Nestorone Acetate

A reversible male contraceptive could be a lot closer to reality than you think. Earlier this summer, doctors were tantalized by preliminary data showing that an experimental drug safely reduced sperm count. But several questions remained unanswered, including how effective the drug was at preventing pregnancies and how it would be commercialized. Now, a small biotech startup that wasn’t involved in the NIH-funded study is providing some answers. Charlottesville, VA-based Contraline won the exclusive rights to finish developing and commercializing the new hormone-based drug, the company exclusively told Endpoints News . The data from the Phase 2 study are still being analyzed and are set to be written up for publication later this year. But CEO Kevin Eisenfrats said in an interview that so far the drug looks more than 99% efficacious at preventing pregnancies. If that number holds, it would rank the drug among the most effective birth control options . IUDs and vasectomies are also more than 99% effective, while female birth control pills are about 93% effective and condoms are only 87% effective. “When I saw the interim data, I was so blown away. I thought, ‘We need to own this product,’” Eisenfrats said. “This is something I want to take. This is something my friends are going to take. This is something that’s going to change the world.” But the effectiveness of the drug will depend on people using it properly. The drug, called NES/T, is made of two hormones — nestorone and testosterone — formulated in a gel that’s rubbed on the shoulders daily. It takes an average of 8 weeks to start working, though it can take longer for some people. Diana Blithe, who helms contraceptive research at the National Institutes of Health, led the Phase 2 trial and presented the sperm count data at the Endocrine Society’s annual meeting in June. She told Endpoints in an email that the study was still ongoing and could not confirm the drug’s 99% efficacy. The study was scheduled to wrap up in July, and Eisenfrats said the efficacy phase of the trial is complete. He plans to start a Phase 3 study of about 400 couples next summer, and if all goes well, submit the drug for approval in 2028. It could become the first pharmaceutical birth control option for men, providing a long-overdue alternative to condoms and vasectomies. NES/T was developed by the Population Council, a nonprofit behind the early development of several birth control products, including the copper IUD and the abortion pill mifepristone . The NIH funded the recent clinical trial of NES/T and might help with the Phase 3 as well, according to Eisenfrats. But neither group takes drugs all the way to the market. Earlier this year, the Population Council began looking for a drug company to carry the torch. At first glance, Contraline might not seem an obvious choice. The 18-person startup has never taken a drug into advanced clinical studies and will need to raise significant funding in order to do so. Eisenfrats estimates that the Phase 3 trial will cost about $50 million, and he’s looking to raise at least $65 million in Series B funding for studies of NES/T and an injectable male contraceptive that Contraline is also developing. Despite that, the startup beat bigger and more experienced companies for the rights to a global exclusive license to NES/T, according to Eisenfrats. James Sailer, co-president of the Population Council and head of its biomedical research center, told Endpoints that the nonprofit is confident that Contraline will be able to raise the needed funds. He was more worried about the drug getting lost during a pipeline reprioritization at a bigger company or after an acquisition of a medium-sized company. “We’ve seen this many times,” Sailer said. There’s a lingering stereotype that men aren’t interested in new contraceptives, but Sailer said that data over the past 20 years have repeatedly, and increasingly, shown this isn’t true. “There are still people who don’t believe it,” he said. “But Contraline does believe it. They have looked carefully at the data and Kevin — he’s a true believer.” Eisenfrats has been obsessed with the idea of male contraception his entire adult life and pointed to the MTV show “16 and Pregnant” as a source of inspiration in his college admissions essay. “There were so many unintended pregnancies, and it just felt like the answer to that was better male methods,” Eisenfrats said. In 2015, just as he was wrapping up his bachelor’s degree in nanomedicine engineering and chemistry at UVA, he co-founded Contraline. In the nine years since Eisenfrats has been working on a hydrogel that’s injected into the vas deferens to block the ducts and prevent sperm from being transported out of the testes. Unlike vasectomies, which cut and tie these tubes, Contraline’s approach, dubbed ADAM, is designed to be easily reversible with a second injection that dissolves the hydrogel. The method, which Eisenfrats calls “the IUD for men,” is currently being tested in a 60-person safety study in Australia, with a Phase 2 trial planned for next year. Until Eisenfrats saw the NES/T data this summer, he never imagined that Contraline would also develop a hormonal contraceptive for men. The hormonal approach got a bad rap in 2016. In a study run by the World Health Organization, scientists injected progestins, synthetic versions of hormones that suppress sperm production, and testosterone in men every 8 weeks. Although the drug showed signs of working, the study was cut short due to frequent side effects, including acne and mood disorders. NES/T aims to overcome those problems by using a safer sperm-reducing progestin called nestorone — previously developed by the Population Council as a female contraceptive for the vaginal birth control ring Annovera — and striking a better balance of that molecule and testosterone, which is needed to maintain baseline levels of the hormone. “I always thought the side effects would make this a non-tolerable, non-useable product,” Eisenfrats said. But in the Phase 2 study, the most common side effects were mild acne and increased libido, he added. The drug might not have to completely stop sperm production to be effective. Having fewer than 15 million sperm per milliliter of semen is considered low. In the Phase 2 trial, having 1 million sperm per milliliter was the threshold for contraception. Half the men in the study, which enrolled 460 couples, hit this benchmark after 8 weeks, and 86% reached it after 15 weeks. Once sperm levels were low enough, the couples stopped using other forms of birth control for a year. The efficacy results have yet to be formally reported, but according to Eisenfrats, “it was better than 99% efficacy, which is virtually unheard of.” That efficacy figure also appears in the company’s investor presentation, which was shared with Endpoints, but it is unclear if the number includes the 14% of participants who hadn’t had their sperm suppressed by 15 weeks. The slide deck also mentions that “100% of patients recovered sperm counts and hormone levels” during a 24-week recovery period at the end of the study, but again it’s unclear if this number discludes some trial participants. Eisenfrats was reluctant to disclose details about the design of the Phase 3 trial because the NIH is still waiting on guidance from regulators. But he hopes that the study will be “similar and confirmatory” to the Phase 2 design since the two hormones in NES/T are already approved drugs on their own. Finding volunteers for the study shouldn’t be a problem. Contraline has a database of nearly 10,000 men, mostly aged 20 to 40, who are on a waitlist to be part of the company’s clinical trials. “We get emails every week from random guys,” Eisenfrats said. “We have done zero advertising of that.” Now the company must find funding to put NES/T through its final test. Contraline disclosed a $10.7 million Series A financing in 2021, but Eisenfrats said he’s raised about $30 million total since the company’s inception, including from investors at the Founders Fund, GV and MBX Capital. Eisenfrats is courting biotech-focused venture capital firms for the first time, pitching peak sales of NES/T between $1 billion and $2 billion in the US, assuming prescriptions cost $50 to $65 a month and are sold through telehealth companies like Hims or Ro. Sailer said that Contraline’s license to NES/T is contingent on the startup’s ability to raise money. If the startup fails, the Population Council will get the drug back. But if the Contraline and the drug are successful, the nonprofit will get royalties on future sales, and the NIH will get a cut, too. Eisenfrats and Sailer both declined to disclose further financial details. “They believe that the market is there, and they are very, very determined to be successful,” Sailer said. “And they understand that it’s going to take some trailblazing.” Editor’s note: This story was corrected. It previously misidentified the headquarters of Contraline.