Within the solid tumor landscape, perhaps no target better exemplifies the complexity of the arms race between mutational oncogenic drivers and targeted therapeutic interventions than those tumors associated with the target KRAS, one of the most commonly mutated RAS genes in cancer. Starting in the 2010s, the discovery and development of the first KRAS inhibitors has been revolutionary. 

This has led to real clinical success and conferred critical benefit to patients, including in diseases like non-small cell lung cancer (NSCLC), and with new therapeutics in development, such as Revolution Medicines’ exciting pan-KRAS inhibitor RMC-6232, promise now exists for patients with other tumor types, including pancreatic cancer. But as often the case in the war against cancer, the enthusiasm around these data comes with caveats: many patients are de-novo resistant, and the vast majority develop resistance.

Colorectal cancer (CRC) is one tumor type that remains stubbornly resistant to novel targeted therapies.  CRC tumorigenesis is driven by multiple successive mutations that activate both pro-survival and proliferation pathways.  KRAS inhibitors have a more limited impact on pro-survival pathways, which may explain the low clinical response rates observed in CRC versus other tumor types, as shown in the figure below.  As slowly growing cells can accumulate new mutations that enable them to evade therapy, an approach that not only impacts proliferation, but also drives tumor cell death (apoptosis), may more effectively attack cancer in this tumor type.

Furthermore, KRAS G12V and G12D mutations are most common in CRC, which align poorly with the currently approved KRAS inhibitors that inhibit only G12C.  Unfortunately, these dynamics largely play out clinically, where response rates and durability of KRAS inhibitors lag substantially behind those of other tumor types.

At HotSpot we have sought to address these two challenges through a novel approach to CRC that (i) inhibits both pro-survival and proliferation pathways and (ii) has the potential to inhibit a broad swath of KRAS G12X mutations. 

Not surprisingly, it’s easier said than done – but at HotSpot, we’re incredibly excited to share that we have discovered a new synthetic lethal relationship between KRAS G12X and the CBM signalosome complex.

The CBM signalosome is made up of three key proteins (CARD11, BCL10 and MALT1) and regulates key pro-survival and proliferation pathways, including NFkB, JNK, mTORC1 and MYC. By controlling these multiple key pathways, the inhibition of the complex itself presents an opportunity to impact the multiple drivers or contributors of both cancer cell survival and proliferation that are often mutationally driven.

To generate the novel data that conclusively demonstrate the linkage between KRAS G12X and the CBM signalosome, we leveraged our proprietary collaboration with Caris Life Sciences to examine the role of the CBM complex in real world patient data where CARD11, a key component of the CBM complex, is a hallmark of CBM-driven colorectal cancer, as shown in the figures below.

Harnessing our Smart Allostery platform, we have developed the first small molecule inhibitors of the CBM complex to demonstrate binding the signalosome and locking it into an inactive conformation.  Critically, we have demonstrated that a CBM inhibitor selectively induced apoptosis and cell death in MSS/KRAS^G12X tumors (see figure below, in blue).

Examination of numerous KRASG12X cell lines, including the SW1643 cell line, demonstrates that CBM inhibitor drives robust apoptosis in comparison to the leading pan-KRAS inhibitor RMC-6236.

As we move into an in vivo setting, we further demonstrate that CBM inhibition can drive regression in an orthotopic model with 9/10 mice experiencing close to 100% tumor regression, as shown in the next figure:

While the targeting of a complex like the CBM signalosome may be a step up in complexity, we  know that even this alone may not be sufficient, as difficult-to-treat cancers like CRC tend to further outwit and evade even the shiniest and newest cancer weapons. So perhaps even more encouraging is the pre-clinical data we’ve demonstrated with our compounds when dosed in combination with KRAS inhibitors. While only in the early days of pre-clinical exploration, we’re encouraged by the promising activity of this combinatorial approach, and as we progress toward the clinic we are excited to further explore the potential synergistic effect enabled by such a combination, as well as the potential for such a combination therapy to further evade the resistance mechanisms that can rapidly emerge in these types of cancers.

As we look to the future, we can forecast the combination of a CBM inhibitor and a KRAS inhibitor as the foundation for a new treatment paradigm in KRASG12X CRC, buoyed by strong mechanistic rationale, promising pre-clinical data showing synergistic activity, and a non-overlapping safety profile. And importantly for patients, the small molecule modality would allow this combination to be orally administered, offering convenience for patients.

Taking a step back, it’s hard not to think about the profound implications revealed by our findings to date. The disease landscape, within oncology and well beyond, is littered with diseases in which the simple, straightforward, and dare I say logical solution is limited or ineffective. More often than not, complex problems require complex solutions. And perhaps, with the targeting of molecular complexes, we’re beginning to scratch the surface of one such approach – and we’re eager to continue to explore these potential implications through this program, and well beyond.

