UC SF A Phase 2 Study of Intravenous Omecamtiv Mecarbil, A Novel - - PowerPoint PPT Presentation

Presenter Disclosure Information

John R. Teerlink, M.D., F.A.C.C., F.A.H.A., F.E.S.C., F.R.C.P.

Professor of Medicine, University of California San Francisco Director of Heart Failure, San Francisco Veterans Affairs Medical Center

• Financial Disclosure

– This study was funded by Amgen Inc. – J.R. Teerlink has received research grants and/or consulting fees from Amgen, Corthera, Cytokinetics, Merck, Novartis, Sorbent, and Trevena

• Unlabeled/unapproved uses disclosure

– Use of omecamtiv mecarbil in patients with heart failure is investigational.

• The technical support of Karen Driver is acknowledged and was supported by Amgen Inc.

UC SF

A Phase 2 Study of Intravenous Omecamtiv Mecarbil, A Novel Cardiac Myosin Activator, In Patients With Acute Heart Failure

John R. Teerlink, G. Michael Felker, John J. V. McMurray, Piotr Ponikowski, Marco Metra, Gerasimos S. Filippatos, Kenneth Dickstein, Justin A. Ezekowitz, John G. Cleland, Jae B. Kim, Lei Lei, Beat Knusel, Andrew A. Wolff, Fady I. Malik and Scott M. Wasserman

• n behalf of the ATOMIC-AHF Investigators and Patients

Omecamtiv Mecarbil (OM) is a Novel Selective Cardiac Myosin Activator

Malik FI, et al. Science 2011; 331:1439-43.

Mechanochemical Cycle of Myosin

Force production

O m e c a m t i v m e c a r b i l

Omecamtiv mecarbil increases the entry rate of myosin into the tightly-bound, force-producing state with actin “More hands pulling on the rope”

Increases in Systolic Ejection Time Underlie Increases in Cardiac Function

Δ Stroke Volume (mL) Δ Fractional Shortening (% points) Δ Ejection Fraction (% points)

Δ = placebo corrected change from baseline Mean ± SEM

Δ SET (msec)

Cleland JGF, et al. Lancet 2011; 378: 676–83. Teerlink JR, et al. Lancet 2011; 378: 667–75.

Healthy Volunteers

Objective:

• To evaluate the safety, pharmacokinetics/ pharmacodynamics,

and efficacy of IV omecamtiv mecarbil (OM) in patients with acute heart failure (AHF)

Hypothesis:

• At least 1 dose level of IV OM will be well tolerated and will

result in improvement of dyspnoea in subjects with left ventricular systolic dysfunction hospitalised for AHF

ATOMIC-AHF

Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure

Study Design: Sequential Dosing Cohort

Cohort 1 Cohort 2 Cohort 3

Omecamtiv Placebo

1:1 Randomization (n≈200)

Omecamtiv Placebo

1:1 randomization (n≈200)

Placebo Omecamtiv

1:1 randomization (n≈200)

DMC DMC Cohort 1 Cohort 2 Cohort 3

15 mg/hr @ 0-4 hr 3 mg/hr @ 4-48 hr Target: 230 ng/mL Cmax: 75-500 ng/mL SET: ~8-55 msec 20 mg/hr @ 0-4 hr 4 mg/hr @ 4-48 hr Target: 310 ng/mL Cmax: 125-700 ng/mL SET: ~14-78 msec 7.5 mg/hr @ 0-4 hr 1.5 mg/hr @ 4-48 hr Target: 115 ng/mL Cmax: 30-250 ng/mL SET: ~3-28 msec

Pharmacokinetic simulations Teerlink JR, et al. Lancet 2011; 378: 667–75; Cleland JGF, et al. Lancet 2011; 378: 676–83.

