Submit dose Justification and international standards data: CDSCO panel Tells Synokem over Sacubitril, valsartan FDC

This came after Synokem Pharmaceuticals presented its proposal along with the clinical trial protocol before the committee for the fixed-dose combination drug Sacubitril plus Valsartan (as sodium salt complex) 100mg (49mg+51mg)/200m g(97mg + 103mg)/ 400mg (194mg+ 206mg) Film-coated sustained release tablet.

Sacubitril is a neprilysin inhibitor used in combination with valsartan as an adjunct to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction.

Sacubitril/valsartan is the first agent to be approved in a new class of drugs called angiotensin receptor neprilysin inhibitor (ARNI). The medication is FDA-approved to treat patients with chronic heart failure with reduced ejection fraction (HFrEF) with NYHA class II, III, or IV.

Sacubitril's active metabolite, LBQ657 inhibits neprilysin, a neutral endopeptidase that would typically cleave natiuretic peptides such as atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and c-type natriuretic peptide (CNP). ANP and BNP are released under atrial and ventricle stress, which activate downstream receptors leading to vasodilation, natriuresis and diuresis. Under normal conditions, neprilysin breaks down other vasodilating peptides and also vasoconstrictors such as angiotensin I and II, endothelin-1 and peptide amyloid beta-protein. Inhibition of neprilysin therefore leads to reduced breakdown and increased concentration of endogenous natriuretic peptides in addition to increased levels of vasoconstricting hormones such as angiotensin II.

Valsartan belongs to the angiotensin II receptor blocker (ARB) family of drugs. ARBs selectively bind to angiotensin receptor 1 (AT1) and prevent the protein angiotensin II from binding and exerting its hypertensive effects, which include vasoconstriction, stimulation, and synthesis of aldosterone and ADH, cardiac stimulation, and renal reabsorption of sodium, among others. Overall, valsartan's physiologic effects lead to reduced blood pressure, lower aldosterone levels, reduced cardiac activity, and increased excretion of sodium.

At the recent SEC meeting for Cardiovascular and Renal held on 9th August 2023, the expert panel reviewed the proposal presented by the drug major Synokem Pharma to conduct a study of the fixed-dose combination drug Sacubitril plus Valsartan (as sodium salt complex) 100mg (49mg+51mg)/200m g(97mg + 103mg)/ 400mg (194mg+ 206mg) Film-coated sustained release tablet.

After detailed deliberation, the committee recommended that the firm should submit justification/data for the below-mentioned points for further review by the committee:

1. The firm should present the justification for a once-daily dose of Valsartan in SR form

2. International approval status.

3. More justification in support of 400mg once daily dose.

4. Any global evidence of a similar product.

5. Justification on dose titration

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