COVID Vaccines Put Anti-Science Activists to Shame
On a rain-soaked day, thousands marched on Washington, D.C. to fight for science funding and scientific analysis in politics.
It turns out that, despite the destruction and heartbreak caused by the COVID pandemic, there is a silver lining: Scientists from academia, government, and industry worked together and, using the tools of biotechnology, created multiple vaccines that surely will put an end to the worst of the pandemic sometime in 2021. In short, they proved that science works, particularly that which comes from industry. Though politicians and the public love to hate Big Ag and Big Pharma, everybody comes begging for help when the going gets tough.
The change in public attitude is tangible. A headline in the Financial Times declared, "Covid vaccines offer Big Pharma a chance of rehabilitation." In its analysis, the FT says that the pharmaceutical industry is widely reviled because of the high prices it charges for its drugs, among other things, but the speed with which the industry developed COVID vaccines may allow for its reputation to be refurbished.
The Media's Role in Promoting Anti-Biotech Activism
Of course, the media is partly to blame for the pharmaceutical industry's dismal reputation in the first place because of journalists' penchant for oversimplifying complicated stories and pinning blame on an easy scapegoat. While the pharmaceutical industry is far from angelic and places a hefty price tag on its products in the U.S., often gone unmentioned is the fact that high drug prices are the result of multiple factors, including lack of competition (even among generic drugs), foreign price controls that allow citizens of other countries to "free load" off of American consumers, and a deliberately opaque drug supply chain (that involves not only profit-maximizing pharmaceutical manufacturers but "middlemen" like distributors). But why delve into such nuance when it's easier to point to villains like Martin Shkreli?
Big Ag has been subjected to identical mistreatment by the media, with outlets such as the New York Times among the biggest offenders. One article it published compared pesticides to "Nazi-made sarin gas," and another spread misinformation about a high-profile biotech scientist. The website Undark, whose stated mission is "true journalistic coverage of the sciences," once published an opinion piece written by a person who works for an anti-GMO organization and another criticizing Monsanto for its reasonable efforts to defend itself from disinformation. These aren't cherry-picked examples. Overall, the media clearly has taken sides: Science is great, unless it's science from industry.
If the scientific community can use the powerful techniques of biotechnology to cure a previously unknown infectious disease in less than a year, then why shouldn't it be able to cure genetic diseases in humans?
Now, the very same media – which has portrayed the pharmaceutical and biotech industries in the worst possible light, often for political or ideological reasons – is wondering why so many Americans are reluctant to get a COVID vaccine. Perhaps their reportage has something to do with it.
Tech Strikes Back
For years, the agricultural, pharmaceutical, and biotech industries fought back, but to no avail. GMOs are feared, pharma is hated, and biotech is misunderstood. Regulatory red tape abounds. But that may be all about to change, not because of a clever PR campaign, but thanks to the successful coronavirus vaccines produced by the pharma/biotech industry.
All of the major vaccines were created using biotechnology, broadly defined as the use of living systems and organisms to develop products intended to improve human life or the planet. The Pfizer/BioNTech and Moderna vaccines rely on mRNA (messenger RNA), which is essentially a molecular "photocopy" of the more familiar genetic material DNA. The mRNA molecules were tweaked using biotech and then shown to be 95% effective at preventing COVID in human volunteers. The AstraZeneca/Oxford vaccine is based on an older technology that genetically modifies a harmless virus to resemble an immunological target, in this case, SARS-CoV-2. Their vaccine is 62% to 90% effective.
Even better, the pharma/biotech industry showed that it can work hand-in-hand with the government, for instance the FDA, to produce vaccines in record-breaking time. Operation Warp Speed provided some financing to facilitate this process. History will look back at this endeavor and likely conclude that the unprecedented level of cooperation to develop a vaccine in less than 12 months was one of the greatest triumphs in public health history. (The bungled slow rollout is another story.)
Perhaps the most important lesson that society will learn is that the scientific method works.
