In today’s post we answer some reader mailbag questions pertaining to targeting BET/bromodomain inhibitors and what we’ve learned since our original landscape review from early 2016 when they were an emerging new class in the oncology R&D space – how time flies!
Is it time-up for the bromodomain class?
Of course, as usually happens in the targeted therapy space we see a glut of pan inhibitors trying to block everything in sight to a greater or lesser degree… we’ve see this with BRAF, FGFR, PI3K, and even KRAS inhibitors, as well as numerous others, yet these rarely turn out to be the bees knees we’re secretly looking for. Bromodomains, I have long argued, were ripe to fall in this category as well.
Instead, it is better to patiently wait for the next generation molecules where they are much more selective in their actions and matched to the tumour target we are looking to hit.
Think about the BRAFV600E vs. pan BRAF inhibitors or KRASG12C/D vs. pan KRAS inhibitors, for example, or even FGFR2 or FGFR3 vs. pan FGFR inhibitors.
The same evolution may possibly happen in the BET/bromodomain space too.
The first generation of agents seemed to hit everything – BRD1, 2, 3, 4, and often BET as well. They suffered, however, with weak efficacy largely driven by challenges with the on-target, off-tumour effects that necessarily impact the therapeutic window.
Now we are starting to learn from a more focused approach with these agents. Four years on from our original landscape review, what’s hot and what’s not? Who’s in and who’s out? In terms of the magic roundabout of oncology R&D, are there any new gems we should eagerly be watching out for?
The short answer is yes… but what are they and who owns them?
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Gems from the poster halls yielded some fascinating novel approaches and new twists on old targets
In this latest post ASH review, we explore some intriguing early developments from several small and large companies alike, explain why they matter and why we should be interested in them.
Sometimes the wisdom of the crowds isn’t always the best indicator of what’s coming down the pike in terms of oncology pipelines.
Part of our cunning plan this year involved going to ‘off Broadway’ sessions where we thought others would skip in favour of a more obviously popular session (the ones in the big halls) and merrily tweet them so you could easily follow along in parallel while the smaller rooms rapidly filled up and quietly closed to those desperately trying to get in late.
Our selections here include several gems from the poster halls (imagine trying to just pick a few highlights out of 4,000 poster options?!), as well as a couple of oral presentations that were missed by many – not surprising given how jam-packed the schedule was with double and even triple choices of selections in parallel to choose from!
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Time for some reflection
Before we get to the World Congress in Lung Cancer (WCLC) taking place this weekend, I want to take a moment to reflect on some of the things we have learn over the last few weeks.
It’s time for a reader mailbag as we answer reader questions on the recent MYC mini-series, as well as covering bromodomain inhibitors (what’s going on there?) and discuss a new PROTAC compound in early development that looks quite interesting.
We also explain why that is the case…
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We’re continuing our mini-series on the MYC oncogene and associated super-enhancers and transcription factors, with a look at some of the molecular mechanisms driving epigenetic accessibility and how they interact with the immune system. It turns out that the two appear to be inextricably linked.
Dr Jay Bradner (NIBR)
It’s an exciting and emerging area in oncology R&D as companies and researchers begin to leverage basic science with a convergence between scientific fields to drive new opportunities for therapeutic intervention in cancer.
Included in this post are excerpts from an interview with Dr Jay Bradner from the Novartis Institutes of Biomedical Research. He’s most well known for his academic research on chromatin and bromodomain fields. As Dr Bradner told me during our discussion:
“MYC has so many target genes that I would imagine one might find any number of immune factors as augmented in their expression by MYC.”
As always, we covered a lot of ground and dived into more detail. There’s also been a number of recent research papers published since our discussion that have shed more light on the topic.
This is the second post in our latest mini-series. If you’d liked to read this and our coverage from the forthcoming ESMO, SITC and ASH annual meetings, do sign up to keep up to date…
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Many of the questions we received from BSB readers this month was a plea from several folks to answer numerous queries about small cell lung cancer (SCLC) and the anti-DLL3 ADC, Rova-T, in particular.
Of course I’m happy to oblige, but this was way too big a topic for inclusion in Friday’s mailbag.
Cornish Tin Mine
What makes a lot more sense here is a short two-part mini series where we look at the dismal landscape of the disease and then consider the red and green flags that arise from the Rova-T development.
With the interim results expected from the phase 2 TRINITY trial in 2H17, this is a timely moment to sit down and reflect on what to expect.
In the first part of the series, we walk through SCLC as a disease, including what is known and what to consider when contemplating a new therapy here.
In the second part tomorrow we will focus more specifically on Rova-T and what to watch out for.
So let’s rock and roll with a look at the SCLC landscape…
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Much of the focus in multiple myeloma over the last decade has focused on two key drug classes – proteasome inhibitors and IMiDs – with some recent approvals for monoclonal antibodies targeting key proteins on the surface of malignant myeloma cells such as CD38.
#ASH16 in San Diego
Combinations of these core therapies have lead to a noticeable improvement in outcomes for people living with the disease – from 3-4 years over a decade ago to now approaching 10 years post diagnosis.
If we want to continuously beat the status quo and improve on the chronicity, however, it is likely that several things will need to happen:
- Better understand mechanisms of resistance that induce relapse
- Develop predictive biomarkers of response
- Identify novel therapeutic targets
Here. we focus on the latest preclinical findings that were recently presented at the American Society of Hematology (ASH) in San Diego and explore where the future might be headed in this disease.
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Post 2016 US Election, we move on and get back to business with an in-depth review of some new science and clinical data.
Yes, it’s time for another Bushidō – “Way of the Warrior” – guide to the key ASH abstracts!
Here we focus on acute myeloid leukemia (AML), a difficult and challenging disease to treat with a high unmet medical need for new effective therapies.
In this Preview we look at key companies in the AML space, as well as a look at what’s happening in classic targets and also some new ones that are receiving notable attention, both preclinically and also in the clinic.
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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).
In 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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This week certainly turned out to be a defining tale of two drugs with a chequered history…
First off, the FDA approved AbbVie/Genentech’s venetoclax, now known as Venclexta, in a subset of CLL patients with 17p deletions. These patients have a historically poor prognosis and the approval goes some way to addressing the high unmet medical need.
Secondly, another biotech company, Clovis Oncology, got slammed by ODAC with a 12-1 vote to wait for phase 3 data from the TIGER-3 trial for rociletinib to better determine the efficacy:safety benefit profile.
For a long while it seemed that AbbVie had nothing but toil and trouble over the tumour lysis syndrome (TLS) issues giving them some significant challenges to overcome, while Clovis were one of the new darlings of Wall Street.
In the final dash to the market, the tables were turned almost at the 11th hour and fortunes stunningly reversed. Yet a mere eighteen months ago, few industry watchers would have predicted the difference in outcomes.
In our latest AACR Preview series, we take a look at Bcl2 inhibition and where some of the emerging opportunities might lie based on new preclinical research that is being presented here in New Orleans this weekend. It makes for interesting reading.
While one tiger is licking its wounds, another is smacking it chops at what the future might hold for new combination approaches; how the tails have literally turned.
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In today’s post, it’s time to address a bunch of questions we’ve received over the last few weeks from subscribers about the latest and – not so greatest – in cancer research.
ASCO 2015 Chicago
Sometimes these queries are fairly straightforward to answer, other times requires some sleuthing and hunting down thought leaders for some additional context and insights… For obvious reasons, these folks are best caught in person at cancer conferences such as AACR and ASCO. The feedback isn’t always sparkly and positive though, it can also be gloom and doom, just like the inclement weather!
So here goes, questions on the following are covered in the article below:
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