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January 25, 2022 / eMedClub PR News / -- Alnylam recently announced that a Phase 3 trial, HELIOS-A, of its RNAi therapy vutrisiran for the treatment of transthyretin-mediated (ATTR) amyloidosis, in All of its secondary endpoints were met at 18 months in adult patients with hereditary transthyretin amyloidosis polyneuropathy (hATTR-PN) compared with placebo in neuropathy impairment, quality of life (QoL), gait There were statistically significant improvements in speed, nutritional status and overall disability
.
In addition, the reduction of serum transthyretin (TTR) in the vutrisiran group met the non-inferiority criterion relative to another approved RNAi therapy, patisiran
.
Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, progressively debilitating and fatal disease caused by mutations in the TTR gene
.
The TTR protein is mainly produced in the liver and is normally a carrier of vitamin
A.
Mutations in the TTR gene lead to abnormal amyloid accumulation and damage to body organs and tissues, such as peripheral nerves and the heart, resulting in intractable peripheral sensorimotor neuropathy, autonomic neuropathy and/or cardiomyopathy, among other disease manifestations
.
hATTR amyloidosis has a significant unmet medical need, affecting approximately 50,000 people worldwide
.
Median survival after diagnosis was 4.
7 years, compared with 3.
4 years for patients with cardiomyopathy
.
Vutrisiran is a subcutaneously administered RNAi therapy for the treatment of ATTR amyloidosis, including hATTR and wild-type ATTR (wtATTR) amyloidosis
.
It is designed to target and silence specific mRNAs, potentially blocking wild-type and variant transthyretin production
.
Quarterly (or every six months) administration of vutrisiran may help reduce deposits in tissues, promote clearance of TTR amyloid deposits, and hopefully restore function in these tissues
.
Vutrisiran utilizes Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc conjugated delivery platform and is designed to improve potency and metabolic stability, potentially allowing for infrequent subcutaneous injections
.
HELIOS-A (NCT03759379) is a global, randomized, open-label Phase 3 study to evaluate the efficacy and safety of vutrisiran
.
The study included 164 patients with hATTR-PN and randomized 3:1 to receive either vutrisiran 25 mg subcutaneously every 3 months (N=122) or patisiran 0.
3 mg/kg by intravenous infusion (N=122).
42) for 18 months and compared the results obtained with vutrisiran with the placebo arm in another phase 3 clinical trial evaluating the efficacy of patisiran
.
▲ Introduction of ONPATTRO® (patisiran) and vutrisiran (Image source: Alnylam official website) HELIOS-A 18-month study results At 18 months, vutrisiran achieved all secondary endpoints of HELIOS-A, compared with placebo, its There was a statistically significant improvement in clinical endpoints
.
Compared with the patisiran group, the reduction of serum TTR in the vutrisiran group met the non-inferiority criteria
.
The details are as follows: The Vutrisiran group (N=122) had a mean decrease (improvement) from baseline in the Modified Neuropathic Impairment Score (mNIS+7) of 0.
46 points, while the placebo group (N=77) had a mean increase (worsening) of 28.
09 points; 48% of Patients in the Vutrisiran group showed an improvement in mNIS+7 compared to only 4% in the placebo group
.
The Norfolk QoL-DN score, which assessed quality of life in the vutrisiran group, decreased (improved) by an average of 1.
2 points compared to baseline, while the placebo group increased (worsened) by an average of 19.
8 points; 57% of the patients in the vutrisiran group experienced an improvement in quality of life relative to baseline, The placebo group was 10%
.
Patients in the Vutrisiran group achieved statistically significant improvements in gait speed (10-MWT), nutritional status (mBMI), and disability (R-ODS) compared to placebo
.
The Vutrisiran group achieved rapid and sustained reductions in serum TTR levels, with a mean reduction of 88% from baseline, meeting the criteria for non-inferiority relative to the patisiran control group
.
Patients in the vutrisiran arm also showed improvements in exploratory cardiac endpoints, continuing to support vutrisiran's potential to reduce cardiac amyloid burden and improve cardiac disease in patients
.
At 18 months, Vutrisiran demonstrated an encouraging safety profile in HELIOS-A
.
By month 18, in the vutrisiran group, 3 (2.
