Our systematic review assessed the efficacy of novel drugs for polyneuropathy in ATTRv amyloidosis (Patisiran and Vutrisiran). The current investigation followed the guidelines specified within the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) framework to conduct a thorough systematic review and meta-analysis in accordance with established protocols (19). The design protocol for our study was appropriately registered in the Open Science Framework (OSF). The hyperlink supplied leads to the OSF database, which houses a unique identification number record.¹

In the initial stage, relevant keywords were determined using Medical Subject Headings (MeSH) terminology. Subsequently, a thorough inquiry was conducted till September 16, 2023. The investigation utilized the following databases: PubMed, Google Scholar, Scopus, Web of Science, and Cochrane Central. The search strategy was executed by considering the title, abstract, and pertinent keywords and tags, utilizing sophisticated search functionalities for each search engine. To enhance the accuracy of the search, the search strategy involved three primary subgroups of keywords and MeSH. One subgroup encompassed terms associated with the generic, brand, and premarketing titles of Patisiran and Vutrisiran. The second subgroup included keywords and terminology of Amyloid Neuropathies. Finally, the subgroups were merged using the ‘AND’ operator. No specific limitations or restrictions were placed on the date, type of publishing, or language. The search methodology utilized in this investigation is illustrated in Supplementary Table 1.

This research is dedicated to examining the criteria for inclusion and exclusion within the research framework. The investigators utilized specific parameters to identify suitable publications. The eligibility requirements for this study were delineated as follows:

Conversely, the exclusion criteria were defined as follows:

The present analysis focused exclusively on observational cohort studies, including retrospective and prospective designs and randomized controlled trials. Early-phase clinical trials published in peer-reviewed journals were also considered, and comprehensive evaluations were conducted. Our main aim was to thoroughly examine scholarly literature that explores the effects of Patisiran and Vutrisiran on the polyneuropathy associated with ATTRv. After an exhaustive search, eliminating duplicate entries, and retrieving relevant articles, two researchers meticulously reviewed the titles and abstracts of selected studies. In instances of inconsistencies, a third author was consulted to facilitate resolution through deliberation. Subsequently, the next phase involved thoroughly analyzing the full text of identified articles to ascertain their precise alignment with the established inclusion criteria. All studies meeting the predetermined inclusion criteria were incorporated into the analysis, and a third reviewer resolved any discrepancies. The two reviewers systematically gathered pertinent study data using a pre-established data collection table. This encompassed details such as the author’s identification, study methodology, year of publication, sample size, duration, and characteristics of the patient groups. Additionally, the researchers collected various patient characteristics, including gender, age, dosage, follow-up duration, ethnicity, and outcomes. The screening procedure is illustrated in the 2020 PRISMA checklist, as shown in Supplementary Figure 1.

Three reviewers individually evaluated the full texts of the articles for suitability, employing critical appraisal instruments sourced from the website specified. ² They resolved any disagreements by discussion and consultation with the corresponding author. Three reviewers independently collected the data using a predetermined template. This template encompassed the subsequent information: study title, publication year, publication journal, study characteristics (study design, participants, mean age, administered dose, follow-up duration), and primary outcomes (neurologic and cardiologic parameters and adverse events).

A comprehensive search of primary literature databases encompassing Embase, PubMed, Web of Science, Cochrane Central, and Google Scholar identified 858 studies relevant to the present analysis. After removing duplicate items, the dataset was narrowed down to 676 distinct research studies. Subsequently, a meticulous review of titles and abstracts excluded 577 articles considered irrelevant to the research. Consequent analysis was applied to 99 remaining records, involving a comprehensive examination of their complete texts. Out of this group, 89 papers were excluded because they contained irrelevant or unnecessary information, resulting in a final collection of relevant studies for thorough examination. Finally, 10 articles with a total population of 756 were reviewed.

Coelho et al. (20) employed Phase 1 randomized, single-blind, placebo-controlled, dose-ranging trials to assess the safety and dosage response of two RNAi therapies, ALN-TTR01 and ALN-TTR02 (Patisiran). Several research centers across Portugal, Sweden, France, and the United Kingdom actively participated in this study. The recruitment process entailed including 32 patients for ALN-TTR01 and 17 patients for ALN-TTR02, with 56% being male in the former group and all participants being male in the latter group. The mean age recorded for participants in the ALN-TTR01 trial was 32 years, whereas for those in the ALN-TTR02 trial, it was 27 years. The dosage range for ALN-TTR01 was 0.01 to 1.0 mg/kg, and for ALN-TTR02, it was 0.01 to 0.5 mg/kg (20).

