Growth Hormone Deficiencies/Abnormalities

December 19, 2016

AstraZeneca issued results of a phase III study of TAGRISSO (osimertinib) for epidermal growth factor receptor (EGFR) T790M mutation-positive metastatic non-small cell lung cancer (NSCLC). AURA3 data showed TAGRISSO offered a statistically significant improvement in PFS versus standard platinum- based doublet chemotherapy (10.1 months vs 4.4 months, hazard ratio [HR] 0.30; 95% confidence interval (CI): 0.23, 0.41; p<0.001). In an investigator-assessed, prespecified exploratory subgroup analysis of 34% of patients with central nervous system (CNS) metastases at baseline, PFS was 8.5 months with TAGRISSO versus 4.2 months with platinum-pemetrexed chemotherapy (HR 0.32; 95% CI: 0.21, 0.49). The AURA3 safety data for TAGRISSO were in line with previous experience. Grade =3 drug-related adverse events (AEs) were reported in 6% of patients (n=16) treated with TAGRISSO and 34% (n=46) treated with platinum-based doublet chemotherapy. The most common drug-related AEs in the TAGRISSO group, were diarrhea (29% overall; 1% Grade =3) and rash (28% overall; <1% Grade =3) and, in the chemotherapy group, they were nausea (47% overall; 3% Grade =3) and decreased appetite (32% overall; 3% Grade =3). TAGRISSO was granted accelerated approval by the FDA in November 2015, conditional marketing authorization by the EMA in February 2016, approval in Japan in March 2016 and is currently under Fast Track review in China.

February 8, 2016

Zafgen issued results of a pivotal, double-blind, placebo-controlled, phase III trial evaluating the safety and efficacy of beloranib for Prader-Willi syndrome (PWS). The bestPWS ZAF-311 study randomized 107 patients to receive twice-weekly subcutaneous injections of either 2.4mg or 1.8mg of beloranib or placebo. Seventy-four patients completed the full 26 weeks of treatment per the trial protocol, and 27 patients completed at least 75% of the randomized treatment period prior to the suspension of dosing in the trial in October 2015. There were six patients who discontinued early. The co-primary efficacy endpoints for this trial were improvement in hyperphagia-related behaviors and reduction in body weight. Patients in the trial were on average 20 years old, had an average BMI of 40kg/m2 and an average hyperphagia total score of 16.9, consistent with moderate to severe hyperphagia, at the beginning of randomized treatment. Treatment with the 2.4mg and the 1.8mg doses of beloranib resulted in reductions of hyperphagia-related behaviors of 7 units (p=0.0001) and 6.3 units (p=0.0003) relative to placebo, respectively, as measured by the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Patients randomized to receive placebo displayed substantial (4.15%) gain in body weight over the course of the six months of randomized treatment. Patients treated with beloranib, in contrast to placebo, lost weight, with the 2.4mg dose arm displaying a 5.3% reduction from baseline, with a placebo-adjusted weight loss of 9.45%. In December 2015, the FDA placed the beloranib IND application on complete clinical hold due to an imbalance in severe venous thromboembolic events, including two patient deaths. Zafgen plans to present to the FDA the efficacy and safety data from the bestPWS ZAF-311 study, data from the phase IIb trial of beloranib in severe obesity complicated by type 2 diabetes and a proposal for a risk mitigation strategy for beloranib in PWS.

February 1, 2016

ViroMed has announced the publication of the results from successfully completed phase II clinical study of VM202 for the treatment of critical limb ischemia in the January issue of Gene Therapy. The study, “A phase II, Double-blind, Randomized, Placebo-controlled, Multicenter Trial of the Safety and Efficacy of Plasmid DNA Expressing two Isoforms of Hepatocyte Growth Factor in Patients with Critical Limb Ischemia,” examined 52 patients at 16 hospitals and research centers in the United States and Korea. Results from the clinical study showed VM202 to be safe and well tolerated with clinical benefits in CLI patients. VM202 was intramuscularly injected in four series in the muscle of diseased legs in patients, spaced 2 weeks apart, and observed for 12 months. Patients were randomly divided into three groups of placebo, low-dose (8 mg total), high-dose (16 mg total). While both VM202 treated groups showed better improvement compared to the placebo group, patients treated with high-dose VM202 showed significantly better ulcer healing and tissue oxygenation (TcPO2 levels) than patients from the placebo group. “These positive results are exciting, and VM202 shows great promise for treating patients with this debilitating disease who often have limited therapeutic options,” said Dr. Emerson C. Perin, Director of the Stem Cell Center at the Texas Heart Institute and the principal investigator of the study. “We are looking forward to conducting a phase III trial to better understand the potential of this novel approach, especially in treating non-healing ulcers, which is a serious symptom that often leads to amputation because of the lack of medical therapies available.” 