The post A “Complex” Solution to a “Complex” Problem? Attacking KRASG12X Colorectal Cancer Through the CBM Signalosome appeared first on HotSpot Therapeutics.

While the successful therapeutic targeting of transcription factors is a relatively new undertaking by industry, these proteins themselves are nothing new. Transcription factors are well-known entities – they are the hairclip-shaped molecules that when activated, travel into to the nucleus, grab onto DNA, and drive the transcription of genes into proteins.

Moreover, transcription factors have been shown to play a role in a broad range of diseases, ranging from cancer to autoimmune disease, to cardiovascular disease, to neurological disorders. The roles of certain transcription factors in disease pathogenesis have been well-elucidated and scientifically substantiated:

• Robust genetic validation: Through reviewing genome-wide association studies, we are able to unearth correlations between upregulated levels of certain transcription factors across patients with certain diseases.
• Substantial biological validation: As transcription factors play central roles in the up-/down-regulation of distinct signaling cascades, we have the ability to look to other pathway regulators, whether that be upstream or downstream, to understand the degree to which a given pathway’s modulation has on disease.

Given this ever-increasing body of evidence, why is it that for so long, they have not been the focus of drug discovery? The short answer is that it has not been for lack of effort – an understanding of transcription factors themselves, and how they are regulated, helps explain.

Traditional drug discovery is largely “active-site directed” – meaning inhibitors of proteins have historically been designed to latch onto the active, or catalytic, sites of proteins, thereby blocking their ability to undertake further action or function. And herein lies the challenge for transcription factors! Lacking active sites entirely, transcription factors are instead largely regulated by post-translational modification, which in turn impacts changes in conformation, behavior, and interaction with other proteins.

However, in recent years, huge leaps have been made in drug discovery – ranging from novel technologies unearthing new techniques for small molecule development to new modalities like targeted protein degradation – that are beginning to open the door to a promising wave of transcription factor-directed therapeutic candidates.

One area of interest is that of oncology, where growing evidence has shown the role that transcription factors play in driving various cancers. C4 Therapeutics is one company leading the therapeutic application of protein degradation, a process by which target proteins are “tagged” with ubiquitin to cause degradation of the target. C4’s leading program, cemsidomide, is focused on targeting IKZF1/3, transcription factors that drive cancer cell proliferation and survival in multiple myeloma and Non-Hodgkin lymphoma. Other companies, like Vividion Therapeutics and Flare Therapeutics, are applying new approaches to small molecule drug development to unearth previously undetectable druggable pockets that play important roles in transcription factor activation, with clinical-stage programs in distinct cancer settings.

Another promising area of scientific advancement is in the treatment of autoimmune disease, where numerous biotechnology companies are deploying innovative techniques to target transcription factors that are directly implicated in disease. Companies like Kymera Therapeutics and Nurix Therapeutics are applying their respective protein degradation drug discovery platforms to the development of transcription factors including STAT6, a regulator of the IL-4/IL-13 pathway that is implicated in a range of Th2-mediated allergic diseases. Another company pursuing a novel approach to transcription factor targeting is Recludix Pharma, which is leveraging its SH2 domain-directed platform to selectively target STAT6 and STAT3, another transcription factor in the STAT family that is implicated in Th17-driven autoimmune disease.

At HotSpot, we too have homed in on the transcription factor target class as an exciting application for our allosteric drug discovery platform. Our platform allows us to identify and unlock the control mechanisms that exert functional influence on a protein’s activity – a technology ideally suited to the targeting of transcription factors. Through our platform, our early research has enabled dozens of transcription factors implicated across a wide range of disease, from immunology, to oncology, and beyond.

Leading our pipeline is our IRF5 inhibitor program, a transcription factor that functions as a master regulator of innate immunity. IRF5 utilizes a triple-mechanism approach, impacting autoantibody production, interferon levels, and the production of pro-inflammatory cytokines:

IRF5 has been shown to have striking genetic validation in numerous diseases, including systemic lupus erythematosus, Sjögren’s syndrome, rheumatoid arthritis, and other autoimmune disorders. Moreover, each of the signaling pathways regulated by IRF5 have varying degrees of clinical validation, with drugs either approved or producing promising clinical data that play a role in regulating upstream or downstream factors. Given this profound genetic, biologic, and clinical validation, it’s no surprise that an IRF5 inhibitor has been long sought-after by industry – yet the unique challenges presented by IRF5 have led to failure after failure.

At HotSpot, our platform has uniquely enabled the discovery and development of highly potent and selective small molecule inhibitors of IRF5, which are in turn yielding compelling in vivo data proving out the triple-mechanism effects of an IRF5 inhibitor. As we progress our program through pre-clinical development and into the clinic, we aim to marry this activity with a favorable tolerability profile and convenient oral dosing to bring forward a highly differentiated and convenient treatment option for patients.

