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New Study Finds that Ramelteon Shows Potential for Circadian Phase Shifting

May 22, 2006

Sandestin Beach, Fla., May 22, 2006 – Results from a new study to further explore the
mechanistic action of ramelteon suggest it may have the ability to shift the biological circadian rhythm – one’s natural 24-hour sleep-wake cycle – based on a study model designed to examine this potential.

Ramelteon has a unique mechanism of action that selectively targets two receptors located in the brain’s suprachiasmatic nucleus (SCN). The SCN is known as the body’s “master clock” because it regulates 24-hour, or circadian, rhythms, including the sleep-wake cycle.

“For many people, especially those who need to fall asleep earlier than their normal bed time or
travelers entering a new time zone, these changes can create a disruption, confusing their natural 24-hour ‘body clock,’ which keeps them aligned with their environment,” asserted Gary Richardson, senior research scientist at Henry Ford Hospital, Detroit, Mich., and lead author in the study.

“This study was designed to look at the potential to help people adjust to this time shift, and shows the need for additional studies on the effects of ramelteon in this area.”

According to the study, patients who received ramelteon before they went to bed five hours
earlier than their normal bed time experienced an advancement of dim light melatonin secretion offset compared to placebo, a model used to evaluate a circadian phase-shifting effect. The results were presented today at the 10th Biennial Meeting of the Society for Research of Biological Rhythms.

About the Study
This double-blind, placebo-controlled trial was designed to assess the circadian phase-shift
potential of ramelteon. The study enrolled 75 healthy adults who were randomized to receive ramelteon (1 mg, 2 mg, 4 mg or 8 mg) or placebo. Patients were housed for six days in a sleep laboratory under constant dim lighting and went to bed five hours earlier than their habitual bedtime. Study drug was given 30 minutes before lights out.

Eight hours after lights out, patients were awakened, and melatonin levels were measured every
60 minutes for 10 hours. Melatonin is a hormone that plays a key role in sleep. It was found that
ramelteon (1 mg, 2 mg, and 4 mg) produced a significantly greater and more rapid circadian phase advance compared to placebo (P=0.002, P=0.003 and P=0.001, respectively), as indicated by endogenous melatonin secretion offset time. Although circadian phase advance was also more rapid and greater with ramelteon 8 mg (currently marketed as ROZEREM™), the difference did not achieve statistical significance in this study. Additionally, the safety profile of ramelteon across all dosages was similar to that of placebo.

“While these early research findings need to be further explored in larger studies, these data are
important in helping us further understand how ramelteon works in the SCN,” said Louis Mini, MD, medical director, Neuroscience, at Takeda Pharmaceuticals North America, Lincolnshire, Ill. “This study will help us identify where future areas of research with ramelteon may be warranted.”

Ramelteon is marketed in the United States by Takeda Pharmaceuticals North America under the
trade name ROZEREM™ (ramelteon), a prescription for the treatment of insomnia characterized by difficulty with sleep onset. Due to its unique mechanism of action, ROZEREM has shown no evidence of abuse and dependence in clinical studies,* and as a result, has not been designated as a controlled substance.

*Ramelteon is not a controlled substance. A clinical abuse liability study showed no differences
indicative of abuse potential between ROZEREM and placebo at doses up to 20 times the
recommended dose (N=14) . Three 35-day insomnia studies showed no evidence of rebound insomnia or withdrawal symptoms with ROZEREM compared to placebo (N=2082).
Important Safety Information ROZEREM is indicated for the treatment of insomnia characterized by difficulty with sleep onset.

ROZEREM can be prescribed for long-term use. ROZEREM should not be used in patients with
hypersensitivity to any components of the formulation, severe hepatic impairment, or in combination with fluvoxamine. Failure of insomnia to remit after a reasonable period of time should be medically evaluated, as this may be the result of an unrecognized underlying medical disorder. Hypnotics should be administered with caution to patients exhibiting signs and symptoms of depression.

ROZEREM has not been studied in patients with severe sleep apnea, severe COPD, or in children or adolescents. The effects in these populations are unknown. Avoid taking ROZEREM with alcohol.

ROZEREM has been associated with decreased testosterone levels and increased prolactin levels. Health professionals should be mindful of any unexplained symptoms possibly associated with such changes in these hormone levels. ROZEREM should not be taken with or immediately after a high-fat meal. ROZEREM should be taken within 30 minutes before going to bed and activities confined to preparing for bed.

The most common adverse events seen with ROZEREM that had at least a 2% incidence
difference from placebo were somnolence, dizziness, and fatigue.

For complete Prescribing Information, visit www.ROZEREM.com .

Takeda Pharmaceuticals North America, Inc.
Based in Lincolnshire, Ill., Takeda Pharmaceuticals North America, Inc. is a wholly owned
subsidiary of Takeda Pharmaceutical Company Limited, the largest pharmaceutical company in Japan. In the United States, Takeda currently markets oral diabetes, insomnia, cholesterol-lowering and gastroenterology treatments, and through the Takeda Global Research & Development Center, Inc. the company has a robust, pipeline with compounds in development for diabetes, cardiovascular disease and other conditions. Takeda is committed to striving toward better health for individuals and progress in medicine by developing superior pharmaceutical products. To learn more about the company and its products, visit www.tpna.com .

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