Insights into GHD and Long-Acting Growth Hormone Therapy With Robert Rapaport, MD

Introduction:

Rare Disease 360 presents, Growth Hormone Deficiency With Robert Rapaport, MD.

Robert Rapaport, MD:

I’m a Professor of Pediatrics and a Pediatric Endocrinologist at Mount Sinai, and the Icahn School of Medicine, and the Children’s Hospital. I’ve been involved in pediatric endocrinology for a very long time and especially my interest is growth. One of things that we’re pioneering is a Comprehensive Growth Center, which I’m directing.

Question:

Can you provide us with a brief overview of any clinical guidelines surrounding the use of long-acting growth hormones in children with growth hormone deficiency (GHD)?

Robert Rapaport, MD:

I think there aren’t any specific indicators for long-acting growth hormone or treatment as opposed to growth hormone treatment in general so I think I’d like to kind of put a point of caution to your audience and that is, how do we make a diagnosis of growth hormone deficiency, which is really the indication that long-acting growth hormone is approved for. There are lots of controversies about (1) diagnosis of growth hormone deficiency, and many parents ask that sometimes when they’re seen in their first visit for short stature. I think there have been a lot of changes, a lot of controversy about it but generally what I tell parents is that, first we’ll need to do basic tests to exclude any non-hormonal, non-growth hormone–related conditions that may affect your growth.

A common one we see is, for example, celiac disease. I just had a child the other day who came in, is quite short, so now we want that treatment to work first. Then, if all those other conditions that could affect growth are excluded, we measure a baseline IGF-1 level, which can be affected by nutrition or various other things. If that is low and if a child isn’t growing well, then we do a growth hormone stimulation test, which is a 3-hour test to assess the production of growth hormone. There are tons of controversies and we’ve written about some of this, about how to conduct that test, what influences it, should it be prime, should it not, what’s the peak level, etc.

Once you have all those in place, then you make the diagnosis of growth hormone deficiency and, if that’s the case, that suggests a pituitary defect in the production of growth hormone so most of us would recommend obtaining a pituitary MRI, and in the vast majority of cases, that will be normal. Occasionally, it may show a variant in the size or in the location of the pituitary gland and if that’s indeed normal then we discuss treatment. There aren’t any special indications for long-acting versus short-acting, therefore, the way we do that is we discuss the options with the parents and then ask whether or not they’d be inclined to use daily or long-acting.

As you know well, most of the decisions about growth hormone and growth hormone preparations are, for better or for worse, taken out of our hands and they’re in large part in the purview of the insurance company. If the insurance company can tell you that you could use either of the preparations, then we discuss with the parents and see who would prefer the long-acting versus the daily. Then, I think what your question was really after is that any particular group of children that we would recommend long-acting versus not. That starts with children who’ve been on growth hormone for a while who’ve had knowledge about the development of the long-acting, who will say, many of them have said to me, “Howabout can I go and try the long-acting growth hormone month?” Certainly, the answer to that is yes, of course you can, assuming your insurance company does it.

I see that probably more often in some of the adolescent children who are on growth hormone because they’ve had the daily growth hormone for a long time, they’re somewhat tired of it, they would like to do something different, and they would be very interested in an alternative to daily injections. The other group that sometimes is very interested in this is where would the parents give the injections? For example, very young children who do not do their own injections and the parents do it and the parent isvery busy, the parent is traveling here and there and says, “Could I give a shot upon intended to the long-acting growth hormone?” Those were the kind of categories that would be interested in discussing the long-acting.

One of the supposed rationales behind the development of the long-acting is to improve adherence and if there are children, or parents for that matter, who have a good history of non-adherence to daily injections, obviously those would be ideal for switching to that.

Question:

What measures or protocols should healthcare providers take if a dose is missed? If a dose is missed by a patient, are there any specific considerations or adjustments that need to be made?

