Sequana Medical announces initial positive data from MOJAVE, a US Phase 1/2a study of DSR® 2.0 for treatment of heart failure through breaking vicious cycle of cardiorenal syndrome

• First two US patients from non-randomized cohort successfully treated with DSR 2.0

• Initial data indicate that DSR 2.0 is safe and well tolerated, restores diuretic response and improves cardiorenal status

• Biomarker analysis from RED DESERT and SAHARA studies supports DSR mechanism of action as breaking vicious cycle of cardiorenal syndrome (CRS)

• Start of randomized cohort of up to 30 US patients planned for Q1 2024 following DSMB (i) review

Dr. Jeffrey Testani, Associate Professor at Yale University and Heart Failure Scientific Advisor to Sequana Medical, commented: “Cardiorenal syndrome is an area of key unmet clinical need in heart failure with complex, vicious cycle of negative interactions between the heart and the kidney. Based on extensive biochemical analysis, DSR appears to have the potential to interupt this vicious cycle of disease through effectively managing congestion while avoiding the widely appreciated negative effects on CRS from loop diuretics, resulting in improved cardiorenal status. This is highly encouraging and together with the positive initial data from MOJAVE, indicates the potential for DSR therapy as a promising treatment for diuretic-resistance and cardiorenal syndrome in heart failure.”

Dr. Oliver Gödje, Chief Medical Officer of Sequana Medical, commented: “We are pleased that the first two patients ever treated with DSR in the US were enrolled smoothly and continue to show similar beneficial effects of DSR therapy as seen in RED DESERT and SAHARA. We are confident that after the third patient is treated and based on these favorable results, the multi-centric roll-out in Q1 2024 will start as planned and expect that DSR will demonstrate its full benefits compared to the loop diuretic control group. We are excited about the potential for DSR in cardiorenal syndrome where there is a clear need for improved therapeutic options.”

Positive interim data from non-randomized cohort of MOJAVE study

The first two patients treated in the non-randomized cohort of the MOJAVE study had heart failure with preserved ejection fraction (HFpEF) and severe diuretic resistance at baseline (mean furosemide equivalent dose of respectively 1,280 and 800 mg per day). At the start of the study treatment period, loop diuretics were withheld, and patients were treated with DSR 2.0 up to daily for four weeks.

After the four-week DSR treatment period, both patients maintained euvolemia without the need of loop diuretics and showed improved cardiorenal status. Their diuretic response (ii) nearly normalized with a mean increase of 454% in their six-hour urinary sodium excretion versus baseline. These interim data also show a broad improvement in their kidney function with an improvement in eGFR (iii), as well as blood urea nitrogeniv post-treatment vs baseline. Since both patients had HFpEF, their NT-proBNP (v) levels were within normal ranges at baseline and were maintained post-treatment, indicating that their stable cardiovascular status was preserved.

To date, no clinically relevant changes in serum sodium levels or progressive hyponatremia were observed and no serious adverse events occurred, indicating that DSR 2.0 was safe and well tolerated in these first two US patients.

Both patients are currently in the follow-up period without any loop diuretics (since commencing DSR therapy, the first patient is 9.5 weeks off loop diuretics and the second patient is 4 weeks off loop diuretics). The third patient in the non-randomized cohort has been enrolled and will have completed DSR treatment and initial follow-up before year end. An independent Data and Safety Monitoring Board (DSMB) meeting to review the data from the three patients in the non-randomized cohort is planned in early Q1 2024 to approve the start of the randomized cohort, planned for Q1 2024.

Breaking the vicious cycle of cardiorenal syndrome (CRS)

Cardiorenal syndrome is a key clinical challenge in heart failure and results from the combined vicious cycle of dysfunction of the heart and kidney with hypothesised complex and interconnected mechanisms such as aberrations in hemodynamic, neurohormonal, inflammatory, and sodium handling pathways. Despite the complex multidimensional pathophysiology, the resultant clinical profile is thought to manifest as a self-reinforcing negative feedback cycle characterized by decreased glomerular filtration, increased renal sodium avidity, and congestion, despite escalating diuretic doses.

No current therapies have been shown to improve patient outcomes in this complex and poorly understood indication. Reducing congestion is a key element of therapy but loop diuretics exacerbate many of the core mechanisms thought to underly CRS, thus even worsening diuretic resistance and CRS. Through effective control of the volume status for an extended period of time and thereby avoiding the negative consequences of loop diuretics, DSR has the potential to break the negative feedback cycle of this important indication with clear unmet clinical needs.

Extensive analysis of validated biomarkers from patients in the RED DESERT and SAHARA studies shows the benefit from DSR therapy on i) volume status, ii) normalized diuretic response and dramatically reduced loop diuretic dosing, iii) improvement in kidney function, iv) neurohormonal status and signalling, as well as v) cardiovascular parameters. As previously disclosed, in these patients there were no congestion-related re-hospitalizations, a one class improvement in their NYHA (vi) status and a reduction of 75% in their predicated one-year mortality (based on the Seattle Heart Failure model).

Data from the RED DESERT and SAHARA proof-of-concept studies have been submitted for publication in a peer-reviewed journal. The Company will update the market as soon as it is published.

(i) DSMB: Data Safety Monitoring Board
(ii) Diuretic response assessed by 6-hour excretion of sodium after IV administration of 40mg furosemide
(iii) eGFR: estimated Glomerular Filtration Rate, a measure of kidney function
(iv) Blood urea nitrogen is a waste product normally cleared by the kidneys
(v) NT-proBNP: N-terminal pro B-type natriuretic peptide, a key cardiac function parameter
(vi) NYHA: New York Heart Association classification (data collected outside study protocols of RED DESERT and SAHARA)