August 17, 2015

Ascendis Pharma announced positive topline results from a six-month, phase II study of once-weekly TransCon Growth Hormone in 53 treatment-naïve, pre-pubertal children with growth hormone deficiency (GHD). The multicenter, randomized, open-label study compared three dose levels of TransCon Growth Hormone (0.14mg; 0.21mg; and 0.3mg hGH/kg/week), administered once per week, to the active control Genotropin (0.21mg hGH/kg/week), administered as a daily injection. The mean annualized height velocities among the three dosing levels administered weekly ranged from 11.9cm for the 0.14mg/kg/week dose to 13.9cm for the 0.3mg/kg/week dose, which were comparable to 11.6cm for the active comparator, daily injections of Genotropin at a 0.21 mg/kg/week dose. There were no reports of drug-related, serious or unexpected adverse events. The company plans to initiate a phase III pediatric study of TransCon Growth Hormone in mid-2016.

July 6, 2015

BioMarin Pharmaceutical released results of a phase II study of BMN 111 (vosoritide) in children with achondroplasia. The trial was an open-label, sequential cohort dose-escalation study. Patients were treated with either 2.5μg/kg/daily, 7.5μg/kg/ daily or 15μg/kg/ daily. A total of 26 children with achondroplasia with an average age of 7.8 years were enrolled. The 10 children in cohort three treated with 15 micrograms per kilogram per day had a mean increase of 50% (p=0.01) in their annualized growth velocity compared to their annualized prior six month natural history baseline growth velocity. Changes from baseline in proportionality as measured by upper to lower body ratio were not observed. Based on the safety profile observed to date across the three dose cohorts, all subjects have been switched to the highest dose of 15μg/kg/ daily for the duration of the 18 month extension study. Vosoritide has Orphan designation in both the U.S. and Europe.

October 14, 2013

Versartis issued results from a phase Ib/IIa trial of VRS-317 in pre-pubertal children with growth hormone deficiency (GHD). The study is being conducted in approximately 30 U.S. pediatric endocrinology centers and will enroll up to 72 naïve-to-treatment, pre-pubertal children with GHD documented by auxologic criteria and two GH stimulation tests. VRS-317 dosing began at 0.80mg/kg, with dose increases to 1.20mg/kg, 1.80mg/kg, 2.70mg/kg, 4mg/kg and 6mg/kg (equivalent to 4.8, 7.4, 11.1, 16.7, 24.7 and 37.0mcg rhGH per kg per day taken for 30 days). 48 subjects (27M, 21F) with mean age 7.2 years were studied in six dose cohorts (eight per cohort). VRS-317 plasma concentrations reach a maximum at a mean time of three days post-dose, are proportional to dose and remain detectable for up to 30 days from a single dose in all subjects tested. Maximal changes in IGF-I SDS occur between two to 14 days after a single dose on day one. The amplitude and duration of IGF-I responses increase with increasing VRS-317 dose. The increase in average IGF-1 SDS over 30 days also was proportional to dose and sufficient to support up to once-monthly dosing of VRS-317. Importantly, the prolonged IGF-I responses do not come at the expense of over-exposure to high IGF-I levels, where only a single value of IGF-I SDS in each of two patients has exceeded +2.

