Sequana Medical N.v · EURONEXT:SEQUA
Sequana Medical — Key Opinion Leader Webinar with Jeffrey Testani, MD, MTR (December 2020)
78 slides from Sequana Medical's conference presentation, Dec 11, 2020
Slide 1: The challenge of diuretic resistance in the management of heart failure patients
The challenge of diuretic resistance in the management of heart failure patients and the potential for alfapump® DSR therapy Key Opinion Leader Webinar with Jeffrey Testani, MD, MTR 11 December 2020
Slide 2: Disclaimers
Disclaimers Important Notice IMPORTANT: You must read the following before continuing. The following applies to this document, the oral presentation of the information in this document by Sequana Medical NV (the "Company") or any person on behalf of the Company, and any question-and-answer session t
Slide 3: Disclaimers
Disclaimers Regulatory disclaimer: • The alfapump® system has not yet received regulatory approval in the United States and Canada. Any statement in this presentation about safety and efficacy of the alfapump ® system does not apply to the United States and Canada. In the United States and Canada, t
Slide 4: Agenda and Presenters
Agenda and Presenters 09:00 – Ian Crosbie, CEO Sequana Medical • Welcome and Introduction Ian Crosbie, CEO 09:05 – Dr. Jeffrey Testani, Associate Professor at Yale University and Heart Failure Scientific Advisor of Sequana Medical • Cardio-Renal Syndrome and Diuretic Resistance: Mechanism and Clinic
Slide 5: The challenge of diuretic resistance in the management of heart failure patients
The challenge of diuretic resistance in the management of heart failure patients: The potential for alfapump® DSR therapy Jeffrey M. Testani, M.D., M.T.R. Associate Professor Director of Heart Failure Research Section of Cardiovascular Medicine Yale University New Haven, CT
Slide 6: Disclosures
Disclosures: Grants and/or consulting fees from BMS, Lexicon, Sequana Medical, AstraZeneca, Novartis, 3ive Labs, Cardionomic, Bayer, Boehringer Ingelheim, MagentaMed, Otsuka, Reprieve Medical, Sanofi, FIRE1, Abbott, W.L. Gore, Windtree Therapeutics, Regeneron
Slide 7: Congestion is the major cause of and therapeutic target in HF Hospitalization
Congestion is the major cause of and therapeutic target in HF Hospitalization 2% 6% 9% N=3,580 Volume Overload or Pulmonary Edema HTN HF 83% Cardiogenic Shock Right heart failure Adapted from Nieminen, M et al Eur Heart J 2006
Slide 8: Congestion is the disease, not just a nuisance symptom
Congestion is the disease, not just a nuisance symptom Schrier, Seminars in Nephrology 2011;31:503
Slide 9: Volume overload is prognostically incredibly important in heart failure
Volume overload is prognostically incredibly important in heart failure any way you measure it – Physical exam – Bioimpedance – Natriuretic peptides – IVC collapse – Blood volume – Weight gain – Swan-Ganz parameters
Slide 10: Hemodynamic Predictors of Heart Failure Morbidity and Mortality
Journal of Cardiac Failure Vol. 22 No. 3 2016 Clinical Investigation Hemodynamic Predictors of Heart Failure Morbidity and Mortality:[Fluid or Flow LAUREN B. COOPER, MD,'? ROBERT J. MENTZ, MD,'? SUSANNA R. STEVENS, MS,' G. MICHAEL FELKER, MD, MHS,'* CARLO LOMBARDI, MD,’ MARCO METRA, MD,’ LYNNE W. ST
Slide 11: Last
Last --— PCWP <20 PCWP 220 S f=} S o + a (%) jueidsuey pue ‘dsoy OeIpsed ‘yeep WO 2el4 (%) }ueidsuey pue ‘“dsoy deIPIeD ‘Yyyeeq Wold ee14 Yale SCHOOL OF MEDICINE
Slide 12: Aggressive diuresis is associated with improved survival
Van der Meer et al., Testani et al., Circulation 2010 JACC 2013 Aggressive diuresis is associated with improved survival Greene et al., Oh et al., IJC 2013 EJHF 2013
Slide 13: CHAMPION trial of cardioMEMS illustrates the importance of chronic volume management
CHAMPION trial of cardioMEMS illustrates the importance of chronic volume management Rehospitalization Death Abraham, Lancet 2011 Givertz, JACC 2017
Slide 14: CardioMEMS Technology
CARDIOMEMS TECHNOLOGY AN NW HEART FAILURE St. Jude Medical website Z COLLABORATIVE ; tena)
Slide 15: Having the sensor in the patient has no direct therapeutic value
Having the sensor in the patient has no direct therapeutic value….it’s the medication changes Primarily driven by change in diuretics Costanzo, JACC:HF 2016
Slide 16: Volume=Bad
Volume=Bad Give a little Live forever Lasix
Slide 17: We actually do a terrible job removing fluid from decompensated HF patients
