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Titan Initiates Randomized, Double Blind, Placebo Controlled Phase II Clinical Study of DITPA In Congestive Heart Failure
Tuesday December 14, 7:01 am ET

SOUTH SAN FRANCISCO, Calif., Dec. 14 /PRNewswire-FirstCall/ -- Titan Pharmaceuticals Inc., announced today that the company has initiated a randomized, double blind, Phase IIb study of DITPA, its novel product in development for treatment of cardiovascular disease. This study will evaluate DITPA in the treatment of advanced congestive heart failure (CHF) associated with low serum thyroid hormone levels. DITPA, or 3,5-diiodothyropropionic acid, is a novel analogue of thyroid hormone selected for its potential to improve congestive heart failure while avoiding limitations inherent in the use of current thyroid hormone medications in patients with cardiovascular disease.

Thyroid hormone is an important regulator of the heart and blood vessels, and adequate levels of thyroid hormone are essential for proper function of the cardiovascular system. Thyroid hormone improves the ability of the heart to fill properly (improves diastolic function), reduces the pressure against which the heart pumps by relaxing small blood vessels (reduces peripheral vascular resistance), and improves the efficiency of contraction of the heart so that a greater amount of blood is pumped per contraction (improved systolic function).

Researchers have demonstrated that approximately 30% of patients with advanced (NYHA Class III and IV) congestive heart failure have abnormally low levels of T3, the active form of thyroid hormone needed by heart cells, and that low levels of T3 are a strong independent predictor of increased mortality in CHF patients. It is estimated that approximately 1 million CHF patients collectively in the U.S. and Europe have low levels of thyroid hormone (T3). Importantly, these patients generally have normal levels of T4, another form of thyroid hormone which is made by the thyroid gland. As a result, these patients generally show no symptoms of hypothyroidism, although the form of thyroid hormone needed by the heart and blood vessels, T3, is significantly reduced.

The important role of thyroid hormone in maintaining heart and blood vessel function, and the association of low T3 and increased mortality in CHF suggest a potential role for DITPA as a thyroid hormone replacement therapy in CHF. Currently available thyroid hormone medications are generally not suitable for chronic use in CHF, because they are primarily T4 preparations, or have too short a half-life, and have the potential to increase heart rate, which is an unwanted side effect in CHF patients.

DITPA is a novel analogue of thyroid hormone (T3), that has demonstrated in preclinical and preliminary, placebo controlled pilot clinical testing the ability to improve measures of diastolic function, reduce peripheral vascular resistance, and improve systolic function, without increasing heart rate. Such pilot clinical testing in CHF patients over 4 weeks also demonstrated no significant adverse effects.

Titan's current Phase IIb randomized, placebo controlled study will evaluate 150 patients with NYHA Class III-IV CHF and low serum T3 levels. Patients will receive either of two doses of DITPA or placebo for six months. The study will be performed at 35 centers in the U.S. In addition to safety, the study will evaluate clinical and laboratory parameters related to severity of CHF, including change in global clinical status, echocardiographic parameters, BNP levels, exercise testing and quality of life measurements.

"We are pleased to initiate this clinical study of DITPA, an important milestone in the DITPA development program," stated Dr. Louis R. Bucalo, Chairman, President and CEO of Titan.

In addition to evaluating DITPA in CHF patients with low T3 levels, the Company believes that DITPA may also have potential utility in the treatment of diastolic dysfunction, and the treatment of patients with left ventricular dysfunction after myocardial infarction.

Diastolic dysfunction, or failure of the heart to fill adequately, is the primary cause of cardiac dysfunction in approximately 25 percent of the estimated 8 million people in the US and Europe with CHF. In diastolic dysfunction, the heart takes longer to relax after each contraction, causing difficulty in filling the heart fully with blood. Preclinical research studies indicate that thyroid hormone and DITPA can shorten diastolic filling time, potentially improving diastolic function.

Left ventricular dysfunction after myocardial infarction is characterized by subsequent extension of the area of infarction, hypertrophy of the surviving heart muscle without increase in its blood supply leading to inadequate heart muscle perfusion, and gradual replacement of heart muscle cells with fibrosis, a process called pathological ventricular remodeling. Worsening of CHF due to subsequent infarct expansion, and pathologic ventricular hypertrophy and remodeling is a major cause of morbidity and mortality in patients with CHF.

Thyroid hormone is known to promote growth of small blood vessels in the heart, and has also been demonstrated in animal models to convert pathologic hypertrophy to more adequately perfused heart muscle. Recent preclinical studies demonstrate that DITPA also stimulates coronary small blood vessel growth after myocardial infarction, and reduced extension of infarct size by approximately 80 percent. In these studies, DITPA was also shown to reduce ventricular remodeling subsequent to myocardial infarction, and improve heart function.

Additional support for evaluation of DITPA in this setting is the finding that thyroid hormone levels decrease in patients after myocardial infarction, and the extent of the decrease correlates with long term outcome. Specifically, patients whose thyroid hormone levels remain below normal in the weeks following myocardial infarction have a significantly increased mortality two years after myocardial infarction.

Based on these and other research studies, the Company may pursue approaches to evaluation of DITPA in these additional clinical settings.

DITPA is also currently being evaluated in a second randomized, double blind, placebo controlled Phase II study in 150 patients with NYHA Class II-IV CHF, sponsored by the Department of Veterans Affairs Cooperative Studies Program and funded by a $3.8 million grant.

Source: Titan Pharmaceuticals Inc.

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