The Phase 2 study by Coelho et al. (21) was conducted internationally across seven countries, including the United States, Brazil, France, Germany, Portugal, Spain, and Sweden. The research comprised a cohort of 27 individuals diagnosed with ATTRv, manifesting mild-to-moderate neuropathic symptoms. The median age of the participants was 64, with 18 being male. The participants received intravenous administration of Patisiran at a dosage of 0.3 mg/kg every 3 weeks (Q3W) for a duration of approximately 2 years (21).

The study conducted by Suhr et al. (22) was characterized by its multicenter and international nature, employing an open-label design focusing on multiple-dose escalation in a phase two clinical trial. A total of 29 individuals met the eligibility criteria for participation in the study. The cohort included patients from diverse nationalities, including Brazilian, French, German, Portuguese, Spanish, Swedish, and American. Notably, all enrolled patients identified as of Caucasian ethnicity, with 69% being male, and the average age of the participants was 55.6 years. In the context of this phase 2 investigation, individuals diagnosed with familial amyloid polyneuropathy (FAP) were subjected to two intravenous infusions of Patisiran, each administered at varying doses: 0.01 (n = 4), 0.05 (n = 3), 0.15 (n = 3), or 0.3 (n = 7) mg/kg every 4 weeks (Q4W). Additionally, a subset of patients received a dosage of 0.3 mg/kg Q3W, amounting to a cohort of 12 participants (22).

The HELIOS-A was a worldwide, open-label phase 3 clinical trial conducted by Adams et al. (13). In this study cohort, 122 individuals were designated for the Vutrisiran cohort, 42 for the Patisiran reference cohort, and 77 subjects for the external placebo cohort. Notably, there was a significant male predominance observed within the HELIOS-A cohort, comprising 64.6% (n = 106), and within the APPOLO cohort (placebo), constituting 75.3% (n = 58). The study encompassed participants aged 18 to 85, recruited from 57 different sites across 22 countries. They were randomly assigned to receive either Vutrisiran at a dosage of 25 mg subcutaneously every 3 months (Q3M) or Partisan at a dosage of 0.3 mg/kg intravenously Q3W over a period of 18 months (13).

Merkel et al. (23) carried out a comparative study, utilizing data from phase three randomized controlled trials involving three distinct groups: the Fx-005, HELIOS-A trial, and APOLLO trial cohorts, comprising 125, 164, and 77 patients, respectively. The Fx-005 trial focused on transthyretin amyloidosis patients with polyneuropathy, and the Val30Met in the TTR variant was a multinational, multicenter, randomized, double-blinded, and placebo-controlled study. It enrolled 125 patients in an intention-to-treat (ITT) group, allocated in a 1:1 ratio to receive either 20 mg of Tafamidis orally (n = 64) or placebo (n = 61) daily for 18 months. The HELIOS-A trial, also a phase three study, was a randomized, worldwide, open-label investigation assessing the efficacy of Vutrisiran in patients with transthyretin amyloidosis and polyneuropathy. This trial involved 164 patients randomly assigned in a 3:1 ratio to receive either Vutrisiran (n = 122; 25 mg subcutaneously, Q3M) or Partisan (n = 42; 0.3 mg/kg intravenously, Q3W), which served as the reference comparator. The treatment duration was 18 months, with data from the APOLLO trial, a phase 3 study of Patisiran, used as an external placebo in this investigation. The primary objectives of the study were to evaluate the improvement or stability of the Neuropathy Impairment Score in the Lower Limbs (NIS-LL) and changes in the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) total score following 18 months of Fx-005 treatment. The HELIOS-A trial assessed changes in the modified Neuropathy Impairment Score + 7 (mNIS +7) from the baseline measurement at either 9 or 18 months, depending on jurisdictional requirements (23).

The original study by Adams et al. (24) was a phase 3 study conducted across multiple international centers, employing randomization, a placebo control, and a double-blind methodology. It enrolled 225 participants from 44 sites situated in 19 different countries. The study cohort comprised 167 male participants, representing 74% of the total sample, with a median age of 62. These individuals were subjected to random assignment, wherein they were allocated to receive either Patisiran or a placebo as part of a meticulously controlled clinical trial. In this study, 148 individuals were administered Patisiran intravenously at 0.3 mg/kg, with each infusion lasting about 80 min. This treatment regimen was administered Q3W for a total duration of 18 months. In contrast, the remaining 77 participants were subjected to a placebo intervention (24).

