What's New in ADCs this Decade! Jan 27th, 2020

What's New in ADCs - Jan 27th, 2020

Happy New Year Everyone,

I think we can all agree that clearly we need to start off with a big round of applause for AstraZeneca, Daiichi Sankyo, and Seattle Genetics.  With a shoutout to the FDA for clearing their desk off at the end of the year for us all.

Clearly a rising tide lifts all boats, and so there is no other way to see this than an unmitigated win for the entire industry.  And now I am very optimistic that 2020 is a going to be a great year for ADCs.

On to the update.  But first:

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The plan is for these articles to evolve a little bit for 2020, so stay tuned, and sign up so that you don’t miss out.

Also, these articles have been indirectly sponsored by Novasep all along, but as we begin 2020 it’s time to ensure the longevity of these articles. So, I am going to use this platform to nerd out a bit on you. I will pose a question that you need to be asking your CDMO, and hopefully at the same time shed some light on how Novasep approaches some of the problems that we all face during ADC manufacturing.

 Choosing A CDMO : ADC Regulatory Strategy As we all know, most of the ADC manufacturing work is done through CDMOs.  This came about through a combination of the particular safety requirements of ADCs in conjunction with the fact that most companies don’t have enough ADC manufacturing needs to justify a stand-alone highly potent cGMP facility.  That all is well and good, but what happens when you take your preclinical asset and hand it over to someone else?  One area that always screams high risk to me is analytical method transfer into the GMP space.So the question that I would ask is, what does the tech transfer process between analytical development and Quality Control look like?  Who defines and writes the protocol, and who tests that protocol prior to validation?  And most importantly, what is going to happen in the event of a deviation upon that first GMP campaign?At Novasep, we start all of our analytical development scientists with QA certifications so that they know exactly what is going to be needed at the GMP level even when we are working in development.  From there, we have a fully comprehensive plan to ensure a smooth tech transfer all the way from day one to material release.  I don’t want to give away all of our secrets to LinkedIn, but if you are interested in learning more about our approach, call my cell at (724) 506 – 2469, and I would love to get into the nitty gritty with you.

1. A Happy Little bit of Shameless Self-Promotion

And while we're already doing some Novasep branding, take a look at this breakdown of the ADC naming scheme. If this looks like something that would look good on your desk. Comment below and let me know. We are having some printed out now, and once they are ready I can get them to anyone interested.


ADC Naming Scheme Deconstructed by Novasep

2. Pop the Champagne, it’s party time!

Obviously, I need to put these on here.  It’s impossible to imagine that this comes as new information. 

Why wait? The FDA stamps an ultra-fast OK on a HER2+ drug expected to create AstraZeneca's next blockbuster franchise

Endpoints News

- Of course we have to mention the major news of the month in the world of ADCs.  The $7B acquisition of DS-8201 my AZ doesn't seem so crazy anymore.  Is it just me, or does this feel like when the house next to you sells for way more than you expected.  I get almost giddy, because I know that sets a new bar for the value of my own house.  ADCs have just had their Zestimate go up.

As well as:

FDA Grants Accelerated Approval to Astellas’ and Seattle Genetics’ PADCEV™ (enfortumab vedotin-ejfv) for People with Locally Advanced or Metastatic Urothelial Cancer, the Most Common Type of Bladder Cancer

SeattleGenetics

- And not to be outdone, SeaGen has secured a nod from the FDA for their enfortumab vedotin molecule (now known as Padcev).  They now have two commercial ADCs on the market and one non-ADC oncology treatment on the books as well.  Is it a coincidence that they continue to be an industry leader and that their stock went up 109% in 2019?  No.  Very clearly No.

Now if there is one thing that is clearly a good sign for our industry it’s this:

Drug Developers Take Fresh Aim at 'Guided-Missile' Cancer Drugs

The New York Times

- Success begets success, and nothing says the ADC industry is on a nice run like a long form article in the New York Times.  Obviously the content will likely not be terribly new to the audience of this blog.  But I for one do a little happy dance every time our niche breaks out into the national spotlight.

3. Self Assembled ADCs

Shout out to Ed Ha for finding this little gem. 

Computationally designed antibody–drug conjugates self-assembled via affinity ligands

Nature Biomedical Engineering

- What’s cooler than an ADC?  A self-assembling ADC that uses computational biology to build a mAb-payload combination that allows for the AD(c) to come together in as little as 8 minutes.  Yes, I am thinking about all of the logistical issues that would inevitably come up too.  But it is also undeniably cool.  Can’t wait to see what else they come up with.