July 1, 2013

Versartis released results from a phaseIb/IIa trial of VRS-317 for the treatment of Growth Hormone Deficiency (GHD). The trial enrolled 72 naïve-to-treatment, pre-pubertal children with GHD and consisted of two stages. VRS-317 dosing began at 0.80 mg/kg, a dose shown to be safe and well-tolerated in GHD adults in a previously completed trial, with planned dose increases to 1.2mg/kg, 1.8mg/kg, 2.7mg/kg, 4mg/kg and up to 6mg/kg. The typical dose of daily rhGH in children with GHD is approximately 40mcg/kg/day. Related adverse events have been reported in 12 subjects to date and all have been mild and transient. Single doses of up to 2.7mg/kg are safe and well-tolerated. In addition, dose proportional increases in VRS-317 levels and IGF-I responses were observed, indicating the ability to select doses and dose regimens for up to once monthly dosing. The only approved growth hormone treatments require daily injections.

May 6, 2013

Versartis released results from a phase I trial of VRS-317 for the treatment of growth hormone deficiency (GHD). This multi-center, double-blind, placebo-controlled, single ascending dose study enrolled 50 adults with GHD. Subjects received VRS-317 0.05mg/kg, 0.10mg/kg, 0.20mg/kg, 0.40mg/kg or 0.80mg/kg. Results showed that after a single 0.80mg/kg dose, serum IGF-I was maintained in the normal range between -1.5 to 1.5 standard deviations (SD) for a mean of three weeks. Furthermore, the 0.80mg/kg dose of VRS-317 had a mean terminal elimination half-life of 131 hours, which is 30-60-fold longer over those reported in package inserts for daily rhGH and stimulates more durable IGF-I responses than previously studied rhGH products. VRS-317 was well tolerated. No unexpected or serious adverse events were observed. Based on this data, Versartis is now investigating the safety and efficacy of VRS-317 in a phase Ib/IIa clinical trial in pre-pubertal children with GHD.

October 29, 2012

Aeterna Zentaris issued results from a phase III trial of AEZS-130 as an oral diagnostic test of adult growth hormone deficiency (AGHD). This multi-center, open-label study enrolled 101 patients. Subjects received either AEZS-130 or placebo. Results showed mean peak growth hormone (GH) levels in AGHD patients and controls following AEZS-130 administration were 2.36ng/mL (range 0.03-33) and 17.71ng/mL (range 10.5-94), respectively. The receiver operating characteristic (ROC) plot analysis yielded an optimal GH cut-point of 2.7ng/mL, with 82% sensitivity, 92% specificity and a 13% mis-classification rate. Obesity (BMI>30) was present in 58% of cases and controls, and peak GH levels were inversely associated with BMI in controls. AEZS-130 was well tolerated. Of the 50 subjects studied with both stimulation tests, 70% expressed a preference for AEZS-130 over L-ARG+GHRH. Aeterna plans to submit an NDA for AEZS-130.

May 14, 2012

Prolor Biotech issued results from a phase II trial of hGH-CTP, a long-acting drug for the treatment of growth hormone deficient adults. This study enrolled 42 patients who were well titrated on daily growth hormone therapy and had previously participated in the phase II trial that tested once-weekly hGH-CTP regimen. Subjects received hGH-CTP in single weekly injections for four months, beginning with an initial dose containing 50% of the hGH-CTP found in the next doses. Patients who achieved IGF-1 levels within the Narrow Normal Range ± 1.5 SDS increased from 69% at the start of the study to 81% at its completion. Data confirmed safety and tolerability of hGH-CTP, with no unexpected adverse events. Prolor Biotech did not note if it plans to move on to phase III trials.