We look forward to the continued advancement not only of our own IRF5 program, but also to the collective advancement of this novel class of therapies with broad-ranging potential across disease. As this wave of programs progress into and through clinical development, we’ll begin to uncover if these innovative drug discovery technologies are finally able to scratch the surface of the therapeutic promise of targeting the transcription factor class – which, in the long run, has the potential to yield many more waves in the years to come.

The post A New Wave of Therapeutic Innovation Through Targeting Transcription Factors appeared first on HotSpot Therapeutics.

Of note, ESMO also provided a unique opportunity to learn about important progress happening across the oncology landscape, including some intriguing new datasets for other I-O agents that have been in the clinic far longer than HST-1011.

Second-Generation I-O Agents Beginning to Show Positive Data in Phase 2 Combo Studies

The power of leveraging the body’s own immune system to target cancer has been well-established by first-generation I-O therapeutics, but the biopharma community has struggled to find success stories beyond the anti-PD-(L)1 class. Despite significant time and capital deployment since first-generation anti-PD-(L)1 inhibitors opened an I-O supernova a decade ago, improving such a paradigm-shifting therapeutic approach has been difficult. That said, two presentations at ESMO in non-small cell lung cancer (NSCLC) were perhaps “green shoots” for the field.

The first presentation of interest was the Phase 2 data set for belrestotug, an inhibitor of the immune checkpoint receptor TIGIT, in front-line NSCLC patients with PD-L1 expression of greater than 50%. Anti-TIGIT antibodies have been clinically evaluated since 2016, and an absence of single-agent data has left a void in the scientific community’s understanding of the mechanism. However, the data presented at ESMO 2024 showed that the combination of belrestotug with a PD-1 inhibitor led to an encouraging 30% improvement in ORR compared with anti-PD-1 alone.

The second presentation of note was the Phase 2 data for relatlimab, an inhibitor of LAG3, another checkpoint receptor, in patients with NSCLC. Relatlimab has been in the clinic since late 2013, where similar questions have existed about the mechanism due to an absence of disclosures of single-agent pharmacodynamic and efficacy data. Despite achieving approval in melanoma when combined with anti-PD-1, relatlimab faced persisting doubts because of clinical setbacks in other indications. At ESMO 2024, the combination of relatlimab with anti-PD-1 and chemotherapy showed a promising benefit in NSCLC patients compared to anti-PD-1 and chemotherapy alone, most notably, in the subgroup of patients with PD-L1 levels in the 1-49% range.

In spite of somewhat arduous clinical development pathways, these data sets are now providing some cautious optimism for each mechanism’s potential to drive benefits for NSCLC patients.

Phase 1 CBL-B Inhibitor Data Set Builds Early Confidence Ahead of Phase 2

As we look to HST-1011, we’re aiming to differentiate from these other more advanced programs to help guide our own development program.

One of the reasons for the length of time it takes to understand novel I-O mechanisms is the challenge of interpreting early clinical data. This is due to a myriad of reasons – the advanced nature of Phase 1 patient populations (very progressed disease, multiple prior lines of therapy), the broad heterogeneity of the patients enrolled (across tumor type, state), and the typical rapid advancement into combination studies, which can make it difficult to distill the individual behavior of the novel agent itself.

At HotSpot, we designed an early clinical development program for HST-1011 focused on establishing critical linkages among exposure, upstream and downstream pharmacology, and trends toward clinical activity to enable an early understanding of the mechanism.

To that end, our Phase 1 monotherapy data hit the mark and showed early evidence of precisely what we were looking for:

• A dose-dependent pharmacokinetic profile that achieved target exposures at dose levels that were well-tolerated by patients.
• Changes in both proximal measures of CBL-B inhibition and downstream measures of its ability to activate the immune system.
• Clear early signals of clinical activity in heavily pre-treated patients who have failed to respond or are no longer responding to any other treatment.

These Phase 1 data have provided critical insights into CBL-B inhibition as a mechanism, offering a strong foundation upon which we plan to advance HST-1011 through the clinic. While the TIGIT and LAG3 examples highlighted at ESMO 2024 have offered glimmers of hope in the I-O world, with our Phase 1 data now in-hand, we believe we are optimally positioned to drive forward the development of HST-1011 to ensure we can fully exploit the potential substantial value that exists. Moreover, rich biomarker datasets, including those recently highlighted, underscore the substantial potential that exists to enrich patient populations in future clinical studies, particularly in this era of AI and machine learning. With our novel mechanism and a purposeful clinical development program, we believe we have a unique opportunity to advance HST-1011 and aim to ultimately bring the power of I-O to more patients.

