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Adult and pediatric patients with Type 1 Gaucher disease were switchedfrom imiglucerase (15-60 U/kg every other week) to the same number of unitsof VPRIV in the Phase III switch study (40 patients) and the ongoing UStreatment protocol (>150 patients). In study TKT-034, no patients developedIgG antibodies to VPRIV, including 3 patients who tested positive foranti-imiglucerase antibodies at screening. In addition, hemoglobinconcentration, platelet counts, and liver and spleen volumes remained stableover the course of the one year study, demonstrating safety and maintenanceof efficacy over this time frame. One patient in the Phase III trialdiscontinued due to a serious hypersensitivity reaction and the most commonside effects reported in the two studies were infusion-related reactions.
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"Results from the Phase III study provide important information regardingthe safety and sustained efficacy of VPRIV for patients with Type 1 Gaucherdisease who were previously on imiglucerase and should help inform treatmentdecisions during and after the imiglucerase supply shortage," said Dr.Gregory Grabowski, Director of the Division of Human Genetics, CincinnatiChildren's Hospital Medical Center and Principal Investigator of the 034study. "These data confirm what many physicians have experienced."
A post hoc analysis from a third study, TKT-025EXT, designed to examineattainment of long-term therapeutic goals in 8 patients with Type 1 Gaucherdisease treated with velaglucerase alfa, was also presented at the meeting.The initial dose of 60 U/kg was lowered to 30 U/kg after patients achieved atleast 2 of 4 predefined therapeutic goals following 1 year of treatment.Clinically meaningful achievement of long-term therapeutic goals forhemoglobin concentration, platelet counts, and liver and spleen volumes wasobserved within 4 years of initiation of treatment.
Shire also reported important findings that suggested substantialantigenic differences when antibody response to treatment with VPRIV andimiglucerase were compared. Among the 99 patients who enrolled in the PhaseIII studies the seroconversion rate was 1% (1 of 82) against VPRIV versus 23%(4 of 17) against imiglucerase.
Velaglucerase alfa is manufactured in Shire's facility in Cambridge MA,which was inspected and approved by the FDA for the commercial production ofVPRIV.
Study Results and Design for TKT-034, HGT-GBC-058 and TKT-025EXT
TKT-034
In this global, open-label, multicenter study, patients were enrolled inthe US (11 sites), Europe (3 sites) and Israel (1 site), and of the 41patients enrolled, 40 received study drug. One patient discontinued due to aserious hypersensitivity reaction and one patient discontinued at week 31 dueto a perceived lack of improvement. At the time of discontinuation, thispatient's clinical parameters were stable and consistent with those of theentire group of patients in the study.
Hemoglobin concentration, platelet counts, and spleen and liver volumewere sustained at therapeutic levels through one year of treatment withVPRIV, as demonstrated by pre-specified efficacy criteria for clinicallysignificant change:
Study design
The primary objective of TKT-034 was to evaluate the safety of VPRIV inpatients with Type 1 Gaucher disease who transitioned from imiglucerase toVPRIV. The secondary objectives were to evaluate changes from baseline inhemoglobin concentration, platelet counts, and spleen and liver volumes byMagnetic Resource Imaging (MRI) after every other week dosing of VPRIV.
Patients over the age of two years and receiving imiglucerase at a dosebetween 15 and 60 U/kg every other week for at least 30 months with no dosechange in the last 6 months were eligible, provided they had demonstratedstable hemoglobin concentration and platelet counts. Patients were infused inone hour with the same number of units of VPRIV as their prior imiglucerasedose.
HGT-GCB-058
This ongoing multicenter, open-label treatment protocol was initiated atthe request of the Food and Drug Administration (FDA) to provide VPRIV topatients who otherwise have limited or no access to imiglucerase due to acontinuing supply shortage.
Between September 1, 2009 and January 31, 2010, more than 150 patients inthe US enrolled into HGT-GCB-058 and received at least one infusion of VPRIV.Of these, 3 were treatment naive and the rest were previously treated withimiglucerase. Following the administration of the first three infusions ofVPRIV at the clinical site, patients who experienced no treatment-relatedserious adverse events or infusion-related adverse events were eligible totransition to home therapy at the discretion of the investigator. Patientswere required to return to the clinic site quarterly for observation.
An interim safety analysis of the more than 150 patients on the treatmentprotocol was conducted. Among those patients previously treated withimiglucerase, a total of 18% experienced a treatment emergent adverse eventthat was possibly or probably related to the study drug. The most commonlyobserved treatment emergent adverse events among switch patients included atleast one infusion-related reaction, nasopharyngitis, nausea, fatigue,headache, dizziness and influenza. Approximately 1% of patients experienced asevere adverse event that was considered to be possibly or probably relatedto the study drug.
TKT-025EXT: Study Results and Design of Therapeutic Goal Analysis
This post-hoc analysis of data from the Phase I/II and extension trial ofvelaglucerase alfa showed that clinically meaningful long-term therapeuticgoals were achieved within 4 years of initiation of velaglucerase alfatreatment.
