Real-world evidence study finds no new-onset diabetes or drug-related hyperglycemia in Pompe disease patients treated with avalglucosidase alfa

Abstract

Avalglucosidase alfa therapy for Pompe disease is diluted in dextrose 5% solution in water (D5W) for infusion, which raises questions about the potential for hyperglycemia or worsening diabetes. Using United States insurance claims data, we assessed the impact of biweekly infusions on hyperglycemia, new-onset diabetes mellitus, insulin resistance, and prediabetes in patients with Pompe disease. After starting avalglucosidase alfa treatment, 1 of 26 patients had one claim for hyperglycemia, which was attributed to acute pancreatitis.

1. Background

Pompe disease is a rare, progressive neuromuscular disorder caused by deficiency of acid α-glucosidase (GAA) and lysosomal accumulation of glycogen resulting in progressive muscle weakness, respiratory dysfunction and functional disabilities [1]. The infantile-onset form is characterized by cardiomyopathy and rapid progression to death within the first year of life, whereas the late-onset form develops as progressive muscle damage leading to respiratory and mobility dysfunction [[1], [2], [3], [4], [5]]. Avalglucosidase alfa (Nexviazyme/Nexviadyme, Sanofi, Cambridge, MA, USA) is a next-generation recombinant human GAA (rhGAA) enzyme replacement therapy approved for treatment of patients with Pompe disease in several countries, including the United States and the European Union [6,7]. Avalglucosidase alfa is designed for enhanced targeting of mannose-6-phosphate (M6P) receptor-mediated uptake, the essential pathway for cellular uptake and trafficking to the lysosome [8,9], and has approximately 15-fold higher M6P content compared with its predecessor, alglucosidase alfa (Myozyme/Lumizyme, Sanofi, Cambridge, MA, USA [10,11]) [12,13].

Data from an internal stability study showed that avalglucosidase alfa diluted in saline resulted in increased formation of high molecular weight aggregates, which did not occur when it is diluted in dextrose. Thus, avalglucosidase alfa is diluted in dextrose 5% solution in water (D5W) for infusion, while normal saline is the dilutant used for alglucosidase alfa infusion [6,7]. The use of D5W as a dilutant has raised concern among healthcare providers and patients regarding the potential for hyperglycemia or worsening diabetes in patients who have Pompe disease and preexisting diabetes mellitus, insulin resistance or prediabetes. This is an important issue given that the Centers for Disease Control and Prevention estimated 37 million adults with diabetes and 96 million adults with prediabetes in the United Staes in 2022 [14].

For a patient of average weight (70 kg), an infusion of avalglucosidase alfa diluted in D5W provides approximately 18 g of dextrose, a carbohydrate, during the 4–6-h infusion time. This amounts to, at most, 5 g of dextrose per hour. The Dietary Guidelines for Americans recommend daily carbohydrate intake of 45–65% of total calories for the general adult population [15]. Current American Diabetes Association nutritional guidelines do not specify a different range for individuals with diabetes or prediabetes [16].

Below is the calculation for carbohydrate content in a biweekly infusion of avalglucosidase alfa (AVA) in a patient weighing 70 kg. The total of 18 g of sugar over 4–6 h is equivalent to approximately one slice of bread over 5–6 h [17].

$$70\mathrm{kg}\times 20\mathrm{mg}/\mathrm{kg}\mathrm{AVA}=1400\mathrm{mg}\mathrm{AVA}\text{needed}$$

$$1400\mathrm{mg}/100\mathrm{mg}\text{vials}=14\text{vials of}\mathrm{AVA}\text{needed}$$

Each vial needs 10 mL sterile water for injection

$$10\mathrm{mL}\times 14\text{vials}=140\mathrm{mL}\text{sterile water for injection}\left(\mathrm{SWI}\right)\text{needed}$$

$$\text{Total volume for patient weighing}60–99.9\mathrm{kg}=500\mathrm{mL}$$

$$500\mathrm{mL}-140\mathrm{mL}\mathrm{SWI}=360\mathrm{D}5\mathrm{W}@5\%=18\mathrm{g}\text{sugar over}4–6\mathsf{h}$$

