Thursday, October 17, 2019

ADCDaily - What's New in ADCs this Week - Oct 18th, 2019




Hello all,

It's been a full month since the last update already, which means there is a big backlog of news to get to.  In order to digest it down a little bit, I am going to tackle the older stuff first, and then get another post out next week to get us back up to date.

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

In addition to the articles that I post on LinkedIn, I also have a post which aggregates all of the relevant links that I have found related to the ADC world.  So if you want the full list, you can only get that by subscribing.  

There is a ton to talk about today, but I would like to first thank everyone who reached out to me at World ADC saying that they enjoy these articles.  It was a very nice boost to hear that people like these articles.  They end up taking quite a bit of time and energy, so hearing that they are having an impact really helps keep the motivation going.  

Also at World ADC,  I was able to give my first ever presentation for Novasep on DoEs.  Thank you to all who were able to attend.  For those who weren't able to attend, the content was eerily similar to the Webinar I hosted a couple weeks back and which can be seen here.  Hopefully they will have me back at the next conference because it was fun being up on stage talking about DoE.

So thank you all.

But for now, lets go to the links


1. The Highs and Lows of Clinical Oncology

There were two major studies released at ESMO this year.  First the good news:

SeattleGenetics
- Mark another success down for SeaGen at ESMO.  71% ORR is pretty impressive, and this demonstrates a steady march towards front line treatment.  There continues to be a significant cohort with heavy side-effects (51% in this study), but it seems mostly managable as only 9 patients stopped treatment so far

Unfortunately, we had some unfortunate news over at Immunogen:

ADC Review
- Esmo is here, so its time for an update on how the current ongoing trials are looking.  And IMGN853 (Immunogens FRa-DM4 ADC) is starting out with a miss.  Based on the presentation at World ADC, the reason is that they used a different method to select the patient population with overexpressed biomarkers.  If they had applied the same method as in the first study, then they would have met their endpoint.  As such, they are redoing the study with the original selection plan

The toughest part of the Immunogen results as described at World ADC was that the company had to choose between spending their existing cash on another Phase III study, or continuing to fund their R&D department.   They chose the former and let go of almost all of their scientific research team.  Hopefully this is only a temporary setback, but I've been part of this side of the industry before, and it's not an enviable position for anyone to be in

2. Have you heard?  Cancer is complex

There were a couple of different stories that all went together describing how cancer is not a static system.  We so often get lulled into thinking about a particular patient having cells with high over-expression of FRalpha as a measurable constant.  But it turns out the reality is a lot more complex than that

Endpoints News
- A new company names Divide and Conquer is coming at oncology from a different angle.  They argue that cancer is difficult to treat because the individual cells can behave in unison almost like an organ in fighting against apoptosis.  Therefore, if you can focus on decoupling the individual cells, then current oncology treatments should be more effective.  It's out there, but maybe effective at the same time?

The complexity doesn't stop there either, with an in-depth look at prostate cancer, this paper discusses the plasticity of prostate cancer and how the changing tumor microenvironment can change receptor availability:

Cancers

And if all of that wasn't enough evidence of a vastly more complex world than I want to admit to myself...

Drug Resistance Updates
- As targeted therapies emerge as a treatment option, the reality of drug resistance becomes a little more stark.  Here is a nice paper discussing the principles of drug resistance and the mechanisms of their action


3. Manuscript update - the very cool and the very scary

Lets start with the cool:

ACS Med. Chem
- Here is a new linker construction with a sulfur bearing maytanisoid payload and a cleavable tripeptide region to enable breakdown within the cell.  The cool part of the paper is that once the sulfur residue is exposed, it becomes S-methylated.  This results in a negligible effect on immediate efficacy, but also an increase in bystander effect after the first cell is dead

Drug Metabolism and Disposition
- I love this paper.  The team at Genentech did some foundational research comparing multiple linkers and payloads against two different mAb in xenograft models, and then analyzed for both internal and external concentrations of mAb, ADC, and released payload.  Read this one, it's worth the time

But then I came across this paper basically saying that our entire understanding of targeted therapy might be wrong

Cancer
- This report is a little bit scary.  These researchers used CRISPR to knock out the putative target antigen on a bunch of molecules currently undergoing clinical trials and showed that in many cases there was no effect on efficacy.  Which throws a little wrench into the whole target therapy idea.  At a minimum maybe this means that researchers should look into CRISPR as the go-to knock out technique above the tried and true RNAi?