The post ESMO Reflections: Glimmers of Hope with the Next Wave of I-O Therapies? appeared first on HotSpot Therapeutics.

I don’t need you to remind you just how cold this most recent “biotech winter” was for many companies and investors. With painfully high levels of negative data read-outs and clinical setbacks, as well as company restructurings and underperformance, we saw negative sentiment persist throughout the sector. When you’re in a winter like that, it’s tempting to think you’ll never emerge. And yet, following a steady and growing drumbeat of M&A, positive data read-outs, and improving macroeconomic conditions, things finally started to thaw toward the end of 2023. You can feel that new life is starting to be breathed into the biotech sector.

While we’re seeing these green shoots start to poke through on a broader level, I’d like to hone in on one area that’s near to our hearts at HotSpot – immuno-oncology (I-O).

In contrast to recent enthusiasm for the clinical and commercial success of GLP1 analogs to address the obesity epidemic, immuno-oncology (I-O) has been on a steady downward trajectory. Instead of generating excitement and interest, the I-O space has instead been frought with disappointments and clinical setbacks.It’s been ten years since anti-PD-1 agents upended the oncology treatment landscape, transforming the treatment paradigm for cancer patients and in turn, generating substantial value for the companies that developed these drugs. With such dramatic success, it came as no surprise that industry dove headfirst into the I-O space, working to develop second-generation I-O therapeutics to address the substantial need that still persists for many cancer patients with a range of tumor types.

That is where the first snowflakes of a long “winter” in I-O therapeutic advancement started to fall. Despite lots of buzz across industry, the scientific community, and healthcare investors for a number of these second-generation agents, the vast majority came up short in critical ways:

1. The majority of second-generation immune checkpoint inhibitors offer only a singular mechanistic solution for a highly complex, multi-factorial problem that likely requires a “poly-pharmacology” approach.
2. The vast majority of efforts were unable to establish the critical connections between PK, target engagement, biological effects, and changes in tumor. These connections provide all-too-important ‘reasons to believe’ for further investment and movement into earlier lines of therapy.
3. These agents largely lacked the ability, or even the potential, to demonstrate any single-agent clinical activity, defaulting instead to combinations with approved standard-of-care therapies that muddy the ability to detect the true effect of the novel agent.

With incomplete mechanistic rationale, datasets that didn’t draw clear lines between dose – PK/PD – activity, and no clear single agent clinical activity, it’s very difficult to see where value creation would emerge…. and usually it didn’t. As a class, novel I-Os have seen limited successes in only select patient populations since the likes of pembrolizumab and nivolumab stormed onto the scene.

However, despite this long winter, new approaches, ranging from CD3 bi-specifics, to cell therapies, to cancer vaccines, and more recent novel intracellular mechanisms have started to turn the tide.

Take Janux Therapeutics, a biotech focused on developing immunotherapies that generate tumor-specific immune responses to attack and kill tumors without destroying a patient’s healthy tissue. In February of this year, Janux shared an early look at the data they’ve generated for two programs, including emerging data from Phase 1 studies of their PSMA-directed, anti-CD3, and EGFR-directed, anti-CD3 T-cell engager antibodies. Janux reported signs of clear monotherapy activity, with promising efficacy in heavily pretreated, metastatic, castration-resistant prostate cancer with their PSMA-directed T-cell engager and an impressive confirmed partial response in a patient with non-small cell lung cancer with their EGFR-directed T-cell engager. While early, these data demonstrate clear promise to advance this modality.

The world of cell therapy is another that has driven forward the I-O landscape, a scientific approach that involves engineering T cells to drive anti-tumor immune responses when infused into patients. One such company, Arcellx, recently reported the continued long-term responses from a Phase 1 study of their lead CAR-T development candidate in multiple myeloma. The compelling data excited the industry, as well as drove pharma engagement through an expansion of their partnership with Kite Pharma (a Gilead Company).

Another promising approach to I-O is cancer vaccines. A notable late-stage therapeutic candidate is Moderna and Merck’s mRNA-4157, which is advancing through Phase 3 clinical development. This candidate leverages AI technology to sequence a patient’s tumor and healthy tissue and in turn harness this information to create a vaccine construct, which is designed to induce an immune response against tumor cells that harbor these biomarkers. The application of Moderna’s vaccine technology to cancers is yet another example of innovative approaches to I-O, with these data eagerly anticipated by the scientific community and industry, as well as health authorities who appear ready and willing to to engage with sponsors on this approach.

