Novartis drugs Rydapt® (midostaurin) and Votubia® (everolimus) recommended for NHS funding in Scotland, providing new treatments to patients who previously had limited options
Jun 12, 2018
Adults in Scotland with newly diagnosed FLT3-mutated acute myeloid leukaemia (AML), who are fit for intensive chemotherapy, now have access to Rydapt® (midostaurin), first new treatment for AML in more than 25 years1,2
Votubia® (everolimus) is now available as adjunctive treatment for children and adults in Scotland with TSC-associated refractory partial-onset seizures and gives the possibility of reducing the frequency of seizures
Both cost-effective treatments will be available on the NHS in Scotland with immediate effect
Camberley, 12 June, 2018 - Novartis has announced Rydapt® (midostaurin) and Votubia® (everolimus) have been recommended for routine use on the NHS by the Scottish Medicines Consortium (SMC).
Midostaurin has been recommended for adult patients newly diagnosed with acute myeloid leukaemia (AML) who are FMS-like tyrosine kinase 3 mutation-positive (FLT3+) in combination with chemotherapy and for patients with complete response followed by Rydapt single agent maintenance therapy3.
AML is a rare and aggressive cancer of the blood and bone marrow4 that affects over 3,000 patients in the UK each year5. AML prevents white blood cells from maturing, causing an accumulation of “blasts”. As a result of the rapid proliferation of these blasts, normal blood cells are also prevented from forming4. Many cases of AML will also carry genetic mutations that can impact the course of the disease, therefore genetic testing in newly diagnosed AML patients can help to determine prognosis and potential treatment strategies6. Around one-third of patients with AML have a mutation in the FLT3 gene6.
“Different mutations associated with AML can affect a patient’s prognosis – we know that the FLT3 gene mutation can result in lower rates of survival than those without the mutation,” says Prof Mhairi Copland, Professor of Translational Haematology, Paul O'Gorman Leukaemia Research Centre, University of Glasgow. “The reimbursement of midostaurin by SMC ensures that Scottish patients with this type of cancer now have access to a targeted medicine that could significantly extend their lives."
The SMC recommendation is based on results from the Phase III RATIFY (CALGB 10603 [Alliance]) clinical trial, which demonstrated that newly diagnosed FLT3+ patients who received midostaurin in combination with chemotherapy followed by midostaurin monotherapy after complete response as maintenance therapy experienced significant improvement in overall survival with a 22% reduction in the risk of death compared with chemotherapy alone (hazard ratio [HR] = 0.78, 95% confidence interval [CI], 0.63, 0.95; 2 sided p=0.016)7.
In addition, median overall survival (OS) achieved with midostaurin plus chemotherapy was significantly higher at 74.7 months versus 25.6 months with chemotherapy alone plus placebo (p=0.0078)3,7.
Votubia (everolimus) has been recommended for routine use on the NHS by the SMC as an adjunctive treatment for patients aged two years and older whose refractory partial-onset seizures, with or without secondary generalisation, are associated with tuberous sclerosis complex (TSC).
Tuberous sclerosis complex is a rare genetic disorder affecting up to one million people worldwide8. Approximately 85% of people with TSC are affected by epilepsy, and uncontrolled seizures associated with TSC can be debilitating for patients9. Patients with TSC-associated epilepsy are at high risk of brain damage, neuro-developmental deficits, and autism10,11. In particular, patients with refractory seizures are at high risk for neuropsychiatric problems and cognitive deficits from ongoing seizures, resulting in declining quality of life that, in some patients, may not be reversible12.
With the SMC recommendation, approximately 60 people in Scotland with TSC-associated epilepsy could benefit from everolimus treatment, giving the possibility of reducing refractory partial-onset seizures13.
The SMC recommendation was based on efficacy and safety data from a pivotal Phase III study, EXIST-3, which found that when used as an adjunctive therapy, everolimus reduced the frequency of refractory partial-onset seizures associated with TSC compared to placebo. Patients who received everolimus showed improved responses, measured as proportion of patients who achieved a reduction in seizure of 50% or more. The responses were of 28.2% and 40% in the low and high everolimus exposure groups respectively, compared to 15.1% in the placebo arm. The reduction in number of seizures experienced was also higher, with a median reduction of 29.3% and 39.6% in the low and high everolimus exposure groups respectively, compared to 14.9% in the placebo arm14.
"We are absolutely delighted with today’s announcement. We are grateful to the SMC for providing us with the opportunity to speak directly to the decision-making panel along with our patient representative, who was able to share the community’s experiences of taking everolimus,” said Maxine Smeaton, Chief Executive of the Tuberous Sclerosis Association (TSA). “For people living with TSC-related refractory epilepsy this will have a tremendous impact on both their physical and mental health and the quality of life for their families and carers.”