We actually do a terrible job actually removing fluid from decompensated HF patients N=285 US hospitals, >100,000 patients 33% 35 30 24% 53% lose <5 lbs Patients (%) 25 20 13% 15 15% 7% 10 6% 3% 5 2% 0 (<-20) (-20 to - (-15 to - (-10 to - (-5 to 0) (0 to 5) (5 to 10) (>10) 15) 10) 5) Change in Weigh
Slide 18: We actually do a terrible job removing fluid from decompensated HF patients
We actually do a terrible job actually removing fluid from decompensated HF patients N=285 US hospitals, >100,000 patients 33% 35 20% lose 30 24% nothing or gain weight Patients (%) 25 20 !!!!!!!!! 13% 15 15% 7% 10 6% 3% 5 2% 0 (<-20) (-20 to - (-15 to - (-10 to - (-5 to 0) (0 to 5) (5 to 10) (>10)
Slide 19: Poor management of volume status also true in outpatients
Poor management of volume status also true in outpatients
Slide 20: Blood volume determined in non-edematous stable outpatients
Blood volume determined in non-edematous stable outpatients Androne, AJC 2004
Slide 21: Mortality was worse in the expanded blood volume group
Not too surprising, mortality was worse in the expanded blood volume group Normal blood volume Increased blood volume Androne, AJC 2004
Slide 22: We talk about volume overload but it's really all about the sodium
We talk about “volume overload” but it’s really all about the sodium • Sodium is the key driver of extracellular volume expansion – The kidney regulates extracellular volume by the quantity of sodium it reabsorbs • The fluid follows the sodium as the major extracellular osm – The kidney regulates wa
Slide 23: It's actually all about the sodium
It’s actually all about the sodium
Slide 24: Furosemide results in dilute watery urine
Furosemide results in dilute “watery” urine Isotonic urine Hodson, JACC:HF 2019
Slide 25: Why do we have so much untreated volume overload?
If sodium/volume overload is so important, why is it we have so much untreated volume overload?
Slide 26: Diuretic resistance is nearly ubiquitous
Diuretic resistance is nearly ubiquitous Diuretic response in HF Normal diuretic response Testani et al, Circ HF 2014
Slide 27: Diuretic resistance is associated with mortality
Diuretic resistance is associated with mortality Diuretic resistance with either high or low loop dose Testani et al, Circ HF 2015
Slide 28: How do we treat this diuretic resistance
How do we treat this diuretic resistance • …..more diuretics • Unfortunately there is a large body of literature showing diuretics are associated with – Mortality – Rehospitalization – Kidney dysfunction – Electrolyte abnormalities • These are dose dependent associations – The more diuretic you give
Slide 29: Some of this association may be causal
Some of this association may be causal • The kidney “sees” salt through chloride entry into the macula densa through the Na-K-2Cl cotransporter • This is the same transporter that loop diuretics antagonize Francis et al, Ann Intern Med 1985;103:1
Slide 30: Macula Densa and neurohormonal activation
Macula Densa Loop Diuretic Neurohomonal activation
Slide 31: Net result is neurohormonal activation
Net result is neurohormonal activation Francis et al, Ann Intern Med 1985;103:1
Slide 32: Neurohormonal activation is critical in HF
Neurohormonal activation is critical in HF: most of our proven therapies block it
Slide 33: So why do we see so much diuretic resistance?
So why do we see so much diuretic resistance? • Teleology: A human is basically a bag of salt and water – Our ability to exist outside of the ocean depended on millions of years of evolution developing a system to keep the right amount of salt and water in this bag • Given that human life can not ex
Slide 34: Mechanism for diuretic resistance in HF
Mechanism for diuretic resistance in HF: It’s really “acute renal success” • Diuretic is getting to the site of action – And in most patients it is blocking sodium reabsorption at the site of action • Renal tubules downstream are just pumping all the salt back into the patient – This is exactly what
Slide 35: Which recent strategies have had positive clinical trials
Which recent strategies have had positive clinical trials and improved our care of volume overload in HF? • …..essentially none of them • Closest was the DOSE-AHF trial – Technically negative study as primary endpoint (global assessment of symptoms) was not significant (p=0.06) • Design: Randomized
Slide 36: List of recent failed novel agents
List of recent failed “novel” agents • Adenosine antagonists • High dose nesiritide • Low dose nesiritide • Vasopressin antagonists • Ularitide • Renal dose dopamine • Serelaxin • An array of additional drugs and devices you never heard of
Slide 37: Mechanism of current (and failed) therapies?