At HotSpot, we hope to be part of the new growth in I-O with our CBL-B inhibitor, which is currently progressing through Phase 1 dose-escalation. CBL-B is a target we selected because it has the potential to avoid the pitfalls that have plagued other drug candidates. Mechanistically, CBL-B serves as a master regulator of the immune system, and its inhibition offers a poly-pharmacology approach to enhance the activation of T and NK cells, drive a more robust and sustained anti-tumor immune response in the tumor micro-environment, and make tumor-killing immune cells less susceptible to inhibition. We’ve designed and are executing a Phase 1 study to draw clear connections between target engagement, biological effect, and clinical activity. And critically, this mechanism and study design will enable us to see signs of monotherapy activity. We’re encouraged by our early progress and are eagerly looking forward to sharing clinical data as our program advances.

All in all, while It’s early – these green shoots are still just shoots – emerging data and reinvigorated industry focus leads us to believe the hopes of next generation I-O is starting to become reality. Let’s hope that as we roll toward summer, that some of these green shoots continue to grow and ultimately blossom into a next generation I-O field.

The post Has Spring Sprouted New Growth in Immuno-Oncology? appeared first on HotSpot Therapeutics.

As we continue to evolve our Smart Allostery platform, we recognized a fundamental analogy when scrutinizing these naturally occurring pockets; they exhibit certain characteristics implicative of recurring patterns, akin to repeatable images with special characteristics. The primary challenge, however, resides in the precise identification of these patterns within extensive and intricate deep datasets. To address this challenge, we took lessons from facial recognition, a specific subset of pattern recognition. By deploying principles akin to facial recognition patterns such as eyes, nose, mouth, and overall facial structure to locate the “face” of natural hotspots, we aim to bridge the gap between the visual typology discernible to a seasoned scientist and the potent and high throughput capabilities of machine learning for drug discovery.

Given that the applications and the technologies supporting accelerated pattern recognition are evolving rapidly, we thought it would be helpful to shed light on the significance of pattern recognition in drug discovery and its role in potentially solving complex biological problems. We will explore the essential ingredients necessary for successful pattern recognition, emphasizing the importance of bringing together the right visual data coupled with the right human drug hunter’s insights and the right algorithms.

Cracking the Code for Successful Pattern Recognition

We believe that solving complex problems with data insights and predictions requires the following:

1. A Good Problem: The first ingredient for successful pattern recognition is to define a good problem. This involves identifying a task or challenge that can benefit from pattern recognition techniques. Whether it’s image or speech recognition, fraud detection, or predicting customer behavior, a well-defined problem lays the foundation for effective pattern recognition. Success in drug discovery is critically dependent on selecting the right target biology and how to interrogate that biology. This approach recognizes that proteins have regions beyond their primary functional sites that can be strategically targeted to achieve desired therapeutic outcomes.

For HotSpot, our primary focus is to systematically deliver first and only allosteric small molecules across multiple target classes relevant to oncology and immunology.  A crucial element requires gaining a deeper understanding of the intricate mechanisms that underlie these diseases and their associated biological pathways. We believe that by comprehending the holistic functionality of potential drug targets within these pathways, as well as understanding the pathways’ roles in the context of the disease they affect, will ultimately pave the way for groundbreaking approaches to drug discovery.

• A Good (and Large) Data Set: Data is the lifeblood of pattern recognition: A substantial and diverse data set is essential to extract meaningful patterns. The data set should accurately represent the problem domain, capturing the variations and nuances that need recognition and understanding. The availability of a large and high-quality data set enables the model to learn robust patterns and generalize well to new data. Datasets to address these problems are plentiful, spanning mutations, genomic sequencing, protein structure and small molecules. With that said, the challenges of collecting and cleaning such data should not be underestimated, due to its scattered sources and various formats. Fortunately, the good news is that machine learning is making significant advancements in handling noisy data and extracting valuable information from diverse data types.

We have applied these key learnings and created a comprehensive database inside the SpotFinder component of our platform. It is meticulously curated to incorporate the essential data required for the application of large-scale machine learning and pattern recognition algorithms. The data are gathered from widely used publicly accessible databases, as well as information extracted from scientific literature through advanced natural language processing techniques.

• A Key Insight into the Problem: Insight plays a vital role in pattern recognition. It involves understanding the problem domain, identifying relevant features, and discerning the underlying patterns that lead to accurate predictions or decisions. This insight could come from domain expertise, exploratory data analysis, or prior research. Having a deep understanding of the problem enables the development of effective algorithms that capture the relevant patterns.   This is the point of interaction between machine learning/pattern recognition.  

• The Right Algorithm to Interpret the Data: Selecting the appropriate algorithm is crucial for pattern recognition. Different algorithms, such as decision trees, support vector machines, neural networks, or clustering methods, have varying strengths and limitations. The choice of algorithm depends on the problem at hand, the nature of the data, and the desired outcomes. The selected algorithm should be capable of capturing and interpreting the patterns identified through insights, leading to accurate predictions or classifications.

