Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

The BET Bromodomain market is a meaty epigenetics topic we have followed for several years now, including a look at the space back in 2013 on the old Pharma Strategy Blog (Link). The last update on this was ironically at AACR last year when we discussed MYC and bromodomains (Link).

Nawlins Mardi GrasIn a remarkable tale of two cities in real life, two companies we discussed in those posts – Constellation Pharma and Tensha Therapeutics – have had markedly different fortunes since then. Roche decided to end their collaboration with the former and went on to acquire the latter instead.

Since we first wrote about bromodomains and BET inhibitors, the niche has exploded in a wildly stunning way… More drugs in the pipeline, more tumour targets being explored, and even novel combinations being evaluated preclinically for synergistic or additive effects. Even I was surprised by how competitive this niche has become based on the offerings at AACR this year.

With all the wealth of new data at the AACR annual meeting and also some other recent presentations I’ve attended elsewhere, it’s time for a more in-depth look at the BET/Bromodomain landscape.

Who are the new players, which tumour targets are now being evaluated, which combinations might be useful?

A word to the wise – this is neither a nerdy science post nor a comprehensive literature review – instead we take a look at the emerging landscape from a new product development perspective.

Science has been absolutely critical to success in all of the cancer therapeutics from targeted therapies to immunotherapies that have emerged in the last decade.

It really doesn’t matter whether you come from a marketing and commercial organisation or the investment community – if you want to make great decisions, you need to understand the basics of the science underpinning the R&D, where the strengths and weaknesses are. The alternative is play Roulette and put everything on Black 11 as a euphemism for whichever company/product/target you have an interest in.

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Aduro Biotech LogoWe’re almost at the end of our coverage of AACR 2016. Post number 30 (!!) is on Aduro Biotech ($ADRO) and their STING (Stimulator of interferon genes) agonist currently in development.

On the final day of AACR, in a packed session chaired by Tom Gajewski, MD PhD (Chicago), the meeting heard from Tom W. Dubensky, Jr, PhD Chief Scientific Officer of Aduro Biotech in a presentation (SY39-02) entitled:

“Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity.”

Dr Tom Dubensky Aduro CSO

Dr Tom Dubensky, Aduro CSO

I spoke with Dr Dubensky (pictured) afterwards. In my interview recording you can hear Vice President Biden’s cavalcade arrive at the Ernest Morial convention center in New Orleans for his plenary presentation.

Since AACR 2016, Aduro announced that the first patient has been dosed with ADU-S100 (MIW815) in a May 12 press release.  This triggered a $35M milestone payment from Novartis, who are undertaking the clinical trial (NCT02675439).

In March 2015, Aduro entered a collaboration with Novartis that, according to the Aduro press release, led to an initial payment of $200M and an additional $50M in equity investment.

After the recent failure of their pancreatic cancer vaccine, announced in a May 16 press release, there is a lot riding on ADU-S100 for both Aduro and Novartis.

I had the privilege to interview Dr Gajewski last year at Immunity 2015, where we talked about his work on STING (see post: Tom Gajewski takes the STING out of cancer). You can hear a short excerpt from the interview on Episode 2 of the Novel Targets Podcast.

So a year later it’s a good time to return to the STING pathway and take a fresh look at what Aduro/Novartis are doing.

For this post, I’ve chosen to write this up as a SWOT (Strengths, Weaknesses, Opportunities and Threats) analysis of ADU-S100 based on what I learnt at AACR from talking with Dr Dubensky and other experts.

Your SWOT analysis of ADU-S100 may be different from mine, you may have access to other sources of information, an alternative opinion, or reach an entirely different conclusion. There is no right or wrong answer. We all view the world through our own individual bias and lens.

Before you read this post, I heartily encourage you to map out on the “back of an envelope” – or as I’d say in England, on the “back of a fag packet” – what your SWOT analysis looks like. That way you can compare yours to mine.

By definition, we’re dealing with a new product in early clinical development, where many questions remain unanswered. It’s always easier to see the picture after all the cards have been dealt……

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If you had told me several weeks ago that we would write over 28 posts on #AACR16 and become very interested in mouse models, then most likely I would have laughed out loud and told you not to be so ridiculous!  Here we are with the 29th one and, another, on the bromododomain landscape yet to go.  Such was the vast richness of data and concepts being discussed or presented in New Orleans for those who chose to look.

