Duvoglustat HCl Increases Systemic and Tissue Exposure of Active Acid α-Glucosidase in Pompe Patients Co-administered with Alglucosidase α.

Duvoglustat HCl (AT2220, 1-deoxynojirimycin) is an investigational pharmacological chaperone for the treatment of acid α-glucosidase (GAA) deficiency, which leads to the lysosomal storage disorder Pompe disease, which is characterized by progressive accumulation of lysosomal glycogen primarily in heart and skeletal muscles. The current standard of care is enzyme replacement therapy with recombinant human GAA (alglucosidase alfa [AA], Genzyme). Based on preclinical data, oral co-administration of duvoglustat HCl with AA increases exposure of active levels in plasma and skeletal muscles, leading to greater substrate reduction in muscle. This phase 2a study consisted of an open-label, fixed-treatment sequence that evaluated the effect of single oral doses of 50 mg, 100 mg, 250 mg, or 600 mg duvoglustat HCl on the pharmacokinetics and tissue levels of intravenously infused AA (20 mg/kg) in Pompe patients. AA alone resulted in increases in total GAA activity and protein in plasma compared to baseline. Following co-administration with duvoglustat HCl, total GAA activity and protein in plasma were further increased 1.2- to 2.8-fold compared to AA alone in all 25 Pompe patients; importantly, muscle GAA activity was increased for all co-administration treatments from day 3 biopsy specimens. No duvoglustat-related adverse events or drug-related tolerability issues were identified.

Papillary thyroid cancer in a patient with MUTYH-associated polyposis (MAP).

We describe a patient with MUTYH-associated polyposis diagnosed with colon cancer at 33 years of age, as well as gastric polyps at a later age. She was also diagnosed with papillary thyroid cancer at age 35. MUTYH-associated polyposis is an autosomal recessively inherited disease which has clinical overlap with Familial adenomatous polyposis and its attenuated form, in that it is associated with risk of colon cancer at a young age. Extra-intestinal cancers have also been reported in patients with MUTYH-associated polyposis; however the tumor spectrum is still evolving. National Comprehensive Cancer Network guidelines recommend screening for colon, duodenal and gastric polyps in individuals with MUTYH-associated polyposis. Screening for extra-intestinal cancers i.e. thyroid cancer is presently not part of these recommendations. These will likely continue to evolve as the MUTYH-associated polyposis tumor spectrum is better understood as a result of future case reports and research.