Wainua (Eplontersen), jointly developed by AstraZeneca and Ionis Pharmaceuticals, has been approved by the FDA in the United States for ***Hereditary transthyretin-mediated polyneuropathy with amyloidosisThe disease is commonly referred tohattr-pn or attrv-pn.
hattr-pn is made up ofTransthyretin (ttrCaused by a mutation in a gene that provides instructions for making the protein TTR. This results in the production of an abnormal version of TTR, forming toxic clumps that accumulate in tissues, mainly in nerves outside the brain and spinal cord, leading to nerve damage.
WAINUA is an antisense oligonucleotide-galnac conjugate that causes degradation of mutant and wild-type TTR mRNA by binding to TTR mRNA, thereby reducing TTR protein deposition in serum and tissues. It is designed to slow the progression of the disease and improve the quality of life of patients by inhibiting the production of misfolded mutant TTR proteins.
The drug is the fourth approved drug for this disease. Of these, two are Amvuttra and Onpattro from Alnylam Pharmaceuticals;There is also Tegsedi, which was developed by IONIS.
Wainua is essentially the same as Tegsedi in its mechanism of action, but is designed for better access to the liver, which is the primary producer of TTR. Both subcutaneous** can be self-administered at home with proper training. Tegsedi is administered weekly, but Wainua is administered subcutaneously once a month, which may reduce the patient's burden.
AstraZeneca and Ionis Pharmaceuticals said WAINUA is currently the only drug approved globally for self-administration of the disease via autoinjector, and is the second antisense oligonucleotide approved for this indication. It is expected to be available in the U.S. in January 2024.
The FDA's approval of Wainua was based on the results of a 35-week interim analysis of the global, open-label, randomized, Phase 3 Neuro-Ttransform trial (NCT04136184), which was administered as a 66-week double-blind and open-label extension period to evaluate the efficacy and safety of Wainua in patients with HATTR-PN.
In the clinical trial, patients were randomized in a 6:1 ratio to receive 45 mg of wainua once every four weeks (n=144) or 284 mg of tegsedi once weekly (n=24) subcutaneously. Ninety-seven percent of patients with Wainua** and 83% of patients with Tegsedi** completed at least 35 weeks of designation**.
Efficacy evaluation was based on a comparison of the WANUA arm of the study with an external placebo group (n=60) in another study (NCT01737398) consisting of a comparable population of adult patients with polyneuropathy caused by HATTR amyloidosis.
The efficacy endpoint is:Modified Neuropathy Impairment Scale +7 (MNIS+7).Change in composite score from initial to week 35, as well as NorfolkQuality of life - diabetic neuropathy (QoL-DN).Change in total score from initial to week 35.
MNIS+7 is an objective assessment of neuropathy and includes a Neuropathy Impairment Score (NIS) and a modified +7 composite score. In the MNIS+7 version used in the trial, NIS objectively measured deficits in cranial nerve function, muscle strength, reflexes, and sensation, while the modified +7 assessed heart rate response to deep breathing, quantitative sensory testing (touch pressure and heat pain), and peripheral nerve electrophysiology.
The validated version of the MNIS+7 score used in the trial ranged from -223 to 346A score of 3, with higher scores representing more severe disease.
Through Norfolkqol-dnChange in total score from initial to week 35 to assess the clinical significance of the effects of MNIS+7. The Norfolk QoL-DN Scale is a patient-reported assessment that assesses subjective experience of neuropathy in the following domains: physical function macrofibroneuropathy, activities of daily living, symptoms, microfibrillary neuropathy, and autonomic neuropathy. The Norfolk version of the QOL-DN used in the trial ranged from -4 to 136 points, with higher scores representing greater impairment.
The results showed that at week 35, WAINUA** resulted in a statistically significant improvement in MNIS+7 and Norfolk QoL-DN total scores compared to an external placebo control. Serum transthyretin (TTR) concentrations were reduced by 81 compared to the initial WAINUA as assessed by MNIS+72%, indicating a decrease in TTR protein production compared to 148%。In addition, according to the Norfolk Qol-DN assessment, there was a significant improvement in the patient's quality of life.
Patients who received WAYNUA achieved similar improvements in MNIS+7 and Norfolk QoL-DN scores (including age, sex, ethnicity, region, Val30MET variant status, and disease stage) compared to the external placebo group.
In the trial, WAINUA demonstrated a good safety profile and tolerability.
The results of the analysis up to 85 weeks, published in the Journal of the American Medical Association in September 2023, further demonstrated the benefit of WAYNUA for all HATTR-PNs at 35, 66, and 85 weeks.
Currently, Eplontersen is being evaluated in the Cardio-Ttransform Phase 3 trial in patients with transthyretin-mediated amyloid cardiomyopathy (ATTR-CM), a systemic progressive condition that typically leads to heart failure and often death within three to five years. The study has enrolled 1,400 patients and results are expected in 2025.
Reference: Wainua (Eplontersen) granted first-ever regulatory approval in the US for the treatment of adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis', press release. astrazenecaï¼›Released on December 21, 2023.
Note: The purpose of this article is to introduce medical and health research, and does not make any basis for medication.