Jazz Pharmaceuticals' Late-Stage Multiple Sclerosis Study Misses Primary Endpoint

 Jazz Pharmaceuticals 

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 announced top-line results from the Phase 3 clinical trial investigating nabiximols oromucosal spray (JZP378) on clinical measures of spasticity in individuals with multiple sclerosis (MS).

The RELEASE MSS1 study evaluated the safety and efficacy of nabiximols oromucosal spray in 68 patients with multiple sclerosis (MS) spasticity, was the first and smallest, of the three clinical trials in the current program.

The clinical trial failed to meet the primary endpoint of change in Lower Limb Muscle Tone-6 (LLMT-6) between baseline and Day 21, as measured by the Modified Ashworth Scale (MAS).

Rob Iannone, M.D., M.S.C.E., executive vice president, said, “We remain committed to the nabiximols program and are actively assessing the RELEASE MSS1 trial results. We look forward to additional data from two other ongoing trials that have the potential to support a U.S. FDA New Drug Application submission.”

The company is planning to share data readout from the RELEASE MSS1 study in a future medical meeting.

https://www.benzinga.com/general/biotech/22/06/27885853/jazz-pharmaceuticals-late-stage-multiple-sclerosis-study-misses-primary-endpoint

Icosavax Shares Plummet Following Interim Results From Initial-Stage RSV Vaccine Study

Icosavax 

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 announced interim results from its Phase 1/1b clinical trial of IVX-121, respiratory syncytial virus (RSV) F antigen, in young and older adults.

The Phase 1/1b clinical trial is designed to evaluate the safety and immunogenicity of three dose levels of IVX-121.

The Phase 1 part of the trial enrolled 90 healthy young adults aged 18-45 years, while the Phase 1b part of the trial enrolled 130 healthy older adults aged 60-75 years.

Adam Simpson, Chief Executive Officer, commented : "I'm delighted to share these topline, interim data from our Phase 1/1b trial in RSV, in which IVX-121 demonstrated a robust immunologic response in both young and older adult groups. Importantly, we believe these Phase 1/1b data provide initial validation of our underlying VLP technology. They also reaffirm our strategy to combine multiple pathogen targets in one vaccine.”

The clinical data readout from the Phase 1/1b study will also support a Phase 1b extension study.

Additionally, Icosavax is planning towards the development of IVX-121 combined with a human metapneumovirus (hMPV) VLP, as its IVX-A12 bivalent vaccine candidate.

The company intends to submit an Investigational New Drug (IND) application for IVX-A12 to the U.S. Food and Drug Administration (FDA) followed by initiation of Phase 1 clinical trial in the second half of 2022.

https://www.benzinga.com/general/biotech/22/06/27891632/icosavax-shares-plummet-following-interim-results-from-initial-stage-rsv-vaccine-study

Facebook, Instagram Remove Posts Offering Abortion Pills

 Facebook and Instagram have begun removing posts and temporarily banning users that offer abortion pills to women who may not be able to access them after the Supreme Court overruled Roe v. Wade.

After the decision was overturned on Friday, social media posts exploded across platforms during the weekend, explaining how women could legally obtain abortion pills in the mail. Some offered to mail the prescriptions to women in states that now ban the procedure.

General posts about abortion pills, as well as ones that mentioned specific versions such as mifepristone and misoprostol, spiked on Friday morning across Facebook, Instagram, Reddit, and Twitter. By Sunday, more than 250,000 mentions had been posted, the media intelligence firm Zignal Labs told The Associated Press.

But Meta, the parent company of Facebook and Instagram, began removing some of these posts almost right away, the AP reported. Journalists at news outlets saved screenshots of posts that offered pills and were removed minutes later. Users were notified that they were banned, according to Vice.

On Friday, a Vice reporter posted the phrase "abortion pills can be mailed" on Facebook, which was flagged within seconds for violating the platform's community rules against buying, selling, or trading medical or nonmedical drugs. The reporter was given the option to "agree" or "disagree" with the decision, and after they chose to "disagree," the post was removed.

On Monday, the post that Vice "disagreed" had violated the standards was reinstated, the news outlet reported. The reporter wrote a new post with the phrase "abortion pills can be mailed," which was flagged instantly for removal. After the reporter "agreed" with the decision, the account was suspended for 24 hours.

Similarly on Monday, a reporter for the AP wrote a post on Facebook that said, "If you send me your address, I will mail you abortion pills." The post was removed within 1 minute, and the account was put on a "warning" status for the post. Other posts that offered "a gun" or "weed" were not flagged or removed, the AP reported.

