Biotech Strategy Blog

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

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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Orchid at Vizcaya Museum in Miami – always thought they looked like chemical structures showing us the gaps!

We highlighted a number of different types of antibody drug conjugates (ADCs) recently – yes, there’s much more to this category than simply dropping a chemo cargo on cancer cells!

In this review, we explore one of those flexible functionalities in more depth.

The cool thing about having an antibody base is creative chemists can bolt different things onto them, depending on what their goal is.

There are some really cool technology ideas being explored in research right now, which may improve not only what we can do with ADCs but also another modality.

If we think of the ADC as a modern day Trojan Horse to hide or mask the real payload in some way, the possibilities become limited only by our imagination.

The good news is there’s more than one example of this new genre to explore…

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Shining a beacon on key GI trials

After covering a lot of science of late it’s now time to review some recent clinical data, discuss some of the implications of the findings, and their potential impact.

After all, science doesn’t exist in a vacuum and how it translates into outcomes in people living with cancer is an important part of the process.

Can we help them live longer and feel better are two important questions to ask when looking at study readouts.

Let’s not forget there’s quite a difference when considering the exposure of light from a lighthouse beacon versus a typical torch.

The former is designed to produce an extremely powerful, far-reaching beam that can propagate over long distances. A torch has much more modest lighting capabilities suitable for short-range use. The exact brightness difference depends on the specific lighthouse and torch, but it can reasonably be assumed the lighthouse beam is orders of magnitude more intense.

In a similar fashion, we need to look at phase 1 and 3 trials through different lenses, just as we ought to do with the potential 14th agent to market versus the first…

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We are still on a quest – a patient journey, if you like – to find new agents capable of addressing the inherent issue of why do some patient’s tumours lack immune infiltrate and how do we go about fixing it?

Chihuly Glass sculptures always remind me of upregulating MHC

Over the last decade on BSB we have explored a veritable telephone directory of immune agonists, cancer vaccines, cytokines, bispecific and trispecific antibodies, additional inhibitory checkpoints, oncolytic viruses, small molecules, chemotherapy, CAR-T cell therapies, and various others.

Few have got the job well done in advanced solid tumours. Once MHC is downregulated, it becomes much harder to generate an immune response.

Stop and think about this for a moment.

It’s been a long slog to find the next big thing and a frustrating one at that for cancer researchers slaving away at the coal face. A lot of promising agents have come and gone – some quietly, others loudly – to end up in what Dr Patricia LoRosso wittily described as ‘dog drug heaven’. It is also dispiriting to write about so many ending in failure.

The good news is there are some new signs of life coming through, although it’s too early to declare a spring rennaisance. Over the next couple of weeks we’re going to highlight a number of young biotechs with encouraging or fresh ideas being explored in the clinic.

I also don’t want to raise too many hopes – especially as I have long been sceptical about some approaches with all their breathless hype – but here’s something to keep an eye on with an open mind because if it holds up where others failed then the company could be on to something…

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I’ve heard quite a few people frequently exclaim of late how “ADCs are hot!” Alrighty then, yet this is really only the end of the beginning because old hands know they have actually been around for quite a while.

If one was cynically minded then there’s an obvious reason – chemotherapies are usually generic these days, while ADCs bring in much higher ticket prices.

They won’t all succeed though – we’ve already seen a steadily growing graveyard of failures, which started out promising on paper then unfortunately flopped in the clinic.  Just because an area is suddenly declared hot (again) doesn’t guarantee success because these are complex molecules to design compared to small molecules with a lot of factors impinging on their performance.

What many observers have missed, however, is the deeper and broader opportunities offered beyond the often plain vanilla examples.

This is because the modality has greater flexibility than chemotherapies – you can design them such that other things can be bolted on or even hidden, Trojan horse style.

In other words, what we are seeing is an early trend with few enlightened companies starting to ‘think outside the box’ in this niche.

In the near to medium future we will see a greater volume of clinical data on these emerging approaches, which could lead to improved outcomes and longer lives for people living with cancer.

So what are these new fangled things, how do they work, and which companies are active in the futuristic ADC markets?

In this review we highlight half a dozen emerging areas around ADC technology with examples of products and companies active in these niches…

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