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United Therapeutics inhaled treprostinil may have limited efficacy due to a lack of improvement on the New York Heart Association (NYHA) functional class scale, physicians told Pharmawire.
Inhaled treprostinil is currently in Phase III development for the treatment of pulmonary arterial hypertension (PAH).
The New York Heart Association (NYHA) functional class scale is used to determine patient’s stage of disease in PAH. It is also used to measure the effects of drugs in clinical trials. Altogether, there are four classes of severity, with level 1 representing mild disease and level 4 being severe illness. When a drug has an impact on the NYHA in a clinical trial, it causes a patient’s NYHA functional class to decrease.
In the TRIUMPH-1 study of Viveta, patients taking the drug showed a significant improvement on the 6 minute walk distance (6MW distance) test, which was the primary endpoint, but failed to improve secondary endpoints such as the NYHA functional class scale.
Dr Marius Hoeper, an expert in pulmonary arterial hypertension at the University of Hanover Medical School, said the NYHA functional class scale is indicative of drug quality and is a good predictor of the patient response in a large population. Other physicians agreed and added that if the study was conducted properly and the endpoint was still not met, it may mean that the drug is not effective.
A United Therapeutics spokesperson expressed confidence in the drug because it had met its primary endpoint of 6MW distance. He said that the company would be unlikely to rerun the trials in an attempt to prove the secondary endpoints.
Physicians consider the NYHA scale a very useful patient classification instrument, according to Dr Norbert Voelkel, a professor at Virginia Commonwealth University. Still, assessing improvement on this scale can be confusing, Voelkel said.
The significance of moving patients from one NYHA class to another depends on the class of patients recruited to the study. For example, if a patient moves from class 4 to class 3 during a clinical study, the improvement is considered enormous, Voelkel explained. However, if patients change from class 3 to 2, the improvement is modest.
Patients in the TRIUMPH-1 study probably had late NYHA disease (class 3), who were ”on the brink of decompensation”, or functional deterioration, Voelkel said. If therapy with inhaled treprostinil did not cause a change in the NYHA scale, then it is likely that the patients enrolled in the TRIUMPH-1 study experienced disease progression.
”Most of the recent trials say that with the cohort, there is an improvement with one classification,” Voelkel added.
When the administration of a drug causes significant improvements on the NYHA class scale, it greatly impacts physicians prescription practices, said Dr Fraser Rubens, a cardiac surgeon at the University of Canada Ottawa Heart Institute. This scale is more than just a ”surrogate marker” for pulmonary arterial hypertension, he said.
If this classification was missed as a secondary study endpoint, then the study might not have been conducted properly or the drug might lack merit, speculated a physician who spoke on the condition of anonymity. Also, since this endpoint was missed, it ”makes it [inhaled treprostinil] a lot harder to sell.”
The TRIUMPH-1 study enrolled approximately 235 patients with pulmonary arterial hypertension. Approximately 98% of the patients enrolled were classified as having NYHA class 3 disease. Out of the 235 patients enrolled, 55% had idiopathic or familial PAH, 35% had vascular disease, and 10% had PAH associated with anorexigens, HIV or other disease conditions. Still, Rubens speculated that inhaled treprostinil might not have caused a significant change on the NYHA scale because not enough patients were recruited. Trials are designed to measure statistically significant responses on primary endpoints, and researchers tend to choose primary endpoints that require a fewer number of patients to achieve statistical significance, he said.
”Maybe they needed too many patients to prove that this improvement was real and not just by chance,” Rubens said.
In the TRIUMPH-1 study of Viveta, the drug demonstrated statistically significant improvements on the 6 minute walk distance (6MW distance) test at week 12. Still, based on a premature analysis of secondary endpoints, the drug failed to improve outcomes on the NYHA functional class, time to clinical worsening, Borg Dyspnea Scale Rating and the 6MW distance on day 1, according to a company press release. United Therapeutics is still in the process of analyzing other secondary endpoints such as signs and symptoms of disease as well as quality of life.
The minute improvement in the 6MW distance achieved by inhaled treprostinil in the TRIUMPH-1 study is reinforced by the fact that the drug did not make an impact on the NYHA scale, Hoeper said. This indicates that ”the drug had some effects, but they’re modest at best.”
If approved, some industry analysts project inhaled treprostinil could generate sales of USD 117m by 2010. United Therapeutics has a market capitalization of USD 1.82 bn.
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