FDA Considers Whether COVID Boosters Could Be the Next Flu Shot

 Programmatic implications for regular COVID boosters will be foremost on the agenda at an FDA advisory committee meeting on Wednesday, according to briefing documents released by agency staff.

At the April 6 meeting, FDA is asking its Vaccines and Related Biological Products Advisory Committee (VRBPAC) to not only lay out parameters for how to determine when it might be necessary to update the composition of COVID boosters, but how often and how it might be applied to both approved and authorized vaccines.

In the documents released on Monday, FDA staff appear to be nudging VRBPAC toward a structure similar to that of influenza vaccines, "an approach where strain modifications could be supported by manufacturing information alone," which would be supported by clinical immunogenicity and safety data, as opposed to the current policy that requires clinical data.

At its core, agency staff argued for the need to expand the scope of COVID vaccines to a more global scale with "coordinated strain selection," similar to influenza. They also noted that while the World Health Organization and FDA coordinate on selecting strains for the seasonal influenza vaccine every year, there are a number of key differences between influenza and SARS-CoV-2 to take into account.

The most important difference is that unlike influenza, COVID does not have "predictable winter seasonality," where manufacturers can implement recommendations based on flu patterns in the Northern or Southern hemispheres. By contrast, "a predictable pattern for SARS-CoV-2 has yet to emerge," FDA staff noted.

"At this time, it is not clear if or when the epidemiology of SARS-CoV-2 will fall into a pattern that will make a global recommendation for an updated COVID-19 vaccine composition obvious or needed," they wrote.

Agency staff recommended three criteria for potentially changing the COVID vaccine strain composition:

• Sufficient data exist to "suggest the need for a better matched vaccine"
• Evidence that a new vaccine "will provide a significantly better outcome than current vaccines"
• Manufacturers have the ability and capacity to produce these new vaccines

Manufacturing was listed as another sticking point for changing COVID booster strains. Influenza vaccines are on similar platforms, making it easier to update, with agency staff writing, "it is not clear whether the various platforms used for authorized and approved COVID-19 vaccines can accommodate an updated composition in similar timeframes."

Finally, FDA staff addressed timing of future booster doses, as well as populations, noting that additional boosters should "optimally prevent hospitalization and death in those at greatest risk," with the idea that these future variants could emerge essentially during the 2022-2023 flu season or "at least a significant portion" of it.

They also emphasized the importance of preventing symptomatic disease, in the hopes of preventing long COVID. And while they addressed the potential associated risks of additional boosters, such as vaccine-associated myocarditis, they also hypothesized that "the potential benefits of the generation of a broader immune response that may address emerging variants across the entire population may be determined to outweigh known and potential risks."

FDA staff also asked VRBPAC to discuss topics related to COVID epidemiology, vaccine effectiveness, as well as "practical aspects and goals of public health vaccination programs."

https://www.medpagetoday.com/infectiousdisease/covid19vaccine/98041

Turn to Tapentadol in a Post-Oxycodone World?

 This is the third of a three-part series on opioid analgesic management for the aftermath of the prescription opioid epidemic. Today we'll be discussing tapentadol (Nucynta), a unique/next-generation broad-spectrum analgesic agent that happens to be a weak, atypical opioid. At the outset, I would like to disclose that I've never received financial nor material benefits of any sort from any drug manufacturer including Ortho-McNeil-Janssen, Johnson & Johnson, Depomed, or Collegium.

Tapentadol is a tramadol analog but has significant advantages over that parent compound, including no active metabolite (in contrast to O-desmethyltramadol, which is notably more potent than tramadol), and nearly insignificant serotonergic component (in contrast to tramadol, which markedly impacts the safety profile of the latter drug in terms of drug-drug interactions).

It is a weak opioid agonist (1/18^th of the potency of morphine in terms of mu-opioid receptor binding/activation), but in concert with norepinephrine reuptake inhibition (NRI) it yields significantly synergistically increased analgesic efficacy, as well as reduced tolerance and reduced adverse effect profile discussed in much greater detail below. Unfortunately, in the post-OxyContin era, with prevalent misinformation regarding opioids, tapentadol has gotten a bad rap. One major issue is that CMS and most morphine milligram equivalent (MME) conversions -- which of course are all based upon subjective pain relief report -- are very inaccurate/misleading: the MME for tapentadol is generally thought to be 0.4, but in reality is actually closer to 0.06 based on actual pharmacologic data.

