Tuesday, April 30, 2019

Integrin a10 - a new target for glioblastomas

As we have discussed before,


getting after glioblastoma is hard.  Here a group from Lund Sweden has identified a new potential target for ADC therapeutics.


The preliminary results look very encouraging, however the fact remains, that if curing cancer in humans was as easy as curing cancer in mice, cancer would have been eliminated a long time ago.

What do you think?  Are these types of discoveries things to get excited about? Seeds for a new biotech company?  Or just another academic discovery with no application in the real world?

Bispecific Antibody Review


Here is a review paper out of the Netherlands about bispecific antibodies and their development.  This is an increasingly interesting direction for ADCs and there are already multiple different bispecific ADC constructs.

One bi-specific like molecule was MedImmunes 4276 HER2 bispecific, however, as presented at World ADC in London, there was significant unexpected issues owing to the complexity of the dual targeting nature of that molecule.  It was a little bit of a weird beast (https://www.ncbi.nlm.nih.gov/pubmed/26766593)
but still the lessons learned were that more complex doesn't always mean more better.

Happy reading

ADC Offsite Toxicity Review


The team at AbbVie has put together a great review of the mechanisms behind the offsite toxicity of ADCs.  Take a look.

Is offsite toxicity, something that can be overcome, or will it become the downfall of the ADC approach?

Immunomedics is going to China


In what is billed as the largest single-asset pharma license agreement in Chinese history, sacituzumab govetecan is going to China.  This deal gives Immunomedics $65M upfront with another $60M based on FDA approval. 

This money is probably timed well and will go a long way towards getting them back on track after a rough couple of months based on both their BLA rejection from the FDA and the departure of their CEO.  Hopefully this is the first step back on track, and back towards their FDA approval and beyond

Monday, April 29, 2019

SeaGen's Adcetris sales are lagging, but AZ is going All-In

Do you pay much attention to the financial reports of ADC companies?   I didn't think so, but here is why you should.

SeaGen just announced that they are seeing slowing sales with Adcetris.  Here is the latest graph:

And the investors did not like this one bit.  The stock price looked like this over the last month:

You might be wondering why this matters to a scientist.  And on the surface it doesn't.  But if the people with money don't get paid, then they start looking at R&D budgets and think that they are a clearly poor investment.  And that starts a trend that none of us want to see.

No need to polish your resume immediately, but we need to see these trends changing if the ADC market at really going to take off.  And rest assured, with only 4 candidates on the market, there are a lot of eyes paying attention to the few companies who are actually forced to publish commercial data publicly.

Conversely, AstraZeneca recently announced that they are partnering with Daiichi Sankyo on trastuzumab deruxtecan,
and that the deal could amount to up to $5.5 billion for Daiichi.  This amount of money shows how strongly AZ believes in this type of therapy, and in the way that the SeaGen news is viewed poorly by potential investors, this AZ news is exactly the opposite.
If you want to see the full report on their earnings, check here:

Genentech pushes forward with PBDs


Here is a nice summary article about the pursuit of treatments for Acute Myeloid Lukemia.  In it they lay out the best prospects for new therapies and there are two ADCs mentioned which are worth taking a look at.

This CLL target is interesting because it is strongly overexpressed in AML cancer cells, however antibody binding does not illicit an immunogenic effect necessary to use the mAb only therapy as an efficient treatement.

The first is Genentechs labile PBD.  It is described as, "A novel anti–CLL-1-ADC, with a highly potent pyrrolobenzodiazepine (PBD) dimer conjugated through a self-immolative disulfide linker, was developed."

Cellerant Therapeutics is also building a very similar molecule which they have called CLT030.
Their molecule is unique in that only targets the stem cells of AML after undergoing the transformation to cancerous, thereby leaving the health HSC cells alone.  Both are showing good results in the xenograft studies, it will be interesting to watch what comes out of the clinic.  Especially because these are both use DNA intercolation as their mechanism of action, and currently PBDs are having a bit of a rough go (see AbbVie's Rova-T)

Friday, April 26, 2019

ADCT and Adagene partner up

ADC Therapeutics and Adagene have partnered up to combine ADCT's PBD Technology with Adagenes SAFEbody technology.