The efficacy parameters were evaluated against the therapeutic goalsdescribed by Pastores et al (Seminars in Hematology, 2004) aand includedabsolute and percent changes in hemoglobin levels, platelet counts, andspleen and liver volumes as measured by MRI. Evaluation in this study waslimited to those patients who were exposed to velaglucerase alfa for aminimum of 48 months and for whom a complete clinical data set correspondingto the study endoints was available at baseline and annually through 48months (8 patients, 4 male, 4 female). Patients were evaluated for theachievement of each individual therapeutic goal. The percentage of patientsachieving each specific goal over time was determined. In addition thepercentage of patients with a complete response (achieved all 4 therapeuticgoals) over time was also evaluated.
At baseline, no patient was at goal for all 4 clinical parameters: 4 of 8patients were at goal for hemoglobin concentration, 0 of 8 for plateletcount, 4 of 8 for liver volume, and 0 of 8 for spleen volume. After 1 year oftreatment, all patients achieved at least 2 therapeutic goals, and allpatients maintained clinical parameters for goals that were already at therecommended targets when treatment began. All 8 patients were eligible forand began step-wise dose reduction to velaglucerase alfa 30 U/kg EOW startingbetween 12 and 18 months. By year 4 of treatment, all patients met goals forall 4 clinical parameters; therefore, 100% achievement was observed for eachof the 4 long-term, therapeutic goals.
More about VPRIV
VPRIV (velaglucerase alfa for injection) was approved by the US FDA as along-term enzyme replacement therapy for adult and pediatric patients withType 1 Gaucher disease on February 26, 2010. A marketing application forVPRIV has also been granted accelerated assessment by the European MedicinesAgency in the European Union (EU). Shire expects to launch VPRIV in the EU bythe end of 2010 and in other countries beginning in 2011.
VPRIV is for patients who are treatment naive as well as patients whohave been treated with imiglucerase. The most serious adverse reactions seenwith VPRIV were hypersensitivity reactions. Infusion-related reactions werethe most commonly observed adverse reactions in patients treated with VPRIVin clinical studies. The most commonly observed symptoms of infusion-relatedreactions were: headache, dizziness, low or high blood pressure, nausea,tiredness and weakness, and fever. Generally the infusion-related reactionswere mild and, in treatment-naive patients, onset occurred mostly during thefirst 6 months of treatment and tended to occur less frequently with time.Adverse reactions more commonly seen in pediatric patients compared to thoseobserved in adult patients (>10% difference) include rash, upper respiratorytract infection, prolonged activated partial thromboplastin time, and fever.
As with all therapeutic proteins, there is a potential forimmunogenicity. In the clinical studies 1 of 54 treatment-naive patientstreated with VPRIV developed IgG class antibodies. It is unknown if thepresence of IgG antibodies to VPRIV is associated with a higher risk ofinfusion reactions.
Full prescribing information for VPRIV can be found athttp://www.VPRIV.com.
Notes to editors
SHIRE PLC
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.
"SAFE HARBOR" STATEMENT UNDER THE PRIVATE SECURITIES LITIGATION REFORMACT OF 1995
Statements included herein that are not historical facts areforward-looking statements. Such forward-looking statements involve a numberof risks and uncertainties and are subject to change at any time. In theevent such risks or uncertainties materialize, the Company's results could bematerially adversely affected. The risks and uncertainties include, but arenot limited to, risks associated with: the inherent uncertainty of research,development, approval, reimbursement, manufacturing and commercialization ofthe Company's Specialty Pharmaceutical and Human Genetic Therapies products,as well as the ability to secure and integrate new products forcommercialization and/or development; government regulation of the Company'sproducts; the Company's ability to manufacture its products in sufficientquantities to meet demand; the impact of competitive therapies on theCompany's products; the Company's ability to register, maintain and enforcepatents and other intellectual property rights relating to its products; theCompany's ability to obtain and maintain government and other third-partyreimbursement for its products; and other risks and uncertainties detailedfrom time to time in the Company's filings with the Securities and ExchangeCommission.- Hemoglobin concentration: the mean change from baseline was -0.1 g/dL, with a 90 percent confidence interval of -0.3 to 0.1 g/dL, within the predefined efficacy criterion of plus or minus 1 g/dL. - Platelet counts: the percent change from baseline was +7.0%, with a 90 percent confidence interval of 0.5 to 13.5%, within the predefined efficacy criterion of plus or minus 20%. - Spleen volume: the percent change from baseline was -5.6%, with a 90 percent confidence interval of -10.8 to -0.4% within the predefined efficacy criterion of plus or minus 15%. - Liver volume: the percent change from baseline was -0.0%, with a 90 percent confidence interval of -2.6 to 2.6% within the predefined efficacy criterion of plus or minus 15%.
SOURCE Shire plc
