https://orcid.org/0000-0002-9961-4576
To the Editor,
Thank you for the opportunity to respond to Sanofi’s communication related to our recently published article titled “The budget impact of enzyme replacement therapy in type 1 Gaucher disease in the United States”Citation1.
We believe that the authors of the letter to our publication have erred in interpreting the objectives of our study. Their contention that our budget impact analysis (BIA) is invalid because it did not consider all first-line therapies does not warrant merit since our study has not claimed to evaluate all treatment options for Gaucher disease type 1 (GD1).
The purpose of our budget impact model (BIM) was to compare only enzyme replacement therapies (ERTs) that are currently approved for GD1 treatment. While we agree that there is an appropriate place in therapy for substrate reduction therapies (SRTs), these are not considered interchangeable with ERTs and are only approved with restrictions among adult patients. Consequently, our publication focused on understanding the economic value of the GD1 ERT velaglucerase alfa via a BIM that was developed from a United States (US) payer perspective. In this study, we estimated how increasing the uptake of velaglucerase alfa versus the other ERTs, including imiglucerase and taliglucerase alfa, would impact the budget of a hypothetical US healthcare plan. Payers may have limited awareness of the economic differences among the ERTs due to the small population of GD1 patients. For that reason, our intention was to compare alternatives within enzyme replacement as a treatment modality via a BIM to highlight these economic differences. Thus, we were not trying to influence decisions regarding the choice of treatment modality.
Historically ERT has been the mainstay for treatment of GD (type 1 and 3), and as a modality is very safe for all ages as documented in clinical trials, by pharmacovigilance of each of the manufacturers, and real world evidence via disease or drug registriesCitation2. A recent review on GD treatment options noted that ERT is preferred for the management of Gaucher disease, with SRT only being an option for patients who do not tolerate or cannot receive ERTCitation3.
Eliglustat tartrate (CerdelgaFootnotei)Citation4, the SRT of focus in the Letter to the Editor, was approved by the FDA in 2014 as first-line therapy for patients with GD1. However, this therapy has a higher incidence of adverse effects than ERTs, and long-term reduction of GLC may affect several different cell functionsCitation3. In addition, SRTs should be avoided in pregnant women and in men and women attempting to conceiveCitation2,Citation5. Another concerning consideration related to the safety of eliglustat deals with a certain percentage of cardiac AEsCitation6 as well as issues of drug-drug interactions with the CYP2D6 pathway. Despite being a first-line therapy, the efficacy of eliglustat as compared to established ERTs remains unclearCitation2. In the ENGAGE trial, the magnitude of the clinical response to each of the outcomes measured was inferior to what has been reported with the ERTsCitation7. Independent reports suggest that 15% have failed to maintain stability on eliglustat as also noted by the Australian Therapeutic Goods AdministrationCitation8 and by the Canadian Agency for Drugs and Technologies in HealthCitation9. In summary, eliglustat may not be recommended for patients with any of the conditions listed in the label where caution is required, such as an underlying cardiac disorder, liver or renal abnormalities, women who wish to start a family and patients receiving any medications that may lead to drug-drug interaction. Hence, a question regarding the choice among the ERTs is pertinent.
Despite the availability of three ERTs, the enzymes are not biosimilars and are distinct molecules. Velaglucerase alfa stands out among other enzyme replacement therapies for Gaucher disease due to its wild-type amino acid sequence and unique production process. Unlike imiglucerase and taliglucerase alfa, which have an amino acid substitution at position R496H, velaglucerase alfa’s amino acid sequence is identical to the natural, wild-type form. Furthermore, velaglucerase alfa is produced by culturing humanized cell line with kifunensine, an inhibitor of α-mannosidase I, resulting in an enzyme with highly mannosylated N-glycosylation residuesCitation10. This modification enables velaglucerase alfa to be internalized into macrophages at a rate at least two-fold greater than imigluceraseCitation11. In addition to better uptake efficiency, it has been postulated that the differences in glycosylation patterns and manufacturing process from a human cell line2 may explain the lower immunogenicity of velaglucerase alfa, contributing to its improved efficacy. More recently an independent study comparing the impact of the three ERTs on repeated measurements of glucosylsphingosine (lyso-Gb1; the most sensitive and GD-specific biomarker) revealed steeper and faster decreases of the lyso-Gb1 levels in velaglucerase alfaCitation12. Velaglucerase alfa can be safely administered during pregnancyCitation13, and normal outcomes in untreated pregnancies were similar to that in pregnancies exposed to ERTCitation14. Additionally, velaglucerase alfa’s safety profile and clinical response in pediatric patients are consistent with results reported in adultsCitation15. Considering these facts, as well as the impact of velaglucerase alfa on GD outcomesCitation16, we developed a budget impact model focusing on ERTs to assess potential cost savings for the US health plans with increased use of velaglucerase alfa for GD1 among patients treated with ERTs.
