This Technical Brief addresses four Guiding Questions to examine the state of evidence on the use of ERT in patients with an LSD for which an FDA-approved product is available. To address Guiding Questions 1 and 2, we summarized indications and dose regimens from the FDA-approved prescribing information for each of nine available products, as well as information from review articles on how, where, and by whom ERT may be administered. Results summarized under Guiding Question 3 provide a picture of clinical studies for each product, from a search of the published literature. Guiding Question 4 integrates information from a series of semi-structured interviews with five highly experienced Key Informant physicians and end-users of ERT, relevant published clinical studies, narrative review articles, and FDA summary documents. The information compiled in this Technical Brief is intended as a resource with which health care providers and decision-makers may educate themselves about the ERT products available, how they are used, and clinical issues articulated by clinical experts and patient advocates.

Given the rarity of these diseases individually, the overall evidence base comprises small randomized, controlled trials, cohort studies, prospective single-arm studies, case series, case reports, and registry summaries. The volume of published literature correlates roughly with the FDA marketing approval dates. Thus, about 34 percent of the articles we identified in our scan were about ERT (all available products) in type I Gaucher disease, which was followed by articles on Fabry disease, which comprised 25 percent of the literature volume. The other four LSDs together make up about 31 percent of the published articles we found.

We recognize that our outcome reporting could be construed as limited by the inclusion primarily of randomized and other complementary prospective studies, excluding a larger number of case series, case reports, and foreign-language articles. The inclusion of higher-level evidence in the form of RCTs is supportable in that the trials were typically complete in capturing the key clinical outcomes of importance with a lower risk of bias than case series and case reports. Furthermore, as we state in the Methods section of this report, exclusion of non-English language reports has been shown to have little effect on the findings of systematic reviews.³¹ All of the citations we considered in the second-level literature screen are compiled in Appendix E of this report.

The clinical studies compiled in the Technical Brief map the characteristics of available evidence, including patient populations, sample size, study methods, and what outcomes have been reported for each product. Across the six LSDs, as outlined in Table 1, and clinical studies (Table 8 through Table 13), the reported patient characteristics are highly heterogeneous, as each exhibits a disease-specific constellation of signs and symptoms. Further, the expression of symptoms often varies greatly among and within the six diseases, ranging from early infancy for Pompe disease to perhaps mid-adulthood for type I Gaucher disease. However, some commonalities in symptoms clearly exist between these LSDs: for example hepatomegaly or splenomegaly, bone and other skeletal abnormalities, abnormal hematological measures (anemia, thrombocytopenia), cardiac dysfunction, pulmonary dysfunction, and impaired ambulation.

The conundrum of these orphan diseases is that they are very rare and genetically unique within and between types; however, because the macromolecular compounds accumulate within lysosomes—which are found in every cell type in the body—they can exhibit similar individual pathologies. Yet, each ERT product is effective for only one LSD, and ERT outcomes may vary among patients with the same disorder. This heterogeneity may complicate decision-making as it relates to initiating ERT—when is the optimal time? The majority of clinical studies we examined for this Technical Brief did not address this issue; all patients in the studies we summarized were symptomatic, to a greater or lesser degree, and required therapy. However, several of the Key Informants indicated that timing of treatment is very important as it relates to disease progression and development of irreversible damage.

We identified a few reports that showed the effect of early initiation of ERT. For example, the impact of early initiation of agalsidase beta on renal function and disease progression has been studied in adult patients with Fabry disease.⁹³ Others reported the impact of early ERT on manifestations of type I Gaucher disease.^{94, 95} Several published clinical studies have investigated the impact of early detection and initiation of ERT in infants with Pompe disease.^{75, 96–100} A sibling-control study in two children (8 weeks and 3.6 years old) reported a benefit of earlier initiation of galsulfase to slow or prevent the development of significant pathological changes of MPS VI.¹¹⁰

Information contained in several sources, including the FDA-approved label for each product; narrative and systematic reviews; clinical studies; and, Key Informant interviews suggests that ERT glycoproteins have few, if any, specific adverse effects on recipients. The vast majority of adverse events are infusion-associated reactions, which are generally mild and easily controlled or self-limiting. Immune sensitization and anaphylactic responses have been reported; the former may rarely affect therapy, whereas the latter will usually preclude further administration of the specific agent and are the subject of FDA-mandated Black Box warnings on the approved label for alglucosidase alfa, laronidase, and idursulfase (intravenous).

