Computer generated transcript

Warning!
The following transcript was generated automatically from the content and has not been checked or corrected manually.

Thank you for inviting me to give this talk entitled Transitioning Patients with growth hormone deficiency, receiving daily growth hormone over to long acting preparations. My name is Kevin Y. I am a medical director and professor from uh Phoenix Arizona. Uh and these are my learning objectives. Uh Mainly aiming at selecting the appropriate candidates uh for consideration of transition of daily therapy to long acting preparations, uh particularly paying attention to the c criteria of the patient and also the patient's individual needs. And by doing so, also at the same time, assessing patient adherence challenges, other comorbidities, treatment goals and setting realistic expectations for the patients to hopefully improve not only long term adherence but also treatment outcomes and finally monitoring and adjusting a long acting growth hormone therapy during the time when the patient is on this, on this treatment uh to maximize uh treatment responses. So the major overriding question is why in the first place would we consider transitioning patients over from daily growth hormone to long acting growth hormone preparations? Given the fact that daily growth hormone has been around for over 30 some years with a good safety outcome data as well Um and the problem is daily growth hormone uh in many patients still uh has a lot of non adherence rates that are high, not only in Children but also in adults. And you can see here that many studies have been published showing the uh rates of non adherence that ranges re reasonably from 7% to almost 60%. So with re reduced adherence rates, treatment outcomes will inevitably be a problem. Then the question is, well, why is non adherence be uh being so common with daily growth hormone injections? Well, injections are never convenient. I mean, if you are having to get somebody to self inject, it is often convenient can be painful at the site of injections. And if you're doing these injections on a daily basis, uh treatment fatigue can occur. Uh patients are are distressed especially if they're having to give the injections to themselves, the parent and the caregiver and also life circumstances to take over, especially when you're so busy and you are also managing other medications. Uh not only that and then you're having to remember to take these injections on a daily basis. So with that in mind, the uh thinking was that maybe long acting growth hormone preparations may help to at least reduce the non adherence rates by reducing the number of injections. However, it's important to realize that um there are differences between daily and long acting growth hormone preparations for starters. Uh the duration of growth hormone exposure is uh definitely going to be different when you're having a daily growth hormone preparation versus a weekly or even a biweekly growth hormone preparation. Uh And with the long acting preparations, you can end up having high levels of growth hormone and IGF one levels and low levels of growth hormone and IGF one levels uh at different times of the week. Uh And with this in mind, there may be also relationship changes that occurs because growth hormone also has uh downstream effects on other binding proteins that binds with um uh IGF one to promote its circulation in in the circulatory circulatory system. Then there's also the uh differences in molecular structures which actually can affect uh and uh uh the tissue distribution of growth hormone, remember, growth hormone uh receptors are found in pretty much most organs. And so with the changes in the growth hormone molecular structure, uh that can be that you can certainly find differences in terms of tissue distribution. So it's important to realize that neither long acting or daily growth hormone preparations, neurophysiological growth hormone secretion. And this um figure is certainly what I'm trying to emphasize. You can see here uh patients uh who have no were normal patients. You can see the peak growth hormone that tends to occur uh in evenings. Uh and then there is a reduction in the in the peak growth hormone levels in a patient with growth hormone deficiency. And when you inject yourself with a growth hormone, a daily growth hormone uh injection, you can see there is a peak and a trough that occurs after four hours of injection that gradually goes down. And so it's by no means uh mi and mirrors the uh the changes that occurs in physio with physiological growth hormone secretion from the pituitary gland. So we talk about long acting growth hormone preparations. There has been changes and improvements in technology that allows growth hormone actions to, to uh to be prolonged. Um And it essentially there are four uh major or or main uh mechanisms of how growth hormone action is prolonged. You can have the daily absorption, uh a delay in the absorption of the subcutaneous space. Uh So you can have pegulation uh which incorporates into micros, uh microspheres. Uh You can also have slowing of circulation from the uh so uh slowing clearance from the circulation, you can have fusion proteins uh that, that you can bind these with uh naturally occurring proteins such as the HCG albumin and immunoglobulin chains. You can also modify uh the circulatory binding proteins, particularly albumin uh that promotes uh the prolongation. So, there are many ways of act many clever ways actually of actually increasing the uh action of growth hormone through these technologies that we have that are available at our disposal. Now, so with that in mind, I'd like to talk about the three long acting growth hormone preparations that are kind of in the forefront uh and is already uh being made available for pediatrics and adults uh with growth hormone deficiency. The first one is on the Paan uh which is a once weekly reversible albumin binding growth hormone derivative with a small albumin binding moiety, roughly about 1.3 kg alton attached to the growth hormone molecule. This uh mole structure facilitates the reversibility uh and the bi of binding of circulating endogenous albumin. And by doing so, enables the reduction of clearance and extension of the half-life of this drug allowing once weekly administration. It's a well established technique. In fact, it's used uh to extend the half lives of insulin detemir and other GLP one agonists like uh semaglutide. So, uh there's a lot of experience in this technology as well. And this slide essentially shows the PK PD of Silva pace both in Children and adults with growth hormone deficiency. Uh And you can see here is that uh uh on the left hand side, uh you have the subjects with ADHD single dose and on the bottom. Uh you can see Children with a single dose and there are different doses ranging from 0.02 mg per kilogram, up to 0.16 mg per kilogram. So this is a weight based dosing and as you can see the different colors representing the dose response relationship, you can see also that the uh uh some of pine levels goes up within the 1st 24 hours or so and then gradually tapers down over uh 50 hours or so. And with the data on the right hand side, single doses, you can see there again that Children tends to be exposed to higher levels of SOMA past 10 because Children uh tends to be exposed to higher doses of uh uh growth hormone anyway. Uh but they tend to be a little bit more resistant. As you can see in the bottom, the changes in IGF one is not as uh pronounced as healthy subjects and also subjects with uh uh adult growth hormone deficiency. Uh This uh this figure shows again, uh it's a nice breakdown just to simplify those complicated figures. I showed you in the previous slide, you have uh avas that show the SOMA pet 10 trough and the SOMA petton uh during the different times of the week. Obviously, the trough is roughly around the midpoint and the uh sorry, the trough is roughly around the end just before the next injection and the peak is actually at the midpoint. So you get the average somewhere in the middle. Um And uh you can see that if you compare that with daily growth hormone, which is in red, on the right hand side, you can see that obviously, daily growth hormone is a little bit more stability seen with IGF one. Whereas um so the past 10, you can see there um uh, peaks in.