But I wasn't the only one to read this paper,  The New York Times published an article about it, so I'll let them tell the rest of the story

NY Times

4. 23andMe is coming to the party

I have been following 23andMe for a long time.  Mostly because the business model always seemed a little suspect.  I can't blame them, they were following the model put forth by the Human Genome sequencing team.

Step 1: Sequence entire Genome
Step 2: ?????
Step 3: Cure all diseases!!!!  
(Bonus points if you can identify this reference in the comments section)

23andMe basically says, gather data first, figure out profit later.  And 15 years later, they are honing in on the profit side:

Stat
- 23andMe is jumping into the clinical trial game.  Taken along with the emerging trend of biomarker selection of patients, this makes a lot of sense, but is wildly different from traditional methods.  I think we all expected cheap DNA sequencing to revolutionize the pharma industry, and this looks like the start of a long road

And not to be completely alone in the space,  this news pairs nicely with the announcement from ADC T and Freenome last month looking to do something very similar but specific to the ADC space

Lymphoma News Today
- One of the trends in World ADC last week was the idea of leveraging biomarkers for patient selection.  In one camp, there is the argument that biomarkers should be the primary selective agent enabling you to be more agnostic to the specific type of cancer.  On the other side, you have the people arguing that biomarkers should be used to target a specific subset of a population of specific cancer patients.  Both sides have their issues: the reality that not all cancers will respond to a treatment in the same way irrespective of biomarker abundance, or significantly reducing the potential patient population, respectively
5. Two last points that I don't want to leave out

Apologies for not thinking of a clever way to integrate these last two points, but both are definitely worth a mention

Center for Biosimilars
- Am I the only one who is fascinated by watching the pharma industry handle biosimilars?  It seems so crass to watch the introduction of biosimilars (a nearly unquestioned win for patients) fight against the loss of innovator profits (making those greedy pharma companies the most hated industry in America -see last post).  The story gets more complicated when you think about where the ADC industry would be if it wasn't almost completely funded by those greedy innovators and their exhorbitant prices.  As for me, I am happy to just grab my popcorn, sit back, and watch the fireworks play out

And lastly, to round out with a little more technical content.  How about a little "Inifinite Selectivity" for your analytical analyses?

Analytical Chemistry
- Infinite selectivity for biopharmaceuticals sounds pretty good to me.  Call me a bit skeptical until I noticed that Alain Beck was the second author.  In my experience, multiple isocratic elutions seems a little messier in practice than in theory, but if these claims hold true, than this could be the new normal for ADC RPLC evaluation


Justin's Thoughts:

As I mentioned before.  Thank you again for everyone who commented on this blog at World ADC.  It means a lot to me, and definitely will keep me juiced to keep generating this content.  In fact, I'd like to figure out how to ramp up and get more.  So if you have any ideas, please let me know.  My email is Justin.Sweeley@novasep.com

Otherwise, I still promised two other articles (ADC Payload book review, and non-oncology ADC indications), and I haven't forgotten, so I will focus on those in the short term, but there is more to come.  I have lots of ideas after World ADC in San Diego last week.

Remember, liking these posts is good, and commenting is great.  They help get the articles seen, and the more eyeballs that see them, the easier it is for me to convince my bosses to keep supporting these articles (thanks bosses by the way!).