Post Hoc Thought

Recognizing that drug development is highly complex and multifaceted, pattern recognition can serve as a fundamental and robust approach to solving complex problems. It encompasses the capability of machines to detect patterns within data and subsequently employ these patterns to inform decision-making or predictions through computer algorithms. This function is an indispensable component of modern AI systems.

By focusing on a well-defined problem, a good data set, key insights, and the right algorithm, scientists can unlock the potential of pattern recognition and make significant strides in solving real-world clinical challenges.

The post Drug Discovery: Taking Inspiration from Facial Recognition appeared first on HotSpot Therapeutics.

An analog for a signaling pathway is the board game “Mouse Trap.” In the game, once properly assembled, one single action – the turning of a crank – leads to a precisely defined series of subsequent actions – the kicking of a marble to roll down a staircase, the swinging of a seesaw, the tipping of a bucket – that ultimately results in the dropping of a cage and the capture of the mouse. In a cell, these actions range from the mechanical, like dimerization or recruitment of other protein components, to the enzymatic, like phosphorylation or ubiquitination.

While some signaling pathway components are linear and relatively straightforward, others involve tremendous complexity, relying on countless proteins to collectively transduce a signal further downstream. These orchestrations depend on the so-called “scaffolding” function of proteins to physically associate with each other in a cell. These resulting protein complexes can enable potent signal perpetuation leading to disease progression.

While the therapeutic potential of targeting signaling pathways is known and established, the majority of therapeutic approaches involve targeting one single component of a pathway, as opposed to the more complicated, though perhaps more impactful, disruption of complex formation.

Imagine you’re trying to block a car’s access to Manhattan. The traditional targeting of a signaling pathway, likened to a selective kinase inhibitor, would be like blocking access to the Brooklyn Bridge or the Holland Tunnel – undoubtedly an initially effective way to prevent a car from accessing the island. However, let’s consider a different approach.  What if we were able to disable the electricity for every single intersection in Manhattan?  Rather than just a single access point being blocked, the entire system would be completely hamstrung, with traffic impeded in all roads, intersections, bridges, and tunnels. A similar degree of control could be achieved in a cell if an entire signaling complex were disrupted, since the pathway’s ability to further perpetuate a downstream signal would be completely disabled.

There is clear precedent for such a complex-directed therapeutic approach in drug discovery. Rapamycin, which targets the mTORC1 complex, has been successfully used in oncology to treat advanced perivascular epithelioid cell tumors, in addition to applications in other disease areas, like organ transplantation. Inflammasome inhibitors are currently being developed for a range of autoinflammatory diseases. Myddosome inhibitors have shown promise in autoimmune disorders and hematological cancers.

One such pathway that we believe holds significant promise for a complex-directed therapeutic approach is the NF-kB pathway. NF-kB is a key mediator of inflammatory responses, playing a crucial role in the regulation of cytokine production, as well as in the activation and proliferation of immune cells. Dysregulation of this pathway is associated with a wide spectrum of diseases, including a number of cancers, such as lymphomas and certain solid tumors, and autoimmune diseases.

Within the NF-kB pathway, one crucial cog in the signaling cascade is mucosa-associated lymphoid tissue lymphoma translocation protein 1, or MALT1. MALT1 is a component of the CBM complex – the “Manhattan” of this pathway – which plays a key regulatory role in the signaling in cells, including in B and T cells.

Within the clustering of the CBM complex, MALT1 has two functions: a scaffolding function, essential to the assembly of the complex, and a protease function, controlling fine tuning, which collectively result in the activation of NF-kB.

The protease function of MALT1 is being extensively targeted by the biopharmaceutical industry, most notably with Janssen’s MALT1 inhibitor, safimaltib, that demonstrated clinical proof of concept in patients with relapsed/refractory Non-Hodgkins lymphoma and chronic lymphocytic leukemia. While these early data have shown promising proof of principle for the therapeutic targeting of MALT1, these initial results suggest challenges not only with potency, but also tolerability, suggesting that a protease function-directed approach may ultimately have limitations on the candidate’s ultimate efficacy in these cancers.

At HotSpot, we believe our proprietary Smart Allostery^TM drug discovery platform affords us a unique understanding of how nature controls proteins through signaling pathways, including at the intricacies of complex formation. A precise understanding of these dual functions points to MALT1’s scaffolding function as the key node for inhibition by a therapeutic agent. Recognizing the therapeutic potential of effectively disrupting the CBM complex in the NF-kB pathway, using our technology, we have developed small molecules that we believe to be the first and only inhibitors of MALT1’s scaffolding function.

At the recent American Society of Hematology (ASH) Annual Meeting, we presented data for the first time supporting the highly differentiated nature of MALT1 scaffolding inhibition. Compared to conventional protease inhibitors, scaffolding inhibition delivered compelling potency and efficacy in in vitro and in vivo models. Moreover, scaffolding inhibitors demonstrated no deleterious effects on effector T cell functions or T-regulatory cell numbers, which we believe enables potential combination with CAR-T or T-cell engagers without any negative effects on those immune therapies.

