A look at upregulated targets outside of the BCR signalling pathway and what small molecules are looking promising
In our final preview of ASH 2020 exploring key abstracts and what to watch out for this weekend, we offer the second half of our discussion around small molecules in early stage development.
There’s always a roller coaster ride in any early stage drug development and small molecule inhibitors are no different from antibodies, bispecifics, or even immunotherapies in this respect.
There are certainly some unexpected and surprising overlaps discussed and uncovered here plus also some novel combination approaches either being considered or which may potentially need to be considered in the future.
So what’s in store this time around?
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It all to easy to focus on the hear, the now and what’s hot in the moment, but let’s also remember that while immunotherapy and KRAS might be the hottest topics out there in oncology R&D at the moment, we still need to induce durable and lasting tumour cell killing or the cancer won’t be penned in.
Resistance mechanisms or immune escape will induce relapse, disease recurrence and off we go again with tumour proliferation, sometimes at a more aggressive rate than before.
Back in the 1970s and earlier all we really had was a bunch of rather nasty and ineffective chemotherapies, often given in sequence, although improvements in dosing, scheduling, and also experimenting with different combinations eventually helped a great deal.
What if we were look at modern methods of inducing cell death without the nihilistic side effects of old?
After a few false starts and quite a lot of agents condemned to dog drug heaven, we saw the emergence of the CDK4/6 inhibitors in HR+ breast cancer. Since then a number of other targets have starting showing up, not just as small molecules but also in quite different modalities.
Is this truly going to be a new revolution to think about or yet another raft of promising agents consigned to the dustbin of screening libraries? The good news is there are some hopeful signs finally peeping out…
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Time for some reflections from ASCO
Many eyes at ASCO this weekend will be eagerly turned towards the plenary session on Sunday and the stunning osimertinib data in the ADAURA (adjuvant osimertinib therapy for EGFR positive disease) where 69% were stage II/IIIA and for those patients, DFS HR was 0.17 with a 2 year DFS rate of 90% (only 44% with placebo).
There is no doubt this is the data of the meeting for me – when was the last time we saw a hazard ratio of 0.17?! More on this development after the data has been presented.
Beyond the plenary there are plenty of interesting studies to discuss and ponder at various stages of development. Over the next couple of days a number of other stories and interviews will be also posted.
Here, we provide an update on one of the early drug development stories we’ve been following longitudinally over the last five years from preclinical through to the clinic and offer some reflections on progress to date.
A KOL interview and commentary are included as well…
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Padstow, Cornwall – It’s May Day or ‘Obby ‘Oss, as it’s known locally in this little corner of south west England. The quaint festival means that it’s the biggest day of the year as over 30,000 people crowd into the tiny fishing village.
Obby Oss Blue
Centuries old traditions are still alive and well in this part of the country and the big question of the day (are you red and white or blue and white?) is a far cry from the complex high tech world of cancer research.
Still, with all the time and attention focused on immunotherapy and targeted therapies of late, it is all too easy to forget what’s happening on the epigenetics front, which is quite a bit in practice.
We often see random allcomer approaches to clinical trials, which are find for phase 1 studies where you want to gather data on responders and non-responders in order to conduct PK/PD and immune profiling, as well as biomarker and signature development, but a potential recipe for disaster in phase 3 if you have no idea exactly what’s driving the efficacy since you can all too easily end up with unbalanced arms that you didn’t control for and thus skew your survival curves in a way you didn’t anticipate.
Why on earth would you use a targeted therapy in an untargeted fashion? Hmmm obvious question and yet, many companies still do this all the time.
There are some biotechs out there, I’m pleased to say, who do conduct extensive translational and biomarker research. Obviously finding those markers is a lot more tricky than choosing red or blue.
One biotech company we have been keenly following for a while is Syros.
We first wrote about them in Spring 2014 and now, five years on, I thought it would be a nice idea to catch up with one of their founders and learn more about the science underpinning what they’ve done and where they’re going with future projects. Not only do they invest in smart medicinal chemists, profiling and translational research, but they also seek to identify rational reasons why people respond to their compounds.
The answers were rather interesting and there’s quite a bit that readers might be curious to learn more about…
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As part of our #JPM18 coverage we like to feature up and coming companies to watch out for, one of these is Syros Pharmaceuticals (NASDAQ: SYRS). In this post we take a look at what’s on the horizon for the company in 2018?
Myelofibrosis has certainly been in the news this week with Celgene acquiring Impact Biosciences for fedratinib and both Celgene and Incyte presenting their annual update at the JP Morgan Healthcare conference in San Francisco.
Yesterday at JPM, Syros and Incyte announced a new collaboration to explore myeloproliferative neoplasms (MPN):
“… The companies have entered into a target discovery, research collaboration and option agreement. Under the agreement, Syros will use its proprietary gene control platform to identify novel therapeutic targets with a focus in myeloproliferative neoplasms (MPNs), and Incyte will receive options to obtain exclusive worldwide rights to intellectual property resulting from the collaboration for up to seven validated targets. Incyte will have exclusive worldwide rights to develop and commercialize any therapies under the collaboration that modulate those validated targets.”
Given the need to find new targets and potential combination agents to partner with JAK2 inhibitors such as ruxolitinib (Jakafi), this deal makes a lot of sense.
It also leaves Syros and Incyte with space to continue developing their existing pipelines in the usual fashion without any undue commitment or conflict.