Study Design

Presentation for AHF Randomisation* 1:1

Placebo IV

72 48 4 Time (hrs) M A N D A T O R Y I N - H O S P I T A L S T A Y Day 30 EOS

Screening

Loading Dose

Omecamtiv mecarbil IV

Month 6

* Randomisation within 24 hours of initial IV diuretic (Amendment 2)

Randomised, double-blind, placebo-controlled, sequential cohort study

6 15 24 Day 6/ DC

Vital Status (phone call)

Study drug administration 1⁰ EP dyspnoea response PK sampling all subjects PK/PD sub-study Echo (PK/PD sub-study)

Maintenance Dose 96

Cardiac troponin/CK-MB

Key Inclusion and Exclusion Criteria

Key Inclusion Criteria

• Male/female ≥ 18 and ≤ 85 y
• History of HF and LVEF ≤40%
• Hospitalised for AHF requiring

IV therapy

• Dyspnoea due to HF at rest or

with minimal exertion ≥2 hours after iv diuretic

• Screening BNP ≥ 400 pg/mL or

NT-proBNP ≥ 1600 pg/mL (BNP ≥ 600 pg/mL or NT-proBNP ≥2400 pg/mL, if the subject has atrial fibrillation) Key Exclusion Criteria

• Receiving IV vasopressor, inotropic
• r mechanical support
• Acute coronary syndrome (ACS) on

presentation

• Recent vascular event or cardiac

procedure

• Severe obstructive valvular or

myocardial disease

• BP >160/100 or SBP <90 mmHg, or

HR >110 or <60 bpm

• eGFR (MDRD) <20 mL/min/1.73m2

Randomised within 24 hours of initial IV diuretic treatment

Primary:

• Dyspnoea symptom response (7-point Likert scale) through 48 hours

Secondary:

• Death (any cause) and/or worsening heart failure within 7 days
• Dyspnoea area under the curve (AUC) (baseline to 5th day or discharge)

as measured by subject self-assessed Numerical Rating Scale (NRS)

• Dyspnoea by 7-point Likert scale at each scheduled assessment
• Patient Global Assessment response through 48 hours
• Change from baseline in NT-proBNP
• Length of initial hospital stay
• Days alive out of hospital until day 30

PK/PD (Echo) Sub-study

Efficacy Endpoints

Characteristic Pooled Placebo (N = 303) Cohort 1 OM (N = 103) Cohort 2 OM (N = 99) Cohort 3 OM (N = 101) Age , mean (SD) 66 (11) 65 (12) 67 (10) 68 (10) Gender – male, % 76 76 82 76 Region, % * Eastern Europe 53 45 56 62 North America 25 37 24 18 Australia 2 1 Western Europe 21 18 19 20 Ischaemic heart disease, % 62 62 59 66 Years from HF diagnosis, mean (SD) 6 (6) 6 (6) 6 (5) 6 (5) Most recent LVEF (%), mean (SD) 26 (8) 26 (8) 25 (7) 28 (7) Persistent Atrial Fibrillation or Flutter, % 33 29 32 36 Diabetes Mellitus, % 45 49 41 42 Hypertension, % 81 84 81 82

Baseline Characteristics (1)

*p < 0.05 for a difference in cohorts 1-3 Placebo arms compared to each other

Characteristic Pooled Placebo (N = 303) Cohort 1 OM (N = 103) Cohort 2 OM (N = 99) Cohort 3 OM (N = 101) Systolic BP (mmHg), mean (SD) 119 (18)* 118 (18) 117 (17) 117 (15) Heart rate (beats/min), mean (SD) 78 (13) 78 (13) 79 (13) 78 (14) Dyspnoea Numerical Rating Scale (NRS), Mean (SD) 6 (2) 6 (2) 6 (2) 6 (2) ACE inhibitors/Angiotensin Receptor Blockers, % 78 79 74 84 Beta blocker, % 86* 90 87 90 Digoxin, % 20 28 26 22 Mineralocorticoid Receptor Antagonist, % 55 54 59 58 Ivabradine, % 3 4 4 6 Troponin-I, median (URL 0.04 ng/mL) 0.044* 0.060 0.044 0.056 NT-proBNP (pg/mL), median 9026 7674 10488 10416 eGFR (mL/min/1.73m2), mean (SD) 53 (18)* 52 (18) 53 (19) 50 (18) Time from presentation to randomisation, mean (SD) 15 (8)* 12 (8) 16 (10) 15 (9)

Baseline Characteristics (2)

*p < 0.05 for a difference in cohorts 1-3 Placebo arms compared to each other;

URL= upper reference limit

Responder defined as:

• Minimally, moderately or markedly better at 6 hours

AND

• Moderately or markedly better at both 24 and 48 hours

WITHOUT

• Worsening heart failure or death for any cause

by 48 hours

Primary Efficacy Endpoint Dyspnoea Response (Likert Scale)

