02/04/09 BLA - Dyax Corp.-ecallantide for the treatment of acute attacks of hereditary angioedema

Disease:
Hereditary Angioedema (HAE) is a rare disease. Approximately 10,000 individual suffers. Less than 50% properly diagnosed. The major symptom is edema (swelling) in various body parts including hands, face, feet and airway. It is a potentially life-threatening disease when HAE attack laryngeal. The reason of HAE is deficiency in C1 esterase inhibitor activity, which are believed to block Kallikrein (血管舒缓素) Synthesis and decrease Bradykinin (血管舒缓激肽).

Medicine:
FDA approved several medicines for short and long term prophylaxis like Androgens, but no for acute attack. (Androgens have SAEs).
Dyax use recombinant technology to produce a protein, called Ecallantide, to specifically inhabit Kallikrein and suppress Bradykinin. Then physiological symptom, Edema, disappear. According to stability study, Ecallantide injection can be stored at 2-8 C for two years and at room temperature for 2 weeks.

Clinical studies:
Due to it is a rare disease, 219 HAE patients (4% of patients seeking treatment) were enrolled in the studies. The 219 HAE patients received 609 doses totally.

Design:
Phase 1 and Phase 2:
4 studies in Healthy subjects: DB, placebo-controlled, IV, PK, dose escalation
EDEMA0 / EDEMA1: single IV dose, 1 open-label, 1 placebo-controlled
EDEMA 2: Multi-dose, IV or Sbq, OL.
Phase 3:
EDEMA 3: DB, single dose, 30mg subq, placebo-controlled
EDEMA 3: RD, 30mg subq, open label
EDEMA 4: DB, Single-dose, 30mg subq, placebo-controlled
Ongoing continuation study: RD, OL

Efficacy measurement tool: Patient-Reported Outcome (PRO) assessment
Refer to FDA guideline: Patient-reported outcome measures.
Tool 1:Mean Symptom Complex Severity (MSCS): Point-in-time assessment of symptom severity
Tool 2:Treatment Outcome Score (TOS): Assessment of response to treatment.

Safety: Ecallantide is a foreign protein. So, the main concern is anaphylaxis and hyperandsensitivity caused by ecallantide.
Adverse events/physical exams/vital signs/routine clinical lab test and urinanalysis/ECG/Serial antibody testing

Sponsor conclusion:
No exception, the data sponsor present are “substantial” and “convincing” evidence of studies.

FDA conclusion:
FDA point out several issues about studies:
1) In EDEMA3: Dose administration error.
2) In EDEMA4: sample size increased from 52 to 96. It leads to the decrease of P value.
3) Pediatric data is limited.
Efficacy:
- EDEMA3 results not statistically significant by the pre-specified analysis
- EDEMA4 results of questionable robustness
- Pediatric data is limited
Safety
- Significant risk of anaphylaxis
- Limited data in pediatric patients.

Advisory committee
Voting (5 questions)
Question 4: Do the safety and efficacy data provide substantial and convincing evidence to support the approval of ecallantide for the treatment of acute attacks of hereditary angioedema?
Yes: 6 No: 5 Abstain: 2

Comments:
data is inadequate.
Rechallenge study is crude. It put patients in extremely dangerous situation.
If approved, post-marketing study is necessary.

My comments:
Apparently, the clinical data is inadequate, especially, pediatric data. In addition, sponsor changed the sample size of EDEMA 4 (add 44 patients) in order to get statistically significant results. Considering it is an orphan drug, advisory committee member may lower their standard of judgment.