ChEMBL

Also this month, on November 10th, FDA has approved Tesamorelin under the trade name Egrifta. Tesamorelin (research code:TH-9507) is an analog of the human growth hormone-releasing factor (GRF) (UniProt:P01286, synonym:Somatoliberin, synonym:GRF, synonym:GHRH) indicated for the reduction of excess abdominal fat in HIV-infected patients with lipodystrophy. Lipodystrophy is a condition in which excess fat develops in atypical areas of the body, most notably around the liver, stomach, and other abdominal organs. This condition is observed as a side effect with many antiretroviral drugs used to treat HIV. Tesamorelin is the first-FDA approved treatment specifically approved for lipodystropy.

The -relin INN stem covers prehormones or hormone releasing peptides, a very broad range of targets and pharmacology. The -morelin stem sub-group covers growth hormone-release stimulating peptides including capromorelin, dumorelin, examorelin, ipamorelin, pralmorelin, rismorelin, sermorelin, somatorelin, and tabimorelin.


Tesamorelin is an N-terminally modified variant of the natural 44 residue long peptide, Somatoliberin, which is a hypothalamic peptide, acting on the pituitary somatotroph cells to stimulate the synthesis and pulsatile release of endogenous growth hormone (GH), which is both anabolic and lipolytic. Somatoliberin is a member of the glucagon family (Pfam:PF00123) of endogenous peptide ligands. Tesamorelin exerts its therapeutic effects by binding to, and being an agonist of GHRHr - a type-2 (or class B, or secretin-like) GPCR (Uniprot: Q02643, ChEMBL:CHEMBL158, Pfam:PF00002), on pituitary somatotrophs; the triggered release growth hormone (GH) in turn acts on a variety of target cells, including chondrocytes, osteoblasts, myocytes, hepatocytes and adipocytes, resulting in a host of pharmacodynamic effects, which are primarily mediated by insulin-like growth factor 1 (IGF-1) produced in the liver and in peripheral tissues.

Tesamorelin has Molecular Weight of 5135.9 Da, absolute bioavailability, following s.c. dosing is less than 4%, with a volume of distribution of 10.5 L/kg (in HIV-infected patients) and an elimination half-life (t1/2) of 38 minutes (again in HIV-infected patients). The recommended dosage is 2 mg injected subcutaneously daily (typically in the abdomen) - a typical daily dose is therefore 0.39 umol).

trans-3-hexenoyl-YADAIFTNSYRKVLGQLSARKLLQDIMSRQQGESNQERGARARL-NH2

Tesamorelin is produced synthetically and is otherwise identical in amino acid sequence to that of human Somatoliberin/GRF. Tesamorelin is then modified by attachment a 3-hexenoyl moiety via an amide linkage to the N-terminal tyrosine residue. This chemical modification blocks proteolytic degradation by endogenous proteins such as DPP-IV, thus prolonging the half-life of the peptide (the inhibition of DPP-IV is itself the basis of a number of therapies for the treatment of type-II diabetes - the gliptins). A further chemical modification is the C-terminal amidation - this p.t.m. is found in the naturally produced peptide. Tesamorelin is closely chemically related to a number of other clinical agents, such as Sermorelin (which is a shorter, but still active version of Somatoliberin/GRF)

The full prescribing information can be found here.

The license holder is EMD Serono, Inc. and the product website is www.egrifta.com.