Questions remain about new drug for hot flashes
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.
New elevators could lift up our access to space
Story by Big Think
When people first started exploring space in the 1960s, it cost upwards of $80,000 (adjusted for inflation) to put a single pound of payload into low-Earth orbit.
A major reason for this high cost was the need to build a new, expensive rocket for every launch. That really started to change when SpaceX began making cheap, reusable rockets, and today, the company is ferrying customer payloads to LEO at a price of just $1,300 per pound.
This is making space accessible to scientists, startups, and tourists who never could have afforded it previously, but the cheapest way to reach orbit might not be a rocket at all — it could be an elevator.
The space elevator
The seeds for a space elevator were first planted by Russian scientist Konstantin Tsiolkovsky in 1895, who, after visiting the 1,000-foot (305 m) Eiffel Tower, published a paper theorizing about the construction of a structure 22,000 miles (35,400 km) high.
This would provide access to geostationary orbit, an altitude where objects appear to remain fixed above Earth’s surface, but Tsiolkovsky conceded that no material could support the weight of such a tower.
We could then send electrically powered “climber” vehicles up and down the tether to deliver payloads to any Earth orbit.
In 1959, soon after Sputnik, Russian engineer Yuri N. Artsutanov proposed a way around this issue: instead of building a space elevator from the ground up, start at the top. More specifically, he suggested placing a satellite in geostationary orbit and dropping a tether from it down to Earth’s equator. As the tether descended, the satellite would ascend. Once attached to Earth’s surface, the tether would be kept taut, thanks to a combination of gravitational and centrifugal forces.
We could then send electrically powered “climber” vehicles up and down the tether to deliver payloads to any Earth orbit. According to physicist Bradley Edwards, who researched the concept for NASA about 20 years ago, it’d cost $10 billion and take 15 years to build a space elevator, but once operational, the cost of sending a payload to any Earth orbit could be as low as $100 per pound.
“Once you reduce the cost to almost a Fed-Ex kind of level, it opens the doors to lots of people, lots of countries, and lots of companies to get involved in space,” Edwards told Space.com in 2005.
In addition to the economic advantages, a space elevator would also be cleaner than using rockets — there’d be no burning of fuel, no harmful greenhouse emissions — and the new transport system wouldn’t contribute to the problem of space junk to the same degree that expendable rockets do.
So, why don’t we have one yet?
Tether troubles
Edwards wrote in his report for NASA that all of the technology needed to build a space elevator already existed except the material needed to build the tether, which needs to be light but also strong enough to withstand all the huge forces acting upon it.
The good news, according to the report, was that the perfect material — ultra-strong, ultra-tiny “nanotubes” of carbon — would be available in just two years.
“[S]teel is not strong enough, neither is Kevlar, carbon fiber, spider silk, or any other material other than carbon nanotubes,” wrote Edwards. “Fortunately for us, carbon nanotube research is extremely hot right now, and it is progressing quickly to commercial production.”Unfortunately, he misjudged how hard it would be to synthesize carbon nanotubes — to date, no one has been able to grow one longer than 21 inches (53 cm).
Further research into the material revealed that it tends to fray under extreme stress, too, meaning even if we could manufacture carbon nanotubes at the lengths needed, they’d be at risk of snapping, not only destroying the space elevator, but threatening lives on Earth.
Looking ahead
Carbon nanotubes might have been the early frontrunner as the tether material for space elevators, but there are other options, including graphene, an essentially two-dimensional form of carbon that is already easier to scale up than nanotubes (though still not easy).
Contrary to Edwards’ report, Johns Hopkins University researchers Sean Sun and Dan Popescu say Kevlar fibers could work — we would just need to constantly repair the tether, the same way the human body constantly repairs its tendons.
“Using sensors and artificially intelligent software, it would be possible to model the whole tether mathematically so as to predict when, where, and how the fibers would break,” the researchers wrote in Aeon in 2018.
“When they did, speedy robotic climbers patrolling up and down the tether would replace them, adjusting the rate of maintenance and repair as needed — mimicking the sensitivity of biological processes,” they continued.Astronomers from the University of Cambridge and Columbia University also think Kevlar could work for a space elevator — if we built it from the moon, rather than Earth.
They call their concept the Spaceline, and the idea is that a tether attached to the moon’s surface could extend toward Earth’s geostationary orbit, held taut by the pull of our planet’s gravity. We could then use rockets to deliver payloads — and potentially people — to solar-powered climber robots positioned at the end of this 200,000+ mile long tether. The bots could then travel up the line to the moon’s surface.
This wouldn’t eliminate the need for rockets to get into Earth’s orbit, but it would be a cheaper way to get to the moon. The forces acting on a lunar space elevator wouldn’t be as strong as one extending from Earth’s surface, either, according to the researchers, opening up more options for tether materials.
