Ionis Pharmaceuticals, Inc. has announced that its partnership with AstraZeneca has led to the approval of WAINZUA (eplontersen) by the European Union (EU) for the treatment of hereditary transthyretin-mediated amyloidosis (hATTR) in adults with stage 1 or stage 2 polyneuropathy. This approval marks a significant milestone in the management of ATTRv-PN (hereditary transthyretin-mediated polyneuropathy), offering a new treatment option that is self-administered monthly via an auto-injector.

Approval and Key Clinical Data

The approval by the European Commission (EC) follows a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) and is based on the results of the NEURO-TTRansform Phase 3 trial. The trial demonstrated that after 66 weeks of treatment, patients administered with WAINZUA showed consistent and sustained improvements in the co-primary endpoints. These included:

• Serum transthyretin (TTR) concentration
• Neuropathy impairment measured by the modified Neuropathy Impairment Score +7 (mNIS+7)
• Quality of life (QoL) as measured by the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN)

Additionally, WAINZUA continued to show a favorable safety and tolerability profile throughout the trial. This approval comes as a crucial step forward in the treatment of hATTR-PN, a severe and often fatal disease.

WAINZUA: A Breakthrough Treatment

WAINZUA is an RNA-targeted treatment designed to reduce the production of TTR protein at its source in the liver. TTR is a protein that, when misfolded, accumulates in various tissues, causing severe organ damage, including nerve damage that results in neuropathy. The once-monthly treatment is delivered subcutaneously via an auto-injector, making it a convenient option for patients.

Dr. Brett P. Monia, CEO of Ionis, expressed pride in the approval, stating, “Today’s approval of WAINZUA in Europe offers adults with hereditary transthyretin-mediated amyloidosis with polyneuropathy a new, self-administered treatment option that provides consistent suppression of transthyretin production and improves neuropathy impairment and quality of life.”

This approval represents a major step in global accessibility for WAINZUA, with approvals in North America, the UK, and now across the EU.

Understanding hATTR-PN and Its Impact

Hereditary transthyretin-mediated amyloidosis (hATTR) is a debilitating genetic condition caused by mutations in the TTR gene, leading to the production of misfolded transthyretin proteins that accumulate in various organs. This buildup can result in neuropathy, cardiovascular issues, and organ failure.

When the polyneuropathy form (ATTRv-PN) is present, it typically causes peripheral nerve damage that leads to significant motor and sensory dysfunction. Without proper treatment, individuals with hATTR-PN generally experience motor disability within five years of diagnosis, and the disease is fatal within a decade. Treatment options have been limited, making this approval of WAINZUA a critical advancement.

The NEURO-TTRansform Trial

The NEURO-TTRansform trial was a global, open-label, randomized study that aimed to evaluate the efficacy and safety of eplontersen in treating hATTR-PN. The trial enrolled adult patients with stage 1 and stage 2 neuropathy, evaluating treatment efficacy at 35, 66, and 85 weeks.

The final analysis of the trial, completed at week 66, showed that eplontersen consistently reduced TTR protein levels, which is associated with improved neuropathy scores and quality of life. Following the primary study period, patients had the option to continue treatment in an open-label extension study.

Results Published in JAMA

Full results from the NEURO-TTRansform trial were published in The Journal of the American Medical Association (JAMA), showcasing the significant benefits of eplontersen across all stages of ATTRv-PN. The findings provided robust evidence supporting its use as an effective treatment for this debilitating condition.

The Broader Impact of WAINZUA

With this approval, WAINZUA provides a self-administered, once-monthly treatment for hATTR-PN, which is a significant shift from traditional treatments requiring intravenous administration. The ease of self-administration via an auto-injector adds to the appeal of this treatment, offering patients more flexibility and reducing the burden of frequent clinic visits.

Moreover, this approval further reinforces the growing body of evidence supporting RNA-targeted medicines for conditions like hATTR. By directly targeting the gene responsible for producing the defective TTR protein, WAINZUA offers a precise and effective solution to reduce disease progression.

Expanding Access Globally

The approval in the European Union builds on the success of earlier approvals in the U.S., Canada, and the UK, where WAINZUA has been available under the brand name WAINUA™. As part of a global development and commercialization agreement, AstraZeneca and Ionis are collaborating to bring WAINZUA to markets worldwide. While AstraZeneca holds exclusive rights for commercialization in certain regions, both companies are actively working to expand the availability of this important treatment.