Marijuana is illegal under federal law and can't be sent through the mail, the AP reported. But abortion pills can be obtained through the mail legally.

Meta won't allow people to gift or sell pharmaceuticals on its platform but will allow posts that share information about accessing pills, Andy Stone, a Meta spokesperson, wrote in a Twitter comment in response to the Vice article on Monday.

"Content that attempts to buy, sell, trade, gift, request, or donate pharmaceuticals is not allowed," he wrote. "Content that discusses the affordability and accessibility of prescription medication is allowed. We've discovered some instances of incorrect enforcement and are correcting these."

U.S. Attorney General Merrick Garland said Friday that the FDA has approved the use of mifepristone for medication abortion up to 10 weeks. In 2021, the FDA also made it possible and legal to send abortion pills via mail.

"States may not ban mifepristone based on disagreement with the FDA's expert judgment about its safety and efficacy," he said in a statement.

At the same time, some Republican lawmakers have tried to stop residents from getting abortion pills through the mail, the AP reported. States such as Tennessee and West Virginia have prohibited providers from prescribing the medication through telemedicine consultations, and Texas has made it illegal to send abortion pills through the mail.

Sources

The Associated Press: "Instagram and Facebook remove posts offering abortion pills."

Vice: "Facebook Is Banning People Who Say They Will Mail Abortion Pills."

Twitter: @andymstone, June 27, 2022.

U.S. Department of Justice: "Attorney General Merrick B. Garland Statement on Supreme Court Ruling in Dobbs v. Jackson Women's Health Organization."

https://www.medscape.com/viewarticle/976315

End the public health emergency carefully

 The end of the pandemic emergency has happened already in the minds of a great part of the public. This is so from a practical point of view, at least for now, despite persistent appearances of new variants and high case numbers in many areas.

However, the public health emergency (PHE), as legally defined, continues at the federal level, even if no longer in practice on the ground in many areas. And while we all welcome the end of the pandemic and the attendant emergency from a practical point of view, there are reasons to be concerned about the end of the legally defined ‘emergency’ and how it is handled by Congress and the Biden administration.

By way of background, the president and the secretary of Health and Human Services (HHS) declare and renew the public health emergency declaration that allows the use of certain special powers, every 90 days. These powers have been used throughout the COVID emergency from the beginning, when a public health emergency was declared in January 2020, less than a month after the virus was known to exist in the United States. Congress then passed laws that added flexibility and capacities to deal with the emergency and these have been widely used for the past two years.

Early in 2020, many state and local governments forced lockdowns that largely barred non-emergency care from being offered by hospitals and other providers. This in turn meant that much of the money supporting providers immediately dried up, because most care in the U.S. is non-emergency care. And that then caused an immediate spiral downward by the healthcare system broadly, along with much furloughing and firing of crucial personnel, with the paradoxical result that our healthcare system was beginning to wither right in the middle of a healthcare crisis.

One major, bipartisan step forward to combat the crisis by Congress and the Trump administration was the creation in late March 2020 of a $175 billion Provider Relief Fund (PRF). The fund was supported by both the CARES Act and the Paycheck Protection Program and Health Care Enhancement Act to cover providers’ healthcare-related outstanding expenses and lost revenues due to the COVID crisis. The PRF started almost immediately getting money to many medical providers to save them from going under. And added to that quick shot in the arm were day-to-day changes in regular reimbursement and ways of doing business that helped providers cope with the challenging circumstances.

During the emergency, the most fragile parts of our system, such as rural areas, were the most problematic sectors to address. Rural systems, for example, serve a population that is by and large, older, sicker and poorer. Rural providers are also dependent on Medicaid for financing in many areas. These providers are a part of our healthcare safety net that serves one-sixth of the U.S. population and are perpetually under strain, challenged both by the inherent problems of serving patients in remote areas across large distances, as well as difficult financing, technological, and staffing issues.

The direct payments from the Provider Relief Fund, as well as its flexibilities, enabled rural providers to stay open and continue saving lives throughout the crisis. What’s more, the CARES Act and the Provider Relief Fund increased payments to rural hospitals and medical providers, specifically to compensate for the added costs of providing services in rural and tribal communities. These relief efforts also provided massive resources to the Departments of Agriculture and HHS to expand digital health and telemedicine services to rural and underserved populations.