Primary Efficacy Endpoint: Dyspnoea Response (Likert Scale)

Pooled Placebo

Response Rate Ratio* 1.03 1.15 1.23 95% CI (0.79, 1.35) (0.90, 1.47) (0.97, 1.55) *Ratio of response rate to Pooled Placebo p-value of a CMH test among all 3 Placebo arms = 0.32 Overall p-value = 0.33

Pooled Placebo OM Cohort 1 OM Cohort 2 OM Cohort 3 Dyspnoea Response Rate (% Responders) 5 10 15 20 25 30 35 40 45 50 55 42% 47% 51% 41%

Supplemental Primary Analysis: Dyspnoea Response (Likert Scale)

Paired Placebo

Response Rate Ratio 1.02 1.02 1.41 95% CI (0.74, 1.42) (0.76, 1.37) (1.02, 1.93) Response rate ratio: ratio of response rate to Placebo within each cohort

Cohort 1 OM OM OM 42% 41% Cohort 2 47% 46% Cohort 3 Placebo 51% 37% Dyspnoea Response Rate (% Responders) 5 10 15 20 25 30 35 40 45 50 55 Placebo Placebo

p = NS p = NS p = 0.03

For Increases

• f…

Response Rate Ratio Increases… 95% CI P-value Dose* 50 mg total OM administered 5.5% 0.7% – 10.6% 0.025 Plasma concentration* 4000 hr*ng/mL AUC48h 6.4% 1.7% – 11.4% 0.007

Exploratory Analyses: Dose and Concentration Relationship to Dyspnoea Response

* Adjusted for region, cohort, age, baseline NRS, presentation-randomisation duration (continuous)

Within 7 days of IP initiation Pooled Placebo (N = 303) Cohort 1 OM (N = 103) Cohort 2 OM (N = 99) Cohort 3 OM (N = 101) Death or WHF* Yes - n(%) 52 (17) 13 (13) 9 (9) 9 (9) Relative risk 0.67 0.54 0.54 (95% CI) (0.38, 1.18) (0.28, 1.04) (0.27, 1.08) p-value 0.151 0.054 0.067 WHF* Yes - n(%) 51 (17) 13 (13) 8 (8) 9 (9) Relative risk 0.68 0.49 0.55 (95% CI) (0.38, 1.21) (0.24, 0.98) (0.28, 1.09) p-value 0.179 0.034 0.075

Secondary Efficacy Endpoint: Worsening Heart Failure (WHF)

*Worsening heart failure is defined as clinical evidence of persistent or deteriorating heart failure requiring at least one of the following treatments:

• Initiation, reinstitution or intensification of IV vasodilator
• Initiation of IV positive inotropes, or IV vasopressors
• Initiation of ultrafiltration, hemofiltration, or dialysis
• Initiation of mechanical ventilatory or circulatory support

Pooled Placebo (N = 303) Cohort 1 OM (N = 103) Cohort 2 OM (N = 99) Cohort 3 OM (N = 101) Dyspnoea Numerical Response AUC through Day 6, mean (95% CI)

3.5 (3.3, 3.8)

3.5 (3.1, 3.9) 3.6 (3.2, 4.0) 3.7 (3.3, 4.0) Patient Global Assessment response, n (%) 127 (42) 44 (43) 48 (48) 51 (50) Length of initial hospital stay, median days (95% CI) 9 (8, 9) 8 (7, 9) 7 (7, 8) 9 (8, 10) Days alive out of hospital through 30 days, median (95% CI) 22 (21, 23) 23 (21, 24) 23 (23, 24) 22 (21, 23) NT-proBNP change from BL (pg/mL) at 48 hours, median (95% CI)

• 1805

(-2271, -1370)

• 2076

(-2746, -1292)

• 2161

(-4273, -1336)

• 1742

(-2517, -1017)

Other Secondary Efficacy Endpoints

All comparisons to Pooled Placebo not significant (p > 0.05)

