EXECUTIVE SUMMARY
Use of implants and intrauterine devices increased among U.S. contracepting women from 8.5% in 2009 to 11.6% in 2012. With the growth in interest in long-acting reversible contraceptive methods, options are under development.
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Researchers are looking at the VeraCept copper intrauterine device, which has a smaller insertion profile, a smaller and more flexible frame, and a lower copper dosage than the current option.
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Science also is eyeing longer-acting injectable products to fill in the gap between the three-month injection and the three-year implant or intrauterine device.
With the growth in interest in long-acting reversible contraceptive (LARC) methods, what new options may be available to U.S. women?
There are encouraging developments on the forefront, says Anita Nelson, MD, professor emeritus in the Obstetrics and Gynecology Department at the David Geffen School of Medicine at the University of California in Los Angeles. Use of implants and intrauterine devices (IUDs) increased among contracepting women from 8.5% in 2009 to 11.6% in 2012.1 (Contraceptive Technology Update reported on the research. See the article “More women reported to be moving to long-acting reversible contraceptives” in the January 2016 issue, which can be accessed at http://bit.ly/1RPnIeh.)
“Unintended pregnancy rates dropped from 51% in 2008 to 45% in 2011,”2 notes Nelson, who presented on the subject of contraceptive development at the 2016 Contraceptive Technology conferences in San Francisco and Boston. “Providers hope that newer options may provide women the tools they need for contraceptive success.” (Get a complete overview of the latest information from the reproductive health field. Read CTU’s coverage of the 2016 Contraceptive Technology conference in the upcoming July 2016 issue.)
The VeraCept copper IUD (ContraMed of Campbell, CA) is undergoing Phase II testing in the United States, says Nelson. The most notable differences in the investigative device lie in its smaller insertion profile, its smaller and more flexible frame, and its lower copper dosage (175 mm2 of copper.) The copper is concentrated near the tubal ostia and internal cervical os. In a small comparative trial with the copper T380s IUD (ParaGard, Teva Women’s Health, North Wales, PA), use of the VeraCept resulted in less pain at insertion, fewer expulsions, and higher total continuation than the T380S, with equal contraceptive efficacy to date.3
More than 250 women have been enrolled at 12 centers across the United States in the Phase II study, which is designed to evaluate the safety and effectiveness of the device in a population of parous and nulliparous women seeking long-acting reversible contraception.
What about injections?
Science also is eyeing long-acting injectable contraceptives, notes Nelson. There is a need for products to fill in the gap between the three-month injection and the three-year implant or IUD, she states.
Injectable contraception has been a cornerstone of international family planning programs for decades, states Vera Halpern, MD, scientist at FHI 360 in Durham, NC. More than 40 million women worldwide use injectable contraceptives to prevent pregnancy. Depo-Provera CI (150 mg/mL, Pfizer, New York City), also known as depot medroxyprogesterone acetate (DMPA), provides contraceptive protection for three months if injected intramuscularly and is the most popular injectable contraceptive worldwide, Halpern states.
“Despite broad and increasing use, DMPA carries a heavy burden of side effects including bleeding disturbances, weight gain, metabolic effects, and reduced bone density,” says Halpern. “Therefore, lowering the dose and improving the safety profile of DMPA has been an appealing goal.”
This goal has been partially achieved with the development of the lower dose subcutaneous formulation of DMPA, which is Depo-subQ provera 104 (104 mg/0.65 mL; Depo-subQ 104), observes Halpern. The subcutaneous route of administration results in lower peak levels, lower overall exposure, and slower absorption than intramuscular administration. As a result, Depo-subQ 104 provides the same duration of contraceptive protection as Depo-Provera CI, but at a 30% lower dose, she states. However, despite a reduced drug load, the use of Depo-subQ 104 still is associated with side effects, some of which are believed to be dose-dependent; therefore, further decrease of the contraceptive dose of medroxyprogesterone acetate might likely lead to reduced side effects and increased acceptability, Halpern states.
