European Commission Grants Marketing Authorisation for Gilead’s Zydelig® (Idelalisib) for the Treatment of Chronic Lymphocytic Leukaemia and Follicular Lymphoma

– First-in-Class Oral Treatment for Two Incurable Blood Cancers –

– 82 Percent Reduction in Risk of Disease Progression or Death in Relapsed Chronic Lymphocytic Leukaemia (CLL) Patients When Combined with Rituximab Compared to Rituximab Alone (clinical trial events 14.5% vs 53.6% respectively, HR=0.18; p<000.1 over 18 months) –

Foster City, CA, 19 September 2014 – Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the European Commission has granted marketing authorisation for Zydelig (idelalisib), 150 mg tablet, a first-in-class oral treatment for two incurable blood cancers – chronic lymphocytic leukaemia (CLL) and follicular lymphoma (FL). Idelalisib is licenced for use 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 has also been licenced as a monotherapy for the treatment of adult patients with FL that is refractory to two prior lines of treatment.  Idelalisib inhibits PI3K delta, a protein that is overexpressed in many B-cell malignancies and plays a role in the viability, proliferation and migration of these cancer cells. Following approval for inclusion on the Cancer Drugs Fund, idelalisib is now immediately available for eligible patients with relapsed CLL in England.

CLL and FL are slow-growing incurable blood cancers1,2that can lead to life-threatening complications such as anaemia, serious infection and bone marrow failure requiring treatment.1,3,4  It is estimated that there will be 19,400 new cases of CLL in the EU5 (France, Germany, Spain, Italy and the UK) in 2014 5 and there are an estimated 112,000 patients living with FL.6  The goal of therapy for patients with these cancers is to improve overall survival and quality of life.7,8

Furthermore, some patients have genetic alterations in their CLL cells.  A chromosome 17 deletion – 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.9  Treatment options are very limited and idelalisib in combination with rituximab offers an effective treatment option for these patients. In a sub-group analysis of treatment-naive patients with del (17p) and/or TP53 mutation, idelalisib plus rituximab was also shown to be effective10.

The marketing authorisation of idelalisib in CLL is supported primarily by data from a randomised, placebo-controlled Phase 3 trial (Study 116) of idelalisib 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 benefit 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).  Median PFS was not reached in the idelalisib plus rituximab arm (95 percent CI: 10.7 months, NR) and was 5.5 months in the placebo plus rituximab arm (95 percent CI: 3.8, 7.1)11,12. Idelalisib plus rituximab was similarly effective in patients with del (17p) and/or TP53 mutation13.

The marketing authorisation of idelalisib in FL, the most common type of indolent non-Hodgkin lymphoma (iNHL), is supported by data from a single-arm Phase 2 study (Study 101-09) of idelalisib monotherapy in 125 NHL patients refractory to rituximab and alkylating-agent-containing chemotherapy (FL: n=72).  In the study, idelalisib achieved an overall response rate of 54 percent (range: 42-66 percent) in FL patients and of the responses observed, eight percent (n=6) were complete responses.  The median duration of response (DOR) among all 125 iNHL patients was 12.5 months, however, median DOR was 7.4 months in the FL group14,15. Results of Study 11611 and Study 101-0914 were published in The New England Journal of Medicine in March 2014.

Adverse drug reactions (including Grade ≥3) reported in clinical studies in patients with haematological malignancies receiving idelalisib included infections, neutropenia, pneumonitis, diarrhoea/colitis, increased transaminase (indicator of liver function), rash and pyrexia11,14. For additional safety information, see the Summary of Product Characteristics at www.ema.europa.eu.16

 

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 has also been approved as a monotherapy for the treatment of adult patients with FL that is refractory to two prior lines of treatment. Idelalisib is administered orally twice-daily and is available as 150 mg and 100 mg dose strengths.

 

Important Safety Information16

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 (see section 4.2).  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 (see section 4.5).  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 5 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.

[Only for 100 mg strength]

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

For the Summary of Product Characteristics please visit www.ema.europa.eu.

 

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need.  The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide.  Headquartered in Foster City, California, Gilead has operations in North and South America, Europe and Asia Pacific.

 

Forward-Looking Statement

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the risk that physicians and patients may not see advantages of idelalisib over other therapies and may therefore be reluctant to prescribe the product.  Further, additional studies of idelalisib may produce unfavourable results.  These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements.  The reader is cautioned not to rely on these forward-looking statements.  These and other risks are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2014, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

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For more information on Gilead Sciences, please visit the company’s website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

 Date of preparation: September 2014

Job Code: IDE/UK/14-08/CI/1127

 

References

1. National Cancer Institute(NCI). Chronic lymphocytic leukemia treatment (PDQ). National Cancer Institute (NCI). Available at http://www.cancer.gov/cancertopics/pdq/treatment/CLL/Patient/page1/allpages Accessed September, 2014.
2. National Cancer Institute (NCI). Adult Non-Hodgkin Lymphoma Treatment (PDQ). Available at http://www.cancer.gov/cancertopics/pdq/treatment/adult-non-hodgkins/HealthProfessional/page1/AllPages Accessed September, 2014.
3. National Cancer Institute(NCI). What you need to know about non-Hodgkin lymphoma. Available at http://www.cancer.gov/cancertopics/wyntk/non-hodgkin-lymphoma.pdf Accessed September, 2014.
4. Lymphoma Association. Follicular lymphoma. Available at http://www.lymphomas.org.uk/sites/default/files/pdfs/Follicular-lymphoma.pdf Accessed September, 2014.
5. Cancer Epidemiology Service. Epic Oncology. Epiphany Partners Inc. Available at http://www.time4epi.com/home/our-platforms/epic-oncology Accessed September, 2014.
6. European Medicines Agency. Public Summary of Opinion on Orphan Designation. Idelalisib for the treatment of follicular lymphoma. Available at http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2013/08/WC500148277.pdf  Accessed September, 2014.
7. Shanafelt TD & Kay NE. Comprehensive management of the CLL patient: a holistic approach. Hematology Am Soc Hematol Educ Program 2007:324-331.
8. Pettengell R et al. The impact of follicular lymphoma on health-related quality of life. Ann Oncol 2008; 19:570-576.
9. Seiffert M et al. Exploiting biological diversity and genomic aberrations in chronic lymphocytic leukemia. Leuk Lymphoma 2012; 53:1023-1031.
10. O’Brien SM et al. A phase 2 study of the selective phosphatidylinositol 3-kinase delta (PI3K?) inhibitor idelalisib (GS-1101) in combination with rituximab in treatment-naïve patients ≥65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) [Presentation]. Presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; May 31-June 4 2013.
11. Furman RR et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014; 370:997-1007.
12. Data on File – Gilead Sciences Europe Ltd. – ONC14000002
13. Furman RR et al. Supplementary Appendix. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 2014; DOI: 10.1056/NEJMoa1315226
14. Gopal AK et al. PI3K? inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 2014; 370:1008-1018.
15. Data on File – Gilead Sciences Europe Ltd. – ONC14000004
16. Zydelig DRAFT summary of product characteristics  (100 & 150mg film-coated tablets) – September 2014.

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