What is the difference between Onpattro and AMVUTTRA?

Hereditary transthyretin-mediated (hATTR) amyloidosis affects an estimated 50,000 people worldwide [1.5.3, 1.5.4]. This article explores what is the difference between Onpattro and AMVUTTRA, two RNA interference (RNAi) therapies used to treat its symptoms.

Quick Summary

Onpattro and AMVUTTRA both treat hATTR amyloidosis by silencing the TTR gene. Key distinctions include AMVUTTRA's less frequent quarterly injection versus Onpattro's three-week IV infusion.

Key Points

• Core Function: Both Onpattro and AMVUTTRA are RNAi therapies that silence the TTR gene to reduce the protein that causes hATTR amyloidosis [1.2.1].

• Administration Method: Onpattro is an intravenous (IV) infusion, while AMVUTTRA is a subcutaneous (under-the-skin) injection [1.8.1].

• Dosing Frequency: Onpattro is given every 3 weeks, whereas AMVUTTRA is administered only once every 3 months (quarterly) [1.8.1].

• Technology: AMVUTTRA uses a more recent GalNAc-conjugate delivery technology, enabling its less frequent, subcutaneous dosing [1.4.2, 1.4.3].

• Efficacy: Clinical trials show that both drugs are similarly effective at slowing neuropathy progression and improving quality of life [1.2.6].

• Convenience: AMVUTTRA's quarterly injection schedule offers greater convenience and a lower treatment burden compared to Onpattro's frequent infusions [1.8.1, 1.8.5].

• Safety: Both require vitamin A supplementation [1.3.5, 1.4.1]. Onpattro requires premedication to prevent infusion reactions, which is not needed for AMVUTTRA [1.2.1].

Understanding hATTR Amyloidosis

Hereditary transthyretin-mediated amyloidosis (hATTR) is a rare, progressive, and life-threatening genetic disorder [1.5.1, 1.5.5]. It is caused by a mutation in the transthyretin (TTR) gene, which provides instructions for making the TTR protein [1.5.2, 1.5.3]. The liver is the primary producer of the TTR protein, which normally functions to transport vitamin A and a thyroid hormone throughout the body [1.3.5, 1.5.2].

In individuals with hATTR amyloidosis, the TTR gene mutation leads to the production of unstable and misfolded TTR proteins [1.3.2, 1.5.5]. These abnormal proteins clump together to form amyloid fibrils, which deposit in various tissues and organs, including the nerves, heart, and gastrointestinal tract [1.3.2, 1.5.3]. This buildup disrupts normal organ function and leads to a wide range of debilitating symptoms.

Common Symptoms of hATTR Amyloidosis:

• Polyneuropathy: This is damage to peripheral nerves, often causing symptoms like pain, numbness, tingling, or weakness in the hands and feet [1.2.1, 1.5.1].
• Autonomic Neuropathy: This affects involuntary bodily functions, leading to issues like dizziness upon standing (orthostatic hypotension), digestive problems (diarrhea, constipation), and bladder control issues [1.5.1, 1.5.5].
• Cardiomyopathy: Amyloid deposits in the heart can cause an enlarged heart muscle, abnormal heart rhythms, and progressive heart failure [1.5.2].
• Gastrointestinal Issues: Patients may experience nausea, vomiting, and unintended weight loss [1.5.1].
• Ocular Symptoms: Issues like glaucoma and cloudy vitreous opacities can occur [1.5.6].

Both Onpattro and AMVUTTRA are approved to treat the polyneuropathy associated with hATTR amyloidosis in adults [1.2.1, 1.3.2, 1.4.2].

Onpattro (patisiran) vs. AMVUTTRA (vutrisiran): The Core Technology

Both Onpattro (patisiran) and AMVUTTRA (vutrisiran) are developed by Alnylam Pharmaceuticals and belong to a class of drugs known as RNA interference (RNAi) therapies, or gene silencers [1.2.1, 1.3.5]. They work by targeting the root cause of the disease: the production of the faulty TTR protein [1.3.2].

