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«FDA Briefing Package Table of Contents I. Division Memorandum II. Clinical Briefing Document III. Statistical Briefing Document IV. Clinical ...»

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FDA Briefing Package

Table of Contents

I. Division Memorandum

II. Clinical Briefing Document

III. Statistical Briefing Document

IV. Clinical Pharmacology Summary

V. Immunoassay Summary

VI. Bibliography

DIVISION MEMORANDUM

Date: January 9, 2009

From: Sally Seymour, MD

Deputy Director for Safety, Division of Pulmonary and Allergy Products

To: Members, Pulmonary-Allergy Drugs Advisory Committee Subject: Overview of the FDA background materials for BLA# 125277, Kalbitor (ecallantide) Injection 30mg, for the treatment of acute attacks of hereditary angioedema (HAE) in patients 10 years of age and older Introduction Thank you for your participation in the Pulmonary-Allergy Drugs Advisory Committee (PADAC) meeting to be held on February 4, 2009. As members of the PADAC you provide important expert scientific advice and recommendation to the US Food and Drug Administration (the Agency) on the regulatory decision making process related to the approval of a drug or biologic product for marketing in the United States. The upcoming meeting is to discuss the Biologic Licensing Application (BLA) from Dyax Corp., seeking approval for ecallantide 30mg for the treatment of acute attacks of hereditary angioedema in patients 10 years of age and older. The proposed trade name is Kalbitor.

Hereditary angioedema (HAE) is a rare, autosomal dominant disorder estimated to affect 1 in 10,000 to 50,000 individuals, without known differences among ethnic groups. HAE is characterized by intermittent, unpredictable attacks of subcutaneous or submucosal edema of the face, larynx, gastrointestinal tract, limbs, and/or genitalia. Attacks can vary in severity and location and can be life-threatening, particularly those attacks involving the airway. In addition to potentially life threatening laryngeal edema, HAE can also cause significant morbidity.

The treatment options for HAE are usually divided into three categories – chronic longterm therapy, short-term prophylaxis to prevent attacks, and treatment of acute attacks1.

Recently, recombinant C1 inhibitor (Cinryze™) administered intravenously was approved for routine prophylaxis of HAE attacks in adults and adolescents in the United States (US).

Androgenic steroids are also approved for use in patients with HAE in the US. Danazol is approved and marketed in the US with the label indication “prevention of attacks of angioedema.” The drug is also used for chronic long-term therapy1,2. Stanazol and oxymetholone are also approved with similar indication, but are no longer marketed in the US. Elsewhere in the world epsilon aminocaproic acid (EACA) and tranexamic acid (TA) are approved for use in HAE patients. EACA and TA are used as chronic long-term therapy in HAE, but these are not thought tobe effective in acute attacks 1,2. Fresh frozen MM Frank. Hereditary angioedema: The clinical syndrome and its management in the United States.

Immunol Allergy Clin N Am 2006; 26:653-668.

MM Frank, Jiang H. New therapies for hereditary angioedema: Disease outlook changes dramatically. J Allergy Clin Immunol 2008; 121:272-280.

plasma is often used for short-term prophylaxis to prevent acute attacks and for treatment of acute attacks, but the use of fresh frozen plasma in HAE is controversial as it may worsen an attack by providing more substrate that can be acted on to release additional mediators such as high molecular weight kininogens1.

Currently, no products are approved for the treatment of acute attacks of HAE in the United States. Ecallantide is a new molecular entity proposed for the treatment of acute attacks of hereditary angioedema in patients 10 years of age and older. Ecallantide is a plasma kallikrein inhibitor, which reversibly binds human kallikrein. Ordinarily, kallikrein activity is regulated by C1-esterase inhibitor (C1 INH). In HAE patients with low or absent levels of functional C1-INH, kallikrein activity goes unchecked and is thought to lead to widespread release of bradykinin. In turn, bradykinin increases vascular permeability which leads to the swelling characteristic of acute HAE attacks.

The materials to be discussed in this meeting and the opinions we are seeking are primarily related to the clinical issues of ecallantide and statistical issues related to the study results.

