Leveling Up: Pediatric Growth Hormone Deficiency Treatment Advances Show Promise

As the desire for a less frequently administered growth hormone treatment intensifies, clinicians are looking to researchers for the latest data on safety and efficacy. Luckily, as more studies are undertaken patients and clinicians may soon have a wealth of options.

Since 1985, children with growth hormone deficiency (GHD) have been prescribed somatropin – recombinant human growth hormone (rhGHG) – to hopefully grow tall enough to be able to stand shoulder to shoulder with their peers. But this medication requires daily injections, which patients find painful, and their caregivers find burdensome, leading to noncompliance rates from 5% to a whopping 82%.

In 2015, the Growth Hormone Research Society recognized the need for long-acting growth hormone (LAGH) therapies, as decreasing the frequency of injections could lead to adherence and better outcomes. And pharmaceutical companies have responded.

In October 2021, a paper appeared in The Journal of Clinical Endocrinology & Metabolism reporting on the results of the Phase 3 heiGHt trial that found that the investigational long-acting, once-weekly prodrug lonapegsomatropin (TransCon hGH) may be more beneficial to treatment-naïve pediatric patients with growth hormone deficiency than daily somatropin of equivalent weekly dose.

The authors of that paper wrote in the conclusion that the fundamental challenge of developing a LAGH is to create a more convenient dosing regimen while retaining the excellent safety, efficacy, and tolerability of daily somatropin. “Building on the concept of releasing unmodified somatropin to maintain physiologic distribution, weekly lonapegsomatropin is the first LAGH with data demonstrating superior efficacy compared to a daily somatropin,” they write. “Lonapegsomatropin may represent an important therapeutic option for children with GHD.”

According to a recent report from the data and analytics company GlobalData, long-acting growth hormones — Novo Nordisk’s Sogroya (somapacitan-beco), Ascendis Pharma’s Skytrofa (TransCon hGH, lonapegsomatropin), Pfizer and OPKO Biologics’ NGENLA (somatrogon), and Hanmi Pharmaceuticals’ efpegsomatropin — are projected to capture more than 90% of the market share in the U.S., Germany, and Japan by 2030. GlobalData predicts TransCon hGH will emerge as the market leader, accounting for approximately 47% of all LAGH sales due to the fact it releases unmodified GH and has been proven efficacious.

If that’s the case, then it’s imperative these innovative therapies are not only efficacious, but safe for the children and adolescents taking them. The Journal of the Endocrine Society recently published a sort of companion piece or follow-up to the JCEM article on lonapegsomatropin/TransCon hGH, providing clinicians with a simplified way to interpret levels of insulin-like growth factor 1 (IGF-1) in pediatric patients taking the prodrug, since the goal is to balance the growth hormone/IGF-1 interaction.

Matching Real-World Data

The authors of the JES paper write that the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of lonapegsomatropin differ from daily somatropin as well as from other LAGHs with different molecular structures and physical-chemical characteristics. Physicians typically monitor IGF-1 levels in patients taking somatropin, but the JES authors point out that given the PK profile of GH released from lonapegsomatropin, the average IGF-1 level may be a more clinically relevant measure to represent overall exposure compared with peak or trough levels and may be useful to physicians.

Alan D. Rogol, MD, PhD, professor emeritus at the University of Virginia School of Medicine, in Charlottesville, and one of the authors of the JES paper, tells Endocrine News that lonapegsomatropin releases growth hormone, lining up with Growth Hormone Research Society guidance that any LAGH molecule needs to act the same as growth hormone, that its tissue distribution needs to be the same, and that the IGF-1 levels need to be safe. So, the questions for this new molecule became: “What do we consider whole-body exposure?” and “How can we help people learn what the average level is?”

Rogol and his co-authors analyzed 49,896 IGF-1 sample data simulated from 105 lonapegsomatropin-treated children with GHD and developed a relatively straightforward prediction formula, showing IGF-1 samples taken once four or five days after the dose lined up with a weekly average IGF-1 at steady state. What struck the researchers was that the prediction models matched exactly what was seen in the real-world data they collected. “I think that is an absolute major point,” Rogol says. “You can do it almost any time, and the modeling from the data and the real data are essentially the same.”