The pharma/biotech industry has thus gained tremendous momentum. For the first time it seems, those who are opposed to scientific progress and biotechnology are on the defensive. If the scientific community can use the powerful techniques of biotechnology to cure a previously unknown infectious disease in less than a year, then why shouldn't it be able to cure genetic diseases in humans? Or create genetically modified crops that are resistant to insects and drought? Or use genetically modified mosquitoes to help fight against killer diseases like malaria? The arguments against biotechnology have been made exponentially weaker by the success of the coronavirus vaccine.
Perhaps the most important lesson that society will learn is that the scientific method works. We observed (by collecting samples of an unknown virus and sequencing its genome), hypothesized (by predicting which parts of the virus would trigger an immune response), experimented (by recruiting tens of thousands of volunteers into clinical trials), and concluded (that the vaccines worked). It was a thing of pure beauty.
Thanks to all the players involved – from Big Government to Big Pharma – we are beginning the process of being rescued from a modern-day plague. Let us hope that this scientific success also deals a fatal blow to the forces of ignorance that have held back technological progress for decades.
[Editor's Note: LeapsMag is an editorially independent publication that receives program support from Leaps by Bayer. LeapsMag's founding in 2017 predates Bayer's acquisition of Monsanto in 2018. All content published on LeapsMag is strictly free of influence, censorship, and oversight from its corporate sponsor. Read more about LeapsMag's organizational independence here.]
Questions remain about new drug for hot flashes
In May, a new drug, Fezolinetant, was approved by the FDA to treat hot flashes associated with menopause.
Vascomotor symptoms (VMS) is the medical term for hot flashes associated with menopause. You are going to hear a lot more about it because a company has a new drug to sell. Here is what you need to know.
Menopause marks the end of a woman’s reproductive capacity. Normal hormonal production associated with that monthly cycle becomes erratic and finally ceases. For some women the transition can be relatively brief with only modest symptoms, while for others the body's “thermostat” in the brain is disrupted and they experience hot flashes and other symptoms that can disrupt daily activity. Lifestyle modification and drugs such as hormone therapy can provide some relief, but women at risk for cancer are advised not to use them and other women choose not to do so.
Fezolinetant, sold by Astellas Pharma Inc. under the product name Veozah™, was approved by the Food and Drug Administration (FDA) on May 12 to treat hot flashes associated with menopause. It is the first in a new class of drugs called neurokinin 3 receptor antagonists, which block specific neurons in the brain “thermostat” that trigger VMS. It does not appear to affect other symptoms of menopause. As with many drugs targeting a brain cell receptor, it must be taken continuously for a few days to build up a good therapeutic response, rather than working as a rescue product such as an asthma inhaler to immediately treat that condition.
Hot flashes vary greatly and naturally get better or resolve completely with time. That contributes to a placebo effect and makes it more difficult to judge the outcome of any intervention. Early this year, a meta analysis of 17 studies of drug trials for hot flashes found an unusually large placebo response in those types of studies; the placebo groups had an average of 5.44 fewer hot flashes and a 36 percent reduction in their severity.
In studies of fezolinetant, the drug recently approved by the FDA, the placebo benefit was strong and persistent. The drug group bested the placebo response to a statistically significant degree but, “If people have gone from 11 hot flashes a day to eight or seven in the placebo group and down to a couple fewer ones in the drug groups, how meaningful is that? Having six hot flashes a day is still pretty unpleasant,” says Diana Zuckerman, president of the National Center for Health Research (NCHR), a health oriented think tank.
“Is a reduction compared to placebo of 2-3 hot flashes per day, in a population of women experiencing 10-11 moderate to severe hot flashes daily, enough relief to be clinically meaningful?” Andrea LaCroix asked a commentary published in Nature Medicine. She is an epidemiologist at the University of California San Diego and a leader of the MsFlash network that has conducted a handful of NIH-funded studies on menopause.