Mechanism of current (and failed) therapies? Sodium avid kidney Standard Kidney “Novel” therapies cardiorenal (e.g., High medications dose lasix) and devices
Slide 38: Current therapies
Current therapies • We don’t have time to review why all the “novel” therapies failed – My short answer is they are all too distal in the sodium avidity pathway and the kidney outsmarts them • I will briefly review some of the traditional therapies that are commonly used in clinical practice
Slide 39: Continuous loop diuretic infusion
Continuous loop diuretic infusion Traditional teaching is that this works primarily by avoiding post-diuretic period of sodium retention Wilcox, J Lab Clin Med. 1983 Sep;102(3):450-8.
Slide 40: Continuous loop diuretic infusion
Continuous loop diuretic infusion Traditional teaching is that this works primarily by avoiding post-diuretic period of sodium retention Wilcox, J Lab Clin Med. 1983 Sep;102(3):450-8.
Slide 41: Infusion wastes less diuretic with the high concentrations after a bolus
Infusion “wastes” less diuretic with the high concentrations after a bolus Bolus Infusion Rudy, Annals of Internal Med, 1991 Adapted from Ellison, Cardiology. 2001;96(3-4):132-43.
Slide 42: Results of the DOSE trial
Results of the DOSE trial: • Double blind randomized trial of continuous infusion vs. bolus (n=308). • Net fluid output at 72 hours: – Bolus: 4.24 L – Continuous: 4.25L • No significant difference in LOS, dyspnea, freedom from congestion at 72 hours, treatment failure • Post hoc analysis: – Patients
Slide 43: DOSE trial is not the only trial to show less than spectacular results
DOSE trial is not the only trial to show less than spectacular results: Alqahtani, J Crit Care, 2014
Slide 44: So why didn't it work?
So why didn't it work? • Lasix is a poison as far as the kidney is concerned so it fights back
Slide 45: Continuous exposure of the kidney to loop diuretic causes structural remodeling
Continuous exposure of the kidney to loop diuretic causes massive structural remodeling Distal tubular cells Control 6 days of furosemide infusion Kaissling B Am J Physiol. 1985 :F374-81.
Slide 46: Possibly worsened outcomes!
Possibly worsened outcomes! Infusion Felker, NEJM. 2011 Mar 3;364(9):797-805 Palazzuoli, Crit Care. 2014 Jun 28;18(3):R134
Slide 47: What do we do when high dose loop diuretic doesn't work: Adjuvant thiazides
What do we do when high dose loop diuretic doesn’t work: Adjuvant thiazides • Observational data on thiazides found associations between thiazide use and: – Deterioration in renal function – Hyponatremia – Severe hypokalemia – Increased death/rehospitalization • Some of this is driven by confounding
Slide 48: We have not been able to prove this
We have not been able to prove this….. Brisco-Bacik, JAHA 2018
Slide 49: Summary so far
Summary so far • Volume overload is the primary driver of HF symptoms, hospitalization, and quite possibly mortality • Despite billions in pharma research, no new therapies have been successful • As a result, we continue to rely on loop diuretics despite – Direct dose dependent adverse effects – Rap
Slide 50: The first non-renal volume management therapy for HF: Ultrafiltration
The first non-renal volume management therapy for HF: Ultrafiltration
Slide 51: The first non-renal volume management therapy for HF: Ultrafiltration (UF)
The first non-renal volume management therapy for HF: Ultrafiltration (UF) • Pros: – Non-renal approach to sodium removal • Thus not dependent on the kidney “cooperating” to get sodium out – High sodium content fluid removed – Large quantities of sodium can be removed • Cons: – Requires venous acces
Slide 52: CARRESS HF dampened enthusiasm for UF
CARRESS HF dampened enthusiasm for UF: • Demonstrated how hard this therapy was to use • Despite this being conducted in the premiere HF centers of excellence – Delay of 8 hours from randomization to initiation of UF – UF was only 40 out of the 96 planned hours – ~10% of patients included in the int
Slide 53: Results: Similar weight loss with worse renal function
Results: Similar weight loss with worse renal function Bart, N Engl J Med. 2012:2296-304
Slide 54: My diuretic resistance algorithm
My diuretic resistance algorithm: Maximize loop diuretic dose (Bumetanide 12.5mg TID ) Maximize Thiazide diuretic (metolazone 10mg TID) Maximize other segment blockade (spironolactone 100mg TID, acetazolamide 1000mg BID, ±empagliflozin 25 QD, ± amiloride 10 BID) Dopamine 3 mcg/kg/min Hypertonic sali
Slide 55: The peritoneum is an alternative membrane for ultrafiltration
The peritoneum is an alternative “membrane” that can be used for ultrafiltration • The peritoneal membrane is a large surface area natural membrane in the body that can be used for dialysis (toxin removal) or ultrafiltration (fluid and solute removal) • Peritoneal dialysis (PD) is a commonly utilize
Slide 56: Why is peritoneal dialysis not used more frequently in HF?
