The expected availability of long-acting glucagon-like peptide-1 (GLP-1) mimetics for type 2 diabetes may not just provide more convenience, but also better performance in patients with type 2 diabetes, researchers suggested here.
The FDA is expected to approve a once-weekly version of exenatide (Bydureon) within a few months, but several others are moving through the pipeline as well, said Alan Garber, MD, PhD, of Baylor College of Medicine in Houston.
Garber reviewed the future of GLP-1 mimetics in a platform presentation here at the World Congress on Controversies to Consensus in Diabetes, Obesity, and Hypertension.
He suggested that, although the once-weekly version of exenatide, known generically as exenatide LAR, will be welcomed by patients and physicians, its future competitors may outperform it once they reach the market.
All drugs in this class are large peptide molecules and hence must be administered by injection. The currently approved version of exenatide (Byetta) has such a short half-life that it must be given twice daily; even then the trough concentrations dip nearly to zero, Garber said.
A once-daily GLP-1 analogue, liraglutide (Victoza), is also available and it has better pharmacokinetics and is also somewhat less immunogenic than exenatide, Garber said. Nevertheless, most clinicians agree that adherence with treatment, if nothing else, will be improved with drugs that can be taken on a weekly basis.
Among the other products coming along are taspoglutide, now entering phase III development; and two others now in phase II testing, albiglutide and LY2189265.
All are modeled after the native GLP-1 protein but with modifications to keep them in circulation for days rather than hours.
The developers of taspoglutide, for example, altered the peptide’s amino acid sequence at the location where it’s bound by the enzyme that normally chops up GLP-1, slowing the degradation dramatically.
Albiglutide, on the other hand, is a combination of two GLP-1 analogue molecules plus human albumin proteins.
One of the drawbacks of exenatide LAR is that the extended half-life is achieved by encapsulating the peptide in microspheres. Their physical size requires that the drug be injected with a relatively large needle (gauge 23 to 25), whereas a 29-gauge or smaller needle can be used with standard exenatide, liraglutide, and the other investigational agents, Garber said.
The larger needle is likely to mean more pain and could also lead patients to reject the treatment simply because of the fear factor.
Clinical studies with exenatide LAR suggest it may be more effective than the twice-daily version. In trials with similar designs, the long-acting version produced reductions in glycated hemoglobin (HbA1c) of 1.8% to 1.9%, compared with 1.5% with the standard version.
Exenatide LAR has also outperformed liraglutide and the investigational agents, according to results published thus far, Garber said.
In addition to the improved glycemic control, exenatide LAR also has appeared to be more effective in forcing weight loss, a desirable effect in most diabetic patients.
But its adverse effects also appear to be enhanced, particularly development of antibodies against the peptide.
Some 35% of patients taking exenatide LAR developed antibodies during the first months of treatment, about twice as many as seen with the twice-daily version, according to Garber. In both cases, antibody titers dropped with continued treatment, and only a minority of antibodies appeared to deactivate the agent in vitro.
But treatment efficacy is reduced with neutralizing antibodies, and the other once-weekly agents appear to be substantially less immunogenic, he said.
Hypoglycemic episodes have also appeared to be more common with exenatide LAR than with taspoglutide, albiglutide, or LY2189265, Garber said, with rates of 15% for exenatide LAR compared with 0% to 4% for the others.
Taspoglutide may be the most advanced of these alternatives for once-weekly treatment, but it’s still a long way from commercial approval, noted Itamar Raz, MD, of Hadassah Medical Center in Jerusalem, co-chair of the CODHy meeting.
In a presentation at a satellite symposium here, sponsored by taspoglutide’s manufacturer, Raz described a complicated phase III development plan.
A total of eight studies are planned, with a total of more than 6,000 patients. These trials will evaluate taspoglutide in combination with other standard drugs, including metformin, sulfonylureas, and pioglitazone (Actos), as well as in monotherapy.
The largest of these studies will be a trial in 2,000 patients at high risk for cardiovascular events, according to Raz. Current FDA policies require at least two years of cardiovascular safety data for all new diabetes drugs.
According to the trial’s listing at clinicaltrials.gov, it is scheduled for completion in mid-2013.
Ralph DeFronzo, MD, of the University of Texas Health Science Center in San Antonio, said that GLP-1 mimetics as a class “have the most powerful effect, in my opinion, to improve beta cell function,” which, in turn, is the key factor in patients’ long-term prognosis.
He said these agents correct more of the metabolic abnormalities in type 2 diabetes than another type of antidiabetic drug.
But Raz said compliance problems with the frequent injections undermine that potential.
Henry Ginsberg, MD, of Columbia University in New York City, said he expected that the once-weekly agents would become the preferred products in this class when they finally reach the market.
The companies sponsoring exenatide LAR announced in March that the FDA was satisfied with their clinical data submissions. They said they expected final approval when they submit an acceptable risk evaluation and mitigation strategy and technical information on the manufacturing process.
The FDA has given itself a deadline of October 22 for final action on the product.
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Primary source: World Congress on Controversies to Consensus in Diabetes, Obesity, and Hypertension
Source reference:
Garber A, “Future therapy of type 2 diabetes: long-acting GLP-1” CODHy 2010.
