "no evidence on the interchangeability," Reuters reported.

The E.U.'s European Medicines Agency (EMA) is permitting as long as six weeks between inoculations of the Pfizer/BioNTech vaccine, but Spanish and Irish health authorities recommend following Pfizer/BioNTech's schedule.

Tweeted Wachter: "The debate is healthy. There are pros and cons to the current strategy and the alternative we present, and there are real uncertainties associated with them both.... The context for the debate is the near certainty that we'll lose another 50-100K [sic] Americans this month, and we're threatened by a mutation that may accelerate the tragedies. So time is a crucial variable.... Let's put our best minds, data, and models to this question, so we can make the best choices."

Operation Warp Speed aimed to administer 20 million doses by the end of December. As of Tuesday, only 17 million doses had been distributed and only 4.8 million doses had been administered, according to the CDC.

https://www.medpagetoday.com/infectiousdisease/covid19/90561

U.S. to send COVID-19 vaccine to pharmacies in hopes of speeding shots

 The United States plans to start distributing COVID-19 vaccines through pharmacies around the country earlier than expected this week as states have struggled to use the supply they have been allocated, top health officials said on Wednesday.

The partnership with 19 pharmacy chains will eventually let the Operation Warp Speed vaccination program deliver to as many as 40,000 locations around the country, Warp Speed officials said at a news conference on Wednesday.

Pharmacies could provide a more efficient platform for distributing the vaccines than hospitals, they said.

As of Tuesday morning, more than 70 percent of the more than 17 million vaccine doses that have been delivered around the country since December were still sitting in freezers, according to data from the Centers for Disease Control and Protection (CDC).

U.S. Health and Human Services Secretary Alex Azar also said at the news conference that states should not let recommendations to prioritize certain groups like health care workers slow the pace of vaccinations.

He said states should not keep vaccines sitting in freezers too long for distribution to healthcare workers and has encouraged governors to skirt CDC recommendations if it can speed inoculation.

“Those are simply recommendations, and they should never stand in the way of getting shots in arms,” Azar said.

If states are struggling to distribute the vaccine, “then by all means you want to be opening up to people 70 and over or 65 and over,” he said.

https://www.reuters.com/article/us-health-coronavirus-vaccines/u-s-to-send-covid-19-vaccine-to-pharmacies-in-hopes-of-speeding-shots-idUSKBN29B2G1

Hinge Health eyes IPO after raising $300M

 Hinge Health plans to go public next year after raising $300 million from investors led by Coatue Management and Tiger Global Management at a valuation of $3 billion, the U.S. digital health firm’s chief executive told Reuters in an interview.

The latest funding round came after the digital physical therapy platform quadrupled its revenue in 2020, as more consumers accessed the healthcare system from home during the COVID-19 pandemic.

Hinge Health was last valued at $428 million in February 2020, according to a person familiar with the company.

Based in San Francisco, the company provides digital solutions for chronic musculoskeletal pain, including wearable sensors, exercise therapy and health coaching. It sells to over 300 self-insured employers, counting enterprises like Boeing Co and Walgreens Boots Alliance among its customers.

“We’re targeting a 2022 IPO,” Daniel Perez, chief executive at Hinge Health, said. “We’ve passed $100 million revenue with clear momentum to $200 million. There is a secular trend towards digitization and healthcare, and we were feeling these tailwinds even pre COVID.”

Perez said his firm will look for innovation in pricing in an IPO to eliminate huge first-day trading pops some tech companies have seen. Airbnb Inc, for example, opened at $146 per share on its first day of trading, more than doubling the $68 per share price set by underwriters and the company and causing concerns about leaving money on the table.

The latest funding round will make Hinge one of the most valuable startups in digital health. It plans to use the fresh capital for hiring medical staff, expanding to new geographies including Germany and the UK, and acquisitions.

Last year was the largest funding year ever in U.S. digital health sector, with over $10 billion in venture funding, according to Rock Health. Notable deals include telehealth company Ro’s $200 million funding round, and American Well Corp AMWL.N landing $194 million in a private round before going public last September.

https://www.reuters.com/article/us-hinge-health-ipo/hinge-health-eyes-ipo-after-raising-300-million-idUSKBN29B20R

Covid-19 Vaccine Rollout by CVS at Nursing Homes Off to a Slow Start

 Hesitancy on the part of long-term-care-facility staffers to receive Covid-19 vaccinations is slowing the rollout of the shots to the nation's nursing homes and assisted-living centers, CVS Health Corp. said Wednesday.

Another factor driving lower-than-anticipated rollout numbers: Initial estimates by the facilities overstated the number of people living in them by about 20% to 30%, CVS said. During the pandemic, families have been reluctant to send relatives to nursing homes, which have been linked to more than 115,000 deaths.

"Based on feedback from our field teams, we've encountered more vaccine hesitancy among staff when compared with residents," a CVS spokesman said. Facilities are also staggering dosing to staff because of potential side effects, which has extended the process.

The pharmacy giant said it is still on track to reach federal goals to deliver first doses at about 8,000 skilled-nursing facilities by Jan. 25. CVS said it is also preparing to provide vaccinations to the general public by appointment at its drugstores in coming weeks. Currently CVS and Walgreens are only authorized to administer vaccines at long-term-care facilities under a federal contract.

Walgreens Boots Alliance Inc. said Wednesday that it expects to complete the administration of the first doses in skilled-nursing facilities by Jan. 25. "Since receiving our first allotments of vaccines in late December, Walgreens has remained on track in vaccinating our most vulnerable populations," President John Standley said in a statement.

The federal government fell far short of its promise to vaccinate 20 million people by the end of 2020. Of the more than 17 million doses of vaccines from Moderna Inc. and Pfizer Inc. with BioNTech SE that have been shipped, only 4.8 million have been administered, according to federal figures.

More than 429,000 doses have been administered at long-term medical-care centers. Facilities are getting shots at varying rates via drugstore chains CVS and Walgreens because states met the requirements to begin the distribution program at different times.

CVS said long-term-care facilities based their population estimates on bed count, which is significantly higher than the number of residents living in them at any given time. CVS also said the shortfall is due in part to a lag in reporting data, which is shared publicly 48 to 72 hours after state registries and the Centers for Disease Control and Prevention receive the information.

Larry Merlo, CVS Health's chief executive, said the vaccination effort is challenging because it requires health-care providers to make in-room visits to each resident at the facilities that are part of the program.

The company said it is administering vaccines in skilled-nursing facilities in 49 states, after it added 36 states and Washington, D.C., to its rollout last week. By next week, states will have given CVS the go-ahead to begin vaccinations at nearly 31,000 assisted-living facilities, the company said.

https://www.marketscreener.com/quote/stock/CVS-HEALTH-CORPORATION-12230/news/Covid-19-Vaccine-Rollout-by-CVS-at-Nursing-Homes-Off-to-a-Slow-Start-Update-32133064/