Biotech Strategy Blog

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

Posts tagged ‘LAG-3’

The start of a New Year is a good time to take stock of where we’ve come from and where we’re going in the fast-paced world of oncology new product development.

Upregulation doesn’t always mean a protein is a valid target, but in some cases it just might…

In this latest post, we’re revisiting T cell immunoglobulin and mucin domain-containing protein 3 – or TIM-3 in short – and taking a closer look at the evolving competitive landscape in this niche.

One company targeting it is Novartis, who have an anti-TIM–3 antibody MBG453 in development. In this post we have an expert interview with a scientist who is a pioneer in the emerging field of TIM-3 biology.

There’s also a review of some of the recent important scientific papers on TIM-3 biology, as well as commentary on data presented at ASH19 that we expect may feature in presentations at JPM20 next week, not to mention be the focus of future interim updates should the data turn out to show some promise in certain settings.

If you have an interest in targeting novel immune checkpoints and want to find out more about where the field is at with TIM-3, then this post is for you.

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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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Following the success of anti-CTLA4 and PD(L)1 therapies over the last five years or so, there is much time and attention being focused on addressing a key question, namely – what’s the next viable checkpoint target?

There are quite a few possibilities emerging, although to be fair, some of them will no doubt go by the wayside over the next year or two.  There has already been quite a bit of attrition since 2015/16.  Figuring out which ones will be a target versus being a useful marker is also an important aspect of new product development.

Competition is a fine thing – as long as they’re going in the direction you want to go.

For most of our ASCO coverage over the last few years we have tended to include a variety of approaches in the pre-conference Preview series that can run from a tumour type, a up and coming modality, an emerging target, and various other ways of looking at or making sense of the sea of data.

Here, we take a look at an IO target that is receiving much interest and explore what we know and where this might be headed… and ask whether the early promise is living up to the billing in practice?

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SITC Phase 1 Review Part 1 – It’s time for a two-part mini-series on recent phase 1 clinical trials and how to interpret the findings.

Are we at a crosswords with IO combos?

As a former new products development professional, this is something that I’m particularly enthusiastic about.

While it is fascinating to see other people’s reactions to early oncology trials, these should often be taken with a very large pinch of salt, in my view.

In Part 1, it’s time to take a step back and understand not only what companies are doing, but also how they set the trials up and what they are looking for. We highlight some examples of data readouts to illustrate the points.

In Part 2 on Monday we take a rock around the clock at some of the other recent phase 1 readouts and explain what we can learn from what was presented. The devil is often in the small details that many observers miss at first glance.

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Summer time always seems a good opportunity to explore new cancer targets or approaches on BSB and we’ve covered quite a few interesting concepts over the last couple of years.

ASCO18 Gems from the Poster Halls

This particular approach is an up and coming immuno-oncology target that I noticed is quietly gaining increased interest amongst pharma companies and not all the usual players either.

Consider typing in [target] + cancer in PubMed…

What I got was one single paper in 2000, nothing until 2006 (two more papers), then one to four new ones a year dribbled out until 2014 when nine appeared, followed by a big jump to 17 in 2015, over 20 the following year, then finally more than 30 last year.

At the current rate there will likely be 40–50 such articles in 2018, making for a typical sigmoid growth rate of interest.  Boom!

Clinical trials (montherapy and combinations) are already in early phase studies in the clinic, so this is a good time to take stock and look at progress to date. It also makes for interesting reading when put together as a whole!

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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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One of the (many) highlights for me at the recent annual meeting of the American Association for Cancer Research (AACR) was a “Meet the Expert” session presented by Professor George Coukos.

Prof George Coukos AACR 2016

Prof George Coukos AACR 2016

Professor Coukos is Director of Oncology at the University Hospital of Lausanne and Director of the Ludwig Institute for Cancer Research in Switzerland.

Ovarian cancer is becoming a fascinating battleground for cancer immunotherapy, with multiple challenges that must be overcome before we see improvements in outcomes, especially for women advanced disease.

The interview with Prof Coukos is a follow-on to the one we did on advanced ovarian cancer and checkpoint blockade at ECCO 2015 in Vienna with Dr Nora Disis (Link).

If you missed it, you can still listen to highlights in Episode 7 of the Novel Targets Podcast (Link).

After his AACR presentation, Prof Coukos kindly spoke with BSB and in a wide ranging discussion, highlighted some of the innovative clinical trial strategies he is working on to move the cancer immunotherapy field forward in ovarian cancer.

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Iwakuni Bridge

Cherry Blossoms and Iwakuni Bridge

We’re continuing our countdown to the 2016 AACR annual meeting in New Orleans with a look at anti TIM-3 and LAG-3 inhibitory checkpoints and highlighting some of the companies with noteworthy abstracts.

In case you missed it, yesterday AACR announced that Vice President Biden will be delivering remarks on the final day of the meeting, Wednesday, April 20th in the “Highlights 2016: Vision for the Future” Plenary Session. As conference diehards, we will be there in person, but AACR have announced they plan to livestream it to the world. It’s a fitting finale to what is set to be a “must attend” meeting for those with an interest in cancer new product development and in particular, cancer immunotherapy.

What can we learn from AACR abstracts on TIM–3 and LAG–3?

There is some early clinical data that we will be checking out (no pun intended) on TIM-3 and LAG-3.

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Port Sunglight SpringSpring has arrived in many parts of the world, and with it I am always reminded of William Wordsworth’s classic poem, “I Wandered Lonely as a Cloud:”

I wandered lonely as a cloud 
That floats on high o’er vales and hills, 
When all at once I saw a crowd, 
A host, of golden daffodils; 
Beside the lake, beneath the trees, 
Fluttering and dancing in the breeze.

 

So what does the future hold for cancer immunotherapy?

Inspired by Wordsworth, I’ve sat on my cloud and have looked at some of the recent review papers and thought pieces published by experts in the field. Do they offer a Jerry Maguire – like mission statement: “The Things We Think and Do Not Say: The Future of Our Business” or will we have to wait till AACR 2016 in New Orleans to learn more?

 

This is the latest in our pre-AACR 2016 annual meeting series. Subscribers can login to read more or you can purchase access.

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Over the last couple of years we have heard much about targeting various checkpoints that exert an inhibitory effect on the immune system and the T cells, in particular.  The main targets where we have a growing body of evidence to date are CTLA-4, PD-1 and PD-L1, but there are others including LAG-3, TIM-3, ICOS etc.

Earlier this year at AACR, we saw new evidence that combining two checkpoints (anti-CTLA4 and anti-PD1) was superior to monotherapy in metastatic melanoma, albeit with a concomitant increase in toxicities.

What about the other inhibitory signals though?  Are they bystanders, much like passenger mutations that have little effect, or do they matter, at least in some tumor types?  If so, which ones?

We took a look at some of the emerging data associated with targeting TIM-3 – the results may well surprise some observers.

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