• Mulpleo (lusutrombopag) is the first licensed treatment to be made available through the National Health Service (NHS) in England, Wales and Scotland to treat severe thrombocytopenia in adults with chronic liver disease (CLD) who are undergoing invasive procedures^1,2,3

• Thrombocytopenia is the most common blood-related complication of CLD, and severe thrombocytopenia can prevent or lead to delays in crucial interventions, so new and effective treatments are urgently needed ^4,5,6,7

• Oral treatments like lusutrombopag would result in several benefits for patients, including fewer transfusions, fewer hospital stays, a decreased chance of transfusion-related complications and a longer treatment window in which to do planned invasive procedures ²

• The positive recommendations from NICE and the SMC are principally based on data from two pivotal Phase III randomised clinical trials, L-PLUS 1⁸ and L-PLUS 2⁹, in which lusutrombopag met the primary endpoints of superiority to placebo in reducing the need for platelet transfusions in thrombocytopenic patients with chronic liver disease undergoing invasive procedures by raising platelet counts above recommended treatment guidelines¹⁰ of 50,000/µL for an average of 20.9¹¹ days

OSAKA, Japan & AMSTERDAM, Netherlands–(BUSINESS WIRE)–FOR MEDICAL AND PHARMACEUTICAL TRADE MEDIA ONLY

Shionogi & Co., Ltd. and its European subsidiary, Shionogi B.V. (hereafter “Shionogi”), today announce that the National Institute for Health and Care Excellence (NICE) and Scottish Medicines Consortium (SMC) have published positive appraisals recommending the use of Mulpleo^® (lusutrombopag) by the NHS in England, Wales and Scotland for the treatment of severe thrombocytopenia in adult patients with chronic liver disease (CLD) undergoing planned invasive procedures.^2,3

These two recommendations are based principally on evidence from L-PLUS 1⁸ and L-PLUS 2⁹, two multicentre, randomised, double-blind, parallel-group, placebo-controlled, phase III studies where 312 patients with CLD, severe thrombocytopenia with a platelet count of <50,000/µL and a scheduled invasive procedure received either lusutrombopag or placebo once daily for up to seven days. Lusutrombopag met the pre-specified primary endpoint and all key secondary endpoints with statistically significant results. In L-PLUS 1, 79.2% (38/48) of patients receiving lusutrombopag required no platelet transfusion prior to the primary invasive procedure, compared with 12.5% (6/48) receiving placebo (P< 0.0001).⁸ In L-PLUS 2, 64.8% (70/108) of patients who received lusutrombopag required no platelet transfusion prior to the primary invasive procedure or rescue therapy for bleeding within seven days post-procedure, compared to 29% (31/107) receiving placebo (P< 0.0001)^1,9. Across the two trials, platelet counts remained above 50,000/µL for a median of 20.9 days in patients treated with lusutrombopag not requiring platelet transfusion vs a median of 9.5 days in patients treated with placebo and requiring platelet transfusion.¹¹ The rate of adverse events observed in the trials, including that of thromboembolic events, was comparable between lusutrombopag and placebo. The most common adverse reactions were headache (4.7% in the lusutrombopag arm vs 3.5% in the placebo arm), nausea (2.3% vs 4.1%), portal vein thrombosis (1.2% vs 1.2%) and rash (1.2% vs 0%).¹

“Currently there are no available treatments for thrombocytopenia in patients with chronic liver disease besides supportive care and platelet transfusions. Thrombocytopenia is the most common haematological consequence of chronic liver disease and it can complicate or delay lifesaving invasive procedures,” commented Dr Yiannis Kallis, Consultant Hepatologist and Gastroenterologist at the Royal London Hospital (Barts Health NHS Trust) and the Royal Free Hospital London. “The NICE and SMC recommendations for lusutrombopag are fantastic news for both patients and clinicians as we urgently require new and effective treatments which will help enable these interventions to go ahead safely and on time.”

In the UK, over 600,000 people have a form of serious liver disease and 60,000 have cirrhosis.¹² Currently, the only option available to doctors and their patients to manage platelet counts is a transfusion of platelets. An estimated 3,300 patients with cirrhosis in the UK receive prophylactic platelet transfusions prior to a procedure every year.¹³ This is an invasive procedure itself, often requiring a hospital inpatient stay and careful scheduling of the subsequent planned procedure within the narrow therapeutic window provided by a platelet transfusion. Platelet transfusions also carry the general risks associated with the transfer of blood products between humans and may be particularly undesirable for some patients.