“The decision by SMC to fund midostaurin and everolimus marks an important milestone for patients in Scotland who are in great need of new advances in treatments,” said Mari Scheiffele, General Manager of Novartis Oncology UK & Ireland. “We will continue to work hard to deliver our commitment to bring breakthrough medicines to patients with serious and hard-to-treat diseases who have few treatment options."
About Acute Myeloid Leukaemia (AML) AML is the most common acute leukaemia in adults; in the UK, it accounts for about 1 in 3 cases of leukaemia in adults overall and about 9 in 10 cases of acute leukaemia5.
About Rydapt (midostaurin) Midostaurin is an oral, multi-targeted inhibitor of multiple kinases, including FLT3 and KIT, which help regulate many essential cell processes, interrupting cancer cells’ ability to grow and multiply3.
Midostaurin is indicated for use in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation chemotherapy, and for patients in complete response followed by midostaurin single agent maintenance therapy, for adult patients with newly diagnosed AML who are FLT3 mutation-positive3.
Midostaurin is available in 25 mg capsules and the recommended dosage is 50 mg orally twice a day on days 8 to 21 each cycle of induction therapy and consolidation therapy. For patients in complete response, it is dosed every day as single agent maintenance therapy until relapse for up to 12 cycles of 28 days each. In patients receiving a haematopoietic stem cell transplant (SCT), midostaurin should be discontinued 48 hours prior to the conditioning regimen for SCT3.
In RATIFY, the most frequent adverse reactions (incidence greater than or equal to 20%) in the midostaurin plus chemotherapy arm were febrile neutropenia, nausea, vomiting, mucositis, headache, musculoskeletal pain, petechiae (small red skin spots), device-related infection, epistaxis, hyperglycaemia and upper respiratory tract infections. The most frequent Grade 3/4 adverse reactions (incidence greater than or equal to 10%) were febrile neutropenia, device-related infection and mucositis. The safety profile of the midostaurin arm is comparable to the placebo arm in the clinical trial3,7.
About Tuberous Sclerosis Complex Tuberous Sclerosis Complex (TSC) may cause non-cancerous tumours to form in vital organs including the brain, kidney, heart, lungs, and skin, as well as resulting disorders such as epilepsy, autism, cognitive impairment, behavioural problems, and psychiatric disorders. Many people with TSC show evidence of the disease in the first year of life. However, because manifestations vary from person to person and can take years to develop, many children are not diagnosed until later in life, often with the onset of seizures, skin lesions or other significant symptoms, such as developmental delays. Because TSC is a lifelong condition, the latest professional diagnostic guidelines issued in 2012 advise that individuals be monitored by a doctor experienced with the disorder to ensure tumour growth or new symptoms are identified early15,16.
About Votubia (everolimus) In the European Union (EU), everolimus is approved as Votubia tablets for the treatment of adult patients with renal angiomyolipoma associated with TSC who are at risk of complications (based on factors such as tumour size or presence of aneurysm, or presence of multiple or bilateral tumours) but who do not require immediate surgery. The evidence is based on analysis in sum of angiomyolipoma volume. Votubia tablets and dispersible tablets are also indicated in the EU for the treatment of patients with subependymal giant cell astrocytoma (SEGA) associated with TSC who require therapeutic intervention but are not amenable to surgery. The evidence is based on analysis of change in SEGA volume. Further clinical benefit, such as improvement in disease-related symptoms, has not been demonstrated.
Votubia dispersible tablets are also indicated in the EU as an adjunctive treatment for patients aged 2 years and older whose refractory partial-onset seizures, with or without secondary generalization, are associated with TSC.
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Patel JP, Gönen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012; 22;366(12):1079-1089.
Stone RM, Mandrekar S, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukaemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454-464.
Budde, K. and Gaedeke, J. Tuberous sclerosis complex-associated angiomyolipomas: focus on mTOR inhibition. American Journal of Kidney Diseases. 2012:276-283.
Chu-Shore C.J., et al. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia. 2010: 51(7): 1236-1241.
O'Callaghan FJ, Harris T, Joinson C, Bolton P, Noakes M, Presdee D, Renowden S, Shiell A, Martyn CN, Osborne JP. The relation of infantile spasms, tubers, and intelligence in tuberous sclerosis complex. Arch Dis Child. 2004 Jun;89(6):530-3.
Vignoli A, La Briola F, Peron A, Turner K, Vannicola C, Saccani M, et al. Autism spectrum disorder in tuberous sclerosis complex: searching for risk markers. Orphanet J Rare Dis. 2015;10:154.
Zupanc ML, Rubio EJ, Werner RR, Schwabe MJ, Mueller WM, Lew SM, et al. Epilepsy surgery outcomes: quality of life and seizure control. Pediatric neurology. 2010;42(1):12-20.
Novartis Data on File.
French JA, et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016 Oct 29;388(10056):2153-2163.
National Institute of Neurological Disorders and Stroke fact sheet. 2010.
Northrup, H. et al. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 international tuberous sclerosis complex consensus conference. Pediatric Neurology. 2013; 49: 243-254
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