Diflunisal Approved for New Use in Treating Hereditary Amyloidosis with Polyneuropathy

Diflunisal, a non-steroidal anti-inflammatory drug (NSAID), has re-emerged in Germany as a treatment option for adults with hereditary transthyretin-mediated amyloidosis with polyneuropathy (ATTR-PN) in stages 1 or 2. Previously, Diflunisal was available as an anti-rheumatic medication but was withdrawn from the European market for economic reasons. Its recent approval introduces a new therapeutic avenue for patients with this rare and progressive condition.

Hereditary transthyretin-mediated amyloidosis (hATTR-PN) is a disorder caused by abnormal folding of the transthyretin (TTR) protein, which is primarily produced in the liver and is responsible for transporting thyroxine, a thyroid hormone. Misfolded TTR proteins form amyloid fibrils that accumulate in tissues, particularly impacting the heart and peripheral nervous system. The disease often leads to significant impairment of quality of life and can be life-threatening if left untreated.

Mechanism of Action and Dosage

Diflunisal acts as a potent stabilizer of the transthyretin tetramer, preventing it from breaking down into monomers that contribute to amyloid formation. By maintaining the stability of this protein, Diflunisal helps slow the progression of nerve damage associated with amyloidosis. The recommended dosage is 250 mg twice daily, with tablets taken whole, preferably during meals to reduce the bitter taste. Patients are advised to allow at least a two-hour interval between taking Diflunisal and antacids to ensure optimal absorption.

Clinical Efficacy

The efficacy of Diflunisal for ATTR-PN was demonstrated in a randomized, double-blind, placebo-controlled Phase III clinical trial involving 130 patients. Over a two-year period, those treated with Diflunisal experienced a significantly slower progression of neurological symptoms compared to the placebo group. Notably, nearly 30% of patients on Diflunisal maintained neurological stability, whereas only around 9% of placebo recipients did so. However, only 63 participants completed the full study, with many discontinuing due to disease progression or the need for liver transplantation.

Safety Profile and Contraindications

While Diflunisal offers therapeutic benefits, it is associated with a range of potential side effects. Gastrointestinal disturbances are among the most common adverse events. Due to the risk of gastrointestinal, renal, and cardiovascular complications, especially with long-term NSAID use in older adults, regular medical monitoring is recommended.

Diflunisal is contraindicated in patients with a history of acute asthma attacks, urticaria, rhinitis, or angioedema triggered by acetylsalicylic acid or other NSAIDs, as well as those with gastrointestinal bleeding, severe heart disease, or significant liver or kidney dysfunction. Additionally, it should not be used during the third trimester of pregnancy or in breastfeeding women.

Drug Interactions

Caution is advised when combining Diflunisal with other medications due to potential pharmacokinetic and pharmacodynamic interactions. It should not be co-administered with other NSAIDs, acetylsalicylic acid, corticosteroids, platelet aggregation inhibitors, anticoagulants, selective serotonin reuptake inhibitors, acetazolamide, methotrexate, or tacrolimus.

Therapeutic Landscape

Globally, there are an estimated 40,000 individuals affected by hereditary ATTR-PN. The disease is characterized by slow but relentless progression, often resulting in severe neurological disability. Over recent years, several new therapies have expanded the treatment landscape for ATTR-PN, including injectable options such as eplontersen, patisiran, vutrisiran, and inotersen. The reintroduction of Diflunisal as an oral therapy provides an important alternative, especially for patients in the early stages of the disease who are still ambulatory.

In summary, the renewed availability of Diflunisal in Germany offers a significant new option for managing hereditary transthyretin-mediated amyloidosis with polyneuropathy, complementing existing therapies and addressing an unmet need for patients with this rare disorder.