Sorena Kiani
New HAE Drugs
Barts Health NHS Trust
Overview
• Review mechanism of HAE swelling
• Review of bradykinin pathway
• Opportunities for intervention in BK pathway
• New monoclonal antibody for HAE
• New oral therapy for HAE
• Future oral therapies for HAE
Angioedema • Localised swelling
• Extravasation of fluid in deep subcutaneous or submucosal tissue
• Lip, tongue, larynx, periorbital, hands, feet, genitalia, bowel
https://www.sciencedirect.com/science/article/pii/S1568997216302786
Coagulation cascade
Fibrinolytic system Kinin system
Complement system
The Contact system
• 32 healthy volunteers in Kansas, USA
• Men: 13 drug, 3 placebo
• Women: 11 drug, 5 placebo
• Age 20-52: mean age 32
• Single injection of different doses or placebo
• Pharmacokinetics and pharmacodynamics
• Multicentre RDBPC trial for type I & II HAE • Phase 1b; 2 inj. (2/52); 37 pts: 24 drug (4 doses) vs 13
placebo • Age 18-71 • Criteria: 1 attack/yr with at least 1 in last 6/12 • Real data: mean attacks in last 3/12: 6 (0-36)
Lanadelumab Phase 1b safety
• No serious adverse events
• Headaches and site pain
• 2 patients developed non-neutralising Abs
Lanadelumab Phase 1b
Dose
Less attack
Attack free
300 100% 100%
(5/5)
400 88% 82%
(9/11)
Placebo --- 27%
(3/11)
HELP study
• Type I and Type II HAE: Efficacy and Safety
• 41 sites in the US, UK, Italy, Germany, Canada and Jordan
• 03 March 2016 - 13 April 2017
Study withdrawal
HELP
• 125 pts /HAE Type I or II; Age ≥ 12 years of age • 26 week treatment period • 3 dosing arms
– 150 every 4 weeks – 300 mg every 4 weeks – 300mg every 2 weeks vs. placebo
• HAE disease activity spectrum – baseline 3.7 mean attacks/month – 52% > 3 attacks/month – 65% history of laryngeal attacks – 56% on long term prophylaxis
HELP study- 0-182 days
P<0.001 P<0.001 P<0.001
HELP study- 0-182 days
P<0.001 P<0.001 P<0.001
HELP results
• Monthly attack rate reduction vs. placebo
– 300mg every 2 weeks: 87% (p <0.001)
– 300mg every 4 weeks: 73% (p<0.001)
– 150mg every 4 weeks: 76% (p<0.001)
• Significantly higher proportion of patients
remained attack free
Common side effects
HELP safety
• No treatment related serious adverse events
• Most common adverse event was mild to moderate injection site pain (29% placebo vs. 43% across all Lanadelumab arms)
• 96% of patients volunteered to enter the ongoing long-term extension safety study
Lanadelumab (Takhzyro)
• Approved by FDA on August 23, 2018
• HAE type I and II
• Patients age 12 years and above
• 2 injections per month
• Approximately $12,000 per injection in USA
• 75 patients: Europe, Canada, Australia
• August 2016-August 2017
BCX7353 blocking activity
Quality of Life
after 6h
within 6h
Time to onset of symptom relief (hrs)
% with symptom
relief
20 IU/kg C1INH
Placebo
within 6h
0
5
10
15
20
25
Attack Duration if treated within ... ofonset
< 1 h ≥ 1 to 2h ≥ 2 to 5h ≥ 5h
Attack duration
(hrs)
IMPACT-1 and IMPACT-2 Icatibant Outcome Survey (IOS) (n=207 attacks)1
Early intervention, Faster resolution
On demand treatment at attack onset
Intercritical Mature attack
Swelling /
Pain
Early
Attack onset
Prophylaxis “Classical” acute Rx. Prodromal
Intervene early during PK
activation