Justify dose and rationality: CDSCO Panel Tells Dr. Reddy's Lab on Sacubitril-Valsartan tablets 25 mg

New Delhi: Noting that the proposed protocol is insufficient to prove the clinical relevance of the lower strength of Sacubitril/Valsartan (12mg/13mg), the Subject Expert Committee (SEC) functional under the Central Drug Standard Control Organisation (CDSCO) has opined the drug major Dr. Reddy’s Lab to submit a revised protocol with more justification on the proposed dose and its rationality for further evaluation.

This came after Dr. Reddy’s Lab applied for the manufacture and market of Sacubitril and Valsartan tablets 25mg (as additional strength) indicated 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 with bioequivalence (BE) and clinical trial (CT) waiver.

However, in light of an earlier SEC recommendation held on 09/01/2024 on a similar proposal deliberated for another firm wherein the committee opined that the firm should provide more justification on the proposed dose and its rationality.

In line with the above, the firm submitted a Phase II clinical trial protocol titled “A double blind, multicentre, comparative, Phase II study to evaluate the efficacy and safety of low dose sacubitril/valsartan (12mg/13mg) twice daily of Dr. Reddy’s Laboratories Limited in comparison to sacubitril/valsartan (24mg/26mg) twice daily in adult patients with heart failure and reduced left ventricular ejection fraction” and presented their proposal before the committee.

Sacubitril and valsartan combination is used together with other medicines to treat chronic heart failure in adults and cut down on the number of hospital visits for heart problems. It is also used to treat symptomatic heart failure in children 1 year of age and older.

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's active metabolite, LBQ657 inhibits neprilysin, a neutral endopeptidase that would typically cleave natriuretic peptides, which includes: 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.

Valsartan is an angiotensin-receptor blocker used to manage hypertension alone or in combination with other antihypertensive agents and to manage heart failure in patients who are intolerant to ACE inhibitors.

Valsartan belongs to the angiotensin II receptor blocker (ARB) family of drugs, which selectively bind to angiotensin receptor 1 (AT1) and prevent angiotensin II from binding and exerting its hypertensive effects. These 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.

Sacubitril/valsartan's combined action increases endogenous natriuretic peptides while inhibiting the renin-angiotensin-aldosterone system and exerting cardioprotective effects.

At the recent SEC meeting for Cardiovascular held on 21st March 2024, the expert panel reviewed the application presented by the drug major Dr Reddy's Lab to manufacture and market Sacubitril and Valsartan tablets 25mg (as additional strength) and Phase II clinical trial protocol to evaluate the efficacy and safety of low dose sacubitril/valsartan (12mg/13mg) twice daily of Dr. Reddy’s Laboratories Limited in comparison to sacubitril/valsartan (24mg/26mg) twice daily in adult patients with heart failure and reduced left ventricular ejection fraction.

After detailed deliberation, the committee opined that the proposed protocol is insufficient to prove the clinical relevance of the lower strength of Sacubitril/Valsartan (12mg/13mg).

Hence, the expert panel suggested that the firm should submit a revised protocol with more justification on the proposed dose and its rationality for further review by the committee.

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