Monday, October 28, 2019

What's New in ADC's This Week - Oct 28th, 2019



Hello all,

I'm back, and in record time.  As promised, I have completed my link aggregation to get us all back up to date with the world of ADC.  So please enjoy the latest news and happenings related to antibody-drug conjugates.

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

Yes, this will get you this article in your inbox.  Also, you will get the full list of links that I have found and thought was interesting.  But coming very soon, I am working on how to get you all involved in this with me.  So if you are interested in being directly plugged in to the latest ADC news, and contributing on anything from answering a poll question to who knows what, then sign up here.  

As a first example of subscriber participation.  Coming soon, I will be putting out a summary of World ADC San Diego highlighting all of the most interesting points from the conference this year.  But instead of just my opinions, I am enlisting the help of some fellow readers who were also conference attendees.  It should be fun.  So expect to see that article coming soon.

And as always, please reshare this article to spread the love and keep these articles coming.  But for now, lets go to the links


1. ADCs in Space!!!


International Space Station
I cannot describe how happy this article makes me.  On one hand I can espouse the logic of testing cancer therapies in microgravity because it more closely mimics a tumor microenvironment than a typical cell culture would.  But the reality is, this is just combining two awesome things to make for something even awesome-er.  

A smart man once proposed a theory to me:  You can take anything in the world, and make it cooler by putting it in space.  

Pen --> Space Pen.  
Monkey --> Space Monkey.  
And now, 
Tumor Regression --> Space Tumor Regression.

Way to go AngieX team, you have made my day


2. Lots of New Companies Jumping into the ADC Space


There is a ton of new companies jumping into the fold.  And while their each coming from a very different place.  It's great to see all of the diversity and interest coming into the space: 

Cancer Therapy Advisor
- Oxford has been in the oncology space for a long time, but this is their first forray into ADCs. They have received approval to start a clinical trial for their ADC targeting CD205 with a DM4 payload in pancreatic cancer in partnership with Menarini. All I can say is, Welcome to the ADC party Oxford. Best of luck with your trials

Now for the next company, I saw their presentation at World ADC and was really impressed.  It does sound like an added complication on top of a complicated process, but it is an interesting approach along with prodrugs like CytomX is working on.  The benefit here is that the change is reversible so it can go back to inert when it leaves the area:

USPatent Office
- I generally don't report on patents, but I just love the technology of BioAtla. The primary technology allows for mAbs which are only active in the tumor microenvironment, but this patent is leveraging their tech to enable crossing through the blood-brain barrier. As far as unique approaches, BioAtla, is looking pretty interesting right now

And last but not least, another conjugation technology focused company is bringing in the big guns to its Board of Directors

Biospace
- Rakesh Dixit and John Lambert are joining the board at Araris.  Both of whom can bring an extensive amount of experience to the table and a long rolodex of connections as well.  Paired with some cool conjugation tech, it will be fun to watch what types of moves Araris takes next.

3. Unique Applications of ADC technologies

Clearly this is my favorite category of new stories to write about.  Each one coming with their own complexities and novel modalities.  First up, Oncomatrix:


Annals of Oncology
- Oncomatryx is yet another company looking at a novel approach to ADC treatments.  For them the focus is not the tumor itself but the stromal cells surrounding it.  They looked a individual treatment and a combination with Pembrolizumab and showed decent results in both cases.  Is this going to be a fruitful avenue for cancer treatment?  I don't know, but I'm glad that someone is trying to find out

And if oncomatryx is going down a more traditional ADC path, this team was going in a completely different direction entirely.  One could argue that this isn't an ADC, but one can't argue that this isn't really cool:

Systems and Synthetic Biology
- OK, the chemical engineer in me is very happy right now.  This team out of the University of Alabama is attempting to harvest exosomes from cell culture which include integrated mAbs in the outer membrane that can specifically bind to cancer cells.  This sounds ridiculously complicated to me, but that complication is matched in equal amounts by cool factor that must be appreciated

4. PBDs aren't dead

Until a PBD based ADC is commercially approved, there will always be the sting of some recent failures hanging around in the background. However, that doesn't mean that great stuff isn't underway:

Technology Networks
- ADC T and Avacta are partnering up to attach PBD payloads to their proprietary affimer technology that builds small peptide strands that are specific to certain targets.  It's an interesting approach to ADCs without all of the mess of mAbs, and the ADC T partnership makes a bunch of sense since they can provide the payload

