Biotech Strategy Blog

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

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Posts by MaverickNY

Degrading Expectations – BTK’s New Challenge

The importance of nuance when considering different subtle flavours

Just when we thought we had BTK inhibition figured out, along come the protein degraders to disrupt the party!

While covalent BTK inhibitors transformed CLL treatment and non-covalent inhibitors aimed to tackle resistance, a new class of drugs is taking a more radical approach: why just inhibit BTK when you can eliminate it entirely?

At ASH this month, two BTK degraders stepped into the spotlight. With response rates approaching 80% in heavily pretreated patients – including those with notorious resistance mutations – both BGB-16673 and NX-5948 are challenging our expectations of what’s possible in relapsed/refractory CLL.

As the dust settles on these early phase 1 results, the real story may lie in the nuances…

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The ADC Frontier: Are We Ready for the Next Leap?

The headline for today’s post reflects a mix of forward looking optimism with some (hopefully) balanced critical analysis.

The KA-pow! Effect – Created by DALL-E

Gone are the days of what I think of as the old school heavy handed antibody-drug conjugates (ADCs), where they were rather challenging to finesse in terms of the therapeutic window because you couldn’t dose high enough to exert the desired effect before the dreaded dose limiting toxicities whacked everything out of balance.

In the real life game of snakes and ladders, many an investigator would quickly become frustrated with too few little ladders up and long snakes back down trying to find an acceptable sweet spot in the dose schedules for their patients.

In terms of framing the new ADC frontier – these days things are a’changing much more rapidly when we consider the sheer number of novel molecules coming through company pipelines. Of course, not all agents in Phase 1 will succeed when considering there’s a long way to go to the approval line.

In this review we talk about some recent clinical and scientific developments, including two emerging and unexpected biomarkers of interest.

We thought about each update in the context of three key areas:

  • Innovations leading the charge
  • Challenges on the horizon
  • The ADC ecosystem in transition

As always, not all of the early promise in clinical trials will be completely rosy since there are tricky or unexpected hurdles to consider…

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Too Fragile to Succeed? Uncovering Hidden Weaknesses

When the crowd cheers the loudest, it’s often time to question the play.

Amid a wave of bullish investor enthusiasm for the Summit and BioNTech PD(L)1x VEGF bispecifics plus a raft of topo-I ADCs from China, the risks underpinning this rallying cry have been pushed to the shadows.

What if the foundations of the optimism are built on assumptions that don’t necessarily hold up to scrutiny?

In this analysis from the San Antonio Breast Cancer Symposium (SABCS), we unpack some of the overlooked vulnerabilities and present a case that might not win popularity contests, but could save companies and investors from costly missteps…

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Revolution and Rivalry: Anito-Cel Challenges Cilta-Cel in Myeloma

The ASH Dash continues apace!

Over the last decade CAR-T cell therapy has revolutionised the treatment landscape for relapsed/refractory multiple myeloma (RRMM), offering a lifeline to patients with few remaining options.

These engineered immune cells have demonstrated remarkable activity although their progress has also revealed a complex interplay of benefits and risks, which continue to evolve with longer follow up data and real world use.

As the field matures, new insights from clinical trials shape our understanding of these therapies and also serve to highlight critical distinctions between products.  By delving into these details, we can identify patterns, anticipate challenges, and explore opportunities to improve outcomes for patients.

There’s also the excitement of the proverbial ‘new kid on the block’ coming later behind the leaders.  ArcellX’s anitocabtagene autoleucel (anito-cel) is one we have been following since it was in preclinical development and were intrigued by their different scientific approach to tackling the same issues.

The big question was always going to be what happens in the clinic?

In the latest update, things are now getting interesting to say the least…

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ASH24 The Battle of Menin

The landscape of Menin inhibition in acute myeloid leukemia (AML) continues to evolve rapidly, with several competitors vying for position in this emerging therapeutic niche. At this year’s American Society of Hematology (ASH) meeting in San Diego, we saw important updates presented across the field, which shed new light on both the potential and challenges of targeting the Menin-MLL interaction in advanced disease.

San Diego street art

The therapeutic goals in advanced AML have always been clear – achieve deep remissions, bridge to transplant where possible, and ultimately extend survival. What makes the Menin inhibitor story particularly compelling is how these agents are reshaping our expectations for molecularly targeted therapy in AML, especially in difficult to treat populations harbouring KMT2A rearrangements or NPM1 mutations.

What’s also particularly striking about this year’s updates is the emerging differentiation between compounds in the class. While all share the core mechanism of disrupting the Menin-MLL interaction, we’re beginning to see distinct profiles emerge in terms of efficacy, safety, and potential positioning.

The battle lines are being drawn in what promises to be a fascinating commercial race as more clinical data become available over time.