Why is peritoneal dialysis (PD) not used more frequently in HF? • Standard PD has several limitations: – Large volumes (~8 to 10 liters) and long dwell times with the patient connected to PD cycler – External catheter with infection risks – Dialysis stigma • Only modest fluid and sodium removal with
Slide 57: Can we use the peritoneal membrane more efficiently to remove sodium in HF?
Can we use the peritoneal membrane more efficiently to directly remove sodium in HF patients? • Most HF patients have acceptably functioning kidneys – No need to “clean” the blood • Standard PD solutions have ~7.5 grams of salt per liter – Nearly isotonic to plasma (~132 mmol/L) – Very small gradien
Slide 58: Direct Sodium Removal (DSR) concept
Direct Sodium Removal (DSR) concept • The salt is necessary in traditional PD solutions to make them safe to use to clean the blood – This is not needed for most HF patients • With a zero sodium solution, we should be able to get much more sodium removal with less volume than standard PD fluid – In
Slide 59: DSR: Proof of concept porcine experiment
DSR: Proof of concept porcine experiment • 1L instillation of 10% dextrose in water, zero sodium • Dwell time of 6 hours 6 H o u r D w e ll 6 H o u r D w e ll U ltr a filtr a tio n V o lu m e S o d iu m R e m o v e d 2000 6 5 1500 V o lu m e ( m L ) S o d iu m (g ) 4 1000 3 2 500 1 0 0 0 60 120 180
Slide 60: DSR: Osmotic gradient is maintained over time
DSR: Osmotic gradient is maintained over time O s m o la r ity (m O s m /L ) 500 G lu c o s e O s m s 400 300 200 Plasma osmolality 100 0 0 30 60 90 120 150 180 210 240 270 300 330 360 T im e (m in u t e s )
Slide 61: DSR: Osmotic gradient is maintained over time
DSR: Osmotic gradient is maintained over time O s m o la r ity (m O s m /L ) 500 G lu c o s e O s m s 400 N o n -g lu c o se O sm s 300 200 Plasma osmolality 100 0 0 30 60 90 120 150 180 210 240 270 300 330 360 T im e (m in u t e s )
Slide 62: DSR: Osmotic gradient is maintained over time
DSR: Osmotic gradient is maintained over time T o ta l O s m s 500 O s m o la r ity (m O s m /L ) G lu c o s e O s m s 400 N o n -g lu c o se O sm s 300 200 100 Plasma osmolality 0 0 30 60 90 120 150 180 210 240 270 300 330 360 T im e (m in u t e s )
Slide 63: DSR: Huge quantities of sodium can be removed
DSR: Huge quantities of sodium can be removed R e d u c t io n in P la s m a V o lu m e • 10L of 10% dextrose cycled over 6 hours A f t e r 1 0 L C y c le d 6000 • 52.8 +/- 8.2 g of salt was removed p = 0 .0 0 2 P la s m a V o lu m e ( m L ) • 65% reduction in plasma volume 4000 2000 0 P r e C y c l
Slide 64: What happens in HF?