Response to specific comments:
Based on the labelled descriptionCitation12,Citation13, 90% of adult patients with GD1 are eligible for eliglustat treatment at the highest dose of two capsules (84 mg) per day.
The above statement does not elaborate a number of key considerations around the use of eliglustat, which we would like to highlight for the readers’ considerations:
The use of eliglustat in patients is dependent on their CYP2D6 metabolizer status, which can only be determined through genotyping. Ultra-rapid metabolizers and indeterminate metabolizers who have not undergone testing are currently ineligible for eliglustat therapy, as a recommended dose has not been established for these groups. Additionally, the effectiveness of eliglustat may be compromised in patients taking strong CYP3A inducers, making it an unsuitable treatment option for these individualsCitation17. These limitations underscore the need for assessment of drug-drug interaction, considering patient eligibility and dosing regimens when prescribing eliglustat.
At higher than the usual therapeutic concentration, eliglustat is predicted to increase PR, QRS, and QTc intervals on ECG, which could lead to cardiac complications. As a result, eliglustat is not recommended for patients with congestive heart failure, recent acute myocardial infarction, bradycardia, heart block, or ventricular arrhythmia. Additionally, it should not be used in combination with certain classes of antiarrhythmic medicationsCitation4, including Class IA, Class IC, and Class III drugs. For patients taking a short course of a QT-prolonging drug, physicians should consider temporarily discontinuing eliglustat until the QT-prolonging drug regimen is completedCitation17. These risks highlight the importance of careful consideration of patient history and medication use when prescribing eliglustat.
Although eliglustat is classified as Pregnancy Category C, indicating no adequate and well-controlled studies in humans, it is not contraindicated for use during pregnancy and breastfeeding according to the US Prescribing InformationCitation4. However, due to the absence of controlled studies on the use of eliglustat in these populations and the evidence supporting the safety of enzyme replacement therapy during pregnancy and lactationCitation18–20, eliglustat should not be used in pregnant or breastfeeding women. It is unknown whether eliglustat is excreted in breastmilk, but as a small molecule, it may be present in the milk of mothers taking eliglustat.
The effect of eliglustat in patients with renal insufficiency, dialysis, post-kidney transplantation, or those with hepatic impairment have not been evaluated. Therefore, the use of this drug is not recommended in patients with moderate to severe renal impairment (GFR < 60 mL/min/1.73 m2)Citation4, patients on dialysis, patients post-kidney transplantation, or those with hepatic impairmentCitation4 (e.g. evidence of portal hypertension, ascites, or varices).
In addition, a BIA assuming all eligible patients would switch treatment modality (from ERT to SRT) lacks credibility and therefore should not be considered. In the Letter to the Editor, the authors even state “we concede that not all stable GD patients eligible for eliglustat would switch to or initiate treatment with eliglustat.” Finally, the objective of our paper was not to evaluate the impact of switching treatment modalities.
The SRT for second-line treatment of GD1, miglustat (ZavescaFootnoteii)Citation21 was also not included in the BIA, reducing the generalizability of the published results.
As stated previously, the key objective of our publication was to compare the budget impact of ERTs as a treatment modality, not all first-line treatments. Further, the role of SRTs for second-line treatment are not germane to the objective and thus would not impact the generalizability of the published results.
In summary, this BIA analyses did not consider all the first-line therapies that can impact velaglucerase alfa reported cost-savings.
Again, our objective was to assess the budget impact of shifting the market distribution among alternative ERTs towards greater use of velaglucerase alfa. In fact, the primary result reported in our paper holds even if we had included other first-line therapies: that shifting an additional 10% of the patients each year from other ERTs to velaglucerase alfa would result in a savings of $8.67 million over 3 years.
Transparency
Declaration of funding
Funding was provided by Takeda Pharmaceuticals U.S.A., Inc., Lexington, MA, USA.
Declaration of financial/other relationships
TJI is a former full-time employee of OPEN Health. OPEN Health received funding from Takeda for medical writing support in relation to this work.
GP is a former full-time employee of OPEN Health. OPEN Health received funding from Takeda for medical writing support in relation to this work.
SF is a full-time employee of Takeda and a stockholder of Takeda Pharmaceutical Company Limited. Takeda provided medical writing support in relation to this work.
EW is a full-time employee of Takeda and a stockholder of Takeda Pharmaceutical Company Limited. Takeda provided medical writing support in relation to this work.
RRP is a full-time employee of Takeda and a stockholder of Takeda Pharmaceutical Company Limited. Takeda provided medical writing support in relation to this work.
MB is a full-time employee of Takeda and a stockholder of Takeda Pharmaceutical Company Limited. Takeda provided medical writing support in relation to this work.
Acknowledgements
None stated.
Notes
i Cerdelga is a trademark of Sanofi/Genzyme, Waterford, Ireland.
ii Zavesca is a registered trademark of Janssen-Cilag/Actelion, San Francisco, CA, USA.
References
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