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Ixazomib (Ninlaro®)

This Horizons Infosheet contains information on ixazomib (also known as Ninlaro®), a drug being investigated for the treatment of myeloma.

The Horizons Infosheet series Horizons Infosheets may not be provides information relating licensed and/or approved for use to novel drugs and treatment in myeloma. You may, however, strategies that are currently being be able to access them as part of investigated for the treatment of a . myeloma. The series also aims to highlight the considerable What is ixazomib? amount of research currently Ixazomib is a new drug being taking place in the field of investigated for the treatment of myeloma. myeloma. The drugs and treatment Like (Velcade®) and strategies described in the carfilzomib (Kyprolis®), ixazomib

Horizons Clinical trials Infosheet and novel drugs Series Infoline: 0800 980 3332 1 belongs to a group of drugs more sensitive to ixazomib. Velcade known as inhibitors. Myeloma cells appear to be even Unlike bortezomib and more dependent on the actions carfilzomib which are given of than other types subcutaneously (under the skin) of cancer cells. This may be due and intravenously (into the vein), to the need of the myeloma ixazomib is the first oral (by cells to dispose of the abnormal mouth) protein (paraprotein) they to be developed – this means it produce. can be taken at home as a tablet By blocking the function of the instead of being administered in proteasome, ixazomib prevents the hospital. the myeloma cells from growing and multiplying. What are proteasomes? small protein tags Proteasomes are large molecules small protein tags which are present in all cells in the body. They are involved in the removal, breakdown and recycling of damaged proteins or protein tagged those that are no longer needed protein tagged for recycling by the cell. for recycling proteasome proteasome protein How does ixazomib work? protein fragments fragments Ixazomib works by binding to proteasomes and temporarily proteasome inhibitors block the proteasome inhibitors block the proteasome causing proteins to blocking their function, which proteasome causing proteins to build up build up stops them from breaking down drug unwanted proteins (Figure 1). This drug causes proteins to build up and become toxic, killing the cell. Myeloma cells multiply more quickly than normal healthy cells and rely more heavily on proteasomes as they produce unwanted proteins at a faster

rate. They are therefore much Figure 1. Mechanism of action of proteasome inhibitors.

www.myeloma.org.uk Figure: MUK10_proteasome_inhib-CMYK ©www.myeloma.o2rg.uk design by www.blink.biz Figure: MUK10_proteasome_inhib-2COL ©www.myeloma.org.uk design by www.blink.biz How is ixazomib given? TOURMALINE MM-1 clinical Ixazomib can be given as a trial showed that relapsed monotherapy (used on its own and/or refractory myeloma and not in combination with patients receiving ixazomib in other drugs) but it has been combination with shown to be most effective when and had nearly used in combination with other 6 months longer progression myeloma treatments such as free survival (the length of time lenalidomide (Revlimid®) and following treatment before dexamethasone. the myeloma starts to come back) compared to patients The optimal dosage for ixazomib who received lenalidomide and is 4mg taken on days 1, 8 and dexamethasone alone. 15 of a 28 day treatment cycle. However, if you are unable to Phase I/II clinical trials looking at tolerate the side-effects of this the same combination in newly dosage or if you have liver or diagnosed patients showed a kidney damage, it can be lowered high overall response rate - 80% to 3mg or 2.3mg accordingly. in patients treated with weekly ixazomib and 92% in patients When given in combination with given twice-weekly ixazomib. ixazomib, lenalidomide is taken Median progression free survival orally on days 1 to 21 and low- in this group of patients was dose dexamethasone is taken found to be over two years in orally on days 1, 8, 15 and 22 of patients treated both once- and each cycle. twice-weekly. The treatment is continuous until disease progression. What are the possible known side-effects of ixazomib? What evidence exists to support The most common side-effects the use of ixazomib? of ixazomib include: nausea, Results from clinical trials to date vomiting, constipation, diarrhoea, have shown that ixazomib can oedema (the retention of produce effective responses abnormally large amounts of fluid in both relapsed and newly in the body, causing swelling), diagnosed patients. skin rash and back pain. Data from the Phase III Like bortezomib, ixazomib can