4. ADCs in the clinic – We are growing up

The Evolving Role of Brentuximab Vedotin in Classical Hodgkin Lymphoma

Oncology Nurse Advisor

- This article discusses the evolution of Kadcyla through the years.  It is a pretty interesting look at seeing the life of an ADC post approval.  As will likely be the case with these new approvals, it is not a fixed quantity but a series of progressive steps and expansion which can last for years and years.

And to be honest, this set of data makes me particularly happy:

Loncastuximab tesirine appears effective for relapsed or refractory DLBCL

Immuno-Oncology Resource Center

- ADC T continues to take the lead on PBDs in the clinic.  They were pretty much written off as too potent less than a year ago, but ADC T has continued forward and here is a perfect example of why.  Their ADCT-402 Phase II trial exceeded their primary endpoint and is looking good.  I have never believed in all of the PBD pessimism, but it's easier to talk than to be like ADC T and back that belief with research and clinical dollars.

4. And my two favorite topics for 2020 will be…

First, was a trend that we saw at World ADC.  There seemed to be a heightened interest in linkers, and I expect them to get their due this year:

Bioorthogonal Tetrazine Carbamate Cleavage by Highly Reactive Trans-Cyclooctene

ChemRxiv

- Paying attention to the linker has certainly been in vogue as of late, and the team at Tagworks is leading the pack.  Their paper describes a new method of cleavable linkers which can cleave faster and more efficiently than the current tranche of products available today.

Severing Ties: Quantifying the Payload Release from Antibody Drug Conjugates

Cell Chemical Biology

- And as if on cue from the last article, here is a nice review about cleavable payload release mechanisms using novel fluorescence based linkers in order to monitor release rate.

And my second favorite topic for 2020, Tumor Microenvironment:

Cancer Drug Delivery Systems Based on the Tumor Microenvironment

Springer Nature

- I think a major trend that I will be watching this year is the evolution of this focus on tumor microenvironment.  There are a number of companies out there already looking into this, but here is a nice review with multiple chapters discussing labile linkers and the current technology in the market.

5. One last point that I don't want to leave out

FDA grants orphan drug designation to OBI-999 for pancreatic cancer

Healio

- As anyone who incessantly follows the ADC world knows - or anyone listening to Beacon Intelligence - the ADC market get the most press in the US and EU, but things are moving very fast in Asia as well.  OBI Pharma has just received orphan drug designation for pancreatic cancer.  Current trials are ongoing.

Justin's Thoughts:

Things are rolling for the ADC world right now.  Three approvals last year, and the potential to match that again this year. 

I am particularly excited to watch ADC Therapeutics this year as I think they are really in store for some good things.  Also, I will be paying close attention to Synaffix as well.  It clearly looks like their tech is being well received, so it is only a matter of time before the clinical results start coming down the pike. 

Outside of that, welcome back to the working world everyone.  Let’s go do some science!  Or to be more accurate, You go do some science, and I will keep writing about it.  Best of luck to everyone in 2020.

Have a great week everyone!

-Justin

ADC Links - Jan 16th, 2019

Regulatory -

Why wait? The FDA stamps an ultra-fast OK on a HER2+ drug expected to create AstraZeneca's next blockbuster franchise
Endpoints News
- Of course we have to mention the major news of the month in the world of ADCs.  The $7B acquisition of DS-8201 my AZ doesn't seem so crazy anymore.  Is it just me, or does this feel like when the house next to you sells for way more than you expected.  I get almost giddy, because I know that sets a new bar for the value of my own house.  ADCs have just had their Zestimate go up.

FDA Grants Accelerated Approval to Astellas’ and Seattle Genetics’ PADCEV™ (enfortumab vedotin-ejfv) for People with Locally Advanced or Metastatic Urothelial Cancer, the Most Common Type of Bladder Cancer
SeattleGenetics
- And not to be outdone, SeaGen has secured a nod from the FDA for their enfortumab vedotin molecule (now known as Padcev).  They now have two commercial ADCs on the market and one non-ADC oncology treatment on the books as well.  Is it a coincidence that they continue to be an industry leader and that their stock went up 109% in 2019?  No.  Very clearly No.