5%) study discontinuations were due to adverse events, 1 due to a non-fatal heart failure event and 2 due to death, both of which were considered related to The study drug is irrelevant
.
During the 18-month treatment period, investigators identified two serious adverse events (SAEs) associated with vutrisiran, including dyslipidemia and urinary tract infection
.
The two deaths and two associated SAEs were previously reported at month 9
.
Rena Nassr Denoncourt, TTR program lead at Alnylam, said: "The results from HELIOS-A show that the improvement in neuropathic impairment and quality of life observed with vutrisiran at 9 months persisted through month 18, with treatment effects over time.
increased over time with an encouraging safety profile
.
Additionally, we are encouraged by the exploratory cardiac endpoint results, particularly the new data showing that the majority of patients had reduced technetium uptake in the heart compared to baseline, suggesting amyloidosis Potential for protein regression
.
” Currently, Vutrisiran has been granted Orphan Drug Designation in the United States and European Union (EU) for the treatment of ATTR amyloidosis
.
In addition, Vutrisiran was granted Fast Track designation by the U.
S.
Food and Drug Administration (FDA) for the treatment of hATTR amyloidosis polyneuropathy in adults with a Prescription Drug Applicant Fees Act (PDUFA) target date of April 14, 2022
.
The RNAi therapy track is hot.
RNAi is a gene silencing phenomenon whose discovery has been hailed as a "major scientific breakthrough that occurs every decade or so" and won the 2006 Nobel Prize in Physiology or Medicine
.
Currently, four RNAi therapies, ONPATTRO® (patisiran), GIVLAARI® (givosiran), OXLUMO™ (lumasiran) and Leqvio® (inclisiran), have been approved for marketing worldwide
.
With the accelerated approval and marketing of RNAi therapy in recent years, RNAi therapy has gradually emerged, and many companies have entered the RNAi field
.
In January 2022, Arrowhead Pharmaceuticals initiated PALISADE, a Phase 3 clinical study of the RNAi therapy ARO-APOC3 in familial hyperchylomicronemia
.
ARO-APOC3 is an RNAi therapy that targets APOC3 mRNA.
By silencing APOC3 expression, it reduces harmful lipoprotein indicators (ie TG and VLDL levels) and increases the level of "good" cholesterol HDL
.
Recommended reading: The field of RNAi starts again! Another small nucleic acid therapy for rare diseases is nearing launchYimai Meng broke the news for the treatment of patients with chronic hepatitis B virus (HBV) infection
.
Recommended reading: RNAi combination therapy is expected to functionally cure hepatitis B, phase 2 clinical trial startsYimai Meng broke the news Use Disorder (AUD)
.
DCR-AUD is a drug candidate developed by Dicerna's GalXC RNAi technology for the treatment of alcohol use disorder (AUD) and is designed to selectively silence ALDH2 mRNA expression in the liver
.
Recommended reading: Are you afraid of blush when drinking? In September 2021, Phio Pharmaceuticals announced the results of a new study demonstrating local treatment in vivo using its proprietary self-delivering RNAi (INTASYL™) therapy It can cure tumors and generate durable and tumor-specific systemic tumor immunity
.
Recommended reading: ESMO Conference recently announced the latest results of RNAi nucleic acid drugs, dual-target design can generate durable and specific systemic tumor immunityYimai Meng broke the newsIn July 2021, Arbutus Biopharma Corporation and Vaccitech plc announced a clinical trial cooperation Agreement to evaluate innovative therapeutic combinations of RNAi therapy in combination with immunotherapeutics for the treatment of chronic hepatitis B virus (HBV) infection already receiving standard-of-care nucleoside reverse transcriptase inhibitor (NrtI) therapy
.
Recommended reading: Clinical study of RNAi combined with viral vector vaccine for the treatment of chronic hepatitis B is about to startYimai Meng broke the news IND application for a clinical IIb study in cutaneous squamous cell carcinoma in situ
.
Recommended reading: The IND application for the clinical IIb study of Sirnaro’s new dual-target RNAi therapy for in situ cutaneous squamous cell carcinoma has been accepted by the Food and Drug AdministrationYimai Meng broke the news that with the maturity of RNAi technology, and new drug delivery With the continuous updating of the system, RNAi therapy has become one of the most promising new therapies.
It is expected that more research results will emerge in this field and bring new treatment options to patients
.
