 The study compares the cost-effectiveness of enzyme replacement therapy, ERT, bone marrow transplantation, BMT, and supportive therapy, ST, the mild to moderate alpha manacidosis using a discrete event simulation model from the perspective of the Serbian Health Insurance Fund. The results show that ERT is not cost-effective compared with ST or BMT, while BMT can be cost-effective compared to ST but only if the willingness to pay threshold is increased. To make alpha manacidosis therapy widely accessible, criteria for assessing the cost-effectiveness of orphan drugs should include other aspects like equity weightings of QAL-wise, risk-sharing, reimbursement of severe forms of a disease only, or availability of dedicated funding. This article was authored by Anna Antonasković, Ivana Stedik, Reflect Gojek, and others.