The advantages here are clear.  PBDs have been having a rough go lately (see AbbVie's Rova-T results), and ADCT would like to see their PBDs be able to more specifically target cancer cells to get around the high toxicity of PBDs.

And if you are working for CytomX your ears should be ringing, because this is the exact type of argument that CytomX is making with their Probody technology:

Are targeting strategies like this going to be enough to make PBDs viable, or are PBDs dead? What do you think?

A different way to approach Commerical Launches


This is a little bit of a step away from the R&D arms that we normally focus on.  But it is very interesting and directly applicable to ADCs since they are primarily focused on small markets.

Indegene is attempting to use an AI driven software to specifically target marketing revenue where it will be most beneficial.  No super bowl ads here, just targeted approaches to where the revenue will be at its most effective.

In the case of ADCs for example, the Adcetris market was in the order of $500 million last year (http://bit.ly/2IWQw6I), which is right in the sweet spot for this type of approach.

ADCs are a bit of a goldilocks in terms of market, and really in terms of production as well.  They are not profitable through scale, but through specificity, and maybe looking at the marketing approach in the same light makes sense.

What do you think?  Is Indegene onto something, or is this a pipedream?

ADCs for Glioblastoma

 Glioblastoma is a particularly nasty form of cancer, and has the unfortunate issue of being located behind the blood-brain barrier.  This adds a significant complication to treatment, and as such has made it very difficult for treatments to have any more than incremental patient benefit.

Because of this, researchers at Columbia University are doing some really interesting trials where you add in multiple different therapies into a single cohort.  In this was a traditional blind study can be extended to more treatments.  This saves time, increases the likelihood that the best path forward is discovered, and also increases the likelihood of a patient receiving treatment instead of placebo.

One of these treatments being tested is a glioblastoma treatment from AbbVie called Depatuxizumab Mafodotin. Depatuxizumab Mafodotin (ABT-414) is an antibody drug conjugate (ADC) targeting EGFR-amplification that is being investigated to treat glioblastoma (GBM).

The preliminary results from Phase I trials are encouraging, and as such it is progressing into late phase trials currently. The Phase I results can be viewed here:

And if there isn't enough information for you yet, here is a very interesting discussion with Dr. Manmeet Ahluwalia from the Cleveland Clinic about the currently ongoing UPFRONT clinical trial:

The Circular Firing Squad of Biotech News

Yesterday I posted this on LinkedIn:

IQVia has just released an incredible report focused on "The Changing Landscape of Research and Development: Innovation, Drivers of Change, and Evolution of Clinical Trial Productivity" http://bit.ly/2IXLVl0 Among the many gems in here is the observation that overall 11% of Preclinical candidates make it to commercialization, but only 8% of oncology candidates do the same. However this is expected to change with the advancement of Next-Generation Biotherapeutics such as gene therapy and bi-specific antibodies, in addition to genome based patient selection and a better understanding of Immunotherapy resistance. What do you think? Are we at the cusp of a revolution, or one step further on a very long journey? hashtagmanufacturing hashtagscience hashtagcrispr hashtagadc

Today, there is this from Forbes:

And then there is this from Fierce Biotech:

With everyone citing the IQVia report for their numbers.  What does this mean for you?  It means that there is only a limited amount of information for which the many (many) independent journalists get to look at and put their spin on.

We will continue to provide the most relevant information for the ADC industry right here at ADC Daily, and when appropriate, articles will be amended to include all of the extra links so that you can have all of these things in one place.

What source do you trust for you biotech news updates?  Where are you looking for new information?

Thursday, April 25, 2019

Spotlight Company - Avacta Bio


Check out this new approach to bispecific molecule design by Avacta Bio out of Cambridge.  They are building single chain peptides with target binding regions designed through phage display screening libraries.

