Imatinib – where are we now. What about generic imatinib Imatinib – where are we now? What about generic imatinib? CML patient & carer meeting 2016 Manchester, 24th September 2016 Richard Clark Royal Liverpool University Hospital 1

Audience participation! Please stand up if you have ever had CML No pressure! 2

Please sit down if diagnosed before 1953 You predated modern treatment which can readily control the blood count 3

Please sit down if diagnosed between 1953 & 1983 ! Please sit down if diagnosed between 1953 & 1983 You had treatment which can readily control the blood count, but no prospect of clearing the marrow 4

Please sit down if diagnosed between 1983 & 1999 ! Please sit down if diagnosed between 1983 & 1999 You probably initially had interferon. This can readily control the blood count, and may partially clear the marrow; completely in 5% of cases. Given by injection. Many side effects! 5

Please sit down if diagnosed between 1999 & 2003 ! Please sit down if diagnosed between 1999 & 2003 You probably had imatinib (maybe after initial interferon). Imatinib readily controls the blood, and completely clears the marrow in at least 70% of patients. Some side effects……………………… 6

Please sit down if diagnosed between 2003 & 2012 ! Please sit down if diagnosed between 2003 & 2012 You probably had imatinib though might have had one of the newer ‘TKIs’ in a clinical trial. All the TKIs readily control the blood, and completely clear the marrow in at least 70% of patients. Some side effects……………………… 7

Please sit down if diagnosed from 2013 onward ! Please sit down if diagnosed from 2013 onward You could have had either imatinib or nilotinib on the NHS, though might have had one of the 3 other TKIs in a clinical trial. All the TKIs readily control the blood, and completely clear the marrow in at least 70% of patients. Some side effects……………………… 8

CML: Natural history (1980s) Initial chronic phase Accelerated phase Blast crisis

CML: Natural history (2016) After 2-3 years: ~93% still fine in chronic phase After ~10 years: ~almost all still well in chronic phase Initial chronic phase Accelerated phase ~ 7% in blast crisis

PRIMARY GOAL of treatment: No More Progression Can we reliably predict those who will progress?

Disease Burden and Cytogenetic Response Number of Leukaemic Cells 1012 1011 1010 109 108 107 106 RUGBY BALL Complete haematological response Normal blood count GrapeFruit Walnut Overall survival Complete cytogenetic response No Ph+ chromosomes

Event-free Survival in IRIS by Molecular Response: 18-Month Landmark Analysis BCR-ABLIS ≤ 0.1% (MMR) at 18 months predicted for prolonged Event-free Survival at 84 months ≤ 0.1% (n = 164) >0.1-1% (n = 47) >1-10% (n = 25) >10% (n = 13) BCR-ABL % (IS) Without Event, % 10 20 30 40 50 60 70 80 90 100 Months Since Start of Treatment 12 24 36 48 72 84 * MMR defined as BCR-ABL% (IS) ≤ 0.1. IRIS, International Randomized Study of Interferon and STI571; MMR, major molecular response. Hughes et al., Blood. 2010.116(19):3758-3765

Achieving Complete Cytogenetic Response Complete cytogenetic response is a surrogate marker for the clinical outcome

Moving to molecular response

Disease Burden and Molecular Response Number of Leukaemic Cells 1012 1011 1010 109 108 107 106 RUGBY BALL GrapeFruit Complete cytogenetic response Walnut Overall survival Grain of rice Major molecular response BCR-ABL 0.1% or less Stable response No risk of progression

Event-free Survival in IRIS by Molecular Response: 18-Month Landmark Analysis BCR-ABLIS ≤ 0.1% (MMR) at 18 months predicted for prolonged Event-free Survival at 84 months ≤ 0.1% (n = 164) >0.1-1% (n = 47) >1-10% (n = 25) >10% (n = 13) BCR-ABL % (IS) Without Event, % 10 20 30 40 50 60 70 80 90 100 Months Since Start of Treatment 12 24 36 48 72 84 * MMR defined as BCR-ABL% (IS) ≤ 0.1. IRIS, International Randomized Study of Interferon and STI571; MMR, major molecular response. Hughes et al., Blood. 2010.116(19):3758-3765

Overall Survival by Landmark Analysis of Molecular Response by 12 Months Hehlmann et al., J Clin Oncol. 2011;29(12):1634-42.

