CAMBRIDGE, Massachusetts, February 11 Shire plc(LSE: SHP, NASDAQ: SHPGY), the global specialty biopharmaceutical company,today presented positive results from its first Phase III study (TKT 032)evaluating safety and efficacy of velaglucerase alfa, its investigationalenzyme replacement therapy for the treatment of Type 1 Gaucher disease. Thedata were presented in an oral presentation at the Lysosomal Disease Network(LDN) World Symposium in Miami, Florida. Data from a pediatric subgroup ofthis study and five year follow-up results from a long-term Phase I/IIextension study (TKT025 EXT) conducted in adults were also reported and addto the available data on the long-term safety and efficacy of velaglucerasealfa in patients with Type 1 Gaucher disease.
Both studies (TKT032 and TKT025 EXT) met their primary end-points.
Additionally, Shire reported important findings from a study thatcompared patient antibody response to velaglucerase alfa and imiglucerase.All patients enrolled in the velaglucerase alfa Phase III clinical studiesunderwent a comprehensive panel of tests that were developed and validated toassess antibody response. In each study, samples were first screened using anelectrochemiluminescence (ECL) assay. Positive samples were confirmed using aquantitative radioimmunoprecipitation (RIP) assay. Positive cut-points wereestablished for the ECL assay as 5 ng/mL as well as in terms of fixed rawcounts, and for the RIP assay as 4 ng/mL. The results suggest significantantigenic differences between velaglucerase alfa and imiglucerase, with only1% seroconversion rates against velaglucerase alfa.
"The combined data presented today provides additional and compellingsupport for the long-term clinical efficacy and safety of velaglucerasealfa," said Pramod Mistry, MD, PhD, FRCP, Professor of Pediatrics & InternalMedicine at Yale University School of Medicine. "The Gaucher community isvery fortunate to have velaglucerase alfa as an option for patients."
Results from Study TKT032 in Adults and Children
TKT032 was a 12-month, randomized, double-blind, parallel-group globalstudy in 25 treatment-naive patients aged two years and older that evaluatedvelaglucerase alfa at 45 U/kg and velaglucerase alfa at 60 U/kg. Patientswere eligible to participate in the study if they presented withdisease-related anemia and had at least one of the following clinicalmanifestations of Gaucher disease: thrombocytopenia, moderate splenomegaly ora readily palpable enlarged liver.
The primary endpoint was change in hemoglobin concentrations frombaseline at 60 U/kg. Secondary endpoints for both doses were changes inplatelet counts, changes in organ volumes, changes in surrogate markers ofGaucher disease, and for the 45 U/kg dose only, change in hemoglobinconcentrations from baseline.
At 12 months, in the 60 U/kg group, statistically significant changes inmean hemoglobin concentration increased 23.3%, +2.43 +/- 0.32 g/dL, P<0.0001;mean platelet count increased 65.9%, +50.9 +/- 12.2x10(9)/L, P=0.0016; andmean spleen volume decreased 50%, -1.92 +/- 0.51% body weight, P=0.0032, from14.0 multiples of normal [MN] at baseline to 5.75 MN. Mean liver volumedecreased 17%, -0.84 +/- 0.33% body weight, P=0.0282, from 1.46 to 1.22 MN.
Results for 45 U/kg were consistent with those observed with 60 U/kg;however a dose-related effect in favor of velaglucerase alfa at 60 U/kg wasobserved by platelet count increase and liver volume reduction between the 2dose groups.
Adverse events reported by at least 20% of all patients includedheadache, nasopharyngitis, injury, arthralgia, cough, pyrexia, dizziness,influenza, nasal congestion, vomiting, bone pain, and activated partialthromboplastin time (aPTT) prolonged. No drug-related serious adverse eventswere reported. No patient withdrew from the study due to an adverse event.One patient developed antibodies to velaglucerase alfa.
A subpopulation analysis of study TKT032 was conducted to assess theefficacy and safety of velaglucerase alfa among children aged 2-17. Of 25patients in the trial, 7 pediatric patients (28%) were enrolled andrandomized to receive velaglucerase alfa at 60 U/kg (n=4) or 45 U/kg (n=3) asa 1-hour infusion, every other week for 12 months. In this analysis the twodose groups were pooled and results are shown as a percent change frombaseline.
Following 12 months treatment with with velaglucerase alfa the meanhemoglobin concentration increased 20%, mean platelet counts increased 54%,mean spleen volume, normalized by body weight, decreased 47% (median value5.0 multiples of normal (MN) decreased from 13.5 MN). Mean liver volumenormalized by body weight decreased 13% (median value 1.04 MN decreased from1.40 MN). Outcomes reported in children were consistent with those seen inthe overall population. Due to the small sample sizes, the results did notachieve statistical significance.