This technology can be used to target single antigens, bi-specifics, and checkpoint inhibitor targets.  Beyond that, they are applying this to ADCs to make what they call TMAC molecules.

Their idea is that a small peptide chain can be manufactured more easily while still providing all of the advantages of a bispecific antibody therapy.

It looks interesting, but will the body tolerate this molecule for long periods of time, or is there something evolved into an antibody structure which cannot be mimicked with a peptide chain approach?

Zymeworks and Daiichi Sankyo move forward with Bispecifics collaboration


And in another vote of confidence for the bispecific mAb market, Daiichi Sankyo has decided to exercise its option with Zymeworks Azymetric technology.

This isn't an ADC yet, but that could change quickly as I'm sure that Zymeworks would be happy to expand its ZLA platform as well.

As the bispecific market continues to heat up, look for more of these types of deals.  Daiichi Sankyo knows how to develop targets, and Zymeworks can build the bispecific mAbs.

Are we getting closer to the tipping point?  I know I've asked in the past, but each article gets a little closer.

Serum presence of BCMA prevents ADC Targeting


The researchers at Oncotherapeutics have discovered something very interesting about the BCMA targeting biologic therapies in multiple myeloma patients.  This paper documents the presence of BCMA antigen in serum which effectively acts as a competitive inhibitor for the antibody attempting to reach to tumor cells. 
The levels of this inhibition were high enough to interfere with tumor binding and to inhibit the effectiveness of the therapy.

This is interesting as it adds another level of complexity to the choice of antigen targeting when developing a biologic.  Is it possible that a rapid internalization would be correlated with a rapid explusion and presence of inhibitory levels in the serum?  Or is this likely a non-consequential side effect which should not cause much concern?

Nobody wants this much info from the FDA, but you NEED it

You can't get more TL;DR (too long; didn't read, for the non-millenials in the audience) than this document from the CBER and the FDA, but there is so much important stuff in here it can't be ignored.
Here are some of the highlights:

There is a lot to digest here, but it will be time well-spent.
Is there any area where you think the FDA is falling behind?  They clearly are trying to be proactive, but they are still going to move at the speed of bureaucracy.  What are they missing? 

Biopharma Lobby Effort creates a conflict of interest

Mark Terry at BioSpace published a great article dissecting the lobbying efforts of the biopharma industry.
And not to be outdone, Kyle Blankenship at FierceBiotech also has an article out about the pharma lobbying effort in 2018:

Both of these articles are in response to the recent release of the lobbying numbers by the center for responsive politics on Mar 19th.

I have always been conflicted about the effect of money in the pharma industry.
On one hand, the significant amount of profit potential is the number one reason that the US has such a vibrant biotech industry, and why so many life saving therapies have been created and continue to be created.
On the other hand, this profit margin is a significant contributor to the incredibly high cost of healthcare in the US. And because other countries fix the prices of these drugs, the high development cost is subsidized by Americans while the world benefits from the discoveries.

Is this an accurate reading of the state of the industry? And what are your thoughts? Is anyone else conflicted about the fact that the profits of the pharma industry is intimately linked with the rising cost our healthcare?

Wednesday, April 24, 2019

How complex can the Tumor microenvironment be?

The authors of this review exhaustively detail the different tumor microenvironment (TME) regulatory pathways in classic Hodgkins Lymphoma tumors and identify some of the methods being used to get around them.

They include many of the standard of care therapies as well as some clinical trials that are underway.

The conclusion states that a more complete understanding of the TME is necessary to build biomarkers as well as effective therapies that will be able to treat the cancer cells, but also to treat the "educated" support cells that are enabling the TME itself.


Bispecific mAbs can solve the problem of ADC internalization

Clearly the similarities between ADCs and lobsters are unmistakable.
Although nature has solely evolved a DAR of 8 for these little guys.  

