We at the aim to keep you up on the most incredible, latest innovations in biotech. Bonus: we might also help you win Jeopardy. Ready? The category is Rare Diseases for $1,000. The clue is “Amyloidosis.”

Ding ding ding! Alex, what is a group of diseases caused by the abnormal buildup of proteins in tissues and organs? You win!

Maybe some reader out there will win Jeopardy. Meanwhile, it’s the patients who suffer from maladies associated with these protein clogs and their families who are really poised to win. Because in 2018, the FDA approved two new drugs to treat hereditary transthyretin amyloidosis (hATTR). FDA approved Alnylam’s (Cambridge, MA) vutrisiran in June 2022. We explore the science behind this uncommon but debilitating illness and look at the brand-spanking new treatments for it.

First, more about amyloidosis. What the heck are amyloids? Short answer: proteins that build up in organs like the liver, spleen, and other tissues. Scientists call the collections amyloid fibrils–clumps of proteins that fold into a shape that allows many copies to stick together.

Many different proteins form amyloids. Perhaps the best known comes from amyloid-beta and is associated with Alzheimer’s disease.

The protein transthyretin can also cause amyloidosis. Produced in the liver, transthyretin transports thyroid hormones and vitamin A throughout the body. Mutations cause transthyretin to form amyloid fibrils, which accumulate, especially in the heart and nervous system. These deposits result in a range of symptoms, including cardiomyopathy–congestive heart failure, and abnormal heart rhythms. Amyloid accumulation in nerves can cause tingling, numbness, or burning pain anywhere in the body. It also sometimes leads to weakness and loss of mobility. Doctors call this assembly of problems polyneuropathy. If protein clumps damage the nerves that assist organ function, digestion and kidney complications follow.

Let’s look at the new drugs approved to prevent this problem.

The first drug approved to treat polyneuropathy associated with hATTR was Alnylam Pharmaceutical’s (Cambridge, MA) Onpattro in August 2018. Onpattro was also the first FDA-approved drug to work by RNA interference (RNAi), or gene silencing. This approach aims to reduce how much protein a specific gene produces – in this case, the mutated transthyretin gene. Onpattro does this by destroying the gene’s RNA – recall that the information in genes is first converted to RNA, which is then translated to a protein. Less mutated transthyretin protein means fewer amyloid fibrils, which means reduced polyneuropathy.

How does gene silencing work? RNAi takes advantage of existing cellular pathways that target and destroy double-stranded RNA (dsRNA).Researchers introduce a double-stranded or “hairpin” shaped RNA to activate the pathway. In the case of Onpattro, this RNA hairpin is the drug. The enzyme DICER cuts it up to produce a “short interfering RNA” (siRNA). The siRNA binds to a second enzyme, RNA-induced silencing complex (RISC). RISC alters the RNAi, so only a guide strand complementary to the target RNA remains. This guide strand/RISC complex then attaches to the problematic transthyretin mRNA and destroys it.

Patients receive Onpattro through IV infusion every three weeks.

Tegsedi, from Ionis Pharmaceuticals (Carlsbad, CA) and Akcea Therapeutics (Boston, MA), was the second drug approved for hATTR-associated polyneuropathy in October 2018. Tegsedi is an antisense drug. Like Onpattro, antisense drugs activate a cellular pathway that destroys a targeted RNA. They are short, synthetic pieces of RNA whose sequence complements the RNA that codes for a disease-associated protein. When the drug enters a patient’s cells, it binds to the disease-causing RNA. This binding triggers an enzyme called RNAse H to wipe out the antisense-target RNA duo. Once again, no RNA means no protein to form amyloid fibrils.

Patients self-administer Tegsedi weekly. This is more convenient than the Onpattro infusions. However, some patients and doctors may prefer the Alnylam medication due to its better safety profile.

The European Medicines Agency (EMA) has approved Pfizer’s (New York, NY) drug tafamidis for hATTR polyneuropathy. The FDA also approved the drug in May 2019 for hATTR cardiomyopathy. Unlike the previous treatments, which act on RNA, tafamidis is a pharmaceutical chaperone. In other words, it’s a small molecule drug that helps transthyretin fold correctly, resulting in fewer garbled proteins forming amyloid fibrils and causing disease. Like most small molecule drugs, it is administered orally.

Although hAATR is very rare – estimated to affect about 50,000 people worldwide – non-mutated transthyretin forms amyloid fibrils in ten to twenty percent of the elderly, contributing to cardiomyopathy.

We’ll widen our focus from a rare disease to a growing public health epidemic: Nonalcoholic Steatohepatitis (NASH).

Amyloidosis, a group of diseases characterized by the abnormal buildup of proteins in tissues and organs, presents a unique challenge in the medical world. With the advent of innovative treatments like Onpattro, Tegsedi, and Tafamidis, there is renewed hope for patients suffering from this debilitating condition. These groundbreaking drugs, which target the root cause of the disease at the RNA level or assist in protein folding, signify a paradigm shift in how we approach and treat amyloidosis. As the biotech industry continues to push the boundaries of what is possible, patients stand to benefit from more effective and less invasive treatments, heralding a brighter future for those affected by this rare but impactful disease.

1. WHAT IS AMYLOIDOSIS?

Amyloidosis refers to a group of diseases caused by the abnormal accumulation of proteins, known as amyloids, in various tissues and organs of the body.

2. HOW DOES THE PROTEIN TRANSTHYRETIN RELATE TO AMYLOIDOSIS?

Transthyretin is a protein produced in the liver that can cause amyloidosis when mutations lead it to form amyloid fibrils. These fibrils accumulate, especially in the heart and nervous system, causing various symptoms.

3. WHAT IS THE MECHANISM OF ACTION OF ONPATTRO?

Onpattro works through RNA interference (RNAi) or gene silencing. It targets and destroys the RNA of the mutated transthyretin gene, reducing the production of the problematic protein and, consequently, the formation of amyloid fibrils.

4. HOW DOES TEGSEDI FUNCTION DIFFERENTLY FROM ONPATTRO?

While both drugs target RNA, Tegsedi is an antisense drug. It introduces short, synthetic pieces of RNA that bind to the disease-causing RNA, triggering its destruction. This prevents the production of the disease-associated protein.

5. WHAT IS THE ROLE OF TAFAMIDIS IN TREATING AMYLOIDOSIS?

Tafamidis is a pharmaceutical chaperone, a small molecule drug that aids transthyretin in folding correctly. This reduces the number of misfolded proteins that can form amyloid fibrils.

6. HOW PREVALENT IS HAATR?

hAATR is quite rare, estimated to affect about 50,000 people globally. However, non-mutated transthyretin forms amyloid fibrils in 10-20% of older people, leading to cardiomyopathy.

7. HOW ARE THESE NEW TREATMENTS ADMINISTERED TO PATIENTS?

Onpattro is given through IV infusion every three weeks. Tegsedi is self-administered weekly, and tafamidis, like most small-molecule drugs, is taken orally.