Biotech Strategy Blog

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

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Update on Amgen’s KRAS inhibitor in solid tumours

Barcelona – Today is going to be a very long and complex day at ESMO, with a multitude of key data expected from several trials ranging from the phase 1 Amgen data update on their KRASG12C inhibitor, AMG 510, AstraZeneca’s osimertinib in the FLAURA study plus a raft of others, including the phase 3 PAOLA–1 and CheckMate–227 trials.

In order to keep all the information straight and manage the various embargo deadlines at wildly different times, we’re going to break with tradition and post three different articles at different times on KRAS, FLAURA, and the daily running log of various studies and posters that catch our interest. Yes it’s a lot more work, but it’s the only way to manage all the deadlines!

This post will focus solely for the KRAS updates at ESMO19, including the initial data release, the presentation, analyses, and commentary. No doubt that means a series of updates will ensue so do check back regularly or follow the alerts on Twitter via @biotechstrategy.

Let’s roll!

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ESMO19 Highlights from Day 1

Old Post Office in Barcelona

Barcelona – After the torrential rains that hit here earlier in the month at WCLC, it’s glorious weather in Barcelona for the 2019 Congress of the European Society for Medical Oncology (#ESMO19).

Each day we’ll be providing highlights from the Congress with news, commentary and analysis from various presentations we’ve attended and thought leaders we’ve spoken to.

This ESMO Congress is a really exciting meeting, perhaps one of the busiest we’ve seen in recent years with multiple sessions in parallel to choose from. There are no shortage of data to discuss and review.  In distant years past, ESMO used to be known as the metaphorical dumping ground for negative trials that undoubtedly got lost in hurly burly – no longer! That changed after they started appearing in the Presidential Symposia and having the spotlight shone on the data. It’s now a much more vibrant meeting for clinical development, with an increasing translational focus thrown in too to explain the why and not just the what.  That’s good news for all of us.

To kick off our daily live ESMO coverage, we begin with sharing some useful insights gleaned from what we’ve heard so far plus more will be added throughout the day as we hear from the educational sessions later…

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ESMO19 Preview 3 – Tackling immune suppression

It has to be said that this is one of the most jam-packed ESMO schedules that I’ve seen in a while!

Usually one has a few sessions they are interested in and lots of ‘free’ time to conduct interviews. That is definitely not the case this year with even parallel sessions at the same time as the Presidential (plenary) symposia, making for some very hard choices that need to be made.

Barcelona

Immune suppression can take the form of many targets – just taking out one of them may not be enough

As we start to see a renewed focus evolve on how to make immunotherapy work in or help more patients, there has been much attention on what we can learn from the addition of chemotherapy, additional checkpoint targets, immune agonists, various innate targets from KIR and NK cell checkpoints to TLRs and STING, neoantigen and dendritic cell vaccines, a telephone directory of cytokines, oncolytic viruses, etc etc to name a few, all with varying degrees of success.

What about exploring the inhibitory factors that induce immune suppression?  If we can reduce the cloaking and hostile tumour microenvironment, would that lead to more effectiveness with checkpoint blockade?  Maybe, maybe not.

In principle, it’s a sound idea yet these factors are both broad and incredibly varied in scope as a topic as to seem overwhelming at first.  The good news is that there are some emerging targets and hints of activity to come that are slowly beginning to emerge, making ESMO a good place from which to take stock of some new early stage developments.

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The many faces of lung cancer

The many faces of lung cancer requires an appreciation of nuance in treatment

Barcelona – Many observers seem to so be single mindedly focused on immunotherapies of late that they may well be forgiven that, hey, there’s still much going on the world of targeted therapies!

If there is one thing we can learn from the lung cancer (and CML) communities it is their dedication to identifying resistance mechanisms and along with them, novel targets for subsequent therapy in order to set about improving outcomes for people with the disease.

As a result, lung cancer can now be segmented into many subsets, each requiring careful consideration of appropriate therapy options, not only in newly diagnosed disease, but also what to do with subsequent lines of therapy.

In this review, our third from the WCLC 2019 meeting, we pull together a lot of disparate loose ends on targeted therapies and draw some important themes together…

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New developments in immunotherapy from WCLC19

A rare dry spell in Barcelona as the clouds roll in bringing yet more rain

Barcelona – While the weather for the World Congress on Lung Cancer (WCLC) has been largely gloomy with plenty of rainy spells, there’s much good news to report on the clinical front.

After yesterday’s review of the Amgen KRAS inhibitor data in G12C mutation positive patients receiving AMG 510, it’s now time to turn our attention to immunotherapy developments with several important trial readouts and in-depth analyses to discuss.

