The heart-pounding clofenac-bringing you closer to the rare disease "heart amyloidosis"

I have been short of breath and chest tightness, and I can’t see the problem in the respiratory medicine department, and I can’t see it in the endocrinology department.
So let me see the neurology department.
After reading the neurology department, he said, you go to the psychiatric department, and it includes a biopsy.
The genetic mutation was diagnosed as cardiac amyloidosis
.
Searching on PubMed with "cardiac amyloidosis" as the keyword, only 6188 pieces of data were retrieved in the 80 years from 1936 to 2021
.
"His father wants to be treated.
He wants his father to live longer and live better.
However, because clofenac is mentioned just now, it is a very expensive medicine, and the monthly cost of treatment is about five.
Ten thousand to sixty thousand"
.
In the latest season of "Exciting Offer", Teacher Liu Chang's report made everyone start to pay attention to the rare disease of cardiac amyloidosis, and mentioned the therapeutic drug chlorfenacon for many times
.
Cardiac amyloidosis (CA) is a restrictive cardiomyopathy characterized by the accumulation of misfolded protein fragments outside of myocardial cells or between tissues.
Some patients develop refractory congestive heart failure, which is a rare But a disease that has not been fully diagnosed
.
Most cardiac amyloidosis is caused by the deposition of immunoglobulin light chains or transthyretin (TTR), the latter including genetic TTR-mediated (m-ATTR) and wild-type TTR-mediated (wt-ATTR) Heart amyloidosis
.
It is estimated that 100,000 people in the United States suffer from Transthyretin Amyloid Cardiomyopathy (ATTR-CM).
However, the diagnosis rate is only 1-2%.
If no treatment is taken, the risk of wt-ATTR patients The median survival time is 2.
7-3.
6 years, and the median survival time of m-ATTR patients is 2.
1-2.
5 years
.
In China, as Teacher Liu Chang said, due to the late start of CA research, there were missed diagnosis and misdiagnosis during the treatment process, and there was a lack of relevant epidemiological data.

.
TTR is a plasma transport protein, which is mainly synthesized by the liver and combines with thyroxine and retinol in the form of tetramers for transport
.
TTR is a soluble homotetramer, which can be broken down into monomers, which can be misfolded and eventually form amyloid fibers
.
TTR amyloidosis can affect multiple organs and tissues, including the heart, and it becomes cardiomyopathy in the heart
.
(Reference 5) The discovery that tetramer dissociation is the rate-limiting step in the amyloidosis process provides a theoretical basis for the design of TTR stabilizers.
Clofenac is a selective TTR stabilizer, which can interact with TTR tetramers.
The thyroxine binding site binds and inhibits its decomposition into monomers
.
However, since clofenconazole cannot degrade amyloid deposits, taking clofenconazole can only relieve the condition, and cannot cure or reverse ATTR-CM
.
As a first-in-class drug, although Pfizer’s clofenac was approved by the European Medicines Agency as early as 2011, it was not approved by the FDA until May 3, 2019, and it was approved for marketing in China in 2020.

.
Its orphan drug status even makes clofenconazole the most expensive cardiovascular treatment drug.
The annual treatment cost for patients is as high as 225,000 US dollars.
The price of capsules (61mg, 30 capsules) has been adjusted from 64,100 yuan/box to 24,650 yuan/box, and the high drug prices still daunt patients
.
Transthyretin cardiac amyloidosis (ATTR-ACT, NCT01994889) is the largest clinical study of clofenac to treat ATTR-CM so far
.
ATTR-ACT is a three-phase, multi-center, parallel design, placebo-controlled, double-blind randomized trial that evaluated the efficacy and safety of clofenac in the treatment of 441 patients with ATTR-CM
.
The patients were randomly assigned at a ratio of 2:1:2, taking 80 mg meglumine meglumine meglumine meglumine megluminate (n=176), 20 mg meglumine meglumine meglumine megluminate 20 mg (n=88) or placebo (n=177) ), once a day for 30 months
.
The mortality (29.
5%) of patients in the clofenac treatment group was significantly lower than that in the placebo group (42.
9%), and the hospitalization rate due to cardiovascular disease was also lower than that in the placebo group (clofenconazole: 0.
48, placebo : 0.
70)
.
Compared with placebo, taking 80 mg of meglumine meglumine megluminate can significantly reduce all-cause mortality, cardiovascular hospitalization rates and composite endpoints, but taking 20 mg of meglumine meglumine megluminate could not reduce all-cause mortality.
, 80 mg meglumine meglumine meglumine meglumine chlorfenac is clinically the first choice for ATTR-CM treatment
.
In general, clofenac was well tolerated in patients, and the adverse reactions during treatment were mostly mild to moderate.
In the ATTR-ACT study, the incidence of diarrhea and urinary tract infections in the clofenac treatment group was higher than that of placebo Group is lower.
Analysis of the Phase 2/3 clinical safety data of patients with ATTR-PN treated with chlorfenazole acid found that the most common adverse reactions were diarrhea (26.
3%), urinary tract infection (25.
5%) and influenza (21.
2%) ), 42 healthy subjects did not prolong the QTc interval after a single dose of 400 mg meclofenac
.
Theoretically, clofenac can reduce the concentration of serum total thyroxine, but the change of thyroid stimulating hormone has not been reported
.
So far, no clinical observation has been made of patients with hypothyroidism after taking clofenazole acid
.
As the first-in-class molecule in TTR stabilizers, clofenac is the only drug approved by the FDA for the treatment of ATTR-CM.
Phase II clinical studies have confirmed that during the treatment with clofenac, genetic TTR and The TTR stability of patients with wild-type TTR cardiac amyloidosis has been improved.
The ATTR-ACT phase 3 clinical study has shown that all-cause mortality and cardiovascular-related diseases hospitalization rates have been significantly reduced
.
Among NYHA Class I/II (heart failure classification) patients, clofenac is the most effective, which illustrates the importance of early diagnosis and intervention
.
Although there are still many problems in the treatment of clofenconazole, such as how to choose the therapeutic dose, the effect of NYHA III patients after treatment, and the social problems caused by high treatment costs, there is no doubt that clofenconazole is approved.
The listing has become a milestone event in the treatment of cardiac amyloidosis
.
*This article is only for academic content exchange, and does not constitute any medication advice! References (1) Burton, A.
; Castano, A.
; Bruno, M.
; Riley, S.
; Schumacher, J.
; Sultan, MB; See Tai, S.
; Judge, DP; Patel, JK; Kelly, JW Drug Discovery and Development in Rare Diseases: Taking a Closer Look at the Tafamidis Story.
Drug Des Devel Ther.
2021, 15, 1225-1243.
(2)Park, J.
; Egolum, U.
; Parker, S.
; Andrews , E.
; Ombengi, D.
; Ling, H.
Tafamidis: A First-in-Class Transthyretin Stabilizer for Transthyretin Amyloid Cardiomyopathy.
Ann Pharmacother.
2020, 54 (5), 470-477.
(3)Nawarskas, JJ; Shephard , EA Tafamidis: A Novel Treatment for Transthyretin Amyloid Cardiomyopathy.
Cardiol Rev.
2020, 28 (3), 156-160.
(4) Huber, P.
; Flynn, A.
; Sultan, MB; Li, H.
; Rill, D.
; Ebede, B.
; Gundapaneni, B.
; Schwartz, JH