Cambridge, Ma. – December 19, 2017 – Shire plc (LSE: SHP, NASDAQ: SHPG), the global leader in rare diseases, today announced top-line results from its Phase II/III clinical trial evaluating SHP609, previously known as HGT-2310. SHP609 is an investigational formulation of idursulfase administered intrathecally for a new potential indication for the treatment of pediatric patients with Hunter syndrome (mucopolysaccharidosis II or MPS II) and cognitive impairment.
The study did not meet either its primary or its key secondary endpoint. The primary endpoint evaluated the difference in cognition between the SHP609-treated and control groups, as measured by change from baseline in General Conceptual Ability (GCA) scores in children with Hunter syndrome after 12 months of treatment. The key secondary endpoint evaluated the difference between the SHP609-treated and control groups as measured by the change from baseline in Adaptive Behavior Composite (ABC) score.
“Shire is disappointed that the top-line data from this study did not meet the primary and key secondary endpoints and remains committed to patients and families living with MPS II,” said Howard Mayer, M.D., Senior Vice President and Global Head of R&D (ad-interim), Shire. “We are grateful to the children, their families and healthcare providers for participating in this challenging trial and will continue our ongoing dialogue with the community as we conduct an analysis of the full data set. Further analysis of the data will be presented at forthcoming congresses.”
“Hunter syndrome is a severely debilitating rare genetic disorder caused by an enzyme deficiency which typically presents in early childhood,” said Joseph Muenzer, M.D., Ph.D., Professor of Pediatric Genetics and Metabolism Genetics, University of North Carolina Chapel Hill School of Medicine. “Two out of three patients exhibit progressive cognitive decline which is a high unmet need. This can be devastating for patients and their families as it severely diminishes a child's functional ability and typically leads to death in the teenage years.”
ELAPRASE® (idursulfase) for intravenous use continues to be an important medication for patients with Hunter syndrome in its current indication. It remains approved in 70+ countries worldwide and is unaffected by these results.1,2,3
About Hunter Syndrome
Hunter syndrome affects 1 in 162,000 total live births, and almost exclusively males.4 It is a severely debilitating, rare lysosomal storage disorder (LSD) caused by a deficiency of iduronate-2-sulfatase, an enzyme that is needed to break down substances in the body called glycosaminoglycans (GAGs).5 Without this enzyme, GAGs can build up in and damage various organs, causing a range of disease-related signs and symptoms such as hearing loss, declined cardiac function, obstructive airway disease, enlargement of the liver and spleen and decreased range of motion and mobility. Physical manifestations may include distinct facial features, a large head and enlarged abdomen. In many cases the central nervous system may also be affected.5,6
Roughly two of every three patients with Hunter syndrome are also affected with progressive cognitive decline.7 SHP609 has been specifically developed to be directly administered via an injection into the cerebrospinal fluid as a means of delivering the drug to the central nervous system (intrathecal).7
About the Trial
SHP609 is an investigational formulation of idursulfase administered intrathecally for a new potential indication for the treatment of pediatric patients with Hunter syndrome (mucopolysaccharidosis II or MPS II) and cognitive impairment. SHP609 is being investigated and developed for use with Shire’s current treatment for Hunter syndrome, ELAPRASE (idursulfase) which is administered intravenously and does not cross the blood-brain barrier in clinically relevant amounts.7
The Phase II/III study is a controlled, randomized, open-label, multi-center, assessor-blinded study designed to evaluate the effect of monthly intrathecal administration of SHP609 for 12 months on clinical parameters of neurodevelopmental status in pediatric patients with Hunter syndrome and cognitive impairment.8 The trial had an enrollment of 48 patients with Hunter syndrome and cognitive impairment who continued to receive and tolerate therapy with intravenous idursulfase.8
In the Phase II/III study, cognition was assessed by the Differential Ability Scale, Second Edition (DAS-II). One of the key secondary endpoints measured adaptive ability based on the Vineland Adaptive Behavioral Scales, Second Edition (VABS-II).8 VABS-II assesses the development of personal and social skills, including talking, walking and motor skills, as well as interpersonal relationships and coping skills.9
The safety profile observed was generally consistent with that seen in previous studies.7,10 Idursulfase-IT has been well studied with up to 67 months of patient exposure data. Of 15 patients in the Phase I/II trial of SHP609, all had ≥1 Treatment-Emergent Adverse Events (TEAE) and all had ≥1 drug-related TEAE. Of 54 serious TEAE types, 2 were believed to be causally related to idursulfase-IT: pyrexia (71 events, 3.3%) and vomiting (63 events, 2.9%).10
For more information, visit https://clinicaltrials.gov/ct2/show/NCT02055118 or https://www.clinicaltrialsregister.eu/ctr-search/search?query=2013-002885-38.