In a Phase 3b study conducted by Schmidt et al. (25), 24 individuals with ATTRv amyloidosis and post-LT polyneuropathy were investigated. They were administered a 0.3 mg/kg Patisiran intravenous infusion once every 3 weeks for 12 months. The multinational study encompassed participants from seven countries: France, Germany, Italy, Portugal, Spain, Sweden, and the United Kingdom. The participants had an average age of 58.1 and a mean BMI of 23.5. Males accounted for 56.5% (n = 13) of the sample, with 95.7% identifying as white. Notably, the majority of participants identified as non-Hispanic or Latino (25).

The original article by Bleecker et al. (26) is a retrospective study conducted across six Belgian neuromuscular reference centers. The study encompassed a cohort of nine patients, with a median age of 63, who underwent treatment with Patisiran. The Partisan administration was conducted via an 80-min intravenous infusion at 300 μg/kg dosage, administered in Q3W intervals as part of an Expanded Access Program (EAP) (26).

The original study by Fontana et al. (27) encompassed 32 participants diagnosed with transthyretin cardiomyopathy (ATTR-CM). The cohort was divided into two distinct groups: one designated as the treatment group consisting of 16 patients, and another identified as the control group with equal participants. The median age of subjects in the treatment group was 62 years, with 13 male participants, while the control group exhibited a median age of 69 years, encompassing 14 male participants. All patients were administered 0.3 mg/kg Patisiran via infusion Q3W. Of the 16 patients, 12 were given Diflunisal, a TTR-stabilizing drug, orally at 250 mg twice daily. The study participants underwent serial monitoring at 12 months through cardiac magnetic resonance, cardiac biomarkers, bone scintigraphy, 6-min walk tests (6MWTs), and echocardiography (27).

Adams et al. (28) conducted an international, open-label extension (OLE) study across 43 medical facilities spanning 19 countries. This investigation enrolled individuals who had successfully concluded either the phase 3 APOLLO trial or the phase 2 OLE parent trials and could tolerate the experimental medication. The eligible participants from both the APOLLO trial (including both the patisiran and placebo cohorts) and the phase 2 OLE trial (Patisiran cohort) were included in this global extension study, receiving intravenous Patisiran at a dosage of 0.3 mg/kg Q3W, with a planned study period of up to 5 years. Recruitment took place between July 13, 2015, and August 21, 2017, with 211 out of 212 eligible patients enrolled, comprising 137 from the APOLLO-Partisan group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE partisan group. As of the data cutoff on September 24, 2018, completion rates for the 12-month assessments were 92% (126 out of 137) for the APOLLO-Partisan group, 78% (38 out of 49) for the APOLLO-placebo group, and 100% (25 out of 25) for the phase 2 OLE Patisiran group (28).

The summary of the study’s characteristics is presented in Table 1.

Coelho et al. (20) investigation focused on assessing the safety and efficacy of two RNAi therapies, ALN-TTR01 and ALN-TTR02 (Patisiran), focusing on TTR levels within individuals diagnosed with ATTRv and a control group of unaffected individuals. In the ALN-TTR01 trial involving 32 ATTRv patients, single doses of ALN-TTR01 (ranging from 0.01 to 1.0 mg/kg) or placebo were administered. Notably, the 1.0 mg/kg dose demonstrated a significant 38% mean TTR knockdown at day seven compared to the placebo, affecting both mutant and nonmutant TTR similarly. Infusion reactions of mild to moderate severity occurred in 20.8% of the ALN-TTR01 group. In the ALN-TTR02 Phase 1 trial with 17 healthy volunteers, single doses of ALN-TTR02 (ranging from 0.01 to 0.5 mg/kg) or placebo were given. The study revealed potent, dose-dependent TTR lowering, with a mean 82–87% TTR knockdown at nadir for 0.15 and 0.3 mg/kg doses. Remarkably, a durable knockdown of 56–67% persisted on day 28, with only one mild infusion reaction reported in the 0.5 mg/kg group (20).

In summary, ALN-TTR01 and ALN-TTR02 demonstrated a significant capacity to suppress TTR production via an RNAi mechanism, thereby establishing proof of concept. ALN-TTR02 exhibited notably enhanced potency compared to ALN-TTR01, and both RNAi therapies were generally well-tolerated. Additional research is crucial to assess these interventions’ clinical effectiveness and long-term safety thoroughly (20).

