NIH study in NEJM shows Novartis drug eltrombopag as

• NIH study found 58% of patients with treatment-naïve severe aplastic anemia (SAA) achieved a complete response when eltrombopag was given at the initiation of and concurrently with standard immunosuppressive therapy[1]  
• The historical complete response rate was 10% for untreated patients with SAA on immunosuppressive therapy alone[1]   
• Findings were published in The New England Journal of Medicine (NEJM) and will be submitted to regulatory bodies for treatment-naïve SAA

Basel, April 19, 2017 - Novartis today announced the publication of a study conducted by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) demonstrating that 58% of patients with treatment-naïve severe aplastic anemia (SAA) achieved complete response at six months when treated with eltrombopag at the initiation of and concurrently with standard immunosuppressive treatment[1]. The study evaluated three sequential treatment groups, or cohorts. Cohort 3 added eltrombopag at the initiation of immunosuppressive therapy and showed a higher complete response rate than cohorts 1 and 2, where eltrombopag was initiated on day 14. The data is published in the latest issue of The New England Journal of Medicine .

SAA is a rare and serious blood disorder in which a patient's bone marrow fails to make enough red blood cells, white blood cells and platelets[2]. As a result, people living with SAA may experience debilitating symptoms and complications, such as fatigue, trouble breathing, recurring infections and abnormal bruising or bleeding that can limit their daily activities[2]. The current standard of care includes immunosuppressive therapy (IST) or hematopoietic stem cell transplantation. However, one-quarter to one-third of patients will not respond to IST and 30-40% of responders will relapse, causing symptoms to return[3].

"Our research in NEJM shows that eltrombopag plus standard immunosuppressive therapy appeared to increase the overall response rate and substantially increase the frequency, speed and robustness of hematologic recovery in patients with SAA compared to historical controls," said the study's lead author, Danielle Townsley, MD, researcher in the NHLBI.

In the NIH study, the primary efficacy endpoint of complete response rate with eltrombopag plus standard immunosuppressive treatment at six months exceeded the historic rate (10%) across all three treatment cohorts (cohorts differed in length of eltrombopag administration; dose adjusted by age)[1]. Patients in cohort 1 received eltrombopag from day 14 to six months and achieved a complete response rate of 33%. The complete response was lowest in cohort 2 (26%), in which eltrombopag exposure was shortest (day 14 to three months). Furthermore, overall increases in platelet and neutrophil blood level counts were higher in comparison to the historic cohort, which is a key treatment goal for SAA[1],[4]. The overall survival rate at a median follow-up of two years was 97% (95% CI, 94-100%) for all cohorts[1].

"We are committed to improving the care of people living with serious conditions over the long term, particularly those with few options and great unmet need," said Vasant Narasimhan, Global Head, Drug Development and Chief Medical Officer, Novartis. "Eltrombopag is the  only thrombopoietin receptor agonist to be used in the second-line treatment of SAA, and these results from the NIH study now show its potential as a first-line treatment, which we look forward to discussing with health authorities."

The study also looked at clonal evolution, which is a major complication of SAA (with potential for development of myelodysplastic syndrome and acute myeloid leukemia)[1]. As of May 25, 2016, the addition of eltrombopag did not increase the rate of clonal evolution and was not higher compared to historical data[1],[5],[6],[7] . Clonal cytogenetic evolution occurred in 7 patients at 2 years (95% CI, 1-14%)[1].

The safety profile was consistent with the known safety profile of eltrombopag. Eltrombopag was briefly discontinued during the first two weeks in 7 patients who experienced transient liver enzyme elevations. Two severe adverse events, grade 2-3 cutaneous eruptions, were attributed to eltrombopag and required discontinuation of the drug. Adverse events not attributed to eltrombopag were due to neutropenic infections and known toxicities from immunosuppressive therapy[7]. One death occurred on study in a non-responding patient with thymoma three months following treatment, due to paraneoplastic encephalopathy[1].