FDA grants orphan drug designation to OBI-999 for pancreatic cancer
Healio
- As anyone who incessantly follows the ADC world knows - or anyone listening to Beacon Intelligence - the ADC market get the most press in the US and EU, but things are moving very fast in Asia as well.  OBI Pharma has just received orphan drug designation for pancreatic cancer.  Current trials are ongoing.

FDA Accepts Immunomedics' BLA Refiling for Breast Cancer Drug
Zacks Equity Research
- Wow.  2020 is going to be a banner year.  Immunomedics has been down but never out.  Their NDA was rejected by the FDA because of manufacturing issues, not efficacy.  Hopefully that means they were able to fix the issues, and this leads to yet another ADC approval later this year.

Industry -

Drug Developers Take Fresh Aim at 'Guided-Missile' Cancer Drugs
The New York Times
- Success begets success, and nothing says the ADC industry is on a nice run like a long form article in the New York Times.  Obviously the content will likely not be terribly new to the audience of this blog.  But I for one do a little happy dance every time our niche breaks out into the national spotlight.

Boehringer Ingelheim Venture Fund and PPF lead the closing of a USD 22M Series C financing round for NBE-Therapeutics
NBE Therapeutics
- And here is the first example of what I expect will be many more articles like this.  Obviously this deal was likely worked out prior to the latest ADC approvals, but it seems inconceivable that funding doesn't start flowing towards ADCs quite a bit faster for the rest of the year.


Manuscripts -

A Convergent Total Synthesis of the Death Cap Toxin α‐Amanitin
Angewantde Chemie
- For all of you a-amanitin fans out there, here is a nice paper describing a fully synthetic route for its synthesis. 

Bioorthogonal Tetrazine Carbamate Cleavage by Highly Reactive Trans-Cyclooctene
ChemRxiv
- Paying attention to the linker has certainly been in vogue as of late, and the team at Tagworks is leading the pack.  Their paper describes a new method of cleavable linkers which can cleave faster and more efficiently than the current tranche of products available today.

Severing Ties: Quantifying the Payload Release from Antibody Drug Conjugates
Cell Chemical Biology
- And as if on cue from the last article, here is a nice review about cleavable payload release mechanisms using novel fluorescence based linkers in order to monitor release rate.

LARGE SCALE PRODUCTION PROCESS FOR CAPPED AND UN-CAPPED ANTIBODY CYSTEINES AND THEIR USE IN THERAPEUTIC PROTEIN CONJUGATION
US Patent Application
- This is a pretty cool approach from the team at Pfizer.  They are looking at producing site-specific cysteine conjugations without the need for a complete reduction and oxidation as is standard in the normal Thio-mAb process.

Cancer Drug Delivery Systems Based on the Tumor Microenvironment
Springer Nature
- I think a major trend that I will be watching this year is the evolution of this focus on tumor microenvironment.  There are a number of companies out there already looking into this, but here is a nice review with multiple chapters discussing labile linkers and the current technology in the market.

Critical considerations in the formulation development of parenteral biologic drugs
Drug Discovery Today
- A nice overview about formulation development for biologics and the inherit troubles of dealing with pesky things like tertiary structure and activity.


Clinical Results -

The Evolving Role of Brentuximab Vedotin in Classical Hodgkin Lymphoma
Oncology Nurse Advisor
- This article discusses the evolution of Kadcyla through the years.  It is a pretty interesting look at seeing the life of an ADC post approval.  As will likely be the case with these new approvals, it is not a fixed quantity but a series of progressive steps and expansion which can last for years and years.

Loncastuximab tesirine appears effective for relapsed or refractory DLBCL
Immuno-Oncology Resource Center
- ADC T continues to take the lead on PBDs in the clinic.  They were pretty much written off as too potent less than a year ago, but ADC T has continued forward and here is a perfect example of why.  Their ADCT-402 Phase II trial exceeded their primary endpoint and is looking good.  I have never believed in all of the PBD pessimism, but it's easier to talk than to be like ADC T and back that belief with research and clinical dollars.

Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study
The Lancet
- GSK continues to make progress on their BCMA ADC candidate.  This paper discusses the results from the DREAMM-2 study which is still ongoing.  But it is clearly yet another sign that this is a good candidate for approval in the very near future.

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Thats it for today. There are always more coming down the pike. Is there something I missed? Contact me. Justin@ADCDaily.com
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