And if one collaboration was not enough for ADC T, they are continuing along the approval path with internal products as well:

Biospace
- ADC T is starting dosing of their cohort of patients in their pivotal trial for ADCT-301 which means that their PBD is going to be tested for efficacy instead of just safety for the first time.  Fingers crossed for good results

And lastly, Iksuda is using some Femtogenix tech to push forward their folate receptor candidate:

Annals of Oncology
- Iksuda (formerly Glythera) is coming into the ADC space with some high powered help.  Bob Lutz from Immunogen has joined the team, and they have an incredible tagline : "We build superior ADCs"  They are using a combination of their proprietary permalink tech along with Femtogenix unique take on PBD warheards to target FRa with their ADC.  Models are showing good response with pM potency, but as any statistician will tell you.  All models are wrong...some are useful.  Only time will tell which on Iksuda has on their hands


5. When the FDA speaketh - thou shalt Listen

New England Journal of Medicine
- When the directors of CDER and CBER come together to write an op-ed about individualized therapies.  Its probably worth taking the time to read.  Gene and Cell therapies are certainly big right now, but like ADCs they are an unknown quantity and everyone is proceeding cautiously

Justin's Thoughts:

If you ask most people in the industry, they will tell you that there are 5 commercial ADC products right now.  But Wikipedia says that there are 6. And while using Wiki as a primary source is never a good idea, it makes you wonder why Moxteumomab pasudotox is flying under the radar of our general consciousness.  Well not anymore:

Blood Advances
- Moxetumomab pasudotox, the mystery ADC which doesn't ever get invited to the ADC party.  There is an Fv antigen binding region, a linker section, and a toxin.  All of which are internalized into a cancer cell, and broken apart in order to induce apoptosis.  It has shown a 30% complete remission rate and is commercially available right now, so why don't we ever talk about it as an ADC?

And if you have made it this far, then maybe you would be willing to go one step further and answer a question for me:
What is the next ADC related event that you are planning to attend?  Be it conference, seminar, industry happy hour, or whatever.  Obviously World ADC is the big one, but beyond that is there anything else that you look forward to attending?

Have a great week everyone!
-Justin

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

Friday, October 25, 2019

ADC Links - Oct 23rd, 2019

Finance -

Sutro Biopharma to Receive Milestone Payment for Novel Bispecific Antibody Drug Conjugate Targeting Solid Tumors
Biospace
- Sutro is hitting payday in their collaboration with Merck KGaA on their bispecific ADC collaboration.  Their ADC has been approved for IND enabling studies using Sutro's cell-free tech along with Merck's bispecific-like molecule

ADC Therapeutics isn't going public in the US after all, while three other biotech IPOs bring in $319M
Endpoints News
- ADC T is pulling back from their planned IPO.  As I mentioned in a previous post, they are having no trouble generating cash, so maybe this isn't too surprising.  But I guess with the luxury of a strong bank account, the allure of FOMO can be held back for a little while longer.

Regulatory -

Daiichi Sankyo Submits New Drug Application for Trastuzumab Deruxtecan to Japanese Regulators
ADCReview
- Daiichi continues to be the odds-on favorite for the next commercial ADC approval

The FDA will hustle up an expedited review for AstraZeneca’s next shot at a blockbuster cancer drug franchise
Endpoints News
- And with the priority review designation, the DS-8201 review should be completed in Q2 of next year.

Drug Regulation in the Era of Individualized Therapies
New England Journal of Medicine
- When the directors of CDER and CBER come together to write an op-ed about individualized therapies.  Its probably worth taking the time to read.  Gene and Cell therapies are certainly big right now, but like ADCs they are an unknown quantity and everyone is proceeding cautiously

Industry-

Conditionally Active Biological Proteins
USPatent Office
- I generally don't report on patents because many of them are not likely to become real, but I just love the technology of BioAtla.  The primary technology allows for mAbs which are only active in the tumor microenvironment, but this patent is leveraging their tech to enable crossing through the blood-brain barrier.  As far as unique approaches, BioAtla, is looking pretty interesting right now

First-in-Class Antibody-Drug Conjugate Advances to Clinical Trial
Cancer Therapy Advisor
- Oxford Bio has received approval to start a clinical trial for their ADC targeting CD205 with a DM4 payload in pancreatic cancer.  All I can say is, Welcome to the ADC party Oxford.  Best of luck with your trials

CEO Paul Hudson's turning 'clear eyes' on Sanofi—and hinting at changes ahead
FiercePharma
-There's a new chief in town at Sanofi.  And that inevitably means a company reorg can't be too far away. (Just ask the people at AstraZeneca).  Other than just being interesting to pay attention to what CEO's do when they are objectively looking as an outsider about how to make their mark.  There is also a strong chance that changes come along to their ADC portfolio as well.  Stay tuned...

