Tuesday, September 17, 2019

ADCDaily.com - Sep 17th, 2019 - This Week in ADCs


Hello all,

It's been another big couple of weeks in the ADC world.  I'm still astonished at how quickly the news comes flying at us.    But hopefully that is exactly why this series of articles exists.

If you want to receive these updates directly to your inbox, then all you need to do is click on the link below:
Click Here to Subscribe to ADC Daily

Right now, this means that you will receive one link with all of the relevant links that I have found throughout my searching over the past week or two.  And then you will receive a copy of the 5 Things articles as they are published.   And I can tell you as I go through the articles this week.  There are way too many than I can talk about, so if you want a full picture, then you are going to want to subscribe.

We are just getting started, so don't miss out.  I mean, where else are you going to find a custom tailored list of ADC news and manuscripts specifically put together for the scientists and researchers in the world of ADC?

And now, on to the good stuff.


1. Webinar Alert : DoEs in ADCs presented by me

Now clearly this is a nice healthy dose of shameless self-promotion.  So click here, and register now!

Webinar: When to Apply Design of Experiments (DoE) to ADC Development

I have been trying to put together this presentation for the last 4 years, and thanks to the spectacular team in Le Mans, I've got some really good data to demonstrate the power of DoE in ADC development.  I absolutely love nerding out about DoEs, so at the very minimum you can watch me get entirely too excited about this stuff.  And, perhaps, you might learn something at the same time.  So if it sounds interesting, please register and check it out.


2. Have you heard?  ADCs can cure cancer!

Long-term remission by brentuximab vedotin for non-mediastinal gray zone lymphoma refractory to autologous stem cell transplantation
Clinical Lymphoma Myeloma and Leukemia

Here is a nice case study of a woman undergoing multiple rounds of chemotherapy without success until receiving 9 doses of Kadcyla.  This treatment resulted in a complete response that has lasted for 3 years.
Now we all know at an intellectual level that the work that we are doing has real impacts on humanity.  But when I see something like this, I just like to pause for a minute...

And for one brief moment lets forget about all of the other details, revenue targets, profit margins, FDA approvals...  And remember what it is that brings us into work on Monday morning.


3. Light Responsive ADCs

A light-responsive, self-immolative linker for controlled drug delivery via peptide- and protein-drug conjugates†‡
Royal Society of Chemistry

I don't know why, but I have always thought photosensitive prodrugs are an elegant solution to the toxicity issues often associated with ADCs.   This team shows a mechanism to deliver and release doxorubicin intracellularly through antibodies and light.
Most of the time when I see these types of things, I start worrying that you are adding extra complexity to an already complex endeavor, but I guarantee that is exactly what people in the mAb industry were saying during the start up of ADCs.  But wait, there's more...

Near Infrared Photoimmunotherapy: Photo-Activatable Antibody-Drug Conjugates (ADCs)
Bioconjugate Chemistry

If you thought I was excited about one photoactivated ADC. How about two?  This one using a near-infrared photoactivatable dye. 

4. Pay Attention to ADC Therapeutics

Now I can admit, I love economics, and it's possible that I pay too much attention to financials instead of just focusing on the science.  But my question to you all is this...

Currently, PBDs are having a little bit of a rough patch (as I have discussed before).  So based on technology alone, one would think that a company who's primary technology is based on PBDs would be having a little trouble raising money.

Swiss biotech ADC Therapeutics guns for $150M IPO
FiercePharma

So then why is ADC T, after coming off of a very impressive funding round of over $275M and reaching a total funding of over $500M still able to look at another $150M in their upcoming IPO?

I've said this before, but it's worth repeating.  Good clinical results are vitally important, but they are a lagging indicator.  If you want to know what is coming up on the horizon.  Follow the money.

All I'm saying is, these guys are legit, and are definitely a company that you should keep your eye on.


5. The FDA wants to modernize

FDA to roll out modernization plan in push for data interoperability
Endpoints News\

FDA to Roll Out Modernization Plan in Push for Data Interoperability
Regulatory Focus

Alright, I have now read these two articles twice each.  And I am still confused.  So here is my summary:

The goal of the FDA is interoperability.  And with more interoperability, they will be more interoperable.  Did I mention that the FDA wants to modernize and increase their interoperability?  All things considered, this is a good thing, the FDA wants to move faster and get drugs to market faster, but if they are going to use the "I" word that many times it would probably be worth defining it.

However, you cannot change something without the inevitable pushback:

Academics and researchers raise concerns with FDA’s plan for ‘integrated reviews’
Endpoints News

And with any change, such as the above link, there is going to be pushback.  If the goal is faster, then at some point that means less of something.  And less of something usually means you are not including something which used to be included.  Apparently that has some researchers concerned that valuable information can be expunged.  Only time will tell, but it seems like this type of back and forth is usually the best way to get a good final outcome.