Reference: https:// -with-hattr-amyloidosis-with-polyneuropathy/Disclaimer: The contents of this article are only used to explore the frontier progress of biomedicine and do not constitute any medical guidance.
If necessary, please go to a regular hospital for treatment
.
.
In addition, the reduction of serum transthyretin (TTR) in the vutrisiran group met the non-inferiority criterion relative to another approved RNAi therapy, patisiran
.
Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, progressively debilitating and fatal disease caused by mutations in the TTR gene
.
The TTR protein is mainly produced in the liver and is normally a carrier of vitamin
A.
Mutations in the TTR gene lead to abnormal amyloid accumulation and damage to body organs and tissues, such as peripheral nerves and the heart, resulting in intractable peripheral sensorimotor neuropathy, autonomic neuropathy and/or cardiomyopathy, among other disease manifestations
.
hATTR amyloidosis has a significant unmet medical need, affecting approximately 50,000 people worldwide
.
Median survival after diagnosis was 4.
7 years, compared with 3.
4 years for patients with cardiomyopathy
.
Vutrisiran is a subcutaneously administered RNAi therapy for the treatment of ATTR amyloidosis, including hATTR and wild-type ATTR (wtATTR) amyloidosis
.
It is designed to target and silence specific mRNAs, potentially blocking wild-type and variant transthyretin production
.
Quarterly (or every six months) administration of vutrisiran may help reduce deposits in tissues, promote clearance of TTR amyloid deposits, and hopefully restore function in these tissues
.
Vutrisiran utilizes Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc conjugated delivery platform and is designed to improve potency and metabolic stability, potentially allowing for infrequent subcutaneous injections
.
HELIOS-A (NCT03759379) is a global, randomized, open-label Phase 3 study to evaluate the efficacy and safety of vutrisiran
.
The study included 164 patients with hATTR-PN and randomized 3:1 to receive either vutrisiran 25 mg subcutaneously every 3 months (N=122) or patisiran 0.
3 mg/kg by intravenous infusion (N=122).
42) for 18 months and compared the results obtained with vutrisiran with the placebo arm in another phase 3 clinical trial evaluating the efficacy of patisiran
.
▲ Introduction of ONPATTRO® (patisiran) and vutrisiran (Image source: Alnylam official website) HELIOS-A 18-month study results At 18 months, vutrisiran achieved all secondary endpoints of HELIOS-A, compared with placebo, its There was a statistically significant improvement in clinical endpoints
.
Compared with the patisiran group, the reduction of serum TTR in the vutrisiran group met the non-inferiority criteria
.
The details are as follows: The Vutrisiran group (N=122) had a mean decrease (improvement) from baseline in the Modified Neuropathic Impairment Score (mNIS+7) of 0.
46 points, while the placebo group (N=77) had a mean increase (worsening) of 28.
09 points; 48% of Patients in the Vutrisiran group showed an improvement in mNIS+7 compared to only 4% in the placebo group
.
The Norfolk QoL-DN score, which assessed quality of life in the vutrisiran group, decreased (improved) by an average of 1.
2 points compared to baseline, while the placebo group increased (worsened) by an average of 19.
8 points; 57% of the patients in the vutrisiran group experienced an improvement in quality of life relative to baseline, The placebo group was 10%
.
Patients in the Vutrisiran group achieved statistically significant improvements in gait speed (10-MWT), nutritional status (mBMI), and disability (R-ODS) compared to placebo
.
The Vutrisiran group achieved rapid and sustained reductions in serum TTR levels, with a mean reduction of 88% from baseline, meeting the criteria for non-inferiority relative to the patisiran control group
.
Patients in the vutrisiran arm also showed improvements in exploratory cardiac endpoints, continuing to support vutrisiran's potential to reduce cardiac amyloid burden and improve cardiac disease in patients
.
At 18 months, Vutrisiran demonstrated an encouraging safety profile in HELIOS-A
.
By month 18, in the vutrisiran group, 3 (2.
5%) study discontinuations were due to adverse events, 1 due to a non-fatal heart failure event and 2 due to death, both of which were considered related to The study drug is irrelevant
.
During the 18-month treatment period, investigators identified two serious adverse events (SAEs) associated with vutrisiran, including dyslipidemia and urinary tract infection
.
