Human growth hormone (GH) stimulates growth, cell reproduction, regeneration, and understandably is an important part of the development process. GH stimulates another hormone, insulin-like growth factor 1 (IGF-1), which works in conjunction with GH and regulates one another. Together, GH and IGF-1 affect nearly all tissues and organs, and stimulate the differentiation and proliferation of chondrocytes at the growth plate (Kaplan 2007). Optimal growth occurs only when these two hormones are at physiological levels, as several studies have shown that children that are given GH only, or IGF-1 only, do not see the same growth rate as both GH and IGF-1 (Backeljauw 2015).
In cases of GH deficiency, recombinant human GH has been commercially available as daily injections since the 1980’s. In theory, children on daily GH therapy are expected to achieve normal adult heights. However, real-world data has contradicted this hypothesis. Much of this is due to lack of adherence, and a steady decline in persistence rates of up to 67% in pediatric patients has been observed in the first 11 months of treatment (Saenger 2016). Patients who miss more than 1 injection per week show statistically lower growth than to their peers (Cutfield 2011). Lack of adherence is mainly due to stigma of daily GH, scheduling issues, and disappointment over apparent effectiveness (Fisher 2013). Several strategies to reduce injection frequency have been attempted.
One idea has been to modify growth hormone to slow renal clearance, and thus reduce the amount of needed injections. One recent attempt was by Versartis. VRS-317 (somavaratan) was a fusion protein, with the active portion of GH bound to long hydrophilic amino acid chains. This reduced renal clearance, and Versartis believed they could lower the injection frequency to once every two weeks. However, VRS-317 ultimately failed to show non-inferiority with daily GH (Yuen 2017). One reason may be due to the size of the modified molecule. Normal human GH is 22 kDa, while VRS-317 was 119 kDa. Several studies have shown an inverse relationship between size of molecules and tissue penetrance (Farnum 2006). More specifically, a group found that adding PEG moieties reduced renal clearance, but also reduced the affinity of GH for its receptor. The EC50, the concentration needed for a half-maximal response, was increased by up to 1500x as the molecular weight increased (Clark 1996). It is also interesting to note that any modified GH therapies has yet to be approved (Sprogue 2017).
In contrast, Ascendis’s TransCon GH releases unmodified GH bound bound to an inactive PEG carrier in order to reduce renal clearance, and thus reduce the frequency of injections to once a week (Chatelein 2017). Interestingly, once-weekly injections may show higher adherence rates than once every two weeks, as Versartis still ran into adherence issues in their Phase 3 (per protocol patients met non-inferiority). One injection every Monday may be easier to remember than one injection every other Monday. Studies have shown that pulsatile administration is equal in efficacy and safety to continuous GH (Jorgenson 1989), but careful monitoring of GH and IGF-1 is still required. Safety issues can arise with IGF-1 levels rising to supraphysiological levels, including increase in BMI, intracranial hypertension, and neoplasia (Allen 2016). Several tested long-acting GH have not shown adequate IGF-1 profiles. Importantly, TransCon GH has shown to increase IGF-1 to normal levels, in contrast to sharp spikes in IGF-1 seen in some modified GH (Hoybye 2017). TransCon has shown equivalent growth to daily GH in smaller Phase 2 trials, without incidence of neutralizing antibodies (vs 3% to VRS-317). As one expects, TransCon GH has also shown a similar side effect profile known to daily GH.
While possible that TransCon has lower adherence in longer and larger studies, use of an unmodified hormone and potentially more convenient dosing schedule gives me confidence that it will show non-inferiority to daily GH in the upcoming Phase 3 readout. Ascendis also uses the same carrier platform for sustained release of other modified parent drugs. Positive readout for GH will have a strong read through for the rest of the pipeline.
MS Biotech Thoughts 