Most frequently reported adverse events in the pediatric subpopulationwere headache, nasopharyngitis, pyrexia, nasal congestion, productive cough,vomiting, and injury. No pediatric participants experienced severe or serioustreatment-emergent events. No pediatric patients developed antibodies tovelaglucerase alfa.
"We are very pleased with the opportunity to present the findings fromthe first of three Phase III studies for velaglucerase alfa," said WhaijenSoo, MD, PhD, Senior Vice President, Research and Development, Shire HumanGenetic Therapies (HGT). "Our program is the largest and most comprehensiveset of Phase III clinical trials conducted to date for Gaucher disease, andwe look forward to presenting the results from the remaining trials at futurescientific meetings."
Results from Five-Year Study
Ten of 11 adult patients who completed the Phase I/II study ofvelaglucerase alfa administered at 60 U/kg every other week, enrolled in along-term extension study. After month-12, all patients were eligible toreceive a step-wise dose reduction from 60 U/kg to 45 U/kg (13 weeks) andthen to a 30 U/kg maintenance dose upon the achievement of specifictherapeutic goals. All patients met therapeutic goals and their dose wassubsequently titrated down to the 30 U/kg dose. Seven of 10 patients receivedhome infusions during the extension period. Eight patients (4 male, 4 female)have now received velaglucerase alfa treatment for 60 months.
After 5 years, velaglucerase alfa continued to be generally welltolerated and demonstrated substantial and prolonged increases in hemoglobinconcentration and platelet count, and substantial and prolonged decreases inliver and spleen volumes in these patients with Type 1 Gaucher disease.
At 60 months, the mean increase in hemoglobin concentration from baselinewas +2.4 g/dL (95% CI: 1.6, 3.2; 21.3% change) and the mean increase inplatelet count from baseline was +85.1 x10(9)/L (95% CI: 59.8,110.4; 157%change). At 57 months, mean percent reduction in normalized liver volume frombaseline was 39% (95% CI: -49.1%,-28.5%) and mean percent reduction innormalized spleen volume from baseline was 74% (95% CI: -89.3%,-58.6%).
Velaglucerase alfa was found to be generally well tolerated in these 10patients with no drug-related serious adverse events reported.Treatment-emergent adverse events reported by at least 50% of patientsincluded arthralgia, back pain, pyrexia, upper abdominal pain,pharyngolaryngeal pain and headache. Most adverse events were of mild tomoderate severity. No patients withdrew from the trial due to an adverseevent. No patients in the 5 year extension study developed antibodies.
About velaglucerase alfa
Velaglucerase alfa is an investigational enzyme replacement therapy forType 1 Gaucher disease. Velaglucerase alfa is made using Shire'sgene-activation technology, in a human cell line. The enzyme produced has theexact human amino acid sequence and has a human glycosylation pattern.
The United States Food and Drug Administration (FDA) has granted PriorityReview for the New Drug Application (NDA) for velaglucerase alfa and hasissued an action date for the NDA for velaglucerase alfa of February 28, 2010under the Prescription Drug User Fee Act (PDUFA).
About Gaucher disease
Gaucher disease is an autosomal recessive disorder caused by mutations inthe GBA gene which results in a deficiency of the lysosomal enzymebeta-glucocerebrosidase. This enzymatic deficiency causes an accumulation ofglucocerebroside, primarily in macrophages. In this lysosomal storagedisorder (LSD), clinical features are reflective of the distribution ofGaucher cells in the liver, spleen, bone marrow, skeleton, and lungs. Theaccumulation of glucocerebrosidase in the liver and spleen leads toorganomegaly. Bone involvement results in skeletal abnormalities anddeformities as well as bone pain crises. Deposits in the bone marrow andsplenic sequestration lead to clinically significant anemia andthrombocytopenia.
Gaucher disease is the most prevalent LSD. Gaucher disease hasclassically been categorized into 3 clinical types. Type 1 is the mostcommon; it is distinguished from Type 2 and Type 3 by the lack ofneurological symptoms. Type 1 Gaucher disease is characterized by variabilityin signs, symptoms, severity, and progression.
Notes to editors
Shire's strategic goal is to become the leading specialtybiopharmaceutical company that focuses on meeting the needs of the specialistphysician. Shire focuses its business on attention deficit hyperactivitydisorder (ADHD), human genetic therapies (HGT) and gastrointestinal (GI)diseases as well as opportunities in other therapeutic areas to the extentthey arise through acquisitions. Shire's in-licensing, merger and acquisitionefforts are focused on products in specialist markets with strongintellectual property protection and global rights. Shire believes that acarefully selected and balanced portfolio of products with strategicallyaligned and relatively small-scale sales forces will deliver strong results.
For further information on Shire, please visit the Company's website:http://www.shire.com.
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