Akela Pharma Announces Positive Results From Growth Hormone Releasing Hormone Trial

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Akela Pharma announced positive final results from its pilot GHRH Phase II study. Within only 4 weeks of treatment, Akela GHRH induced a highly significant stimulation of endogenous growth hormone (GH) secretion and a marked increase of circulating insulin-like growth factor(IGF-1) as compared to placebo in patients with chronic kidney disease.

These endocrine effects were associated with a significant increase in Fat Free Mass (FFM), and concomitant reduction in Fat Mass (FM) when measured by DEXA scan and bioelectrical impedance (BIA). As we reported in July 2007, the study did not reveal significant changes between treatment groups in total body protein turnover. Total body protein turnover, as measured by 13C leucine kinetics, was normal in both treatment groups already at baseline, most probably reflecting adaptative changes of metabolic balance in the chronic disease state.

ABOUT THE STUDY:

The study was conducted at 3 European sites. It was designed to evaluate the clinical potential of GHRH analogue (AKL-0707) administration in improving body composition, nutritional and metabolic parameters in malnourished patients with stage IV or pre-dialytic stage V chronic kidney disease (CKD). Malnutrition was defined by either serum albumin <40 g/l, body mass index (BMI) <23, or a greater than 5% loss of body weight in the last 6 months.

Twenty-eight patients were randomized to either GHRH analogue subcutaneously (sc.) (13 patients) or placebo sc. (15 patients). Twenty-six subjects completed the study as planned. The mean age was 61.8 and 63.4 in the GHRH analogue and placebo groups, respectively. The treatment was administered twice daily (AM & PM) for 28 days, at a dose of approximately 15 (micro)g/kg body weight (BW).

The measurement of protein turnover as assessed by 13C-leucine kinetics was selected as the primary parameter to monitor the trend in protein metabolism as published clinical data suggested an improvement in lean body mass was not to be expected within one month of treatment. In addition, the study focused on the effect of GHRH analogue on endogenous 24-hour growth hormone (GH) secretion, circulating total insulin-like growth factor (IGF-1) and its binding proteins IGFBP-1 and IGFBP-3, fat-free mass (FFM) and fat mass (FM) as assessed by Dual X-ray absorptiometry (DEXA) and bioimpedance (BIA), biochemical parameters of nutritional and metabolic states, as well as safety and tolerability.

FINDINGS

In the Intention to Treat (ITT) population, a 4-week treatment with GHRH analogue produced the following statistically significant (p<0.05) changes in comparison to placebo:

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- A 393% increase in mean 24-hour integrated GH secretion rate as compared to a 22% increase in the placebo group (24h AUC). GHRH analogue treatment did not affect the natural pulsatile rhythm of endogenous GH secretion.

- A 104% increase in median total circulating IGF-1, mean 26.7% decrease in IGFBP-1 and no significant change in IGFBP3 concentration, indicating an increase in the free circulating IGF-1 available to tissues, as compared to 3.5% increase in IGF-1 and 2.4% increase in IGFBP concentrations in the placebo group.

- A marked improvement in the global nutritional state as assessed by the physicians. In the GHRH group, 6 out of 9 patients rated malnourished at baseline were classified well-nourished after 4 weeks of therapy. By contrast, the nutritional assessment remained unchanged in each of 11 patients classified malnourished in the placebo group.

- An increase from baseline in FFM (median 3.3 kg by BIA and 1.6 kg by DEXA) and a concomitant decrease in FM (median 1.8 kg by BIA and 0.4 kg by DEXA). These changes were observed in all but one (11/12) patients in the GHRH analogue group on day 28, and contrasted with a decrease in FFM and an increase in FM in the placebo arm. The increase in FFM was most pronounced in the leg and trunk regions.

- A GH-mediated increase in median extracellular water (ECW) by 1.9 L and intracellular water (ICW) by 1.2 L. While ratio of median ECW/ICW (1.2) on day 28 remained unchanged, indicating no negative impact in terms of extracellular fluid retention.

- A significant increase in fasting insulin levels, as typically observed with human growth hormone treatment. The change in fasting insulin was not associated with adverse changes in fasting glucose or glycosylated hemoglobin levels, indicating that the GHRH analogue treatment did not adversely affect the glucose balance of the patients.

There were no statistically or clinically significant differences between the treatment groups in terms of safety assessments. There were no human anti-GHRH antibodies detected in any of the patients.

There were altogether 128 on-treatment adverse events (AE) reported by 26 subjects: 70 with GHRH analogue and 58 with placebo. Only one AE, injection site bruising, was classified as definitely caused by GHRH analogue treatment. Four serious adverse events (SAE) were reported, 3 in the placebo and one in the GHRH analogue groups. None of the SAEs were considered to be related to the study medication.

"The positive final results of our GHRH Phase II clinical trial confirm the substantial therapeutic potential of GHRH analogue, and clearly justify pursuing further clinical studies in not only chronic renal failure but also in other wasting diseases such as severe COPD and HIV-infection associated wasting." said Dr. Halvor Jaeger, Chief Executive Officer of Akela Pharma Inc.

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