Survival for 282 Patients Treated with Imatinib First Line According to Molecular Response Achieved at 3 Months BCR-ABL/ABL<9.8% OS= 93.3% Probability of survival BCR-ABL/ABL>9.8% OS= 54% p<0.0001 Time from onset of imatinib therapy (years) Marin et al, JCO 2011

8-year cumulative incidence of CMR on imatinib therapy according to the BCR-ABL transcript level at 3 months 3-month transcript ratio ≤0.61% (n=57) 8-year CI of CMR of 84.7%, Cumulative incidence of CMR p<0.0001 3-month transcript ratio >0.61% (n=222) 8-year CI of CMR of 1.5% Time from onset of imatinib therapy (years) Marin et al, JCO 2011

BCR-ABL transcript levels at 3 months predicts 2 year cumulative incidence of CCyR and MMR BCR-ABL/ABL <10%, n=117 BCR-ABL/ABL <10%, n=117 BCR-ABL/ABL >10%, n=11 Cumulative incidence of CCyR Cumulative incidence of MMR BCR-ABL/ABL >10%, n=11 p<0.001 p<0.001 Time from start of therapy (months) Time from start of therapy (months) Marin et al, Blood 2012

Disease Burden and Molecular Response Number of Leukaemic Cells 1012 1011 1010 109 108 107 106 RUGBY BALL GrapeFruit Complete cytogenetic response Overall survival Walnut Stable response No risk of progression Grain of rice Major molecular response Less than grain of sand ‘MR4’ BCR-ABL less than 0.01% (or undetectable) Possibility to discontinue therapy

The ‘Glivec’ imatinib UK patent expires in December 2016. Generic imatinib A generic drug = ‘equivalent to a brand-name product in dosage, strength, route of administration, quality, performance, and intended use’. The ‘Glivec’ imatinib UK patent expires in December 2016. To get a licence, it is not necessary to carry out clinical trials – just to demonstrate equivalence. 23

How to make imatinib Making it suitable for clinical use requires crystallisation.

Imatinib crystallisation The easy way of crystallisation creates an ‘α stereoisomer’. Glivec is a ‘β stereoisomer’; the patent covers its synthesis Several α stereoisomers have been widely used in India, Turkey, etc. There are no clinical trials of α stereoisomers. DOES ALL THIS MATTER? Possibly not …… 25

The generic imatinibs from: Accord Teva CIPLA Sandoz Mylan Wockhardt all have ‘approved marketing authorisation’ (i.e. a licence), though they may not necessarily all manufacture imatinib long-term. Each will cost well under £2000 a year (‘Glivec’ costs ~£21,000 a year (400mg per day). NHS England and Scotland are tendering to procure generic imatinib for a Jan 2017 start . Colleagues in Canada and Poland are ~ 2 years ahead of us and report no problems with several of the generics 26

Changing Goals of Treatment 1960 1970 1980 1990 2000 2010 Typ ? e Busulphan IFN Imatinib 2nd Gen TKIs Optimal Treatment Aim MCyR Improved OS ~ 1.5Y MMR Optimal OS in some Deeper/faster MR Optimal OS in more? “Cure” ? CHR Improved QoL No effect on OS Tumour Reductiona ≤10% ≈ 1-log ≤1% ≈ 2-log Tumour Burden MR4 and beyond ≤0.1%IS ≈ 3-log ≤0.01%IS ≈ 4-log ≤0.0032%IS ≈ 4.5-log ≤0.001%IS ≈ 5-log a Compared with baseline levels. CMR, complete molecular response; IFN, interferon; IS, international scale.

GOALS of treatment Prevention of progression: Of course Essential Normal (low) blood count by 3 months: Molecular (PCR) less than 10% at 3 months: Might be important Cytogenetic response/less than 1% by 12 months: Definitely Important MMR is a “safe haven”, but is CCyR enough? Probably useful Is a deeper response (MR4 or better) essential? Maybe not