As such, falsely elevated potency claims (in concert with aggressive and expected denials from payers owing to patented/brand-name drug status without generics available) have led to reticence among providers, pharmacists, and healthcare plans to offer this novel and highly effective agent to many of the tens of millions of people who would doubtless benefit.

Let's take a closer look at the data...

Efficacy

Any prescription should follow an informed benefit-risk ratio analysis. Along those lines, let's start with potential benefit.

One clue should be the fact that the federal government (which, in case you've slept through the past two decades, has been increasingly and understandably advocating against chronic opioid therapy in chronic non-cancer pain) has approved tapentadol for the treatment of not only severe acute and severe chronic pain, but also specifically for diabetic peripheral neuropathy pain, a distinction awarded otherwise only to duloxetine and pregabalin.

Neuropathic pain is notoriously difficult to control, and from a pharmacologic standpoint options are limited by a fairly broad adverse effect profile from anticonvulsants, tricyclics, etc. The data on opioid efficacy in neuropathic pain is mixed at best (with the atypical opioids tramadol, tapentadol, buprenorphine, and methadone showing the most success) and I don't need to remind anybody of the even broader adverse effect profile from opioids.

Having said that, tapentadol shows unusual benefit in neuropathic pain -- likely owing to the conjoint NRI activity, which among other things, increases dorsal horn modulation of afferent nociceptive transmission. And this isn't limited to DPN; several recent meta-analyses and systematic reviews have demonstrated clear benefit in numerous neuropathic pain states. To the extent that chronic pain represents central sensitization, with maladaptive CNS neural plasticity at the core of the pathologic state, tapentadol may well be among the most logical candidates to prevent such chronification of pain -- again bearing in mind the FDA approval for severe acute pain.

From a more mundane antinociceptive perspective -- acute and especially chronic pain -- tapentadol also shows tremendous benefit in widely prevalent difficult-to-manage conditions including chronic low back pain and osteoarthritis/degenerative joint disease.

Safety and Abuse Liability

From the risk side of the equation, tapentadol has shown markedly reduced harms in comparison to traditional opioids to date, which is of course to be expected given its weak MOR agonism. Respiratory, gastrointestinal, and neurologic adverse effects are notably less prevalent than with other opioids.

Not surprisingly, there is strong real-world evidence of minimal abuse liability despite DEA Schedule II status. In all fairness, limited availability of the agent may be partially responsible for decreased abuse and diversion statistics. Having said that, in our practice tapentadol is the most commonly prescribed opioid (followed by tramadol and buprenorphine), and we have seen zero cases over the past decade of dependence and addictive behaviors such as requests for continuous escalation or early refill requests. This is in line with data showing that when adjusted for utilization, tapentadol still shows markedly less abuse and diversion. Furthermore -- and again in sharp contrast to any other opioid molecule including tramadol and buprenorphine -- we have never seen a single case of withdrawal upon discontinuation, whether abrupt or tapered. Given that opioid withdrawal comprises a huge contributor to chronic seeking and use, this phenomenon is not trivial.

One final fun fact to consider: naloxone administration doesn't reduce the analgesic efficacy of tapentadol. Besides giving support and pharmacologic context to virtually everything discussed above, it begs the question: might tapentadol also have a unique niche in treating folks on naltrexone (Vivitrol)? This is something we will be exploring more in the near future...

Tapentadol in the Therapeutic Armamentarium

In short, accumulating evidence demonstrates that tapentadol is a highly effective broad-spectrum analgesic with minimal adverse effects and abuse liability -- safer in many cases than NSAIDs and certainly in comparison to traditional opioids. Its widely publicized MME is erroneously high, and multiple lines of convergent evidence show that its main analgesic effect is most likely owing to CNS NRI activity rather than opioid activity, as evidenced by failure of naloxone to reverse therapeutic benefit. It deserves greater attention and consideration in the therapeutic armamentarium for an increasingly prevalent and difficult-to-treat spectrum of both acute and especially chronic pain conditions.

