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.
Tom Patterson holding an image of Acinetobacter baumannii and Steffanie Strathdee holding an image of a bacteriophage.
An attacking rogue hippo, giant jumping spiders, even a coup in Timbuktu couldn't knock out Tom Patterson, but now he was losing the fight against a microscopic bacteria.
Death seemed inevitable, perhaps hours away, despite heroic efforts to keep him alive.
It was the deadly drug-resistant superbug Acinetobacter baumannii. The infection struck during a holiday trip with his wife to the pyramids in Egypt and had sent his body into toxic shock. His health was deteriorating so rapidly that his insurance company paid to medevac him first to Germany, then home to San Diego.
Weeks passed as he lay in a coma, shedding more than a hundred pounds. Several major organs were on the precipice of collapse, and death seemed inevitable, perhaps hours away despite heroic efforts by a major research university hospital to keep Tom alive.
Tom Patterson in a deep coma on March 14, 2016, the day before phage therapy was initiated.
(Courtesy Steffanie Strathdee)
Then doctors tried something boldly experimental -- injecting him with a cocktail of bacteriophages, tiny viruses that might infect and kill the bacteria ravaging his body.
It worked. Days later Tom's eyes fluttered open for a few brief seconds, signaling that the corner had been turned. Recovery would take more weeks in the hospital and about a year of rehabilitation before life began to resemble anything near normal.
In her new book The Perfect Predator, Tom's wife, Steffanie Strathdee, recounts the personal and scientific ordeal from twin perspectives as not only his spouse but also as a research epidemiologist who has traveled the world to track down diseases.
Part of the reason why Steff wrote the book is that both she and Tom suffered severe PTSD after his illness. She says they also felt it was "part of our mission, to ensure that phage therapy wasn't going to be forgotten for another hundred years."
Tom Patterson and Steffanie Strathdee taking a first breath of fresh air during recovery outside the UCSD hospital.
(Courtesy Steffanie Strathdee)
From Prehistoric Arms Race to Medical Marvel
Bacteriophages, or phages for short, evolved as part of the natural ecosystem. They are viruses that infect bacteria, hijacking their host's cellular mechanisms to reproduce themselves, and in the process destroying the bacteria. The entire cycle plays out in about 20-60 minutes, explains Ben Chan, a phage research scientist at Yale University.
They were first used to treat bacterial infections a century ago. But the development of antibiotics soon eclipsed their use as medicine and a combination of scientific, economic, and political factors relegated them to a dusty corner of science. The emergence of multidrug-resistant bacteria has highlighted the limitations of antibiotics and prompted a search for new approaches, including a revived interest in phages.
Most phages are very picky, seeking out not just a specific type of bacteria, but often a specific strain within a family of bacteria. They also prefer to infect healthy replicating bacteria, not those that are at rest. That's what makes them so intriguing to tap as potential therapy.
Tom's case was one of the first times that phages were successfully infused into the bloodstream of a human.
Phages and bacteria evolved measures and countermeasures to each other in an "arms race" that began near the dawn of life on the planet. It is not that one consciously tries to thwart the other, says Chan, it's that countless variations of each exists in the world and when a phage gains the upper hand and kills off susceptible bacteria, it opens up a space in the ecosystem for similar bacteria that are not vulnerable to the phage to increase in numbers. Then a new phage variant comes along and the cycle repeats.
Robert "Chip" Schooley is head of infectious diseases at the University of California San Diego (UCSD) School of Medicine and a leading expert on treating HIV. He had no background with phages but when Steff, a friend and colleague, approached him in desperation about using them with Tom, he sprang into action to learn all he could, and to create a network of experts who might provide phages capable of killing Acinetobacter.
"There is very little evidence that phage[s] are dangerous," Chip concluded after first reviewing the literature and now after a few years of experience using them. He compares broad-spectrum antibiotics to using a bazooka, where every time you use them, less and less of the "good" bacteria in the body are left. "With a phage cocktail what you're really doing is more of a laser."
Collaborating labs were able to identify two sets of phage cocktails that were sensitive to Tom's particular bacterial infection. And the FDA acted with lightning speed to authorize the experimental treatment.
A bag of a four-phage "cocktail" before being infused into Tom Patterson.
(Courtesy Steffanie Strathdee)
Tom's case was scientifically important because it was one of the first times that phages were successfully infused into the bloodstream of a human. Most prior use of phages involved swallowing them or placing them directly on the area of infection.
The success has since sparked a renewed interest in phages and a reexamination of their possible role in medicine.
Over the two years since Tom awoke from his coma, several other people around the world have been successfully treated with phages as part of their regimen, after antibiotics have failed.
The Future of Phage Therapy
The experience treating Tom prompted UCSD to create the Center for Innovative Phage Applications and Therapeutics (IPATH), with Chip and Steff as co-directors. Previous labs have engaged in basic research on phages, but this is the first clinical center in North America to focus on translating that knowledge into treating patients.
In January, IPATH announced the first phase 2 clinical trial approved by the FDA that will use phages intravenously. The viruses are being developed by AmpliPhi Biosciences, a San Diego-based company that supplied one of the phages used to treat Tom. The new study takes on drug resistant Staph aureus bacteria. Experimental phage therapy treatment using the company's product candidates was recently completed in 21 patients at seven hospitals who had been suffering from serious infections that did not respond to antibiotics. The reported success rate was 84 percent.
The new era of phage research is applying cutting-edge biologic and informatics tools to better understand and reshape the viruses to better attack bacteria, evade resistance, and perhaps broaden their reach a bit within a bacterial family.
Genetic engineering tools are being used to enhance the phages' ability to infect targeted bacteria.
"As we learn more and more about which biological activities are critical and in which clinical settings, there are going to be ways to optimize these activities," says Chip. Sometimes phages may be used alone, other times in combination with antibiotics.
Genetic engineering using tools are being used to enhance the phages' ability to infect targeted bacteria and better counter evolving forms of bacterial resistance in the ongoing "arms race" between the two. It isn't just theory. A patient recently was successfully treated with a genetically modified phage as part of the regimen, and the paper is in press.
In reality, given the trillions of phages in the world and the endless encounters they have had with bacteria over the millennia, it is likely that the exact phages needed to kill off certain bacteria already exist in nature. Using CRISPR to modify a phage is simply a quick way to identify the right phage useful for a given patient and produce it in the necessary quantities, rather than go search for the proverbial phage needle in a sewage haystack, says Chan.
One non-medical reason why using modified phages could be significant is that it creates an intellectual property stake, something that is patentable with a period of exclusive use. Major pharmaceutical companies and venture capitalists have been hesitant to invest in organisms found in nature; but a patentable modification may be enough to draw their interest to phage development and provide the funding for large-scale clinical trials necessary for FDA approval and broader use.
"There are 10 million trillion trillion phages on the planet, 10 to the power of 31. And the fact is that this ongoing evolutionary arms race between bacteria and phage, they've been at it for a millennia," says Steff. "We just need to exploit it."