Robert Rapaport, MD:

The question is how does one monitor growth hormone treatment? Again, that’s an area of controversy, but the way we frequently do that is to measure a serum IGF-1 level, but there are inherent controversies in that. The specific assay I use for measuring IGF-1 may be different from the one somebody else uses, but, in general, if a child is on growth hormone treatment and you measure an IGF-1 that’s low on treatment, that is a suggestion that they may not be taking the growth hormone. Of course, it could be very unusual conditions when they do not respond to growth hormone but the vast majority of cases would be that they’re not taking it.

With the daily, we think that there’s a level that accumulates an IGF-1 level is fairly good measure of that. With the weekly, it’s a little bit different because the level of IGF-1 varies during the week, from having a trough level to a peak level, and that’s something we’re still learning exactly how to do that. The suggestions have been from all 3 companies that currently have long-actings on the market, is to measure a level about 3 to 4 days after their injection, which, given when the child is seen, when the child gets the injection may or may not be all that feasible all the time.

Question:

Have there been any notable advancements or updates in the use of long-acting growth hormones in clinical practice since approval? How have these developments influenced treatment approaches?

Robert Rapaport, MD:

There haven’t been any major developments but, obviously, the longer it is on the market and the longer it proves to be safe the more encouraging that is to the population that wants to use it. There was a recent meta-analysis looking at safe data in such patients on long–active growth hormone based in Asia and that, at least for the amount of time this has been used, it seems to be quite safe. I’m not sure that there are any ongoing studies yet to look prospectively at both the safety and efficacy of the long-acting growth hormone.

As you know, the FDA approval for these preparations was based on a head-to-head comparison with daily growth hormone. In those comparisons, all the long-acting growth hormone preparations that have been approved have demonstrated that they’re equally as safe and equally as effective as the daily preparation.

Question:

Can you discuss any challenges or limitations that healthcare providers may encounter when utilizing long-acting growth hormone therapy in clinical practice? How do we navigate these challenges effectively?

Robert Rapaport, MD:

The challenges are (1) there’s not a long-term safety record of these compounds and there’s not a long-term efficacy more than the trials that have been conducted. As you know, when we see a child with growth hormone deficiency on treatment, what we do is we look at their growth velocity, compare that with the IGF-1 level, and based on that, we see if we need to alter the dose, either increase or decrease. With the long-acting, the challenges, as I think I alluded to a minute ago, is when do you measure the IGF-1 level? How accurate is that in predicting the growth response?

The simple paradigm might be the better the IGF-1 level the better the growth rate, although I’m not sure that’s always true. The other challenge is that a child has an appointment on Tuesday but the growth hormone injection the family always gives on Sunday, so that’s only 2 days later. How do we interpret that IGF-1 level then? Should we then have them do it not at the time of the visit? That increases the challenge to both us and to the parents and to the children so it’s really a multiplicity of challenges that one needs to navigate with a long-acting growth hormone.

Question:

Are there any specific patient populations or conditions where the use of long-acting hormone therapy is particularly beneficial or contradicted? How do you tailor treatment approaches accordingly?

Robert Rapaport, MD:

The specific approval that the FDA gave was for children with growth hormone deficiency, and I think there are a lot of challenges in the definition of growth hormone deficiency. But once one wants to make that decision that the child does have what’s accepted as growth hormone deficiency, then long-acting growth hormone is in fact indicated. Therefore, other conditions that we use, for which we use growth hormone on a daily basis, are not necessarily the ones for whom long-acting growth hormone is either indicated or approved. For example, children with Turner syndrome, children who are born small for gestational age, even though one of the companies is working on that approval, so there’s a number of different challenges depending on the conditions that you use.

The ones in whom I think it’s particularly useful are the ones I started off the conversation with. For example, adolescents who have a long history of daily injection and they have kind of injection fatigue and they’re tired of taking it every day, we have now an alternative and they just take it once a week. The other, I think, very good companies for families in whom the parents are the primary provider of the injections. Infants, young children, and the parents have busy lives, they’re not always around for the daily injections, that would be another. Traveling is another key issue. If you travel for a short time, if a child has a sleepover and doesn’t want his friends to know, those are special circumstances and certainly the long–acting preparation seems to obviate the need to take it every day and, therefore, gives the children and their families a little bit of extra flexibility.