A decade ago, Elizabeth Summers' options for birth control suddenly narrowed. Doctors diagnosed her with Factor V Leiden, a rare genetic disorder, after discovering blood clots in her lungs. The condition increases the risk of clotting, so physicians told Summers to stay away from the pill and other hormone-laden contraceptives. "Modern medicine has generally failed to provide me with an effective and convenient option," she says.
But new birth control options are emerging for women like Summers. These alternatives promise to provide more choices to women who can't ingest hormones or don't want to suffer their unpleasant side effects.
These new products have their own pros and cons. Still, doctors are welcoming new contraceptives following a long drought in innovation. "It's been a long time since we've had something new in the world of contraception," says Heather Irobunda, an obstetrician and gynecologist at NYC Health and Hospitals.
On social media, Irobunda often fields questions about one of these new options, a lubricating gel called Phexxi. San Diego-based Evofem, the company behind Phexxi, has been advertising the product on Hulu and Instagram after the gel was approved by the Food and Drug Administration in May 2020. The company's trendy ads target women who feel like condoms diminish the mood, but who also don't want to mess with an IUD or hormones.
Here's how it works: Phexxi is inserted via a tampon-like device up to an hour before sex. The gel regulates vaginal pH — essentially, the acidity levels — in a range that's inhospitable to sperm. It sounds a lot like spermicide, which is also placed in the vagina prior to sex to prevent pregnancy. But spermicide can damage the vagina's cell walls, which can increase the risk of contracting sexually transmitted diseases.
"Not only is innovation needed, but women want a non-hormonal option."
Phexxi isn't without side effects either. The most common one is vaginal burning, according to a late-stage trial. It's also possible to develop a urinary tract infection while using the product. That same study found that during typical use, Phexxi is about 86 percent effective at preventing pregnancy. The efficacy rate is comparable to condoms but lower than birth control pills (91 percent) and significantly lower than an IUD (99 percent).
Phexxi – which comes in a pack of 12 – represents a tiny but growing part of the birth control market. Pharmacies dispensed more than 14,800 packs from April through June this year, a 65 percent increase over the previous quarter, according to data from Evofem.
"We've been able to demonstrate that not only is innovation needed, but women want a non-hormonal option," says Saundra Pelletier, Evofem's CEO.
Beyond contraception, the company is carrying out late-stage tests to gauge Phexxi's effectiveness at preventing the sexually transmitted infections chlamydia and gonorrhea.
Phexxi is inserted via a tampon-like device up to an hour before sex.
Phexxi
A New Pill
The first birth control pill arrived in 1960, combining the hormones estrogen and progestin to stop sperm from joining with an egg, giving women control over their fertility. Subsequent formulations sought to ease side effects, by way of lower amounts of estrogen. But some women still experience headaches and nausea – or more serious complications like blood clots. On social media, women recently noted that birth control pills are much more likely to cause blood clots than Johnson & Johnson's COVID-19 vaccine that was briefly paused to evaluate the risk of clots in women under age 50. What will it take, they wondered, for safer birth control?
Mithra Pharmaceuticals of Belgium sought to create a gentler pill. In April, the FDA approved Mithra's Nextstellis, which includes a naturally occurring estrogen, the first new estrogen in the U.S. in 50 years. Nextstellis selectively acts on tissues lining the uterus, while other birth control pills have a broader target.
A Phase 3 trial showed a 98 percent efficacy rate. Andrew London, an obstetrician and gynecologist, who practices at several Maryland hospitals, says the results are in line with some other birth control pills. But, he added, early studies indicate that Nextstellis has a lower risk of blood clotting, along with other potential benefits, which additional clinical testing must confirm.
"It's not going to be worse than any other pill. We're hoping it's going to be significantly better," says London.
The estrogen in Nexstellis, called estetrol, was skipped over by the pharmaceutical industry after its discovery in the 1960s. Estetrol circulates between the mother and fetus during pregnancy. Decades later, researchers took a new look, after figuring out how to synthesize estetrol in a lab, as well as produce estetrol from plants.
"That allowed us to really start to investigate the properties and do all this stuff you have to do for any new drug," says Michele Gordon, vice president of marketing in women's health at Mayne Pharma, which licensed Nextstellis.
Bonnie Douglas, who followed the development of Nextstellis as part of a search for better birth control, recently switched to the product. "So far, it's much more tolerable," says Douglas. Previously, the Midwesterner was so desperate to find a contraceptive with fewer side effects that she turned to an online pharmacy to obtain a different birth control pill that had been approved in Canada but not in the U.S.
