Skin in the Game?

Abstract

Multiple recent studies have confirmed that osteoanabolic agents reduce fractures earlier and to a greater extent than antiresorptive agents; however, clinical use is limited by the need for injection. Multiple prior attempts at transdermal or oral delivery failed for a variety of reasons, and the lack of noninjectable anabolic regimens is one of the greatest gaps in the osteoporosis treatment armamentarium. To that end, the current issue of JBMR includes a noninferiority trial that randomized 511womenwith osteoporosis to receive 1 year of treatment with transdermal abaloparatide 300 μg/day or standard subcutaneous abaloparatide 80 μg/day, previously demonstrated to be an effective and safe osteoanabolic medication in the pivotal Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE; 6). Study participants in the new investigation were similar to those enrolled in the pivotal trial with a mean age of 69, a mean spine T-score of –2.6, a mean total hip T-score of –2.2, and 80% with a prior fracture. The transdermal product is an abaloparatide-coated microneedle array applied with a reusable applicator to affix a patch to the skin. In a prior Phase 1 study, transdermal application of 300 μg to the thigh for 5 min produced a pharmacokinetic profile similar to that seen with the standard dose of 80 μg administered subcutaneously. The thigh was chosen over the abdomen for transdermal application because of a superior pharmacokinetic profile. The primary endpoint was change in the lumbar spine bone density (BMD), and noninferiority was to be achieved with a BMD difference of ≤2% between the two regimens. Regrettably, while BMD increased in both groups, spine BMD gain with subcutaneous abaloparatide (10.9%) exceeded that for transdermal abaloparatide (7.1%) by more than the noninferiority margin. Mean increments in total hip BMD were 3.7% with subcutaneous and 2.0% with transdermal administration. Even though the transdermal regimen did not meet the noninferiority endpoint in this trial, the BMD gains in both spine and hip were substantial, indicating the efficacy of the transdermal formulation. There were several interesting observations, which remain unexplained but may have contributed to the study findings. With subcutaneous administration, the serum C-telopeptide (CTX) level increased within 1 month; in contrast, with the transdermal regimen, the CTX level declined at 1 month. Themechanism of this differential CTX response to the two regimens is unclear. Beyond 1 month, serum CTX was elevated in both groups, though the increments were higher for subcutaneous than transdermal abaloparatide throughout the year. Serum levels of the bone formation marker PINP were also higher with subcutaneous application. At 1 year, the median procollagen Type I N-propeptide (PINP) increment was 75% with subcutaneous and 53% with transdermal abaloparatide. One of the most perplexing findings was the unexpected observed difference in pharmacokinetic profiles between the two abaloparatide regimens. The greater abaloparatide exposure with subcutaneous administration likely played a role in explaining group differences. The geometric mean area under the curve (AUC) for the transdermal regimen (843 pg h/mL) was less than half that seen for subcutaneous administration (1756 pg h/mL). The AUC for transdermal abaloparatide was similar to that seen in the Phase 1 study; however, the AUC for subcutaneous administration in the current trial was 50% greater than that seen with subcutaneous administration in ACTIVE. Baseline body weight and body mass index were similar in the participants here compared with the pivotal study population, and the big difference in AUC remains unexplained. Consistent with greater abaloparatide exposure, the subcutaneous group in the current study had larger increments in biochemical markers and BMD compared to those seen in ACTIVE. As noted above, in this study, CTX was elevated already at 1 month with subcutaneous exposure, whereas median CTX was slightly below baseline at 1 month in ACTIVE. At 12 months, with subcutaneous administration here, the median PINP increment was 75%, compared with an increment of about 40% with subcutaneous abaloparatide in ACTIVE. Similarly, with subcutaneous exposure, the median CTX increment at 12 months here was about 28%, compared to an increment of less than 10% in ACTIVE. Consistent with the greater biochemical marker increases with subcutaneous exposure in this study, mean BMD gains at 12 months also exceeded those seen with subcutaneous administration in ACTIVE (mean 9.8% in the spine and 3.4% in the total hip). While there were more application site reactions (pain, swelling, erythema) with the transdermal preparation, systemic adverse events (palpitations, dizziness, nausea, fatigue) were more frequently reported in the subcutaneous group. There were also more withdrawals associated with adverse events in the subcutaneous than transdermal group. There was also a difference in the development of antidrug antibodies, with much higher antibody formation seenwith the transdermal formulation. Although a high proportion of these were neutralizing antibodies, the authors report that there were no clinically meaningful effects of neutralizing antibodies on BMD, biochemical biomarkers, or safety.