Novartis announce safety data of Revolade in adults with chronic immune thrombocytopenia





Novartis announced data from the largest study of its kind confirming the long-term safety profile of Revolade (eltrombopag) in adults with chronic immune (idiopathic) thrombocytopenia (ITP), with data for up to 6 years in some patients (median exposure was 2.4 years).
 
[1,2] Additional data from the study will also be presented that showed long-term oral administration of Revolade was effective in increasing and maintaining platelet counts in adult patients who had their spleens removed (splenectomized) as well as those who did not (non-splenectomized)[4]. The final results of the study and sub-analysis will be presented at the 21st Congress of the European Hematology Association (EHA) in Copenhagen, Denmark.
ITP is a rare and potentially serious blood disorder where the blood doesn't clot as it should due to a low number of platelets. As a result, patients experience bruising, bleeding and, in some cases, serious hemorrhage that can be fatal. ITP may also affect a patient's quality of life, as it is often associated with fatigue and depression as well as a fear of bleeding that may limit everyday activities[3].
"Patients living with chronic diseases will likely remain on therapy for many years, so data about the long-term use of treatments, particularly around safety, are critical," said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. "EXTEND is the largest study of its kind and reinforces Revolade as a trusted option that adults with chronic ITP can use for the long-term."
The safety profile of Revolade seen in the EXTEND trial is consistent with that observed in the pivotal 24-week Phase III RAISE study[1,2]. Long-term use of Revolade was not associated with a clinically relevant increase in bone marrow reticulin or collagen fibers[5]. The most common adverse events were headache (28%), nasopharyngitis (25%), upper respiratory tract infection (23%), and fatigue (17%)[1,2].
The efficacy results of EXTEND demonstrated that median platelet counts were elevated to >=50 × 109/L within two weeks of Revolade treatment, with median platelet counts >50 × 109/L maintained for more than four years. Post-baseline, overall bleeding rates declined and the majority of bleeding that occurred during more than six years of the study was Grade 1 according to the World Health Organization bleeding scale[1,2]. In addition, 91.4% (276/302) of patients achieved platelet counts >=30 × 109/L without rescue treatment, and 85.8% (259/302) achieved platelet counts >=50 × 109/L without rescue treatment[1,2].
About the EXTEND Clinical Trial
EXTEND, an open-label extension study of four trials (including the pivotal trial) of Revolade, enrolled 302 adults with chronic ITP who had received prior therapy for their ITP, and is the largest study of its kind. The objectives were to assess the safety and efficacy of long-term treatment with Revolade, including the proportion of patients achieving stable platelet counts during treatment with Revolade; maximum duration of platelet count elevation >=50×109/L or >=30×109/L during treatment with Revolade, and the effect of Revolade on reducing and/or sparing concomitant ITP therapies, while maintaining a platelet count >=50×109/L[1,2].
Revolade was started at a dose of 50 mg/day and titrated to 25-75 mg/day or less often based on platelet counts. Maintenance dosing continued after minimization of concomitant ITP medication and optimization of Revolade dosing. The overall median duration of exposure was 2.4 years (range, 2 days to 8.8 years) and mean average daily dose was 50.2 (range, 1-75) mg/day[1,2]. One hundred thirty-five adult patients (45%) completed the study and 75 adult patients (25%) were treated for four or more years. Most patients were aged <65 years, female, and had platelet counts >15 ×109/L at baseline. About one third were using concomitant medications at baseline, and 53% had received three or more prior ITP therapies[1,2].