The question that is being asked by researchers into bi-specific mAbs is this:  How do we find a target antigen that is both highly expressed, and also undergoes rapid internalization upon binding?
And the solution being pursued by companies is to use bi-specific mAbs that can find two unique antigens for each of those goals.  In this way, it could be possible to find one well internalized antigen for one "claw" of the mAb, and then you could target multiple tumor specific antigens on the other "claw".

To date, there have not been any approved commercial bi-specific ADCs, but that could be changing in the near future is some of the clinical trials underway are successful.

Is this the future of ADCs, or another fad that will come and go?  What do you think?  Or is anyone currently working on this right now?

Monday, April 22, 2019

Lilly taps Avidity's antibody-oligonucleotide conjugate tech in $35M deal

An interesting look at a different way to apply antibody conjugation to non-oncology based therapeutics.


GT Biopharma approved for Phase I Clinical Trials

I am always a fan of novel approaches to oncology therapies and GT Biopharma clearly falls within this realm.  Their single-chain tri-specific scFV fusion protein technology is nothing if not novel. 

If you would like to learn more about it, they have a very detailed powerpoint presentation on their website here:

And now they are bringing this into the clinic:

This is great news, because theories are nice, and pre-clinical tox studies are informative, but nothing matters until you get it into patients.  And while most companies are looking at incremental steps forward with the minimum possible risk profile (I'm looking at you companies targeting HER2 with a DM1 payload), some companies are willing to get out there with something truly novel, and be OK with accepting failure for the sake of making a giant leap forward. 

Best of luck in your trials.  We'll be watching for the results.

What do you think?  Are the moonshot based companies interesting, or are they distracting from the incremental and often more successful standard technologies?

Gene Therapy is on a Tear

Catalent acquires gene therapy specialist Paragon for $1.2bn

If there is one thing that is always true, it's that FOMO (Fear Of Missing Out - for those not raised in Silicon Valley) is an incredibly powerful motivator.  The problem is that you never know if this fear is misguided or if this is truly the "next" thing.  This was observed in the ADC world back when Adcetris was approved by the FDA, and the subsequent deluge of investment propelled the ADC market to where it stands currently.
In the ADC market today there is considerable cooling based on the reality that curing cancer is hard.  And promising candidates can always fail in the clinic.  And it turns out that biology is complicated.

The most recent trend is clearly in gene therapy, and the money has been a-flowing.  Take for example Catalent:

Or even look at Novartis buying up and expanding multiple facilities in order to gear up for their Zolgensma AAV therapy roll-out:

I can smell a little FOMO going on as there are still significant issues with gene therapy approaches, namely, since this is both personalized medicine, and complicated.  How can you scale to a point where you can supply materials in a timely manner for your patients, many of which have a short timeline for effective treatment?

What do you think, which side of the FOMO coin are we looking at?  A revolution in personalized therapy?  Or initial excitement before the inevitable reality that gene therapy will find a place in the world, but will be much harder and more complication than we can currently imagine?


Friday, April 19, 2019

Macrogenics is targeting B7-H3 with a Duocarmycin linked ADC


Macrogenics is working to use Duocarmycin along with the Synthon based linker conjugation technology to build ADCs targeting tumor vasculature.
Preclinical results have been positive as demonstrated at 2017 AACR.

If you can stem the growth of tumor vasculature can you cut off the nutrient supply of the tumor?  Has this approach been effective with other treatments?

AstraZeneca reviews the ADC Therapeutic Window

A great new paper from the Team at AstraZeneca about the problem of small therapeutic window in ADC therapies


Out of the 55 traditional ADCs whose clinical development has been halted, an estimated 23 were due to poor therapeutic index.

Dose toxicity resulted in skipped doses, dose reductions, or complete discontinuation.  Many of which occured prior to reached to maximum efficacious dose.

The reported toxicity in many cases matches that of the warhead toxicity.  This indicates that despite the "targeted" nature of ADCs, the systemic toxicity is still being caused by the release of the warhead into non-tumor cells.

The 4 approved ADCs have demonstrated clear clinical benefits, and this is likely to the conjugate allowing a slightly higher dosing than a systemic administration of "naked" chemotherapeutics.