What happens in HF? P o s t -f lu id 150 10 P re s su re (m m H g ) 8 C O (L / m in ) 100 6 4 50 P o s t-ta m p o n a d e 2 C O SBP M AP 0 0 30 60 90 120 30 P o s t -f lu id P re s su re (m m H g ) 20 P o s t-ta m p o n a d e 10 PCW P CVP P e r ic a r d ia l 0 30 60 90 120 T im e (m in u t e s )
Slide 65: Substantially greater UF and salt removal in setting of HF
Substantially greater UF and salt removal in setting of HF 6000 p < 0.0001 20 p < 0.0001 15 Volume (mL) Sodium (g) 4000 10 2000 5 0 0 Normal HF Normal HF
Slide 66: DSR first in human proof of concept: Design
DSR first in human proof of concept: Design • Design: – Randomized open label crossover of DSR vs. standard PD solution – Conducted in prevalent PD patients rather than normal subjects due to the risks of PD catheter placement • Intervention: – DSR solution: Sodium free 10% dextrose – Standard PD so
Slide 67: Primary endpoint: Safety and tolerability
Primary endpoint: Safety and tolerability • Primary endpoint: – All patients completed the 2 hour dwell without adverse event or significant discomfort causing protocol discontinuation • Mild cramping during fluid instillation lasting <30 minutes occurred in 2 patients – One had cramping with DSR so
Slide 68: Secondary efficacy endpoint: Sodium removal was substantially greater with DSR
Secondary efficacy endpoint: Sodium removal was substantially greater with DSR 1000 DSR 6 DSR Standard PD Solution Standard PD Solution 800 Volume (mL) Sodium (g) 4 600 400 2 200 0 0 0 30 60 90 120 0 30 60 90 120 Time (minutes) Time (minutes) 1000 p < 0.0001 6 p < 0.0001 800 Volume (mL) Sodium (g) 4
Slide 69: Proof of concept conclusion
Proof of concept conclusion • These data provide proof of concept that Direct Sodium Removal with a sodium-free peritoneal solution is feasible in humans • Safety/tolerability: – Well tolerated – Minimal off target solute removal – Did not result in significant electrolyte disturbances or prolonged
Slide 70: alfapump DSR – Potential chronic therapy for heart failure patients
alfapump® DSR – Potential chronic therapy for heart failure patients with fluid overload not well controlled on diuretics Administration of sodium-free DSR infusate to 1 peritoneal cavity via implanted port 2 Sodium diffuses into DSR infusate 1 alfapump pumps sodium-rich DSR infusate into the 3 blad
Slide 71: RED DESERT study design
RED DESERT study design Repeated dose proof-of-concept study of alfapump® DSR in up to 10 diuretic-resistant heart failure patients * intravenous dose of 40mg dose furosemide Safety: absence/rate of device, procedure and/or therapy related serious adverse events Feasibility: ability of the alfapump
Slide 72: RED DESERT Interim results
RED DESERT Interim results • 5 participants have completed the study • Main findings: – Repeated dose alfapump® DSR is well tolerated – Majority of patients lost weight and had reduction in natriuretic peptide levels • Despite volume loss all signs point toward improved renal function which is the o
Slide 73: Innovators in the management of fluid overload
Innovators in the management of fluid overload liver disease – malignant ascites – heart failure
Slide 74: Proven alfapump platform in the management of fluid overload
Proven alfapump® platform in the management of fluid overload alfapump – Liver disease / NASH CE mark + key clinical practice guidelines FDA breakthrough device designation Over 800 implants to date POSEIDON pivotal study in North America ongoing 74
Slide 75: Proven alfapump platform in the management of fluid overload
Proven alfapump® platform in the management of fluid overload alfapump – Liver disease / NASH CE mark + key clinical practice guidelines FDA breakthrough device designation Over 800 implants to date POSEIDON pivotal study in North America ongoing alfapump DSR – Heart Failure Built on prove
Slide 76: alfapump DSR development strategy
alfapump® DSR development strategy* Study description 2020 2021 2022 2023 Proof-of-concept repeated dose alfapump DSR study RED DESERT D10% infusate; stable heart failure patients FDA discussions on regulatory pathway alfapump DSR dose-ranging feasibility study** SAHARA D10% infusate; decompensated
Slide 77: Expected core value drivers & outlook
Expected core value drivers & outlook POSEIDON NASH in North Liver disease / Q4 20: Q1 21: H1 21: Q1 22: America POSEIDON POSEIDON POSEIDON interim analysis 1 enrolment full interim primary endpoint completion analysis read-out Q4 2020 2021 Q1 2022 Heart failure in North America Q4 20: & Europe H
Slide 78: Q&A
Q&A
Sequana Medical — Key Opinion Leader Webinar with Jeffrey Testani, MD, MTR (December 2020) on 6ix