ADCs in Clinical Trials: What Does the Global Landscape Look Like? James Eslea MacDonald Hanson Wade

ADCs in Clinical Trials: What Does the Global Landscape Look Like? James Eslea MacDonald Hanson Wade

Welcome Today I d like to talk about some work we ve been doing recently to carry out some metaanalysis of the trends in ADC clinical development. The work I will highlight has largely been carried out by Heather Donaghy our dedicated research analyst but who can t be here today. I hope to be able to share some new and interesting observations on the current status of ADC clinical trials. Disclosure: The majority of the insights we have generated have been produced by Beacon a proprietary subscription database product that we have been licensing to the ADC community

Where did it start? Joined Hanson Wade in 2009 Worked on our World ADC series since 2010 In 2013 organised our first World ADC Mastermind brainstorming sessions In 2014 co-lead the effort to develop clinical trials database Beacon March 2015 Beacon launches

Problems The field is moving rapidly It is difficult to stay on top of the diversity of information The results of failed and successful ADC trials are the most informative source of information It takes time and effort to keep abreast of changes especially outside your knowledge comfort zone Imprecise information undermines good intentions If it is not clear who is doing what then efforts are bound to be unnecessarily reproduced and alongside the cost implications this has a clear negative impact on patients

How accurate is your knowledge? 1. How many ADCs are currently in clinical trials? 2. How many companies currently have ADCs in the clinic? 3. How many ADCs have begun clinical trials in the last year alone? Today I plan to share the answers to these questions and more

Number of trials Amazingly there are 59 ADCs in active clinical development! 14 12 The number of ADC drugs commencing clinical testing 10 8 6 4 2 0 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 Trial Start Date

Companies with ADCs in the clinic (n=24) Genentech, Inc. 7 Novartis Pharmaceuticals 2 Pfizer 6 Curagen 1 Seattle Genetics, Inc. 5 Daiichi Sankyo, Inc. 1 Abbvie 4 ADC Therapeutics SARL 1 Agensys, Inc. 4 Progenics Pharmaceuticals, Inc 1 ImmunoGen, Inc. 3 GlaxoSmithKline 1 Immunomedics, Inc. 3 Biotest Pharmaceuticals Corporation 1 Bayer 3 Eli Lilly and Company 1 Sanofi 3 Synthon BV 1 Stemcentrx 3 ZheJiang Medicine Co. Ltd 1 Amgen 2 GenMab 1 Bristol-Myers Squibb 2 Millennium Pharmaceuticals, Inc 1

Beginning Achilles-Poon, Safety Evaluation of Antibody Drug Conjugates, Presented at SOT 2010

2015 Detail of information is improving

Beacon ADC clinical trials database Beacon has captured 460+ clinical trials This includes 332 unique trials for ADCs (the remaining trials are for smdc, and IT) There are a total of 80 different ADCs (active and discontinued) We also have ~1000 references

Number of trials Patterns emerge 35 30 25 20 The number of new trials on ADC drugs Phase I Phase II Phase III 15 10 5 0 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 Trial Start Date

Step change in number of new trials beginning with ramp up evident from 2011 Growth in number of trials as well as anticipated number of drugs Lots yet to read out so plenty of data in the pipeline Still not much Phase III activity which is disappointing. Lots going in but not enough coming out

What has happened in the last year? PF06647020 BAY1187982 DS-8201a LOP628* PCA-062 LY3076226 SYD985 BMS986148 ABBV-838 ARX788 ABBV-085 ADCT-301 SC-002 SC-003 Sep-14 Dec-14 Mar-15 Jun-15 Sep-15 Timeline of new ADCs going into the clinic

And more

The last year alone has seen 15 new ADCs enter clinical trials What is most exciting about this is: Great variety in companies running the trials Diverse set of payloads being utilised Broad target pool This is the fruit of much hard work to improve upon ADC designs and realise the next generation of drugs.

What else is interesting about the data for the last year? PF06647020 BAY1187982 DS-8201a LOP628* PCA-062 LY3076226 SYD985 BMS986148 ABBV-838 ARX788 ABBV-085 ADCT-301 SC-002 SC-003 Sep-14 Dec-14 Mar-15 Jun-15 Sep-15 Timeline of new ADCs going into the clinic

ADCs targeting solid vs liquid cancers The last 12 months has seen 13/15 target solid tumors which is a weighty bias. Typically blood cancers have been perceived as attractive due to their accessibility but is greater competition driving a shift towards more challenging to treat indications? Or could it be a lack of viable targets? We took a look at Beacon to see if this was a trend or an anomaly.