Preferred Term Patient Incidence, n (%) Pooled Placebo (N = 303) Pooled OM (N = 303) Cohort 1 OM (N = 103) Cohort 2 OM (N = 99) Cohort 3 OM (N = 101) Number of subjects reporting AEs of Supraventricular or Ventricular Tachyarrhythmia 34 (11.2) 26 (8.6) 13 (12.6) 5 (5.1) 8 (7.9) Supraventricular Tachyarrhythmias 20 (6.6) 10 (3.3) 6 (5.8) 0 (0.0) 4 (4.0) Atrial Fibrillation or Atrial Flutter 15 (5.0) 6 (2.0) 3 (2.9) 0 (0.0) 3 (3.0) Atrial Tachycardia 3 (1.0) 1 (0.3) 1 (1.0) 0 (0.0) 0 (0.0) Sinus Tachycardia 1 (0.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Supraventricular Tachycardia 2 (0.7) 4 (1.3) 3 (2.9) 0 (0.0) 1 (1.0) Ventricular Tachyarrhythmias 18 (5.9) 17 (5.6) 8 (7.8) 5 (5.1) 4 (4.0) Ventricular Arrhythmia 4 (1.3) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Ventricular Extrasystoles 1 (0.3) 2 (0.7) 1 (1.0) 1 (1.0) 0 (0.0) Ventricular Fibrillation 2 (0.7) 1 (0.3) 0 (0.0) 1 (1.0) 0 (0.0) Ventricular Tachyarrhythmia 0 (0.0) 1 (0.3) 1 (1.0) 0 (0.0) 0 (0.0) Ventricular Tachycardia 11 (3.6) 13 (4.3) 7 (6.8) 3 (3.0) 3 (3.0) Extrasystoles 0 (0.0) 1 (0.3) 0 (0.0) 0 (0.0) 1 (1.0)

Supraventricular and Ventricular Tachyarrhythmias

Patient Incidence, n (%) Pooled Placebo (N = 303) Pooled OM (N = 303) Cohort 1 OM (N = 103) Cohort 2 OM (N = 99) Cohort 3 OM (N = 101) Death 10 (3.3) 8 (2.6) 1 (1.0) 4 (4.0) 3 (3.0) Cardiovascular 10 (3.3) 8 (2.6) 1 (1.0) 4 (4.0) 3 (3.0) ACS/MI (fatal) 1 (0.3) 1 (1.0) All Rehospitalisations 37 (12.2) 29 (9.6) 11 (10.7) 11 (11.1) 7 (6.9) Acute MI 1 (0.3) 1 (0.3) 1 (1.0) Unstable angina Heart failure 19 (6.3) 22 (7.3) 6 (5.8) 11 (11.1) 5 (5.0) Other 18 (5.9) 7 (2.3) 4 (3.9) 3 (3.0) All Index hospitalisation MI (non-fatal) 2 (0.7) 5 (1.7) 1 (1.0) 4 (4.0) Investigator reported 0 (0.0) 2 (0.7) 0 (0.0) 2 (2.0) Troponin triggered 2 (0.7) 3 (1.0) 1 (1.0) 2 (2.0) Total MIs (Fatal + Rehosp + Nonfatal Index Hosp) 3 (1.0) 7 (2.3) 2 (1.9) 5 (5.0)

Post-Randomization Adjudicated Events

ACS/MI = Acute Coronary Syndrome/Myocardial Infarction. 66 patients had 73 positively adjudicated rehospitalisations.

Troponin-I Change from Baseline (ng/mL) Compared with Pooled Placebo

Baseline TnI (ng/mL)

Pooled Placebo Cohort 1 Cohort 2 Cohort 3

Median 0.044 0.060 0.044 0.056 (Q1, Q3) 0.023, 0.080 0.028, 0.141 0.030, 0.084 0.026, 0.092 4 hours 15 hours 24 hours 48 hours Day 4 Day 6

Time

Troponin Change from Baseline (ng/mL) Q3 Median Q1

0.03 0.02 0.01 0.00 –0.01 –0.02 –0.03 –0.04 –0.05

Omecamtiv Mecarbil Concentrations vs. Troponin-I Maximal Change from Baseline

Red lines represent linear regression line and its +/- SE. Baseline troponin-I is adjusted. Omecamtiv mecarbil Cmax Omecamtiv mecarbil AUC0-48

p=0.83 p=0.95

Max Troponin Change from Baseline(ng/mL) Max Troponin Change from Baseline(ng/mL) OM Cmax (ng/mL) OM Cmax (ng/mL) OM AUC0-48 (ng*hr/mL) OM AUC0-48 (ng*hr/mL)

