1. ADCs in Clinical Trials: What Does the
Global Landscape Look Like?
James Eslea MacDonald
Hanson Wade
2. Welcome
Today I’d like to talk about some work we’ve been doing recently to carry out some meta-
analysis 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
3. 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
4. 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
5. 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
6. Amazingly there are 59 ADCs in active clinical development!
0
2
4
6
8
10
12
14
2005 2006 2007 2008 2009 2010 2011 2012 2013 2014
Numberoftrials
Trial Start Date
The number of ADC drugs commencing clinical
testing
7. 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
10. 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
12. • 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
13. What has happened in the last year?
SYD985
PF06647020
LOP628*
BMS986148
BAY1187982
ADCT-301
PCA-062
ABBV-838
SC-002
ARX788
LY3076226
DS-8201a
SC-003
ABBV-085
Sep-14 Dec-14 Mar-15 Jun-15 Sep-15
Timeline of new ADCs going into the clinic
16. 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.
17. What else is interesting about the data for the last year?
SYD985
PF06647020
LOP628*
BMS986148
BAY1187982
ADCT-301
PCA-062
ABBV-838
SC-002
ARX788
LY3076226
DS-8201a
SC-003
ABBV-085
Sep-14 Dec-14 Mar-15 Jun-15 Sep-15
Timeline of new ADCs going into the clinic
18. 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.
19. Number of ADCs targeting blood cancer or solid tumors that
commenced clinical testing in 2008 and 2014
0
2
4
6
8
10
12
2008 2014
Blood Cancer
Solid Tumor
2008: 75% target solid tumors
2014: 85% target solid tumors
Overall: 72% target solid tumors
20. Increasing payload diversity – cause for celebration?
Number of trials evaluating a given payload
• Now over 11 distinct payloads
have been disclosed as being
testing in trials
• Another portion of “unknown”
payloads will increase this further
21. 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.
22. 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.
23. 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/m2 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/m2/day for 3 days
Multiple myeloma – MTD – 112mg/m2 (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)
24. 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
25. 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.
26. 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
27. 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
28. 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
