Side-effect doubts cloud future of Pargluva and Galida
pharmafile | June 24, 2005 | News story | Sales and Marketing |
A study comparing novel treatment Pargluva with a best-selling diabetes drug has yielded some positive results for the new drug, but side-effects could prove to be a serious concern.
Pargluva (muraglitazar) is a type II diabetes treatment in phase III development by Merck and Bristol-Myers Squibb and is the latest in a class of candidate drugs from the glitazars class or dual alpha/gamma peroxisome proliferator activated receptors (PPARs).
A number of glitazars have fallen in late stage clinical trials because of serious side-effects including Novo Nordisk's ragaglitazar and GlaxoSmithKline's farglitazar and Merck's MK-767. Takeda's TAK559 is the latest to fail, its development discontinued in March 2005.
Most seriously, Warner Lambert's Rezulin (troglitazone) was withdrawn in 2000 because of rare but fatal hepatotoxicity, and doubts have persisted about the class ever since.
Merck filed Pargluva with the FDA earlier this year, and will have to convince the regulator the drug does not suffer from the same side-effect profile as the other candidates in its class.
The companies presented data from a head-to-head trial between the drug and Takeda's Actos (pioglitazone), the best-selling drug in the closely related glitazone class.
All patients on the trial took either Actos (30mg) or Pargluva (5mg) in conjunction with metformin with the affects on A1C levels of average blood glucose being measured as the primary endpoint.
After 24 weeks on the trial, 60% of patients on Pargluva reached the recommended blood glucose levels compared to only 45% of patients on Actos, with the new drug also helping to reduce fasting plasma glucose more effectively.
Datamonitor analyst Nick Karachalias said: "The study is good news for Merck and BMS, but not totally bullet proof – they have managed to show quite good efficacy, but you have to balance that with its side-effects profile."
Karachalias added that Pargluva's lipid-lowering profile could give it the same sort of boost that Actos enjoyed with its own lipid-lowering profile over GSK's Avandia.
Pargluva also demonstrated superiority in a number of secondary endpoints, including reducing triglycerides and increasing insulin sensitivity but it also produced more worrying side-effects than Actos.
Discontinuation rates and adverse effects were marginally higher in patients on Pargluva than on Actos, while rates of oedema or fluid retention and weight gain were also significantly higher.
Four patients on the study developed symptoms of heart failure – three of them on Pargluva – but recovered with diuretic therapy and/or withdrawal from the trial. An extension of the study produced three further cases of heart failure, with Pargluva accounting for two and Actos one.
There were no hypoglycaemia-related serious adverse effects or withdrawals in the study, but indications that the new drug has a less favourable safety profile than Actos is not good news for its co-developers.
A separate phase II trial to investigate different doses of Pargluva suggested the drug's effectiveness in controlling blood glucose increased with the dose, but incidence of side-effects also rose significantly.
"The weight gain, oedema and fluid retention are going to concern physicians, but Actos had similar side-effects [when it was launched] and that didn't prevent it from becoming a blockbuster," Datamonitor's Karachalias said.
But he concluded: "However, if Pargluva gets conclusively linked with heart failure, this will diminish its patient potential dramatically."
Meanwhile, AstraZeneca has released data from a phase II dose-ranging study of its glitazar candidate Galida (tesaglitazar).
An FDA request for a worldwide regulatory review into the safety and toxicology of all PPAR agonists last year has sent Galida back into phase II studies after already having begun phase III trials.
The new phase II data shows Galida achieved significant reductions in fasting plasma glucose and fasting triglycerides, as well as an increase in levels of HDL-C and a reduction in LDL-C.
There were no fatal or serious non-fatal adverse effects seen, though three to five cases of oedema were recorded, compared to two cases in the placebo group.
AstraZeneca hope the data showing the drug's positive affects on lipid abnormalities as well as glucose levels will be attractive to prescribers, but lingering doubts about the overall safety of the class will remain a problem to surmount.