SHP609 is an investigational formulation of idursulfase administered intrathecally for a new potential indication treatment of pediatric patients with Hunter syndrome (Mucopolysaccharidosis II or MPS II) and cognitive impairment.7
In clinical trials, SHP609 is administered to patients using an intrathecal drug delivery device.7 SHP609 is administered directly into the cerebrospinal fluid as a means of delivering the drug to the central nervous system.7
SHP609 has not been approved for use by the U.S. Food and Drug Administration, European Medicines Agency or other regulatory authorities.
About ELAPRASE (idursulfase)
ELAPRASE is an intravenous enzyme replacement therapy approved for the treatment of patients with Hunter syndrome in 70+ countries worldwide including countries in Africa, Asia Pacific, Europe, Latin America and North America.1
In the E.U., ELAPRASE▼ is indicated for the long-term treatment of patients with Hunter syndrome.2
▼This medicinal product is subject to additional monitoring in the E.U. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed here.
U.S. Indication and Usage
ELAPRASE (idursulfase) is indicated for patients with Hunter syndrome (mucopolysaccharidosis II or MPS II). ELAPRASE has been shown to improve walking capacity in patients 5 years and older.3
In patients 16 months to 5 years of age, no data are available to demonstrate improvement in disease-related symptoms or long-term clinical outcome; however, treatment with ELAPRASE has reduced spleen volume similarly to that of adults and children 5 years of age and older.
The safety and efficacy of ELAPRASE have not been established in pediatric patients less than 16 months of age.
U.S. Important Safety Information
WARNING: RISK OF ANAPHYLAXIS
Life-threatening anaphylactic reactions have occurred in some patients during and up to 24 hours after ELAPRASE infusions. Anaphylaxis, presenting as respiratory distress, hypoxia, hypotension, urticaria and/or angioedema of throat or tongue have been reported to occur during and after ELAPRASE infusions, regardless of duration of the course of treatment. Closely observe patients during and after ELAPRASE administration and be prepared to manage anaphylaxis. Inform patients of the signs and symptoms of anaphylaxis and have them seek immediate medical care should symptoms occur. Patients with compromised respiratory function or acute respiratory disease may be at risk of serious acute exacerbation of their respiratory compromise due to hypersensitivity reactions, and require additional monitoring.
- Hypersensitivity Reactions Including Anaphylaxis: Ensure that personnel administering product are adequately trained in cardiopulmonary resuscitative measures, and have ready access to emergency medical services (EMS).
If anaphylactic or other acute reactions occur, immediately discontinue the infusion of ELAPRASE and initiate appropriate medical treatment. Observe patients closely for an appropriate period of time after administration of ELAPRASE, taking into account the time to onset of anaphylaxis seen in premarketing clinical trials and postmarketing reports. Inform patients of the signs and symptoms of anaphylaxis, and instruct them to seek immediate medical care should signs and symptoms occur. When severe reactions have occurred during clinical trials, subsequent infusions were managed with antihistamine and/or corticosteroids prior to or during infusions, a slower rate of ELAPRASE infusion, and/or early discontinuation of the ELAPRASE infusion.
- Risk of Hypersensitivity, Serious Adverse Reactions, and Antibody Development in Hunter Syndrome Patients with Severe Genetic Mutations: Hunter syndrome patients aged 7 years and younger with complete gene deletion, large gene rearrangement, nonsense, frameshift or splice site mutations experienced a higher incidence of hypersensitivity reactions, serious adverse reactions and anti-idursulfase antibody development.
- Risk of Acute Respiratory Complications: Patients with compromised respiratory function or acute febrile or respiratory illness may be at higher risk of life-threatening complications from hypersensitivity reactions. Careful consideration should be given to the patient’s clinical status prior to administration of ELAPRASE and consider delaying the ELAPRASE infusion.
- Risk of Acute Cardiorespiratory Failure: Caution should be exercised when administering ELAPRASE to patients susceptible to fluid overload, or patients with acute underlying respiratory illness or compromised cardiac and/or respiratory function for whom fluid restriction is indicated. These patients may be at risk of serious exacerbation of their cardiac or respiratory status during infusions. Appropriate medical support and monitoring measures should be readily available during ELAPRASE infusion, and some patients may require prolonged observation times that should be based on the individual needs of the patient.