“[T]he necessary strength of the material is much lower than an Earth-based elevator — and thus it could be built from fibers that are already mass-produced … and relatively affordable,” they wrote in a paper shared on the preprint server arXiv.
After riding up the Earth-based space elevator, a capsule would fly to a space station attached to the tether of the moon-based one.
Electrically powered climber capsules could go up down the tether to deliver payloads to any Earth orbit.
Adobe Stock
Some Chinese researchers, meanwhile, aren’t giving up on the idea of using carbon nanotubes for a space elevator — in 2018, a team from Tsinghua University revealed that they’d developed nanotubes that they say are strong enough for a tether.
The researchers are still working on the issue of scaling up production, but in 2021, state-owned news outlet Xinhua released a video depicting an in-development concept, called “Sky Ladder,” that would consist of space elevators above Earth and the moon.
After riding up the Earth-based space elevator, a capsule would fly to a space station attached to the tether of the moon-based one. If the project could be pulled off — a huge if — China predicts Sky Ladder could cut the cost of sending people and goods to the moon by 96 percent.
The bottom line
In the 120 years since Tsiolkovsky looked at the Eiffel Tower and thought way bigger, tremendous progress has been made developing materials with the properties needed for a space elevator. At this point, it seems likely we could one day have a material that can be manufactured at the scale needed for a tether — but by the time that happens, the need for a space elevator may have evaporated.
Several aerospace companies are making progress with their own reusable rockets, and as those join the market with SpaceX, competition could cause launch prices to fall further.
California startup SpinLaunch, meanwhile, is developing a massive centrifuge to fling payloads into space, where much smaller rockets can propel them into orbit. If the company succeeds (another one of those big ifs), it says the system would slash the amount of fuel needed to reach orbit by 70 percent.
Even if SpinLaunch doesn’t get off the ground, several groups are developing environmentally friendly rocket fuels that produce far fewer (or no) harmful emissions. More work is needed to efficiently scale up their production, but overcoming that hurdle will likely be far easier than building a 22,000-mile (35,400-km) elevator to space.
New tech aims to make the ocean healthier for marine life
A defunct drydock basin arched by a rusting 19th century steel bridge seems an incongruous place to conduct state-of-the-art climate science. But this placid and protected sliver of water connecting Brooklyn’s Navy Yard to the East River was just right for Garrett Boudinot to float a small dock topped with water carbon-sensing gear. And while his system right now looks like a trio of plastic boxes wired up together, it aims to mediate the growing ocean acidification problem, caused by overabundance of dissolved carbon dioxide.
Boudinot, a biogeochemist and founder of a carbon-management startup called Vycarb, is honing his method for measuring CO2 levels in water, as well as (at least temporarily) correcting their negative effects. It’s a challenge that’s been occupying numerous climate scientists as the ocean heats up, and as states like New York recognize that reducing emissions won’t be enough to reach their climate goals; they’ll have to figure out how to remove carbon, too.
To date, though, methods for measuring CO2 in water at scale have been either intensely expensive, requiring fancy sensors that pump CO2 through membranes; or prohibitively complicated, involving a series of lab-based analyses. And that’s led to a bottleneck in efforts to remove carbon as well.
But recently, Boudinot cracked part of the code for measurement and mitigation, at least on a small scale. While the rest of the industry sorts out larger intricacies like getting ocean carbon markets up and running and driving carbon removal at billion-ton scale in centralized infrastructure, his decentralized method could have important, more immediate implications.
Specifically, for shellfish hatcheries, which grow seafood for human consumption and for coastal restoration projects. Some of these incubators for oysters and clams and scallops are already feeling the negative effects of excess carbon in water, and Vycarb’s tech could improve outcomes for the larval- and juvenile-stage mollusks they’re raising. “We’re learning from these folks about what their needs are, so that we’re developing our system as a solution that’s relevant,” Boudinot says.
Ocean acidification can wreak havoc on developing shellfish, inhibiting their shells from growing and leading to mass die-offs.
Ocean waters naturally absorb CO2 gas from the atmosphere. When CO2 accumulates faster than nature can dissipate it, it reacts with H2O molecules, forming carbonic acid, H2CO3, which makes the water column more acidic. On the West Coast, acidification occurs when deep, carbon dioxide-rich waters upwell onto the coast. This can wreak havoc on developing shellfish, inhibiting their shells from growing and leading to mass die-offs; this happened, disastrously, at Pacific Northwest oyster hatcheries in 2007.
This type of acidification will eventually come for the East Coast, too, says Ryan Wallace, assistant professor and graduate director of environmental studies and sciences at Long Island’s Adelphi University, who studies acidification. But at the moment, East Coast acidification has other sources: agricultural runoff, usually in the form of nitrogen, and human and animal waste entering coastal areas. These excess nutrient loads cause algae to grow, which isn’t a problem in and of itself, Wallace says; but when algae die, they’re consumed by bacteria, whose respiration in turn bumps up CO2 levels in water.