Existing pharmacokinetic and pharmacodynamic data suggest that if injected subcutaneously, the 150 mg dose of DMPA may be sufficient to provide contraceptive protection for six months and that a dose less than 100 mg may be sufficient to provide three months of contraceptive protection, reports Halpern. To test the former hypothesis, FHI 360 is conducting a study to evaluate the pharmacodynamics and pharmacokinetics following a single subcutaneous administration of 150 mg/mL Depo-Provera CI (NCT02456584; study no. 702179). To test the latter hypothesis, FHI 360 is preparing to initiate the proof-of-concept pharmacokinetic/pharmacodynamic study to evaluate if Depo-Provera CI at doses ranging between 45 and 105 mg may be effective for at least three months of contraceptive protection if injected subcutaneously (study no. 834119).
Recruitment has been ongoing for the first study (no. 702179) since September 2015, notes Halpern. Interim results will be available in February 2017, with final results available in spring 2018. If the results show that Depo-Provera CI 150 mg/mL injected subcutaneously has potential to provide contraceptive protection for six months, it will be further investigated in effectiveness studies, she states.
Study initiation for the second study (no. 834119) is tentatively scheduled for August 2016, reports Halpern. If the study demonstrates that Depo-Provera CI, subcutaneously administered at lower doses, has a potential to prevent pregnancy when injected every three months, the lowest effective dose (within the range tested) will be further investigated in effectiveness studies.
While efforts are under way to invest in novel sustained drug delivery technologies that hold promise for the development of a new longer-acting injectable contraceptive product, the adaptation of existing methods such as Depo-Provera CI carries a distinct comparative advantage by shortening the time to market and reducing development costs, says Halpern.
With funding from the Bill & Melinda Gates Foundation of Seattle, FHI 360 has launched a project to support early testing of innovative approaches with the goal of developing an injectable contraceptive that would last six months. This project is a first step toward bringing a game-changing injectable contraceptive to market, says FHI 360.
In 2012, FHI 360 issued a Request for Proposals for proof-of-concept testing of candidates that have the potential to be developed into a longer-acting injectable. Proposals were received from lead drug delivery research groups in the United States, Europe, India, and China, and they represented a wide range of innovative approaches. (CTU reported on it. See “Research focuses on development of a longer-acting injectable contraceptive,” June 2015, at http://bit.ly/1VObT9s, “Longer-acting method that is injectable probed,” in the March 2013 issue, at http://bit.ly/1RPD2Yi, and “The search has begun for long-acting contraceptives,” December 2013, at http://bit.ly/1TNeWyJ.)
FHI 360 is partnering with the following projects:
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poly(lactide) and poly lactic-co-glycolic acid microspheres releasing levonorgestrel (Shanghai [China] Institute of Planned Parenthood Research);
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poly lactic-co-glycolic acid microspheres releasing etonogestrel (Orbis Biosciences in Kansas City);
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nanostructured porous silicon microparticles releasing a contraceptive steroid (University of California, San Diego in La Jolla).
The goal is to develop and bring to market a six-month injectable within 10-15 years and possibly sooner, say researchers.
REFERENCES
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Kavanaugh ML, Jerman J, Finer LB. Changes in use of long-acting reversible contraceptive methods among U.S. women, 2009-2012. Obstet Gynecol 2015; 126(5):917-927.
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Finer LB, Zolna MR. Declines in unintended pregnancy in the United States, 2008-2011. N Engl J Med 2016; 374(9):843-852.
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Reeves MF, Hathaway MJ, Canela Oleaga JM, et al. A randomized single-blinded trial of VeraCept, a novel nitinol low-dose copper intrauterine contraceptive compared with a copper T380S intrauterine contraceptive. Presented at the 2015 annual clinical meeting of the American College of Obstetricians and Gynecologists. San Francisco; May 2015.