Questions Remain
LaCroix and others have raised questions about how Astellas, the company that makes the new drug, handled missing data from patients who dropped out of the clinical trials. “The lack of detailed information about important parameters such as adherence and missing data raises concerns that the reported benefits of fezolinetant very likely overestimate those that will be observed in clinical practice," LaCroix wrote.
In response to this concern, Anna Criddle, director of global portfolio communications at Astellas, wrote in an email to Leaps.org: “…a full analysis of data, including adherence data and any impact of missing data, was submitted for assessment by [the FDA].”
The company ran the studies at more than 300 sites around the world. Curiously, none appear to have been at academic medical centers, which are known for higher quality research. Zuckerman says, "When somebody is paid to do a study, if they want to get paid to do another study by the same company, they will try to make sure that the results are the results that the company wants.”
Criddle said that Astellas picked the sites “that would allow us to reach a diverse population of women, including race and ethnicity.”
A trial of a lower dose of the drug was conducted in Asia. In March 2022, Astellas issued a press release saying it had failed to prove effectiveness. No further data has been released. Astellas still plans to submit the data, according to Criddle. Results from clinical trials funded by the U.S. goverment must be reported on clinicaltrials.gov within one year of the study's completion - a deadline that, in this case, has expired.
The measurement scale for hot flashes used in the studies, mild-moderate-severe, also came in for criticism. “It is really not good scale, there probably isn’t a broad enough range of things going on or descriptors,” says David Rind. He is chief medical officer of the Institute for Clinical and Economic Review (ICER), a nonprofit authority on new drugs. It conducted a thorough review and analysis of fezolinestant using then existing data gathered from conference abstracts, posters and presentations and included a public stakeholder meeting in December. A 252-page report was published in January, finding “considerable uncertainty about the comparative net health benefits of fezolinetant” versus hormone therapy.
Questions surrounding some of these issues might have been answered if the FDA had chosen to hold a public advisory committee meeting on fezolinetant, which it regularly does for first in class medicines. But the agency decided such a meeting was unnecessary.
Cost
There was little surprise when Astellas announced a list price for fezolinetant of $550 a month ($6000 annually) and a program of patient assistance to ease out of pocket expenses. The company had already incurred large expenses.
In 2017 Astellas purchased the company that originally developed fezolinetant for $534 million plus several hundred million in potential royalties. The drug company ran a "disease awareness” ad, Heat on the Street, hat aired during the Super Bowl in February, where 30 second ads cost about $7 million. Industry analysts have projected sales to be $1.9 billion by 2028.
ICER’s pre-approval evaluation said fezolinetant might "be considered cost-effective if priced around $2,000 annually. ... [It]will depend upon its price and whether it is considered an alternative to MHT [menopause hormone treatment] for all women or whether it will primarily be used by women who cannot or will not take MHT."
Criddle wrote that Astellas set the price based on the novelty of the science, the quality of evidence for the drug and its uniqueness compared to the rest of the market. She noted that an individual’s payment will depend on how much their insurance company decides to cover. “[W]e expect insurance coverage to increase over the course of the year and to achieve widespread coverage in the U.S. over time.”
Leaps.org wrote to and followed up with nine of the largest health insurers/providers asking basic questions about their coverage of fezolinetant. Only two responded. Jennifer Martin, the deputy chief consultant for pharmacy benefits management at the Department of Veterans Affairs, said the agency “covers all drugs from the date that they are launched.” Decisions on whether it will be included in the drug formulary and what if any copays might be required are under review.
“[Fezolinetant] will go through our standard P&T Committee [patient and treatment] review process in the next few months, including a review of available efficacy data, safety data, clinical practice guidelines, and comparison with other agents used for vasomotor symptoms of menopause," said Phil Blando, executive director of corporate communications for CVS Health.
Other insurers likely are going through a similar process to decide issues such as limiting coverage to women who are advised not to use hormones, how much copay will be required, and whether women will be required to first try other options or obtain approvals before getting a prescription.
Rind wants to see a few years of use before he prescribes fezolinetant broadly, and believes most doctors share his view. Nor will they be eager to fill out the additional paperwork required for women to participate in the Astellas patient assistance program, he added.