Have a great week everyone!
-Justin

ADC Links - Oct 17th, 2019

Regulatory -

FDA Grants Priority Review to Enfortumab Vedotin for Advanced Urothelial Cancer
Targeted Oncology
- This is pretty old news by now, and as I have talked about extensively - priority review is the norm for ADCs.  However, get ready for 2020, because it is getting poised to be a banner year for ADC approvals.  And nothing fuels new research like recent success

FDA's Technology Modernization Action Plan
FDA
- The FDA continues their march into the 21st century.   The crux of this plan is basically to better prepare for the incorporation of real-world data into FDA applications.  But the most interesting part for me was this, "enhancing FDA's capabilities to develop technology products to support its regulatory mission."  Products?  I'm not sure what that means, but it sounds like a big jump from the regulatory oversight that they are built for

Industry -

ESMO 2019: Iksuda Therapeutics’ IKS01 Demonstrates Effective Tumor Regression
ADC Review
- Iksuda (previously Glythera) is announcing positive results on their first ADC in a tumor model.  Like IMGN853, they are targeting FRa but using their proprietary Perlink linker tech along with Femtogenix's FGX2-62 payload

Tubulis and Glycotope Announce Research and Feasibility Agreement for the Discovery of Antibody Drug Conjugates
Business Wire
- Glycotope and Tubulis are partnering up to make some ADCs.  Glycotope has previously outlicensed their mAb assets to Daiichi Sankyo for ADCs so it looks like this time there are keeping it within house and bringing in some conjugation expertise (and IP) by partnering with Tubulis.  I will be interested to watch how this collaboration works out

Partnership Aims to Identify DLBCL Patients Likely to Benefit from ADCT-402
Lymphoma News Today
- One of the trends in World ADC last week was the idea of leveraging biomarkers for patient selection.  In one camp, there is the argument that biomarkers should be the primary selective agent enabling you to be more agnostic to the specific type of cancer.  On the other side, you have the people arguing that biomarkers should be used to target a specific subset of a population of specific cancer patients.  Both sides have their issues: the reality that not all cancers will respond to a treatment in the same way irrespective of biomarker abundance, or significantly reducing the potential patient population, respectively

As Biosimilars Close in for Its Blockbusters, Roche Looks to New Agents to Shore Up Sales
Center for Biosimilars
- Am I the only one who is fascinated by watching the pharma industry handle biosimilars?  It seems so crass to watch the introduction of biosimilars (a nearly unquestioned win for patients) fight against the loss of innovator profits (making those greedy pharma companies the most hated industry in America -see last post).  The story gets more complicated when you think about where the ADC industry would be if it wasn't almost completely funded by those greedy innovators and their exhorbitant prices.  As for me, I am happy to just grab my popcorn, sit back, and watch the fireworks play out

Ex-Ionis/Akcea exec Sarah Boyce takes charge at Avidity
FierceBiotech
- Avidity is an interesting company targeting Antibody Oligo Conjugates (AOCs).  The theory being that RNA can be specific and targeted, but is limited by its internalization into the cell.  Hence, using the natural internalization of mAbs can bring it into the cell and enable it to operate.  At the same time, this would be non-highly potent so the toxicity issue common in ADCs wouldn't be as much of a problem

Manuscripts -

Peptide-Cleavable Self-immolative Maytansinoid Antibody–Drug Conjugates Designed To Provide Improved Bystander Killing
ACS Med. Chem
- Here is a new linker construction with a sulfur bearing maytanisoid payload and a cleavable tripeptide region to enable breakdown within the cell.  The cool part of the paper is that once the sulfur residue is exposed, it becomes S-methylated.  This results in a negligible effect on immediate efficacy, but also an increase in bystander effect after the first cell is dead

Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials
Cancer
- This report is a little bit scary.  These researchers used CRISPR to knock out the putative target antigen on a bunch of molecules currently undergoing clinical trials and showed that in many cases there was no effect on efficacy.  Which throws a little wrench into the whole target therapy idea.  At a minimum maybe this means that researchers should look into CRISPR as the go-to knock out technique above the tried and true RNAi?

Why Aren’t Cancer Drugs Better? The Targets Might Be Wrong
NY Times
- It looks like I'm not the only one to read the last article.  Here is the team from the above article being interviewed about their research.  With the final outcome being, maybe we have been misguided by some previous RNAi research.

