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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Dr Bernie Fox (@BernardAFox) is a man on a mission to #FinishCancer, a Twitter hashtag he uses to reflect his vision.
A cancer immunotherapy rockstar, Bernard A Fox, PhD, is the Harder Family Endowed Chair for Cancer Research at Providence Center Center and Chief of the Laboratory of Molecular and Tumor Immunology at the Earle A. Chiles Research Institute in Portland, Oregon.
Fox is also a past president of the Society for Immunotherapy of Cancer (SITC) and CEO of UbiVac, a biotechnology company focused on therapeutic cancer vaccines.
Readers of the Blog and Novel Targets Podcast listeners will recall we had the privilege to interview Dr Fox back at the American Association for Cancer Research (AACR) annual meeting in New Orleans in 2016: “AACR Cancer Immunotherapy Insights from Dr Bernard Fox.”
Fast forward 18 months… it is now time for a detailed update on this issue, as a few interesting events have since come to light in this niche with Genentech/Roche abandoning development of their OX40 agonist, coupled with several new publications from different labs suggesting that concurrent administration of an anti-OX40 antibody with an anti-PD1 antibody attenuated the effect of anti-OX40 and resulted in poor treatment outcomes in mouse models.
Dr Fox kindly spoke to Biotech Strategy Blog about some of the key learnings from this research, where he sees the future potential for OX40, and what his vision for cancer immunotherapy is.
Here’s a short clip from the fireside chat…
He’s definitely a man on a mission to #FinishCancer!
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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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It’s Day 6 of our Countdown to the AACR 2016 annual meeting in New Orleans. We’re at the halfway, 6 posts written and 6 more to go! Then it will be daily Live blogs from the meeting.
There’s a lot of cancer immunotherapy at AACR this year, so after yesterday’s post on GITR we’re continuing our mini-series with a look at another immune agonist.
Today, we’re moving onto OX40 (CD134) as a novel immuno-target. Regular readers will know that we’ve been following this target for some time.
Immune agonists such as GITR, OX40, CD40, CD27 and 4-1BB help to rev up T cells. As Dr Tom Gajewski (Chicago) told us last year, in an interview published on the blog and excerpted in Episode 6 of the Novel Targets Podcast: Stepping on the Gas:
…there are inhibitory receptors on activated T cells that are involved with shutting immune responses down. There are also activating receptors that help to rev up those T cells. You might question whether you can push an activator and block an inhibitor, and maybe get a good anti-tumor response going as well.
When we drive a car, we both lift our foot off the break and we step on the accelerator. We have really beautiful data in animals that that this is exactly the case, that if you hit one of those strong positive regulators, and block just one of the negative regulators, you can have complete disappearance of the tumors in mice.
Several of those positive agonistic antibodies against costimulatory receptors are in the clinic. One of them is anti-OX40 that a couple of groups have in the clinic. We’re working with Genentech, that has one of those agents in phase I.
What does the OX40 competitive landscape look like?
In those post we’ve provided commentary on some of the new products in development from companies and highlighted a surprising number of abstracts that you’ll want to watch out for at AACR 2016 if you’re on the cancer immunotherapy track.
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Ovarian cancer is an often neglected area in cancer drug development and historically has often been one of the last solid tumours to be evaluated as part of a life cycle management program. There are a number of reasons for this, but recently that situation has begun to change as our knowledge of the underlying biology improves and new agents are developed that target the particular oncogenic aberrations.
It is a tumour type that ranks 5th in cancer deaths amongst women and accounts for more deaths than any other gynaecologic cancer. Indeed, in 2014 nearly 22,000 women are estimated to be diagnosed with this cancer in the U.S. and approx. 14,000 will likely die from the disease.
Earlier this month the FDA approved bevacizumab (Avastin) in combination with chemotherapy (paclitaxel plus pegylated liposomal doxorubicin or topetecan) for the treatment of platinum-resistant, recurrent epithelial ovarian cancer (EOC), fallopian tube, or primary peritoneal cancer who have received no more than two prior therapies. The approval was based on the phase 3 AURELIA trial (n=361), which demonstrated an improvement in median progression free survival (PFS) of 6.8 vs. 3.4 months (HR 0.38, P<0.0001). This means that the women in the trial saw a 62% reduction in the risk of their symptoms worsening compared to chemotherapy alone.
Surprisingly, this advance represented the first new treatment option in this setting for 15 years!
The good news is that beyond Avastin, there are a number of other promising agents in development for ovarian cancer. At this year’s EORTC-AACR-NCI Molecular Targets meeting held in Barcelona, new data was presented on several such compounds that are well worth highlighting.
