New drug on the block
Etanercept for TNF inactivation
In the hunt for more chemical barricades to block the paths leading to advanced congestive heart failure, some researchers are saying there’s at least one more road they need to close. Studies have pointed out that tumor necrosis factor, or TNF, can lead to the progression of heart failure. But investigators are just beginning to test what can happen when TNF is inactivated.
Testing the safety one such blocking agent, etanercept, a group of Houston and Seattle researchers says the drug was well-tolerated and seemed to help a small group of CHF patients with class III disease.1 The drug lowered the amount of functional TNF in the patients randomized to the drug, and patients experienced an improvement in their functional status, compared with six patients who received a placebo.
"This is a novel concept that is not addressed by any other form of therapy that is currently being used for heart failure," says Douglas L. Mann, MD, lead researcher of several studies on the drug. "That is the importance of this first study."
TNF is a cytokine. The drug that makes it inactive, which is also used to treat rheumatoid arthritis under the brand name Enbrel, works by binding to TNF so it cannot bind with other tissues. "As long as TNF remains bound to Enbrel, it [TNF] is biologically inactive," says Mann, a cardiology investigator from the VA Medical Center in Houston. He notes researchers still don’t know if Enbrel’s effect is permanent, but they theorize TNF bound to the drug is excreted by the body.
Details of the safety study
Mann’s group looked at a group of 18 patients with class III CHF. All subjects had an ejection fraction below 35% and elevated levels of TNF. Patients were divided into three groups of six participants each, where two would get the placebo and the remaining four would receive the drug.
In the three drug groups, patients received progressive doses of Enbrel. The first group received a dose believed to be too low to detect changes in TNF. The remaining two groups of four patients received higher doses, which would be able to show what happens when TNF is blocked (1 mg/ m2, 4 mg/m2 and 10 mg/m2 respectively, given in a single intravenous infusion over 30 minutes).
The patients also were being treated with other CHF medications:
• All were on an ACE inhibitor.
• Nearly everyone was taking digoxin.
• 11% were on amlodipine, and 11% were on a beta-blocker.
In the first six hours after the drug was administered, the team checked blood pressure, heart rate, and clinical status repeatedly. Patients then were checked at the start of the study and on days one, two, seven, and 14. The researchers also checked TNF in the circulation during these increments.
The group reported that none of the patients developed side effects after receiving the drug, and there were no significant differences in heart rate, blood pressure, or hematology (or serum parameters) between the two groups.
Mann’s group reported that biologically active TNF decreased by 50% in patients who received the drug. When the team tested six-minute walk distance, quality of life, and ejection fraction overall between the drug and placebo group, only ejection fraction showed borderline significance in the drug group.
When each level of drug dose was compared to placebo, the Enbrel patients had improved quality of life and a higher ejection fraction. When the no-dose/placebo group was removed from consideration, patients on the two higher doses of the drug had higher six-minute walk distances, quality of life improvement, and a higher ejection fraction.
Mann notes the small size of the study made it difficult to compare the results between groups of patients. In an editorial on the study, Gary S. Francis, MD, from the cardiology department at the Cleveland Clinic, wrote that the small number of patients is a caveat of the study, yet the implications of the results may provide the "green light" to go on to larger studies.2
"We designed this as a phase 1 safety study that was designed to test safety and potential efficacy of TNF antagonism in patients with heart failure. It is a first step. We are now taking the larger step. This is how drug development is done," Mann responds.
That larger step is a multicenter study, the Randomized Etanercept North American Strategy to Study Antagonism of Cytokines (RENAISSANCE). Mann notes it should be completed by the end of 2000. There also is a sister trial being conducted in Europe.
In his editorial, Francis suggested slightly higher doses of the drug may be more effective, but Mann responds by saying for a phase I study, the FDA regulations prevented using higher doses. In a subsequent phase II study, which is usually the place to adjust dosages, higher amounts of the drug were used without issues arising in patient safety. RENAISSANCE will use a higher dose of etanercept than this phase I trial. Francis could not be reached for further comment.
References
1. Deswal A. Safety and efficacy of a soluble P75 tumor necrosis factor receptor (Enbrel, etanercept) in patients with advanced heart failure. Circulation 1999; 99:3,224-3,226.
2. Francis GS. TNF-alpha and heart failure: The difference between proof principle and hypothesis testing. Circulation 1999; 99:3,213-3,214.
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