Mecasermin dosage and evidence

What is Mecasermin?

How does Mecasermin work?

Mecasermin locks onto the IGF-1 receptor on cells. That switches on growth signals inside the cell, called PI3K/Akt and MAPK. They drive cell growth, protein building and, at the growth plates, bones getting longer. It also fits the insulin receptor fairly well. That is the direct reason low blood sugar is its main side effect, and why it is given with a meal. The body's own IGF-1 travels in the blood almost entirely bound to carrier proteins, IGFBP-3 and one called the acid-labile subunit. Building that carrier depends on growth hormone signals. In a severe primary IGF-1 shortage those signals are broken, so the carrier proteins are low. After a shot, more IGF-1 is free, and it is cleared faster than the body's own would be. That is the real difference between replacing IGF-1 and making it yourself.

What have studies in people found about Mecasermin?

A good deal of evidence in people, in one rare condition. Almost all of it comes from studies where everyone knew they were treated, or from patient registries, with no dummy group. None of it is in adults or for anything other than growth.

• European registry, 306 patients: 80 had at least one low blood sugar episode. That came to 0.11 episodes per patient per year overall, and 0.01 serious ones. Laron syndrome and past low blood sugar made episodes more likely.
• European registry, 242 patients: among children not treated before and not yet in puberty, 56 percent of those without Laron syndrome counted as responders in the first year. 65.3 percent of patients had some side effect.
• Registry patients who reached the end of puberty: boys moved from 3.7 to 2.6 standard deviations below average height, and girls from 3.1 to 2.3. Puberty started about 1.5 years late.
• 76 children with growth hormone resistance, treated for up to 12 years: growth went from 2.8 cm a year before treatment to 8.0 cm a year in year one. It stayed above the starting rate for up to 8 years.
• Same study, side effects: low blood sugar in 49 percent, lumpy fat where the shots went in for 32 percent, and enlarged tonsils or adenoids in 22 percent.
• We found no trial of mecasermin in adults, against a dummy treatment, for muscle, recovery, age-related muscle loss or ageing.

What this does not tell you: The main study was mostly one where everyone knew they were treated, and the follow-up comes from patient registries. So each child's growth is compared with their own starting point, not with a group given a dummy treatment. That makes sense in a condition this rare, but it is still not the strongest kind of test. Nothing here tells you what mecasermin does in someone with normal IGF-1. All the evidence is about topping up a level that starts out far too low. Low blood sugar is common, not rare. And in studies of the general population, higher IGF-1 is linked to more cancer. That is a reason for caution about raising IGF-1 in someone who is not short of it. It is not a finding about treated children.

The state of the research

The evidence, in charts

The studies we cite

• Study in people2007
  Long-term treatment with recombinant insulin-like growth factor (IGF)-I in children with severe IGF-I deficiency due to growth hormone insensitivity

  Children who cannot make their own IGF-1 grew much faster on the replacement, and kept growing for years. 76 children were treated for up to twelve years with shots under the skin twice a day. Growth went from under three centimetres a year to eight in the first year, and stayed above where it started for up to eight years. Low blood sugar was the commonest problem, in about half the children. Almost everybody knew they were on the drug and there was no comparison group.

  The long-term efficacy and safety experience behind the approval. 76 children with IGF-1 deficiency due to growth hormone insensitivity treated with recombinant human IGF-1 for up to 12 years under a predominantly open-label design, at 60 to 120 micrograms per kilogram subcutaneously twice daily. Height velocity rose from a mean of 2.8 cm per year at baseline to 8.0 cm per year in the first year (p less than 0.0001) and was dose dependent; velocities were lower in subsequent years but stayed above baseline for up to 8 years. The most common adverse event was hypoglycaemia, reported by 49 percent of treated subjects and observed both before and during therapy, followed by injection site lipohypertrophy (32 percent) and tonsillar or adenoidal hypertrophy (22 percent). Note the design: predominantly open label, not randomised against placebo.

  PMID 17192294 Journal of Clinical Endocrinology and Metabolism
• Study in people2023
  Frequency and Predictive Factors of Hypoglycemia in Patients Treated With rhIGF-1: Data From the Eu-IGFD Registry

  Low blood sugar is the main hazard of this treatment, and this registry shows how often it actually happens. 306 patients were tracked from 2008 to 2021, most of them with severe IGF-1 deficiency. 80 had at least one low blood sugar episode and 224 had none. Serious episodes were rare. Children who had low blood sugar before starting, and children with Laron syndrome, were the ones most likely to have more. Nobody was given anything for this study. It counted what happened to patients already on treatment.