Contraceptive Access
Even if a contraceptive lands FDA approval, access poses a barrier. Getting insurers to cover new contraceptives can be difficult. For the uninsured, state and federal programs can help, and companies should keep prices in a reasonable range, while offering assistance programs. So says Kelly Blanchard, president of the nonprofit Ibis Reproductive Health. "For innovation to have impact, you want to reach as many folks as possible," she says.
In addition, companies developing new contraceptives have struggled to attract venture capital. That's changing, though.
In 2015, Sabrina Johnson founded DARÉ Bioscience around the idea of women's health. She estimated the company would be fully funded in six months, based on her track record in biotech and the demand for novel products.
But it's been difficult to get male investors interested in backing new contraceptives. It took Johnson two and a half years to raise the needed funds, via a reverse merger that took the company public. "There was so much education that was necessary," Johnson says, adding: "The landscape has changed considerably."
Johnson says she would like to think DARÉ had something to do with the shift, along with companies like Organon, a spinout of pharma company Merck that's focused on reproductive health. In surveying the fertility landscape, DARÉ saw limited non-hormonal options. On-demand options – like condoms – can detract from the moment. Copper IUDs must be inserted by a doctor and removed if a woman wants to return to fertility, and this method can have onerous side effects.
So, DARÉ created Ovaprene, a hormone-free device that's designed to be inserted into the vagina monthly by the user. The mesh product acts as a barrier, while releasing a chemical that immobilizes sperm. In an early study, the company reported that Ovaprene prevented almost all sperm from entering the cervical canal. The results, DARÉ believes, indicate high efficacy.
A late-stage study, slated to kick off next year, will be the true judge. Should Ovaprene eventually win regulatory approval, drug giant Bayer will handle commercializing the device.
Other new forms of birth control in development are further out, and that's assuming they perform well in clinical trials. Among them: a once-a-month birth control pill, along with a male version of the birth control pill. The latter is often brought up among women who say it's high time that men take a more proactive role in birth control.
For Summers, her search for a safe and convenient birth control continues. She tried Phexxi, which caused irritation. Still, she's excited that a non-hormonal option now exists. "I'm sure it will work for others," she says.
Sammy Basso is one of around 400 young people in the world with progeria.
Just 400 or so people in the world live with progeria: The mutation that causes it usually arises de novo, or "of new," meaning that it is not inherited but happens spontaneously during gestation. The challenge, as with all rare diseases, is that few cases means few treatments.
"When we first started, there was absolutely nothing out there," says Leslie Gordon, a physician-researcher who co-founded the Progeria Research Foundation in 1999 after her own son, also named Sam, was diagnosed with the disease. "We knew we had to jumpstart the entire field, so we collected money through road races and special events and writing grants and all sorts of donors… I think the first year we raised $75,000, most of it from one donor."
"We have not only the possibility but the responsibility to make the world a better world, and also to make a body a better body."
By 2003, the foundation had collaborated with Francis Collins, a geneticist who is now director of the National Institutes of Health, to work out the genetic basis for progeria—that single mutation Sammy has. The discovery led to interest in lonafarnib, a drug that was already being used in cancer patients but could potentially operate downstream of the mutation, preventing the buildup of the defective progerin in the body. "We funded cellular studies to look at a lonafarnib in cells, mouse studies to look at lonafarnib in mouse models of progeria… and then we initiated the clinical trials," Gordon says.
Sammy Basso's family had gotten involved with the Progeria Research Foundation through their international patient registry, which maintains relationships with families in 49 countries. "We started to hear about lonafarnib in 2006 from Leslie Gordon," says Sammy's father, Amerigo Basso, with his son translating. "She told us about the lonafarnib. And we were very happy because for the first time we understood that there was something that could help our son and our lives." Amerigo used the Italian word speranza, which means hope.
Still, Sammy wasn't sure if lonafarnib was right for him. "Since when I was very young I thought that everything happens for a reason. So, in my mind, if God made me with progeria, there was a reason, and to try to heal from progeria was something wrong," he says. Gradually, his parents and doctors, and Leslie Gordon, convinced him otherwise. Sammy began to believe that God was also the force behind doctors, science, and research. "And so we have not only the possibility but the responsibility to make the world a better world, and also to make a body a better body," he says.
Sammy Basso and his parents.
