A scientist who worked on early clinical studies of Eli Lilly/Daiichi Sankyo’s new clotbuster prasugrel has called regulators to reject the drug “because it is neither safe nor effective”.

In a letter sent to US Food and Drug Administration Commissioner Margaret Hamburg, Victor Serebruany and the influential US consumer group Public Citizen have asked the agency to halt its review of prasugrel. The letter cites “serious flaws” in TRITON-TIMI 38, the 13,000-patient Phase III trial that compared the drug to Sanofi-Aventis/Bristol-Myers Squibb’s blockbuster Plavix (clopidogrel), in patients with acute coronary syndrome.

The letter claims that “perhaps the greatest problem in TRITON-TIMI 38 was the incorrect and unsafe dose of prasugrel used”. As early as May 2004, Dr Serebruany told Lilly and investigators conducting the study that the 10mg daily dose of prasugrel they were planning to use “was about 2.5 times more potent than the dose of clopidogrel used in the study”, and that a much lower dose of the new drug should be studied.

Dr Serebruany, who sold licensing rights for the patent to Lilly. says that an earlier clinical study showed that a 10mg daily dose of prasugrel “was far too potent, and I raised concerns that it might result in an increased bleeding risk”. He added that “this is exactly what was seen in the TRITON-TIMI 38 study” and “considering that bleeding rates grow over time, the effects of this drug could be even worse in real-life scenarios”.

The letter also notes that while prasugrel does not appear to be a carcinogen, it may act as a cancer promoter through its excessive antiplatelet activity. In addition to these safety concerns, Public Citizen and Dr Serebruany claim that the effectiveness of prasugrel is in question “because the design of the study favoured it unfairly, and many of the supposedly bad outcomes the drug prevented were not medically important”.

James Floyd, a Public Citizen researcher. Said that at a lower dose, “prasugrel may, indeed, be a useful antiplatelet drug, but until a new Phase III study can be conducted with an appropriate dose, we urge the FDA to stop its current review of this drug”.

Prasugrel is already approved in Europe, and been launched under the brand name Efient, and analysts believe it will be a blockbuster. In February, the FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 9-0 in favour of approval although a row broke out later about the make-up of the panel after it emerged that Sanjay Kaul, a cardiologist at Cedars-Sinai Heart Institute in Los Angeles, who had authored several papers critical of the treatment, was pulled from the committee.

Lilly resubmits Cymbalta application
Meantime, Lilly announced that it has resubmitted an application for Cymbalta (duloxetine) to the FDA for the management of chronic pain.

The Indianapolis-based major said that the resubmission now contains data from a recently-completed trial in chronic pain due to osteoarthritis, “the extension phase of a chronic low back pain study, and previously completed studies in pain due to osteoarthritis and chronic low back pain”.

John Hayes of Eli Lilly Research Laboratories, remarked that "the additional chronic osteoarthritis pain and chronic low back pain data were not available at the time of the initial submission, made in May last year, and the updated package “will provide a broader clinical basis for the FDA to review the application".

Lilly pulled its initial application for Cymbalta in this indication at the end of last year, after reviewers “raised questions about the drug's effectiveness and dosing that revolved primarily around statistical methodology and study design”. The drug is currently approved as a treatment for major depressive disorder and generalised anxiety disorder, as well as for fibromyalgia and pain associated with diabetic peripheral neuropathy.