Syros are a company we have been following for three years now, with several updates on BSB, including thought leader and C-suite interviews.
With new data presented at ASH and SABCS last month, it was a good time for an update on this topic, so we sat down with Dr Nancy Simonian (CEO) for a chat about where they are and where they are going with their current small molecule pipeline ahead of their presentation at JPM18.
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One of my favourite areas to follow in oncology research is Developmental Therapeutics, whether they be targeted, genomic, epigenetic or immune therapies. At some point, even currently approved products started off life in this category, either in preclinical research or in early phase 1 trials.
It’s almost like a primordial soup from which future pipelines spring.
Following these initial approaches over time can be useful in many ways – you can pick up new trends and emerging drugs earlier than most, and can also step back to see a broader picture of the landscape as it evolves.
While there are no formal developmental therapeutics sessions at the American Society for Hematology (ASH) annual meeting per se, that doesn’t stop the intrepid scientist from creating their own selection, in fact it’s a lot more fun this way!
That’s exactly what I’ve attempted here…
Be warned though, this year, the mix is much more complex and intriguing with a lot of interesting and, in some cases, novel targets to explore and consider, including the deeper and tricky protein-protein ones to hit, which are now receiving more attention as researchers find more creative and indirect ways to tackle the problem.
Our second ASH 2017 Preview goes deep into what for many BSB readers will be intriguing, yet for others… completely unknown.
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Have you ever sat in a freezing cold scientific session and been so engrossed in the compelling presentations that followed, you simply forgot to take notes? Not one. That actually happened to me at the American Association for Cancer Research (AACR) in Philadelphia this year in one of the many fringe sessions that I attended.
Reading Terminal Clock, Philadelphia
Granted, the hot topic of the conference was undoubtedly checkpoint inhibition, but I was anxious to escape to the comfort of some meaty and familiar basic and translational science, namely MYC. MYC is largely thought to be a difficult to target, even undruggable protein, and along with RAS and p53, represents a formidable challenge for cancer researchers. These three oncogenic proteins alone are probably responsible for more drug resistance developing and even death from cancer than any other proteins in a patient with advanced disease.
For cancer patients with advanced disease, the clock is ticking on time they have left.
Solve these three problems (MYC, RAS and p53) and we may have a shot at dramatically improving outcomes. As Dr Gerard Evan (Cambridge) noted:
“I think it’s fair to say that we don’t really know why interruption of any oncogenic signal actually kills cancer cells, but one of the reasons that we’re interested in MYC is because it seems to be a common downstream effector of many, maybe all cancers.”
Sure, the road to success is paved with an enormous graveyard of failures, just as metastatic melanoma was before checkpoint blockade came along, ironically. What I heard at AACR both inspired and filled me with greater confidence… we’re finally getting somewhere.
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We have written about small biotechs and big pharma a lot on this blog, particularly when they have exciting new developments in their pipeline to review and consider. Increasingly, we have also begun to look at the early phase companies because often, that is where some fresh ideas and approaches are being developed and tested.
They’re also not beholden to the norm in terms of thinking that’s non-linear and many are academic start-ups that began life as thought leaders doing their own research and eventually VCs get interested, enabling financing to be raised. The downside of this for some of our readers is that they’re usually not investable as a private company (sorry about that), but we have a broad church here on BSB and instead these small companies attract the interest of enlightened pharma companies who want to license early compounds in areas they are interested in or gain knowledge about a new field of research before buying elsewhere. In other cases, the approach pays off in clinical trials and we see the IPOs emerge from companies such as Juno Therapeutics.
One company that neatly fits this bill is Syros Pharmaceuticals, an academic spin-off from the Whitehead Institute of MIT and Dana Farber Cancer Institute in Boston based on the pioneering work of Drs Richard Young, Jay Bradner and Nathanael Gray.
Regular readers will remember our original article their the scientific work on gene transcription factors at AACR last year, which included a fascinating interview with Dr Young. That was probably one of my favourite interviews of 2014 – I was inspired!
It’s now time to look at the company and entertain some strategic thinking about where they’re coming from and where they’re going with clinical development. The CEO, Dr Nancy Simonian, kindly agreed to an interview and be put in the ‘hot seat,’ so to speak.
This screenshot from the Syros website sums up their philosophy: Better medicines through gene control.
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Sometimes you get lucky before a conference and catch an interview with a thought leader ahead of time when it’s more relaxed and less fraught with all the demands of meetings etc while there.
Dr R Young, Source: WI
That good fortune happened to me on the Friday before the recent AACR conference in San Diego, when I recorded an interview with Dr Richard Young, (Whitehead Institute & MIT and scientific co-founder of Syros), who was giving a plenary talk on the Sunday at AACR entitled, “Transcriptional and Epigenetic Control of Tumor Cells.”
Epigenetics and transcriptional changes are fascinating concepts to me because they get right to the heart of what’s going on deep in the oncogenes and how they control processes in cancer. Clearly, in simplistic terms, if we can understand how things change and evolve, then we can potentially devise better strategies to overcome them. Instead of targeting a protein kinase with a small molecule or a cell surface antigen with a monocloncal antibody, this is an altogether different approach. Protein-protein interactions such as MYC, RUNX1, p53/TP53 etc have long been the bugbear and frustration of many good researchers, precisely because they are challenging to target with conventional approaches.
So what’s new and why am I really excited about these new developments?
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