The Literature Review BHV 390: Research Methods Kimberly Porter Martin, Ph.D.
A Phase 1 Study to Evaluate Bioequivalence...
Transcript of A Phase 1 Study to Evaluate Bioequivalence...
A Phase 1 Study to Evaluate Bioequivalence Between BHV-0223 40 mg Zydis® Sublingual Formulation and Riluzole 50 mg Oral Tablet in Healthy Volunteers
Irfan A. Qureshi1, Vladimir Coric1, Kimberly Gentile1, Richard Larouche2, Mario Tanguay2, Matt Anderson,3 Robert M. Berman1
1Biohaven Pharmaceuticals, Inc., New Haven, CT, USA2Syneos Health, Québec City, Canada3Certara, Princeton, NJ
Dr. Berman is an employee and shareholder of Biohaven Pharmaceuticals
This material is being made available through Biohaven’s Medical Affairs Department.
Background
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease • The disease is characterized by progressive muscle weakness• Median survival is 2 to 5 years following diagnosis
Riluzole prolongs survival and time to tracheostomy in patients with ALS• The registration trial demonstrated a life extension of 2 to 3 months• Postapproval observational studies suggest improved survival of 12 to 17 months• Yet approximately half of diagnosed patients are not prescribed medication
The optimal use of riluzole in clinical practice is limited by…• Difficulty swallowing (dysphagia) for many patients• A food effect limiting bioavailability that requires fasting• Dose-related hepatotoxicity
2
Novel Sublingual Formulation
• Manufactured via a proprietary lyophilization process: Zydis® technology developed by Catalent Pharma Solutions
• Multiple prototypes and 3 years of formulation development
• Tablet rapidly dissolves in seconds when placed under tongue
4
BHV-0223: Novel Riluzole 40 mg Rapidly Dissolving Zydis Formulation
No clinicallymeaningfulfood effect
PK, pharmacokinetics.
Designed to provide following attributes
Study Objective: Bioequivalence Study in Healthy Volunteers
Objectives
• Primary– To compare the rate and extent of absorption of BHV-0223 40 mg with riluzole 50 mg tablet in
healthy volunteers under fasting conditions– To evaluate the effect of food on the PK of BHV-0223 40 mg
• Secondary – To assess the safety and tolerability of BHV-0223– Assess the rate of absorption of BHV-0223 compared with crushed riluzole 50 mg tablet
5
ü
6
Study Design
BHV-022340 mg
Riluzole50 mg
Riluzole50 mg
BHV-022340 mg
BHV-022340 mg ³ 10 Hour Fast³ 10 Hour Fast
³ 4 Day Wash Out
³ 4 Day Wash Out
³ 4 Day Wash Out
Fed
Part 1BIOEQUIVALENCE
Part 2FOOD EFFECT
N = 138 N = 72
Supervised fast followed by ~800-1000 calorie (~50% from fat) meal
Sequence A
Sequence B
7
BHV-0223 Sublingual Riluzole 40 mg is Bioequivalent to Riluzole 50 mg Tablet
Parameter Ratio (N/R) 90% CI
AUC0-t 89.9% 87.3%-92.5%
AUC0-inf 89.8% 87.3%-92.4%
Cmax 112.7% 105.5%-120.4%
200,000
100,000
50,000
20,000
10,000
5,000
2,000
1,000
0 5 10 15 20 25
Time (h)
Plas
ma
Conc
entr
atio
n (p
g/m
L)
BHV-0223 40 mg Zydis sublingual - fasted
Riluzole 50 mg tablet swallowed with water - fasted
AUC, area under the concentration-time curve; 0-t, time zero to last nonzero concentration; 0-inf, time zero to infinity; CI, confidence interval; Cmax, maximum serum concentration; N/R, BHV-0223/Riluzole.
FDA-defined bioequivalence criteria fulfilled (i.e., 90% CI within 80 to 125% of reference drug)
8
BHV-0223 Associated With Less PK Variability
1st quartile 2nd quartile 3rd quartile 4th quartile
2,000,000
1,500,000
1,000,000
500,000
Rilu
zole
AU
C inf
(pg
• h/
mL)
BHV-0223Riluzole
Exposure Quartile
9
BHV-0223 is Not Subject to a Clinically Meaningful Food Effect based on AUC
200,000
100,000
50,000
20,000
10,000
5,000
2,000
1,000
0 5 10 15 20 25
Time (h)
Plas
ma
Conc
entr
atio
n (p
g/m
L)
Fasted state
Fed state
Parameter Ratio (Fed/Fast) 90% CI
AUC0-t 91.2% 88.1%-94.3%
AUC0-inf 92.0% 89.0%-95.1%
Cmax 38.9% 36.3%-41.6%
Safety Profile
• No serious adverse events• Most common AEs (reported in more than 2 subjects)
– Headache• mostly mild; transient
– Oral hypoesthesia• all mild and transient with median duration of 34 min
– Dysphagia• all mild and transient with median duration of 30 min• Separate Phase 1 Video Fluoroscopic Swallowing Evaluation Study in Healthy Volunteers revealed no aspiration
and no clinically meaningful effect on swallowing function – including 1 subject reporting dysphagia
• Local tolerability and oral cavity assessments (visual inspection)– No clinically important effects
• No significant lab abnormalities or vital sign changes
10AE, adverse event.
• Convenient formulation that does not require swallowing or administration of liquids
• No unexpected safety concerns were observed• Oral hypoesthesia was mild and transient
• BHV-0223 bypasses first-pass liver metabolism and reduces the dosage size that needs to be administered, thereby potentially reducing risk for hepatic enzyme elevations
• No clinically meaningful food effect on total drug exposure as measured by AUC
• BHV-0223 40 mg sublingual formulation of riluzole is bioequivalent to riluzole 50 mg oral tablet
BHV-0223: Summary
11