Their mechanism involves using small interfering RNA (siRNA) to find and degrade the messenger RNA (mRNA) from the TTR gene inside liver cells [1.3.2, 1.4.3]. By intercepting these genetic instructions, the drugs effectively reduce the liver's production of both the mutated and normal (wild-type) TTR protein [1.3.1, 1.4.4]. This lowers the amount of TTR protein circulating in the blood, thereby reducing the formation and accumulation of new amyloid deposits [1.3.5]. Clinical studies have shown that both drugs lead to a rapid and sustained reduction of serum TTR levels by over 80% [1.3.5, 1.6.3].

While they share the same fundamental mechanism, key differences in their molecular design and delivery platforms lead to significant distinctions in how they are used in clinical practice.

Key Differences Explained

The choice between Onpattro and AMVUTTRA often comes down to administration frequency, delivery method, and patient lifestyle factors [1.2.1].

Administration and Dosing Frequency

One of the most significant differences is the dosing schedule and method of administration [1.8.1].

• Onpattro (patisiran) is administered as an intravenous (IV) infusion every three weeks [1.8.2]. Each infusion takes approximately 80 minutes and must be done in a clinical setting by a healthcare professional [1.3.4, 1.3.5]. This means a patient will have around 17 treatments per year [1.8.1]. Patients also typically receive premedications like corticosteroids and antihistamines to reduce the risk of infusion-related reactions [1.3.6].
• AMVUTTRA (vutrisiran) is given as a subcutaneous (under the skin) injection once every three months (quarterly) [1.8.2]. This reduces the number of yearly treatments to just four [1.8.1]. It is administered by a healthcare professional, but its subcutaneous route and lack of premedication requirements make it more convenient for many patients [1.2.1, 1.6.3].

Delivery Technology

This difference in administration is possible due to advancements in drug delivery technology.

• Onpattro uses a lipid nanoparticle (LNP) to encapsulate the patisiran siRNA and deliver it to the liver [1.3.6].
• AMVUTTRA utilizes Alnylam's Enhanced Stabilization Chemistry (ESC) GalNAc-conjugate delivery platform [1.4.2]. The vutrisiran siRNA is linked to a sugar molecule (GalNAc) that specifically targets receptors on liver cells, allowing for enhanced stability, higher potency, and the convenient subcutaneous, quarterly dosing schedule [1.4.3, 1.9.1].

Efficacy and Clinical Trial Data

Both drugs have demonstrated effectiveness in slowing or halting the progression of polyneuropathy and improving quality of life.

• Onpattro's approval was supported by the Phase 3 APOLLO study, which showed that it improved neuropathy, quality of life, and overall health status compared to a placebo over 18 months [1.2.4, 1.7.4, 1.7.5].
• AMVUTTRA's approval was based on the Phase 3 HELIOS-A study. At 9 and 18 months, AMVUTTRA showed significant improvements in neuropathy, quality of life, and gait speed compared to a historical placebo group from the APOLLO trial [1.6.3, 1.6.6]. The HELIOS-A study also directly compared AMVUTTRA to Onpattro (as a reference group) and found that both treatments demonstrated comparable efficacy in stabilizing neuropathy symptoms and improving quality of life over 18 months [1.2.6].

Safety and Side Effects

Both medications have acceptable safety profiles, with most adverse events being mild to moderate [1.2.6, 1.6.3].

• Onpattro: Due to its IV administration, infusion-related reactions (like flushing, shortness of breath, or back pain) can occur, which is why premedication is required [1.2.1, 1.3.6]. Other common side effects include peripheral edema and diarrhea [1.3.6].
• AMVUTTRA: The most common side effects include pain at the injection site, joint pain (arthralgia), and shortness of breath (dyspnea) [1.4.1]. It is generally less likely to cause systemic infusion-related reactions [1.2.1].

Both treatments reduce the body's ability to transport vitamin A, so daily vitamin A supplementation is recommended for all patients to avoid deficiency and related symptoms like night blindness [1.3.5, 1.4.1].