Heath McAnally, MD, MSPH, is a board-certified anesthesiologist, pain physician, and addictionologist practicing in Alaska .

https://www.medpagetoday.com/opinion/pain-points/98052

Mixed Bag for Fourth Dose of Pfizer Vaccine vs Omicron

 Rates of confirmed Omicron-related COVID infection and severe disease were lower after a fourth dose of the Pfizer-BioNTech vaccine, according to real-world data from Israel, although protection against confirmed infection seemed short-lived.

Among adults ages 60 and up, the adjusted rate of confirmed infection 4 weeks after the fourth dose was twice as low compared to those who received three doses (171 vs 340 cases per 100,000 person-days), reported Yair Goldberg, PhD, of Technion-Israel Institute of Technology in Haifa, and colleagues.

Moreover, the adjusted rate of severe illness after 4 weeks was three times lower in the four-dose group (1.6 vs 5.5 per 100,000 person-days), they wrote in the New England Journal of Medicine.

Adjusted rates of both infection and severe disease were both higher in a third "internal control" group, who received a fourth vaccine dose only 3 to 7 days earlier (308 and 3.6 cases per 100,000 person-days, respectively), they noted.

However, Goldberg and colleagues added that from week 5 onward, the rate ratio for confirmed infection began to decline, with the adjusted rate of infection 8 weeks after the fourth dose being "very similar to those in the control groups."

The authors concluded that a fourth dose provided "only short-term protection and a modest absolute benefit," for confirmed infection, but that it did increase protection against severe disease. They highlighted that "protection against severe illness did not appear to decrease by the sixth week after receipt of the fourth dose," but acknowledged that "More follow-up is needed in order to evaluate the protection of the fourth dose against severe illness over longer periods."

In January, Israeli authorities approved a fourth dose of Pfizer vaccine for adults ages 60 and up, high-risk populations, and healthcare workers, 4 months after a third dose, they noted. FDA recently authorized a second booster dose of Pfizer or Moderna vaccine for adults, ages 50 and up, and those with immunocompromising conditions, in part using real-world Israeli data as the basis for their decision.

Goldberg's group examined data on adults ages 60 and older who received three doses of Pfizer at least 4 months prior to the end of the study. The study period was defined as January 10 to March 2 for confirmed infection, and until February 18 for severe disease. The four-dose group completed their fourth dose at least 8 days prior to infection or severe COVID, they said.

Overall, 1,252,331 adults were included in the study, with 623,355 receiving four doses of vaccine and 628,976 not receiving four doses of vaccine. The aggregated four-dose group and internal control group had more person-days over age 80 (about 25% apiece vs 16.2%).

At 4 weeks, the adjusted rate of confirmed infection in the four-dose group was lower by a factor of 2.0 (95% CI 1.9-2.1) versus the three-dose group and lower by a factor of 1.8 (95% CI 1.7-1.9) versus the internal control group.

For severe disease at 4 weeks, the adjusted rate differences were 3.9 fewer cases per 100,000 person-days (95% CI 3.4-4.5) versus the three-dose group and 2.1 fewer cases per 100,000 person-days (95% CI 1.4-3.0) versus the internal control group.

Limitations to the data include unmeasured confounders, such as behavioral differences between adults who chose to receive the fourth dose and those who did not. Pre-existing conditions could have affected risk for severe disease, and the authors added they did not adjust for those as this information is not available in the national database. Different COVID treatment may have also affected the results, they noted.

Disclosures

The study authors reported no disclosures.

Primary Source

New England Journal of Medicine

Source Reference: Bar-On YM, et al "Protection by a fourth dose of BNT162b2 against Omicron in Israel" N Engl J Med DOI: 10.1056/NEJMoa2201570.

https://www.medpagetoday.com/infectiousdisease/covid19vaccine/98061

More states consider Florida-style ‘Don’t Say Gay’ bills

 Conservative state lawmakers across the country are considering new legislation that would bar teachers from introducing concepts of sexual orientation or gender identity to young students, imitating a new Florida law that opponents have dubbed the “Don’t Say Gay” bill.

Lawmakers in Ohio and Louisiana have filed legislation that mimics the Florida law, signed last month by Gov. Ron DeSantis (R). In Texas, Lt. Gov. Dan Patrick (R), who controls the state Senate, said he would make his state’s version of the bill a top priority in the next legislative session.