Araris Biotech AG establishes Scientific Advisory Board
Biospace
- Rakesh Dixit and John Lambert are joining the board at Araris.  Both of whom can bring an extensive amount of experience to the table and a long rolodex of connections as well.  Paired with some cool conjugation tech, it will be fun to watch what types of moves Araris takes next.

Immunomedics plans to refile its new drug application
The Motley Fool
- You'll need to scroll down about half-way to find the part about Immunomedics - Here is a lesson in cognitive dissonance between the researchers and the financiers.  No one who had ever touched this process, or worked with these people could write this article.  But such is the price that must be paid for the fat IPO paycheck.

Sanofi U.S. plant sets new bar for biologics production
FiercePharma
-Is this the biologics plant of the future.  Corobots, automation, PAT all resulting in "intensified, continuous biologics production technology."  Very Cool

Pioneering the Wild West of Spaceflight Research
International Space Station
- I cannot describe how happy this article makes me.  On one hand I can espouse the logic of testing cancer therapies in microgravity because it more closely mimics a tumor microenvironment than a typical cell culture would.  But the reality is, this is just combining two awesome things to make for something even awesome-er.  Way to go AngieX team, you have made my day

Developing Potent Affimer-drug Conjugates
Technology Networks
- ADC T and Avacta are partnering up to attach PBD payloads to their proprietary affimer technology that builds small peptide strands that are specific to certain targets.  It's an interesting approach to ADCs without all of the mess of mAbs, and the ADC T partnership makes a bunch of sense since they can provide the payload

Manuscripts -

IKS01, a next generation antibody drug conjugate (ADC) designed to be efficacious in tumors with low and moderate levels of folate receptor expression
Annals of Oncology
- Iksuda (formerly Glythera) is coming into the ADC space with some high powered help.  Bob Lutz from Immunogen has joined the team, and they have an incredible tagline : "We build superior ADCs"  They are using a combination of their proprietary permalink tech along with Femtogenix unique take on PBD warheards to target FRa with their ADC.  Models are showing good response with pM potency, but as any statistician will tell you.  All models are wrong...some are useful.  Only time will tell which on Iksuda has on their hands

FORWARD I (GOG 3011): A phase III study of mirvetuximab soravtansine, a folate receptor alpha (FRa)-targeting antibody-drug conjugate (ADC), versus chemotherapy in patients (pts) with platinum-resistant ovarian cancer (PROC)
Annals of Oncology
- As mentioned in the last post, here is the paper discussing the results from ImmunoGens Phase III FRa study which did not meet its primary endpoints.  Hopefully the next study shows the efficacy that we are all hoping to see

An anti-CD103 antibody-drug conjugate prolongs the survival of pancreatic islet allografts in mice
Cell Death and Disease
- Here is another cool use of ADCs for non-oncology.  This team shows that they can use an ADC to fight back against allograft rejection through the administration of the CD103-MC-MMAF ADC.  In mouse models they were able to see allograft survival extend from <18 days="" to="">60 days with addition of the ADC.  Pretty cool, and very novel

Tumour stroma targeting and modulation by OMTX705 ADC, a novel and potent immunotherapeutic treatment of solid tumours
Annals of Oncology
- Oncomatryx is yet another company looking at a novel approach to ADC treatments.  For them the focus is not the tumor itself but the stromal cells surrounding it.  They looked a individual treatment and a combination with Pembrolizumab and showed decent results in both cases.  Is this going to be a fruitful avenue for cancer treatment?  I don't know, but I'm glad that someone is trying to find out

Targeted Exosomes for Drug Delivery: Biomanufacturing, Surface Tagging, and Validation
Systems and Synthetic Biology
- OK, the chemical engineer in me is very happy right now.  This team out of the University of Alabama is attempting to harvest exosomes from cell culture which include integrated mAbs in the outer membrane that can specifically bind to cancer cells.  This sounds ridiculously complicated to me, but that complication is matched in equal amounts by cool factor that must be appreciated