Novartis released results from a phase III study of long-acting release SOM230 for the treatment of acromegaly. This randomized, double-blind study enrolled 358 patients who were de novo with a visible adenoma on MRI or medically-naïve. Subjects received intramuscular injections of SOM230 40mg (n≡176) or octreotide long-acting release 20mg (n≡182) every 28 days for 12 months. At months three and seven, dose titration to SOM230 60mg or octreotide 30mg was permitted if patients had excess growth hormone(GH) >≡2.5µg/L and/or IGF-1 > upper limit of normal (ULN). The 12-month study was completed by 80.1% (141/176) and 85.7% (156/182) of SOM230 and octreotide recipients, respectively, with dose up-titration performed in 50.6% and 67.6% of SOM230 and octreotide recipients. At baseline, mean GH was 21.9 µg/L and 18.8µg/L in the SOM230 and octreotide arms, respectively; mean IGF-1 was 2.6xULN and 2.8xULN. The primary endpoint was achieved by 31.3% of SOM230 recipients and 19.2% of octreotide recipients (p≡0.007). Mean GH and IGF-1 decreased by month three and remained suppressed. At month 12, 48.3% of patients receiving SOM230 had mean GH<2.5µg/L compared to 51.6% of those on octreotide (p≡0.536), while normal IGF-1 was achieved by 38.6% of patients receiving SOM230 and 23.6% of patients receiving octreotide (p≡0.002). SOM230 was well tolerated and its most adverse events included diarrhea, cholelithiasis, headache and hyperglycemia. At the completion of the study, Novartis invited subjects to participate in a six-month extension phase (now ongoing).

January 23, 2012

PROLOR Biotech reported results from a post-phase II trial evaluating their long-acting CTP-modified version of human growth hormone (hGH-CTP) for growth hormone deficiencies in adults. The trial enrolled 12 subjects who were switched from daily injections of conventional hGH to a regimen of two injections of hGH-CTP over a period of 30 days. The two injections of hGH-CTP contained either 15% or 50% of the total cumulative dose of hGH the subjects would usually inject over the 30-day period. Data showed a clear correlation between dose and IGF-1 response, and subjects receiving the 50% dose showed promising IGF-1 response to the twice-monthly hGH-CTP injection regimen.

August 8, 2011

Prolor Biotech issued results from a phase II trial of their long-acting CTP-modified version of human growth hormone (hGH-CTP) for growth hormone deficient adults. This global, randomized, open-label, dose-finding study enrolled 39 subjects with growth hormone deficiency who were receiving daily injections of growth hormone. The subjects were placed in three cohorts and received a single weekly dose of hGH-CTP for four weeks, containing 30%, 45% or 100% of the equivalent cumulative commercial hGH dose these subjects would usually inject each day over the course of seven days. Efficacy was defined by measuring daily insulin-like growth factor 1 (IGF-1) levels within the desired therapeutic range over a period of seven days during the last week of treatment. All three cohorts achieved average IGF-1 levels that were within the normal range on 100% of the days when they were assessed. In addition, the subjects in each of the cohorts achieved average IGF-1 levels within the narrow definition of the normal range on many or most of the days when they were assessed. hGH-CTP demonstrated excellent safety and tolerability across all trial cohorts.

April 18, 2011

Prolor Biotech released interim results from a phase II trial of their long-acting human growth hormone (hGH-CTP) for growth hormone deficient adults. The global, randomized, open-label, dose-finding study plans to enroll up to 56 subjects with growth hormone deficiency who are receiving daily injections of growth hormone. Data are from the two low dose cohorts (n≡34) who received a single weekly dose of hGH-CTP, containing 30% or 45% of the cumulative commercial hGH dose these subjects would usually inject each day over the course of seven days. Efficacy for the cohorts receiving a single weekly injection of hGH-CTP is defined by measuring whether insulin-like growth factor 1 (IGF-1) levels can be maintained within the desired therapeutic range over a period of seven days. The interim results suggest that this efficacy endpoint is achievable; potentially allowing for the replacement of seven consecutive daily injections of hGH with a single injection of hGH-CTP.

February 8, 2010

PROLOR issued positive results from a phase I trial of hGH-CTP, their long -acting version of human growth hormone. This randomized, double-blinded, placebo-controlled, single-dose, dose escalating study enrolled 24 healthy subjects at the Tel-Aviv Medical Center in Israel. The subjects received one of three doses of hGH-CTP (4mg, 7mg, or 21mg) or placebo. All safety and tolerability endpoints were met with each of the doses. The potential clinical efficacy of hGH-CTP was assessed by measuring the extent to which hGH-CTP induced insulin-like growth factor-1 (IGF-1) in subjects. Based on this measure, data suggests that the daily injections currently required by conventional hGH-users can potentially be replaced with just two monthly injections of hGH-CTP.

