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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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

Thats it for today. There are always more coming down the pike. Is there something I missed? Contact me. [email protected]
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