Justin's Thoughts:

Alright, there was one article that I wanted to share, but that I couldn't get myself to put in the 5 Things section

Big Pharma Sinks to the Bottom of U.S. Industry Rankings
Gallup

Sure, its depressing to be the last in anything.  I mean, I can handle our industry being behind the Airlines, Banking, and Lawyers (to be honest, lawyers hurts a bit).  But to find out that pharma ranks behind Government in favorability is just adding insult to injury.  I guess people don't really care about cures for cancer, blind people regaining sight, or antibiotics and vaccines.  I mean, Polio wasn't really all that bad.

And on that note: One last plug for the Webinar because I can...

Webinar: When to Apply Design of Experiments (DoE) to ADC Development

Have a great week everyone!

-Justin


Wednesday, September 11, 2019

ADC Links - Sep 11th, 2019

Webinars -

Webinar: When to Apply Design of Experiments (DoE) to ADC Development
ADCReview
- Clearly there is a little home-town bias going on here.  But come check out my webinar in two weeks.  I will be diving into some examples of DoE application in ADC development

Regulatory -

FDA to roll out modernization plan in push for data interoperability
Endpoints News
- The goal of the FDA is interoperability.  And with more interoperability, they will be more interoperable.  Did I mention that the FDA wants to modernize and increase their interoperability?  All things considered, this is a good thing, the FDA wants to move faster and get drugs to market faster, but if they are going to use the "I" word that many times it would probably be worth defining it.

Academics and researchers raise concerns with FDA’s plan for ‘integrated reviews’
Endpoints News
- And with any change, such as the above link, there is going to be pushback.  If the goal is faster, then at some point that means less of something.  And less of something usually means you are not including something which used to be included.  Apparently that has some researchers concerned that valuable information can be expunged.  Only time will tell, but it seems like this type of back and forth is usually the best way to get a good final outcome.

FDA in Brief: FDA encourages inclusion of male patients in breast cancer clinical trials
FDA
-Lookout men, it's time for us to get involved in the breast cancer trials business.  The occurance of male breast cancer is rare so the clinical trials have been non-existant.  The FDA is issuing this guidance to change that.

Don’t Give Up on Biosimilars—Congress Can Give Them a Boost
Wall Street Journal
Scott Gottlieb - former FDA commissioner - has put out an opinion article attempting to get congress to move forward with a plan to bolster the biosimilars market.  Clearly this is a sign that biosimilar adoption has not gone well in the US and that it is going to take some serious muscle to bring it around.

Drug pricing looms large on Congress' September agenda
Politico
- Ok, now I get it.  Scott Gottlieb is one smart cookie.  Conveniently placing an Op-Ed in a place that congressman can't ignore, immediately prior to the committees taking this up after their summer recess.  Smart move.

Industry -

ADCendo Secures Funding to Fill Gap After Market Withdrawal of Olaratumab in STS
ADCReview
- There is a new kid on the block.  ADCendo has secured initial funding to test their novel ADCs at the BioInnovation Institute in Copenhagen.

Swiss biotech ADC Therapeutics guns for $150M IPO
FiercePharma
- Clearly $276 M isn't enough cash to fund ADC T's dreams, so they are looking at adding another $150 M from public financing.  I don't think you can find another player in the ADC world that is pushing so hard to become a massive player in the space.  Definitely keep you eye on them as they are shooting for the stars

The case for single-use architecture in pharma
Manufacturing Chemisty
- Here is a look at the future.  It doesn't include only single-use architecture, but also the augmented reality infused operation of them.  Pretty wild idea, but you have to appreciate the ambition.

Cancer drugs' share of new FDA approvals doubled this decade thanks to smarter R&D: report
FiercePharma
-The good news, cancer drugs are growing like gangbusters.  The bad news, cancer drugs are still incredibly expensive.  It costs increasingly more money to get a drug to market, and unsurprisingly, that cost passes along to patients.  One would expect that higher approval rates and lower approval times would help, but you can't see that in the data

OBI Pharma Announces U.S. FDA Clearance of IND Application for a Phase 1/2 Study of its Antibody-Drug Conjugate (ADC) targeted cancer therapy, OBI-999
OBI Pharma
-OBI pharma is announcing that they will be starting their first ADC in clinical studies.  They are targeting a Globo H antigen which definitely means they shouldn't expect much competition on the antigen side.  We'll have to keep an eye out to see how the do in the future

Big Pharma Sinks to the Bottom of U.S. Industry Rankings
Gallup
- Sure, its depressing to be the last in anything.  But to find out that pharma ranks behind the government in favorability is just adding insult to injury.  I guess people don't really care about cures for cancer, blind people regaining sight, or antibiotics and vaccines. 

