Biotech Strategy Blog

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

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Posts by MaverickNY

On the interaction between transcription factors and the immune system

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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Through the window on the MYC oncogene

Through the window of aiming at tough to hit targets – with new approaches will we soon see more than before?

One of my big dislikes in oncology is the tendency to describe certain areas of R&D with the characterisation around the popular media epithet, “Drugging the undruggable.”

When we think of ‘undruggable’ in oncology R&D the first three targets that many people think of are MYC, RAS and TP53.

Quite aside from the issue that implies we can do little or nothing for those patients unfortunately affected is that it results in a more closed mind, a bit like half empty versus half full; it’s only undruggable in the context of what has gone before us and offers little in the way of future possibilities that lie ahead of us.

The RAS pathway is a great example of this phenomenon.

For years it was considered undruggable and yet despite that we now we have several selective BRAF mutation inhibitors, plus some nice approaches now emerging against KRAS mutations such as G12C (e.g. Amgen, Mirati, Araxes/J&J) and G12D, plus let’s not forget the potential for tipifarnib against HRAS mutant squamous cell carcinoma of the head and neck (SCCHN). All of these have shown some nice preclinical promise with some (BRAFV600E) already approved by Health Authorities.

There are other tough targets to think about too, including MYC and TP53, but rather than consider them undruggable, I’d rather think it just takes a little bit of time (and a lot research) before we understand the underlying biology better in order to figure what we can optimally target.

With that thought in mind, we have a new five part mini-series to share focusing on MYC. It’s actually been three or four years in the making ever since I heard a wonderful talk on the topic about improved mouse models that allow us to interrogate the biology more profoundly in order to understand how things work.

Not all of the interviews were theoretical in nature – we also talked to a leading scientist in this area involved in a largely unheard of start-up/spinoff with the goal of developing new therapeutic approaches against hard to target oncogenic drivers.

Before we go there on our journey, however, we need to begin with some basic understanding to set the scene…

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Novel DDR combinations and regimens that could make a difference

It’s the dog days of summer and yet there’s a lot happening on the DDR front from multiple angles.

After a short break from science, this makes now a really good time to reflect and take stock in order to explore some of the key issues facing the field, especially in terms of future combination approaches.

Research that’s appearing now may influence future trial designs – always a nagging worry in Pharmaland that the standard of care can change before you even get your own phase 3 readout! No one likes to be pipped to the post, after all.

With the early WEE–1 news this week and a raft of new PARP readouts, there is much to discuss and also plenty of nuance and subtlety to consider carefully because what looks obvious at first blush may not actually be the case based on prior evidence that many will have forgotten about.

So grab a cup of iced coffee and shades and settle down under your sunbrellas for a pleasant and easy to read review of the various trials, settings, combinations and DDR pathway considerations…

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A STING in the long tail?

In the enlightened realm of phase 1 oncology trials there generally more unknown unknowns than there are known unknowns, especially with new target approaches.

Who knew it was so beautiful outside of the cold dark halls?!

You could say that makes for a more interesting world, but it also makes for more caution, especially when the FDA is considering agonists that induce stimulatory effects.  What it means is that you start off very low – in this latest example it was 50µg and going up to 1600µg to determine the safety profile of a combination.

We have covered the STING pathway quite extensively over the last four or five years now, so it’s time for a new update and a look at some of the much awaited combination data. What can we learn?

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Is the BMS CheckMate-227 trial a hit or miss in lung cancer?

Yesterday afternoon BMS provided an announcement and update on the controversial phase 3 CheckMate-227 trial in first line non-small cell lung cancer (NDCLC).

Lightning bolt

Does lightning strike twice?

This large study compares the combinations of nivolumab with either ipilimumab or chemotherapy to chemotherapy alone in both squamous and non-squamous patients with previously untreated advanced disease.

Ahead of the data presentation what can we expect and what will the impact be on the broader landscape?

There is no doubt that BMS have had a chequered history in lung cancer since the miss with the earlier CheckMate-026 study. Is their run of missteps over or can we expect yet more controversy to befall them?

In our latest analysis we take a look at what going on in this niche.