NIH Study Design The Phase I-II, non-randomized study is being conducted by the National Heart, Lung and Blood Institute through a Cooperative Research and Development Agreement (CRADA) with Novartis Pharmaceuticals Corporation. The primary analysis included 92 patients with treatment-naïve severe aplastic anemia in three treatment cohorts, and nearly 80% of patients were over the age of 18. Eltrombopag was administered at 150 mg daily for patients 12 years or older, 75 mg daily for those 6 to 11 years, and 2.5 mg/kg/day for children 2 to 5 years. Duration of treatment with eltrombopag varied per cohort (cohort 1: day 14 to six months; cohort 2: day 14 to three months; cohort 3: day one to six months). ATG and cyclosporine were administered as standard immunosuppression therapy[1].

The study's primary efficacy endpoint was hematologic complete response at six months defined by absolute neutrophil count >=1,000/Mu l, hemoglobin >=10 gm/dL, and platelets >=100,000/Mu l. Secondary endpoints included partial and overall hematologic responses at three months, six months, and yearly; survival; self-reported health outcomes; relapse, paroxysmal nocturnal hemoglobinuria (PNH) and clonal evolution as defined by a new clonal cytogenetic abnormality or characteristic dysplastic or leukemic changes in marrow consistent with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML)[1].

About Eltrombopag Eltrombopag, marketed as Promacta ^® in the US and Revolade ^® in countries outside the US, is approved in more than 100 countries worldwide for the treatment of thrombocytopenia in adult patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an inadequate response or are intolerant to other treatments, in over 45 countries worldwide for the treatment of patients with severe aplastic anemia (SAA) who are refractory to other treatments, and in more than 50 countries for the treatment of thrombocytopenia in patients with chronic hepatitis C to allow them to initiate and maintain interferon-based therapy. Eltrombopag is approved in the United States and in the European Union for the treatment of thrombocytopenia in pediatric patients 1 year and older with chronic immune (idiopathic) thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy.

Important Safety Information for Revolade ^®  (eltrombopag) Revolade may cause serious side effects, such as liver problems, high platelet counts and a higher chance for blood clots, bleeding after stopping treatment, and bone marrow problems.   Revolade may damage the liver and cause serious, even life threatening, illness. Blood tests to check the liver are needed before taking Revolade and during treatment. When certain antiviral treatments are given together with Revolade for the treatment of thrombocytopenia due to hepatitis C virus (HCV) infections, some liver problems can get worse.

A doctor will order the blood tests and any other tests required. In some cases, Revolade treatment may need to be stopped. Patients should tell a doctor right away if they have any of these signs and symptoms of liver problems: yellowing of the skin or the whites of the eyes (jaundice), unusual darkening of the urine, unusual tiredness, right upper stomach area pain.

Patients have a higher chance of getting a blood clot if their platelet count is too high during treatment with Revolade, but blood clots can occur with normal or even low platelet counts. Patients who have cirrhosis of the liver are at risk of a blood clot in a blood vessel that feeds the liver. Patients may have severe complications from some forms of blood clots, such as clots that travel to the lungs or that cause heart attacks or strokes. A doctor will check the patient's blood platelet counts, and change the dose or stop Revolade if platelet counts get too high. Patients should tell their doctor right away if they have signs and symptoms of a blood clot in the leg, such as swelling or pain/tenderness of one leg.

When patients with chronic ITP stop taking Revolade, their blood platelet count will drop back down to what it was before they started taking Revolade. These effects are most likely to happen within 4 weeks after patients stop taking Revolade. The lower platelet counts may increase risk of bleeding. A doctor will check platelet counts for at least 4 weeks after patients stop taking Revolade. Patients should tell their doctor or pharmacist if they have any bruising or bleeding after they stop taking Revolade.

Patients being treated for the disease may have problems with their bone marrow. Medicines like Revolade could make this problem worse. Signs of bone marrow changes may show up as abnormal results in blood tests. A doctor may also carry out tests to directly check the bone marrow during treatment with Revolade.