We are now focused on advancing our Development Candidate, HST-1021, into the clinic to patients. This is an exciting development both for HotSpot and for the field – not only has the CBM complex been successfully targeted in vitro and in vivo for the first time, but we believe we now have a roadmap for drugging other signaling assemblies relevant to disease.

The post Signaling Complexes: A Ripe Opportunity for Drug Development appeared first on HotSpot Therapeutics.

From my perspective as a medical oncologist with experience across academic practice, industry drug development, and life sciences investing, the energy at this meeting is uniquely palpable. Even though the scale of the meeting can be daunting, it’s one of the few times when (almost) everyone on the list of one’s colleagues and contacts might be under one very large roof. And sometimes when data is shared publicly for the first time—whether from an early proof-of-concept study like the 100% response rate in advanced myeloma in the first-in-human Ph1 of the LCAR-B38M BCMA cell therapy that became Carvykti® (ciltacabtagene-autoluecel) or from a pivotal Ph3 trial like the Destiny-Breast04 study showing a 50% reduction in death or progression with the HER2-antibody drug conjugate Enhertu® (fam-trastuzumab deruxtecan-nxki) in women with advanced HER2-low breast cancer—you know that you are witnessing history.    

The landscape of clinical oncology is almost unrecognizable from the standard of care even 10 years ago, and with this year’s meeting theme of “Partnering with Patients: The Cornerstone of Cancer Care and Research” selected by 2022-2023 ASCO President Eric P. Winer, MD, FASCO, here are my takeaways from the first week of June in Chicago.

1. Novel Mechanisms Not As Front and Center

Although previous ASCO meetings in recent memory have been notable for spotlighting the emergence of a clearly game-changing mechanism-of-action (PD-1 inhibitors, cell therapies, and bispecific antibodies come to mind), the 2023 Annual Meeting repeatedly highlighted the evolving and expanding use of validated targets and/or therapeutic mechanism-of-action.

In keeping with the theme of this year’s meeting, this is a great step forward for patients. The majority of new cancer drugs will be approved in late-line settings in patients with advanced disease. It is always meaningful to provide new options for patients who no longer have any, but what is perhaps even more impactful is the opportunity to take a winning drug in late-line patients and show that it can drive truly long-term durable response, maybe even cures, when used in patients with early-stage disease. The KEYNOTE-671 (pembrolizumab) and ADAURA (osimertinib) studies both illustrate this to striking effect and remind us that the path to progress has only begun with the first approval of a novel agent: both pembrolizumab and osimertinib were initially approved as monotherapy for advanced NSCLC in 2015.

2. Immunotherapy for the Win

The transformative power of immunotherapy continues to dominate the landscape of standard-of-care oncology treatment as well as a significant number of trials across all stages of development. The previously mentioned KEYNOTE-671 study was just one of many presented trials across multiple tumor types and practice settings in which moving immunotherapy into earlier lines of therapy continues to drive ever-increasing benefit for a larger group of patients. In addition, we are also starting to see studies in which novel combinations of immunotherapies or immunotherapy/targeted therapy combinations suggest that in the right tumor context, two highly active immunotherapies or a targeted combination can perhaps be even more impressive than the sum of their parts. Finally, as the S1826 study from the SWOG study group demonstrated in the plenary session, in a head-to-head comparison of a highly effective immunotherapy regimen vs a highly effective targeted therapy regimen in Hodgkin lymphoma, the immunotherapy regimen emerged with a striking progression-free survival benefit at 1 year.

3. Trial Design in Early Phase Development Matters

One of the most discussed late-stage studies presented at this year’s meeting was the NATALEE trial establishing the survival benefit of endocrine therapy plus the CDK4/6 inhibitor ribociclib as adjuvant therapy in women with hormone receptor+/HER2- Stage II-III breast cancer. In addition to the data, the execution of this study is an achievement in itself: it required the randomization of over 5100 patients in a global trial. As therapeutic options become both more effective and more numerous, the cost, complexity, and time required to advance the standard-of-care continues to grow. Effectively leveraging emerging therapies and doing so in an efficient way—a process that begins with the strategic decisions made in early development—will continue to require increasing levels of collaboration across the clinical practice and industry continuum to shape the development plan of promising new agents. The utilization of flexible Ph1/2 study protocols, the use of predictive/prognostic biomarkers whenever possible to identify patient subgroups most likely to benefit from an intervention, and the use of adaptive trial designs are some of the strategies that will continue to be relevant as we move into a future where the existing standard of care is increasingly a higher and higher bar.