The two deaths and two associated SAEs were previously reported at month 9
.
Rena Nassr Denoncourt, TTR program lead at Alnylam, said: "The results from HELIOS-A show that the improvement in neuropathic impairment and quality of life observed with vutrisiran at 9 months persisted through month 18, with treatment effects over time.
increased over time with an encouraging safety profile
.
Additionally, we are encouraged by the exploratory cardiac endpoint results, particularly the new data showing that the majority of patients had reduced technetium uptake in the heart compared to baseline, suggesting amyloidosis Potential for protein regression
.
” Currently, Vutrisiran has been granted Orphan Drug Designation in the United States and European Union (EU) for the treatment of ATTR amyloidosis
.
In addition, Vutrisiran was granted Fast Track designation by the U.
S.
Food and Drug Administration (FDA) for the treatment of hATTR amyloidosis polyneuropathy in adults with a Prescription Drug Applicant Fees Act (PDUFA) target date of April 14, 2022
.
The RNAi therapy track is hot.
RNAi is a gene silencing phenomenon whose discovery has been hailed as a "major scientific breakthrough that occurs every decade or so" and won the 2006 Nobel Prize in Physiology or Medicine
.
Currently, four RNAi therapies, ONPATTRO® (patisiran), GIVLAARI® (givosiran), OXLUMO™ (lumasiran) and Leqvio® (inclisiran), have been approved for marketing worldwide
.
With the accelerated approval and marketing of RNAi therapy in recent years, RNAi therapy has gradually emerged, and many companies have entered the RNAi field
.
In January 2022, Arrowhead Pharmaceuticals initiated PALISADE, a Phase 3 clinical study of the RNAi therapy ARO-APOC3 in familial hyperchylomicronemia
.
ARO-APOC3 is an RNAi therapy that targets APOC3 mRNA.
By silencing APOC3 expression, it reduces harmful lipoprotein indicators (ie TG and VLDL levels) and increases the level of "good" cholesterol HDL
.
Recommended reading: The field of RNAi starts again! Another small nucleic acid therapy for rare diseases is nearing launchYimai Meng broke the news for the treatment of patients with chronic hepatitis B virus (HBV) infection
.
Recommended reading: RNAi combination therapy is expected to functionally cure hepatitis B, phase 2 clinical trial startsYimai Meng broke the news Use Disorder (AUD)
.
DCR-AUD is a drug candidate developed by Dicerna's GalXC RNAi technology for the treatment of alcohol use disorder (AUD) and is designed to selectively silence ALDH2 mRNA expression in the liver
.
Recommended reading: Are you afraid of blush when drinking? In September 2021, Phio Pharmaceuticals announced the results of a new study demonstrating local treatment in vivo using its proprietary self-delivering RNAi (INTASYL™) therapy It can cure tumors and generate durable and tumor-specific systemic tumor immunity
.
Recommended reading: ESMO Conference recently announced the latest results of RNAi nucleic acid drugs, dual-target design can generate durable and specific systemic tumor immunityYimai Meng broke the newsIn July 2021, Arbutus Biopharma Corporation and Vaccitech plc announced a clinical trial cooperation Agreement to evaluate innovative therapeutic combinations of RNAi therapy in combination with immunotherapeutics for the treatment of chronic hepatitis B virus (HBV) infection already receiving standard-of-care nucleoside reverse transcriptase inhibitor (NrtI) therapy
.
Recommended reading: Clinical study of RNAi combined with viral vector vaccine for the treatment of chronic hepatitis B is about to startYimai Meng broke the news IND application for a clinical IIb study in cutaneous squamous cell carcinoma in situ
.
Recommended reading: The IND application for the clinical IIb study of Sirnaro’s new dual-target RNAi therapy for in situ cutaneous squamous cell carcinoma has been accepted by the Food and Drug AdministrationYimai Meng broke the news that with the maturity of RNAi technology, and new drug delivery With the continuous updating of the system, RNAi therapy has become one of the most promising new therapies.
It is expected that more research results will emerge in this field and bring new treatment options to patients
.
Reference: https:// -with-hattr-amyloidosis-with-polyneuropathy/Disclaimer: The contents of this article are only used to explore the frontier progress of biomedicine and do not constitute any medical guidance.
If necessary, please go to a regular hospital for treatment
.
