RESUMO
Hypoparathyroidism (HypoPT) is a rare disease, often inadequately controlled by conventional treatment. PARALLAX was a mandatory post-marketing trial assessing pharmacokinetics and pharmacodynamics of different dosing regimens of recombinant human parathyroid hormone 1-84 (rhPTH[1-84]) for treating HypoPT. The present study (NCT03364738) was a phase 4, 1-yr open-label extension of PARALLAX. Patients received only 2 doses of rhPTH(1-84) in PARALLAX and were considered treatment-naive at the start of the current study. rhPTH(1-84) was initiated at 50 µg once daily, with doses adjusted based on albumin-corrected serum calcium levels. Albumin-corrected serum calcium (primary outcome measure), health-related quality of life (HRQoL), adverse events, and healthcare resource utilization (HCRU) were assessed. The mean age of the 22 patients included was 50.0 yr; 81.8% were women, and 90.9% were White. By the end of treatment (EOT), 95.5% of patients had albumin-corrected serum calcium values in the protocol-defined range of 1.88 mmol/L to the upper limit of normal. Serum phosphorus was within the healthy range, and albumin-corrected serum calcium-phosphorus product was below the upper healthy limit throughout, while mean 24-h urine calcium excretion decreased from baseline to EOT. Mean supplemental doses of calcium and active vitamin D were reduced from baseline to EOT (2402-855 mg/d and 0.8-0.2 µg/d, respectively). Mean serum bone turnover markers, bone-specific alkaline phosphatase, osteocalcin, procollagen type I N-terminal propeptide, and type I collagen C-telopeptide increased 2-5 fold from baseline to EOT. The HCRU, disease-related symptoms and impact on HRQoL improved numerically between baseline and EOT. Nine patients (40.9%) experienced treatment-related adverse events; no deaths were reported. Treatment with rhPTH(1-84) once daily for 1 yr improved HRQoL, maintained eucalcemia in 95% of patients, normalized serum phosphorus, and decreased urine calcium excretion. The effects observed on urine calcium and the safety profile are consistent with previous findings. Clinical trial identifier: NCT03364738.
RESUMO
The first documented case of diabetes mellitus occurred earlier than 4000 BC. Since then; many of the brightest minds in medicine have dedicated their time and effort toward developing treatments that can reverse the course of this deadly disease. As our understanding of the pathogenesis of diabetes increases; so does the availability of treatment options. The fight against diabetes once only had metformin and sulfonylureas as the cornerstone of oral treatment; but now; multiple classes have been added to this armamentarium including thiazolidenediones (TZDs) and dipeptidyl peptidase IV (DDP IV) inhibitors. These therapies provide reasonable durable glycemic control but are unable to arrest the natural progression of diabetes or the eventual need for insulin. By utilizing our growing knowledge on the pathogenesis of diabetes; a number of new therapeutic agents are in development to overcome the shortcomings of current therapies. Promising options on the horizon include sodium-coupled glucose co-transport 2 (SGLT2) inhibitors; ranolazine; salicylates; second-generation peroxisome proliferator-activator receptor agonists (PPARs); and 11-beta hydroxysteroid dehydrogenase type 1 inhibitors (11-beta HSD1 inhibitors). Various molecules; including some enzymes; are also in development; particularly to address beta-cell preservation and its sensitivity to glucose; while minimising hypoglycaemia. Most of these new classes of drugs consist of daily administration; simplifying the regimen for patients and likely increasing medication compliance. This article reviews the new agents that are advancing through clinical trials; their mechanism of actions; glucose lowering effect and possible side effects and limitations