Bradley S. Miller, MD, PhD, division director of Pediatric Endocrinology at the University of Minnesota Masonic Children’s Hospital in Minneapolis and another of the JES paper authors, says that with this formula, physicians will have a day that they can use for convenience sampling. “If it’s four days after the medication is given, it’s going to be your average,” he says. “And if it works to have labs done on that day for the patients, then that’s going to be the easiest to interpret your values. Even if they come in on day two or day seven, there will be a way to estimate what their average was, using this tool. And I’m hoping that this tool will then be, in addition to being in a paper, will be available as some other method that it’ll be easier for us to use.”

Parental Guidance

Lonapegsomatropin last year received FDA approval for treating pediatric patients one year and older who weigh at least 11.5 kg (25.4 lb.) and have growth failure due to inadequate secretion of endogenous growth hormone, as well as positive opinion recommending the granting of a marketing authorization from the European Medicine Agency’s Committee for Medicinal Products for Human Use (CHMP). Still, if the prodrug is to corner the market by the end of the decade, it will have to clear some hurdles. Drugs explode on the scene all the time, only to just as quickly burn out or fade away.

For Rogol, some physicians may be hesitant to switch to a LAGH, whether it’s because of inertia or lack of knowledge, or not wanting the headache of switching products because of prior authorization. “On the other hand,” he says, “parents will hear about this, and they’ll be beating on our doors.”

Miller says that in his experience, the most common reason patients say no to the new treatment is because they didn’t want to “rock the boat” and deal with all the red tape that switching drugs can carry. “I’ve probably had 50% of people who I’ve offered it to say no, just because they didn’t want to change things,” he says. “They were worried that trying to switch might somehow prevent them from continuing on what they were on, or not be approved for the new drug and they’d be without anything. My early experience in offering it to kids and their families, has been, ‘I don’t want to upset the current thing that’s working.’”

On the “LAGH Track”

But it’s a new year, and payers may be re-evaluating what they’re covering, and there seems to be an appetite for once-weekly injections over daily jabs. Patients and physicians aren’t likely to try to put the genie back in the bottle once they start on LAGHs. And whatever happens with this market, the first therapy on the scene is likely the one to shape it. Each one of these LAGHs is a different chemical entity, and they’re going to have their own efficacy and safety data. (Some may even carry their own unique formulae for measuring IGF-1 levels.) This is all still new, so currently there aren’t enough data to rightly speculate what the market looks like a decade from now. “It is, in my opinion, going to be a universe of long-acting growth hormone four or six years down the road,” Rogol says. “What is the percentage of each player, that’s absolutely unknown.”

At the University of Minnesota, Miller and his team have an ongoing study they dubbed “UMN LAuGH Track” [https://growth.umn.edu/clinical-research-studies/laugh-track-umn], in which they look at kids who are on daily injections versus kids who chose to switch to LAGHs as a group, determining quality of life, adherence markers, and some metabolic changes – insulin resistance, body composition changes – to see the differences in those groups. The LAGH patients are all on lonapegsomatropin, and somapacitan is expected to be approved this year.  (Pfizer and OPKO’s somatrogon was recently denied FDA approval, but the companies say that will continue to work with the agency to find a path forward.) “I think it still is on the companies to capture that information on the long-term,” Miller says. “And I think each company is probably going to do that slightly differently.”

Miller says he’s working with Faisal Ahmed, MD, a pediatric endocrinologist in Glasgow, and Lars Sävendahl, MD, PhD, a pediatric endocrinologist in Stockholm, to generate a global registry for children with growth disorders so that we can capture some of this information, where investigators will enter their own data for their patients and then share that information globally. “The difference from the previous growth hormone registries is that this will now be something where, when the companies have closed the registry, this is something that we as investigators can continue” he says. “And we can follow children into adulthood if they choose to remain.”

For now, the JES paper authors hope that the model they established will help clinicians collect and easily interpret their own safety and efficacy data during long-term lonapegsomatropin therapy.

“The thing we want to be known is, hey, doc, you can measure IGF-1 at any time,” Rogol says. “You can pull out an app or a table on a laminated card, and you can say, this means the average level of IGF-1 is 20% more or 20% less than the one that you have measured at a particular time after administration , and you’re okay, so let’s keep the present dose. The whole thing is meant to be something quite practical.”

Miller is a consultant for Abbvie, Ascendis Pharma, BioMarin, EMD Serono, Novo Nordisk, Orchard, Pfizer, Tolmar and Vertice and has received research support from Aeterna Zentaris, Alexion, Abbvie, Amgen, Ascendis Pharma, Lumos Pharma, Novo Nordisk, OPKO and Pfizer.

Bagley is the senior editor of Endocrine News. He researched, compiled, and wrote the 2021 Progress Report in the December issue.