By Jeffrey T. Jensen, MD, MPH, Editor

Leon Speroff Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland

Dr. Jensen reports he is a consultant for and receives grant/research support from HRA Pharma, Bayer Healthcare, Merck, Agile Pharm, Population Council, AbbVie, Evofem, and ContraMed; and is a consultant for Teva Pharmaceuticals and MicroChips.

Synopsis: Initial clinical results with a new 52 mg levonorgestrel intrauterine system (LNG-IUS) recently introduced to the market and approved for 3 years of use are similar to those seen with the existing LNG-IUS.

Source: Eisenberg DL, et al. Three-year efficacy and safety of a new 52-mg levonorgestrel-releasing intrauterine system. Contraception 2015; Apr 24 [Epub ahead of print].

A new 52 mg levonorgestrel intrauterine system (LNG-
IUS) was evaluated in an open-label, Phase 3 study conducted at 29 clinical sites in the United States. The device uses the same 32 mm x 32 mm T frame as the existing LNG-IUS, and a similar release rate-controlling membrane over the drug reservoir on the stem of the device designed to deliver 20 mcg/day of LNG.

A total of 1600 women aged 16-35 years and 151 women aged 36-45 years underwent attempted placement of the new LNG-IUS in the study. Of these, 1011 (57.7%) were nulliparous and 438 (25.1%) were obese women. Up to two placement attempts were allowed, and successful placement occurred in 1714 out of 1751 (97.9%) women. Of the 37 failed placements, 15 did not undergo an attempt at IUS insertion due to failed cervical dilation, a small uterine cavity, or other reasons unrelated to the product.

Subjects were seen at 1, 3, and 6 months after IUS placement, and then followed every 6 months. All subjects were required to be sexually active with a male partner and at risk for pregnancy. Subjects kept a diary of symptoms and sexual activity.

A total of six pregnancies occurred during the 3-year study for a cumulative life-table pregnancy rate of 0.55 (95% confidence interval [CI], 0.24-1.23); the Pearl Index for the 34,711 women-cycles of LNG-IUS use in the efficacy cohort of women ages 16-35 was 0.15 (95% CI, 0.02-0.55) through year 1, 0.26 (95% CI, 0.10-0.57) through year 2, and 0.22 (95% CI, 0.08-0.49) through year 3. Of the six pregnancies, four were ectopic. By the end of 3 years of use, 39% of subjects aged 16-35 and 32% aged 36-45 discontinued study participation. The most frequent reasons for discontinuation were adverse event (12%), lost to follow-up/withdrawal of consent (8%), and desire for pregnancy (5.5%). Of note, among those women who discontinued to become pregnant, 87% conceived within 12 months. The expulsion rate was 3.5%, and most (81%) of these occurred during the first year of use.

Commentary

A new LNG-IUS (Liletta) was approved in the United States in February and will be marketed by Actavis. The device is manufactured in Belgium, and the clinical trial to bring the device to the United States was conducted by Medicines360, a company that describes itself as a non-profit women’s heath pharmaceutical company. The clinical trial was made possible through generous funding from an anonymous foundation. While it is tempting to consider this a “generic” version of Bayer Healthcare’s Mirena, it is important to note that no regulatory pathway exists for approval of a generic drug-releasing device. Therefore, a clinical trial was required to bring this product to market.

While not a generic, Liletta (the new device) shows a remarkable resemblance to Mirena (the existing device). Both use the same 32 x 32 mm Nova-T plastic frame, and position a 52 mg reservoir of levonorgestrel on the stem of the device. Both utilize a rate-controlling membrane to titrate release of the hormone. From the package insert, the initial release rate is listed at 20 mcg/day for the existing IUS and 18.6 mcg/d for the new product. The release gradually decreases over time for both devices. Given that the release rates are essentially the same, the clinical performance for the new device would be expected to be the same as the existing device.

Important differences do exist, but most of these will impact clinicians and not patients. The most important will be noticeable when you open the box of the new device. Compared to the well-engineered insertion device of the existing 52 mg LNG-IUS, the insertion device of the new IUS appears somewhat crude. This is not surprising given that Bayer has spent more than 20 years improving its insertion system and has tied up a number of important patents on the mechanism of insertion devices along the way. But even though the insertion process of the new system is not as fluid as with the existing device, the clinical performance appears to be the same; the failed placement rate of 2% is similar to that seen with the existing IUS. The removal threads are blue, compared to the brown removal threads of the existing device. Practically speaking, both appear dark or black when seen protruding through the cervix. The ultrasound appearance will also be the same, so it will be difficult to tell the two devices apart on a clinical exam.

Although a head-to-head comparison was not done, the clinical performance of the new system over 3 years is virtually identical to that of the existing device.1 One important difference is that more than half of the women who participated in the clinical trial of the new device were nulliparous. Thus, this study provides additional safety information about the use of the LNG-IUS in this important (and growing) group of users. Clinical sites provided same-day insertion, collecting tests for chlamydia at the time of placement with no delay for results (those screening positive received treatment without removing the IUS). This provides another important pearl; of the 23 of 1751 (1.3%) subjects who tested positive for chlamydia at the time of IUS placement, none developed a pelvic infection. Only three subjects (0.2%) underwent premature removal for pelvic infection during the course of the study. The most important consideration for patients is that the device has initial labeling for only 3 years of use. However, 5-year efficacy data are currently being analyzed for Liletta™, and a cohort of subjects from the pivotal trial will continue for an additional 2 years to obtain data in support of approval for 7 years of use for contraception. As these data become available, the labeling will be modified. Another important point is that unlike the existing IUS, the new product does not have FDA approval for treatment of heavy menstrual bleeding.

So if this new product is not different from the existing IUS, why was it developed? The major concern with the existing LNG-IUS has been high cost, not clinical performance, as cost presents a barrier to access. It is expected that the price for the new LNG-IUS will be substantially lower than the existing IUS, at least in publicly funded clinics. It is likely that private clinics and health plans will also enjoy a price reduction due to competition between the existing and new product. Having another hormone-releasing IUS on the U.S. market is a good thing and should expand options for women. But this is only a start. We can also look forward to additional copper devices coming to the U.S. market in the next few years.

REFERENCE

  1. Jensen JT, et al. Subject and clinician experience with the levonorgestrel-releasing intrauterine system. Contraception 2008;77:22-29.