Keep in mind that in the regulatory decision making process to determine approvability of a product, the Agency takes into consideration various factors in addition to clinical issues, including manufacturing and controls of a product and preclinical considerations. These will not be the focus of this Advisory Committee meeting.

Attached are the background materials for this meeting. The background materials include the following: a clinical briefing document, a statistical briefing document, a brief summary of the clinical pharmacology program, a brief summary of the immunoassays utilized in the ecallantide program, the proposed product label for Kalbitor, and reference articles.

This memorandum summarizes the contents of the Agency background material and the key issues and questions for discussion at the meeting. The materials prepared by the Agency contain findings and opinions based on reviews of information submitted by Dyax.

These background materials represent preliminary findings, and do no represent the final position of the Agency. An important piece in our decision on this application will be the opinions and input that we receive from you at this meeting.





Background Ecallantide is a recombinant human plasma kallikrein inhibitor, which reversibly binds human kallikrein. Ecallantide is a 60 amino acid protein containing 3 intra-molecular disulfide bonds, with a molecular weight of 7054 Daltons. It was identified through iterative selection and screening of phage display libraries of the first Kunitz domain of human tissue factor pathway inhibitor. Ecallantide is produced by expression in the yeast, Pichia pastoris, then recovered and purified by chromatography. Biologic activity is determined by an in vitro activity assay. Glycosylation, oxidation, and N-terminal truncation can occur forming ecallantide related variants. The product related variants have been characterized and are biologically active.

The drug product is a sterile solution for injection containing ecallantide in phosphate buffered saline. There are no preservatives and the pH of the solution is 7.0. The solution is contained in a clear glass vial, in which each vial contains 1mL of ecallantide solution 10mg/mL. The proposed dose of ecallantide is 30mg (3mL), which is to be administered subcutaneously (SC) in three (1mL) divided doses away from the angioedema location. No dilution is necessary.

Pharmacology/Toxicology Dyax submitted a complete pharmacology/toxicology program to support the chronic intermittent use of ecallantide. The program included 6 month, repeat dose, subcutaneous toxicology studies in rats and monkeys as well as other short term toxicology studies.

Reproductive toxicology assessment included a fertility study in rats, teratology studies in rats and rabbits, and a perinatal/postnatal study in rats.

In the 6-month rat and monkey toxicology studies, the primary finding was local injection site reaction. In the rat study, deaths were noted in the high dose group and control group.

Brain necrosis was observed in one of these high dose females. The causes of death were not determined except one of the male rat deaths was considered procedure-related. In rats, an increase in transaminases was also noted, but no associated histology changes in the liver. The No Observed Adverse Effects Level (NOAEL) in the rat study was determined to be the mid-dose group, which provides a safety margin of approximately 4-fold or 10-fold for the proposed human dose. There were no deaths or other significant systemic toxicities observed in monkeys.

In terms of immunogenicity, ecallantide antibodies were noted in both rats and monkeys and at a higher frequency in the high dose groups. Based upon the pharmacokinetic data, clearance of ecallantide was reduced and systemic exposure was increased following the development of ecallantide antibodies. However, there was no increase in toxicity noted with the higher exposure.

In animal studies, ecallantide caused a dose-dependent, reversible prolongation of aPTT, which is thought to be due to ecallantide inhibition of activation of factor XII to factor XIIa in the clotting cascade. However, there was no evidence of gross bleeding in the animals with the increase in aPTT.

Clinical Pharmacology The bioavailability of ecallantide following SC administration is approximately 90% and maximum plasma concentrations are observed approximately 2 to 3 hours after dosing.

The elimination half-life is approximately 2.0 hours. As a small polypeptide, ecallantide is expected to be eliminated by metabolic catabolism and renal elimination. But no clinical or preclinical studies were conducted to assess mass balance, route of excretion, or metabolism of the drug. Details regarding the pharmacokinetic data are summarized in the clinical pharmacology memorandum. It should be noted that there is a question of assay validation, so the pharmacokinetic data should be considered preliminary until assay validation is confirmed.