- Adverse Reactions: In clinical trials, the most frequent serious adverse reactions following ELAPRASE treatment were hypoxic episodes. Other notable serious adverse reactions that occurred in the ELAPRASE treated patients but not in the placebo treated patients included one case each of: cardiac arrhythmia, pulmonary embolism, cyanosis, respiratory failure, infection, and arthralgia.
The most common adverse reactions occurring in at least three patients (≥9%) aged five years and older were headache, pruritus, musculoskeletal pain, urticaria, diarrhea, and cough. The most common adverse reactions occurring in at least three patients (≥10%) aged seven years and younger were pyrexia, rash, vomiting, and urticaria. In all clinical trials, the most common adverse reactions requiring medical intervention were hypersensitivity reactions, and included rash, urticaria, pruritus, flushing, pyrexia, and headache.
- Immunogenicity: In clinical trials in patients 5 years and older, 32 of 63 (51%) patients tested positive for anti-idursulfase IgG antibodies (Ab) at least one time. Of the 32 Ab-positive patients, 23 of 32 (72%) tested positive for Ab at three or more different time points (persistent Ab). The incidence of hypersensitivity reactions was higher in patients who tested positive for Ab than those who tested negative.
Thirteen of 32 (41%) Ab-positive patients also tested positive for antibodies that neutralize idursulfase uptake into cells (neutralizing antibodies, NAb) or enzymatic activity at least one time, and 8 (25%) of Ab-positive patients had persistent NAb. There was no clear relationship between the presence of either Ab or NAb and therapeutic response.
In the clinical trial in patients 7 years and younger, 19 of 28 (68%) patients treated with ELAPRASE 0.5 mg/kg once weekly tested Ab-positive, with 16 of 19 (84%) having persistent Ab. In addition, 15 of 19 (79%) Ab-positive patients tested positive for NAb, with 14 of 15 (93%) having persistent NAb.
- Postmarketing Experience: Late-emergent symptoms and signs of anaphylactic reactions have occurred up to 24 hours after initial treatment and recovery from an initial anaphylactic reaction. In addition, patients experienced repeated anaphylaxis over a two to four month period, up to several years after initiating ELAPRASE treatment.
Serious adverse reactions that resulted in death included cardiorespiratory arrest, respiratory failure, respiratory distress, cardiac failure, and pneumonia.
Please click here for Full US Prescribing Information, including Boxed Warning.
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NOTES TO EDITOR
Shire is the global leader in serving patients with rare diseases. We strive to develop best-in-class therapies across a core of rare disease areas including hematology, immunology, genetic diseases, neuroscience, and internal medicine with growing therapeutic areas in ophthalmics and oncology. Our diversified capabilities enable us to reach patients in more than 100 countries who are struggling to live their lives to the fullest.
We feel a strong sense of urgency to address unmet medical needs and work tirelessly to improve people’s lives with medicines that have a meaningful impact on patients and all who support them on their journey.
Statements included herein that are not historical facts, including without limitation statements concerning future strategy, plans, objectives, expectations and intentions, the anticipated timing of clinical trials and approvals for, and the commercial potential of, inline or pipeline products, are forward-looking statements. Such forward-looking statements involve a number of risks and uncertainties and are subject to change at any time. In the event such risks or uncertainties materialize, Shire’s results could be materially adversely affected. The risks and uncertainties include, but are not limited to, the following:
- Shire’s products may not be a commercial success;
- increased pricing pressures and limits on patient access as a result of governmental regulations and market developments may affect Shire’s future revenues, financial condition and results of operations;
- Shire conducts its own manufacturing operations for certain of its products and is reliant on third party contract manufacturers to manufacture other products and to provide goods and services. Some of Shire’s products or ingredients are only available from a single approved source for manufacture. Any disruption to the supply chain for any of Shire’s products may result in Shire being unable to continue marketing or developing a product or may result in Shire being unable to do so on a commercially viable basis for some period of time;
- the manufacture of Shire’s products is subject to extensive oversight by various regulatory agencies. Regulatory approvals or interventions associated with changes to manufacturing sites, ingredients or manufacturing processes could lead to, among other things, significant delays, an increase in operating costs, lost product sales, an interruption of research activities or the delay of new product launches;
- certain of Shire’s therapies involve lengthy and complex processes, which may prevent Shire from timely responding to market forces and effectively managing its production capacity;
- Shire has a portfolio of products in various stages of research and development. The successful development of these products is highly uncertain and requires significant expenditures and time, and there is no guarantee that these products will receive regulatory approval;