Courtesy of Basso
Sammy began taking lonafarnib, with the Progeria Research Foundation intermittently flying him, and other international trial participants, to Boston for tests. He was immediately beset by some of the drug's more unpleasant side effects: Stomach problems, nausea, and vomiting. "The first period was absolutely the worst period of my life," he says.
At first, doctors prescribed other medicines for the side effects, but to Sammy it had as much effect as drinking water. He visited doctor after doctor, with some calling him weekly or even daily to ask how he was doing. Eventually the specialists decided that he should lower his dose, balancing his pain with the benefit of the drug. Sammy can't actually feel any positive effect of the lonafarnib, but his health measurements have improved relative to people with progeria who don't take it.
While they never completely disappeared, Sammy's side effects decreased to the point that he could live. Inspired by the research that led to lonafarnib, he went to university to study molecular biology. For his thesis work, he travelled to Spain to perform experiments on cells and on mice with progeria, learning how to use the gene-editing technique CRISPR-Cas9 to cut out the mutated bit of DNA. "I was so excited to participate in this study," Sammy says. He felt like his work could make a difference.
In 2018, the Progeria Research Foundation was hosting one of their biennial workshops when Francis Collins, the researcher who had located the mutation behind progeria 15 years earlier, got in touch with Leslie Gordon. "Francis called me and said, Hey, I just saw a talk by David Liu from the Broad [Institute]. And it was pretty amazing. He has been looking at progeria and has very early, but very exciting data… Do you have any spaces, any slots you could make in your program for late breaking news?"
Gordon found a spot, and David Liu came to talk about what was going on in his lab, which was an even more advanced treatment that led to mice with the progeria mutation living into their senior mouse years—substantially closer to a normal lifespan. Liu's lab had built on the idea of CRISPR-Cas9 to create a more elegant genetic process called base editing: Instead of chopping out mutated DNA, a scientist could chemically convert an incorrect DNA letter to the correct one, like the search and replace function in word processing software. Mice who had their Lamin-A mutations corrected this way lived more than twice as long as untreated animals.
Sammy was in the audience at Dr. Liu's talk. "When I heard about this base editing as a younger scientist, I thought that I was living in the future," he says. "When my parents had my diagnosis of progeria, the science knew very little information about DNA. And now we are talking about healing the DNA… It is incredible."
Lonafarnib (also called Zokinvy) was approved by the US Food and Drug Administration this past November. Sammy, now 25, still takes it, and still manages his side effects. With luck, the gift of a few extra years will act as a bridge until he can try Liu's revolutionary new gene treatment, which has not yet begun testing in humans. While Leslie Gordon warns that she's always wrong about things like this, she hopes to see the new base editing techniques in clinical trials in the next year or two. Sammy won't need to be convinced to try it this time; his thinking on fate has evolved since his first encounter with lonafarnib.
"I would be very happy to try it," he says. "I know that for a non-scientist it can be difficult to understand. Some people think that we are the DNA. We are not. The DNA is a part of us, and to correct it is to do what we are already doing—just better." In short, a gene therapy, while it may seem like science fiction, is no different from a pill. For Sammy, both are a new way to think about fate: No longer something that simply happens to him.
There is a lot to be optimistic about regarding the new safe and highly effective vaccines, which are moving society closer toward the goal of close human contact once again.
To be clear, these vaccine candidates for COVID-19, both authorized and not yet authorized, are highly effective and safe. In fact, across all trials and sites, all six vaccines were 100% effective in preventing hospitalizations and death from COVID-19.
All Vaccines' Phase 3 Clinical Data
Complete protection against hospitalization and death from COVID-19 exhibited by all vaccines with phase 3 clinical trial data.
This astounding level of protection from SARS-CoV-2 from all vaccine candidates across multiple regions is likely due to robust T cell response from vaccination and will "defang" the virus from the concerns that led to COVID-19 restrictions initially: the ability of the virus to cause severe illness. This is a time of hope and optimism. After the devastating third surge of COVID-19 infections and deaths over the winter, we finally have an opportunity to stem the crisis – if only people readily accept the vaccines.
Amidst these incredible scientific advancements, however, public health officials and politicians have been pushing downright discouraging messaging. The ubiquitous talk of ongoing masks and distancing restrictions without any clear end in sight threatens to dampen uptake of the vaccines. It's imperative that we break down each concern and see if we can revitalize our public health messaging accordingly.
