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.
Conner Curran, now 10 years old, can walk more than two miles after gene therapy treatment for his Duchenne's muscular dystrophy.
That the medical world is on the cusp of a successful treatment for a crippling and deadly disease is the culmination of more than 35 years of work by Dr. Jude Samulski, a professor of pharmacology at the University of North Carolina School of Medicine in Chapel Hill. More recently, he's become a leading gene therapy entrepreneur.
But Samulski likens this breakthrough to the frustrations of solving a Rubik's cube. "Just because one side is now all the color yellow does not mean that it is completely aligned," he says.
Although Conner's life and future have dramatically improved, he's not cured. The gene therapy tamed but did not extinguish his disorder: Conner is now suffering from the equivalent of Becker's muscular dystrophy, a milder form of the disease with symptoms that appear later in life and progress more slowly. Moreover, the loss of muscle cells Conner suffered prior to the treatment is permanent.
"It will take more time and more innovations," Samulski says of finding an even more effective gene therapy for muscular dystrophy.
Conner's family is still overjoyed with the results. "Jude's grit and determination gave Conner a chance at a new life, one that was not in his cards before gene therapy," says his mother Jessica Curran. She adds that "Conner is more confident than before and enjoys life, even though he has limitations, if compared to his brothers or peers."
Conner Curran holding a football post gene therapy treatment.
Courtesy of the Curran family
For now, the use of gene therapy as a treatment for diseases and disorders remains relatively isolated. On paper at least, progress appears glacially slow. In 2018, there were four FDA-approved gene therapies (excluding those reliant on bone marrow/stem cell transplants or implants). Today, there are 10. One therapy is solely for the cosmetic purpose of reducing facial lines and folds.
Nevertheless, experts in the space believe gene therapy is poised to expand dramatically.
"Certainly in the next three to five years you will see dozens of gene therapies and cell therapies be approved," says Dr. Pavan Cheruvu, who is CEO of Sio Gene Therapies in New York. The company is developing treatments for Parkinson's disease and Tay-Sachs, among other diseases.
Cheruvu's conclusion is supported by NEWDIGS, a think tank at the Massachusetts Institute of Technology that keeps tabs on gene therapy developments. NEWDIGS predicts there will be at least 60 gene therapies approved for use in the U.S. by the end of the decade. That number could be closer to 100 if Chinese researchers and biotech ventures decide the American market is a good fit for the therapies they develop.
"We are watching something of a conditional evolution, like a dot-com, or cellphones that were sizes of shoeboxes that have now matured to the size of wafers. Our space will follow along very similarly."
Dr. Carsten Brunn, a chemist by training and CEO of Selecta Biosciences outside of Boston, is developing ways to reduce the immune responses in patients who receive gene therapy. He observes that there are more than 300 therapies in development and thousands of clinical trials underway. "It's definitely an exciting time in the field," he says.
That's a far cry from the environment of little more than a decade ago. Research and investment in gene therapy had been brought low for years after the death of teenager Jesse Gelsinger in 1999 while he had been enrolled in a clinical trial to treat a liver disease. Gene therapy was a completely novel concept back then, and his death created existential questions about whether it was a proper pathway to pursue. Cheruvu, a cardiologist, calls the years after Gelsinger's death an "ice age" for gene therapy.
However, those dark years eventually yielded to a thaw. And while there have been some recent stumbles, they are considered part of the trial-and-error that has often accompanied medical research as opposed to an ominous "stop" sign.
The deaths of three patients last year receiving gene therapy for myotubular myopathy – a degenerative disease that causes severe muscle weakness – promptly ended the clinical trial in which they were enrolled. However, the incident caused few ripples beyond that. Researchers linked the deaths to dosage sizes that caused liver toxicity, as opposed to the gene therapy itself being an automatic death sentence; younger patients who received lower doses due to a less advanced disease state experienced improvements.
The gene sequencing and editing that helped create vaccines for COVID-19 in record time also bolstered the argument for more investment in research and development. Cheruvu notes that the field has usually been the domain of investors with significant expertise in the field; these days, more money is flowing in from generalists.
The Challenges Ahead
What will be the next step in gene therapy's evolution? Many of Samulski's earliest innovations came in the laboratory, for example. Then that led to him forming a company called AskBio in collaboration with the Muscular Dystrophy Association. AskBio sold its gene therapy to Pfizer five years ago to assure that enough could be manufactured for stage 3 clinical trials and eventually reach the market.
Cheruvu suggests that many future gene therapy innovations will be the result of what he calls "congruent innovation." That means publicly funded laboratories and privately funded companies might develop treatments separately or in collaboration. Or, university scientists may depend on private ventures to solve one of gene therapy's most vexing issues: producing enough finished material to test and treat on a large scale. "Manufacturing is a real bottleneck right now," Brunn says.
The alternative is referred to in the sector as the "valley of death": a lab has found a promising treatment, but is not far enough along in development to submit an investigational new drug application with the FDA. The promise withers away as a result. But the new abundance of venture capital for gene therapy has made this scenario less of an issue for private firms, some of which have received hundreds of millions of dollars in funding.
There are also numerous clinical challenges. Many gene therapies use what are known as adeno-associated virus vectors (AAVs) to deliver treatments. They are hollowed-out husks of viruses that can cause a variety of mostly mild maladies ranging from colds to pink eye. They are modified to deliver the genetic material used in the therapy. Most of these vectors trigger an antibody reaction that limits treatments to a single does or a handful of smaller ones. That can limit the potential progress for patients – an issue referred to as treatment "durability."
Although vectors from animals such as horses trigger far less of an antibody reaction in patients -- and there has been significant work done on using artificial vectors -- both are likely years away from being used on a large scale. "For the foreseeable future, AAV is the delivery system of choice," Brunn says.
Also, there will likely be demand for concurrent gene therapies that can lead to a complete cure – not only halting the progress of Duchenne's in kids like Conner Curran, but regenerating their lost muscle cells, perhaps through some form of stem cell therapy or another treatment that has yet to be devised.
Nevertheless, Samulski believes demand for imperfect treatments will be high – particularly with a disease such as muscular dystrophy, where many patients are mere months from spending the remainder of their lives in wheelchairs. But Samulski believes those therapies will also inevitably evolve into something far more effective.
"We are watching something of a conditional evolution, like a dot-com, or cellphones that were sizes of shoeboxes that have now matured to the size of wafers," he says. "Our space will follow along very similarly."
Jessica Curran will remain forever grateful for what her son has received: "Jude gave us new hope. He gave us something that is priceless – a chance to watch Conner grow up and live out his own dreams."