We will be posting a separate summary of the key highlights on targeted therapy, but first let’s consider what we learned on the immunotherapy front, including some of the science behind it all…

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Targeting KRAS – Highlights from WCLC 2019

Chariots of Fire in Barcelona?

Barcelona – Gosh, what a weekend chock full of lung cancer data at the World Congress on Lung Cancer hosted by the IASLC!

There’s nothing like a bit of controversy to get riled up or crash with disappointed hopes under the weight of expectation, but if we go under the hood and look carefully, what do we find?

There was a lot of topics that we’re going to cover the important highlights and learnings in a two parter series – today we focus on KRAS with targeted therapy, while tomorrow we look at other topics of interest, both targeted and immunologic.

Without much ado, let’s roll with the Amgen update as there are many subtleties and nuances to consider…

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Will bromodomain inhibitors and PROTACs make an impact?

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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Can a new class of agents therapeutically target the MYC or RAS oncogenes?

Cambridge – Amongst the historic colleges and cloistered walls of one of the world’s oldest universities there is pioneering research going on, and not only that, it’s potentially being translated into potential new cancer treatments.

Dr Laura Itzhaki (Twitter: @LauraItzhaki) is professor of structural pharmacology at the University of Cambridge. She is also founder and chief scientific officer of a start-up biotech company, which is focused on the discovery and development of a new class of drugs called polyproxin molecules.

University of Cambridge

Prof Itzhaki’s research is the basis of the science and intellectual property behind PolyProx Therapeutics, and the company earlier this year received £3.4 million in seed financing. This may not be a huge deal in US terms, where we’ve seen some truly mind blowing Series A financing rounds for start-up cell therapy companies, but it’s not inconsequential in UK terms. We’ve also seen with today’s £100M Series B funding announcement for Stevenage based Achilles Therapeutics (whom we profiled a year ago) that early stage UK companies can indeed go on to big things.

Basic science is the backbone of cancer research – let’s not forget that translating the new discoveries into the clinic is how new products are developed and it’s exciting to see an increasing number academics take the next step on that journey.

During a visit to Cambridge this year, Prof Itzhaki kindly spoke with BSB about her research and the direction PolyProx hopes to travel. It’s very early stages for the company, yet it’s a story we very much look forward to following, and one I expect we will hear more from, as other companies look to partner with them in the future….

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Gerard Evan discusses inflammation and immune suppression in cancer

Yesterday we posted the first part of an extended interview with Professor Gerard Evan (Cambridge), where we discussed the oncogene MYC and what we have learned from his and others work in this emerging field.

It hard not to be in Cambridge and think of biology as anything but an seriously intellectual pursuit, and yet there are many lessons to be gained from a better understanding of why things do what they do – in both health and disease – if we are to even think about going about manipulating them therapeutically.

The river Cam in Cambridge earlier this year

Without much ado, here’s the second part of the interview with Prof Evan, where we channel our inner Socrates and focus on a lot of whys rather than hows.

We turn to discussing the biological principles around how MYC and KRAS behave in concert, what we do and don’t know about p53 as a tumour suppressor, plus a few other related topics of interest, including what happens to immune cells in their lung and pancreas cancer models.  There’s also the little secret of what Prof Evan describes as the ‘dark matter of cancer biology.’

I highly recommend reading the previous post before moving on to digesting this portion of our enlightening discussion…

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Why does Myc drive out T cells?

In the initial parts of the broader story on MYC, we have covered a basic primer on the MYC oncogene, including a look at the key work from the labs of Dean Felsher in Stanford (liver model) and Gerard Evan in Cambridge (lung and pancreas models) to set the scene.

We also heard from Dr Jay Bradner at NIBR about his work wth bromodomains and PRC2 and how deep transcription factors might interact with the immune system.

A couple of years ago at AACR, Prof Evan gave a wonderful talk about his Myc model in a session on ‘Drugging the Undruggable’ and happened to put up a dramatic slide that really caught my attention – MYC and RAS drive out T cells – and I was thinking why, how do they do that? I wanted to know more about this effect because unless we understand how and why it happens, that maybe we can possibly go about tackling cold/non-inflamed tumours in a more informed way when these oncogenes are actively controlling and driving the tumour growth.

Cambridge, UK

For me, the logical next step in this ongoing story on understanding MYC is actually to explore the biology a bit further – what have we learned from animal experiments that might teach us some clues about where to start looking if we want to go about drugging something therapeutically that’s not in the normal kinase domain like many so called ‘druggable’ targets are?

To answer this question and many others, we travelled over 7,000 miles as a the crow flies and tracked down the great man himself in Cambridge UK.  We ended up with one of my all time favourite interviews that we’ve been privileged to hear at BSB…

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