Infoline: 0800 980 3332 3 also cause and involves a review of evidence (damage to the nerves that make from large scale clinical trials. up the peripheral nervous system Normally, the licensed drug causing pain, tingling and altered must then be approved by a sensation). However, in clinical UK drug appraisal body before trials ixazomib has been shown it can be routinely prescribed to cause lower rates of peripheral by NHS doctors. The drug neuropathy than bortezomib, appraisal process differs from possibly due to it being more licensing - it compares how targeted. effective the newly-licensed Ixazomib is known to cause drug is to existing drugs already low counts, which may in use on the NHS and decides increase your risk of nose bleeds whether it offers the NHS good and bruising. value for money. The main body responsible for carrying out Is ixazomib currently available in drug appraisals in England and any UK clinical trials? Wales is the National Institute for Health and Care Excellence For an up-to-date list of UK (NICE). NICE recommendations clinical trials involving ixazomib, are usually adopted in Northern visit the Myeloma Trial Finder on Ireland. Scotland’s drug appraisal www.myeloma.org.uk body is the Scottish Medicines To be enrolled on a clinical trial, Consortium (SMC). patients have to meet certain conditions known as eligibility For more information see the Health criteria. You should speak to your Technology Assessment (HTA) Infosheet doctor in the first instance if you from Myeloma UK are interested in taking part in a trial. Ixazomib has been approved by the European Medicines Availability of ixazomib in the Agency (EMA) for use in UK combination with lenalidomide Before a drug can be widely and dexamethasone for relapsed used, it must first be licensed as myeloma patients who have a safe and effective treatment. received at least one previous This is usually done by regulatory treatment. authorities at a European level In December 2017, NICE

4 www.myeloma.org.uk approved ixazomib in Future directions combination with lenalidomide Ixazomib continues to be studied and dexamethasone for English in different myeloma patient and Welsh patients who groups and in different treatment have received two or three combinations. These trials will prior treatments, through a provide information about the government fund called the safest and most effective way to Cancer Drugs Fund (CDF). use ixazomib in myeloma. Under the CDF, NICE can issue a conditional ‘yes’ to promising About this Horizons Infosheet drugs about which there is still some uncertainty regarding The information in this Horizons clinical effectiveness. Under Infosheet is not meant to replace this agreement, there is a two the advice of your medical team. year period where more data on They are the people to ask if the effectiveness of the drug is you have questions about your collected. NICE then make a fnal individual situation. All Myeloma decision as to whether it should UK publications are extensively be approved for routine use. reviewed by patients and healthcare professionals prior to In Northern Ireland the publication. Department of Health, Social Services and Public Safety usually Myeloma UK wishes to thank reviews NICE guidance within Takeda Pharmaceuticals for three months of publication. reviewing this document for However, there is currently a lack factual accuracy. of clarity about the process for For a list of references used to providing access in Northern develop our resources, visit Ireland to drugs approved via www.myeloma.org.uk/ the CDF. Now that this approval references has been granted via the CDF, To provide feedback on this Myeloma UK will be working publication, email with the DHSPSS to clarify their [email protected] intentions in relation to funding ixazomib for patients in Northern Ireland. The SMC has no current plans to appraise ixazomib.

Infoline: 0800 980 3332 5 Other information available from Myeloma UK Myeloma UK has a range of publications available covering all areas of myeloma, its treatment and management. To order your free copies or to talk to one of our Myeloma Information Specialists about any aspect of myeloma, call our Myeloma UK Infoline on 0800 980 3332 or 1800 937 773 from Ireland. The Infoline is open from Monday to Friday, 9am to 5pm and is free to phone from anywhere in the UK and Ireland. Information and support about myeloma is also available around the clock at www.myeloma.org.uk

6 www.myeloma.org.uk Published by: Myeloma UK Publication date: June 2013 Last updated: January 2018 Review date: July 2018

Infoline: 0800 980 3332 7 Myeloma UK 22 Logie Mill, Beaverbank Business Park, Edinburgh EH7 4HG T: 0131 557 3332 E: [email protected] Charity No: SC 026116

Myeloma Infoline: 0800 980 3332 or 1800 937 773 from Ireland www.myeloma.org.uk

Myeloma Awareness Week 21 - 27 June