Coelho et al. (21) conducted research that revealed that prolonged Patisiran administration was both safe and efficacious in arresting or facilitating the advancement of polyneuropathy in individuals with ATTRv. Patisiran reduced TTR levels by approximately 82% over 24 months, resulting in an average improvement of 6.95 points in mNIS+7 compared to baseline among 19 out of 27 patients at the end of the 24 months. Throughout the duration of the study, assessments of motor function, autonomic symptoms, disease progression, and quality of life showed no notable changes. Likewise, no significant variations were observed in echocardiographic evaluations or cardiac biomarkers among the subgroup of patients with cardiac involvement. Reported adverse events were mainly mild to moderate severity, and none necessitated treatment discontinuation. Flushes and infusion reactions were the most common drug-related incidents, each accounting for 22% of the reported adverse events (21).

Suhr et al. (22) attempted to evaluate the tolerability, safety, pharmacokinetic (PK), and pharmacodynamic (PD) of Patisiran in patients with transthyretin-mediated FAP. The inclusion criteria for this study encompassed adult patients diagnosed with confirmed ATTRv. Baseline serum levels of TTR proteins exhibited uniformity across various dosage cohorts. TTR knockdown was identical between patients with the Val30Met and those with non-Val30Met genotypes. The reduction in TTR levels was strongly correlated with decreased circulating retinol-binding protein (RBP) and vitamin A. After the administration of Patisiran, the mean concentrations of the TTR small interfering RNAs (siRNAs) component decreased (22).

Nevertheless, there was no buildup of siRNAs after administering the second dose. The C_max and AUC0-last increased proportionally with the dose for both the first and second doses. Mild-to-moderate reaction during the infusion was the main side effect associated with their study. It is worthy of note that a few cases also experienced various adverse events, including back pain, asthenia, leukocytosis, neutrophilia, cellulitis, lymphangitis, polyuria, nausea/vomiting, facial erythema, dry mouth, pyrexia, dysphagia (22).

The study HELIOS-A was conducted by Adams et al. (13), which lasted for 18 months, and examined the safety and effectiveness of Vutrisiran for individuals with ATTRv and polyneuropathy. The investigation demonstrated that Vutrisiran exerted a favorable influence on the primary endpoint, specifically the alteration from baseline in the modified Neuropathy Impairment Score + 7 (mNIS+7) at the nine-month mark (−2.24 [Vutrisiran] and + 14.76 [placebo] (p = 3.54 × 10–12)). Furthermore, the compound demonstrated favorable outcomes across various secondary efficacy measures. Vutrisiran exhibited notable advancements in Norfolk QOL-DN during the ninth month compared to the external placebo cohort. The Vutrisiran group demonstrated a 53.4% enhancement, surpassing the 23.4% improvement observed in the placebo group, as indicated by the Norfolk QOL-DN score. By the eighteenth month, these figures further accentuated the positive impact of Vutrisiran, with a 56.8% improvement observed in the Vutrisiran group, in contrast to a mere 10.4% improvement in the placebo group. The 10-meter walk test (10MWT) demonstrated significant improvements at both the nine and 18-month intervals (13).

Additionally, the mNIS+7 results after 18 months showed a notable difference, with a decrease of 0.46 for Vutrisiran and an increase of 28.1 for the placebo. Notably, 48.3% of Vutrisiran recipients exhibited improvement in mNIS+7, in contrast to only 3.9% in the external placebo cohort. Furthermore, favorable results were noted in the modified Body Mass Index (mBMI) and the Rasch-built Overall Disability Scale (R-ODS) after 18 months. The majority of adverse occurrences documented exhibited mild to moderate severity and aligned with the expected course of ATTRv. Noteworthy is the absence of any occurrences necessitating cessation of drug treatment or resulting in fatalities. The research findings underscore that Vutrisiran demonstrated substantial improvements in various disease-related parameters for ATTRv compared to an external placebo while maintaining a commendable safety record (13).