Among all 137 patients who received avalglucosidase alfa infusions in the clinical trials [[18], [19], [20], [21], [22], [23]], one participant in the COMET trial with a 9-year history of type 2 diabetes (independent of the case presented in this study) experienced an adverse event of worsening diabetes during the primary analysis period (baseline to week 49). The event was evaluated as drug-related by the investigator. Avalglucosidase alfa treatment was not interrupted and the participant continued to receive drug in the extended treatment period. Glucose values were consistent with non-fasting hyperglycemia at weeks 69, 78, and 81, after which non-fasting glycemia was normal at subsequent visits up to week 145. However, the COMET trial was not designed to determine the relatedness of an adverse event to the D5W solution. Therefore, we utilized insurance claims data to quantify events of new-onset hyperglycemia and diabetes or worsening diabetes in patients receiving avalglucosidase alfa.

2. Methods

We assessed the impact of avalglucosidase alfa 20 mg/kg biweekly infusion with D5W on new-onset diabetes mellitus, hyperglycemia, insulin resistance, and prediabetes in patients with Pompe disease in a real-world United States population. We retrospectively analyzed data from Optum's de-identified Clinformatics® Data Mart Database (December 2022 release), which captures anonymized longitudinal data from inpatient and outpatient medical and pharmacy insurance claims, including procedure and diagnosis codes. For patients with any avalglucosidase alfa-specific J CODE J0219 or NDC code 58468–0426-01, we investigated the occurrence of hyperglycemia-related ICD codes post initiation of avalglucosidase alfa treatment: R73.9, Hyperglycemia, unspecified; E10.65, Type 1 diabetes mellitus with hyperglycemia; E11.65, Type 2 diabetes mellitus with hyperglycemia; E13.65, Other specified diabetes mellitus with hyperglycemia; E09.65, Drug or chemical induced diabetes mellitus with hyperglycemia; E08.65, Diabetes mellitus due to underlying condition with hyperglycemia; and R73.03, Prediabetes.

3. Results

A total of 26 patients treated with avalglucosidase alfa were identified in the database, including 20 patients who were not previously treated with alglucosidase alfa and 6 patients who had switched from alglucosidase alfa. Codes related to hyperglycemia and diabetes for these patients were extracted. For each patient, Table 1 displays the total number of avalglucosidase alfa infusions, the initial and most recent dates of infusions, the presence/absence of hyperglycemia codes, and the presence/absence of prior alglucosidase alfa treatment. Four patients out of 26 had at least one record of hyperglycemia. Three of these patients had their first hyperglycemia-related codes captured prior to their first available record of avalglucosidase alfa treatment and one patient had a hyperglycemia code recorded after initiation of avalglucosidase alfa treatment. For this patient, all available claims were examined to investigate the potential reason for the episode of hyperglycemia. On the same day that the ICD diagnosis code for “hyperglycemia, unspecified” (R73.9) was recorded, 19 other diagnosis codes - including “Acute pancreatitis without necrosis or infection, unspecified” (K85.90) - were recorded. The first code recorded on that date was “Calculus of gallbladder and bile duct with chronic cholecystitis without obstruction” (K80.64) for which “Resection of Gallbladder, Percutaneous Endoscopic Approach” (0FT44ZZ) was performed. Acute pancreatitis was identified as the likely cause for the hyperglycemia code recorded for this patient, given that hyperglycemia is a common sequela of acute pancreatitis [24,25]. After the procedure, no hyperglycemia codes were recorded for this patient.

Table 1.

Pompe disease patients with claims for avalglucosidase alfa (AVA) infusions.

