Tesamorelin 10 mg

Tesamorelin is a synthetic 44-residue peptide corresponding to the full-length human growth-hormone-releasing factor, GHRH(1-44). Two features distinguish it from the native hormone. The C-terminus is amidated, and the alpha-amino group of the N-terminal tyrosine carries a trans-3-hexenoyl cap, a C6 chain with a double bond at position 3. In one-letter code the chain reads trans-3-hexenoyl-YADAIFTNSYRKVLGQLSARKLLQDIMSRQQGESNQERGARARL-NH2. The free base has the molecular formula C221H366N72O67S and an average mass of 5135.86 g/mol, registered under CAS 218949-48-5. The material is handled as the acetate salt, which carries the separate registry number 901758-09-6 and is written in FDA labelling as C221H366N72O67S x C2H4O2 with x approximately 7.

The sequence itself is not a designed one. GHRH(1-44)-NH2 is the native hypothalamic peptide, so tesamorelin differs from the endogenous molecule at exactly one point, the acyl cap. This is what separates it from the other GHRH-derived research peptides: sermorelin is the truncated 1-29 fragment with no N-terminal modification, and CJC-1295 is a 1-29 analogue carrying amino-acid substitutions and, in the DAC form, a maleimidopropionyl linker. Tesamorelin keeps the whole 44-residue chain and modifies only the terminus. Native GHRH is inactivated by dipeptidyl aminopeptidase-IV, which excises the N-terminal Tyr-Ala dipeptide. In the non-clinical characterisation of the compound, the investigators reported that the hexenoyl-modified peptide was resistant to dipeptidyl aminopeptidase-IV deactivation, that the modification slowed in vitro degradation in rat, dog and human plasma relative to natural hGRF(1-44)-NH2, and that it prolonged in vivo plasma elimination kinetics in animals (Ferdinandi et al., 2007).

The compound was developed by Theratechnologies Inc. of Canada under the code TH9507. FDA labelling describes it simply as produced synthetically. It was approved by the US Food and Drug Administration in November 2010 under the trade name Egrifta (Spooner and Olin, 2012). A centralised European marketing-authorisation application was filed by Ferrer Internacional, S.A. and withdrawn on 21 June 2012; the company's withdrawal letter stated that the CHMP considered the data provided did not allow it to conclude on a positive benefit-risk balance (European Medicines Agency press release EMA/431454/2012, 26 June 2012). There is no Europe marketing authorisation for tesamorelin. Material supplied here is the lyophilised acetate powder for laboratory research use only, not for human consumption.

The published human literature on tesamorelin is unusually concentrated. Almost all controlled data comes from a single clinical programme in HIV-associated lipodystrophy that ran from the mid-2000s to 2019, plus one trial in older adults with mild cognitive impairment. There is no published randomised controlled trial of tesamorelin in healthy young adults, in athletic populations, or in obesity outside the HIV setting.

The pivotal phase-3 trial randomised 412 people with HIV and abdominal fat accumulation to 2 mg tesamorelin daily by subcutaneous injection or placebo for 26 weeks. Visceral adipose tissue measured by computed tomography decreased 15.2 percent in the tesamorelin arm and increased 5.0 percent under placebo. Triglycerides changed by -50 mg/dL against +9 mg/dL, and the total-cholesterol-to-HDL ratio by -0.31 against +0.21 (P less than 0.001 for all three comparisons). IGF-I rose 81.0 percent in the tesamorelin arm and fell 5.0 percent under placebo. No significant between-group difference was observed in glycaemic measures, and overall adverse-event rates did not differ significantly, though more participants on tesamorelin withdrew because of an adverse event (Falutz et al., 2007).

A pooled analysis of the two phase-3 trials covered 806 antiretroviral-treated participants, 543 on tesamorelin and 263 on placebo, with a 26-week extension. At 26 weeks visceral adipose tissue changed by -24 plus or minus 41 cm2 versus +2 plus or minus 35 cm2 (P less than 0.001; treatment effect -15.4 percent), triglycerides by -37 plus or minus 139 versus +6 plus or minus 112 mg/dL (P less than 0.001; treatment effect -12.3 percent), and IGF-I by +108 plus or minus 112 versus -7 plus or minus 64 ng/mL (P less than 0.001). Abdominal subcutaneous adipose tissue did not change significantly (-2 plus or minus 32 versus +2 plus or minus 29 cm2, P equals 0.08). Participants who stayed on treatment through 52 weeks showed a visceral change of -35 plus or minus 50 cm2 (Falutz et al., 2010). The 52-week extension report separately recorded that upon discontinuation of tesamorelin, visceral adipose tissue reaccumulated, and that the effects observed did not last beyond the duration of treatment (Falutz et al., 2008).

Two later single-programme trials examined hepatic fat rather than visceral fat. In a 6-month trial of 50 participants given 2 mg daily, the between-group treatment effect on visceral adipose tissue was -42 cm2 (95 percent CI -71 to -14; P equals 0.005) and the median liver-fat change was -2.0 percent against +0.9 percent under placebo (P equals 0.003). Fasting glucose rose more in the tesamorelin arm at 2 weeks, mean change +9 mg/dL versus +2 mg/dL (treatment effect +7 mg/dL, P equals 0.03), with no significant difference at 6 months (P equals 0.72 across time points) (Stanley et al., 2014). A 12-month multicentre trial enrolling 61 people with HIV and non-alcoholic fatty liver disease, 30 on tesamorelin and 30 on placebo, reported an absolute hepatic fat fraction effect of -4.1 percent (95 percent CI -7.6 to -0.7, p equals 0.018), corresponding to a -37 percent relative reduction from baseline (95 percent CI -67 to -7, p equals 0.016), and hepatic fat fraction below 5 percent in 35 percent of the tesamorelin group against 4 percent on placebo (p equals 0.0069) (Stanley et al., 2019).

The one substantial study outside the HIV setting was a 20-week randomised trial using 1 mg per day in 152 randomised older adults, 66 of whom had mild cognitive impairment; 137 completed. The investigators reported a favourable effect on a cognitive composite (intent-to-treat P equals 0.03; completer analysis P equals 0.002), a significant effect on executive function (P equals 0.005), and a non-significant trend on verbal memory (P equals 0.08), with no effect on visual memory. IGF-1 increased 117 percent and body fat fell 7.4 percent (both P less than 0.001). Mild adverse events were reported by 68 percent of GHRH recipients against 36 percent on placebo (Baker et al., 2012). Readers weighing the overall evidence base should note that this literature was generated in specific clinical populations under sponsor-run protocols, that Europe regulator did not reach a positive benefit-risk conclusion on the same dossier, and that long-term safety data beyond 52 weeks remains limited (Spooner and Olin, 2012).