Proof of Concept To Achieve Infinite Selectivity for the Chromatographic Separation of Therapeutic Proteins
Analytical Chemistry
- Infinite selectivity for biopharmaceuticals sounds pretty good to me.  Call me a bit skeptical until I noticed that Alain Beck was the second author.  In my experience, multiple isocratic elutions seems a little messier in practice than in theory, but if these claims hold true, than this could be the new normal for ADC RPLC evaluation

Exposure-Efficacy Analysis of Antibody-Drug Conjugates Delivering an Excessive Level of Payload to Tissues
Drug Metabolism and Disposition
- I love this paper.  The team at Genentech did some foundational research comparing multiple linkers and payloads against two different mAb in xenograft models, and then analyzed for both internal and external concentrations of mAb, ADC, and released payload.  Read this one, it's worth the time

Therapeutic Targeting of Golgi Phosphoprotein 2 (GOLPH2) with Armed Antibodies: A Preclinical Study of Anti-GOLPH2 Antibody Drug Conjugates in Lung and Colorectal Cancer Models of Patient Derived Xenografts (PDX)
Targeted Oncology
- A new ADC epitope target, GOLPH2.  This paper looks like every other new potential target.  I'll hold my breath for this one becoming reality.  But hopefully it does

The emergence of drug resistance to targeted therapies: Clinical evidence
Drug Resistance Updates
- As targeted therapies emerge as a treatment option, the reality of drug resistance becomes a little more stark.  Here is a nice paper discussing the principles of drug resistance and the mechanisms of their action

Nongenotoxic antibody-drug conjugate conditioning enables safe and effective platelet gene therapy of hemophilia A mice
Blood Advances
- Here is another example of an ADC being used as a pretreatment (I'm looking at you Magenta).  In this case the pretreatment is enabling gene therapy in mice.  Additionally, they are looking a unique saporin payload which goes after ribosome inactivation instead of mitosis (microtubulin and DNA intercolation mechanisms like most common ADC payloads).



Non-ADC Oncology -

'Disconnect the bastards' — one biotech's plan to break cancer cells' unified defenses
Endpoints News
- A new company names Divide and Conquer is coming at oncology from a different angle.  They argue that cancer is difficult to treat because the individual cells can behave in unison almost like an organ in fighting against apoptosis.  Therefore, if you can focus on decoupling the individual cells, then current oncology treatments should be more effective.  It's out there, but maybe effective at the same time?

Neuroendocrine Differentiation of Prostate Cancer—An Intriguing Example of Tumor Evolution at Play
Cancers
- There is no end to the complexity of tumors.  On top of all of the other factors at play, this paper discusses the plasticity of prostate cancer and how the changing tumor microenvironment can change receptor availability.

23andMe, moving beyond consumer DNA tests, is building a clinical trial recruitment business
Stat
- 23andMe is jumping into the clinical trial game.  Taken along with the emerging trend of biomarker selection of patients, this makes a lot of sense, but is wildly different from traditional methods.  I think we all expected cheap DNA sequencing to revolutionize the pharma industry, and this looks like the start of a long road


Clinical Results -

ESMO 2019: FORWARD I Study of Mirvetuximab Soravtansine in Ovarian Cancer Did Not Meet Primary Endpoint of Progression-Free Survival
ADC Review
- Esmo is here, so its time for an update on how the current ongoing trials are looking.  And IMGN853 (Immunogens FRa-DM4 ADC) is starting out with a miss.  Based on the presentation at World ADC, the reason is that they used a different method to select the patient population with overexpressed biomarkers.  If they had applied the same method as in the first study, then they would have met their endpoint.  As such, they are redoing the study with the original selection plan

Investigational ADC is Well Tolerated with Partial Dose-dependent Response in NSCLC
OncoZine
- Daiichi's Trop2 ADC has its first clinical results coming out.  It looks like they had a decent response with a dose dependent response.  The drug was well tolerated and they are proposing to move forward at 8 mg/kg which showed a response rate of 12 out of the 46 patients in the study.  Either way, it's always good news that the trials will continue at this heightened dose and we can get a better idea about the efficacy as work progresses

First-in-Human Phase I Study of Aprutumab Ixadotin, a Fibroblast Growth Factor Receptor 2 Antibody–Drug Conjugate (BAY 1187982) in Patients with Advanced Cancer
Targeted Oncology
- You know what makes this paper unique?  The study failed it's primary endpoint goals.  There is clearly a success bias in reporting of clinical trials (See Daiichi above) for business reasons, but getting a truly quantitative picture about the rates of success within ADCs is critical, and likely underdiscussed, or at least underanalyzed.  I wonder what the failure rate of first in human clinical trials for ADCs is and how that compares to other therapeutic areas.