Additionally, eplontersen is undergoing evaluation in the CARDIO-TTRansform Phase 3 trial, which focuses on the treatment of ATTR-cardiomyopathy (ATTR-CM), a related disease that primarily affects the heart. This trial is the largest of its kind, involving more than 1,400 patients, and aims to further demonstrate the effectiveness of eplontersen in treating TTR-related diseases beyond polyneuropathy.

About TTR Amyloidosis

TTR amyloidosis is a life-threatening condition caused by the buildup of misfolded TTR proteins in various organs. This buildup leads to tissue damage and results in a range of serious health complications, including:

• Heart failure due to ATTR-cardiomyopathy (ATTR-CM)
• Neuropathy as seen in ATTR-polyneuropathy (ATTR-PN)
• Chronic kidney disease as a result of kidney damage

There are two primary types of TTR amyloidosis:

1. Hereditary (ATTRv): Caused by mutations in the TTR gene that are inherited from one or both parents.
2. Wild-type (non-hereditary): A form of the disease that occurs spontaneously without a genetic mutation.

ATTR is a rapidly progressive and fatal disease. Worldwide, an estimated 300,000 – 500,000 patients are affected by ATTR-CM, and approximately 10,000 – 40,000 patients suffer from ATTRv-PN.

Safety Considerations for WAINZUA

As with any medication, WAINZUA comes with some safety considerations. Vitamin A deficiency is one of the most common adverse reactions, occurring in about 15% of treated patients. It is recommended that patients supplement their vitamin A intake while undergoing treatment. Other side effects, such as vomiting, were reported in a smaller proportion of patients (9%).

Additionally, patients should be monitored for ocular symptoms that may suggest vitamin A deficiency.

Conclusion: A Landmark Approval for hATTR-PN Treatment

The European Commission’s approval of WAINZUA represents a significant advancement in the treatment of hereditary transthyretin-mediated amyloidosis. This once-monthly, self-administered treatment offers a critical option for adult patients with stage 1 or stage 2 polyneuropathy, potentially altering the course of this debilitating disease.

With the partnership between Ionis Pharmaceuticals and AstraZeneca advancing treatment options for hATTR globally, WAINZUA holds the promise of improving quality of life for patients, slowing disease progression, and ultimately transforming the landscape of TTR amyloidosis treatment.

As the treatment becomes more widely available, patients across the EU, U.S., Canada, the UK, and other regions can expect broader access to a life-changing therapy.

Ionis Pharmaceuticals and AstraZeneca’s WAINZUA Approved in the EU for Hereditary Transthyretin-Mediated Amyloidosis Treatment

Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) has announced that its partnership with AstraZeneca has led to the approval of WAINZUA (eplontersen) by the European Union (EU) for the treatment of hereditary transthyretin-mediated amyloidosis (hATTR) in adults with stage 1 or stage 2 polyneuropathy. This approval marks a significant milestone in the management of ATTRv-PN (hereditary transthyretin-mediated polyneuropathy), offering a new treatment option that is self-administered monthly via an auto-injector.

Approval and Key Clinical Data

The approval by the European Commission (EC) follows a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) and is based on the results of the NEURO-TTRansform Phase 3 trial. The trial demonstrated that after 66 weeks of treatment, patients administered with WAINZUA showed consistent and sustained improvements in the co-primary endpoints. These included:

• Serum transthyretin (TTR) concentration
• Neuropathy impairment measured by the modified Neuropathy Impairment Score +7 (mNIS+7)
• Quality of life (QoL) as measured by the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN)

Additionally, WAINZUA continued to show a favorable safety and tolerability profile throughout the trial. This approval comes as a crucial step forward in the treatment of hATTR-PN, a severe and often fatal disease.

WAINZUA: A Breakthrough Treatment

WAINZUA is an RNA-targeted treatment designed to reduce the production of TTR protein at its source in the liver. TTR is a protein that, when misfolded, accumulates in various tissues, causing severe organ damage, including nerve damage that results in neuropathy. The once-monthly treatment is delivered subcutaneously via an auto-injector, making it a convenient option for patients.

Dr. Brett P. Monia, CEO of Ionis, expressed pride in the approval, stating, “Today’s approval of WAINZUA in Europe offers adults with hereditary transthyretin-mediated amyloidosis with polyneuropathy a new, self-administered treatment option that provides consistent suppression of transthyretin production and improves neuropathy impairment and quality of life.”

This approval represents a major step in global accessibility for WAINZUA, with approvals in North America, the UK, and now across the EU.

Understanding hATTR-PN and Its Impact

Hereditary transthyretin-mediated amyloidosis (hATTR) is a debilitating genetic condition caused by mutations in the TTR gene, leading to the production of misfolded transthyretin proteins that accumulate in various organs. This buildup can result in neuropathy, cardiovascular issues, and organ failure.

