Amyloidosis, which once led to early death, now shows a fourfold increase in survival rate 10 years after the approval of new drugs
Background
Even with advancements in medical technology, improving the prognosis of patients with rare diseases remains a significant challenge in modern medicine. A prime example is amyloidosis, a condition caused by the abnormal accumulation of proteins. In this disease, misfolded proteins form amyloid deposits, which gradually accumulate in major organs of the body. This accumulation eventually leads to complete loss of organ function.
In the past, this disease was considered a fatal condition with no treatment options. Patients often experienced rapid deterioration of symptoms and early death after diagnosis. The high heterogeneity of the disease and the nonspecific nature of its symptoms also made early diagnosis difficult. Existing medical practices offered only supportive care to slow down organ damage or organ transplantation. The lack of targeted therapies to address the underlying cause significantly worsened the prognosis for patients.
Key Findings
A recent review article published in the international journal The Lancet reveals that since 2018, with the successive approval of new drugs, the survival curve of patients with amyloidosis has begun to show a sharp upward trend. For specific subtypes of patients, the estimated 10-year survival rate has increased from about 5% to approximately 20%, representing a fourfold improvement. This improvement in treatment outcomes is the result of the introduction of various new drugs that comprehensively block the formation of misfolded proteins, from their initial production to the aggregation process.
In particular, the changes in transthyretin amyloidosis (ATTR) are noteworthy. This disease, caused by the denaturation of transthyretin protein produced in the liver, has seen significant progress with the introduction of gene-silencing technology. RNA interference (RNAi) drugs, such as patisiran, and antisense oligonucleotide (ASO) drugs, such as inotersen, have been approved around 2018 and are now blocking the synthesis of the causative protein at the genetic level. Furthermore, the introduction of tafamidis, a stabilizer, has significantly extended the survival period of patients with cardiac amyloidosis.
Progress is also being observed in the treatment of amyloid light-chain (AL) amyloidosis. This disease, caused by the excessive production of light-chain proteins by abnormal plasma cells, has seen the introduction of daratumumab combination therapy. Daratumumab targets CD38 on the surface of plasma cells, eliminating tumor cells and helping to preserve organ function. Thus, the introduction of gene-level inhibitors and stabilizers tailored to each subtype is driving the improvement in treatment outcomes.
Significance and Prospects
The successive introduction of new drugs has provided a foundation for transforming a previously fatal rare disease into a manageable condition. Not only has it slowed down the progression to organ failure and increased the survival period of patients, but it has also had a positive impact by reducing the number of patients on the organ transplant waiting list due to severe heart or kidney failure. From a pharmaceutical industry perspective, it has also been recognized as a demonstration of the effectiveness of platform technologies that control the molecular mechanisms of accumulation diseases in clinical settings.
However, there are still many challenges to overcome. The 10-year survival rate of 20% means that four out of five patients still do not achieve long-term survival. The therapeutic response of new drugs is significantly reduced when amyloid has already caused irreversible damage to the organs. Therefore, it is essential to establish a highly sensitive biomarker and screening system to detect the disease early. Furthermore, social consensus and improved patient access are crucial to address the issue of high prices for new drugs and their coverage by health insurance.
Improving outcomes for people with rare diseases is a major challenge, but it is possible. Amyloidosis is a heterogeneous group of rare disorders in which amyloid (misfolded protein deposits) accumulates in the tissues, causing progressive organ failure. Until recently, it was a rapidly fatal disease with few therapeutic options. However, as detailed in a Review in this issue, several new treatments have been approved since 2018, and for people with some subtypes estimated 10-year survival has increased from about 5% to 20%.
This research provides a driving force for fundamentally changing the diagnostic and therapeutic protocols in clinical practice. In the past, when patients with unexplained heart failure or peripheral neuropathy visited the clinic, even if amyloidosis was suspected, the lack of effective treatments often delayed active differential diagnosis. Now, it is expected that a standard procedure will be established, involving non-invasive scintigraphy and rapid analysis of free light chains in the blood. Immediate diagnosis will allow for personalized prescription of RNAi therapies or CD38-targeted antibodies based on the patient's genetic mutations and amyloid type. This will prevent irreversible myocardial and nerve damage within the golden time window. Industrially, the commercial success of gene regulation and protein stabilization technologies in rare accumulation diseases is expected to accelerate the development of pipelines for other difficult-to-treat diseases with similar aggregation mechanisms.