Pamela Healy, Chief Executive of the British Liver Trust, commented “Chronic liver disease is a huge burden in the UK; the number of deaths has increased by 400% since 1970 and it is now responsible for the highest number of premature deaths in 35-49 year olds. Many people with chronic liver disease require life-saving invasive procedures, so it is vital we have effective medicines to treat common complications such as severe thrombocytopenia (low platelet count), which can make operations too risky to undertake. Up until now, the only option for these patients has been a platelet transfusion, which often involves a hospital stay, so this new treatment which can be taken orally at home has the potential to really improve their quality of life”.

“We are delighted that both NICE and the SMC have recognised the value of lusutrombopag to treat severe thrombocytopenia in patients with chronic liver disease undergoing invasive procedures. It has demonstrated efficacy and tolerability in two pivotal phase III trials, consistently raising platelet counts and avoiding the need for platelet transfusions,” said Dr. Mark Hill, Shionogi Senior Vice President and Global Head of Market Access.

About Thrombocytopenia in Chronic Liver Disease

Thrombocytopenia is defined as a platelet count of less than 150,000/µL. CLD-associated thrombocytopenia may be caused by multiple factors including splenic sequestration and decreased production of TPO. It is the most common haematologic complication of CLD ^4,5,6,7 with studies suggesting that it occurs in up to 78% of patients with cirrhosis. Severe thrombocytopenia (platelet count of less than 50,000/µL) is less common, occurring in up to 11% of patients with cirrhosis.¹⁴ Patients with CLD and severe thrombocytopenia are at increased risk for bleeding, requiring recurrent platelet transfusions, increased ambulatory visits and inpatient hospital stays compared with patients with CLD without thrombocytopenia.¹⁵There is evidence that the annual health care cost of a CLD patient with thrombocytopenia is more than three times that of a CLD patient without thrombocytopenia.¹⁵ In addition to the potential of severe thrombocytopenia to increase surgical or traumatic bleeding, it may also significantly complicate routine diagnostic procedures and patient care, such as liver biopsy and other scheduled procedures for cirrhotic patients, resulting in delayed or cancelled interventions.¹⁶ Currently, platelet transfusion is the standard of care used to mitigate bleeding risks associated with severe thrombocytopenia prior to invasive procedures, but variable efficacy in patient with chronic liver disease and adverse reactions limit the use of platelet transfusions, resulting in a need for new therapies. ⁵

About Mulpleo (lusutrombopag)

Mulpleo (lusutrombopag) 3mg is a once-daily, orally administered, small molecule TPO receptor agonist that triggers the production of endogenous platelets by interacting with the transmembrane domain of human thrombopoietin (TPO) receptors expressed on megakaryocytes to induce the proliferation and differentiation of megakaryocytic progenitor cells from hematopoietic stem cells, and megakaryocyte maturation.

On February 18, 2019, Mulpleo received marketing authorisation by the EC for the treatment of severe thrombocytopenia in adult patients with CLD undergoing invasive procedures. Prior to this, lusutrombopag was approved by the Ministry of Health, Labour and Welfare in Japan in September 2015 for the improvement of thrombocytopenia associated with CLD in patients undergoing an elective invasive procedure, and by the U.S. Food and Drug Administration (FDA) on July 31, 2018 for the treatment of thrombocytopenia in adult patients with chronic liver disease (CLD) who are scheduled to undergo a procedure. It is currently available in Japan and the US, where it is marketed under the brand name Mulpleta^®.

About Shionogi

Shionogi & Co., Ltd. is a 141-year-old global, research driven pharmaceutical company headquartered in Osaka, Japan, that is dedicated to bringing benefits to patients based on its corporate philosophy of “supplying the best possible medicine to protect the health and wellbeing of the patients we serve.” The company currently markets products in several therapeutic areas including anti-infectives, pain, CNS disorders, cardiovascular diseases and gastroenterology. Shionogi’s research and development currently target two therapeutic areas: infectious diseases, and pain/CNS disorders. For more information on Shionogi& Co, Ltd., please visit http://www.shionogi.co.jp/en/.

Shionogi B.V. is the European headquarters of Shionogi & Co., Ltd. For more information on Shionogi B.V., please visit www.shionogi.eu.

