Biotech Strategy Blog

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

Posts tagged ‘STING agonist’

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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Continuing our STING mini series, the third part looks at a company with a next generation agonist that is heading into the clinic soon.

What sort of challenges have the overcome, what can we expect to learn more about? Are they thinking narrowly or broadly?

One of the most exciting times for me in new product development is not when they move from phase 2 to approval, launch, and subsequent commercialisation, but that window between preclinical studies and first-in-man trials. The IND-enabling phase is an intense period with much to get done that can make or break subsequent advanced solid tumour dose finding trials.

Get your various key predictions wrong and you could be looking at a spate of unwanted severe side effects that will rapidly grind your trial to a halt. Sometimes they are a predicted risk at a much higher dose, for example, other times the PK/PD predictions don’t turn out as expected at all (oops). Then there’s scheduling and timing issues to think about on top of dosing and therapeutic window for combination trials.

Despite a lot of research, it’s still a very imperfect science. As one of my mentors used to say, “Better to be lucky than pedantically dotting all the i’s and t’s!”

So imagine a young up and coming IO biotech in that window between preclinical and clinical development – what are they going to do and where do they see themselves fitting in the broader landscape?

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We first wrote about this innate pathway back in early 2015 – before it became famous and controversial – when things seemed much simpler then.

Imagine the basic concept… add an immune agonist – this targets the innate immune system to jumpstart or wake up the immune system in colder tumours – to an established adaptive immune therapy such as checkpoint blockade and see whether any magic happens. In practice, this turned out to be much easier said than done, because in reality mouse and man have quite different immune systems and do not react in the exactly same way, which makes extrapolation from one to the other challenging at the best of times.

Still, back in 2015 there were barely a handful of STING agonists that anyone could really put a name too, now there’s 18 compounds in early pipelines and counting.

Not all the players are small biotechs either, as big Pharma is certainly paying attention to the smaller biotechs (both private and public) generating molecules, especially now that early clinical data (alone and in combination) is beginning to dribble out.

Aside from collaborations and licensing deals, there’s also an increase in patents in this niche, which is often a sign of competitive activity.

Four years on, how has the landscape changed, what does the data look like and what sort of issues need to be addressed?

In the first of our latest three-part mini series, we look at the competitive landscape and how it has changed (quite drastically since 2015, I can assure you!). In parts two and three, we look at two different up and coming players in the STING space with very different approaches.

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Last week we reported on a paper published in Nature by Bakhoum et al that raised the provocative question, Can STING agonists promote metastasis? (Link to BSB post).

As Dr Bakhoum subsequently tweeted an image from the research made the front page of the print edition of Nature:

In this latest post, we continue the story with a perspective on this research from one of the world’s leading experts on the science behind the STING (stimulator of Interferon genes) pathway.

Glen N. Barber, PhD is Chairman of the Department of Cell Biology at the University of Miami Miller School of Medicine and holds the Eugenia J. Dodson Chair in Cancer Research.

He has published extensively on the biology of STING and targeting the innate immune system.

In science we often hear that the truth is what the data tells us, but what does the data by Bakhoum et al really tell us and what conclusions can we draw from it that will guide future translational and clinical research?

Dr Barber kindly spoke to BSB at his office in the Papanicolaou Cancer Research building at the UM medical school and offers a perspective that reignites the controversy over STING and Metastasis.

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Can STING (stimulator of interferon genes) agonists promote cancer metastasis in some patients?

That’s the intriguing question posed by research published recently in the journal Nature by Dr Samuel Bakhoum @Samuel_Bakhoum and colleagues. (doi:10.1038/nature25432who found that, “chromosomal unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs.”

Samuel F. Bakhoum, MD PhD is a Holman research fellow at Weill Cornell Medicine and a senior resident in radiation oncology at Memorial Sloan Kettering Cancer Center in New York. The joint first author of the Nature article is Bryan Ngo, a student in the Weill Cornell Graduate School of Medical Sciences. It’s impressive work from two early career researchers.