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Insights on the Jounce-Celgene collaboration and ICOS agonism

With the Jounce-Celgene announcement that the ICOS agonist, JTX–2011, is being returned and new priorities being pursued there is much to consider. There are quite a few nuances to this story to consider beyond the obvious that BMS already have an ICOS stimulating molecule.

Here we put together a synopsis and some commentary in looking at several relevant targets of interest in the context of the broader landscapes that are evolving.

Are Jounce left high and dry with this latest development or is there still a future in ICOS agonism?

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New developments in Sarcoma

Is the dragon roaring back?

It’s a while since we last looked at new developments in a rare group of cancers called sarcoma so this is a good time to stake stock and explore the positive and negative trial results, as well as look at some of the emerging targets that are being investigated.

Not all of them will likely pan out given the nature of the disease, but some might turn out to be hidden gems.

We’ve had a few negative trial readouts in sarcomas and plenty of new trials with a variety of agents in early development – is the dragon roaring back or whimpering?

Aside from our top 10 review, we also have a thought leader interview to share with commentary from a sarcoma specialist…

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A look at Amgen’s early oncology pipeline

Continuing our bispecific mini-series, we now switch from small to large biotech with a look at what Amgen are doing in this niche. They have both regular bispecifics, as well as T cell bispecifics in their early pipeline.

Our latest company interview focuses on several early phase 1 new product developments.

Aside from the BiTEs, we also discuss the clinical program with one of their most promising small molecules, AMG 510, a KRAS selective inhibitor that has been drawing much attention since the chemical structure was unveiled at AACR earlier this year.

There was much ballyhoo and yet more garish headlines in the media at ASCO regarding ‘Amgen showed it had developed a medicine that shrank tumors in 50% of lung cancer patients’ – in 10 patients. Was it really 10 people or a much higher number if we consider intent to treat amongst evaluable patients? Then of course, taking a small sample size into consideration, the next 10 might produce quite different results. We might also see resistance set in down the road (e.g. at 9 to 12 months as we have with BRAFi), so these are really very early days, something we pointed out during the daily ASCO coverage.

To be clear, I can say that both companies included in yesterday’s (Neon Therapeutics) and today’s (Amgen) articles were sensible, thoughtful, and well measured in how they handled the data rollouts, but the media frenzy that occurred with each is quite something else.

Since we had quite a few BSB readers ask about both sets of data, having discussed Neon’s yesterday, today we offer an interview with an Amgen exec at the heart of their early stage programs…

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An in-depth look at Neon’s updated neoantigen vaccine data

Neon Therapeutics LogoAs we prepare for rolling out some additional expert interviews on a variety of topics together with another mini-series on a tricky target, I wanted to take a moment to explore the Neon Therapeutics data.

Most of the news reports yesterday seemed to be concentrated around a general theme of ’cancer vaccine assist beats immunotherapy drugs alone!’or ‘vaccine boosts Opdivo response in 3 cancers’ … but does the data live up to the breathless hype that ensued? What can we say about the latest clinical update?

As often is the case, the true story around the facts turns out to be much more nuanced and subtle in flavour than the garish headlines might have you believe…

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Will innate bispecifics make a difference in hematologic malignancies and solid tumours?

After yesterday’s look at a biotech company (F-star) who are focused on adaptive approaches with bispecific antibodies using checkpoint and immune agonist targets, we now shift direction within Europe to a completely different concept, although both are tetramer-based.

Oncology R&D can be a stop-start journey that is highly unpredictable and uncertain!

In the third part of our latest mini-series on bispecific antibodies, we now take a look a company who are evaluating this modality as a way to activate NK cells and stimulate the innate immune system. With all the fuss and attention on the adaptive immune system and checkpoint blockade, is there a role for innate immunotherapies?

Rather than look at this aspect as competitive, smart companies are seeking ways to complement existing backbones to determine if the outcomes can be boosted by targeting both innate and adaptive systems in a more coordinated manner.

To find out more about these developments, we talked to Dr Adi Hoess, CEO of Affimed, a German biotech company who are developing innate immunotherapies.

They have certainly been on a roller coaster ride of late, with clinical hold and abandonment of a leading program balanced by encouraging initial data with other projects, so what gives?

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