October 3, 2005

Altus Pharmaceuticals issued positive results of a phase I trial of their long-acting crystalline formulation of human growth hormone (HGH) ALTU-238, for the treatment of HGH deficiency, at the 7th joint meeting of the European Society for Paediatric Endocrinology and the Lawson Wilkins Pediatric Endocrine Society in Lyon, France. Trial data yielded pharmacokinetic and pharmacodynamic data supportive of once-weekly subcutaneous dosing, and a single-dose of the drug produced sustained serum IGF-1 levels comparable to 7 daily injections of an approved HGH formulation. This open-label study enrolled healthy adults, who received a single subcutaneous injection of the drug.

June 6, 2005

Ardana Biosciences has issued positive results of a phase II study of their gonadotrophin-releasing hormone antagonist Teverelix LA, for the treatment of benign prostatic hyperplasia (BPH). Results of the study indicated that the drug yielded a decrease in mean symptom severity score of 12.6% at 2 weeks and 33.9% at 6 weeks on the International Prostate Symptom Score scale, vs. 5.7% (p<0.004) and 7.4% (p<0.001) for placebo. 76% of patients receiving the drug experienced a reduction in symptom severity of at least 25% from baseline, and significant improvements were noted in maximum urine flow rate (43%), quality of life (32.8%) and prostate size (11.5 % reduction) from baseline. This randomized, double-blind study enrolled 81 patients with BPH, who received a single-dose of Teverelix LA (n=41) or placebo (n=40) subcutaneously, with a 6 week follow- up.

Insmed reported results of a pivotal phase III trial of SomatoKine (mecasermin rinfabate), their investigational insulin-like growth factor I (IGF-I) replacement therapy for the treatment of pediatric short stature due to growth hormone insensitivity syndrome (GHIS). Trial results met their primary efficacy endpoint, producing an overall mean increased in annualized height velocity of 5.0 cm/year after 6 months of treatment, compared to pre- treatment rates (p<0.0001). Increases in velocity were seen to be dose dependent: subjects on low fixed dose regimen (0.5-1.0 mg/kg) experienced a mean annualized increase of 4.0 cm/year, while subjects on the high fixed dose regimen experienced an increase of 6.6 cm/year. Additional efficacy was noted in maintaining growth rates through 12 months in the subgroup of patients achieving optimal IGF-I levels after 1 month (p<0.0018). This prospective, multicenter study enrolled 29 children with GHIS, who received daily subcutaneous injections of 0.5-20 mg/kg SomatoKine.

April 25, 2005

AEterna Zentaris and Ardana issued positive results of a phase I trial of their investigational growth hormone (GH) secretagogue EP-1572, for the treatment of GH deficiency disorders. Trial data yielded evidence of bioactivity, with a mean plasma GH concentration of 79.12 ng/ml, vs. 3.58 ng/ml for placebo and a baseline measure of 52.62 ng/ml with GHRH; this increase was statistically significant (p=0.009). No safety concerns or adverse events were reported. This placebo-controlled dose-escalation study enrolled 36 healthy male volunteers, who were divided into one of 3 dosing cohorts (single oral dose of 0.005 mg/kg, 0.05 mg/kg, or 0.5 mg/kg). 9 subjects per cohort received the drug and 3 received placebo.

ConjuChem reported expanded results of a phase II trial of DAC:GLP-1, in combination with metformin, for the treatment of type 2 diabetes. Subjects receiving high dose DAC:GLP-1 in combination with metformin (n=15) experienced a mean change in HbA1c value (a measure of glycemic control) from baseline of -0.70%, vs. +0.15% for subjects receiving placebo plus metformin (n=13); this difference was significant (p=0.003; ITT population). Furthermore, the drug combination reduced HbA1c levels to below 7.0% (the ADA target value) in 58% of subjects who entered the trial above this value. This three-month, double blind, placebo-controlled combination therapy trial enrolled a total 85 subjects already receiving a standard metformin therapy regimen, to which was added either a low or high daily dose of DAC:GLP-1 or placebo. The company announced plans to conduct additional trials of the drug formulated with a new diluent designed to improve tolerability in the near future.

