Novartis receives EU approval for new Revolade® use as first-in-class therapy for patients with severe aplastic anemia

Novartis International AG / Novartis receives EU approval for new Revolade® use as first-in-class therapy for patients with severe aplastic anemia . Processed and transmitted by NASDAQ OMX Corporate Solutions. The issuer is solely responsible for the content of this announcement.

• Revolade is the first approved therapy in the EU for patients with severe aplastic anemia (SAA) who have not responded to other treatments
   

Patients living with SAA, a rare blood disorder, have limited treatment options[1]
 

Of patients treated with standard of care, up to one-third will not respond and approximately 40% of responders will relapse, causing SAA symptoms to return[2]

Basel, September 2, 2015 - Novartis announced today that the European Commission has approved Revolade^® (eltrombopag) for the treatment of adults with severe aplastic anemia (SAA) who were either refractory to prior immunosuppressive therapy or heavily pretreated and are unsuitable for hematopoietic stem cell transplant.

"Today's approval from the European Commission is important news for adults in the EU with severe aplastic anemia, who now have an alternative to standard therapies that have not provided sufficient benefit," said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. "Revolade helps address an unmet need in this community and underscores our commitment to patients affected by rare diseases."

SAA is a blood disorder where the bone marrow does not make enough red blood cells, white blood cells and platelets[1]. Two out of every one million people in Europe are diagnosed with aplastic anemia per year, a portion of which are severe cases[3],[4]. The exact cause of the disease is still unknown, but most cases of SAA are believed to be triggered by an autoimmune reaction where the body attacks blood-forming stem cells located in the bone marrow[1],[2]. As a result, patients with SAA are at risk for life-threatening infections or bleeding[2]. 

Treatment of SAA is focused on increasing the number of healthy cells in the blood (blood cell count). The current standard of care includes IST or hematopoietic stem cell transplantation[2]. Of patients treated with IST, one-quarter to one-third will not respond and 30-40% of responders will relapse, causing symptoms to return[2]. Approximately 40% of SAA patients who don't respond to initial IST die from infection or bleeding within five years of their diagnosis[5].

The approval is based on the results of a pivotal open-label Phase II study (ELT112523) and two supporting Phase II studies (ELT116826 and ELT116643) conducted by the National Heart, Lung and Blood Institute (NHLBI) at the National Institutes of Health (NIH). The pivotal study demonstrated a hematologic response (40%) in SAA patients treated with Revolade who had an insufficient response to IST. The most common adverse reactions (>=20%) in the pivotal single-arm study of 43 patients were nausea, fatigue, cough, transaminase increased, diarrhea, and headache[6].

The European Commission approval applies to all 28 EU member states plus Iceland, Norway and Liechtenstein. In August of 2014, eltrombopag (marketed as Promacta^® in the USA), was approved by the US Food and Drug Administration for once-daily use in patients with SAA who have had an insufficient response to IST. Eltrombopag is also approved for SAA in Canada.

About the NIH Study
In the single-arm, single-center, open-label Phase II study (NCT00922883), eltrombopag was evaluated in 43 patients with SAA who have had an insufficient response to at least one prior IST and who had a platelet count <=30 x 10⁹/L.  At baseline, the median platelet count was 20 x 10⁹/L, hemoglobin was 8.4 g/dL, absolute neutrophil count (ANC) was 0.58 x 10⁹/L, and absolute reticulocyte count was 24.3 x 10⁹/L. The treated population had a median age of 45 years (range 17 to 77 years) and 56% were male. The majority of patients (84%) received at least two prior immunosuppressive therapies[7].

Eltrombopag was administered at an initial dose of 50 mg once daily for two weeks and increased over two-week periods up to a maximum dose of 150 mg once daily. The primary endpoint was hematologic response, which was initially assessed after 12 weeks of treatment with eltrombopag. Treatment was discontinued after 16 weeks if no hematologic response was observed. Additional efficacy assessments included median duration of response in months[7].

About Revolade^® (eltrombopag)
Revolade 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, and in over 45 countries worldwide for the treatment of thrombocytopenia (low blood platelet counts) in patients with chronic hepatitis C to allow them to initiate and maintain interferon-based therapy. Eltrombopag (marketed as Promacta^® in the USA), is approved by the US Food and Drug Administration for once-daily use in patients with SAA who have had an insufficient response to IST and was also recently approved for the treatment of children one year and older with chronic 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 patients with chronic ITP include nausea, diarrhea, increase of liver enzymes, dry mouth, vomiting, unusual hair loss or thinning, rash, back pain, muscle pain, sore throat and discomfort when swallowing, urinary tract infection.

The most common side effects of Revolade when used to treat patients with chronic HCV and antiviral agents include fever, feeling very tired, chills, headache, cough, nausea, diarrhea, unusual hair loss or thinning, muscle pain, itching, feeling weak, difficulty sleeping, loss of appetite, flu-like symptoms, and swelling of the hands, ankles or feet.

The most common side effects of Revolade when used to treat patients with severe aplastic anemia (SAA) include cough, headache, shortness of breath, pain in the nose and throat, runny nose, abdominal pain, diarrhea, bruising, joint pain, muscle spasms, pain in extremities, dizziness, feeling very tired, fever, inability to sleep (insomnia). 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," "commitment," "focused on," or similar terms, or by express or implied discussions regarding potential new indications or labeling for Revolade, or regarding potential future revenues from Revolade and Promacta. 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 Revolade 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 Revolade or Promacta will be commercially successful in the future. In particular, management's expectations regarding Revolade and Promacta could be affected by, among other things, the uncertainties inherent in research and development, including unexpected clinical trial results and additional analysis of existing clinical data; unexpected 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; unexpected safety issues; unexpected manufacturing or quality 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, eye care and cost-saving generic pharmaceuticals. Novartis is the only global company with leading positions in these areas. In 2014, the Group achieved net sales of USD 58.0 billion, while R&D throughout the Group amounted to approximately USD 9.9 billion (USD 9.6 billion excluding impairment and amortization charges). Novartis Group companies employ approximately 120,000 full-time-equivalent associates. Novartis products are available in more than 180 countries around the world. For more information, please visit http://www.novartis.com.

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References
[1] National Heart, Lung and Blood Institute. What is aplastic anemia? Accessed August 26, 2015. Available at: http://www.nhlbi.nih.gov/health/health-topics/topics/aplastic.
[2] 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.
[3] Young NS, Kaufman DW. The epidemiology of acquired aplastic anemia. Haematologica. 2008; 93(4):489-492.
[4] Montané E, Ibáñez L, Vidal X, et al. Epidemiology of aplastic anemia: a prospective multicenter study. Haematologica. 2008; 93(4):518-523.
[5] Valdez JM, Scheinberg P, Nunez O, et al. Decreased infection-related mortality and improved survival in severe aplastic anemia in the past two decades. Clin Infect Dis. 2011; 52(6):726-735.
[6] Revolade Summary of Product Characteristics.
[7] US National Institutes of Health. ClinicalTrials.gov Identifier: NCT00922883. A pilot study of a thrombopoietin-receptor agonist (TPO-R agonist), eltrombopag, in aplastic anemia patients with immunosuppressive-therapy refractory thrombocytopenia. Accessed August 26, 2015. Available at: https://clinicaltrials.gov/ct2/show/NCT00922883?term=eltrombopag+and+saa&rank=1.

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