Merkel et al. (23) conducted an investigation employing Indirect Treatment Comparison (ITC) methodology to evaluate the therapeutic effectiveness of Vutrisiran and Tafamidis across diverse parameters such as NIS-LL, Norfolk QOL-DN score, NIS-LL Response, and mBMI. This investigation seeks to establish the effectiveness of both Vutrisiran and Tafamidis in treating ATTRv with polyneuropathy. The empirical basis for this study is derived from the analysis of data obtained from phase three randomized controlled trials, namely HELIOS-A, APOLLO, and Fx-005 studies. These trials systematically evaluated and compared the outcomes associated with Vutrisiran and Tafamidis interventions in the context of ATTRv with polyneuropathy. The primary analysis demonstrated a statistically significant superiority of Vutrisiran compared to Tafamidis in terms of the average change from baseline at the 18-month evaluation point for two crucial outcome metrics: the NIS-LL (mean difference: −5.3, 95% CI: −9.4 to −1.2, p = 0.011) and the Norfolk QOL-DN (mean difference: −18.3, CI 95%: −28.6 to −8.0, p < 0.001). Additionally, Vutrisiran exhibited superior efficacy in the NIS-LL Responder outcome at the 18-month mark compared to Tafamidis NIS-LL response (odds ratio: 1.7). This ITC study concluded that Vutrisiran has higher efficacy in enhancing multiple measures of polyneuropathy impairment and health-related quality of life (HRQOL) compared to Tafamidis in patients with ATTRv amyloidosis with polyneuropathy (23).

Adams et al. (24) conducted a research study to examine the effectiveness of Patisiran in patients with ATTRv with polyneuropathy. All individuals involved in this research were of adult age and exhibited an NIS ranging from 5 to 130, along with a polyneuropathy disability score of 3b or below, and demonstrated sufficient liver and renal functionality. According to the research, Patisiran demonstrated significant enhancements in both the primary endpoint (mNIS+7) for 56% of the patients who received the treatment, as opposed to only 4% of those who received a placebo. Additionally, regarding the secondary endpoint, Norfolk QOL-DN score, 51% of the patients who received Patisiran displayed an improvement in their Norfolk QOL-DN score, compared to 10% of those who received a placebo. In the subset of individuals within the cardiac subpopulation, Patisiran demonstrated a superior impact on cardiac structural integrity and functionality compared to administering a placebo. It is noteworthy that both cohorts documented the occurrence of adverse events throughout the clinical trial (24).

Schmidt et al. (25) conducted a Phase 3b open-label trial to evaluate the efficacy and safety of Patisiran in patients with ATTRv amyloidosis who experienced polyneuropathy progression following liver transplantation. The study involved mature individuals who had received a liver transplant as a treatment for ATTRv amyloidosis at least a year before the study and had encountered the advancement of polyneuropathy after the transplant. The research findings revealed that Patisiran led to an average reduction of approximately 91% in TTR levels between Months 6 and 12. Additionally, at Month 12, improvements in neuropathy, quality of life, and autonomic symptoms were observed, with mean changes from baseline of −3.7 (SEM 2.7) in the NIS, −6.5 (SEM 4.9) in the Norfolk QOL-DN score, and − 5.0 (SEM 2.6) in the Composite Autonomic Symptom Score-31 (COMPASS-31). Measures of disability, assessed using the R-ODS, and nutritional status, monitored through the mBMI, remained relatively stable with mean changes from baseline of −0.1 (SEM 1.1) and + 4.4 (SEM 21.8), respectively, over the 12-month treatment period. Adverse events reported during the trial were consistent with the known safety profile of Patisiran, including diarrhea and infusion-related reactions (25).

After an 18-month retrospective study, Bleecker et al. (26) investigated 12 patients diagnosed with ATTRv who underwent Patisiran treatment. The comprehensive character of the disease is demonstrated through the manifestation of neurological and/or cardiological symptoms, as indicated by various metrics and assessments. The investigation revealed that 98.9% of the intended treatment regimens were successfully executed throughout the study (26). The median durations of treatment were 551.1 days and 700 days, respectively, spanning from 35 to 815 days. Among the patients, seven exhibited stage 1 polyneuropathy, while the remaining five presented stage 2. The polyneuropathy disability (PND) score varied from 1 to 3b, with a median NIS-LL score of 31. Eleven patients had abnormal Electromyography (EMG) results. The median Functional Independence Measurements (FIM) score was 115, and six patients had cardiac symptoms. Six patients had abnormal electrocardiogram (ECG) and left ventricular ejection fraction (LVEF) findings (26).