When the polyneuropathy form (ATTRv-PN) is present, it typically causes peripheral nerve damage that leads to significant motor and sensory dysfunction. Without proper treatment, individuals with hATTR-PN generally experience motor disability within five years of diagnosis, and the disease is fatal within a decade. Treatment options have been limited, making this approval of WAINZUA a critical advancement.

The NEURO-TTRansform Trial

The NEURO-TTRansform trial was a global, open-label, randomized study that aimed to evaluate the efficacy and safety of eplontersen in treating hATTR-PN. The trial enrolled adult patients with stage 1 and stage 2 neuropathy, evaluating treatment efficacy at 35, 66, and 85 weeks.

The final analysis of the trial, completed at week 66, showed that eplontersen consistently reduced TTR protein levels, which is associated with improved neuropathy scores and quality of life. Following the primary study period, patients had the option to continue treatment in an open-label extension study.

Results Published in JAMA

Full results from the NEURO-TTRansform trial were published in The Journal of the American Medical Association (JAMA), showcasing the significant benefits of eplontersen across all stages of ATTRv-PN. The findings provided robust evidence supporting its use as an effective treatment for this debilitating condition.

The Broader Impact of WAINZUA

With this approval, WAINZUA provides a self-administered, once-monthly treatment for hATTR-PN, which is a significant shift from traditional treatments requiring intravenous administration. The ease of self-administration via an auto-injector adds to the appeal of this treatment, offering patients more flexibility and reducing the burden of frequent clinic visits.

Moreover, this approval further reinforces the growing body of evidence supporting RNA-targeted medicines for conditions like hATTR. By directly targeting the gene responsible for producing the defective TTR protein, WAINZUA offers a precise and effective solution to reduce disease progression.

Expanding Access Globally

The approval in the European Union builds on the success of earlier approvals in the U.S., Canada, and the UK, where WAINZUA has been available under the brand name WAINUA™. As part of a global development and commercialization agreement, AstraZeneca and Ionis are collaborating to bring WAINZUA to markets worldwide. While AstraZeneca holds exclusive rights for commercialization in certain regions, both companies are actively working to expand the availability of this important treatment.

Additionally, eplontersen is undergoing evaluation in the CARDIO-TTRansform Phase 3 trial, which focuses on the treatment of ATTR-cardiomyopathy (ATTR-CM), a related disease that primarily affects the heart. This trial is the largest of its kind, involving more than 1,400 patients, and aims to further demonstrate the effectiveness of eplontersen in treating TTR-related diseases beyond polyneuropathy.

About TTR Amyloidosis

TTR amyloidosis is a life-threatening condition caused by the buildup of misfolded TTR proteins in various organs. This buildup leads to tissue damage and results in a range of serious health complications, including:

• Heart failure due to ATTR-cardiomyopathy (ATTR-CM)
• Neuropathy as seen in ATTR-polyneuropathy (ATTR-PN)
• Chronic kidney disease as a result of kidney damage

There are two primary types of TTR amyloidosis:

1. Hereditary (ATTRv): Caused by mutations in the TTR gene that are inherited from one or both parents.
2. Wild-type (non-hereditary): A form of the disease that occurs spontaneously without a genetic mutation.

ATTR is a rapidly progressive and fatal disease. Worldwide, an estimated 300,000 – 500,000 patients are affected by ATTR-CM, and approximately 10,000 – 40,000 patients suffer from ATTRv-PN.

Safety Considerations for WAINZUA

As with any medication, WAINZUA comes with some safety considerations. Vitamin A deficiency is one of the most common adverse reactions, occurring in about 15% of treated patients. It is recommended that patients supplement their vitamin A intake while undergoing treatment. Other side effects, such as vomiting, were reported in a smaller proportion of patients (9%).

Additionally, patients should be monitored for ocular symptoms that may suggest vitamin A deficiency.

Conclusion: A Landmark Approval for hATTR-PN Treatment

The European Commission’s approval of WAINZUA represents a significant advancement in the treatment of hereditary transthyretin-mediated amyloidosis. This once-monthly, self-administered treatment offers a critical option for adult patients with stage 1 or stage 2 polyneuropathy, potentially altering the course of this debilitating disease.

With the partnership between Ionis Pharmaceuticals and AstraZeneca advancing treatment options for hATTR globally, WAINZUA holds the promise of improving quality of life for patients, slowing disease progression, and ultimately transforming the landscape of TTR amyloidosis treatment.

As the treatment becomes more widely available, patients across the EU, U.S., Canada, the UK, and other regions can expect broader access to a life-changing therapy.

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