Positive Results from Phase III Trials of Icatibant Give New Hope to Patients with Hereditary Angioedema

Information for Medical Journalists and Physicians

• Significantly faster improvement of symptoms
• Excellent safety profile
• Planned submission of license application to EMEA in the first quarter of 2007, to FDA at the end of December 2006

Rhodes, October 6, 2006 (dk)
The efficacy and safety of Icatibant, a bradykinin B2 receptor antagonist used in treating hereditary angioedema, have been strongly supported by the results of two recently completed Phase III clinical studies. Results of the trials, conducted by Jerini AG, were presented today at the annual meeting of the European Academy of Dermatology and Venereology in Rhodes, Greece. "Patients treated with Icatibant demonstrated much faster symptom improvement than those receiving tranexamic acid or placebo. The median time to almost complete symptom relief was also significantly shorter with Icatibant," said principal investigator, Prof. Marco Cicardi of the San Giuseppe University Hospital of Milan in Italy.
Hereditary angioedema is a rare genetic disease characterized by unpredictable and frequently recurring swelling attacks of the face, extremities, genitals, gastrointestinal tract, and laryngeal region. "There is no approved medication allowing patients early self-treatment in the event of an acute attack. We now hope that patients will soon be able to use Icatibant for self-treatment, as it is a drug that works quickly and has an excellent safety profile," said Prof. Werner Aberer of the University of Graz in Austria, referring to the data presented at the meeting.

Michel Raguet, President of the French HAE patients' organization, who is an HAE patient himself, was extremely pleased with the results. "We have been waiting many years for a fast-acting drug giving patients the ability to treat easily themselves at the onset of an attack. Patients could then lead a safer and more independent life, which would clearly improve the quality of our lives considerably."
According to Dr. Jochen Knolle, head of R&D at Jerini AG, submission of license applications to the regulatory agencies is planned to begin in December 2006, which could lead to a potential launch in late 2007.
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Hereditary Angioedema
Hereditary angioedema (HAE) is a rare genetic disease with recurring swelling attacks affecting various parts of the body.  When or where swelling will occur cannot be predicted. Swelling attacks of the hands, feet, and face can be disfiguring and are often painful, which is often stressful for the patient.  Furthermore, the intestinal attacks tend to be accompanied by extreme colic-like pain. "When the larynx is affected, the HAE attack can be life-threatening," said Prof. Aberer. The prevalence of HAE is estimated between 1 in 50,000 and 1 in 10,000 individuals worldwide. Because abdominal symptoms and the swelling of the extremities are unspecific, the disease is often misdiagnosed. "Physicians should always consider the possibility of HAE whenever a patient regularly exhibits these symptoms," said Prof. Aberer.
It has been shown that bradykinin plays a key role in the mechanism of angioedema formation. During an attack, bradykinin reaches an unusually high local level and binds to the B2 receptor. This affects blood vessel dilatation and vascular permeability and results in fluid accumulating in the tissues, causing swelling and pain.

FAST- 2: Icatibant highly effective versus tranexamic acid
Icatibant, a synthetic peptidomimetic, blocks the B2 receptor, thereby reducing the detrimental effects associated with elevated bradykinin levels. In the FAST-2 study, the efficacy of Icatibant was measured in comparison to tranexamic acid. This was a randomized, controlled, multi-center trial randomizing 74 patients in Europe, Switzerland and Israel. Patients received either a single subcutaneous dose of 30mg Icatibant or tranexamic acid, an anti-fibrinolytic agent used in some European countries for both prophylaxis and the acute treatment of HAE. After completing  the randomization phase, patients were referred to an Open Label Extension (OLE) phase. "A total of 30 laryngeal attacks were successfully treated in both FAST studies," added Prof. Cicardi.

A Visual Analog Scale (VAS), a measure of symptom severity generally accepted by regulatory authorities, was used in the trials to measure patient response. The primary endpoint of FAST-2, as measured by a VAS, was met with a median time to onset of symptom relief of 2.0 hours for Icatibant versus 12.0 hours for tranexamic acid (p<0.001).

Secondary endpoints entered in the analysis also showed statistically significant differences in favor of Icatibant. Time to onset of relief of key symptoms, as measured by a preset reduction in the VAS, was highly significant for skin swelling (p<0.001), skin pain (p=0.002), and abdominal pain (p=0.028). Another clinically relevant time point at which patients showed almost complete symptom relief, as measured by VAS, was 10.0 hours for Icatibant versus 35.5 hours for tranexamic acid (p<0.001). "The results obtained look crystal clear and are highly significant," said Prof. Cicardi.

The time point at which patients first reported improvement of symptoms further underlines the efficacy of Icatibant: median times were 0.8 hours for Icatibant versus 7.9 hours for tranexamic acid (p<0.001).

FAST- 1: Icatibant highly effective versus placebo
In a second study comparing Icatibant to placebo, 56 patients were randomized in the United States, Canada, Australia, and Argentina. A clinically relevant response was achieved for the primary endpoint with a  median time to onset of symptom relief of 2.5 hours for Icatibant and 4.6 hours for placebo (p=0.131). This difference, can be explained by the higher proportion of patients with abdominal attacks in the FAST-1 trial (approx. 50% in FAST-1 versus approx. 35% in FAST-2). In this study, an unexpectedly high placebo response was initially observed in patients treated with abdominal pain.