In fact, according to the Polsinelli/TbRK Index, the level of distressed hospitals hit an all-time low in early 2021. But we now see immense losses being reported by large hospital systems, and we have to expect those same financial challenges to arise and multiply as we continue to exit the extraordinary times of the pandemic.

The question that is now immediately on the horizon is: What to do when the ‘emergency,’ legally speaking, is over? Is the U.S. healthcare system prepared for the end of the PHE?

Flexibilities that enabled, for example, widespread use of telehealth, increased reimbursement, lowered regulatory oversight and expanded enrollment in Medicaid may all cease when the PHE is declared over. All of these powers and changes are vastly different and need different approaches. Congress and the administration may not realize the immense challenge posed by the withdrawal of these powers from the healthcare system after two years (and counting) of depending on them.

There is a need to thoughtfully engage in how to wind down these powers and resources, or a challenge could easily turn into a crisis. It is time for the Biden administration to signal when the official emergency is expected to end and how, and what its plans are for dealing with the inevitable problems of transitioning providers back to normal operating procedures. This is regarding both the regulatory and reimbursement issues. For example, both states and providers have noted mixed messages on Medicaid finance and the level of increased oversight to be exercised on providers.

Serious issues like these must be clarified. This is the minimum patients and providers must have to avert a system failure. With multiple crises being managed right now by the Biden administration, there is a possibility of distraction from this real need for transition planning, and a consequent need for the public and stakeholders to focus policymakers and leadership in the administration on this immediate issue, so avoidable disasters are indeed avoided.

If Congress and the administration do not plan and work together, the end of the old emergency will only mark the beginning of a new emergency.

Eric D. Hargan was most recently deputy secretary of the Department of Health and Human Services after having served as acting secretary. He also served at HHS under George W. Bush. Hargan served on the Board of Operation Warp Speed and oversaw the set up and launch of the Provider Relief Fund and other parts of the U.S. pandemic response. Hargan is the founder of The Hargan Group and sits on the boards of University Hospitals in Cleveland; Alio Medical; Tomorrow Health; and HealthTrackRx.

https://thehill.com/opinion/healthcare/3534354-we-must-end-the-public-health-emergency-carefully/

Let's Talk About Nicotine

 Nicotine is an addictive substance; it is THE addictive substance in tobacco, although tobacco’s combustion products are responsible for most of its adverse health effects. Nicotine has been in the news a lot between the plan to remove JUUL, a nicotine delivery system from the market, and the FDA proposal to require cigarettes to have lower nicotine levels. I asked myself a simple question for which I did not have a ready answer, what amount of nicotine is necessary to get you addicted – what dose makes the poison?

Image by Gerd Altmann from Pixabay

The decision by the FDA to require lower nicotine levels in cigarettes is predicated on the idea that by lowering the dose sufficiently, a non-addictive cigarette could be created. What scientific evidence do we have on what that nicotine dosage might be? To find an answer, I looked at a nicotine review from 2012. Here is what I found.

The Family Smoking Prevention and Tobacco Control Act (FSPTCA), passed in 2009, gives the FDA the authority to reduce but not eliminate nicotine from tobacco products. This involved “denicotinization” of tobacco, reducing the amount of nicotine, either by chemical extraction or through modified tobacco crops. It is not a “light” cigarette, which reduces nicotine by placing small ventilation holes in the filter – which has never been shown to reduce nicotine, and this labeling is banned in the US. As the decline in smoking through the current regulations and taxations seem to be “hitting a wall” (declining from 19% to 14% between 2010 and 2018), regulators seeking a science-informed approach have focused on identifying a nicotine-addiction threshold.

Nicotine’s Addiction Threshold

Cigarettes contain between 1 and 1.5mg of nicotine, a variable amount of which will be delivered to the smoker’s bloodstream based upon how deeply and frequently they inhale. Invasive studies using multiple blood samples have demonstrated that smokers maintain nicotine levels between 10-50 ng/ml. Similarly, other blood sample studies rely on cotinine, a non-addictive, metabolic byproduct of nicotine that acts as a biomarker of nicotine levels. More often, to avoid blood sampling altogether, the marker of nicotine levels is the number of cigarettes smoked.

Studies of “chippers,” individuals who smoke intermittently or just a few cigarettes, have identified a blood level of cotinine of 50 ng/ml, nicotine’s biomarker. Chippers smoke roughly five cigarettes (therefore 5 mg of nicotine) daily, and researchers have concluded that a cigarette with 0.17 mg of nicotine would be below an addiction threshold. It is readily apparent that this is, at best, an approximation.

