Heart health greatly influences our quality of life, but a progressive disease called ATTR cardiac amyloidosis threatens it. This disease is caused by proteins that misfold and accumulate in the heart and other organs. In this article, we will start with the basics of ATTR cardiac amyloidosis and then focus on a new treatment, Patisiran, explaining its efficacy and safety in detail. By reading this article, you will deepen your understanding of ATTR cardiac amyloidosis and gain knowledge about the latest treatment options.
Explanatory video
What Is ATTR Cardiac Amyloidosis?
Basic Description of the Disease
ATTR cardiac amyloidosis is a disease caused when a protein called transthyretin (TTR) misfolds, takes on an abnormal form known as amyloid, and accumulates in the heart and other organs. This disease can occur either when a person carries a genetic mutation or as a result of aging. When it is caused by a genetic mutation, it is called “hereditary (variant) ATTR amyloidosis,” and when it is caused by aging, it is called “wild-type ATTR amyloidosis.”
What It Means for the Disease to Be Progressive
ATTR cardiac amyloidosis is a progressive disease, and once amyloid begins to accumulate, the condition gradually worsens. The accumulation of amyloid impairs the function of the heart and may ultimately cause serious symptoms such as heart failure and arrhythmias.
Main Symptoms and Their Impact
The main symptoms of ATTR cardiac amyloidosis include fatigue, shortness of breath, swelling (especially in the legs and ankles), chest pain, dizziness, and fainting. These symptoms can have a major impact on daily life and can markedly reduce a patient’s quality of life. In addition, this disease can be difficult to diagnose, and in many cases it is not diagnosed until symptoms have progressed. As a result, appropriate treatment can be delayed, which becomes a factor that worsens the prognosis.
2. What Is Patisiran?
Mechanism of Action of Patisiran
Patisiran is a therapeutic drug that uses a mechanism called RNA interference (RNAi). RNAi targets a specific messenger RNA (mRNA) and inhibits the production of protein from that mRNA, thereby suppressing the progression of disease. Patisiran targets the TTR mRNA responsible for producing the transthyretin (TTR) protein and lowers its level, aiming to slow the progression of ATTR cardiac amyloidosis.
How It Treats ATTR Cardiac Amyloidosis
Patisiran is administered into the body as a lipid nanoparticle and is delivered mainly to the liver. The liver is the main site of TTR protein production, and Patisiran binds to TTR mRNA there and promotes its degradation. This suppresses the production of TTR protein, reduces the accumulation of amyloid, and is thought to slow the progression of the symptoms of ATTR cardiac amyloidosis.
Comparison with Other FDA-Approved siRNA Therapies
Patisiran is approved by the FDA as a treatment for hereditary TTR amyloidosis with polyneuropathy. This was the first example of a treatment using siRNA, and it provides a new treatment option for ATTR cardiac amyloidosis. Compared with other siRNA therapies, Patisiran was developed specifically for ATTR cardiac amyloidosis, and its efficacy and safety have been confirmed through extensive clinical trials. Among other siRNA therapies, in addition to Onpattro (the brand name of Patisiran), there is, for example, Inclisiran, but this is used mainly for the treatment of hypercholesterolemia.
3. The APOLLO-B Trial: Verifying the Efficacy of Patisiran
Objectives and Design of the Trial
The APOLLO-B trial is a phase 3, randomized, placebo-controlled, double-blind trial designed to evaluate the efficacy and safety of Patisiran in patients with ATTR cardiac amyloidosis. The main objective of the trial was to evaluate whether Patisiran could maintain or improve patients’ functional capacity, health status, and quality of life.
Characteristics of the Patients Who Participated
A total of 360 patients from 69 sites in 21 countries participated in the trial. These patients were randomly assigned to receive either Patisiran or placebo. The median age of participants was 76 years, most were male, and about 80% had wild-type ATTR amyloidosis. In addition, 25% of patients were taking Tafamidis at the start of the trial.
Primary Endpoint and Results
The primary endpoint of the trial was the change in distance on the 6-minute walk test. After 12 months, the median change in this distance was -8.15 m in the Patisiran group and -21.35 m in the placebo group. This indicates that Patisiran has an effect of suppressing the decline in functional capacity. In addition, the KCCQ-OS score, which evaluates health status and quality of life, also improved slightly in the Patisiran group.
Limitations of the Trial and Future Prospects
Owing to the limitations of the trial’s duration and scale, it was not possible to formally evaluate the effect of Patisiran in specific subgroups. In addition, the most severe patients with ATTR amyloidosis were excluded from the trial. Future studies will need to evaluate the long-term effects of Patisiran, particularly its impact on mortality and hospitalization rates.
4. The Safety Profile of Patisiran
Main Adverse Events Observed During the Trial
During the APOLLO-B trial, adverse events were reported in both the group of patients who received Patisiran and the group who received placebo. Adverse events occurred in 91% of patients in the Patisiran group and in 94% of patients in the placebo group. Most of these adverse events were mild or moderate. Adverse events that occurred in 5% or more of patients in the Patisiran group and were more than 3 points higher than in the placebo group included infusion-related reactions, arthralgia, and muscle spasms. All infusion-related reactions were mild or moderate, and one patient discontinued the study drug because of a mild infusion-related reaction.
The Significance of Safety for Patients
The safety profile of Patisiran is considered acceptable for patients, even taking into account the nature and frequency of the adverse events observed during the trial. The incidence of serious adverse events was similar in both groups, and the proportion of patients who were forced to discontinue the study drug was also low. These data suggest that Patisiran may be a safe treatment option for patients with ATTR cardiac amyloidosis. However, patients and healthcare providers need to carefully weigh the benefits and potential risks of treatment and make the best treatment choice according to the needs and circumstances of each individual patient.
5. Summary and Future Prospects
The Importance of Patisiran for ATTR Cardiac Amyloidosis
Patisiran may play an important role in the treatment of ATTR cardiac amyloidosis. This disease is progressive and affects various organs as amyloid fibrils accumulate in the heart, nerves, gastrointestinal tract, and muscle tissue. Patisiran may suppress or reverse the progression of this disease by using RNA interference to silence TTR messenger RNA in the liver and lower the level of circulating transthyretin protein.
What Patients and Healthcare Providers Should Know
Although Patisiran is a promising option in the treatment of ATTR cardiac amyloidosis, patients and healthcare providers need to fully understand its benefits and potential risks and develop a treatment plan tailored to each individual patient’s condition. Further research and long-term data on the safety and efficacy of Patisiran are needed.
Toward Future Research and the Advancement of Treatments
In the treatment of ATTR cardiac amyloidosis, research is expected to continue and the development of new treatments is anticipated. With regard to Patisiran as well, its safety and efficacy need to be further evaluated together with longer-term data. In addition, because early diagnosis and early initiation of treatment for ATTR cardiac amyloidosis are important, efforts are needed to raise awareness of the disease and improve access to diagnosis and treatment.