However, after a short period, the progression of symptom relief in the comparator group was considerably slower than that of the Icatibant group. Additional evidence to support this observation comes from "time to almost complete relief" which shows a median time of 8.5 hours for Icatibant versus 35.2 hours for placebo (p=0.048).

Other secondary endpoints further support Icatibant's efficacy. Time to onset of relief of key symptoms, as measured by VAS, showed a statistically significant reduction of skin swelling (p=0.032), skin pain (p=0.007), and almost statistical significance for abdominal pain (p=0.056). The median time point at which patients first reported improvement of symptoms was 0.8 hours for Icatibant versus 16.9 hours for placebo (p<0.001).

Excellent safety profile of Icatibant
Icatibant has shown an excellent safety profile in previous and ongoing trials sponsored by Jerini and sanofi-aventis, and has been administered in over 1300 subjects to date. This safety profile was confirmed in the FAST-1 and the FAST-2 studies. No drug-related serious adverse events occurred. The most frequent adverse events were injection site reactions such as erythema, swelling, and occasional itching and pain. These symptoms were transient and resolved spontaneously.

Patients' need for a safe self-treatment
Michel Raguet, President of the French HAE patients' organization and a patient himself, gave an account of his personal experience: "In my case, 20 years elapsed between my first HAE attacks and the correct diagnosis," he said. The doctors first suspected that Mr. Raguet and his four affected siblings had a rare allergy. A sister of his died of a laryngeal attack during this time. At the age of 25 years, once the correct diagnosis had finally been made, Mr. Raguet received androgens for prophylactic treatment, but had to stop using them because of serious side effects. When he now suffers an attack, he is given a C1 esterase inhibitor concentrate, which has to be administered intravenously in a hospital and is available in France under a special access program (ATU) for some HAE patients.

Mr. Raguet founded the French patients' organization AMSAO  (Association des Malades Souffrant d'Angio-Oedèmes par déficit en C1 inhibiteur) to enable fellow sufferers to exchange their experiences, learn more about their disease, make themselves heard by the authorities, and improve therapeutic conditions for children in the long term. This group informs both doctors and the public alike about HAE. He says that doctors still know too little about this disease. Moreover, there is no proper treatment for use by the patients themselves. "We would like a drug that we can apply ourselves and which is both safe and effective. This would greatly improve the quality of life of HAE patients. The possibility that Icatibant may soon be available as such a drug urged me to join the FAST-2 study as a patient myself."

Strategy to Market
 "We plan to market Icatibant in a ready-to-use, pre-filled syringe that patients could self-administer at the onset of an HAE attack," said Dr. Hoess, Chief Commercial Officer at Jerini. "This would ensure a safe and independent life with a rapid intervention option at the onset of an attack, which, in the case of laryngeal swelling, for instance, can be life-threatening."

About FAST-1 and FAST-2 Studies
The FAST-1 and FAST-2 studies were randomized, controlled, multi-center trials that screened 425 patients. FAST-1 enrolled patients in the United States, Canada, Argentina, and Australia, whereas FAST-2 enrolled patients in Europe, Switzerland and Israel.

The patients enrolled in FAST-1 were randomized to receive either a single subcutaneous dose of 30mg Icatibant or placebo. Patients enrolled in FAST-2 were randomized and received either a single subcutaneous dose of 30mg Icatibant or tranexamic acid. Tranexamic acid is an anti-fibrinolytic agent that is used in some European countries for the treatment of HAE and was proposed by the EMEA as a comparator. Subsequent to the completion of randomization, patients were referred to an Open Label Extension (OLE) phase.

The primary endpoint was time to onset of symptom relief as measured by a Visual Analog Scale (VAS) by the patient. Onset of symptom relief was defined as a preset reduction on the VAS for key symptoms: abdominal pain, skin pain, and skin swelling. A statistically significant difference between Icatibant and the comparator or placebo had to be reached.

VAS is a measure of symptom severity and has been validated and accepted by regulatory authorities as an instrument for documenting Patient Reported Outcome (PRO). Secondary endpoints were assessed by VAS, symptom scores, and Clinical Global Impression (CGI), as reported by patient and/or physician. Thus, the clinically relevant treatment effects of Icatibant were assessed by three independent measures.

About Icatibant
Icatibant has been granted orphan drug status for the treatment of angioedema by the FDA and the EMEA, potentially securing, upon approval, market exclusivity for seven and ten years, respectively. In addition, the FDA has granted fast-track designation to Icatibant in the indication HAE. Icatibant's subcutaneous administration, along with its excellent safety profile demonstrated in clinical studies to date, and one-year-stability at room temperature, all offer key benefits to HAE patients. Jerini and its US partner Kos Pharmaceuticals, Inc., plan to market Icatibant in a pre-filled syringe that patients could self-administer at the onset of an HAE attack, enabling them to live a safe and independent life.

About Jerini AG
Jerini AG is a pharmaceutical company based in Berlin, Germany focusing on the discovery and development of peptide-based drugs. Having recognized the potential of peptides as natural starting molecules for drug discovery, the company has developed state-of-the-art technologies to identify and transform peptides into drugs.  Based on its technology platform, Jerini has established several in-house development programs, which address indications within ophthalmology, oncology, and inflammatory therapeutic areas.  The most advanced of these programs targets age-related macular degeneration (AMD), the leading cause of vision loss and blindness in people over the age of 55 in developed countries, and is scheduled to begin clinical testing the first half of 2007.

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Contact Jerini AG
Dr. Jens Zimmermann

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10115 Berlin, Germany
Website: www.jerini.de

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