Safety
Astellas is marketing its drug by pointing out risks of hormone therapy, such as a recent paper in The BMJ, which noted that women who took hormones for even a short period of time had a 24 percent increased risk of dementia. While the percentage was scary, the combined number of women both on and off hormones who developed dementia was small. And it is unclear whether hormones are causing dementia or if more severe hot flashes are a marker for higher risk of developing dementia. This information is emerging only after 80 years of hundreds of millions of women using hormones.
In contrast, the label for fezolinetant prohibits “concomitant use with CYP1A2 inhibitors” and requires testing for liver and kidney function prior to initiating the drug and every three months thereafter. There is no human or animal data on use in a geriatric population, defined as 65 or older, a group that is likely to use the drug. Only a few thousand women have ever taken fezolinetant and most have used it for just a few months.
Options
A woman seeking relief from symptoms of menopause would like to see how fezolintant compares with other available treatment options. But Astellas did not conduct such a study and Andrea LaCroix says it is unlikely that anyone ever will.
ICER has come the closest, with a side-by-side analysis of evidence-based treatments and found that fezolinetant performed quite similarly and modestly as the others in providing relief from hot flashes. Some treatments also help with other symptoms of menopause, which fezolinetant does not.
There are many coping strategies that women can adopt to deal with hot flashes; one of the most common is dressing in layers (such as a sleeveless blouse with a sweater) that can be added or subtracted as conditions require. Avoiding caffeine, hot liquids, and spicy foods is another common strategy. “I stopped drinking hot caffeinated drinks…for several years, and you get out of the habit of drinking them,” says Zuckerman.
LaCroix curates those options at My Meno Plan, which includes a search function where you can enter your symptoms and identify which treatments might work best for you. It also links to published research papers. She says the goal is to empower women with information to make informed decisions about menopause.
A company in England has made a test that picks out the compounds from breath that reveal if people have liver disease.
Every year, around two million people worldwide die of liver disease. While some people inherit the disease, it’s most commonly caused by hepatitis, obesity and alcoholism. These underlying conditions kill liver cells, causing scar tissue to form until eventually the liver cannot function properly. Since 1979, deaths due to liver disease have increased by 400 percent.
The sooner the disease is detected, the more effective treatment can be. But once symptoms appear, the liver is already damaged. Around 50 percent of cases are diagnosed only after the disease has reached the final stages, when treatment is largely ineffective.
To address this problem, Owlstone Medical, a biotech company in England, has developed a breath test that can detect liver disease earlier than conventional approaches. Human breath contains volatile organic compounds (VOCs) that change in the first stages of liver disease. Owlstone’s breath test can reliably collect, store and detect VOCs, while picking out the specific compounds that reveal liver disease.
“There’s a need to screen more broadly for people with early-stage liver disease,” says Owlstone’s CEO Billy Boyle. “Equally important is having a test that's non-invasive, cost effective and can be deployed in a primary care setting.”
The standard tool for detection is a biopsy. It is invasive and expensive, making it impractical to use for people who aren't yet symptomatic. Meanwhile, blood tests are less invasive, but they can be inaccurate and can’t discriminate between different stages of the disease.
In the past, breath tests have not been widely used because of the difficulties of reliably collecting and storing breath. But Owlstone’s technology could help change that.
The team is testing patients in the early stages of advanced liver disease, or cirrhosis, to identify and detect these biomarkers. In an initial study, Owlstone’s breathalyzer was able to pick out patients who had early cirrhosis with 83 percent sensitivity.
Boyle’s work is personally motivated. His wife died of colorectal cancer after she was diagnosed with a progressed form of the disease. “That was a big impetus for me to see if this technology could work in early detection,” he says. “As a company, Owlstone is interested in early detection across a range of diseases because we think that's a way to save lives and a way to save costs.”
How it works
In the past, breath tests have not been widely used because of the difficulties of reliably collecting and storing breath. But Owlstone’s technology could help change that.