The specifics of the measures vary between states, but they largely contain provisions that mirror the Florida law. The bills would bar schools from using curriculum that includes topics about sexual orientation and gender identity.

The Louisiana version would bar educators and school employees from discussing their own sexual orientation or gender identity with any student through 12th grade.

“There’s no need for any child to ever know the private life of their educator,” state Rep. Dodie Horton (R), the bill’s chief sponsor, told KSLA-TV. “It’s not prejudice to one group or another. It just doesn’t discuss it at all.”

Patrick, who is running for reelection, told supporters in an email that he was furious at Disney, which came out against the Florida law after pressure from LGBTQ groups.

“Some may think parents, including me, are overreacting. We are not,” Patrick wrote. “If we cannot fight for our children, then what can we fight for?”

Opponents of the measures say they intentionally target students who are already at risk.

“All of these curriculum censorship bills seek to erase and stigmatize young people who already experience marginalization,” said Aaron Ridings, chief of staff and deputy executive director for public policy and research at GLSEN, a group founded by teachers that supports LGBTQ youth. “All elected officials should be getting back to work on reopening schools and making sure that young people can learn and thrive and reach their own potential. These bills are a step backward.”

It is not immediately clear whether or how quickly the copycat legislation will move. Louisiana’s legislature has two months left on its calendar, making progress on its bill unlikely this year. In Ohio, where the legislature is in session year-round, the bill was introduced by state Reps. Mike Loychik (R) and Jean Schmidt (R), the former U.S. congresswoman, without co-sponsors.

Texas lawmakers hold sessions every other year, and the next kicks off in January. As leader of the state Senate, Patrick, who is likely to win reelection, has a heavy influence over the bills that come up for votes, though he has clashed over some priorities with state House Speaker Dade Phelan (R).

The early move to introduce legislation similar to Florida’s new law is reminiscent of how bills focused on other culture war issues in recent years have started in one Republican-led state before becoming a template for others.

Several states this year moved toward adopting a version of a Texas law that not only banned almost all abortion rights, but also allowed individuals to sue abortion providers. Other states moved to bar transgender girls from girls’ sports or to block gender-affirming medical care for transgender children.

Patrick, whose office released a list of priorities for the Senate before returning to Austin next year, also said the state Senate Education Committee would consider how schools handle controversial library books, after several other states have made it easier for parents to challenge ostensibly offensive titles.

Battles over sex education in schools have been a constant front in the culture wars that have raged between liberals and conservatives for decades. More recently, those fights have grown to encompass sexual orientation and gender identity, both in the classroom and on sports fields. GLSEN was founded three decades ago as a way to fight an earlier version of bills that sought to marginalize discussion of sexual orientation, legislation dubbed “No Promo Homo” bills at the time.

“It’s part of the same strategy that reduces and creates barriers to educational opportunities in our schools,” Ridings said. “There’s a chilling effect from all of these bills on people who are LGBTQ+.”

https://thehill.com/news/state-watch/3259642-red-states-consider-florida-style-dont-say-gay-bills/

Biden, Harris call for expanding ObamaCare, making boosted subsidies permanent

 President Biden and Vice President Harris on Tuesday called on Congress to expand the Affordable Care Act (ACA) and make boosted subsidies permanent as they marked proposed updates to the bill with former President Obama.

Tuesday marked Obama’s first visit to the White House since his departure in 2017. During his visit, Biden and Harris commemorated the 12 years that had passed since the legislation was signed into law by the former president himself.

The president signed an executive order directing federal agencies to do “everything in their power” to expand health care coverage. During the signing, Biden vowed to make it easier for people to enroll in health care coverage and to help people avoid low-quality health care.

A senior administration official previously disclosed that the Treasury Department would be proposing a rule change to ObamaCare to fix the “family glitch” in the bill that precluded individuals who received coverage through a family member from receiving financial assistance to pay for their premium subsidies.

“We’re working to change that. Once today’s proposed rule is finalized. Starting next year, working families in America will get the help they need to afford full family coverage. Everyone in the family,” Biden said.

Biden argued that if Republicans “have their way,” hundreds of millions of Americans with preexisting conditions could be denied health care.

“That’s what the law was before ObamaCare,” he said. “Premiums are going to go through the roof. Well, I got a better idea. Instead of destroying the Affordable Care Act, let’s keep building on it.”