The most common side effects of Revolade when used to treat adult patients with chronic ITP include headache, anemia, decreased appetite, insomnia, cough, nausea, diarrhea, alopecia, pruritus, myalgia, pyrexia, fatigue, influenza-like illness, asthenia, chills and peripheral edema.

The most common side effects of Revolade when used to treat pediatric patients with chronic ITP include upper respiratory tract infection, nasopharyngitis, cough, diarrhea, pyrexia, rhinitis, abdominal pain, oropharyngeal pain, toothache, rash, increased AST and rhinorrhea.

The most common side effects of Revolade when used to treat patients with chronic HCV and antiviral agents include headache, anemia, decreased appetite, insomnia, cough, nausea, diarrhea, alopecia, pruritus, myalgia, pyrexia, fatigue, influenza-like illness, asthenia, chills and peripheral edema.

The most common side effects of Revolade when used to treat patients with severe aplastic anemia (SAA) include headache, dizziness, insomnia, cough, dyspnea, oropharyngeal pain, rhinorrhea, nausea, diarrhea, abdominal pain, transaminases increased, ecchymosis, arthralgia, muscle spasms, pain in extremity, fatigue, febrile neutropenia, and pyrexia. Common side effects that may show up in blood tests include increase in some liver enzymes and laboratory tests that may show abnormal changes to the cells in the bone marrow.

Please see full EU Summary of Product Characteristics for Revolade (eltrombopag).

Disclaimer The foregoing release contains forward-looking statements that can be identified by words such as "will," "committed," "over the long term," "potential," "look forward," or similar terms, or by express or implied discussions regarding potential new indications or labeling for eltrombopag, or regarding potential future revenues from eltrombopag. You should not place undue reliance on these statements. Such forward-looking statements are based on the current beliefs and expectations of management regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that eltrombopag will be submitted or approved for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that eltrombopag will be commercially successful in the future. In particular, management's expectations regarding eltrombopag could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; the company's ability to obtain or maintain proprietary intellectual property protection; general economic and industry conditions; global trends toward health care cost containment, including ongoing pricing pressures; safety, quality or manufacturing issues, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.   About Novartis Novartis provides innovative healthcare solutions that address the evolving needs of patients and societies. Headquartered in Basel, Switzerland, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving generic and biosimilar pharmaceuticals and eye care. Novartis has leading positions globally in each of these areas. In 2016, the Group achieved net sales of USD 48.5 billion, while R&D throughout the Group amounted to approximately USD 9.0 billion. Novartis Group companies employ approximately 118,000 full-time-equivalent associates. Novartis products are sold in approximately 155 countries around the world. For more information, please visit http://www.novartis.com .

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References [1] Townsley, D et al. Eltrombopag added to standard immunosuppression for aplastic anemia. The New England Journal of Medicine . 2017;376(16):1540-1550. [2] Aplastic Anemia. U.S. National Institutes of Health website. U.S. National Institutes of Health. Web. 16 Feb 2017. [3] Townsley DM, Desmond R, Dunbar CE, et al. Pathophysiology and management of thrombocytopenia in bone marrow failure: possible clinical applications of TPO receptor agonists in aplastic anemia and myelodysplastic syndromes. Int J Hematology . 2013;98(1):48-55. [4] Your Guide to Understanding Aplastic Anemia. Aplastic Anemia & MDS International Foundation. Web. 17 Feb 2017. [5] Kulasekararaj AG et al. Somatic mutations identify a subgroup of aplastic anemia patients who progress to myelodysplastic syndrome. Blood . 2014. 124:2698-2704. [6] Scheinberg P, Young NS. How I treat acquired aplastic anemia. Blood. 2012;120:1185-96. [7] Townsley, D et al. Myeloid neoplasm gene somatic mutations in patients with severe aplastic anemia treated with eltrombopag and standard immunosuppression. Blood.  2016;128:727.

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