Adverse Events (AEs), Patient Incidence, n (%) Pooled Placebo (N = 303) Pooled OM (N = 303) Cohort 1 OM (N = 103) Cohort 2 OM (N = 99) Cohort 3 OM (N = 101) All AEs 187 (61.7) 175 (57.8) 73 (70.9) 49 (49.5) 53 (52.5) 3 most common AEs Cardiac Failure* 53 (17.5) 46 (15.2) 17 (16.5) 14 (14.1) 15 (14.9) Hypokalaemia 18 (5.9) 20 (6.6) 7 (6.8) 7 (7.1) 6 (5.9) Hypotension 14 (4.6) 24 (7.9) 14 (13.6) 5 (5.1) 5 (5.0) Serious AEs 69 (22.8) 66 (21.8) 24 (23.3) 24 (24.2) 18 (17.8) 3 most common serious AEs Cardiac Failure* 29 (9.6) 26 (8.6) 8 (7.8) 11 (11.1) 7 (6.9) Renal Failure Acute 4 (1.3) 6 (2.0) 2 (1.9) 2 (2.0) 2 (2.0) Hypotension 0 (0.0) 3 (1.0) 3 (2.9) 0 (0.0) 0 (0.0) Deaths 11 (3.6) 9 (3.0) 2 (1.9) 4 (4.0) 3 (3.0) AEs leading to discontinuation of IP 15 (5.0) 15 (5.0) 7 (6.8) 4 (4.0) 4 (4.0)

Adverse Events

N = Number of patients in the analysis set; IP = Investigational Product.

* Cardiac failure includes both “Cardiac failure” and “Cardiac Failure Congestive” Preferred Terms.

PK/PD Substudy Endpoint: Change in Systolic Ejection Time (SET)

PK Concentration Bin Analysis Control OM Concentration Bin 1 OM Concentration Bin 2 OM Concentration Bin 3 OM concentration range (ng/ml) ≥88-200 >200-300 >300-787 Change in SET (msec) N(n) 45 (88) 10 (18) 15 (23) 12 (19) LS mean

• 6.7

16.6 26.9 46.4 Difference from control 23.4 33.6 53.2 95% CI (7.4, 39.4) (19.8, 47.4) (38.0, 68.3) p-value 0.005 <0.0001 <0.0001 Linear regression slope p < 0.0001 Baseline systolic ejection time for all patients was 258 msec. N: number of patients in the bin, n: number of observations in the bin; Control = observations in Placebo + PK below quantification limit; PK bin concentration analysis: repeated measures analysis of covariance; Linear regression slope analysis: repeated measures multiple linear regression.

Change in Heart Rate and SBP

PK Concentration Bin Analysis Control OM Conc. Bin 1 OM Conc. Bin 2 OM Conc. Bin 3 OM concentration range (ng/ml) ≥88-200 >200-300 >300-787 Heart Rate (beats/min) LS means

• 4.3
• 4.4
• 6.3
• 6.5

Difference from control

• 0.1
• 2.0
• 2.3

95% CI (-1.4, 1.1) (-3.6, -0.4) (-3.9, -0.6) p-value 0.835 0.016 0.008 Linear regression slope p < 0.0001 SBP (mmHg) LS means

• 4.6
• 4.4
• 4.0
• 2.2

Difference from control 0.3 0.6 2.4 95% CI (-1.2, 1.7) (-1.2, 2.4) (0.6, 4.2) p-value 0.719 0.521 0.009 Linear regression slope p = 0.0017 N: number of patients in the bin, n: number of observations in the bin. Heart rate measured by

• ECG. Control = observations in Placebo + PK below quantification limit. PK bin concentration

analysis: repeated measures analysis of covariance. Linear regression slope analysis: repeated measures multiple linear regression.