Some of the emerging trends to overcome the limited therapeutic window include modified clinical dosing schedule, biodistribution studies, and optimized patient selection with biomarkers.

Optimizing patient populations is particularly intersting if the focus for selection shifts from tumor expression levels to warhead mechanism of action.  For example, patient populations prone to DNA damage responses could possibly respond more strongly to DNA repair inhibitors such as PBDs.

The authors also identify the potential for improved real-time biomarkers to monitor the effect of an ADC therapeutic treatment.  This could shed light on bystander effects, tumor burden, and patient mutational profiles.  In addition, a more thorough biomarker profile could be implemented to understand the effects of combination therapies which are becoming increasingly more popular.

Similar work has been done by BioMed Valley Discoveries regarding a CD276 tumor vasculature model where they demonstrated significant apoptosis when using a PBD linked antibody, and no effect when using vcMMAE.
The authors state that these data explain why a previous study into glioblastoma multiform was unsuccessful

Eradication of Tumors through simultaneous ablation of CD276 positive tumors and vasculature

So my question is:
1) Why have industry expectations for massive therapeutic windows been so far off of the mark?
2) Matching payload with cancer, mechanism seems logical. Why is this just being brought up as a topic now, 20 years into the ADC lifecycle?

Can a Flexible Clinical Trial Design be applied to Oncology?

Impact Story: A Flexible Clinical Trial Design Suitable for Emerging Disease Outbreaks
FDA CDER statisticians are designing trials with adaptive features to make clinical evaluation of new drug treatments more efficient and informative.

A new study from the FDA is showing how Bayesian statistics can be applied to a clinical trial in real-time.
The gist is this - how can we perform a randomized trial without engaging in an unethical practice of withholding potentially lifesaving treatments from "control" patients?
Their solution - set the "standard of care" as a moving target where promising treatments become standard more quickly and are immediately tested against.

Could this approach be expanded beyond medical emergencies and applied to oncology treatments with significant unmet needs and lacking standard of care options?


Why Biosimilars do not create Effective Competition

“Biologics Are Natural Monopolies (Part 1): Why Biosimilars Do Not Create Effective Competition, " Health Affairs Blog, April 15, 2019.
DOI: 10.1377/hblog20190405.396631

Part 1 : https://www.healthaffairs.org/do/10.1377/hblog20190405.396631/full/
Part 2 : https://www.healthaffairs.org/do/10.1377/hblog20190405.839549/full/

This article presents a fascinating look at biosimilars and proposes a different way to decrease drug prices in the case of biosimilars.  The argument goes like this:
- The small molecule market price of generics is driven by the ability of generic manufacturers to develop generic versions of proprietary drugs cost effectively creating an efficient market and driving costs down 85-95%
- Biosimilars on the other hand, are significantly more difficult to develop.  The approval path is more difficult.  And when actually available, the approved biosimilar only lowers the price of drugs by 20-30%.
- If instead of encouraging biosimilars, we instituted a regulated price control system for the innovator, that would allow a lower price, while maintaining complete market share (and therefore profitability) for the innovator.

The question is... Is this really a viable path forward?  And if not, is the current plan of expecting biosimilars to follow an identical path to that of small molecule generics really a viable path in it's own right?

Zymeworks moves bispecific to Phase IIa


Bispecifics are seen as the next evolution in antibody biologics development. Zymeworks has just progressed their first HER2 bispecific mAb into Phase IIa development.

Zymeworks is attempting to use two different binding regions both targeting different aspects of the HER2 epitope. In this way, the synergistic effect should lead to higher binding on lower expression strains of HER2

In addition to this trial, Zymeworks has multiple more bispecific molecules in the development pipeline targeting multiple different tumor targets.

To further extend the therapeutic window, Zymeworks is also integrating ADCs based on the ZLA (Zymelink Auristatin) Technology in order to further increase the potential therapeutic window of these bispecific mAbs.