Seattle Genetics and Astellas Announce Results from Phase 1 Trial of Investigational Agent Enfortumab Vedotin in Combination with Immune Therapy Pembrolizumab as First-Line Treatment for Advanced Bladder Cancer
SeattleGenetics
- Mark another success down for SeaGen at ESMO.  71% ORR is pretty impressive, and this demonstrates a steady march towards front line treatment.  There continues to be a significant cohort with heavy side-effects (51% in this study), but it seems mostly managable as only 9 patients stopped treatment so far
Here's a little more context about this release from the team at Biopharma Dive


-----------------------------
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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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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Friday, August 30, 2019

ADCDaily.com - Aug 30th, 2019 - 5 Things in ADCs this Week




Hello all,

It’s been almost three weeks since my last update which means that there is a massive amount of material to cover and I can’t get to it all in this little update. 

If you want to check out all of the links that I have aggregated over the past three weeks, go over to https://www.adcdaily.com/ and click on the ADC Links Section Header.  In these posts I just aggregate all of the relevant links that I find before winnowing down for these update articles.  But it you want to quickly see anything and everything that I thought was related to ADCs, then this is the place.

While you’re there, click on the list to join the mailing list, and then you can get every post directly to your inbox.  We had quite a few people join after the last posting, so come join the cool kids and gets your ADCDaily posts automatically.

And one last thing.  I am excited to announce that I will be hosting a Webinar next month.  It will be chock full of ADCs and DoEs.  I will do my best not to get too excited, but I most certainly love geeking out with DoEs and we have some pretty cool case studies planned for you.  It’s being held on Sep 24th at 11 EST.  Hope to see you all there.


And with that, it’s time for our five things this week…

Tuesday, August 27, 2019

ADC Links - Aug 27rd, 2019

Webinars -



Regulatory -

US senators accuse Novartis execs of greed for hiding manipulated Zolgensma data — and the next step could affect the industry
Endpoints News
- This story is huge and won't be going away any time soon.  This line seems pertinent to us, "this attack includes a shot right over the industry’s bow — with potential consequences for all drug developers"

The FDA’s very public slap of Novartis’ red face is a warning to the entire industry — don’t downplay it
Endpoints News
-Wow, this grenade just keeps getting bigger and bigger.  I think we can all expect blowback from this one

Statement on data accuracy issues with recently approved gene therapy
FDA
- It's never a good thing when you have to have a direct statement about your work from Dr. Peter Marks, the Director of CBER at the FDA.  But here is a perfect reason why it is better to read articles from the original source instead of the news aggregators viewpoint.  This line sticks out, "The FDA is carefully assessing this situation and remains confident that Zolgensma should remain on the market."  It sounds to me like there are taking the issue seriously, but that when the dust settles, things are going to be OK for Zolgensma even though there are clearly going to be some casualties along the way

Faced with another ethics scandal, Novartis CEO Vas Narasimhan assures analysts they tried to do 'the right thing'
Endpoints News
- I mean, after all of these reports, I still have to think about what amount of power one scientist can have.  Because really, this doesn't sound like systemic fraud, it sounds like a person or small group of people did a slight augmentation of their results to make their bosses happy.  Obviously this is wrong, but I think it is also something that every single person in lab can relate to

FDA approves third oncology drug that targets a key genetic driver of cancer, rather than a specific type of tumor
FDA
- Here is an interesting trend.  The FDA is getting more open to approvals which are focused on a specific biomarker instead of the tumor type or location.  These are not in the ADC space yet, however this is specifically what ADCs do.  They bind a specific biomarker and then get to work.  Currently, we are seeing ADCs get approved for one type, and then attempt to expand the types over time.  This trend might render that unnecessary and allow for HER2 ADCs to target any tumor with HER2 overexpression

