Letter to the Editor concerning ‘cost-effectiveness of velmanase alfa vs. bone marrow transplantation or no causal therapy in patients with mild to moderate alpha-mannosidosis’

This letter addresses a cost-effectiveness analysis recently published by Antanasković et al. [1], highlighting the limitations and uncertainties associated with the modeling approach used. Antanasković et al. [1] constructed a model for alpha-mannosidosis (AM) that compared the cost-effectiveness of enzyme replacement therapy (ERT) using velmanase alfa (VA) versus alternative treatments, including bone marrow transplantation (BMT) and supportive therapy (ST). The findings, based on a discrete event simulation (DES) model from the Serbian Health Insurance Fund perspective, suggest that velmanase alfa is not cost-effective compared to ST or BMT. The study further indicates that BMT is only cost-effective compared to ST if the willingness-to-pay threshold is increased to nine gross domestic product (GDP) per capita per quality-adjusted life year (QALY) gained. However, in our opinion, it is crucial to approach these results with caution due to important limitations associated with the DES model, including concerns regarding the source of the treatment effect data used to inform the DES analysis, and uncertainties arising from data limitations.

Antanasković et al. [1] considered the time to skeletal and muscular abnormalities (fall) in their analysis, however, they omitted some key AM symptoms from their analysis, such as lung function and motor function. The findings from a randomized controlled trial with VA [2] demonstrated a trend towards improvement in motor function (three-minute stair climb test; 3MSCT) among patients treated with VA compared to placebo. The long-term VA clinical programs (up to 12 years) also show that patients treated with VA had improvements in lung function (forced vital capacity; FVC), motor function in 3MSCT, and six-minute walk test (6MWT), particularly among pediatric patients, some of whom became independent in walking [3,4]. Improvements in mobility and lung function could lead to lower healthcare resource use in the healthcare system and a better quality of life for patients treated with VA and their caregivers. As the authors did not consider these symptoms, the DES analysis likely underestimates the effectiveness of VA.

In addition, most of the time-to-event (symptom) data used in the DES analysis could not inform the differences between VA and other treatment options. These data were primarily derived from two published studies, including a single-center study [5] in Poland and a retrospective survey [6] involving clinicians and patient organizations. Neither of these studies specifically discussed the efficacy of VA, ST, and BMT, and whether the patients considered in these studies were treated with VA is unclear.

VA has not yet obtained marketing authorization and, therefore, does not have a price in Serbia. The DES model relies on an incorrect assumption that a future price in Serbia will be equivalent to current pricing in European countries (taking the average price of VA in Romania, Lithuania, Slovakia, France, Denmark, and Luxembourg). Given that the VA price is related to country-specific reimbursement considerations (e.g. prevalence and overall budget impact), the VA price in the DES analysis did not take into account the AM patient management pathway or other considerations unique to the Serbian healthcare ecosystem. Similarly, certain comparator prices and other cost inputs were informed by data from other countries due to a lack of Serbia-specific inputs. The results of the DES analysis could be misleading due to the use of data from studies that did not report treatment-specific effects (e.g. VA) and cost data that were not relevant to Serbia.

In December 2023, the UK’s National Institute for Health and Care Excellence (NICE) recommended the use of VA as an ERT for the treatment of the non-neurological symptoms of mild-to-moderate alpha-mannosidosis in patients initiating treatment before the age of 18 years [7]. NICE’s decision was based on the results of a Markov cost-effectiveness model comparing VA with ST over a lifetime horizon. After incorporating new evidence of the long-term efficacy of VA (up to 12 years of follow-up data from the rhLAMAN clinical studies [3,4] and real-world evidence from a French registry [8]), the NICE committee considered that the most plausible ICER was £103,600 per QALY gained in children. While acknowledging the uncertainties due to limitations in the evidence and trial outcomes, the committee determined that the Markov modeling approach used was adequate for decision-making. Recognizing the rarity and significant burden of alpha-mannosidosis on patients and their families, the committee concluded that VA provides value for money and recommended VA as an option for the treatment of alpha-mannosidosis if initiated in people aged under 18 years.

Overall, although the DES model used by Antanasković et al. [1] provides potential considerations regarding the cost-effectiveness of VA compared to alternative treatments for AM, the results should be interpreted with caution. This is due to the limitations and uncertainties associated with the model, particularly because key model inputs related to treatment efficacy and costs were not based on published evidence of VA efficacy or evidence specific for patients receiving VA. The recommendation by NICE based on a Markov model incorporating newer and more comprehensive long-term VA evidence indicates that VA provides value for money to treat AM, and it further highlights the complexity of evaluating the cost-effectiveness of VA. Both models could contribute to our understanding of the treatment options for alpha-mannosidosis; however, ongoing research and data collection are necessary to refine the understanding of the clinical effectiveness and cost-effectiveness of VA versus other treatment options.

Disclosure statement

ALS, KA and PD are employees or ex-employees of Chiesi Global Rare Diseases, the manuscfacturer of velmanase alfa.

Additional information

Funding

The drafting of this article was funded by Chiesi Global Rare Diseases.