- the actions of certain customers could affect Shire’s ability to sell or market products profitably. Fluctuations in buying or distribution patterns by such customers can adversely affect Shire’s revenues, financial conditions or results of operations;
- Shire’s products and product candidates face substantial competition in the product markets in which it operates, including competition from generics;
- adverse outcomes in legal matters, tax audits and other disputes, including Shire’s ability to enforce and defend patents and other intellectual property rights required for its business, could have a material adverse effect on the Company’s revenues, financial condition or results of operations;
- inability to successfully compete for highly qualified personnel from other companies and organizations;
- failure to achieve the strategic objectives, including expected operating efficiencies, cost savings, revenue enhancements, synergies or other benefits at the time anticipated or at all with respect to Shire’s acquisitions, including NPS Pharmaceuticals Inc., Dyax Corp. or Baxalta Incorporated may adversely affect Shire’s financial condition and results of operations;
- Shire’s growth strategy depends in part upon its ability to expand its product portfolio through external collaborations, which, if unsuccessful, may adversely affect the development and sale of its products;
- a slowdown of global economic growth, or economic instability of countries in which Shire does business, as well as changes in foreign currency exchange rates and interest rates, that adversely impact the availability and cost of credit and customer purchasing and payment patterns, including the collectability of customer accounts receivable;
- failure of a marketed product to work effectively or if such a product is the cause of adverse side effects could result in damage to Shire’s reputation, the withdrawal of the product and legal action against Shire;
- investigations or enforcement action by regulatory authorities or law enforcement agencies relating to Shire’s activities in the highly regulated markets in which it operates may result in significant legal costs and the payment of substantial compensation or fines;
- Shire is dependent on information technology and its systems and infrastructure face certain risks, including from service disruptions, the loss of sensitive or confidential information, cyber-attacks and other security breaches or data leakages that could have a material adverse effect on Shire’s revenues, financial condition or results of operations;
- Shire incurred substantial additional indebtedness to finance the Baxalta acquisition, which has increased its borrowing costs may decrease its business flexibility; and
a further list and description of risks, uncertainties and other matters can be found in Shire’s most recent Annual Report on Form 10-K and in Shire’s subsequent Quarterly Reports on Form 10-Q, in each case including those risks outlined in “ITEM 1A: Risk Factors”, and in Shire’s subsequent reports on Form 8-K and other Securities and Exchange Commission filings, all of which are available on Shire’s website.
All forward-looking statements attributable to us or any person acting on our behalf are expressly qualified in their entirety by this cautionary statement. Readers are cautioned not to place undue reliance on these forward-looking statements that speak only as of the date hereof. Except to the extent otherwise required by applicable law, we do not undertake any obligation to update or revise forward-looking statements, whether as a result of new information, future events or otherwise.
1 Elaprase. R&D DoF ID: DOF-RDX006A-007. Shire. SME-Medical Communications. August 2017.
2 ELAPRASE Summary of Product Characteristics. European Medicines Agency. Last updated October 2016. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000700/human_med_000757.jsp&mid=WC0b01ac058001d124A.
3 ELAPRASE U.S. PRESCRIBING INFORMATION. United States Food and Drug Administration. Last updated June 2013. Available at http://pi.shirecontent.com/PI/PDFs/Elaprase_USA_ENG.pdf
4 Meikle PJ et al. Prevalence of Lysosomal Storage Disorders. JAMA. 1999. 281(3):249-54.
5 Wraith JE et al. Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy. Eur J Pediatr. 2008. 167(3):267-77.
6 Wraith JE. Idursulfase for enzyme-replacement therapy in mucopolysaccharidosis II. Therapy. 2007. 4(3):231-240.
7 Muenzer J et al. A phase I/II study of intrathecal idursulfase IT in children with severe mucopolysaccharidosis II. Genet Med. 2016. 18(1):73-81.
8 Study of Intrathecal Idursulfase-IT Administered in Conjunction With Elaprase in Pediatric Patients With Hunter Syndrome and Early Cognitive Impairment. ClinicalTrials.gov. Available at: https://clinicaltrials.gov/ct2/show/study/NCT02055118. Accessed December 2017.
9 Sparrow S. Vineland Adaptive Behavior Scales. (Technical Manual)second ed. Pearson, Bloomington, MN; http://www.pearsonclinical.com/psychology/products/100000668/vineland-adaptive-behavior-scales-second-edition-vineland-ii-vineland-ii.html#tab-details. Accessed December 2017.
10 Muenzer J et al. A Long-term Extension Study Evaluating Intrathecal Idursulfase-IT in Children with Hunter Syndrome and Cognitive Impairment. Presented at the 13th Annual WORLDSymposium, February 13-17, 2017, San Diego, CA.