Comparison Table: Onpattro vs. AMVUTTRA

Feature	Onpattro (patisiran)	AMVUTTRA (vutrisiran)
Mechanism of Action	RNA interference (siRNA) to silence TTR gene [1.3.2]	RNA interference (siRNA) to silence TTR gene [1.4.3]
Administration	Intravenous (IV) Infusion [1.8.2]	Subcutaneous (under the skin) Injection [1.8.2]
Dosing Frequency	Once every 3 weeks [1.8.1]	Once every 3 months [1.8.1]
Annual Doses	~17 [1.8.1]	4 [1.8.1]
Delivery System	Lipid Nanoparticle (LNP) [1.3.6]	Enhanced Stabilization Chemistry (ESC) GalNAc-conjugate [1.4.2]
Premedication	Required before each infusion [1.3.6]	Not required [1.6.3]
Common Side Effects	Infusion-related reactions, peripheral edema [1.2.1, 1.3.6]	Injection site reactions, arthralgia [1.4.1]
FDA Approval (Polyneuropathy)	2018 [1.3.2]	2022 [1.4.3]
Vitamin A Supplement	Required [1.3.5]	Required [1.4.1]

Conclusion

Onpattro and AMVUTTRA are both transformative RNAi therapies for patients with the polyneuropathy of hATTR amyloidosis. They work through the same gene-silencing mechanism to reduce the production of the disease-causing TTR protein [1.2.1]. The primary difference lies in their administration and convenience. AMVUTTRA, the newer medication, leverages an advanced delivery platform that allows for a much less frequent, subcutaneous dosing schedule of once every three months, compared to Onpattro's every-three-week IV infusions [1.8.1].

While clinical data shows comparable efficacy between the two, the convenience of AMVUTTRA's regimen may offer a significant lifestyle advantage and reduce the overall treatment burden for patients [1.2.6, 1.8.5]. The decision between the two therapies is personalized and made by a healthcare provider in consultation with the patient, considering factors like medical history, lifestyle, and insurance coverage [1.2.1].

Alnylam Pharmaceuticals Information on ATTR Amyloidosis

Frequently Asked Questions

Are Onpattro and AMVUTTRA made by the same company?

Yes, both Onpattro (patisiran) and AMVUTTRA (vutrisiran) were developed by Alnylam Pharmaceuticals [1.3.2, 1.4.3].

What disease do Onpattro and AMVUTTRA treat?

Both drugs are approved to treat the polyneuropathy (nerve damage) caused by hereditary transthyretin-mediated (hATTR) amyloidosis in adults [1.2.1, 1.3.5].

Is AMVUTTRA better than Onpattro?

Clinical studies, like the HELIOS-A trial, have shown that AMVUTTRA and Onpattro have comparable efficacy in managing the symptoms of hATTR amyloidosis [1.2.6]. The main advantage of AMVUTTRA is its more convenient dosing schedule—a subcutaneous injection every three months versus an IV infusion every three weeks for Onpattro [1.8.1].

How are Onpattro and AMVUTTRA administered?

Onpattro is given as an intravenous (IV) infusion that takes about 80 minutes in a clinical setting [1.3.5]. AMVUTTRA is given as a subcutaneous injection (a shot under the skin) by a healthcare professional [1.8.4].

How often do you need to take AMVUTTRA compared to Onpattro?

AMVUTTRA is administered once every three months (four times a year), while Onpattro is administered once every three weeks (about 17 times a year) [1.8.1].

Do both medications require vitamin A supplements?

Yes, both Onpattro and AMVUTTRA lower serum levels of vitamin A by reducing the TTR protein that transports it. Patients taking either drug are advised to take a daily vitamin A supplement at the recommended daily allowance [1.3.5, 1.4.1].

Why does Onpattro require premedication but AMVUTTRA does not?

Onpattro is given as an IV infusion and carries a risk of infusion-related reactions. Premedications (like steroids and antihistamines) are given to reduce this risk [1.3.6]. AMVUTTRA is a subcutaneous injection and is less likely to cause these systemic reactions, so premedication is not required [1.2.1, 1.6.3].