Gilead Sciences, Inc. has announced that the Scottish Medicines Consortium (SMC) has approved Zydelig (idelalisib) - a new oral treatment - for adult patients with chronic lymphocytic leukaemia (CLL). Idelalisib has been approved for use within NHS Scotland in combination with rituximab for the treatment of adult patients with relapsed CLL who are unsuitable for chemotherapy and treatment naïve patients with 17p deletion or TP53 mutation who are unsuitable for chemo-immunotherapy.

This decision follows the European Commission granting Marketing Authorisation for idelalisib for the treatment of two incurable blood cancers, CLL and double refractory follicular lymphoma (FL) in the European Union, on 19 September 2014.

Dr Angus Broom, Consultant Haematologist, Western General Hospital, NHS Lothian said: "The SMC's decision on idelalisib marks a significant advance for patients with CLL in Scotland, as it is a life-extending treatment with the potential to help alleviate both the emotional and physical impact for patients and families living with CLL. Idelalisib provides physicians with a new treatment option for previously untreated patients with markers of aggressive CLL disease or relapsed CLL."

Approximately 3,200 individuals are diagnosed with CLL in the UK each year.1 CLL is usually a slow growing incurable blood cancer2 that can lead to life-threatening complications, such as anaemia, serious infection and bone marrow failure requiring treatment.3, 4 The goal of therapy for patients with this form of cancer is to improve overall survival and quality of life.5 Chemo-immunotherapy is initially used to treat CLL, however patients eventually relapse and many cannot tolerate the side effects associated with chemo-immunotherapy. Additionally, some patients have genetic alterations in their CLL cells. Deletion of part of chromosome 17 - del (17p) - or a mutation in the TP53 gene in CLL cells have been linked to poor prognosis, being predictive of more rapid disease progression. For these patients most conventional chemo-immunotherapy treatments are not effective and deliver poor responses with relatively short duration.6

The SMC's decision on idelalisib for the treatment of CLL is supported primarily by data from a randomised, placebo-controlled Phase 3 trial (Study 116)7 of idelalisib plus rituximab versus placebo plus rituximab in 220 patients with relapsed CLL who were not able to tolerate standard chemotherapy. Study 116 was stopped early in October 2013 by an independent Data Monitoring Committee due to a statistically significant difference in progression-free survival (PFS) in the idelalisib arm compared with the rituximab only treatment arm (events 14.5% vs. 53.6% hazard ratio = 0.18 (95 percent CI: 0.10, 0.32), p<0.0001). Patients in this study were eligible to continue receiving idelalisib therapy in an open-label extension study (Study 117). Results from the primary and the extension study show that among the 110 patients randomised to receive idelalisib plus rituximab, the median PFS has now been reached, and is 19.4 months8 (placebo plus rituximab media PFS is 7.3 months).8 Idelalisib plus rituximab was similarly effective in patients with del (17p) and/or TP53 mutation.9

The most common Grade ≥3 adverse events in patients receiving idelalisib plus rituximab were neutropenia, transaminase elevations, pneumonia and diarrhoea.10 For additional safety information, see the Summary of Product Characteristics at www.medicines.org.uk.

Further details on the SMC's decision can be found here www.scottishmedicines.org.uk

About Zydelig (idelalisib)

Idelalisib is an oral inhibitor of phosphoinositide 3-kinase (PI3K) delta, a protein that plays a role in the activation, proliferation and viability of B cells, a critical component of the immune system. PI3K delta signalling is active in many B-cell leukaemias and lymphomas, and by inhibiting the protein, idelalisib blocks several cellular signalling pathways that drive B-cell viability. Idelalisib is indicated in combination with rituximab for the treatment of adult patients with CLL who have received at least one prior therapy, or as first-line treatment for CLL patients in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemo-immunotherapy. Idelalisib is administered orally twice-daily and is available as 150 mg and 100 mg dose strengths.

Important Safety Information10
Contraindications: Hypersensitivity to the active substance or to any excipients listed in the idelalisib summary of product characteristics.

Special warnings and precautions for use: The summary of product characteristics of co-prescribed medicinal products should be consulted before starting therapy with idelalisib.

Transaminase elevations
Elevations in ALT and AST of Grade 3 and 4 (> 5 x ULN) have been observed in clinical studies of idelalisib. These laboratory findings were generally observed within the first 12 weeks of treatment, were generally asymptomatic, and were reversible with dose interruption. Most patients resumed treatment at a lower dose without recurrence. ALT, AST, and total bilirubin must be monitored in all patients every 2 weeks for the first 3 months of treatment, then as clinically indicated. If Grade 2 or higher elevations in ALT and/or AST are observed, patients must be monitored weekly until the values return to Grade 1 or below.

Diarrhoea/colitis
Cases of severe drug-related colitis occurred relatively late (months) after the start of therapy, sometimes with rapid aggravation, but resolved within a few weeks with dose interruption and additional symptomatic treatment (e.g., anti-inflammatory agents such as enteric budesonide).

There is very limited experience from the treatment of patients with a history of inflammatory bowel disease.

Pneumonitis
Cases of pneumonitis have been reported in clinical studies with idelalisib. Patients presenting with serious lung events that do not respond to conventional antimicrobial therapy should be assessed for drug-induced pneumonitis. If pneumonitis is suspected, idelalisib should be interrupted and the patient treated accordingly. Treatment must be discontinued for moderate or severe symptomatic pneumonitis.

CYP3A inducers
Idelalisib exposure may be reduced when co-administered with CYP3A inducers such as rifampicin, phenytoin, St. John's wort (Hypericum perforatum), or carbamazepine. Since a reduction in idelalisib plasma concentrations may result in decreased efficacy, co-administration of idelalisib with moderate or strong CYP3A inducers should be avoided.

CYP3A substrates
The primary metabolite of idelalisib, GS-563117, is a strong CYP3A4 inhibitor. Thus, idelalisib has the potential to interact with medicinal products that are metabolised by CYP3A, which may lead to increased serum concentrations of the other product. When idelalisib is co-administered with other medicinal products, the Summary of Product Characteristics (SmPC) for the other product must be consulted for the recommendations regarding co-administration with CYP3A4 inhibitors. Concomitant treatment of idelalisib with CYP3A substrates with serious and/or life-threatening adverse reactions (e.g., alfuzosin, amiodarone, cisapride, pimozide, quinidine, ergotamine, dihydroergotamine, quetiapine, lovastatin, simvastatin, sildenafil, midazolam, triazolam) should be avoided and alternative medicinal products that are less sensitive to CYP3A4 inhibition should be used if possible.

Hepatic impairment
Intensified monitoring of adverse reactions is recommended in patients with impaired hepatic function as exposure is expected to be increased in this population, in particular in patients with severe hepatic impairment. No patients with severe hepatic impairment were included in clinical studies of idelalisib. Caution is recommended when administering idelalisib in this population.

Chronic hepatitis
Idelalisib has not been studied in patients with chronic active hepatitis including viral hepatitis. Caution should be exercised when administering idelalisib in patients with active hepatitis.

Women of childbearing potential
Women of childbearing potential must use highly effective contraception while taking idelalisib and for 1 month after stopping treatment. Women using hormonal contraceptives should add a barrier method as a second form of contraception since it is currently unknown whether idelalisib may reduce the effectiveness of hormonal contraceptives.

Excipients
Zydelig 100mg tablet contains the azo colouring agent sunset yellow FCF (E110), which may cause allergic reactions.