Positive Results for Inhaled GLP-1 CPD

New GLP-1 drug that gets absorbed via the nasal passages shows positive results without the side effect of nausea. It was also found to peak quicker and last longer due to the fact that the DPP-IV via inhalation was not able to break it down as rapidly.

MannKind Corporation which is also working on an inhaled insulin, announced results from a Phase 1a clinical evaluation of  MKC253, a formulation of GLP-1 (glucagon-like peptide) on Technosphere particles that is delivered using the Company’s proprietary inhaler.  The study was designed as an open-label, dose escalation, controlled safety and tolerability trial, involving 26 healthy, adult, male subjects.  Each subject was assigned to one of five dose levels of MKC253 inhalation powder:  0.05 mg, 0.45 mg, 0.75 mg, 1.05 mg or 1.5 mg. 

The primary objective of the trial was to evaluate the tolerability of ascending doses of the investigational product as determined by the incidence and severity of reported adverse events.  Secondary endpoints included pharmacokinetic parameters of plasma GLP-1 and pharmacodynamic parameters of plasma insulin and glucose. 

GLP-1 plasma concentrations peaked very quickly, with a max occurring less than 3 minutes after inhalation.  Even in subjects that achieved plasma GLP-1 concentrations in excess of 100 pmol/L, the nausea and vomiting characteristically associated with such levels was not observed. 

 In these healthy subjects, GLP-1-induced insulin release occurred within 6 minutes of inhalation of MKC253.  The insulin response was dose-dependent.  The release of insulin from the pancreas was confirmed by corresponding significant increases in the levels of C-peptide.  In subjects that received 1.5 mg of MKC253, blood glucose concentrations were observed to decrease for a period of approximately 20 minutes after inhalation.  All subjects were fasted prior to the administration of MKC253. 

A greater proportion of the GLP-1 inhaled as MKC253 remained intact during the period following administration than has been described in the literature following subcutaneous or intravenous injection of GLP-1. 
"Our hypothesis at present is that delivery of active GLP-1 to the arterial circulation via the lung avoids much of the degradation by dipeptidyl peptidase-4 that occurs prior to the compound reaching the primary site of endocrine action.  Thus, we may be able to achieve a different response profile with pulmonary MCK253 than that seen with subcutaneous or intravenous administration of GLP-1.  Moreover, the pulsatile administration of MKC253 achieved with our proprietary Technosphere delivery technology appears to avoid the dose-limiting vomiting characteristically associated with GLP-1 and replaces a physiological response lost in patients with diabetes that cannot be replicated by other forms of GLP-1," said Dr. Peter Richardson, Corporate Vice President and Chief Scientific Officer.  "As well, with pulsatile delivery, we may potentially avoid unusual adverse effects such as the acute pancreatitis that has been described with presently marketed GLP analogues."

"We believe that MKC253 represents a novel approach to the use of GLP-1 as a prandial therapy for diabetes either alone, or in combination with prandial insulin. In addition, if we are able to demonstrate the same weight reduction or satiety effects seen with long-acting analogues of native GLP, MKC253 may have therapeutic potential in obesity.
MannKind news release, Nov. 2007

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