In our latest review, we assess how revumenib, bleximenib, enzomenib, and ziftomenib are shaking out in the relapsed/refractory (R/R) setting and also take a look at ziftomenib and bleximenib in newly diagnosed AML…

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A Critical Juncture

Time for some new directions?

The hematologic niche in the spotlight today at the American Society of Hematology (ASH) is at a critical juncture – while we’re increasingly seeing impressive efficacy with novel combinations, offset by both clinical and financial toxicity profiles presenting significant challenges.

The ultimate goal of moving away from traditional chemotherapy must be balanced against creating sustainable, accessible treatment options capable of optimising both safety and cost considerations.

After all, if we remove one backbone and replace it with another only to swap the nature of the serious adverse events then we’re not going to help as many people as we first supposed or claimed.

Another important aspect to consider is what should these new regimens even look like?

As we stand at the crossroads in novel cancer therapeutics, future trial designs and drug development strategies will both need to address these multiple competing factors, as well as proper sequencing of these regimens to truly advance the field.

In today’s post, we take a look at some important emerging trends, as well as some of the pitfalls and pressures facing companies and researchers in this space alike…

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Beyond R-CHOP: New Frontiers in Lymphoma Treatment at ASH 2024

Even the cars stand out in San Diego

After writing of some trials and tribulations in solid tumours earlier this week (see review of the Janux TRACTR here), it was rather nice to return to my old stamping ground of hematologic malignancies and feel soothed by both the familiar and also incoming novel approaches for a variety of different conditions.

It is exactly twenty five years since the initial phase 1 data for STI-571 (now known as imatinib or Gleevec) were first presented in an ASH Plenary.  31 out of 31 advanced CML patients responded and Dr Brian Druker received an outstanding ovation at the end of his presentation.  It was the kind of stuff that gave you goosebumps – despite the freezing cold hangar.

This is the kind of thing hematologists and companies alike live for; it’s what gets you jumping out of bed in the morning to help make a difference to the lives of cancer patients.

At ASH this year there are some encouraging data on early stage trials coming out in several hematologic malignancies, which kept me occupied and fascinated for most of the first day of the meeting.  There’ll be another detailed write up of one of these areas tomorrow morning, while a different condition offered a raft of choices across single agent therapy and combinations alike.

Here we highlight what to watch out for – both positive and negative – on five agents with encouraging early data, which caught out attention yesterday.  They include bispecific T cell engagers and cell therapies – what’s not to like?

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Death by a thousand cuts

Sharp, thorny plants for the unsuspecting visitor at the Vizcaya museum, Miami

In the fiercely competitive race to develop new treatments for metastatic castrate resistant prostate cancer (mCRPC), biotech companies must present compelling data to stand out from the pack.

However, as a recent example from Janux Therapeutics demonstrates, a closer look under the hood often reveals more spin than substance.

In this article, we’ll dissect Janux’s claims about their bispecific PSMA T cell engager JANX-007, and expose how cherry picking and selective data presentation can skew and even misrepresent a therapy’s true potential.

Read on to learn the red and green flags to watch out for and why extraordinary claims require extraordinary evidence…

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Innovator’s Dilemma – Promise and Potential of Bispecific Combination Strategies

Imagine a scenario… a symphony of therapeutic agents working in harmony, each contributing its part to achieve remission in even the most refractory hematologic malignancies. Yet, as with any great orchestra, a poorly tuned instrument – or in this case, a poorly considered combination – can disrupt the entire performance.

Bispecific T cell engagers have emerged as new virtuosos in cancer therapy especially in refractory settings involving hematologic malignancies such as lymphomas and myeloma, although their integration into combination regimens may be as challenging as it is promising.

Don’t be caught napping though!

In our latest ASH analysis, we’ll explore how some of these combinations perform, where they falter, and whether they can truly expand the therapeutic repertoire or simply shrink the index of possibilities.

In this review we will explore half a dozen different bispecifics when given in combination with an additional therapy to determine if:

  • They add anything to hematologic malignancies over what we would expect for monotherapy
  • Whether or not they shrink the therapeutic index
  • Whether anything else of note stood out (positive or negative)

If they fail on the first and negatively impact the second then they are highly unlikely to be a candidate for further clinical development!

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ASH24 Preview 2 – Early Stage Agents to Watch Out For

San Diego

In our latest ASH analysis, we’re going to focus on some key early stage oncology developments and their associated emerging strategic themes to watch out for.

After all, looking to see what’s coming behind you can be just as important as what’s in front of you.

In this latest review, we highlight and discuss 14 abstracts from a mix of pharma and biotech companies based across several continents, with various intriguing developments spanning preclinical to phase 2 involving a mix of targets and modalities…

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