October 4, 2004

LAB International has announced positive results of a phase I/II trial of their Growth Hormone Releasing Hormone (GHRH) analog, being developed as an inhalable treatment for growth hormone (GH) deficiency caused by a number of diseases, including HIV, chronic renal failure and lipodystrophy. The drug was found to be safe and well tolerated, with no significant adverse events. Furthermore, the drug produced significant increases in serum GH levels up to 12 hours after treatment at all dosing regimens, and demonstrated a higher-than-expected efficacy for this endpoint. No impact on normal nocturnal GH secretion was observed. The placebo-controlled, single-dose safety and efficacy cross-over study enrolled a total of 10 healthy volunteers, all of whom received randomized sequential dosing regimens of 5-25 ug/kg and placebo. LAB announced plans for both indication-driven phase II trials and another phase I/II dose-ranging trial to establish minimum therapeutic dose.

July 26, 2004

Insmed has provided an interim update on their phase III study of SomatoKine (mecasermin rinfabate), which is being developed for children with severe short stature due to growth hormone insensitivity (GHIS). Six-month interim data analysis has shown that the drug is efficacious in treating GHIS, with a highly statistically significant increase in height velocity following once-daily injections (p<0.0001). The ongoing multi-center, open-label study was designed to investigate the safety and efficacy of SomatoKine in pre-pubescent children with GHIS. No serious adverse events were noted. SomatoKine announced that final results are expected in 2005.

July 12, 2004

Zonagen announced positive preliminary results of their phase I/II study of Androxal (clomiphene), an estrogen antagonist, for the treatment of testosterone deficiency in men. Results indicated that the drug was safe and well tolerated, and produced significant increases in testosterone levels over placebo. The trial randomized a total of 70 hypogonadal men into one of 6 treatment arms: one of three doses of oral Androxal, one of two doses of topic Androgel (a currently approved topical gel for testosterone deficiency), or placebo. All subjects received daily dosing for two weeks to analyze safety and tolerability, and half of the subjects in each trial arm were examined on days 1 and 14 for pharmacokinetics and efficacy in increasing testosterone levels. Androxal was found to be comparable to placebo for all adverse events, and it produced significant, dose dependent increases in testosterone levels during a 7-10 day observation period following administration at all dose levels. Zonagen indicated that they would announce final results, including comparative data for Androxal vs. Androgel, later this year.

June 28, 2004

Tercica reported long term safety and efficacy results for their phase III trial of recombinant human Insulin-like Growth Factor-1 (rhIGF-1), for the treatment of severe pediatric short stature caused by IGF-1 deficiency due to growth hormone insensitivity. Results showed that rhIGF-1 significantly increased growth rate, and had an acceptable safety profile. The study enrolled 54 subjects for efficacy investigation and 65 for safety; all subjects received twice daily injections of rhIGF-1 at 80-120 µg/kg for 1-10.5 years. Efficacy-group data demonstrated a 3 fold increase in growth over the first year, and a 2 fold increase over an 8 year study period, compared with literature-established baselines. Safety group data indicated that rhIGF-1 was well tolerated and safe, with no dropouts due to adverse events; transient hypoglycemia was the most common adverse event, and it was effectively managed by eating at injection times. Tercica planned to file an NDA for rhIGF-1 by early 2005.

October 14, 2002

Results from Human Genome Sciences's phase I trial investigating Albutropin, a recombinant growth hormone showed drug was safe and well tolerated. The multi-center, open label, dose-escalating study was designed to determine safety, tolerability, and pharmacology of the drug with 42 subjects enrolled. The drug was shown to have a prolonged half-life, was well tolerated and was biologically active in adults with growth hormone deficiency. There were no drug-related adverse events or discontinuations in the trial and Albutropin remained in the blood substantially longer than is reported for recombinant native human growth hormone. 64% of subjects responded who received single doses of Albutropin at 60 mcg/kg and 66% responded who received two doses seven days apart at 60 mcg/kg.

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