Sacituzumab govitecan: antibody-drug conjugate in triple-negative breast cancer and other solid tumors
Drugs of Today
-A nice paper discussing all of the information to date regarding sacituzumab govitecan and TNBC

Clearance of solvents and small molecule impurities in antibody drug conjugates via ultrafiltration and diafiltration operation
Biotechnology Progress
- A nice summary paper about TFF in ADC purification.  Their conjugates are all well behaved, so this is a nice example of ideal clearance in an ADC.  But be wary in assuming that everything will be this well behaved because every conjugate has it's own particularities and often there is trouble at this step

VISTA is an acidic pH-selective ligand for PSGL-1
Nature
- BioAtla isn't the only player in the conditionally active antibody game.  Here is a paper in Nature describing the characteristics behind their pH sensitive Tcell activating mAb targeting PSGL-1.  True it's not an ADC, but seeing work that specifically looks at the tumor microenvironment is definitely a trend worth keeping an eye on

Chemoselective Methionine Bioconjugation on a Polypeptide, Protein, and Proteome
Biochemistry
- Sure, cysteine gets all of the attention for chemical conjugation to a peptide residue.  But it's not the only amino acid with a conjugatable sulfur residue.  This paper gives methionine a look at a conjugatable amino acid

Excipients for room temperature stable freeze-dried monoclonal antibody formulations
Journal of Pharmaceutical Sciences
- For any formulation scientists out there, here is a cool paper trying to find alternatives to sucrose as a stabilizing agent prior to lyophilization.  Their goal is to be able to store mAbs at RT instead of cold.  I doubt we see this in ADCs anytime soon, but interesting idea nonetheless


Clinical Results -

Seattle Genetics Announces Positive Topline Results from Pivotal Trial of Tucatinib in Locally Advanced or Metastatic HER2-Positive Breast Cancer
SeattleGenetics
- The team at SeaGen just keeps on cranking out good data.

Moxetumomab pasudotox for hairy cell leukemia: preclinical development to FDA approval
Blood Advances
- Moxetumomab pasudotox, the mystery ADC which doesn't ever get invited to the ADC party.  There is an Fv antigen binding region, a linker section, and a toxin.  All of which are internalized into a cancer cell, and broken apart in order to induce apoptosis.  It has shown a 30% complete remission rate and is commercially available right now, so why don't we ever talk about it as an ADC?

Early data look promising for sacituzumab govitecan in metastatic urothelial carcinoma
MedwireNews
- Sacituzumab govitecan is showing promising results in metastatic urothelial carcinoma.  ORR was only 29%, but treatment was well tolerated by patients and for those who it was effective, the treatment continued to be effective for the full 8 month study

Brentuximab vedotin for the treatment of patients with relapsed or refractory Hodgkin lymphoma after autologous stem cell transplantation
British Journal of Haematology
- Not to be crass, but the goal of this paper is to determine if the therapeutic benefits of Adcetris justify the costs for the Australian Pharmaceutical Benefits Advisory Committee.  This seems a bit cold, but this is probably the single most important issue for the uptake of novel therapies like ADCs, and outcomes of studies like this will largely justify implementation of ADCs around the world.  (This of course excludes the US, because we are a whole different beast when it comes to pharmaceutical pricing)

Preliminary Results of Safety and PK of Telisotuzumab Vedotin (T) in Japanese Patients with Advanced Solid Tumors
Annals of Oncology
- Preliminary results for Abbvie's ABBV-399 Telisotuzumab Vedotin molecule in 9 Japanese patients show promise in their early stages

Enfortumab vedotin–pembrolizumab duo has potential in urothelial carcinoma
medwireNews
- Chalk up another win for SeaGen with an ORR of 71% when used in combination with pembrolizumab for first-line treatment of metastatic urothelial cancer

ADC Therapeutics Doses First Patients in Pivotal Phase 2 Clinical Trial of ADCT-301 in Patients with Relapsed or Refractory Hodgkin Lymphoma
Biospace
- ADC T is starting dosing of their cohort of patients in their pivotal trial for ADCT-301 which means that their PBD is going to be tested for efficacy instead of just safety for the first time.  Fingers crossed for good results


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

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
- - - [Main]

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