Egrifta Post-marketing Study On Diabetic Retinopathy Will Include CV Outcomes

FDA’s decision to require a post-approval clinical trial evaluating the cardiovascular effects of Theratechnologies’ HIV lipodystrophy drug Egrifta shows the agency has overcome concerns – both its own and those of its advisory committee – that such a study could not be feasibly and ethically conducted.

FDA approved Egrifta (tesamorelin) on Nov. 10 for the reduction of excess abdominal fat in HIV-infected patients with lipodystrophy, a condition in which excess fat develops in different areas of the body, particularly the liver, stomach and other abdominal organs. The condition is associated with antiretroviral drugs used to treat HIV.

In conjunction with the approval, FDA required that an evaluation of CV outcomes be part of a randomized, placebo-controlled clinical trial on the development or progression of retinopathy in diabetics receiving tesamorelin. This trial design would allow CV events to be studied in an enriched population of patients –those with diabetes – already at heightened risk for such problems.

Retinopathy is a concern because Egrifta increases serum levels of insulin-like growth factor-1, which could cause the eye condition to develop or worsen. The drug was also associated with small increases in glucose levels and a higher risk of diabetes in pivotal trials.

A post-approval clinical trial, an observational study and manufacturing studies are required under the FDA Amendments Act.

Study Required Under FDAAA

FDA invoked its drug safety powers under the FDA Amendments Act to require the post-market trial. The study’s “primary objective is to compare the percentage of subjects with a three-step or greater progression in the Early Treatment Diabetic Retinopathy Study scale after a minimum of three years of treatment with Egrifta versus placebo,” FDA’s approval letter states. “The trial will also evaluate the long-term effect of Egrifta on glucose metabolism and conduct blinded adjudication for major adverse cardiovascular events (MACE).”

The final protocol must be submitted by April 2011, with a final study report due in November 2016.

Although CV outcomes do not appear to be a primary endpoint, the study’s long-term, prospective design would appear to address recommendations of some members of the Endocrinologic and Metabolic Drugs Advisory Committee who believed a post-marketing study of tesamorelin’s impact on glucose and IGF-1 levels, and the resulting CV effects, was necessary given the lack of CV data pre-approval.

At their May review of Egrifta, the committee voted 16-0 in favor of approval, despite concerns about a lack of outcomes data on CV safety and no evidence that reduction in visceral adipose tissue equates to CV benefit (Also see "Egrifta Quality Of Life Deciding Factor In Advisory Panel's Recommendation" - Pink Sheet, 31 May, 2010.).

Panel members recommended post-marketing studies examine CV outcomes and the risk of cancer due to tesamorelin’s effects on glucose levels, diabetes and IGF-1. HIV and diabetes are each CV risk factors.

However, the group was divided on whether the post-marketing studies for CV safety should be observational in nature or in randomized, placebo-controlled trials.

Those who favored an observational study suggested a randomized trial would not be ethical or feasible once tesamorelin was approved and became the only drug indicated for treating HIV lipodystrophy. FDA also appeared to struggle with the issue, questioning whether patients would agree to enter a post-marketing trial in which they had a 50% chance of not being treated.

However, other panelists said CV outcomes data from a randomized, placebo-controlled study were needed to avoid the dilemma faced with type 2 diabetes drugs, which historically were approved on their ability to reduce hemoglobin A1c levels and without evidence of a positive, negative or neutral CV effect. FDA now requires sponsors to exclude threshold levels of increased CV risk pre- and post-approval for type 2 diabetes agents.

The occurrence of major cardiovascular events, diabetic retinopathy and glucose intolerance/diabetes with Egrifta also will be examined as part of a required observational study lasting at least 10 years. This study will evaluate a host of potential safety issues associated with long-term use, including hypersensitivity reactions, malignancies and liver and kidney abnormalities.

The agency is also requiring manufacturing studies to support development of a single-vial formulation. The current daily dose is provided in two separate vials and must be reconstituted with sterile water.

During a conference call discussing the approval, Theratechnologies President and CEO Yves Rosconi said the post-marketing requirements are manageable, but the details need to be worked out with FDA.

Weathering Regulatory Delays

Egrifta managed to weather several regulatory delays en route to approval.

The NDA was submitted in May 2009. An advisory committee meeting originally scheduled for Feb. 24 was canceled. The user fee date was moved from March 29 to July 27, and the committee was convened in May. However, FDA missed the re-set user fee date. In July, Theratechnologies said the agency’s review was progressing and a regulatory action was expected in the fourth quarter.

The end result is a surprisingly clean label and no requirement for a Risk Evaluation and Mitigation Strategy, despite extensive safety concerns raised at the advisory committee. FDA had early on encouraged a REMS submission, and Theratechnologies submitted a proposal for a Medication Guide and communication plan, but in the end the approval came without the REMS.

Approval was based on two pivotal trials in which a subcutaneous daily injection of 2 mg tesamorelin was shown to significantly reduce excess visceral abdominal fat relative to placebo, by an average of 19.6% in one trial and 11.7% in the other.

In briefing documents prepared for the committee meeting, FDA questioned the clinical relevance of visceral adipose tissue reduction and noted the absence of evidence suggesting this is a validated surrogate endpoint for CV benefit (Also see "The Risks Of Surrogacy: Egrifta Faces Twofold Challenge At Advisory Committee" - Pink Sheet, 25 May, 2010.).

Limitations Of Use

The label reflects three “limitations of use” listed alongside the drug's indication but puts no firm limits on duration of use or specific timeframes or thresholds for evaluating patient response. Instead, it recommends “careful consideration” of continued treatment under various circumstances, including in patients who experience elevations of IGF-1 or glucose, or those who develop diabetes (Also see "Delayed Egrifta Approval Brings Clean Label, No REMS For Theratechnologies" - Pink Sheet, 11 Nov, 2010.).

Listed under the “limitations of use” heading is the following statement: “Since the long-term CV safety and potential long-term CV benefit of Egrifta treatment have not been studied and are not known, careful consideration should be given whether to continue Egrifta treatment in patients who do not show a clear efficacy response as judged by the degree of reduction in visceral adipose tissue measured by waist circumference or CT scan.”

The two other limitations of use are that Egrifta is not indicated for weight loss management, and that there are no data supporting improved compliance with antiretroviral therapies in HIV patients.

EMD Serono, a Merck KGaA affiliate that holds exclusive marketing rights in the U.S., said the drug would be commercially available in January. The company declined to provide any details on pricing. However, BMO Capital Markets analysts Jason Zhang and Alex Arfaei predict Egrifta will launch at an average price of approximately $25,000 per patient, per year.

By Sue Sutter