A larger question is wrapped within the term “addiction threshold.” What do we mean by addiction? There is no clear line between “dependent and nondependent smokers.” Some researchers rely on DSM-V criteria [1], others on the Fagerström Test for Nicotine Dependence (FTND) scale [2]. Unfortunately, there is no clear correlation between these two addiction criteria, and “there is still no consensus on what represents the most reliable and valid method for assessing nicotine addiction.”

Nicotine’s Reinforcement Threshold

Adding to the ambiguity of definitions is the concept of nicotine reinforcement – “the lowest nicotine dose that will increase or maintain nicotine self-administration behaviors.” Reinforcement is more easily measured because it involves short-term studies, whereas establishing dependence requires longer time frames. Given the difficulties with identifying a nicotine addiction target, these researchers believed that the reinforcement threshold would be a more science-based, objective target for regulation.

Studies of a reinforcement threshold have their limitations. Because smoking delivers variable amounts of nicotine, most studies have employed pure nicotine delivered either as a nasal spray or intravenously – not exactly replicating the individual and social interactions, e.g., that first cigarette with a cup of coffee or the cigarette break at work, that may be part of tobacco’s addictive nature. Studies using nasal spray have not demonstrated a reinforcement threshold.

Intravenous studies provided additional insight. First, reinforcement was time-mediated; a reinforcing dose, more efficiently delivered intravenously, produced a “rush.” Think of that first puff, long and deep. Second, after a host of studies, there was general agreement that the “ballpark” dose of reinforcing nicotine was between 1.5 and 6.0 µg/kg. But even that range comes with caveats, including the need to identify genetic, gender, or ethnic differences, the possibility that cigarettes contain other substances that facilitate nicotine levels (for example, menthol), and determining how well a reinforcement threshold predicts long-term use.

How would a low nicotine cigarette affect public health?

We should also consider the rationale behind the reduction in nicotine levels. Do new smokers seek a nicotine addiction or some type of social acceptance from their peers? As a professor of health psychology wrote:

“Experimenting with smoking usually occurs in the early teenage years and is driven predominantly by psychosocial motives. For a beginner, smoking a cigarette is a symbolic act … Children who are attracted to this adolescent assertion of perceived adulthood or rebelliousness tend to come from backgrounds that favour smoking …. [and] also tend not to be succeeding according to their own or society's terms …”

Theoretically, if a non-addictive dosage were identified, these cigarettes would no longer be chemically addictive. New smokers would be protected from the chemical addiction that reinforces the social behavior and might more easily stop.

Would a lower nicotine dose help these new smokers and those already smoking quit? The two biggest advocates of lowering nicotine levels reported on three such studies.  In each study, lower nicotine cigarettes resulted in lower nicotine levels, and “some smokers quit smoking spontaneously, and those who continued to smoke reported a lower level of dependence.” Nor did these smokers increase the number of cigarettes they smoked to achieve a higher nicotine level. This suggests that none of these amounts, as low as 0.05 mg of nicotine/cigarette, were below nicotine’s reinforcement level. More importantly, the researchers felt cigarette use did not increase “because of the satiating effect of the tar, chemical irritants and related taste, the levels of which were unchanged in reduced nicotine content cigarettes.” Let me restate this, low-nicotine cigarettes reduced nicotine but did not have any impact on the combustion products associated with cancer – an unintended consequence, at least if we do not consider the scientific data we already have.  

Final Thoughts

The FDA’s proposal to reduce the nicotine in cigarettes has been kicking around for years. The only change was that a proposal will be put forth for public comment next year. Those comments will usher in a contentious debate between tobacco companies and advocates of smoking cessation – we need only consider the recent menthol ban as a harbinger of things to come.

Deliberately inhaling hot gases containing combustion products is stupid and will adversely impact your health. Reducing the nicotine level in cigarettes sounds like a good idea, but what we know about nicotine so far argues that these theoretical low-nicotine cigarettes are not likely to be helpful to current smokers. Whether it might lessen the possibility that a new smoker continues is unknown. Putting the toothpaste back in the tube is difficult, and we should be wary of solutions that sound good but make uncertain assumptions.

Dr. Charles Dinerstein, M.D., MBA, FACS is Director of Medicine at the American Council on Science and Health. He has over 25 years of experience as a vascular surgeon.

https://www.acsh.org/news/2022/06/27/lets-talk-about-nicotine-16392