Kathleen Louden

June 25, 2014

CHICAGO — A new growth-hormone derivative injected once a week for treatment of adult growth-hormone deficiency (AGHD) shows a comparable dose response and tolerability profile to daily-use injectable somatropin (rDNA origin) (Norditropin Nordiflex, Novo Nordisk), according to results of the first trial in adult patients.

Insulinlike growth factor 1 (IGF-1), a surrogate marker for effects of growth-hormone treatment, was elevated at all tested doses of the new once-weekly NNC0195-0092 (Novo Nordisk), researchers told Medscape Medical News.

"We like that it had a similar dose response as daily-use Norditropin because we know it is safe and efficacious," said principal investigator Michael Rasmussen, MD, PhD, international medical director of Novo Nordisk in Copenhagen, Denmark.

NNC0195-0092 is intended to reduce the number of subcutaneous injections required and, according to experts, is among several long-acting growth-hormone treatments under development globally.

Dr. Rasmussen, who presented the research as a scientific poster here at ICE/ENDO 2014, said the company plans to perform phase 3 clinical trials and will also study NNC0195-0092 in children.

Longer-acting formulations of growth hormone are attractive to patients, especially children, because the need for a daily injection is "burdensome," Shalender Bhasin, MD, an endocrinologist at Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, told Medscape Medical News.

Dr. Bhasin, who was not involved with the study, said, "This study establishes the feasibility of giving growth hormone once weekly, which is clearly an advance over what we have now."

Results of 2 other long-acting human growth-hormone treatments, VRS-317 (Versartis) and MOD-4023 (OPKO Health), in phase 2 trials in prepubertal children with growth-hormone deficiency were also reported at the meeting.

"Different Mechanism of Action"

Dr. Rasmussen said NNC0195-0092 possesses a mechanism of action different from that of the other experimental long-acting agents in that it is a reversible albumin-binding growth-hormone derivative.

This study establishes the feasibility of giving growth hormone once weekly, which is clearly an advance over what we have now.

He and his colleagues performed a 4-week randomized, open-label, active-controlled, phase 1/2 trial in 34 adults with adult growth-hormone deficiency (ranging in age from 20 to 70 years). Patients stopped their growth-hormone treatment 14 days before randomization. The investigators tested once-weekly subcutaneous injections of NNC0195-0092 at 4 doses — 0.02, 0.04, 0.08, and 0.12 mg/kg. Six patients each received the 0.04- and 0.08-mg/kg doses, and 7 each received the 0.02-and 0.12-mg/kg doses, for a total of 26 patients in the experimental group. Dose escalation took place after confirmation of safety for the prior level.

For each dose group, 2 additional patients (controls) instead received a daily injection of somatropin at doses ranging from 0.02 to 0.08 mg/kg. In response to a question from a conference delegate, Dr. Rasmussen said these somatropin doses were similar to those prescribed in Europe.

The primary end point was safety, and secondary end points included the pharmacokinetics and pharmacodynamics, according to the poster. Thirty patients completed the study: all 8 in the control group and 22 in the experimental group.

The researchers observed no serious safety problems, and Dr. Rasmussen said the 2 low-dose NNC0195-0092 groups experienced no side effects. At the higher doses, the most common adverse events were peripheral edema, headache, and knee pain, which are similar to those occurring with use of high-dose daily somatropin.

In addition, those receiving the experimental drug had no anti–growth-hormone antibodies in their blood. And there was no statistically significant effect on their mean fasting blood glucose and insulin levels, compared with patients who received a daily injection of somatropin, Dr. Rasmussen reported.

NNC0195-0092 induced a dose-dependent response for IGF-1, with no significant difference reported in mean IGF-1 response between the drug's 0.02- and 0.04-mg/kg doses and once-daily somatropin.

Because of the IGF-1 response, the investigators called NNC0195-0092 "suitable for once-weekly dosing."

But Dr. Bhasin told Medscape Medical News that because the study was only 4 weeks long, it did not have clinically important outcomes, such as growth in height, and he would have liked to have seen data on patients' well-being.

"This is a small, early-phase study with promising data," he said. "It is a prelude to a larger efficacy trial with longer-follow-up."

Phase 2 Data on Long-Acting GH in Children

Also reported at the meeting were data on VRS-317, a novel fusion protein consisting of recombinant human growth hormone (rhGH) with amino acid sequences attached at the N- and C- terminal.

George M. Bright, MD, vice president of clinical development at Versatis, Redwood City, California, presented the findings of the repeat dosing study in 64 prepubertal children (average age, 7.8 years) naive to rhGH treatment, who were randomized to 5.0 mg/kg monthly, 2.5 mg/kg semimonthly, or 1.15 mg/kg weekly (cumulative dose of 3 mg/kg/6 months for all).

Repeat dosing with VRS-317, when given at these intervals over a 6-month period, achieved annualized 6-month height velocity (which was the study's primary end point) comparable to the annual height velocity for similar growth-hormone–deficient children given a dose of daily growth hormone that is the highest approved dose on the label of Norditropin and Genotropin (Pfizer), Dr. Bright reported.

VRS-317 was also safe and well tolerated in the children, and there was a significant and expected increase in the IGF-I levels from baseline.

The company plans to meet with the Food and Drug Administration later this year and hopes to subsequently move VRS-317 into a phase 3 clinical trial, it notes in a statement.

In the second study, up to 56 prepubertal children with growth-hormone deficiency were given 1 of 3 once-weekly doses (0.25, 0.48, or 0.66 mg/kg per week) of the long-acting product MOD-4023 or once-daily hGH (34 µg/kg/day).

The longer-acting product, which was originally developed by Prolor Biotech, Israel, compared favorably with the daily injections and at all 3 doses showed good pharmacokinetic and pharmacodynamics profiles; it therefore appears to have the potential to promote proper growth.

A pivotal phase 3 clinical trial of the product has begun in adults with growth-hormone deficiency and the company anticipates starting a similar study in children shortly.

Novo Nordisk funded the study of NNC0195-0092; Versatis the study of VRS-317; and OPKO Health/Prolor Biotech the study of MOD-4023. Disclosures for the authors are listed in the abstracts. Dr. Bhasin has disclosed no relevant financial relationships.

Joint Meeting of the International Society of Endocrinology and the Endocrine Society: ICE/ENDO 2014; June 22-23, 2014. Abstract LBSU-0377, Abstract MON-0147, Abstract MON-0149


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