The paper raises several important questions that drug developers – several of whom already have STING agonists in the clinic – may need to carefully think about.  It is, however, important to point out that this data is preclinical, so we don’t yet know what may or may not happen in cancer patients.

We first heard about the data published in Bakhoum, Ngo et al’s Nature article, “Chromosomal instability drives metastasis through a cytosolic DNA response,” at last October’s excellent AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics meeting in Philadelphia.

What we learnt at #Targets17 was that chromosomal instability is linked to tumour metastasis through the STING pathway.

Readers of BSB will know that we’ve been covering activation of innate immunity through the STING pathway for several years now (See posts:What we learnt at AACR about Aduro ADU-S100” and “Tom Gajewski takes the STING out of Cancer,” to name but a few.

So how do we reconcile the positive and encouraging data that has led to development of multiple STING agonists, several of which are now in the clinic, with the potential that there might be a harmful aspect to them?

There are some important subtleties and nuances around this critical issue and that is the essence of this post and what we sought to gain more insight into, beyond the obvious superficial answer that there could be harmful effects involved.

The Roman god Janus is depicted as having two faces – one looking to the future and the other to the past.

There are also two faces to cancer immunotherapy: It can be a force for good, we can harness our immune system in a way that results in a positive outcome – people with cancer live longer, some are even cured.  Alternatively, if we harness the immune system in a negative way it can also be a force for harm. 

We heard on the recent Novel Targets Podcast episode that while combination cancer immunotherapies can be effective in a subset of people, they can also lead to rip-roaring toxicities as well as unwanted auto-immune side effects, and in some cases, these can be fatal.  With multiple inhibitory and activating forces at place, cancer immunotherapy can tread a fine line balancing these out.

Dr Bakhoum kindly spoke to BSB about the translational and clinical implications of this latest research.

Given the potential impact of this research, we also sought additional commentary from experts active in STING research such as Jason Luke, MD FACP (@JasonLukeMD). He’s an Assistant Professor in the Department of Medicine at the University of Chicago and a Principal Investigator for early immunotherapy trials, including those with STING agonists.

BSB readers may recall we did an in-depth interview with him at AACR17 (See post: Overcoming Immunotherapy Resistance). This time around, he shared his perspective on Dr Bakhoum’s research and looked at the potential clinical implications.

Like Janus, does the STING pathway really have two faces to it?

Should companies with STING agonists be concerned or not?

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We’ve come a long way over the last two years in the oncology market, with several novel approaches approved, numerous major phase 3 trials evolving and a huge turnaround for many companies in terms of early pipeline activity.

ASCO 2016 Posters 3

The melée at the ASCO 2016 Poster Hall

Unfortunately, this also means that the tendency of lemming activity also increases in the rush to copy everyone else and not be left behind.  Just a couple of years ago, some industry friends grumbled that there were over 20 checkpoint inhibitors chasing them in development; they may be surprised to know that now there are nearly 70!  This is both unprecedented and unsustainable, and yet it’s also a function of the perceived success these agents have had on the cancer R&D landscape to date.  Everyone wants one for fear of being left behind… except that many are indeed way behind already.

You can imagine the tall guy on the left of the picture looking at his watch and wondering, “Ah so many new posters, so little time!”

Meanwhile, as the rate of approved cancer therapies increases, so does the inexorable march in terms of hyper-aggressive basket pricing.  I would argue that at some point, it no longer acceptable or even conscionable to change a premium or even market rate for drugs that give an incremental improvement of a mere 2 months of extra life.

Equally, one thing that many industry observers and the media love to do, and wrongly in my view, is to compare the individual drug prices on an annualized basis.  This is silly for several reasons:

  1. So far, not all patients are treated for a full year
  2. If patients are treated until progression and that happens early, then therapy is stopped
  3. What people should be looking at is the average treatment cost based on the length of therapy – some people will receive a few months and some much more than that
  4. What’s the true cost of a cure or remission to a patient and their family?
  5. How do we quantify the impact of the long lasting durable remissions?