Grade 3 and 4 adverse events (AEs) occurred in 26% and 6% of patients, respectively. Grade 3 cataract occurred in four (1%) patients and Grade 3 pain in extremity in six (2%) patients. Grade 3 AEs occurring in three (<1%) patients each included diarrhea, headache, migraine, dyspnea, platelet count decreased, and menorrhagia; those occurring in five (2%) patients each included pneumonia, fatigue, back pain, alanine aminotransferase increased, aspartate aminotransferase increased, anemia, and hypertension. Grade 4 anemia and thrombocytopenia occurred in three (<1%) and four (1%) patients, respectively. All other Grade 4 events occurred in one patient each[1,2].Sub-analysis in patients with or without splenectomy
In addition, a planned sub-analysis compared the safety and efficacy of long-term Revolade treatment in patients with or without splenectomy in the EXTEND trial[4].Of the 302 adult patients in the trial, 115 with splenectomy (38%) and 187 without splenectomy (62%) had similar characteristics at baseline, except that more splenectomized patients were receiving ITP medications (47% vs 25%) and had a history of clinically significant bleeding (23% vs 13%). More than half of the patients in both groups received Revolade for >=24 months. After Revolade treatment, response rates (patients achieving platelets >=50 ×109/L without rescue therapy) were somewhat higher in the non-splenectomized patients. Overall, rates of some bleeding AEs were higher in splenectomized patients, but most occurred at comparable rates. Events occurring in >=4% of patients in the splenectomized and non-splenectomized groups, respectively, included mouth hemorrhage (4% and 1%), epistaxis (14% and 6%), petechiae (8% and 2%), ecchymosis (2% and 4%), contusion (3% and 4%), and hematuria (2% and 4%). The proportion of patients in each splenectomy group who were able to discontinue or reduce concomitant medications from baseline were similar, with 13% in each group attempting to reduce/discontinue medication and 11-12% stopping at least one medication[4].
About Chronic ITP
People who have ITP often have purple bruises or tiny red or purple dots on the skin. They also may have nosebleeds, bleeding from the gums during dental work, or other bleeding that is hard to stop. In most cases, an autoimmune response in which a person's immune system attacks and destroys its own platelets is thought to cause ITP[3].
ITP is classified by duration into newly diagnosed, persistent (3-12 months' duration) and chronic (>12 months' duration). Chronic ITP is more likely to occur in adults, and women are affected two to three times more often than men[6,7,8].
The goal of treatment in chronic ITP is to maintain a safe platelet count that reduces the risk of bleeding. Treatment is determined by the severity of the symptoms. In most cases, drugs that alter the immune system's attack on the platelets are prescribed to help manage bleeding and bruising in adults[7,8,9].
 References
[1]  Bussel, et al. Final Safety and Efficacy Results from the EXTEND Study: Treatment with Eltrombopag (EPAG) in Adults with Chronic Immune Thrombocytopenia (cITP). 2016 Congress of the European Hematology Association (EHA). Copenhagen, Denmark.
[2]  Novartis Data on File. 
[3]  Immune Thrombocytopenia. US National Institutes of Health website http://www.nhlbi.nih.gov/book/export/html/4917 (link is external). Accessed June 9, 2016.
[4]  Wong, et al. Safety and Efficacy of Eltrombopag in Splenectomized and Nonsplenectomized Patients with Immune Thrombocytopenia: Results from the EXTEND Study. 2016 Congress of the European Hematology Association (EHA). Copenhagen, Denmark.
[5]  Brynes RK, Orazi A, Theodore D, Burgess P, Bailey CK, Thein MM, Bakshi KK. Evaluation of bone marrow reticulin in patients with chronic immunethrombocytopenia treated with eltrombopag: Data from the EXTEND study. Am J Hematol. 2015 Jul;90(7):598-601. doi: 10.1002/ajh.24011. PubMed PMID: 25801698.
[6]  Rodeghiero F, Stasi R, Gernsheimer T, et al. Standardization of terminology, definitions and outcome criteria in immune thrombocytopenic purpura of adults and children: report from an international working group. Blood. 2009;113(11):2386-2393.
[7]  National Organization of Rare Disorders:Immune Thrombocytopenia website. http://rarediseases.org/rare-diseases/immune-thrombocytopenia/ (link is external). Accessed June 9, 2016. 
[8]  Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010;115(2):168-186.
[9]  Cines DB, Blanchette VS. Immune thrombocytopenic purpura. N Engl J Med. 2002;346(13):995-1008.