Understanding hATTR Amyloidosis
Hereditary transthyretin-mediated (hATTR) amyloidosis is a rare, progressive genetic disorder caused by a mutation in the TTR gene. The liver produces a protein called transthyretin (TTR), which is responsible for carrying thyroid hormones and vitamin A. In hATTR amyloidosis, the gene mutation causes the liver to produce abnormal, misfolded TTR proteins. These misfolded proteins clump together to form amyloid deposits (fibrils) that accumulate in the nerves, heart, and other organs throughout the body. This accumulation can lead to organ damage and a range of debilitating symptoms, particularly polyneuropathy, or damage to multiple peripheral nerves.
Symptoms of hATTR amyloidosis-related polyneuropathy can include:
- Tingling sensations or numbness
- Burning pain
- Weakness in the limbs
- Loss of balance or slower reflexes
- Dizziness, particularly when standing up
- Bowel and urinary control problems
How Onpattro Works: The Power of RNA Interference
Onpattro, containing the active ingredient patisiran, is a form of RNA interference (RNAi) therapy, sometimes called a gene silencer. This therapeutic approach uses small interfering RNA (siRNA) molecules to interrupt the process of protein production at its source.
The RNAi Mechanism:
- Targeted Delivery: Onpattro is formulated with lipid nanoparticles that carry the patisiran siRNA directly to the liver cells, which are the primary site of TTR protein synthesis.
- Gene Silencing: Once inside the liver cell, the siRNA binds to the messenger RNA (mRNA) that carries the genetic instructions for making both the mutant and normal TTR protein.
- mRNA Degradation: This binding process triggers the degradation of the TTR mRNA.
- Reduced Protein Production: By destroying the mRNA template, Onpattro effectively prevents the liver from producing the TTR protein, reducing both the mutant and normal forms.
This reduction in TTR protein levels decreases the amyloid deposits throughout the body, helping to relieve nerve damage symptoms and slow the disease's progression.
Administration
Onpattro is administered by a healthcare professional as an intravenous (IV) infusion on a specific schedule. Each infusion takes a defined amount of time. Dosage is determined based on individual patient characteristics.
To minimize the risk of infusion-related reactions (IRRs), all patients must receive premedication at least 60 minutes before each infusion. This typically includes a corticosteroid, acetaminophen, and two types of antihistamines (H1 and H2 blockers).
Potential Side Effects and Precautions
Like all medications, Onpattro can cause side effects. Awareness and management of these are crucial for effective treatment.
Common Side Effects
The most frequently reported side effects in clinical trials were upper respiratory tract infections, infusion-related reactions (IRRs), and peripheral edema. IRRs can manifest with symptoms such as:
- Flushing
- Back pain
- Nausea
- Abdominal pain
- Shortness of breath
- Headache
Important Precautions
- Vitamin A Levels: Onpattro treatment can cause a decrease in serum vitamin A levels. Because TTR protein is involved in vitamin A transport, reducing TTR can lower circulating vitamin A. Patients may be advised to take a daily vitamin A supplement. For patients with eye-related symptoms like night blindness, an eye specialist consultation is advised.
- Pregnancy: It is not known if Onpattro is safe during pregnancy, and adequate contraception is recommended for women of childbearing potential. A pregnancy registry is available for those who become pregnant while on the medication.
Onpattro vs. Amvuttra: A Comparison
While Onpattro was the first RNAi therapy for hATTR amyloidosis, other treatments have since been approved, including Amvuttra (vutrisiran). Both target TTR production, but there are key differences.
| Feature | Onpattro (patisiran) | Amvuttra (vutrisiran) |
|---|---|---|
| Administration | Intravenous (IV) infusion on a periodic basis, over a defined duration. | Subcutaneous (under-the-skin) injection, typically on a less frequent schedule. |
| Infusion Reactions | Infusion-related reactions are common, potentially requiring premedication before every dose. | Generally causes fewer and less severe injection site reactions; may not require routine premedication. |
| Frequency | Requires a higher number of administrations per year, potentially more time-consuming. | Requires fewer administrations per year, potentially offering greater convenience. |
| Approval | First FDA-approved RNAi therapy for hATTR polyneuropathy, approved in 2018. | A newer RNAi therapy, approved in 2022, offering an alternative dosing option. |
| Convenience | May be considered less convenient due to administration route and frequency. | May be considered more convenient due to administration route and less frequent dosing. |
Conclusion
Onpattro is a pioneering RNAi therapy that has revolutionized the treatment of hATTR amyloidosis with polyneuropathy. By directly targeting the genetic cause of the disease and reducing the production of misfolded TTR proteins, Onpattro helps prevent the accumulation of amyloid deposits and slows disease progression. While its administration as an intravenous infusion on a periodic basis requires consistent medical oversight and premedication, it offers a vital, long-term therapeutic option that can significantly improve nerve function and quality of life for eligible adult patients. For individuals considering or undergoing this treatment, managing vitamin A levels and being aware of potential infusion reactions are essential aspects of care.