Fontana et al. (27) investigated for 12 months and found that Patisiran was well tolerated. The median reduction in serum TTR levels among the cohort of treated patients amounted to 86% (interquartile range [IQR]: 82 to 90%). Furthermore, it is noteworthy that 82% of the cases exhibited a TTR knockdown exceeding 80%. The administration of Patisiran therapy showed a remarkable decrease in extracellular volume (ECV), as evidenced by the adjusted mean difference between groups amounting to −6.2% (p = 0.001). Furthermore, there was an evident reduction in levels of N-terminal pro–B-type natriuretic peptide (NT-proBNP) linked with Patisiran treatment, as demonstrated by the adjusted mean difference between cohorts, which amounted to −1,342 ng/L (p = 0.012). Moreover, Patisiran therapy was significantly associated with better distances in the 6MWT, as indicated by adjusted mean differences between groups of 169 meters (p = 0.004). Additionally, a median reduction of 19.6% in cardiac uptake was observed, as determined through bone scintigraphy, and expressed with an IQR of 9.8 to 27.1%. In conclusion, the investigation postulated that reductions in ECV, as discerned through cardiac magnetic resonance, offered compelling evidence of regression in ATTRv affecting the heart in select patients undergoing Patisiran treatment (27). The cardiologic effects, neurologic consequences, and adverse events documented in the encompassed studies have been briefly presented in Tables 2–4, respectively.

Adams et al. (28) extended the phase 3 open-label clinical trial over 12 months. Data were collected systematically at regular intervals, revealing persistent enhancements in polyneuropathy measures following treatment with Patisiran. The analysis also revealed improved QOL, autonomic function, disability, and nutritional condition. Nevertheless, despite a consistent enhancement in polyneuropathy, it did not revert to the baseline levels observed in prior studies. The average alteration in autonomic function demonstrated a decrease of −3.7 following 12 months of treatment. Furthermore, the levels of TTR exhibited a significant reduction of 78% after 6 months of treatment. The study’s primary objective was to evaluate the safety and tolerability of prolonged Patisiran administration. Secondary objectives included investigating disease progression, assessing quality of life, and evaluating nutritional well-being (28).

These investigations offer noteworthy discoveries; nonetheless, it is essential to recognize the conceivable hazards linked to conflicts of interest and biases that could have influenced the research outcomes. An identifiable source of bias in these inquiries is the sponsorship received from specific pharmaceutical companies, introducing the potential for partiality in study design, execution, and reporting. Furthermore, researchers may be inclined to disclose positive results to ensure continued financial support from these entities. To alleviate the risk of bias and conflicts of interest, researchers ought to openly divulge potential conflicts and institute measures to ensure the objectivity and impartiality of the research. The sponsor of the trials is indeed a pharmaceutical company, but this is inevitable since a pharmaceutical company initiates most phase I-III trials.

In the study by Schmidt et al. (25), the authors disclosed conflicts of interest, including employment and stock ownership with Alnylam Pharmaceuticals, as well as consulting fees, honoraria, and research funding from Alnylam Pharmaceuticals, Pfizer Inc., Akcea Therapeutics, Ionis Pharmaceuticals, and Eidos. Additionally, Alnylam Pharmaceuticals supported related research by Adams et al. (13, 24, 28), Merckle et al. (23), and Coelho et al. (20, 21). Furthermore, Adams et al. (28) also reported financial support from Pfizer, while Coelho et al. (20) disclosed funding from the National Institute for Health Research (NIHR) Biomedical Research Center at Guy’s and St. Thomas’ NHS Foundation Trust and King’s College London, specifically allocated to Dr. Mant (20).

The authors of the investigation by Suhr et al. (22) revealed financial affiliations with pharmaceutical enterprises among the involved parties. O Suhr is actively engaged in clinical investigations in collaboration with Pfizer and Alnylam Pharmaceuticals. T Coelho’s medical institution has received remunerations from multiple corporate entities, and Coelho personally has received financial backing from Alnylam Pharmaceuticals and Pfizer. J Buades, J Pouget, and I Conceicao are affiliated with Alnylam Pharmaceuticals, whereas J Berk and M Waddington-Cruz have received financial support from pharmaceutical corporations.

In a study by Bleeker et al. (26), various institutions such as Sanofi-Genzyme, CSL Behring, Pfizer, Alnylam, Biogen, Roche, and Alexion provided compensation between 2008 and 2021. On the other hand, the study by Fontana et al. (27) was financially supported by the British Heart Foundation, with reference number FS/18/21/33447. Furthermore, the authors reported consulting affiliations with Alnylam, Akcea, Eidos, Intellia, Pfizer, and Alexion.