  Surveillance registry data from December 2008 to May 2021, 306 patients enrolled, 84.6 percent with severe primary IGF-1 deficiency. 80 patients had at least one hypoglycaemia adverse event against 224 with none. Total hypoglycaemia events were 0.11 per patient per treatment year and serious events 0.01 per patient per treatment year. Prior history of hypoglycaemia and a Laron syndrome diagnosis both predicted future events. The affected group started treatment younger (mean 8.7 against 9.8 years).

  PMID 37579214 Journal of Clinical Endocrinology and Metabolism
• Study in people2021
  Effectiveness and safety of rhIGF1 therapy in patients with or without Laron syndrome

  The treatment helps children who do not have Laron syndrome as well, just less. 242 children across ten European countries were entered in an ongoing registry. Among the 138 never treated before, first year height gain was bigger in the 21 with Laron syndrome than in the 117 without. Even so, more than half the non Laron children hit the responder mark. About two in three had some side effect, most often low blood sugar. Nobody was picked by chance and there was no untreated group.

  Ongoing open-label observational registry (NCT00903110), 242 children and adolescents from ten European countries enrolled between 2008 and 2017. In the treatment-naive prepubertal cohort of 138, height standard deviation score gain after one year was greater in the 21 patients with Laron syndrome than in the 117 without (p less than 0.05), and 56 percent of the non-Laron group met the responder threshold of a first-year height SDS gain of at least 0.3. Younger age at baseline predicted response (p less than 0.001). Treatment-emergent adverse events occurred in 65.3 percent of patients, hypoglycaemia most commonly. Observational, not randomised.

  PMID 33434161 European Journal of Endocrinology
• Study in people2022
  Pubertal Timing and Growth Dynamics in Children With Severe Primary IGF-1 Deficiency: Results From the European Increlex Growth Forum Database Registry

  Treatment lifts these children a long way toward a normal height without getting them there. 213 registry patients were followed and 36 were tracked all the way through puberty. Boys went from far below average height to much closer to it, and girls did the same. Puberty arrived about eighteen months late and the growth spurt was later and slightly weaker. The height gained before puberty was not lost during it. Nobody was assigned to anything and there is no untreated group to compare against.

  The number that sets expectations honestly. 213 registry patients, 132 boys and 81 girls. Among those reaching the end of puberty, 25 boys and 11 girls, mean height standard deviation score rose from minus 3.7 at registry baseline to minus 2.6 at Tanner stage 5 in boys, and from minus 3.1 to minus 2.3 in girls. Median pubertal peak height velocity was 8.0 cm per year in boys and 6.8 in girls. Puberty started about 1.5 years late and peak height velocity was delayed and slightly lower, but the height gain made before puberty was maintained through it. Treatment improves final height substantially without normalising it.

  PMID 35250870 Frontiers in Endocrinology
• Study in people2021
  Circulating insulin-like growth factor-I, total and free testosterone concentrations and prostate cancer risk in 200 000 men in UK Biobank

  Men with naturally higher IGF-1 in their blood get prostate cancer somewhat more often. Nearly 200,000 men were followed for about seven years. 5,402 were diagnosed with prostate cancer and 295 died of it. The higher a man's level, the higher his risk, and a genetic analysis pointed the same way, which makes a real cause more likely. Nobody was given anything here. These were men with their own natural levels, not patients on mecasermin, and this does not show that treating a deficient child raises his cancer risk.

  The epidemiology that any page about giving people more IGF-1 has to state. 199,698 men in UK Biobank followed a mean of 6.9 years, 5,402 diagnosed with and 295 dying from prostate cancer. Higher circulating IGF-1 was associated with prostate cancer diagnosis (hazard ratio 1.09 per 5 nmol/L increment, 95 percent CI 1.05 to 1.12) and with prostate cancer mortality (1.15, 1.02 to 1.29), with hazard ratios corrected for regression dilution using repeat measurements. A two-sample Mendelian randomisation analysis using genetic instruments and outcome data from 79,148 cases and 61,106 controls supported a causal role (cis-MR odds ratio 1.34 per 5 nmol/L, 1.07 to 1.68). This is an association study in men with naturally varying IGF-1, not a study of mecasermin, and it does not establish that treating a deficient child raises cancer risk.

  PMID 33252839 International Journal of Cancer