Number of ADCs targeting blood cancer or solid tumors that commenced clinical testing in 2008 and 2014 12 10 8 2008: 75% target solid tumors 2014: 85% target solid tumors Overall: 72% target solid tumors 6 Blood Cancer Solid Tumor 4 2 0 2008 2014

Increasing payload diversity cause for celebration? Now over 11 distinct payloads have been disclosed as being testing in trials Another portion of unknown payloads will increase this further Number of trials evaluating a given payload

Caution is needed against over-optimism All the innovation is clustered into phase 1 so the benefits of these new approaches will take time to show. Additionally there is still a heavy reliance on just the technologies developed by ImmunoGen and Seattle Genetics still over 70% of all trials use these payloads.

Some final observations We began by looking at the field as a whole and narrowing down to specific companies and then specific technologies. It would seem that even this is too superficial to produce real insight and understanding of what will work and what won t. Alongside the preparations for today we produced a white paper in August reviewing drug specific toxicities and while I can t share all the details today it did provide some food for thought and further analysis.

Differences in drug performance Many ADCs are being evaluated in different disease indications simultaneously. The MTDs for these vary on account of target biology, patient status and dosing schedule. For example: Inotuzumab ozogamicin CD22 Terminated for futility in NHL, ALL 1.8mg/m 2 on days 1, 8, 15 of 28 day cycle Lorvotuzumab mertansine CD56 For SCLC (when added to carboplatin and etoposide) Terminated for futility but too much toxicity seen leading to infections For Ovarian cancer RP2D 60mg/m 2 /day for 3 days Multiple myeloma MTD 112mg/m 2 (as single agent) once every 3 weeks ABT-414 EGFR Every 2 weeks the MTD is 1.25mg/kg (glioblastoma) but every 3 weeks is 3.0mg/kg (EGFR positive tumors)

A specific comparison Polatuzumab vedotin (CD79b) MTD for NHL is 2.4mg/kg but is 1.0mg/kg for CLL PK profile - lower exposure and faster clearance in patients with CLL compared to NHL, probably due to higher numbers of circulating B cells in CLL caused target mediated clearance Peripheral neuropathy was major side effect. However, the safety profile was improved by reducing the dose and limiting the number of dosing cycles to 8 with limited impact on the clinical benefit (Advani et al. 2015) Image taken from Beacon trial 344

A thought on dosing The individual contributions of these elements are hard to unpick but the analysis has shown that all are important. Most of the dosing for ADCs starts at once every 3 weeks but it looks like this may not be the optimal dosing strategy for ADCs. Most that have looked into it have come up with different dosing strategies mostly more often initially and then less often over time eg once a week for 2 doses then once every 3 weeks for more cycles. Or once a week for 3 out of 4 weeks (ie d 1, 8, 15 of 28 day cycle) Therefore many of the different MTDs reported in different diseases reflect the improvements and identification of different dosing strategies. Of the three areas highlighted this has the highest degree of control associated with it and as such should be interrogated more thoroughly to help improve the therapeutic window of ADCs.

Key drugs to watch in 2016 1. Expecting IND for IMGN779 2. Brentuximab vedotin for Lupus 3. ABT -414 just announced new phase II trial (intellace I) 4. Inotuzumab ozogamicin INO-VATE-ALL met first primary endpoint, waiting for overall survival analysis 5. Expecting results from Echelon I and II brentuximab vedotin (frontline treatment) Many other programs have the potential to also produce existing results so I feel the outlook is wholly positive

Conclusions 1. Enormous program has been made over the last decade but much is still be achieved 2. The last year alone has proved hugely exciting with many of the next generation of ADCs beginning clinical trials 3. More companies than ever are committed to progressing the field and deliver meaningful drugs to patients 4. Deeper understanding of what is driving responses and toxicity will be critical to improve the therapeutic window of ADCs 5. Dosing strategy can play an important role in improving tolerability

Acknowledgements World ADC Beacon Team Heather Donaghy Meg Carter Daniel Moss Simon Daniels Simon Abrams Founding Partners Abzena Agensys Eisai Genmab ImmunoGen MedImmune Pfizer Regeneron Seattle Genetics Takeda All current users of Beacon for their continual feedback

Questions? Further queries can be emailed to: research@hansonwade.com