Industry -

A top analyst spotlights a wave of biotech startups looking to catapult onto Nasdaq — or get bought out
Endpoints News
- As I always say, the best leading indicator for our market is $$$.  So signs like this are a good thing.  Investment is up, and so is M&A.  All of these things make it more profitable to be a biotech startup, and since that is where a big portion of ADC companies live, this is a good thing


The UK company Antikor Biopharma has received a €2.8M ($3.1M) investment from the Hong Kong company Essex Bio-Investment
LabBiotech
- Antikor has a little bit thicker wallets today after a $3.1M investment from Essex Bio-Investment.  Now they will have a chance to further their FDC (Fragment Drug-Conjugates) technology

How Biotech Startup Funding Will Change in the Next 10 Years
YCombinator Blog
- Alright, so lets take this one with a big grain of salt.  As I often say, never ask a barber if you need a haircut.  However, this is an interesting take on the potential future of biotech.  Although there is the inherit difference in that YC makes apps and algorithms while we make complex chemicals for use in even more complex systems and that will always be true.  You don't see YC startups trying to upend Exxon or Anheiser-Busch because it took them 100 years to build the distribution network that they currently have, and the VC model doesn't have that kind of patience

ADC Therapeutics and SOPHiA GENETICS Partner for Biomarker Discovery in Pivotal Phase II Clinical Trial
Global Newswire
- And in a nice corollary to the article directly above this one.  SOPHiA GENETICS is trying to bring some deep learning into ADC clinical trials.  This looks like a fishing expedition for now, but if this bears fruit and they can use this to improve patients outcomes, then this could be a really interesting collaboration

Road Tripping Treatments
AbbVie Blog
- Here is another example of non-oncology ADCs.  The team at AbbVie spent five years researching an application of ADCs in immune-mediated diseases.  After 100 different linkers and 200 different payloads they finally have a candidate.  This is a cool story, and some really incredible work

Araris Biotech AG closes seed financing round of CHF 2.5 million
Global Newswire
- It's time to welcome a newcomer to the ADC world.  Araris has closed their seed round and they are looking to develop their own ADCs using a proprietary conjugation technology which can be applied to native antibodies.  Hopefully this is just the first of many positive news stories

GSK's Hal Barron heralds their second positive PhIII for crucial anti-BCMA therapy, pointing to a push for quick OKs in a crowded field
Endpoints News
- The pressure is on for GSK to have some success with their belantamab mafodotin ADC currently in Phase III trials.  So far, all signs are positive, but win or lose, this is a major event for GSK.  There is a lot of competition for BCMA targets, but as the CEO of SeaGen states, "Its in a vial."  Which at the end of the day is worth way more than any mouse models could be

Manuscripts -
Prodrugs as drug delivery system in oncology
Cancer Chemotherapy and Pharmacology
- Here is a fantastic review of Prodrugs in oncology.  The timing is perfect as in the last article I suggested the possibility of doing something like this but this article is better and more complete than anything I would be able to do.

Synthesis of Highly Potent N-10 Amino-Linked DNA-Alkylating Indolinobenzodiazepine Antibody–Drug Conjugates (ADCs)
ACS Med Chem Letters
- One of the prominent themes of World ADC London this year was the modification of DNA intercolating payloads in order to increase the therapeutic window of ADC therapies.  Here the team at ImmunoGen is showing an example of what this can look like and how to synthesize new and improved payloads for use in ADC trials

Novel Antibody-Drug Conjugate with Anti-CD26 Humanized Monoclonal Antibody and Transcription Factor IIH (TFIIH) Inhibitor, Triptolide, Inhibits Tumor Growth via Impairing mRNA Synthesis
Cancers
- Here is a pretty cool example of a novel payload mechanism on an ADC.  Here the authors were looking at a transcription factor inhibitor (TFIIH) bound to an antibody.  They showed some success in their model but while this is still a long way off, it is interesting to see research moving away from HPAPI as this might be a way to open up that therapeutic window