Clinical Program To support the safety and efficacy of ecallantide for the proposed indication, Dyax submitted a full clinical program including 5 completed studies in HAE patients (EDEMA0, EDEMA1, EDEMA2, EDEMA3, and EDEMA4) and an ongoing open label study. EDEMA0 and EDEMA1 were early phase 2 studies using IV doses of ecallantide and provide some safety information, but limited efficacy data. EDEMA2 is a dose ranging study that includes subcutaneous (SC) administration of ecallantide. EDEMA3 and EDEMA4 are the two phase 3 controlled clinical trials. EDEMA2, EDEMA3, and EDEMA 4 are the main sources of efficacy and safety data and will be the primary focus of this memo.

Dose Selection Dose ranging in HAE patients for the proposed indication can be challenging due to the limited patient population and intermittent nature of HAE attacks. Dyax performed three phase 2 studies (EDEMA0, EDEMA1, EDEMA2) that provide some information regarding dose selection; however, each study has its limitations. EDEMA0 was not controlled and only included 9 HAE patients; thus, the results provide little information regarding dose selection. EDEMA1 was a randomized, placebo-controlled, double blind study that evaluated 4 doses of IV ecallantide in patients with HAE, but did not include a SC dose of ecallantide.

EDEMA2 was a phase 2, open-label dose ranging study designed to assess the safety and efficacy of repeated doses of ecallantide in patients 10 years of age and older with acute HAE attacks. Three IV dosage groups (5 mg/m2, 10 mg/m2, and 20 mg/m2) as well as a more convenient dosage, ecallantide 30mg SC, were included in EDEMA2. The 30mg SC dose of ecallantide was expected to provide exposure similar to a 10-20mg/m2 IV dose group. Although EDEMA2 was not controlled, the results provide some information regarding dose response.

Seventy-seven patients were enrolled and treated with ecallantide for a total of 240 acute HAE attacks in EDEMA2. Of the 240 attacks, there was a range in the number of attacks treated with each dose of ecallantide as shown in the table below. The primary efficacy assessment was the proportion of patients with a successful outcome defined as onset of resolution of symptoms within 4 hours of dosing and continuing for 24 hours. With regards to the primary efficacy assessment, the ecallantide 30mg SC group had the highest proportion of successful outcomes (82%) and lowest proportion of partial response compared to the other treatment groups as shown in the table below.

–  –  –

While the results should be interpreted with caution due to the design limitations of EDEMA2, the results suggest that the selection of ecallantide 30mg SC for the phase 3 program is reasonable.

Patient Reported Outcomes – TOS and MSCS Assessment of efficacy for HAE attacks, which are highly variable in terms of symptoms and location, ideally should be based upon patient symptoms. However, there are no patient reported outcome (PRO) instruments that are the gold standard for assessing symptoms in this population. Therefore, the Applicant developed two PRO scores to assess patient symptoms and response to intervention.

The PROs developed by Dyax are the Mean Symptom Complex Severity (MSCS) and the Treatment Outcome Score (TOS). The MSCS is a global measure of symptom severity at a point in time, while the TOS is a composite measure of response to therapy. The conceptual frameworks for both PROs are shown in the figure below.

Figure 1 Conceptual Framework for TOS and MSCS

Upon presentation, patients identified HAE symptoms grouped by a symptom complex, i.e.

Internal Head/Neck, Stomach/GI, Genital/Buttocks, External Head/Neck, or Cutaneous.

The patient ranked each symptom complex severity as normal (0), Mild (1), Moderate (2),

or Severe (3). Following study medication, patients assessed response as follows:

Significant Improvement (a lot better), Improvement (a little better), Same (unchanged), Worsening (a little worse), or Significant Worsening (a lot worse), scored as 100, 50, 0, respectively.

Using the information recorded in the patient diaries, the TOS at 4 hours was calculated to weight the response for each complex based upon the severity at baseline. In the determination of the TOS, the symptom complex score is the response to treatment (score of -100 to 100) and the complex weight is the severity (0 to 3).

As illustrated in the above paragraphs, the TOS is quite complicated to explain and because of this, the results of the TOS are difficult to interpret. The inclusion of a response score ranging from -100 to 100 is not necessarily intuitive and can possibly amplify small effects.

The MSCS is the arithmetic mean of the severity of the individual symptom complexes.

The MSCS is measured as a change from baseline and is more straightforward to understand and thus, may be easier to interpret.



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