Biotech Strategy Blog

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

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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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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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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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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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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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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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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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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Mononclonal and bispecific antibodies in the immuno-oncology space have certainly had a bit of a roller coaster ride over the last couple of years with various safety concerns including cytokine release syndrome (CRS) and even fatalities coming to the fore following clinical holds on various compounds across several quite different compounds.

Barbara Hepworth sculpture at Downing College, Cambridge

As companies work their way through those issues with FDA and other Health Authorities, can we also learn from our previous experiences with checkpoint blockade, immune agonists and other IO targets in order to develop safer products?

One thing has become clear and that’s how important particular aspects of the engineered molecules can make an impact in terms of both safety and efficacy. There are, after all, quite a few factors that can be manipulated or changed to impact performance, much as the design arrangement and composition of various components into a unified whole is crucial to Formula Once racing cars.

In our second part of the bispecific mini-series, we head over to Europe and interview the CSO of a leading company in the IO bispecific space to learn more about these design features and the potential benefits they might induce.

It makes for rather interesting reading when we consider the next wave of IO clinical trials…

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It’s time to launch a new mini-series where we explore some of the issues and concepts surronding a given topic and then look at how they are being tackled through the lens of different biotech companies.

Storm clouds gathering over immune agonists and bispecific antibodies?

The latest topic is bispecific antibodies, a development we have often covered since 2014/2015 here on BSB. Much has happened in that time and many compounds have fallen by the wayside. In my view, this is a normal part of oncology R&D attrition – it’s not that we encounter problems, it’s how companies handle the road blocks along the way that matters.

What can we learn from the first two waves of immuno-oncology that can be applied to bispecific developments?  There is no doubt that while some have been successful in making it to market, quite a few have encountered various challenges along the journey.  Why is that and how to we address the emerging or thorny issues?

Change is inevitable in the cancer immunotherapy revolution, we can hardly expect to get things right first time, every time. Some approaches will work well, some won’t, others will need tweaking and turn out to be useful tools down the road in future iterations. Learning from past experience to make the next wave better and more effective is an important part of this process rather than putting everything in one basket and then abandoning it if it doesn’t work first time.

One man who has experienced the first and second waves and is ideally placed to candidly discuss the learnings and future changes needed is Dr Dan Chen. He was global head of cancer immunotherapy while at Genentech/Roche and is now spearheading clinical development at IGM Biosciences, a biotech focused on next generation antibodies and bispecifics.

In order to think about what’s needed in the future rather than rush headlong into a different modality, we first have to take stock and then reflect on the learnings of the past clinical trial experiences in order to figure out how to fix them…

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