Lonafarnib, an oral farnesyltransferase inhibitor, is indicated to reduce the risk of mortality in Hutchinson-Gilford progeria syndrome (HGPS). It was also approved for processing-deficient progeroid laminopathies with heterozygous LMNA mutation with progerinlinke protein accumulation or homozygous or compound heterozygous ZMPSTE24 mutations.
Farnesyltransferase is an enzyme involved in modification of proteins through a process called prenylation. Mutation in the LMNA gene causes overproduction of progerin, a farnesylated-aberrant protein. Persistent farnesylation causes progerin accumulation in the inner nuclear membrane and is, at least partly, responsible for HGPS.
Accumulation of the defective lamin A protein makes the nucleus unstable, leading to the process of premature aging in children with progeria.
A multinational, observational study (n=258) showed treatment with lonafarnib monotherapy was associated with a lower mortality rate compared with no treatment after 2.2 years of follow-up. ( JAMA. April 24, 2018;319(16):1687-1695)
Setmelanotide is a melanocortin-4 receptor agonist. MC4 receptors in the brain are involved in regulation of hunger, satiety, and energy expenditure. Setmelanotide is the first drug indicated for long-term weight management in patients aged at least 6 years with obesity due to rare genetic conditions (eg, proopiomelanocortin [POMC], proprotein convertase subtilisin/kexin type 1 [PCSK1], or leptin receptor [LEPR] deficiency).
Phase 3 clinical trials observed 80% of patients with obesity owing to POMC or PCSK1 deficiency achieved greater than 10% weight loss and 45.5% of patients with obesity due to LEPR deficiency achieved greater than 10% weight loss after 1 year of treatment. Additionally, hunger scores improved from baseline to 1 year. ( Lancet Diabetes Endocrinol. December 2020;8(12):960-970 and Imcivree prescribing information)
Somapacitan is a long-acting human growth hormone derivative designed to bind to circulating albumin. This allows for once-weekly subcutaneous injection. It is indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency.
Approval was supported by data from the phase 3 REAL-1 trial. Patients were randomized to receive once-weekly somapacitan, weekly placebo, or daily somatropin. Truncal fat percentage was measured at baseline and at 34 weeks. Somapacitan reduced truncal fat by a mean of 1.53% compared with a mean increase of 0.47% for placebo (P=.009). Percentage of truncal fat reduction with daily somatropin was 2.23%. At 86 weeks, improvements were maintained with both somapacitan and daily somatropin. ( J Clin Endocrinol Metab. April 1, 2020;105(4))
Triheptanoin is indicated as a source of calories and fatty acids for molecularly confirmed long-chain fatty acid oxidation disorders (LC-FAODs) in adults and children. It is a medium-chain triglyceride consisting of 3 odd-chain 7-carbon length fatty acids (heptanoate) that provide a source of calories and fatty acids to bypass the LC-FAOD enzyme deficiencies for energy production and replacement.
For this rare disease, a small double blinded, randomized controlled trial of 32 subjects with LC-FAODs (carnitine palmitoyltransferase-2, very long–chain acylCoA dehydrogenase, trifunctional protein, or long-chain 3-hydroxy acylCoA dehydrogenase deficiencies) were randomly assigned a diet containing 20% of their total daily energy from either triheptanoin or trioctanoin. At 4 months, patients in the triheptanoin group increased left ventricular (LV) ejection fraction by 7.4% (P=.046) while experiencing a 20% (P=.041) decrease in LV wall mass on their resting ECG. They also required a lower heart rate for the same amount of work during a moderate-intensity exercise stress test when compared with patients taking trioctanoin. ( J Inherit Metab Dis. November 2017;40(6):831-843)
Osilodrostat is an orally administered steroidogenesis inhibitor of 11-beta-hydroxylase, an enzyme that catalyzes the final step of cortisol synthesis in the adrenal cortex. It is indicated for Cushing disease in adults for whom pituitary surgery is not an option or has not been curative.
Approval of osilodrostat was based on the phase 3 LINC-3 clinical trial (n=137). It was a multicenter, double-blind, randomized withdrawal study following a 24-week, open-label, single-arm treatment phase. Open-label osilodrostat was initiated at 2 mg twice daily in 137 adults with Cushing disease and mean urinary free cortisol (mUFC; mean of three 24-hr samples) greater than 1.5 times the upper limit of normal (ULN) (ULN=50 mcg/24 h), with dose adjustments every 2 weeks (dose range 1-30 mg BID) up to week 12 based on efficacy (if mUFC > ULN) and tolerability. At week 26, 71 eligible patients (mUFC equal or below ULN at week 24 without a dose increase after week 12) were randomized to continue osilodrostat (n=36) or matching placebo (n=35) for 8 weeks, followed by open-label osilodrostat until week 48. Patients who remained on treatment at week 26, but were not eligible for randomization, continued open-label osilodrostat (n=47).
At baseline, median (range) mUFC was 3.5 times the ULN (0.3-69.6) in enrolled patients. At the end of the randomized withdrawal period (week 34), significantly more patients maintained mUFC equal to or less than the ULN (without a dose increase after week 26) in the osilodrostat group than in the placebo group (86% vs 29%; odds ratio, 13.7; P <.001). ( J Endo Soc. April-May 2019;3(1; Suppl))
Other notable endocrinology approvals
Saxenda (liraglutide) - Indication for adjunctive use for long-term weight management expanded to include adolescents
Gimoti (metoclopramide intranasal) - New dosage form for symptomatic relief of acute and recurrent diabetic gastroparesis
Qutenza (capsaicin transdermal) - New prescription-strength transdermal patch for neuropathic pain associated with diabetic peripheral neuropathy of the feet
Trulicity (dulaglutide) - Indicated for primary and secondary risk reduction of major adverse cardiovascular events in adults with type 2 diabetes who have established cardiovascular disease or multiple risk factors
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Cite this: FDA Approvals, Highlights, and Summaries: Endocrinology - Medscape - Feb 24, 2021.