• Efficacy

– OM did not meet the 1° endpoint of dyspnoea relief – Appeared to improve dyspnoea in Cohort 3 – Trends towards reduction of worsening HF

• Safety

– Overall SAE profile and tolerability similar to placebo – Increase in troponin; no clear relationship to OM concentration – Numerical imbalance in MIs in Cohort 3 – No evidence of pro-arrhythmia

• Pharmacology

– PK similar to healthy volunteers and stable HF patients – Systolic ejection time significantly increased consistent with MOA – Small fall in heart rate & rise in systolic BP at higher doses

Summary

• Executive Committee:

– Michael Felker – John McMurray – John Teerlink (Chair)

• Steering Committee:

– John Cleland – Kenneth Dickstein – Justin Ezekowitz – Gerasimos Filippatos – Marco Metra – Piotr Ponikowski

Committees

• Data Monitoring Committee:

– Henry Dargie – Barry Greenberg – James Januzzi (Advisor) – Julie Johnson (Advisor) – Marv Konstam (Chair) – Joseph Massaro – Barry Massie

Investigators

Joanna Szachniewicz, Mikhail Kotelnikov, Zhanna Kobalava, Jindrich Spinar, Veselin Mitrovic, Janos Tomcsanyi, Bela Merkely, Dinesh Gupta, Mason Weiss, Kalman Toth, Pranas Serpytis, Andrzej Wysokinski, Alain Cohen Solal, Kirkwood Adams, Michel Galinier, Gintare Sakalyte, Hans Vandekerckhove, Fedya Nikolov, Marco Metra, Steven Krueger, Boycho Boychev, Eustathios Iliodromitis, Ioannis Nanas, Jooyoung Shin, Javed Butler, Petar Lazov, Guy Proulx, Gaetano De Ferrari, Dmitry Zateyshchikov, Ivan Gordeev, Boris Goloshchekin, Peter MacDonald, Borislav Atzev, Assen Goudev, Jan Belohlavek, Kumudha Ramasubbu, Nina Shehova-Iankova, Haissam Haddad, Richard Isnard, Kenneth Dickstein, Jadwiga Nessler, Svetlana Boldueva, Glenn Hamroff, John Morrow, Lynne Wagoner, Jiri Vitovec, Jans Stevlik, Stephen Gottlieb, Frank McGrew, Arthur Eberly, Thao Huynh, Henning Ebelt, Thomas Heitzer, Panagiotis Vardas, Dirk Lok, Sergey Tereshenko, Nina Novikova, Marian Hranai, Debra Weinstein, Eugene Chung, David Lanfear, Denise Barnard, Chetan Patel, Mark Dunlap, James Maher, Inder Anand, Marc Vanderheyden, Michel de Ceuninck, Ditmar Raev, Robert Stewart, Pavel Cervinka, Angelika Costard-Jäckle, Athanasios Manolis, Jaroslaw Kasprak, Vladimir Simanenkov, David Smull, Mitchell Saltzberg, Peter McCullough, Andrew Wilson, Filip Charlier, Serge Lepage, Justin Ezekowitz, Gordon Moe, Manohara Senaratne, David Zemanek, Pascal De Groote, Rémi Sabatier, Christian Hengstenberg, Tim Schäufele, Andreas Zeiher, Stephan Felix, Dimitrios Alexopoulos, Bela Herczeg, Laszlo Zoltan, Eelko Ronner, Wlodzimierz Musial, Piotr Jankowski, Eugeny Shlyakhto, Tatyana Novikova, Elena Vasilieva, Arsenio Rodriguez, John Teerlink, Alexander Adler, Andrew McRae, Garrie Haas, Daniel Lenihan, Henry Krum, Carmine De Pasquale, Dariusz Korczyk, Aleksandra Bankova, Stefan Denchev, Debra Isaac, John David Parker, Veli-Pekka Harjola, Heikki Ukkonen, François Roubille, Gérald Roul, Michael Böhm, Ruth Strasser, Sebastian Maier, Gerhard Cieslinski, Hans-Georg Olbrich, Noemi Nyolczas, Maurizio Porcu, Claudio Fresco, Folkert Asselbergs, Lars Gullestad, Andrzej Rynkiewicz, Grigory Aroutiounov, Daniel Pella, Jozef Kaluzay, John Cleland, Hugh Bethell, Angus Nightingale, John McMurray, Philip Adamson, Todd Kovach, Jalal Ghali, Andrew Keller, Adrian Van Bakel, James Mudd, Gregory Ewald, Stephanie Dunlap, Edward McMillan, Freidoon Ghazi, Glenn Barquet, Joshua Larned, Rami Alharethi