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