Today, I want to start the segue from AACR to ASCO coverage.

Nawlins MGRAS FIOne way to do that is through the second part of the Gems from the Post Hall series. This latest one looks at a range of intriguing new targeted therapies and novel targets that are emerging, including a pharma company with a particularly interesting early pipeline.

Several pharma companies presented interesting data on their very early compounds currently in development, plus I noticed a trend for a new class of targeted therapies to emerge, MNK inhibitors, which we will also discuss.

Companies mentioned: Bayer, Orion Pharma, Lilly, Novartis, Pfizer, Agios.

Targets mentioned: PI3K, CDK, Akt, TWEAK, FGFR, BUB1, IDH1, SMYD2, MNK

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New Orleans Sign advertising Voodoo

New Orleans Sign Advertising Voodoo

What I learnt at the recent AACR annual meeting in New Orleans is that cancer immunotherapy studies are requiring industry to think differently about clinical trial design.

As we move into combination trials of novel/novel combinations, how do we efficiently work out not only that each drug is safe, but in what patients they are likely to be most effective?

Readers who listened to the recent Novel Targets Podcast, “Of Mice and Men” will hear about some of the challenges associated with mouse models and how decisions are made moving into the clinic.

What I learnt from the podcast (and I hope you did too) is that if you are doing an immunotherapy trial in patients, the type of mouse model can really matter when it comes to interpretation of the preclinical data.

In response to a subscriber request, today’s post is about some of the statistical challenges in designing combination immunotherapy trials. To many, statistics is like voodoo, so this post does not go into any maths!

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Miami Beach

Miami Beach Lifeguard Tower

This week I’ve been at an American Association for Cancer Research (AACR) conference in Miami on “Targeting the Vulnerabilities of Cancer,” part of their Precision Medicine Series (Twitter #AACRpm16).

What’s interesting about AACR small specialist meetings is as well as listening to high quality talks, they create a relaxed atmosphere for networking and catching up with experts informally. The conference this week was relevant to anyone with an interest in cancer drug discovery.

Dr Bernie FoxAlthough cancer immunotherapy remains the hottest topic in cancer drug development, we shouldn’t forget that there are other therapeutic targets worth exploring; several potential new opportunities were highlighted in Miami.

As readers know we don’t share unpublished data on the blog, so what I’ve done is provide a top-line summary of some of the strategic themes and key take homes I took from several of the presentations.

As an aside, If you haven’t already done so, do listen to the latest episode of the Novel Targets podcast – Of Mice and Men – it features excerpts of interviews recorded at the recent AACR annual meeting in New Orleans. I was surprised by some of what I heard!

For more information on forthcoming AACR meetings and workshops, check out the events calendar on the AACR website.

If you would like to read my commentary from the AACR Precision Medicine Conference in Miami on Targeting the Vulnerabilities of Cancer, subscribers can login below or you can purchase access.

One of the (many) highlights for me at the recent annual meeting of the American Association for Cancer Research (AACR) was a “Meet the Expert” session presented by Professor George Coukos.

Prof George Coukos AACR 2016

Prof George Coukos AACR 2016

Professor Coukos is Director of Oncology at the University Hospital of Lausanne and Director of the Ludwig Institute for Cancer Research in Switzerland.

Ovarian cancer is becoming a fascinating battleground for cancer immunotherapy, with multiple challenges that must be overcome before we see improvements in outcomes, especially for women advanced disease.

The interview with Prof Coukos is a follow-on to the one we did on advanced ovarian cancer and checkpoint blockade at ECCO 2015 in Vienna with Dr Nora Disis (Link).

If you missed it, you can still listen to highlights in Episode 7 of the Novel Targets Podcast (Link).

After his AACR presentation, Prof Coukos kindly spoke with BSB and in a wide ranging discussion, highlighted some of the innovative clinical trial strategies he is working on to move the cancer immunotherapy field forward in ovarian cancer.

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After looking at one important poster yesterday on multiple myeloma, it’s time to explore other equally interesting targets in other tumour types.

Some years reflect the inertia that hit oncology R&D with a lot of old data rehashed or they can be flooded with many me-too compounds.  Not this year, there’s a lot to talk about and review… so much so that we may well have enough for three rounds of Gems from the Poster Halls, time permitting as ASCO is fast approaching!

