AMA: Litster Of The Week – Page 83 – Literotica Discussion Board

The frequency of each event was summarized by severity and by relatedness to the study drug. Three Serious Adverse Events (SAEs) were reported in three subjects and were not considered related to the study drug by the site investigator. All but two study drug-related Adverse Events (AEs) were mild (Grade 1), and all resolved without intervention and were not dose-dependent. All reported adverse events were coded to a standard set of terms using the Medical Dictionary for Regulatory Activities (MedDRA) AE dictionary. All subjects reported treatment emergent adverse events (TEAEs), consistent with ongoing MPS II disease. For both subjects in Cohort 2, total GAGs, dermatan sulfate and heparan sulfate observations remained below baseline throughout the sixteen weeks, with the exception of one time point when a sample was obtained four days after a subject was hospitalized for an SAE of atrial fibrillation, unrelated to study drug, and was hypotensive for several hours.

Table 8 lists the exposure to treatment that each subject had at 32 weeks post trial initiation. The patient demographics are shown below in Table 7, which demonstrates that all patients had attenuated MPS II disease. Cohort 2 subjects who received the 1e13 vg/kg dose (see Table 11 below). The compositions comprising the polynucleotides and AAVs as described in Example 1 were administered to six subjects with attenuated MPS II at a dose of up to 5.00e13 vg/kg and was generally well tolerated in all subjects. At twelve weeks post-dosing with the compositions comprising the polynucleotides and AAVs as described in Example 1, there was a decrease in all GAG biochemical markers in cohort 2. Total urine GAG levels were measured by validated 1,9-dimethylene blue (DMB) colorimetric assay (see Example 4) while urine dermatan sulfate and urine heparan sulfate GAG levels were measured by a validated MS/MS assay (ultra-performance liquid chromatography followed by tandem-mass spectrometry). At sixteen weeks post-dosing with the compositions comprising the polynucleotides and AAVs as described in Example 1, there was a decrease in all GAG biochemical markers in cohort 2. Total urine GAG levels were measured by validated 1,9-dimethylene blue (DMB) colorimetric assay (see Example 4) while urine dermatan sulfate and urine heparan sulfate GAG levels were measured by a validated MS/MS assay (ultra-performance liquid chromatography followed by tandem-mass spectrometry).

Key secondary endpoints included: change from baseline in: IDS activity measured in plasma, total GAG, DS GAG, and HS GAG levels (expressed as a ratio to creatinine) measured in urine; AAV2/6 clearance measured by vector genomes in plasma, best naked webcam saliva, urine, stool, and semen by PCR. Key exploratory endpoints included a change from baseline in: percentage and durability of gene modification at the albumin locus in liver tissue obtained at biopsy; forced vital capacity measured by PFTs; distance walked measured by 6MWT; JROM; MRI of liver to evaluate liver and spleen volume; MRI of brain and cervical spine to evaluate clinical soft tissue and/or bone; neurocognitive abilities by WASI-II, WPPSI-IV, or BSID-III, and by VABS-II; histopathological exam of liver tissue; total GAG, DS GAG, and HS GAG levels measured in liver tissue and CSF and immune response to AAV 2/6 and ZFNs measured in serum. The GAG levels of MPS II patients with attenuated disease who are on ERT can vary but usually within a range that diagnostic models would consider the lower end of diseased all the way to very low end of normal. The absence of detectable levels does not indicate that IDS is not being produced by liver cells edited using the methods and compositions disclosed herein.

Urine GAG levels are a key biomarker of MPS II disease pathophysiology. Urine GAG biomarkers showed a reduction in total GAGs, dermatan sulfate (DS GAG) and heparan sulfate (HS GAG) in a dose dependent manner. Additional secondary endpoints include monitoring monthly frequency and dose of IDS (or equivalent ERT). The analyses of these endpoints was descriptive and exploratory in nature. Therefore, analyses were primarily descriptive and exploratory in nature. Continuous variables were summarized by means, standard deviations, medians, and ranges for all enrolled subjects. Categorical variables were summarized with counts and percentages per category for all enrolled subjects. The study was performed cum on teen tits subjects with MPS II disease. Key eligibility criteria for subjects in the study included: .gtoreq.5 years of age (Adult cohorts 1 through 3: .gtoreq.18 years of age; Pediatric cohorts 4 and 6: 12 to 17 years of age; Pediatric cohorts 5 and 7: 5 to 11 years of age); clinical diagnosis of MPS II based on evidence of hepatosplenomegaly, dysostosis multiplex by X-ray, valvular heart disease and/or obstructive airway disease with IDS deficiency confirmed by gene sequencing; Magnetic resonance imaging (MRI) negative for liver mass.

IDS was measured in this study using a standard validated fluorometric assay using 4-methylumbelliferyl sulfate (4MU) as substrate (see below in Example 4 for exemplary plasma IDS assays). This study will enroll up to 23 subjects (2 subjects in each of 7 cohorts, with potential enrollment of 3 additional subjects at the maximal tolerated dose in each of 3 age cohorts). Two subjects treated at the 1.00e13 vg/kg dose (cohort 2) showed a mean decrease of greater than 60% in urine heparan sulfate at 16 weeks post dosing with the compositions described herein. Specifically, total urinary GAGs declined by 51%, dermatan sulfate by 32%, and heparan sulfate by 62% in Cohort 2 (mid dose) at 16 weeks. For one patient in cohort 1, total GAGs rose slightly, and for the other patient total GAGs declined slightly. For Cohort 2 patients, total urinary GAGs, dermatan sulfate and heparan sulfate each declined below baseline for both patients. Exemplary MS/MS assay procedures are described in Example 4. Reductions in Cohort 2 in total GAGs, and in dermatan sulfate and heparan sulfate, the two GAGs most closely linked to MPS II, were observed. For dermatan sulfate, a mean reduction of approximately 31.8 for cohort 2, including an approximate 47.4% for the first patient and approximately 16.3% for the second patient, was observed.

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