Also during the event on Tuesday, Harris called for Medicare to be given the ability to negotiate drug prices, a move that progressives have supported in Congress.

Harris cited the 12 remaining states that have not adopted or implemented expanded Medicaid, blasting their decisions on the matter as “petty partisan obstruction.”

Harris also called on Congress to make the boosted income-based tax subsidies in the ACA permanent. The expanded subsidies are set to expire at the end of the 2022 coverage year.

https://thehill.com/policy/healthcare/3259702-biden-harris-call-for-expanding-obamacare-making-boosted-subsidies-permanent/

Oklahoma lawmakers approve bill banning abortions

 

• Oklahoma lawmakers passed a bill that bans abortions in the state and it’s now awaiting final sign off by the governor. 

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• It allows only one exception, in the case of a medical emergency where an abortion would save the pregnant women’s life. 

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• Oklahoma joins a growing number of states passing restrictive abortion laws. 

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Oklahoma lawmakers gave their final approval on a bill that would make performing an abortion illegal in the state, with the final sign off being handed to Republican Gov. Kevin Stitt. 

The bill passed the Oklahoma House on Tuesday and if enacted it would make performing an abortion a felony, punishable by up to 10 years in prison. The only exception it leaves is a medical emergency where an abortion would save the pregnant woman’s life. 

Stitt is expected to sign the bill into law, as he has previously said he’d sign any anti-abortion bill that came to his desk, according to The Associated Press. 

Oklahoma has passed a slew of anti-abortion laws, including a bill that would allow citizens of Oklahoma to sue doctors who perform abortions and file civil suits up to $10,000 against anyone who may try to perform an abortion.  

That measure follows the footsteps of a controversial Texas law passed last year that allows private citizens to sue anyone who performs, aids or abets an abortion after fetal cardiac activity is detected—usually after six weeks of pregnancy.  

The Guttmacher Institute found that approximately 862,320 abortions occurred in the U.S. in 2017, resulting in an abortion rate of 13.5 per 1,000 women between the ages of 15 and 44. In the same year, 4,780 abortions were provided in Oklahoma, however some patients may have travelled to Oklahoma from other states and some Oklahoma residents may have travelled out of state for an abortion. 

Oklahoma’s bill comes alongside numerous other bills across the country being enacted that place similar bans and restrictions on abortion. Arizona and Kentucky state legislatures voted to approve a 15-week ban on abortions while Idaho Gov. Brad Little signed a law that bans abortions after about six weeks of pregnancy. 

States like South Dakota and Tennessee have also moved legislation that takes aim at medication abortion, requiring women to make multiple trips to their doctor’s office in order to receive the two-dose regimen.  

Lawmakers and advocates across the country are anxiously awaiting for the Supreme Court to hear Dobbs v. Jackson Women’s Health Organization. That case will directly challenge the historic 1973 ruling on Roe V. Wade by calling into question a Mississippi law that bans abortions after 15 weeks. 

https://thehill.com/changing-america/respect/accessibility/3259829-oklahoma-lawmakers-approve-bill-banning-abortions-heads-to-governors-desk/

Atreca Expands Preclinical Pipeline

 Atreca, Inc. (Atreca) (NASDAQ: BCEL), a clinical-stage biotechnology company focused on developing novel therapeutics generated through a unique discovery platform based on interrogation of the active human immune response, today announced a licensing agreement with Zymeworks Inc. (Zymeworks) (NYSE: ZYME) to utilize their ZymeLink™ technology to develop novel antibody-drug conjugates (ADCs) and declared ATRC-301, an ADC targeting a novel epitope on EphA2, as the Company’s next clinical candidate. Atreca management will discuss the agreement, ATRC-301, and its earlier stage pipeline programs during today’s R&D Day beginning at 4:15pm EDT.

R&D Day Webcast and Conference Call Details

The live R&D Day webcast, including accompanying slides, can be accessed through the Events & Presentations section of the Company's website at https://ir.atreca.com/news-and-events/event-calendar. To access the event by telephone, please dial (800) 373-6606 (United States) or (409) 937-8918 (international) and reference the conference ID 3490903. An archived replay of the webcast will be available on the Company's website following the live event.

https://finance.yahoo.com/news/atreca-announces-expansion-preclinical-pipeline-200100167.html