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There has been a lot of enthusiasm in the immuno-oncology space since ASCO about the possibility of combining a checkpoint inhibitor with an immune stimulator. There are several ideas behind this approach since:
a) Not all patients respond to checkpoint inhibitors
b) Some patients only partially respond, although they can achieve an attenuated response before relapsing
An important question in many people’s mind is what is different about these subsets of patients compared to exceptional responders? How can we change that situation for the better?
Two approaches that have been mooted of late include the following:
- Using a cancer vaccine to ‘prime’ the tumour
- Combining a checkpoint inhibitor with an antibody agonist to stimulate the immune system
At SITC in Maryland this weekend, there were plenty of packed presentations and discussions on both of these classes of agents, so this is a good time to explore the idea of immune stimulators further based on the latest data we heard.
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This last week saw the ASCO Breast Cancer Symposium in San Francisco, although very little caught my attention from a drug development point of view. Much of the attention seemed to be focused on surgery, genetic counselling and screening.
With the 2014 European Society of Medical Oncology (ESMO) conference in Madrid coming up fast in only 2 weeks time, it seems a good point to take a look at what’s on the slate there, since there are some important clinical trials being presented there with new data that we can expect to hear a lot more about.
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Companies mentioned: Roche/Genentech, GSK, Novartis, AstraZeneca, Medivation, Astellas
Drugs mentioned: Pertuzumab, trastuzumab, lapatinib, PI3K inhibitors, olaparib, enzalutamide
There are a couple of important breast cancer trials with data being presented for the first time at Madrid.
The ASCO 2014 season kicks off with the release of the embargo on main abstracts (other than the late breakers and plenary sessions) yesterday evening. Over the next week, I’m planning to cover some of the highlights (positive and negative) that I found interesting or worthwhile discussing. While there was nothing particularly earth shattering or new in the press briefing at lunch time yesterday, that’s not to say there aren’t some important data this year buried amongst the 5000+ abstracts.
Today I’m driving to Orlando and on Friday will be at the American Urological Association (AUA) meeting, so a lighter post will appear here on BSB regarding my initial topline highlights and lowlights tomorrow.
I decided to kick off the ASCO Previews first and focus on an altogether different topic, one that we’ve covered longitudinally on either PSB and BSB – originally with some scientific and translational data – and now with some initial clinical trials that look pretty encouraging thus far. The bench-to-bedside transition is often fraught with many challenges, but occasionally, they actually turn out quite well in practice.
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At the annual AACR meeting last year, I wrote about an awesome piece of research from Meghna Das (NIBR) who looked at intermittent dosing of vemurafenib in animal models of BRAF driven melanoma and found that such an approach reduced resistance and improved outcomes.
Many of us are unlikely to forget the fascinating sequence of photos shown by Levi Garraway (Broad/MIT) two years earlier at the same conference, when he highlighted the before and after impact of vemurafenib therapy on a patient with advanced melanoma in glorious technicolour. Sadly, the subsequent photo six to nine months later showed that the lesions came back with a vengeance and the patient passed away.
Given that the disease is exquisitely sensitive to BRAF inhibitors, how can we improve this situation and overcome the resistance for future patients?
Das’s work was one of the highlights of that conference for me, since it involved creative thinking and a series of very well done, logical experiments that clearly showed an impact. The post drew a lot of ire and attention though, with many researchers emailing me to say they thought the idea was crazy and utterly against their understanding that you need to continually hit the target 24/7 or risk sudden relapse. It drew as much surprised reaction as a related and controversial post on minimally effective dose, where I argued that we needed new approaches to hitting the target.
Today, it’s time for an update on this controversy – what happens when we go from bench to bedside and back again? What can we learn from an N of one that helps us figure out the optimal strategies for overcoming acquired resistance to TKI therapy?
Therapies mentioned: vemurafenib, dabrafenib, trametinib, cobimetinib
Companies mentioned: Roche/Genentech, Novartis, GSK, Exelixis
The story is truly a fascinating one.
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“Nothing lasts forever, because nothing ever has.”
James Shelley, The Caesura Letters
This year’s annual AACR meeting was so good, we could probably write another 50 posts and still not be done! With ASCO fast approaching, however, it’s almost time to draw it to a close and the final post conference note will be published on Monday.
Today is the penultimate report and focuses on the key highlights that caught my attention in immuno-oncology, which covers the gamut from checkpoint inhibitors, co-stimulants, innate immunotherapy and CAR T cell therapy to bispecific antibody TCRs.
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