“Unfortunately, this is occurring at the bottom [of the water column], where shellfish organisms live and grow,” Wallace says. Acidification on the East Coast is minutely localized, occurring closest to where nutrients are being released, as well as seasonally; at least one local shellfish farm, on Fishers Island in the Long Island Sound, has contended with its effects.
The second Vycarb pilot, ready to be installed at the East Hampton shellfish hatchery.
Courtesy of Vycarb
Besides CO2, ocean water contains two other forms of dissolved carbon — carbonate (CO3-) and bicarbonate (HCO3) — at all times, at differing levels. At low pH (acidic), CO2 prevails; at medium pH, HCO3 is the dominant form; at higher pH, CO3 dominates. Boudinot’s invention is the first real-time measurement for all three, he says. From the dock at the Navy Yard, his pilot system uses carefully calibrated but low-cost sensors to gauge the water’s pH and its corresponding levels of CO2. When it detects elevated levels of the greenhouse gas, the system mitigates it on the spot. It does this by adding a bicarbonate powder that’s a byproduct of agricultural limestone mining in nearby Pennsylvania. Because the bicarbonate powder is alkaline, it increases the water pH and reduces the acidity. “We drive a chemical reaction to increase the pH to convert greenhouse gas- and acid-causing CO2 into bicarbonate, which is HCO3,” Boudinot says. “And HCO3 is what shellfish and fish and lots of marine life prefers over CO2.”
This de-acidifying “buffering” is something shellfish operations already do to water, usually by adding soda ash (NaHCO3), which is also alkaline. Some hatcheries add soda ash constantly, just in case; some wait till acidification causes significant problems. Generally, for an overly busy shellfish farmer to detect acidification takes time and effort. “We’re out there daily, taking a look at the pH and figuring out how much we need to dose it,” explains John “Barley” Dunne, director of the East Hampton Shellfish Hatchery on Long Island. “If this is an automatic system…that would be much less labor intensive — one less thing to monitor when we have so many other things we need to monitor.”
Across the Sound at the hatchery he runs, Dunne annually produces 30 million hard clams, 6 million oysters, and “if we’re lucky, some years we get a million bay scallops,” he says. These mollusks are destined for restoration projects around the town of East Hampton, where they’ll create habitat, filter water, and protect the coastline from sea level rise and storm surge. So far, Dunne’s hatchery has largely escaped the ill effects of acidification, although his bay scallops are having a finicky year and he’s checking to see if acidification might be part of the problem. But “I think it's important to have these solutions ready-at-hand for when the time comes,” he says. That’s why he’s hosting a second, 70-liter Vycarb pilot starting this summer on a dock adjacent to his East Hampton operation; it will amp up to a 50,000 liter-system in a few months.
If it can buffer water over a large area, absolutely this will benefit natural spawns. -- John “Barley” Dunne.
Boudinot hopes this new pilot will act as a proof of concept for hatcheries up and down the East Coast. The area from Maine to Nova Scotia is experiencing the worst of Atlantic acidification, due in part to increased Arctic meltwater combining with Gulf of St. Lawrence freshwater; that decreases saturation of calcium carbonate, making the water more acidic. Boudinot says his system should work to adjust low pH regardless of the cause or locale. The East Hampton system will eventually test and buffer-as-necessary the water that Dunne pumps from the Sound into 100-gallon land-based tanks where larvae grow for two weeks before being transferred to an in-Sound nursery to plump up.
Dunne says this could have positive effects — not only on his hatchery but on wild shellfish populations, too, reducing at least one stressor their larvae experience (others include increasing water temperatures and decreased oxygen levels). “If it can buffer water over a large area, absolutely this will [benefit] natural spawns,” he says.
No one believes the Vycarb model — even if it proves capable of functioning at much greater scale — is the sole solution to acidification in the ocean. Wallace says new water treatment plants in New York City, which reduce nitrogen released into coastal waters, are an important part of the equation. And “certainly, some green infrastructure would help,” says Boudinot, like restoring coastal and tidal wetlands to help filter nutrient runoff.
In the meantime, Boudinot continues to collect data in advance of amping up his own operations. Still unknown is the effect of releasing huge amounts of alkalinity into the ocean. Boudinot says a pH of 9 or higher can be too harsh for marine life, plus it can also trigger a release of CO2 from the water back into the atmosphere. For a third pilot, on Governor’s Island in New York Harbor, Vycarb will install yet another system from which Boudinot’s team will frequently sample to analyze some of those and other impacts. “Let's really make sure that we know what the results are,” he says. “Let's have data to show, because in this carbon world, things behave very differently out in the real world versus on paper.”