ESPE 2016 Highlights: Day Three
The final day of the 2016 ESPE conference featured more original research communications, symposia and the final two plenary lectures.
Long-acting growth hormone: a crowded field?
Long-acting growth hormone is getting ever closer to the clinic, with one late-breaking trial plus several presentations in one of the morning’s free communication sessions devoted to the topic. In a packed session, delegates heard the latest phase I and II data on somavaratan, GX-H9 and MOD 4023.
Somavaratan has now entered phase III testing. The phase II extension study data reported in this session were from children receiving a twice-monthly 3.5 mg/kg dose, the dose that will be carried forwards to the phase III trial. All children received this dose during the second year of the study, and achieved a growth velocity of 7.83 cm/year, while the gap between their bone age and chronological age began to close.
GX-H9 is at a slightly earlier stage of testing – pharmacokinetic and pharmacodynamic data from interim phase II analysis show the potential for weekly or 2-weekly dosing, with growth data still to come. And phase II results for TransCon human growth hormone show that patients achieved annualised growth velocities ranging from 11.9 to 13.9 cm/year at once-weekly doses of 0.14 to 0.30 mg, compared with 11.6 cm/year for daily somatropin (accumulated dose 0.21 mg/week)
Several presentations involved MOD 4023 – another weekly dosing formulation that is due to enter phase III testing. The results from the open-label phase II extension study, presented in this session, showed a height velocity of up to 8.74 cm/year among patients taking the 0.66 mg/kg dose – the dose that is to be carried forward to phase III – and no new safety concerns.
MOD 4023 was also the subject of presentations describing its manufacturing process, and a linear regression model that can be used to estimate average and peak insulin-like growth factor-1 levels in patients receiving weekly MOD 4023, irrespective of which day the blood sample is drawn.
Genetics also featured heavily in this session. One study used machine learning to predict growth hormone deficiency from whole-blood gene expression, achieving 100% sensitivity and 96% specificity. The area under the receiver operating characteristic curve was 0.98 (ie, 98% accuracy), a result that session co-Chair Pierre Bougnères (Hôpital Bicêtre, Paris, France) called “a remarkable performance”, given that using the same techniques to predict Type 1 diabetes resulted in an accuracy of only about 80%.
Another genetic study demonstrated the usefulness of exome sequencing in children with short stature and features of growth hormone insensitivity. Sequencing of candidate genes identified causative mutations in 36 of 101 patients, but exome sequencing added an additional 11. These patients’ mutations were missed during candidate gene sequencing because, in the main, their symptoms “did not point towards” the culprit gene.
And in the EPIGROW study, involving 263 children with idiopathic short stature and matched controls, two methods of analysis identified a total of 32 genes that may contribute to short stature. One analysis identified 33 genes and the other identified three. Of note, one gene – A2M – was identified in both analyses, so the researchers consider this to be a particularly strong candidate for a role in short stature.
Long-acting growth hormone also featured in the late-breaking trials session, with the 4-year safety and efficacy results for LB03002, which is now approved for use in Korea. In a trial involving 1084 patients with growth hormone deficiency, the weekly dose achieved similar height velocity and standard deviation scores as a daily formulation, with no difference in adverse event rates.
The diverse mechanisms of obesity
The first of the day’s plenary lectures featured Philippe Froguel (Imperial College London, UK) giving an overview of the genetic contribution to obesity. A large number of contributing genes have been identified, but those underlying monogenic and polygenic obesity are strikingly different. Monogenic obesity, which Frogual said accounts for 3–5% of all obesity cases, is caused by single mutations in specific genes, with all those so far identified belonging to the leptin–melanocortin signalling pathway, and resulting in appetite dysfunction.
By contrast, the genes linked to polygenic obesity are predominantly expressed in the brain – most particularly in areas linked to addiction, behaviour and reward.
Environmental factors are well known to have a strong influence of polygenic obesity, but they even play a part in monogenic obesity; the rate of obesity in patients with culprit mutations was much lower among those in previous generations than among patients growing up in today’s obesogenic environment.
Among the afternoon’s symposia was one devoted to stem cells, in keeping with the conference’s theme of new horizons in paediatric endocrinology. Although first presenter Cynthia Andoniadou (King’s College London, UK) said she doesn’t “envisage that we’ll be sticking pituitary stem cells in anyone’s pituitary anytime soon”, the three speakers demonstrated how stem cells are already helping scientists make new discoveries about endocrine organs.
Andoniadou outlined her team’s work on pituitary stem cells. They established that the pituitary contains stem cells, identifiable by their expression of SOX2, which generate new cells and also act as “niche cells” by releasing signals that promote the division of other cells.
Rudolph Leibel (Columbia University, New York, USA) described the relatively recent technique of taking fully differentiated cells and turning them back into pluripotent stem cells, which, in turn, can be differentiated into the researchers’ choice of mature cells. The technique offers a powerful tool for studying cells taken directly from patients with endocrine disorders, which Leibel illustrated by sharing the results of his work into Wolfram syndrome and Bardet-Biedl syndrome.
He also stressed that the technique can be used to investigate otherwise unknown genetic aetiologies of, for example, obesity and diabetes, and he encouraged clinicians to approach him with potential cases.
In the final talk, David Hodson (University of Birmingham, UK) recounted the discovery of a subset of beta cells he calls “hubs” that act as “pacemakers” of islet responses. These cells, which account for no more than 10% of beta cells, are less differentiated than normal beta cells and are “uniquely vulnerable to diabetes”, he said. They may therefore offer a novel target for Type 2 diabetes treatment.
The last plenary, and also the final presentation of the conference, was given by Bart Roep (Leiden University, The Netherlands), who claimed that we are now “entering a completely new chapter in the treatment of Type 1 diabetes, by actually targeting the cause and stopping the disease.”
His evidence for this is his team’s creation of a “vaccine” for Type 1 diabetes. The process involves extracting monocytes from the blood of patients, incubating them with 25-hydroxyvitamin D3, adding the “vaccine” – proinsulin – and returning them to the patient. Patients with Type 1 diabetes have modified proinsulin produced by stressed beta cells, Roep explained, and this vaccination technique trains patients’ immune systems to ignore the modified proinsulin. The technique is being tested in a phase I trial, which started last Friday.
Session co-Chair Moshe Phillip (Tel Aviv University, Israel) noted that he, as a proponent of the artificial pancreas, is technically in competition with Roep. But he said that, for once, this is a competition that he is happy to lose.