Thursday, November 14, 2019

What's New in ADCs : World ADC Wrap-up



Hello ADC World:

We have something a little different in store for today. Today is a feature on World ADC San Diego that I have been wanting to write for all of the scientists in lab who create the data behind the wonderful slides presented at World ADC but might not get to actually attend the conference itself.

This conference is clearly the best place for ADC folks to get together and discuss the latest and greatest in the world of ADC. The talks range from an always great clinical trial overview from the team at Beacon, to detailed analytical advancements, and of course, the CDMOs giving their updates on the latest advancements in the realm of custom manufacturing.

I was able to get approval from Letrishka Anthony at Beacon Intelligence to show this slide from her always awesome update on the landscape of ADCs in development. While her deck is not public, they always share it with all attendees of World ADC, so if anyone in your company has attended, then you can ask them to share it with you, and I would highly recommend that you do.

Source: Letrishka Anthony, Beacon Intelligence, www.beacon-intelligence.com


Since I end up doing a significant amount of opining on the world of ADC here in these articles, I thought that I would get some other opinions involved so that you can see the perspectives of people beyond just myself. So for this article, we have a panel of ADC experts who were willing to humor me and to participate in one of these articles along with me. Their responses are mostly unedited, and then my commentary follows below. So without further delay, you expert panel is:

GS: Ganapathy Sarma - Magenta Thx - Principal Scientist, and Process Development Guru
EH: Ed Ha - AngieX - Founding Principal Scientist, and Payload Guru
MS: Mike Sun - Crux CMC Consulting - Principal, and ADC CMC Expert
CL: Charley Lu - PanLabs Biologics - Managing Director, and World ADC First Timer
JL: Jens Lohrmann - Novartis - Disease Area Head Oncology, and Senior Big Pharma Voice 
JS: And me, Justin Sweeley - Novasep - Sr. Technology Manager, your CDMO representative



1) The dominant theme of World ADC 2019 was ....

GS : Too difficult to wrap everything up into one theme
EH : Improving Safety/Tox via linkers & via non-microtubule inhibitors like DS8201a, PBD prodrugs/hybrids, and side-shield linkers with PEG attachments
MS : Widespread success, some spectacular, across multiple indications can be achieved with the right combination of target and proven linker-payload technology (vedotin, DXd)
CL : Expanding the therapeutic window/index for ADCs
JL: ADCs are alive, we will see more approvals!

I agree with Mike on this one, as the broad theme for me was “Optimism”. The ADCs that are in late-stage trials and beyond are really showing promise and the excitement in the room was palpable.

2) What presentation stands out in your mind the most?

GS : Philip Howard’s and David Thurston’s talks stood out. Both these talks were focused on one thing: To understand the reasons for the failures and then designing newer and potentially safer molecules. Howard’s glucuronide-capped PBDs and Thurston’s sequence-specific DNA alkylators and cross-linkers have the potential to be safer molecules.

EH: Tie: Brian Mendlesohn - AjiCap & Bioatla’s Bill Boyle

MS: Peter Senter, SeaGen : Peter Senter’s (always entertaining) talk on recent lessons learned, what they tell us about the complexity of ADCs in vivo, and how they can shape future development

CL: John Lambert and Peter Senter played off each other quite well. Their dynamic was fun to watch from the audience given the history and recent progress with both Immunogen and Seattle Genetics.

JL: The patient story at the 10th anniversary celebration was very inspiring! (and of course my workshop... haha, just kidding)

It looks like the crowd has spoken, and clearly Peter Senter was a hit. His presentation was really good, as would be expected from a true founder of the ADC industry. For me, I agree with Ed on this one, as the concept of CABs is very intriguing as a way to get around off-site toxicity in ADCs. And yes Jens, seeing an actual beneficiary of our efforts was incredibly impactful.

3) Were there any unexpected trends that you noticed this year?

GS: ADCs with PBD payloads have not showed any promising results in the past year and the absence of PBD ADC-related presentations and posters were not surprising.

EH: Interesting absence of big biotech/pharma and the equal counter-force of maturing small innovative biotechs.

MS : A new wave of investment into ADCs from startup novel technologies to established big biotech/biopharma

CL: Increasing early-stage discussions regarding developability with target knowledge, known tox/clinical data, and site-specific technologies.