Manuscripts -

Comparison of Analytical Methods for Antibody–Drug Conjugates Produced by Chemical Site-Specific Conjugation: First-Generation AJICAP
Analytical Chemistry
- The team at Ajinomoto has been working on their Ajicap site-specific conjugation technology on native mAbs for a little while now.  Here is a paper demonstrating their progress with a specific focus on the analytical techniques that they employed to demonstrate the site-specificity

A light-responsive, self-immolative linker for controlled drug delivery via peptide- and protein-drug conjugates†‡
Royal Society of Chemistry
- I don't know why, but I think photosensitive prodrugs are an elegant solution to the toxicity issues often associated with ADCs.   This team shows a mechanism to deliver and release doxorubicin intracellularly through antibodies and light.  Pretty cool.

Near Infrared Photoimmunotherapy: Photo-Activatable Antibody-Drug Conjugates (ADCs)
Bioconjugate Chemistry
- If you thought I was excited about one photoactivated ADC. How about two?  This one using a near-infrared photoactivatable dye. 

A Case Study to Identify the Drug Conjugation Site of a Site-Specific Antibody-Drug-Conjugate Using Middle-Down Mass Spectrometry
Journal of Am. Society for Mass Spec
- This team from the University of Strasbourg is looking at using middle-down mass spec to get around some of the complications which arise from doing bottom-up mass spec on ADCs.  Bottom-up is standard practice for mAbs, but the introduction of a hydrophobic linker-payload can lead to issues that they are trying to get around.

CRISPR-Cas9 screens identify regulators of antibody–drug conjugate toxicity
Nature Chemical Biology
- CRISPR is cool.  We get it.  But here is a perfect application of CRISPR in an academic situation (Stanford) to facilitate ADC development.  The team has been able to use CRISPR to knock-out and modify genes involved in the ADC internalization pathway to learn more about he actual mechanism of internalization and breakdown.  This is valuable research which just isn't going to be carried out by pharma companies, and which is perfect for academic labs.

Variation of Trop2 on non-small-cell lung cancer and normal cell membranes revealed by super-resolution fluorescence imaging
Talanta
- I just didn't want to miss an opportunity to share some really cool images about a common ADC target (Trop2).  It's so easy to resort to abstractions when thinking about antibody binding.  It's things like this image that bring everything home and remind me that we are talking about physical things that exist.  A single mAb will reach out and bind to this thing.  And there are real issues like steric hindrance, and antigen saturation to worry about.

Reports -


Clinical Results -

Long-term remission by brentuximab vedotin for non-mediastinal gray zone lymphoma refractory to autologous stem cell transplantation
Clinical Lymphoma Myeloma and Leukemia
- Here is a nice case study of a woman undergoing multiple rounds of chemotherapy without success until receiving 9 doses of Kadcyla.  This treatment resulted in a complete response that has lasted for 3 years.

MDSC targeting with Gemtuzumab ozogamicin restores T cell immunity and immunotherapy against cancers
EBioMedicine
- This is extremely cool.  Myeloid-Derived Suppressor Cells (MDSCs) can form a layer around solid tumors preventing CAR-T therapies from working.  MDSCs also have overexpression of CD33 (the same antigen as Mylotarg).  Researchers found that Mylotarg can reduce the MDSCs around solid tumors and thereby allow the CAR-T therapies to be more effective.

Time‐to‐Event Modeling of Peripheral Neuropathy: Platform Analysis of Eight Valine‐Citrulline‐Monomethylauristatin E Antibody–Drug Conjugates
Pharmacometris and Systems Pharmacology
- This paper is out of Genentech and does a complete analysis of over 700 patients who have received the SeaGen vcMMAE (vedotin) payload in chemotherapies.  The researchers are looking of the aggregate effects of vcMMAE on peripheral neuropathy and found that PN risk was directly linked to dose administered among other things.  Beyond the data being interesting, this is a great thing to see come out of a company like Genentech.  So much of our understanding comes from copying the guy before us, its studies like this that truly define things like vcMMAE and help guide the future

Daiichi Sankyo Advances [Fam-] Trastuzumab Deruxtecan (DS-8201) in Japan with Regulatory Submission in HER2 Positive Metastatic Breast Cancer
PipelineReview
- Daiichi is moving forward with DS-8201 NDA filing in Japan based on their Phase II study results.  Expect this to be closely followed by the US and EU applications early next year.  All of this is good news for their flagship ADC product, and their proprietary DXd payload tech.

Late-breaking Results: HER3 Targeting U3-1402 in Patients with Metastatic EGFR Mutated, TKI Resistant NSCLC Shows Promise
ADCReview
- Daiichi continues their streak of good news with a total response of 22 out of 26 patients in their HER3 Phase I trial




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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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