The bispecific idea can be applied to ADCs effectively as well.  This was demonstrated here:
Molecular Cancer Therapeutics

The researchers are from UCSF and showed that bispecifics are able to separate the cancer target antigen into one target, and the rapid internalization aspect into a second target.
In this way they were able to demonstrate improved internalization over the individual mAbs or a mixture of the two.

It will be interesting to watch the progression. In the meantime, are bispecifics the future of antibody technology, or do they double the chances of off-target binding?

Lonza plagued by supply problems after China plant explosion

An explosion at a chemical plant in China that killed 62 people not only exposed weaknesses in China’s safety oversight but it also exposed weaknesses in the global ingredient supply chain. The disruption from the blast has exacerbated shortages for Swiss pharma and chemical supplier Lonza.

This really makes you wonder.  How secure is your raw material supply chain?  How significant would a disruption be towards meeting your corporate goals?  Is it time to build a thorough and rational contingency plan to ensure raw material supply doesn't halt years of scientific progress?

Immunomedics and Janssen collaborate for marketing of BALVERSA

Janssen has just received approval for their erdafitinib molecule (BALVERSA) for the treatment of metastatic urothelial carcinoma.  Meanwhile, Immunomedics sacituzumab govetecan (IMMU-132) is targeting the same type of cancer and has been showing promise in the clinic:


However, the approval of IMMU-132 has been held up by the FDA:

So in the meantime, Immunomedics is partnering with Jannsen to promote their product with the agreement that the partnership will end upon the approval of IMMU-132 where they will become a competitor.

Is this a great opportunity for Immunomedics to salvage some of the US marketing machinery that they were building for the IMMU-132 rollout?  Or is this going to undercut their marketshare by promoting a competitor?
What do you think?

Astellas and SeaGen plan to file BLA in 2019 for enfortumab molecule

Astellas US

Astellas and SeaGen are moving forward on their enfortumab currently in Phase II clinical trials.  They have seen an overall response rate of 44% for patients previously unresponsive to a chemo + checkpoint inhibitor therapy.

They believe that these topline data are significant enough for a BLA application filed later in 2019 concurrent with Phase III trials for global registration.

Given the cost of these therapies, is there any limit to the size of a population where the therapy would not be worth the cost?  As it appears the answer is no, what is the long game on this?


Cidara has an antiviral ADC candidate

  • the company has selected the antiviral conjugate (AVC) CB-012 as its first clinical development candidate from the company’s Cloudbreak:registered: influenza (antiviral) program
  • Data supporting the selection will be presented today in an oral session at the 29th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)
Cidara is looking to combine the antiviral agent directly applied to the influenza virus while activating a patients immune system at the same time to help fight of the infection. In this was Cidara is looking to use the AVC (anti-viral conjugate) technology to provide both short-term flu infection relief, and also long-term sustained preventative relief.
The ultimate goal is to achieve influenza relief for an entire year through the application of their technology.

Initial results are being shared at the 2019 ECCMID Conference this week.

What do you think of this approach? There are a couple of companies attempting to use oncological ADC principles for non-oncology therapies. Dyne Therapeutics comes to mind. Is this the next stage of ADC development, or a niche off-shoot which is unlikely to gain major traction?


Immunomedics and Janssen sign marketing agreement

Image result for immunomedics
FDA rejects sacituzumab govetecan for CMC issues


Janssen has just received approval for their erdafitinib molecule (BALVERSA) for the treatment of metastatic urothelial carcinoma.  Meanwhile, Immunomedics sacituzumab govetecan (IMMU-132) is targeting the same type of cancer and has been showing promise in the clinic:

However, the approval of IMMU-132 has been held up by the FDA:

So in the meantime, Immunomedics is partnering with Jannsen to promote their product with the agreement that the partnership will end upon the approval of IMMU-132 where they will become a competitor.

Is this a great opportunity for Immunomedics to salvage some of the US marketing machinery that they were building for the IMMU-132 rollout?  Or is this going to undercut their marketshare by promoting a competitor?
What do you think?