JL: I was intrigued by the fact that the ADC platform moves from “simple” chemo-payloads to a true versatile platform to couple various agents, incl. immune stimulatory molecules

Did anyone else notice that Ed and Mike are almost completely diametrically opposed on their response to this question? If that doesn’t demonstrate the value of a panel, nothing will. For me, I was surprised by the recognition that Linkers matter in an ADC. For so long they have either been stable or cleavable and that was the end of the story. This year there was much more talk about how they are active participators in internalization and plasma stability.

4) What was the most innovative new idea you came across?

GS: Ajinomoto’s AJICAP technology. The Fc-region targeting peptide was designed using a structure-based approach. The resulting reactive handle is attached a single, native Lys amino acid thereby eliminating the need to engineer the Ab to achieve DAR 2 site-specific ADC.

EH: AjiCap

MS: There were too many to single out one, but I was pleasantly surprised at the novel ideas at the poster session

CL: The Conditionally Active Biologics (CABs) concept by BioAtla, and also to see how CABs will stack up against ProBodies by CytomX

I am in complete agreement with Mike here. The people participating in the poster session had some really interesting ideas. In particular, I liked the poster about using 2D LC-MS to separate different DAR species and then to clean up the samples prior to MS analysis. Also, the work that Ganapathy is doing with his group at Magenta was very interesting in that they need to make ADCs which are specifically unstable in the plasma for fast clearance, instead of the polar opposite for most other projects.

5) What in your mind is the biggest hurdle that ADCs still need to tackle?

GS: Developing better and more robust models to predict various aspects of PK/PD and ADME considerations is and always has been a challenge

EH: Defeating/decreasing non-specific uptake of ADCs which cause dose-lowering tox. There are several strategies coming to a head.

MS: The notion that ADCs have exhausted their utility and are not worth investing compared to the latest technologies (e.g., cell and gene therapy)

CL: Overcoming negative public sentiment. ~60% of drug candidates fail in Phase I

JL: We still are way too far from a true magic bullet: we didn’t achieve to widen the Ti as hoped/expected

I think the panel nailed this one. Ganapathy, Ed, and Jens are effectively saying therapeutic window, and Mike and Charley are saying that people are getting tired of waiting for ADCs to be the “magic bullet”. I find both to be true, but I’m also fully expecting the shine of cell and gene therapy to come down a little bit when the reality of their difficulties start setting in.

6) Complete the sentence: One year from today, the ADC landscape will be different because of ...

GS: alternate format ADCs (bispecifics, biparatopics etc.) and the emergence of non-chemotherapeutic payloads such as agonists.

EH: improved tox/potency/TI control via several ideas initiated 3-5 years ago.

MS: multiple new approvals and smashing early-phase success of next-gen technologies

CL: trastuzumab deruxtecan (DaiichiSankyo) and enfortumab vedotin (SeaGen)

JL: We will see new MoAs coming along and move beyond Oncology

I’m with Mike and Charley here. New approvals is followed by new money, which will fund the next evolution of ADC development that Ganapathy and Ed are talking about.


Rapid-Fire:

Ganapathy
Ed
Mike
Charley
Jens
Justin
1) What company do you expect the most out in the next year?
Daiichi
SeaGen
Tie: Daiichi
and SeaGen
Daiichi

Daiichi
2) Last year, PBDs and their narrow therapeutic window were dominant themes. 
One year later, are PBDs dead?
No
NO! Prodrugs/
Hybrid PBDs
Yes… for now.
Loncastuximab
tesirine is still
going

No way. 
Never trust
small sample
sizes
3) Currently there are 5 ADCs on the market, and 4 in late stage review. 
How many commercial ADCs will we see at World ADC 2020?
6
6 (plus
Moxy-mAb)
8
7
8
7
4) Which of the following subsection of ADCs is showing the most innovation:
payloads, linkers, mAbs
mAbs (ie.
bispecifics)
Linkers
Linkers
Linkers
Payloads
Linkers


—————————————————————————————————————————

And that's a wrap for the first annual World ADC Wrap-up Article. For all of those who both attended World ADC and saw my presentation, thanks for the support. It was my first chance to represent Novasep on the World ADC stage so I appreciate all of you who attended.

Hopefully this was interesting for everyone that doesn't get to attend these meetings on a regular basis. As usual, if it was, comment and let me know.

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

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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, 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