Simultaneous quantification of total antibody and antibody-conjugated drug for XMT-1522 in human plasma using immunocapture-liquid chromatography/mass spectrometry.
J Pharm Biomed Anal
- This is a pretty cool manuscript describing how they analyze plasma samples for ADC and antibody during their Phase I clinical trial.  If that weren't cool enough, it also shows an example of a mass spec method being validated for clinical results which is both rare and impressive.  Recently the FDA put out a guidance document alluding to their expectation that this would be happening more and more

A Superglue for ADCs: Connecting the Cytsteine Residues of a Tumor-sensing Antibody to a Payload
ADCReview
- German scientists have developed a new and novel linker technology to be applied to ADCs.  They are hoping to go the opposite route of cleavable linkers and build something robust enough to eliminate the problem of free drug cleavage in the bloodstream

A Case Study Comparing Heterogeneous Lysine- and Site-Specific Cysteine-Conjugated Maytansinoid Antibody-Drug Conjugates (ADCs) Illustrates the Benefits of Lysine Conjugation
Mol Pharmaceutics
- The trend in ADCs for the past couple of years is to move away from stochastic conjugation and towards site-specific.  The argument goes that greater homogeneity will result in greater effectivity.  However, this paper serves as a case in point to the contrary.  And as might be expected.  The final result is: its complicated.  Take a look if you are willing to buck dogma and go against the ADC orthodoxy for a bit

Effect of Linker Stereochemistry on the Activity of Indolinobenzodiazepine Containing Antibody–Drug Conjugates (ADCs)
Medicinal Chemistry Letters
- Nice article on the effect of stereochemistry in PBD linker development.  They were looking at different combinations of l- and d-alanyl groups in the labile region of the linker and seeing their effect on therapeutic index.  Its nice to see some work on the foundational science behind ADC construction in a world so heavily biased by what is on trend these days (ie. PBDs are bad, and site-specific conjugation is good)

Alteration of Physicochemical Properties for Antibody Drug Conjugates and Their Impact on Stability
JPharmSci
- An article about how payload conjugation modifies the properties of mAbs and then the impact upon ADC stability

Engineered collagen-binding serum albumin as a drug conjugate carrier for cancer therapy
ScienceAdvances
- Researchers are looking at using a serum albumin carrier conjugated to a collagen-binding domain which is in turn conjugated to a pH-labile Doxorubicin payload.  Its a novel approach to an ADC and is showing some success in mouse models

Incorporation of a Hydrophilic Spacer Reduces Hepatic Uptake of HER2-Targeting DM1 Drug Conjugates
Cancers
- I love seeing all of the work on the linkers.  They are so often left on the sidelines of the discussion but their manipulation can have a significant effect on therapeutic index.  Here the team was looking to decrease hepatic uptake through linker modifications

Reports -



Clinical Results -
Dr. Bhave Discusses [Fam-] Trastuzumab Deruxtecan in HER2+ Breast Cancer
OncLive
- Dr. Bhave talks about the steady progression of Daichii's progress through the clinic as well as the competition with T-DM1

Nivolumab Combined With Brentuximab Vedotin for Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma: Efficacy and Safety From the Phase II CheckMate 436 Study
DocWire
- Chalk another win up for SeaGen and Adcetris.  The combination therapy is showing good results with an ORR of 73% and a full remission rate of 37%.  Not too shabby

The evolving role of trastuzumab emtansine (T-DM1) in HER2-positive breast cancer with brain metastases
Critical Reviews in Oncology/Hematology
- Here is a nice review of Kadcyla in patients with brain metastases.  Apparently HER2 overexpression isn't just a positive indication for Kadcyla, but it also comes with an increased chance for brain metastases.  And, as we know, ADCs cannot get beyond the blood-brain barrier to be effective.  However, despite this, Kadcyla has proven partially effective in these patients.  Maybe the reason isn't clear, but it is definitely interesting

Other - 

Pig to human heart transplants 'possible within three years'
The Guardian
- This is just really cool.  I also like how their microRNA treatment was able to restore heart cells damaged from the heart attack to"almost complete recovery" after a month, but then follows that up with, "most of the treated pigs died after the treatment because the microRNA-199 continued to be expressed in an uncontrolled way."  Oops


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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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