Welcome

This is the first of our monthly updates from the research team at World ADC.

I am Heather Donaghy and have joined the World ADC team as their Research Analyst. I have come from a science research background, having completed my PhD at Imperial College, London and a post-doc at the Westmead Millennium Institute in Sydney, Australia.

The research team are on hand to answer your queries regarding how to use the database or to research any areas of interest for you. Feel free to email my team to ask a quick question, to request in depth analysis of the ADC trials, or just to say hi: research@hansonwade.com

Each month we’ll give you a round up of what is new on the World ADC Trials Intelligence database, as well as look at something that has attracted our attention each month. We hope you will find this a valuable addition.

New Drugs Entering Clinical Trials for the First Time in April

1. BMS986148, a mesothelin targeting ADC from Bristol

Myers Squibb (NCT02341625)

2. BAY1187982, an FGFR2 targeting ADC from Bayer (NCT02368951)

3. MT-3724, a CD20 targeting immunotoxin with a Shiga-like toxin A payload from Molecular Templates (NCT02361346)

What Have we Been Doing in April?

As it’s my first month in this new role I have spent a lot of time getting to grips with all the information in the trials intelligence database - there is a lot of good stuff there. I have been tinkering with some of the trials, adding results and some pre-clinical data. This is by not fully comprehensive just yet, and I will add information as I go.

I have also been adding extra drug classes to the database, focussing mostly on the small molecule drug conjugates from Endocyte and the immunotoxins, starting with DT2219, naptotumomab estafenatox and the compounds from Viventia.

We were all very interested to see the news from Pfizer that the first primary endpoint for their Phase III INO-VATE-ALL had been met and disappointed to hear that IMGN289 has stopped clinical testing.

Updates from AACR

This year’s AACR, held on 18 -22 April 2015 in Philadelphia, featured more than 80 presentations on antibody drug conjugates which were mostly focussed on pre-clinical studies of novel compounds.

What is noticeable from the AACR abstracts is the considerable effort currently underway in novel payload compounds and in altering the site specificity to optimise the drug antibody ratios (DAR) and efficacy.

Where possible, we have included the AACR presentation number in brackets.

Novel Payloads

Whilst the majority of new drugs entering clinical trials at the moment utilise the more traditional auristatin/maytansine payloads, many of the compounds currently progressing at the pre-clinical stage are using novel payloads. The novel payloads currently being reported include alpha Amanitin (Heidelberg Pharma, presentation number 633/2) that acts by inhibiting cellular transcription at very low concentrations by binding to RNA pol II; Indolino-benzodiazepine dimers (ImmunoGen, 652/25); Tubulysin B analogs (Hangzhou DAC biotech, 4532/2) and the DNA cross-linker pyrrolobenzodiazepine (PBD).

Novel Payloads

These new payload drugs are being developed for their greater anti-cancer potency. Both Seattle Genetics and MedImmune are investigating the use of PBD based ADCs, due to their potency (several logs more than the auristatins) and because they may target cancer stem cells as well as bulk tumor cells. They are also being investigated for their capacity to overcome drug resistance (Mao S, 3601/24). SGN-33A, a CD33 targeted ADC with PBD payload, is currently in phase I for acute myeloid leukemia and is reporting emerging clinical safety and anti-tumor activity (presentation number DDT02-02).

Pre-clinical compounds of interest with PBD payloads are hLL2-PBD (ADC Therapeutics, Spirogen MedImmune, 637/7), SGN-70A (Seattle Genetics, 946) and PBD-ADC (Medimmune, 948).

Site-specific Conjugation

Rational design of the ADCs to improve the efficacy, safety and pharmacokinetics of ADCs is becoming an area of hot competition. An increasing number of key technology platforms are available to enable this rational design, including site specific cysteine conjugation such as THIOMAB™ (Genentech); novel linker strategies such as CORDLink (Invictus Oncology, 649/21) and SMARTag™(Catalent, 636/6); and alternative conjugation platforms such as Fleximer™ (Mersana Therapeutics, 641/11) and C-Lock™ & K-Lock™(Concortis Biosystems, 635/4). Not all site specific conjugation is good however, as it can sometimes lead to decreased activity (ImmunoGen 645/16). The development of a high throughput system for testing multiple THIOMAB™ variants to enable identification of antibody sites that are most suitable for conjugation to auristatin derivatives should enable faster identification of suitable ADCs for development (Genentech 650/23).

Compounds Showing Promise in Pre-clinical Testing

Immunomedics challenged the current dogma of using ultra-toxic drugs conjugated at low DARs when they presented results from their phase I/II trial of IMMU-132 (CT236, NCT01631552), an anti-trop2- antibody conjugated to SN-38 (active metabolite of irinotecan), a moderately toxic drug that is conjugated with a high DAR of 7.6. Toxicities experienced in patients with advanced cancers included neutropenia, febrile neutropenia, anemia, diarrhea, fatigue. Overall response rate of 23% for TNBC, 27% NSCLC, 26% SCLC and 4% for CRC. Equally, Mersana Therapeutics are developing an anti-HER2 ADC, XMT-1522 (LB-231/15), with a DAR of 15 using their Fleximer™ conjugation platform. This pre-clinical compound has nanomolar potency in vitro and has shown good tumor regressions in xenograft models. The compound shows good stability in plasma with minimal drug related toxicity in the heart and lungs of non-human primates. Another compound using the Fleximer™ conjugation platform to generated high DARs is the 5T4 targeting ADC ASN004 from Asana Biosciences (1693/26) which is showing promising results in murine xenograft models.

Compounds Showing Promise in Pre-clinical Testing Cont.

Other interesting targets for novel ADCs include fibroblast growth factor receptor 2 (FGFR2), CECAM5 (Sanofi, SAR408701; 1688/21), P-Cadherin (Novartis; 1682/15) and NOTCH3 (Pfizer, PF-06650808; 1697/30). Both Novartis and Bayer are developing ADCS against FGFR2. Bayer’s BAY1187982 is a fully human anti FGFR2 antibody (BAY117470) conjugated via a stable linker to Seattle Genetics novel auristatin agent and has recently started a phase I clinical trial NCT02368951.

The phase I dosing schedules were determined from all available pre-clinical data. Whilst Novartis’ pre-clinical compound is a FGFR2/4 dual targeting ADC that shows promise in both FGFR2 and FGFR4 positive tumors (1680/13). Interestingly, Pfizer initiated studies on 2 different NOTCH3 ADC (1697/30), one inhibitory and one non-inhibitory antibody. They have shown distinct internalisation routes. The non-inhibitory anti-NOTCH-3 ADC (PF-06650808) is in Phase I (NCT02129205).

Things to look our for on World ADC Trials Intelligence

We have started to research the immunotoxins and will continue with this into May. There are more clinical compounds than we first thought (25-30) and over 100 trials to add. We will also continue to layer on additional information on the trials that are currently on the database.

If you have any questions regarding the information that we are adding or just want to check something then please do send an email and we will work to get back to you within 24 hours.

Contact the World ADC Research Team on:

research@hansonwade.com