Thursday, October 17, 2019

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
- 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
- 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
- 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
- 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
- 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
- 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
- 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. [email protected]
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