Biotech Strategy Blog

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

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The romantics wearing rose tinted glasses might well think of successful cancer drug development much like the famous poem by Lord Byron;

“She walks in beauty, like the night
Of cloudless climes and starry skies”

Yet the reality is much more opaque with endless cloudy or wet days and foggy nights much more typical than the exception.

There are often unexpected glitches in the form of serious adverse events, drug interactions, biomarker crashes, narrower therapeutic indexes and poor activity.

None of this stops a raft of companies rushing into a niche when it is suddenly declared ‘hot’ and everyone wants a piece of the action.  This creates an entirely different series of issues to tackle such as acquired resistance and cross resistance.

Some of the numbers in this latest research surprised me and left me pondering a series of provocative questions such as who’s going to stand out from the crowd, who is going finesse things in the clinic – and most importantly – who’s going to break the mould with a different approach?

In this article we explain some of the nuances at play and offer some pointers of new directions the field is taking, not all of them, I’m sorry to say, are for the better…

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Image credit: kevron2002

Every time a new class of agents emerges in oncology, I’m reminded of a partial solar eclipse where there’s just enough sunshine to offer some promise or hope, which needs to be balanced with the much larger area of darkness visible to the naked eye.

This darkness can take many forms from tolerability and a narrow therapeutic window to lack of clinical activity.

In the beginning it’s always hard to see the wood from the trees and often there is more conflicting information available than congruence, at least until things shake out more clearly.

There’s also the tricky matter of cross pathway interactions and how they can influence the broader picture in hidden and obvious ways.

As we head into AACR in a few weeks time, this is a good opportunity to take stock on the various landscape changes and put the situation into perspective.

In this review we look at ten key areas and break down what’s known, what’s not known, and how some of the future directions may take shape…

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While there has been much speculation and rah-rah over the supposed demise of oral therapies thanks to the introduction of the Inflation Reduction Act (IRA) of 2022 including the Part D Redesign, I’m increasingly finding important developments on the targeted therapies front to watch out for.

In the third part of our ongoing mini-series on the PI3K and PIK3CA landscape we’re going to switch to a different example in this niche.

There are some key clinical data due out later this year, which ought to bear watching out for.

The question though, is why – and what ought we to be thinking about in a broader context?

Our latest article reviews the science, the players, the drugs, and explains how we got here…

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Picking the winners in the race

In the second part of this mini-series on an important oncogenic target, we’re going to explore some topics around the theme of coalescence.

This means we can look at how do cancers hijack multiple pathways or co-opt critical cell growth related genes to help drive their own growth, proliferation, and survival.

If we understand the processes involved then we can start thinking about what we can do to interrupt or shut them down then develop relevant therapeutic strategies to tackle them.

Additionally, several targets have now been made druggable where they were considered intractable when this pathway axis was at its peak.  This may offer some fresh opportunities for progress in ways which were not feasible before.

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The moon   Credit: NASA

There was a frustrating point during the development of today’s target focus when one harried researcher turned to me and drolly noted,

“It’s like trying to go to the moon with just a plastic rocket on hand!”

You could see where he was coming from… we had a oncogene, some nice preclinical data, numerous approaches to tackling the target in the clinic and yet none – not one of them – were panning out as expected.

Failure after failure hit the niche, not all for the same reasons…

Too toxic, not enough activity, narrow therapeutic window – it was all there and not all of the issues were predicted in preclinical experiments either.  Some observers even began to question whether the target was in fact, a valid oncogene.

Then came some success and the floodgates opened.

These days we know a lot more about what works, what doesn’t and where things are headed.  We might not be going to the moon yet, but things are headed in the right direction.

In the first of a four-part series we take a look at the troubled waters and learn how the situation was rescued by a few smart scientists and companies invested in finding the right cell/right compartment to aim at…

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Many moons ago the famous English writer Dorothy L. Sawyers wrote a series of novels about an aristocratic amateur sleuth called Lord Peter Wimsey.

When Wimsey attended the Gaudy dinner at Harriet Vane’s Oxford women’s college, the last thing he expected was to get caught up in a murder mystery.

Similarly, we might well wonder if the FDA will be surprised to see GSK, the sponsor of belantamab mafodotin, show up with a re-submission filing in multiple myeloma in an earlier setting several years on, especially since the toxicity profile hasn’t changed.  

In our latest data takedown we explore whether the findings hold water or not, including some expert opinions on the DREAMM-7 readout…

 

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New waves or on the rocks

It’s not that long ago when a certain tumour type saw several waves of promising new agents emerge, quite a few of which made it past the finish line and commercial approval.

These included novel drugs, fast follow-ons, and even me-toos.

The next batch in new development pipelines were not so lucky with a series of disappointing phase 3 misses.

Then radio silence ensued.

As we take another look at this niche, there are a number of early stage agents being put through their paces – small molecule inhibitors, protein degraders, bispecifics, immunotherapies – they’re all there.

Are we going to see some new waves or will they crash and flounder on the rocks?

To find out, we delved into the latest data to determine the current status…

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A beautiful crystal structure at the heart of these pipeline agents    Source: Alphafold

All too often in oncology we look for where there is too much of something such as oncogenic signalling.

Rarely do we actually look at what is missing – and I don’t mean in the context of protein loss like tumour suppressors.

In this case, there is yin and yang at play in terms of R&D. The good old Chinese philosophical concept of dualism is a handy analogy for today’s drug development story.

As one leading big pharma drug in a particular class slinks away quietly – almost unnoticed – to dog drug heaven, another candidate from a small biotech is marching almost stealthily towards the clinic in 2024.

There’s a catch though – while they may share a common target, the fundamental mechanism of action is an entirely different one!

What this means is we may now need to consider additional potential opportunities and complications likely not present with the existing class of agents already in the clinic…

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Pointing the way from Balboa Park

We held off from discussing the Menin inhibitors in AML at ASH last month because we were waiting for Kura’s update in the relapsed/refractory and upfront settings, as well as their initial combination data.

Now is a good time to take another snapshot in time.

The good news is there are some initial data reported on the first twenty patients in Kura Oncology’s KOMET-007 trial, which includes a mix of Menin-naive, previously treated patients who have received Menin inhibitors, as well as those the front-line setting who received combination treatment with standard chemotherapy.

When looked in the context of the prior data, an intriguing body of evidence is now emerging in this space, where a raft of other competitors are also rapidly emerging to compete with Kura Oncology and Syndax.

I came away with a number of impressions from the webcast, here are our takeaways…

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Dark storm cloud warning!

Every now and then we see in Pharmaland what I call ‘the dark storm cloud warning’.

This where things are obvious when you later look back on a small biotech company’s representation of their data and realise the information was right there front and centre for all to see, yet few took note at the time.

Why not?

Likely because you wanted to like something positive and cheering, much like the classic orange beach hut or the whiter clouds to the right in the photo shot on Miami Beach in pre-pandemic days.

Or like the surfer guy in the foreground blithely heading off to the waves, board in hand, seemingly oblivious of the incoming storm from the left – it was quite something that day, let me tell you.

This review is one of those examples…

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