Without much further ado, for round 1 we have explored eight posters spanning four companies with a variety of different targets including chemotherapy, targeted therapies and immunotherapies.  I will say though, that the lines are being blurred as all of these modalities can impact the immune system, sometimes in unexpected ways.

What’s in store for today?  A focus on biotech companies doing intriguing cancer research.

Companies mentioned: Infinity, Innate, Incyte, Agenus

Jounce Poster AACR 2016

The AACR Poster Halls get packed quickly!

It’s time to change direction and take a look at some of the Gems from the Poster Halls at the recent American Association for Cancer Research (AACR) meeting.

One particular abstract that looked interesting related to the Aduro compound, BION–1301, which is a monoclonal antibody targeting the B cell Maturation Antigen and its ligand, A Proliferation Inducing Ligand (BCMA-APRIL) in multiple myeloma.

Increasingly, there has been a lot of clinical interest in the BCMA target, but what about APRIL?

We spoke to one of the scientists involved in the research about this novel agent:

“It is very effective at abrogating the activity of APRIL and, in particular, in our models blocks the growth, survival, drug resistance, migration and adhesion of myeloma cells both in-vitro and in-vivo in our murine models. These models have been predictive for clinical activity of other novel targeted therapies including lenalidomide and bortezomib, and so we think targeting APRIL represents a very promising strategy.”

Sounds pretty good, right?

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New Orleans American Queen

New Orleans, American Queen

After yesterday’s enlightening conversation on novel ways to jumpstart the immune system including OX40, vaccines, and STING with a self-confessed radicalist aka cancer immunologist (Dr Bernard Fox), we now turn to a self-described optimist for an industry perspective on oncology R&D and Part 2 of our anti-OX40 mini-series:

  • What ideas and challenges need to be considered in order to develop a new agent against a novel target, alone or in combination with another unapproved agent?
  • We know that mouse models and biomarkers aren’t optimal yet, so how do those issues and other factors influence decision making and clinical trial design?
  • It’s not so easy as many think – there are way more unknowns than knowns – so how do companies go about tackling them?
  • What can we learn from the readouts?

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At the recent annual meeting of the American Association for Cancer Research (AACR), one controversial area that arose was centred around targeting OX40, a stimulatory checkpoint. We’ve written extensively about anti-OX40 checkpoint agonists on the blog in the past.

Targeting OX40 is an area of interest to several companies looking to improve the effectiveness of checkpoint inhibitors. As a result, several companies have OX40 agonists in development, including AstraZeneca/MedImmune, Roche/Genentech, Pfizer, GSK and Incyte/Agenus, for example, making it a competitive target and interesting race to market.

Meanwhile, in their recent 1Q earnings call, Roche announced that they expect to present clinical data on their PD-L1/OX40 combination at the forthcoming American Society of Clinical Oncology (ASCO) annual meeting in Chicago from June 4th to 7th. This therefore makes it a timely moment to reflect on the data generated so far and what we can expect next month.

In New Orleans, we spoke to several researchers who are active in the OX40 field, since there were both mouse and human data presented at this year’s conference.

The interviews conducted were wide-ranging and informative, so in our latest mini-series we explore Part 1 today with Part 2 tomorrow.  They are relaxed fireside chats with different experts included in each to discuss their data (and other relevant topics) presented in New Orleans.

This way, you’ll be able to follow along and find out where the common areas are, as well as the differences in perspectives, and even where we could be headed in the near future.

This latest series on OX40 agonists raises many intriguing questions that we hope may be answered at ASCO and other clinical meetings going forward. We also discuss the challenges and opportunities associated with research into cancer immunotherapy combinations.

Dr Bernard Fox at #AACR16

Dr Bernard Fox at #AACR16

Intriguing preclinical data in mice models were presented by Dr David Messenheimer (Portland). We spoke with the senior author of that abstract, Dr Bernard Fox.

He is the Harder Family Chair for Cancer Research and Chief of the Laboratory of Molecular and Tumour Immunology at the Earle A. Chiles Research Institute in Portland, Oregon, and a leading cancer immunotherapy expert. He’s also the CEO of UbiVac, a biotech spin-off from Chiles in 2005 to develop therapeutic vaccines for cancer and infectious diseases.

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