Patient No.	AVA Records (N)	Initial AVA Infusion	Most Recent AVA Infusion	Hyperglycemia Code(s)	First Hyperglycemia Code	Most Recent Hyperglycemia Code	Hyperglycemia Code Post AVA Initiation	Patient Switched from ALGLU
1	19	11/5/2021	9/23/2022	No	N/A	N/A	N/A	Yes
2	2	11/23/2021	12/7/2021	No	N/A	N/A	N/A	Yes
3	17	1/24/2022	10/13/2022	No	N/A	N/A	N/A	No
4	18	2/9/2022	11/1/2022	No	N/A	N/A	N/A	Yes
5	19	2/17/2022	10/27/2022	No	N/A	N/A	N/A	Yes
6	19	2/17/2022	10/27/2022	No	N/A	N/A	N/A	Yes
7	17	3/1/2022	10/24/2022	No	N/A	N/A	N/A	Yes
8	16	3/2/2022	9/28/2022	No	N/A	N/A	N/A	Yes
9	15	3/4/2022	10/28/2022	No	N/A	N/A	N/A	Yes
10	6	3/18/2022	6/22/2022	No	N/A	N/A	N/A	Yes
11	15	4/1/2022	10/20/2022	No	N/A	N/A	N/A	Yes
12	12	4/1/2022	9/30/2022	No	N/A	N/A	N/A	No
13	12	4/6/2022	9/14/2022	No	N/A	N/A	N/A	No
14	11	4/8/2022	8/26/2022	No	N/A	N/A	N/A	No
15	14	4/8/2022	10/7/2022	Yes (N = 1, “R73.9”)	9/27/2019	9/27/2019	No	Yes
16	12	4/12/2022	9/27/2022	No	N/A	N/A	N/A	Yes
17	13	4/14/2022	9/29/2022	No	N/A	N/A	N/A	Yes
18	13	5/5/2022	10/6/2022	Yes (N = 1, “R73.9”)	7/13/2022	7/13/2022	Yes	Yes
19	12	5/9/2022	10/24/2022	No	N/A	N/A	N/A	Yes
20	4	5/10/2022	6/21/2022	No	N/A	N/A	N/A	Yes
21	9	5/16/2022	9/19/2022	Yes (N = 3, “R73.9”)	7/27/2018	7/27/2018	No	Yes
22	7	5/20/2022	9/2/2022	No	N/A	N/A	N/A	Yes
23	2	6/30/2022	7/14/2022	Yes (N = 1, “E11.65”)	12/28/2016	12/28/2016	No	Yes
24	6	8/12/2022	10/19/2022	No	N/A	N/A	N/A	No
25	4	9/6/2022	10/17/2022	No	N/A	N/A	N/A	Yes
26	1	10/7/2022	10/7/2022	No	N/A	N/A	N/A	No

AVA: avalglucosidase alfa; ALGLU: alglucosidase alfa. Patient #18 (bolded) had a claim with a hyperglycemia ICD code after initiating avalglucosidase alfa treatment and a code for acute pancreatitis on the same date.

4. Discussion

This real-world analysis of a US healthcare claims database identified only one episode of hyperglycemia after starting treatment with avalglucosidase alfa among 26 Pompe disease patients. Importantly, that one episode was likely attributable to acute pancreatitis [24,25]. The analysis utilized billing codes extracted from claims data, thus detailed clinical information on individual patients, comorbidities and medical care is not known. Additional limitations of the study include a small patient cohort, which prevents potential investigation of risk factors (e.g. patient age), lack of information on patients' lifestyle and the underreporting inherent to real-world data. In the absence of clinical trial data on the impact of biweekly D5W infusion on glycemia, this finding is reassuring for clinicians and patients receiving avalglucosidase alfa infusions. Ongoing observation of this population will be needed to confirm these findings.

The avalglucosidase alfa prescribing information does not contain recommendations for managing patients with diabetes receiving avalglucosidase alfa infusions. Therefore, management of such patients is at the discretion of the treating or diabetes-managing clinician and/or an infusion center's internal protocols for administering a D5W solution in patients with diabetes.

Funding

This work was supported by Sanofi.

CRediT authorship contribution statement

Alexandra Dumitriu: Data curation, Formal analysis, Writing – original draft, Writing – review & editing. Ann Lucas: Conceptualization, Writing – original draft, Writing – review & editing. Raffaella Colzani: Conceptualization, Project administration, Supervision, Writing – original draft, Writing – review & editing.

Declaration of competing interest

The authors are employed by Sanofi and hold stock and/or stock options in the company.

Data availability

The datasets used and/or analyzed during the current study were obtained using standard contracts and data use agreements. The de-identified Clinformatics® Data Mart Database is proprietary to Optum and, therefore, cannot be broadly disclosed or made publicly available at this time. The disclosure of these data to third parties would require a data use agreement with Optum.