Forward Looking Statement

This announcement contains forward-looking statements. These statements are based on expectations in light of the information currently available, assumptions that are subject to risks and uncertainties which could cause actual results to differ materially from these statements. Risks and uncertainties include general domestic and international economic conditions such as general industry and market conditions, and changes of interest rate and currency exchange rate. These risks and uncertainties particularly apply with respect to product-related forward-looking statements. Product risks and uncertainties include, but are not limited to, completion and discontinuation of clinical trials; obtaining regulatory approvals; claims and concerns about product safety and efficacy; technological advances; adverse outcome of important litigation; domestic and foreign healthcare reforms and changes of laws and regulations. Also for existing products, there are manufacturing and marketing risks, which include, but are not limited to, inability to build production capacity to meet demand, unavailability of raw materials and entry of competitive products. The company disclaims any intention or obligation to update or revise any forward-looking statements whether as a result of new information, future events or otherwise. The information set out in this Press Release is not intended for promotional or advertising purposes.

Mulpleo (lusutrombopag) Summary of Product Characteristics: https://www.ema.europa.eu/en/documents/product-information/mulpleo-previously-lusutrombopag-shionogi-epar-product-information_en.pdf

References:

1. Mulpleo (lusutrombopag) SmPC

2. NICE FAD. Available at:. https://www.nice.org.uk/guidance/gid-ta10444/documents/final-appraisal-determination-document. Last accessed December 2019

3. SMC medicines advice lusutrombopag (Mulpleo): Available at: https://www.scottishmedicines.org.uk/media/4939/lusutrombopag-mulpleo-final-november-2019-for-website.pdf Last accessed December 2019

4. Mitchell O, Feldman DM, Diakow M, Sigal SH. The pathophysiology of thrombocytopenia in chronic liver disease. Hepat Med. 2016;8:39–50. Published 2016 Apr 15. doi:10.2147/HMER.S74612

5. Giannini EG. Review article: thrombocytopenia in chronic liver disease and pharmacologic treatment options. Aliment Pharmacol Ther. 2006;23(8):1055-1065.

6. Peck-Radosavljevic, M. Thrombocytopenia in chronic liver disease. Liver International. 2017;37(6):778-793

7. Afdhal N et al. Thrombocytopenia associated with chronic liver disease. J. Hepatol 2008;48(6):1000-1007

8. Hidaka H, et al. Lusutrombopag Reduces Need for Platelet Transfusion in Patients With Thrombocytopenia Undergoing Invasive Procedures. Clin Gastroenterol Hepatol. 2019 May;17(6):1192-1200

9. Peck-Radosavljevic M, et al. Lusutrombopag for the treatment of thrombocytopenia in patients with chronic liver disease undergoing invasive procedures (L-PLUS 2) Hepatology 2019. Oct 70(4):1336-1348

10. NICE Guideline. Blood transfusion (NG24). Available at https://www.nice.org.uk/guidance/ng24/resources/blood-transfusion-pdf-1837331897029 Last accessed December 2019

11. Brown RS et al.: Lusutrombopag is a safe and efficacious treatment option for thrombocytopenia in subjects with chronic liver disease undergoing invasive procedures: a pooled analysis of two Phase 3 trials. P-2016, AASLD 2018

12. British Liver Trust. The alarming impact of liver disease in the UK. Available at: https://www.britishlivertrust.org.uk/wp-content/uploads/The-alarming-impact-of-liver-disease-FINAL-June-2019.pdf Last accessed November 2019

13. Shionogi, data on file

14. De Gottardi, A, Thevenot, T, Spahr, L, et al. Risk of complications after abdominal paracentesis in cirrhotic patients: a prospective study. Clin Gastroenterol Hepatol. 2009;7(8):906-909

15. Poordad F, Theodore D, Sullivan J, Grotzinger K. Evaluating medical resource utilization and costs associated with thrombocytopenia in chronic liver disease patients. J Med Econ. 2012;15(1):112-124.

16. Hayashi, H, Beppu, T, Shirabe, K, et al. Management of thrombocytopenia due to liver cirrhosis: a review. World journal of gastroenterology. 2014;20(10):2595-2605.

Job number: NP-UK-LUS-0055

Date of preparation: December 2019

Contacts

For further information or to arrange a spokesperson interview please contact:

Shionogi Europe

Dr. Mark Hill, Shionogi, mark.hill@shionogi.eu
Dr. Ulrike Forster, Shionogi, ulrike.forster@shionogi.eu
Shionogi & Co., Ltd.

Corporate Communications Department

Telephone: +81-6-6209-7885