These questions will become increasingly important as we see a more aggregated therapy approach emerge over the next few years.

By this, I mean that we are now going beyond monotherapy and even combinations; those trials have already long started and are the low hanging fruit that has been rapidly snapped up by the early players, as we eagerly wait for their data readouts.

If you have new agents coming-out of preclinical and into phase 1 development over the next year, there are a number of important questions to consider:

  • What are you going to do and where do you start?
  • How do you gain an edge when coming from (way) behind?
  • How do you develop unique positioning that could sustain your molecule in a sea of similar competitors?
  • Is it realistic to expect the 17th and 50th checkpoint to have equivalent efficacy as what went on before and will all of these seriously make it to market?

You can see now why even the FDA’s Dr Richard Pazdur was moved to grumble about the surfeit of me-toos here and company expectations that the FDA should consider them – it’s on a massive scale that we haven’t seen before.  For once I agree and empathize with him over that dilemma, it’s madness to think they will all be as good as pembrolizumab or nivolumab.

What we are starting to see emerge now is a surprising synthesis of ideas and a merging of disparate approaches. How will this affect oncology R&D over the next 1–5 years?

A couple of smart readers wrote in asking about these emerging trends, what have we identified so far, and where do we see the oncology space going in the near to medium term future. Now that AACR and ASCO are behind us, what can we learn about the new developments and where they all fit in the oncology landscape strategically?

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Aduro Biotech LogoWe’re almost at the end of our coverage of AACR 2016. Post number 30 (!!) is on Aduro Biotech ($ADRO) and their STING (Stimulator of interferon genes) agonist currently in development.

On the final day of AACR, in a packed session chaired by Tom Gajewski, MD PhD (Chicago), the meeting heard from Tom W. Dubensky, Jr, PhD Chief Scientific Officer of Aduro Biotech in a presentation (SY39-02) entitled:

“Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity.”

Dr Tom Dubensky Aduro CSO

Dr Tom Dubensky, Aduro CSO

I spoke with Dr Dubensky (pictured) afterwards. In my interview recording you can hear Vice President Biden’s cavalcade arrive at the Ernest Morial convention center in New Orleans for his plenary presentation.

Since AACR 2016, Aduro announced that the first patient has been dosed with ADU-S100 (MIW815) in a May 12 press release.  This triggered a $35M milestone payment from Novartis, who are undertaking the clinical trial (NCT02675439).

In March 2015, Aduro entered a collaboration with Novartis that, according to the Aduro press release, led to an initial payment of $200M and an additional $50M in equity investment.

After the recent failure of their pancreatic cancer vaccine, announced in a May 16 press release, there is a lot riding on ADU-S100 for both Aduro and Novartis.

I had the privilege to interview Dr Gajewski last year at Immunity 2015, where we talked about his work on STING (see post: Tom Gajewski takes the STING out of cancer). You can hear a short excerpt from the interview on Episode 2 of the Novel Targets Podcast.

So a year later it’s a good time to return to the STING pathway and take a fresh look at what Aduro/Novartis are doing.

For this post, I’ve chosen to write this up as a SWOT (Strengths, Weaknesses, Opportunities and Threats) analysis of ADU-S100 based on what I learnt at AACR from talking with Dr Dubensky and other experts.

Your SWOT analysis of ADU-S100 may be different from mine, you may have access to other sources of information, an alternative opinion, or reach an entirely different conclusion. There is no right or wrong answer. We all view the world through our own individual bias and lens.

Before you read this post, I heartily encourage you to map out on the “back of an envelope” – or as I’d say in England, on the “back of a fag packet” – what your SWOT analysis looks like. That way you can compare yours to mine.

By definition, we’re dealing with a new product in early clinical development, where many questions remain unanswered. It’s always easier to see the picture after all the cards have been dealt……

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