Endocrinology and Diabetes
Xenpozyme (olipudase alfa)
Olipudase alfa is indicated for non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in adults and children. It is a recombinant enzyme for replacement therapy. ASMD is a lysosomal storage disease that results from reduced activity of the enzyme acid sphingomyelinase (ASM), caused by pathogenic variants in the sphingomyelin phosphodiesterase 1 (SMPD1) gene. ASM degrades sphingomyelin to ceramide and phosphocholine. ASM deficiency causes intra-lysosomal accumulation of sphingomyelin (and cholesterol and other cell membrane lipids) in various tissues.
Approval of olipudase alfa was established by the ASCEND and ASCEND-Peds trials. The ASCEND trial assessed 31 adults with ASMD type A/B or type B and their percent predicted diffusing capacity of the lung for carbon monoxide and spleen volume. The olipudase alfa group demonstrated improved lung function and reduced splenomegaly compared to the placebo group from baseline to week 52 (increased predicted diffusing capacity for carbon monoxide, 22% vs 3%; spleen volume, 39% decrease vs 0.5% increase). In the ASCEND-Peds trial, 9 patients treated with olipudase alfa that were able to perform test at baseline saw improvement in lung performance from baseline to week 52 (mean increase of 33% predicted diffusing capacity for carbon monoxide). Genet Med. 2022 Jul;24(7):1425-1436 and Genet Med. 2021 Aug;23(8):1543-1550
Teplizumab is a humanized monoclonal antibody that targets the cluster of differentiation 3 (CD3) antigen, which is coexpressed with the T-cell receptor (TCR) on the surface of T-lymphocytes. It is indicated to delay the onset of stage 3 type 1 diabetes mellitus (T1DM) in adults and children aged 8 years and older who currently have stage 2 T1DM.
FDA approval was based on a phase 2, randomized, placebo-controlled trial involving 76 at -risk children and adults. The study demonstrated that a single 14-day regimen of daily IV infusions of teplizumab in 44 patients delayed clinical T1DM by a median of 2 years compared to 32 participants who received placebo (p = 0.006). N Engl J Med. 2019 Aug 15;381(7):603-613
Data from 3 years of follow-up (median 923 days) showed 50% of the teplizumab group remained diabetes free, compared to 22% of the placebo group (p = 0.01). Those who received teplizumab had a greater average C-peptide AUC compared to those given placebo, reflecting improved beta-cell function (1.96 vs 1.68 pmol/mL; p = 0.006). C-peptide levels declined over time in the placebo group, but they stabilized in patients who received teplizumab (p = 0.0015). Sci Transl Med. 2021 Mar 3;13(583)
Tirzepatide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It acts by dually targeting glucagonlike peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GIP is an incretin hormone that induces insulin secretion in response to a meal (primarily by hyperosmolarity of glucose in the duodenum) to facilitate the metabolism of carbohydrates, fats, and proteins. GLP-1 receptor agonists increase insulin secretion in the presence of elevated blood glucose, suppress glucagon postprandially, delay gastric emptying to decrease postprandial glucose, and decrease glucagon secretion.
The SURPASS clinical trials investigated the use of tirzepatide. SURPASS-2 was an open-label, 40-week, phase 3 trial. The comparison by Frias et al of tirzepatide versus semaglutide in patients with type 2 diabetes mellitus (SURPASS-2) found that tirzepatide at all doses was noninferior and superior to semaglutide in lowering HbA1c. Tirzepatide was also superior to semaglutide in body-weight reductions. N Engl J Med 2021 Aug 5;385(6):503-515
Other endocrinology/diabetes approvals
Tymlos (abaloparatide) – New indication to increase bone density in men with osteoporosis at high risk for fracture or patients who have failed on or are intolerant to other available osteoporosis therapy
Olpruva (sodium phenylbutyrate) – New oral pellets for suspension indicated as an adjunct to dietary protein restriction and essential amino acid supplementation for the chronic management of patients who weigh at least 20 kg with urea cycle disorders involving deficiencies of carbamylphosphate synthetase (CPS), ornithine transcarbamylase (OTC), or argininosuccinic acid synthetase (AS)
Imcivree (setmelanotide) – Indication for chronic weight management in patients aged 6 years and older with obesity caused by certain genetic disorders expanded to include Bardet-Biedl syndrome
Qsymia (phentermine/topiramate) – Indication for chronic weight management expanded to include adolescents aged 12 years and older with an initial BMI in the 95th percentile or greater for age and sex
Wegovy (semaglutide) – Indicated as an adjunct to a reduced calorie diet and increased physical activity for chronic weight management in pediatric patients aged 12 years and older with an initial BMI ≥95th percentile standardized for age and sex (ie, obesity)
Trulicity (dulaglutide) – Indicated as an adjunct to diet and exercise to improve glycemic control in children aged 10 years and older with type 2 diabetes mellitus
Mavacamten is a first-in-class cardiac myosin inhibitor indicated for symptomatic New York Heart Association class II-III obstructive hypertrophic cardiomyopathy (HCM) to improve exercise capacity and symptoms in adults. Mavacamten modulates the number of myosin heads that can enter “on actin” (power-generating) states, thus reducing the probability of force-producing (systolic) and residual (diastolic) cross-bridge formation. Excess myosin actin cross-bridge formation and dysregulation of the super-relaxed state are mechanistic hallmarks of HCM.
Approval of mavacamten was based on results from the multicenter, phase 3 EXPLORER-HCM trial (n = 251). Of 123 patients randomly assigned to mavacamten, 92 (75%) completed the Kansas City Cardiomyopathy Questionnaire (KCCQ) at baseline and week 30; and of the 128 patients randomly assigned to placebo, 88 (69%) completed the KCCQ at baseline and week 30. At 30 weeks, the change in KCCQ-OS (overall summary) score was greater with mavacamten than with placebo (mean score, 14.9 vs 5.4; difference +9.1; p<0.0001), with similar benefits across all KCCQ subscales. The proportion of patients with a very large change (KCCQ-OS 20 points or more) was 36% in the mavacamten group versus 15% in the placebo group, with an estimated absolute difference of 21%. These gains returned to baseline after treatment was stopped. Lancet. 2021 Jun 26
Other cardiology approvals
Furoscix (furosemide) – New formulation and administration method: SC delivery by on-body infusor for treatment of congestion due to fluid overload in adults with NYHA class II/III CHF
Jardiance (empagliflozin) – Indication to reduce the risk of cardiovascular death plus hospitalization in adults with heart failure (HF) broadened to include HF with either reduced or preserved ejection fraction.
Xigduo XR (dapagliflozin/metformin) – New indication approved to reduce risk of CV death and hospitalization for HF in adults with T2DM who have HF (NYHA class II-IV) with reduced ejection fraction.
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Cite this: Mary L. Windle. FDA Approvals, Highlights, and Summaries: Endocrinology, Diabetes, and Cardiology - Medscape - Mar 02, 2023.