Pompe disease (PD) is a rare disease lysosomal storage disease resulting from a deficiency in the lysosomal enzyme α-glucosidase (GAA), an enzyme responsible for hydrolyzing linkages in various types of carbohydrates, leading to the excessive accumulation of glycogen in cellular lysosomes. The current treatment for PD involves the use of enzyme replacement therapies (ERTs), whereby patients are given intravenous GAA enzyme, allowing patients to break down the glycogen in their tissues. There is currently only one marketed therapy available in this space. Sanofi Genzyme’s Myozyme (agalsidase beta) is available in both Germany and Japan and is marketed under the brand name Lumizyme in the US. The patents on this ERT are expiring and as a result, Sanofi Genzyme has developed a novel ERT to maintain its established share of the PD market. Avalglucosidase alfa is currently in the pre-registration phase in the three major markets (3MM), the US, Germany and Japan. Although this will provide access to a more efficacious ERT for PD patients, an unmet need remains for therapies with novel mechanisms of action (MoAs) that significantly improve long-term outcomes.

Therapies that restore GAA function in the central nervous system (CNS) and offer improved efficacy still remain a largely unmet need, as ERTs are often unable to prevent long-term damage from occurring and only slow down disease progression. Furthermore, improvements in the early diagnosis of PD are critical to prevent some of the irreversible multisystemic damage that occurs in both infantile-onset and late-onset PD (IOPD and LOPD). There are also other drawbacks to the current ERT, with immunogenicity proving a continual challenge and possible toxicity for cardiac and skeletal tissue, which have a low expression of the mannose-6-phosphate IGF2 receptor that GAA binds to. Another therapy that shows some promise is Amicus Therapeutics’ Chaperone Advanced ERT therapy (CHART) combination cipaglucosidase alfa and miglustat, a Phase III combination of an ERT and oral miglustat to reduce the likelihood of immunogenic antibodies being produced in high levels. Patients who are unable to respond well to the current ERT are likely to transfer to either the novel ERT avaglucosidase alfa or the CHART therapy. However, the patient share for the CHART is expected to remain lower than avalglucosidase in the PD market.

Although there are two late-stage pipeline therapies for PD across the 3MM with a high likelihood of approval, overall clinical data from these remains unimpressive with key opinion leaders (KOLs) interviewed by GlobalData reporting that they are unconvinced of the efficacy and primary endpoints of the trials for these therapies. In a direct head-to-head comparison with Myozyme, avalglucosidase alfa demonstrated to have improved respiratory outcomes, but physicians do not view this improvement as significant for the PD treatment paradigm as the therapy is considered to have very similar outcomes to Myozyme and therefore significant unmet needs around efficacy remain.

GlobalData expects the PD market to see significant growth during 2020–2030. The 3MM will increase in market size from total sales of $548.54M in 2020 to $1.95B in 2030, at a Compound Annual Growth Rate (CAGR) of 13.5%. This sales growth will be in line with a steadily increasing disease prevalence and the entrance of novel agents into the market. Several drugs in the pipeline have novel MoAs, including ACTUS-101 a liver-directed adeno-associated virus vector (AAV) gene therapy that offers the promise of a single-dose and potentially curative therapy for PD.

Several gene therapies are currently in Phase I/II and are expected to enter the US PD market in the next decade, with AskBio’s ACTUS-101, predicted to launch later in the forecast period and two others, Spark Therapeutic’s SPK-3006 and Astellas Gene Therapies’ AT-845, expected to launch post-2030. These therapies are designed to be administered intravenously as a single-dose therapy and are potentially curative, although at a minimum they are expected to have long-term efficacy and do not require a regular dosing schedule. The gene therapy inserts a corrected copy of the GAA gene and therefore a correctly folded protein is translated, the GAA enzyme, which can effectively break down glycogen.

Gene therapies will capture a small share of the PD market, as physicians are only likely to prescribe them for a subset of severe PD patients, at least until long-term efficacy data demonstrate a positive benefit for all PD patients who are unresponsive to ERT, or when the cost-to-benefit ratio favours gene therapy over ERT. However, clinical data for patients ages younger than 18 years remain to be determined. In addition to late-stage pipeline agents, another driver of market growth for PD will be an increasing number of early diagnoses. A significant barrier to the growth of the PD market will be the cost of therapies, leading to challenges with insurance coverage and reimbursement. This challenge will remain with novel therapies, particularly gene therapies.

Across the US, several states have undertaken newborn screening (NBS) programs and across the 3MM, physicians have developed a better understanding of the symptoms of PD in pediatric patients and adults, significantly improving diagnosis rates. This has led to improved accuracy in PD diagnosis for patients demonstrating the early neuromuscular, cardiac and respiratory system complications that are associated with PD. This will increase the number of prescriptions for ERTs, and possibly also for gene therapies. Pediatric cases remain the patient population with the highest drug treatment rate (90%) due to signs and symptoms for IOPD appearing from infancy, and LOPD patients tend to have a lower drug treatment rate (~32%) due to a late onset of symptoms and some low-level GAA activity sufficient for them to not all require ERT. However, pediatric cases will only remain a small fraction of the patient share in the PD market, as not all regions across the 3MM are likely to adopt NBS and PD symptoms often do not present until after infancy or late in adulthood.