Our scan of the literature, the Key Informant discussions, and other publicly available information revealed a number of unanswered questions with regard to clinical use of the agents. Thus, optimal dose regimens have not been established. One article cited in Table 9 reported dose optimization studies for imiglucerase in patients with type I Gaucher disease, investigating variation of the amount of product administered or frequency of administration.⁴¹ There are many other clinical reports, editorials, and commentaries on this issue, dating back to the mid-1990s, soon after the first ERT product for type I Gaucher disease became commercially available.^{33, 34, 111–119} We also identified reports on the effect of dose variation for ERT in patients with Fabry disease^{70, 120} and MPS I.⁴⁹ The evidence base is substantially more robust for type I Gaucher disease than for the others, as would be expected given the relative prevalence of these diseases and the chronology of FDA marketing approvals.

Although we did not investigate this issue, some Key Informants voiced concern that the mechanism of action of ERT agents is not well understood. How they are taken up by lysosomes, and how they are distributed into various compartments and tissues is unclear.¹⁵ This bears directly on clinical outcomes of ERT achieved in organs or compartments that are less accessible to large glycoproteins. For example, the blood–brain barrier represents a significant impediment to intravenous ERT for diseases that have a CNS neuronopathic component. Approaches to this obstacle may entail the use of combined therapy comprising chaperone molecules, combined with ERT, or perhaps with intrathecal administration of enzymes.^{19–21, 25, 26} However, chaperone and combination therapies are purely investigational at present.

Several potential issues of interest were raised by peer reviewers of the draft Technical Brief. These include: port infections and repeat port surgeries as a harm associated with ERT, and the apparent lack of Phase IV clinical trials that were mandated by FDA as a condition for accelerated approval. We did not investigate literature on these topics.

In considering the implications of this Technical Brief, the issues are not merely technical or clinical. Although patients with so-called classic symptoms of an LSD can be apparent, atypically presenting patients often require greater consideration.¹²¹ The Key Informants suggested earlier initiation of ERT is preferable compared to later in patients for whom a diagnosis has been made. However, they expressed uncertainty as to whether it is appropriate to initiate ERT in an undiagnosed, asymptomatic individual in whom only a genetic mutation predictive of an LSD has been identified. This reticence is congruent with literature showing the disease genotype-phenotype relationship is not exact.^{80, 121, 122} Furthermore, the phenotypic expression of an LSD may significantly vary among individuals; it may not express itself at all or, symptoms may not manifest for a very long period of time.^{3, 123} Thus, whether to initiate ERT in patients with a genetic mutation specific for an LSD is an issue for which further study will be required.

Information concerning whether or when to stop ERT is also unclear. In our Key Informant interviews, we heard anecdotally of experience where the burden of therapy on the family of a patient with a rapidly progressing or nonresponsive LSD drove a decision to cease and turn to supportive comfort care alone. This raises complex questions related to the psychosocial dynamics of the family unit and also around the ethics of treatment withdrawal. We did not identify clinical studies relating such family issues and ERT. However, it is reasonable to envision disease registries as storehouses and conveyances for this type of information to physicians. Disease registries represent a means to establish treatment benefits as well as understand disease natural history and epidemiology. They can be used to collect long-term longitudinal data on clinical outcomes of rare LSDs, and information related to effects of treatment cessation and the parameters used to make such determinations. However, we are not aware of existing registry data on this topic.

The rarity of the LSDs in typical primary care or pediatric practice, and thus physician recognition and timely initiation of ERT, is a topic that has not been well studied.^{80, 122} In the United States, the National Organization for Rare Disorders and the National Institutes of Health Office of Rare Diseases, estimate that 25 million Americans suffer from a rare disease.⁸⁰ The latter seems a large number, but the LSDs considered in this Technical Brief are individually very rare. Clinical vigilance therefore becomes key to ensure timely initiation of ERT for LSDs.⁶ Primary care physicians—who typically manage common problems in unselected patients—must learn to recognize the occasional zebra in a herd of horses, without working up every horse, because common patients can present with rare diseases.¹²⁴

A generic primary care practice approach to patients with rare disease has been published.⁸⁰ According to the authors, this approach may reduce problems that include a lack of coordinated care, lack of information about rare diseases, delayed diagnosis, and delayed therapy.⁸⁰ The authors of this paper further suggest this approach may ultimately enable primary care physicians to systematically address the problems posed by individuals who present with an unrecognized or rare disorder, presumably including an LSD. Most LSD patients present with symptoms secondary to existing damage. Once an LSD is diagnosed, a comprehensive treatment plan can be developed involving a multidisciplinary team headed by a biochemical geneticist or other physician experienced in treating these diseases.