Study participants breathe into a mouthpiece attached to a breath sampler developed by Owlstone. It has cartridges are designed and optimized to collect gases. The sampler specifically targets VOCs, extracting them from atmospheric gases in breath, to ensure that even low levels of these compounds are captured.
The sampler can store compounds stably before they are assessed through a method called mass spectrometry, in which compounds are converted into charged atoms, before electromagnetic fields filter and identify even the tiniest amounts of charged atoms according to their weight and charge.
The top four compounds in our breath
In an initial study, Owlstone captured VOCs in breath to see which ones could help them tell the difference between people with and without liver disease. They tested the breath of 46 patients with liver disease - most of them in the earlier stages of cirrhosis - and 42 healthy people. Using this data, they were able to create a diagnostic model. Individually, compounds like 2-Pentanone and limonene performed well as markers for liver disease. Owlstone achieved even better performance by examining the levels of the top four compounds together, distinguishing between liver disease cases and controls with 95 percent accuracy.
“It was a good proof of principle since it looks like there are breath biomarkers that can discriminate between diseases,” Boyle says. “That was a bit of a stepping stone for us to say, taking those identified, let’s try and dose with specific concentrations of probes. It's part of building the evidence and steering the clinical trials to get to liver disease sensitivity.”
Sabine Szunerits, a professor of chemistry in Institute of Electronics at the University of Lille, sees the potential of Owlstone’s technology.
“Breath analysis is showing real promise as a clinical diagnostic tool,” says Szunerits, who has no ties with the company. “Owlstone Medical’s technology is extremely effective in collecting small volatile organic biomarkers in the breath. In combination with pattern recognition it can give an answer on liver disease severity. I see it as a very promising way to give patients novel chances to be cured.”
Improving the breath sampling process
Challenges remain. With more than one thousand VOCs found in the breath, it can be difficult to identify markers for liver disease that are consistent across many patients.
Julian Gardner is a professor of electrical engineering at Warwick University who researches electronic sensing devices. “Everyone’s breath has different levels of VOCs and different ones according to gender, diet, age etc,” Gardner says. “It is indeed very challenging to selectively detect the biomarkers in the breath for liver disease.”
So Owlstone is putting chemicals in the body that they know interact differently with patients with liver disease, and then using the breath sampler to measure these specific VOCs. The chemicals they administer are called Exogenous Volatile Organic Compound) probes, or EVOCs.
Most recently, they used limonene as an EVOC probe, testing 29 patients with early cirrhosis and 29 controls. They gave the limonene to subjects at specific doses to measure how its concentrations change in breath. The aim was to try and see what was happening in their livers.
“They are proposing to use drugs to enhance the signal as they are concerned about the sensitivity and selectivity of their method,” Gardner says. “The approach of EVOC probes is probably necessary as you can then eliminate the person-to-person variation that will be considerable in the soup of VOCs in our breath.”
Through these probes, Owlstone could identify patients with liver disease with 83 percent sensitivity. By targeting what they knew was a disease mechanism, they were able to amplify the signal. The company is starting a larger clinical trial, and the plan is to eventually use a panel of EVOC probes to make sure they can see diverging VOCs more clearly.
“I think the approach of using probes to amplify the VOC signal will ultimately increase the specificity of any VOC breath tests, and improve their practical usability,” says Roger Yazbek, who leads the South Australian Breath Analysis Research (SABAR) laboratory in Flinders University. “Whilst the findings are interesting, it still is only a small cohort of patients in one location.”
The future of breath diagnosis
Owlstone wants to partner with pharmaceutical companies looking to learn if their drugs have an effect on liver disease. They’ve also developed a microchip, a miniaturized version of mass spectrometry instruments, that can be used with the breathalyzer. It is less sensitive but will enable faster detection.
Boyle says the company's mission is for their tests to save 100,000 lives. "There are lots of risks and lots of challenges. I think there's an opportunity to really establish breath as a new diagnostic class.”