What is the difference between sparsentan and ambrisentan?

Although sparsentan and ambrisentan have similar names, they have different mechanisms of action, different indications, different side effects, different usage and dosage, etc. Patients need to choose symptomatic drug treatment according to their own condition and under the guidance of a doctor.

1. Different mechanisms of action

1. Sparsentan: It is a new type of non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist.

In vitro tests do not bind to various receptors, transporters and ion channels, including histamine receptors, and have no inhibitory effect on mast cell degranulation reactions. In addition, the inhibitory effect of compound p on the scratching behavior of mice induced by intradermal administration was completely antagonized by the opioid receptor antagonist norepinephrine, which was completely antagonized by intracerebroventricular administration of nor-BNI.

2. Ambrisentan: Ambrisentan is a receptor antagonist that highly binds to ETA and can promote vasoconstriction and cell proliferation. ET-1 may play an important role in the onset and progression of pulmonary hypertension.

2. Different indications

1. Sparsentan: It is suitable for the treatment of reducing proteinuria in adult patients with primary immunoglobulin A nephropathy who are at risk of rapid disease progression.

2. Ambrisentan: used to treat patients with pulmonary hypertension with WHO grade II or III symptoms. It can improve the patient's exercise ability and delay the deterioration of the condition.

3. Different side effects

1. Sparsentan: causes peripheral edema, hypotension, orthostatic hypotension, dizziness, hyperkalemia, anemia, acute kidney injury, elevated transaminases, and fluid retention.

2. Ambrisentan: blood and lymphatic system diseases, such as anemia; nervous system diseases, common headaches; heart abnormalities, common palpitations; respiratory, chest and mediastinal diseases, common nasal congestion, sinusitis, nasopharyngitis; gastrointestinal system diseases, such as abdominal pain, nausea, constipation; systemic diseases and various reactions at the administration site, common fluid retention and peripheral edema.

4. Different usage and dosage

1. Sparsentan: The dose at the beginning of treatment is 200 mg, once a day. After 14 days, increase to 400mg based on tolerance. If treatment is restarted after an interruption, start with 200 mg once daily. After 14 days, increase to the recommended dose of 400 mg once a day.

2. Ambrisentan: The starting dose is 5 mg, once a day. If tolerated, it may be adjusted to 10 mg, once a day. It can be taken on an empty stomach or after meals. Ambrisentan tablets should be swallowed whole and should not be broken, crushed, or chewed.

Sparsentan

Background: To evaluate and compare the effects of sparsentan, a dual endothelin type A (ETA) and angiotensin II type 1 receptor antagonist, with the angiotensin II type 1 receptor antagonist irbesartan in patients with primary FSGS.

Study Methods: The efficacy and safety of a dual endothelin receptor and angiotensin receptor blocker (RE-021) were studied in patients with focal segmental glomerulosclerosis (FSGS) in a phase 2 clinical trial: a randomized, double-blind, active-controlled, dose escalation study (DUET).

Patients were aged 8-75 years with biopsy-confirmed FSGS, eGFR >30 ml/min/1.73 m2, and urine protein/creatinine ratio (UP/C) ≥1.0 g/g. Endpoints at Week 8 were reduction in UP/C from baseline (primary) and proportion of patients achieving the FSGS partial response endpoint (FPRE) (UP/C: ≤1.5 g/g and >40% reduction [minor]).

Study Results: Of 109 patients randomized, 96 received study drug and had baseline and Week 8 UP/C measurements. Compared with patients treated with irbesartan, patients treated with sparsentan had a greater decrease in UP/C, at 45% compared with only 19% in the placebo group.

The FSGS partial response endpoint was achieved in 28% of patients treated with sparsentan and 9% of patients treated with irbesartan. Patients with FSGS treated with sparsentan had significantly greater reductions in proteinuria after 8 weeks compared with irbesartan. Sparsentan is relatively safe and well tolerated.

References:

DUET Study Group. DUET: A Phase 2 Study Evaluating the Efficacy and Safety of Sparsentan in Patients with FSGS. J Am Soc Nephrol. 2018 Nov;29(11):2745-2754. doi: 10.1681/ASN.2018010091. Erratum in: J Am Soc Nephrol. 2019 Mar;30(3):518. PMID: 30361325; PMCID: PMC6218860.

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