The first concern: we currently do not know if the vaccines block asymptomatic infection as well as symptomatic disease, since none of the phase 3 vaccine trials were set up to answer this question. However, there is biological plausibility that the antibodies and T-cell responses blocking symptomatic disease will also block asymptomatic infection in the nasal passages. IgG immunoglobulins (generated and measured by the vaccine trials) enter the nasal mucosa and systemic vaccinations generate IgA antibodies at mucosal surfaces. Monoclonal antibodies given to outpatients with COVID-19 hasten viral clearance from the airways.
Although it is prudent for those who are vaccinated to wear masks around the unvaccinated in case a slight risk of transmission remains, two fully vaccinated people can comfortably abandon masking around each other.
Moreover, data from the AztraZeneca trial (including in the phase 3 trial final results manuscript), where weekly self-swabbing was done by participants, and data from the Moderna trial, where a nasal swab was performed prior to the second dose, both showed risk reductions in asymptomatic infection with even a single dose. Finally, real-world data from a large Pfizer-based vaccine campaign in Israel shows a 50% reduction in infections (asymptomatic or symptomatic) after just the first dose.
Therefore, the likelihood of these vaccines blocking asymptomatic carriage, as well as symptomatic disease, is high. Although it is prudent for those who are vaccinated to wear masks around the unvaccinated in case a slight risk of transmission remains, two fully vaccinated people can comfortably abandon masking around each other. Moreover, as the percentage of vaccinated people increases, it will be increasingly untenable to impose restrictions on this group. Once herd immunity is reached, these restrictions can and should be abandoned altogether.
The second concern translating to "doom and gloom" messaging lately is around the identification of troubling new variants due to enhanced surveillance via viral sequencing. Four major variants circulating at this point (with others described in the past) are the B.1.1.7 variant ("UK variant"), B.1.351 ("South Africa variant), P.1. ("Brazil variant"), and the L452R variant identified in California. Although the UK variant is likely to be more transmissible, as is the South Africa variant, we have no reason to believe that masks, distancing and ventilation are ineffective against these variants.
Moreover, neutralizing antibody titers with the Pfizer and Moderna vaccines do not seem to be significantly reduced against the variants. Finally, although the Novavax 2-dose and Johnson and Johnson (J&J) 1-dose vaccines had lower rates of efficacy against moderate COVID-19 disease in South Africa, their efficacy against severe disease was impressively high. In fact J&J's vaccine still prevented 100% of hospitalizations and death from COVID-19. When combining both hospitalizations/deaths and severe symptoms managed at home, the J&J 1-dose vaccine was 85% protective across all three sites of the trial: the U.S., Latin America (including Brazil), and South Africa.
In South Africa, nearly all cases of COVID-19 (95%) were due to infection with the B.1.351 SARS-CoV-2 variant. Finally, since herd immunity does not rely on maximal immune responses among all individuals in a society, the Moderna/Pfizer/J&J vaccines are all likely to achieve that goal against variants. And thankfully, all of these vaccines can be easily modified to boost specifically against a new variant if needed (indeed, Moderna and Pfizer are already working on boosters against the prominent variants).
The third concern of some public health officials is that people will abandon all restrictions once vaccinated unless overly cautious messages are drilled into them. Indeed, the false idea that if you "give people an inch, they will take a mile" has been misinforming our messaging about mitigation since the beginning of the pandemic. For example, the very phrase "stay at home" with all of its non-applicability for essential workers and single individuals is stigmatizing and unrealistic for many. Instead, the message should have focused on how people can additively reduce their risks under different circumstances.
The public will be more inclined to trust health officials if those officials communicate with nuanced messages backed up by evidence, rather than with broad brushstrokes that shame. Therefore, we should be saying that "vaccinated people can be together with other vaccinated individuals without restrictions but must protect the unvaccinated with masks and distancing." And we can say "unvaccinated individuals should adhere to all current restrictions until vaccinated" without fear of misunderstandings. Indeed, this kind of layered advice has been communicated to people living with HIV and those without HIV for a long time (if you have HIV but partner does not, take these precautions; if both have HIV, you can do this, etc.).
Our heady progress in vaccine development, along with the incredible efficacy results of all of them, is unprecedented. However, we are at risk of undermining such progress if people balk at the vaccine because they don't believe it will make enough of a difference. One of the most critical messages we can deliver right now is that these vaccines will eventually free us from the restrictions of this pandemic. Let's use tiered messaging and clear communication to boost vaccine optimism and uptake, and get us to the goal of close human contact once again.