4. Less is More: Limiting Therapy Without Sacrificing Efficacy

The history of cancer therapies is one of intensive and aggressive interventions that often carried a morbidity and mortality risk that wasn’t entirely dissimilar to the underlying diagnosis. In an era of ever more effective therapies, it is encouraging to see studies start to emerge that help answer the question of how much is enough—and when can we do less and still have the same outcome? From limiting the use of lymph node dissection in some patients with melanoma to utilizing biomarker strategies to tailor the use of neoadjuvant immunotherapy or chemotherapy in women with early-stage breast cancer to minimizing the use of radiation in patients with lymphoma, the future of oncology treatment strategies will continue to focus on maximizing benefit while minimizing the clinical and financial toxicities of oncology therapy.

While the themes and trends in emerging data may vary from ASCO to ASCO, the one theme that remains constant is the critical role of the patient as a partner in any clinical development journey. In his presidential address, outgoing ASCO president Dr. Eric Winer shared an inspiring and deeply personal set of reflections on the patient experience, drawing from not only his career as an oncologist, but also his experience as a patient living with hemophilia. His remarks are worth reading in their entirety. And as Dr. Winer so eloquently stated in his remarks, no matter what data may be ready for topline presentation at ASCO 2024, we know this to be true: “Science really matters. We owe it to our patients to step firmly on the scientific accelerator.”

The post On the Road at ASCO 2023: Key Takeaways, Observations and Reflections appeared first on HotSpot Therapeutics.

HotSpot has gained recognition for its groundbreaking approach to innovation, pushing the boundaries to target previously-unexplored pockets on proteins with small molecule inhibitors. This impressive track record includes developing a range of pioneering achievements, including the potential first-ever selective CBL-B inhibitor and first small molecule inhibitor targeting the key transcription factor IRF5. Moreover, our Smart Allostery platform is the cornerstone of our impressive pipeline of differentiated allosteric small molecules, targeting cancer and autoimmune diseases with the potential for transformational impact on both the science of drug development and clinical medicine.

The company’s differentiated approach to work we do, or “how,” truly sets us apart. HotSpot’s values were developed from the ground up, reflecting the authentic commitment of “HotSpotters” to achieving what others may consider impossible. As a result, we have built a culture that values courage and goes deeper into building trust, teamwork, and accountability. We prioritize ‘Keeping it Human’ in all our endeavors and strive to uphold the highest standards of integrity and follow-through.

Drug development takes a village, and as we transition into becoming a clinical-stage company, we’re committed to integrating our values even more deeply into the fabric of our work to drive meaningful impact. Twenty years ago, the very first precision therapy for oncology was approved; ten years ago, the immune therapies that have transformed clinical oncology were still in their infancy. The future for our field is bright, and we understand that the only way to continue making strides in pushing the envelope is by staying true to our values. We are eager to embark on this journey and excited to see where it takes us.

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Such is the story of targeting casitas B-lineage lymphoma-B (CBL-B) that was highlighted in a recent scientific review article published in the Journal for ImmunoTherapy of Cancer. Ryan C. Augustin, Riyue Bao and Jason J. Luke, all with the UPMC Hillman Cancer Center at the University of Pittsburgh, summarized the challenges previously encountered in targeting costimulatory pathways and the compelling scientific rationale for targeting CBL-B as a master regulator of the immune system that is downstream of proven mechanisms like CD28, CTLA4 and PD1.

Importantly, they also pointed to something that we at HotSpot Therapeutics and a small group of other researchers and companies recognized several years ago – that scientific advances have made this attractive, but once considered ‘undruggable,’ target druggable. This was recently underscored by Nurix Therapeutics who presented multiple posters at the Society for Immunotherapy of Cancer Annual Meeting on their Phase One CBL-B program. And in early January, we bolstered the potential of CBL-B inhibition by announcing clearance of our first IND based on robust preclinical data.

Learning from Past Failures to Drive Toward a More Durable Immune Response

Following the initial clinical successes of blocking inhibitory receptors, like CTLA4 and PD1, many in the immuno-oncology field explored the potential to further enhance anti-tumor immunity by simultaneously enhancing co-stimulatory pathways. The idea was simple – while one takes your proverbial foot off the brake with checkpoint inhibition, another can simultaneously boost those effects by pressing your proverbial foot on the gas with immune stimulation. Unfortunately, despite attempts at many costimulatory mechanisms by many companies, none of those approaches have proven to be clinically effective.

Augustin et al point to several potential explanations including transient expression of those target receptors and sometimes opposing effects of these pathways on various immune cell subsets. They also highlighted why targeting the CD28 pathway overcomes some of these challenges and why CBL-B modulation, downstream of CD28 and other signaling receptors with clinical validation, may be more advantageous.

The authors highlighted how both genetic knockdown and pharmacologic inhibition of CBL-B, including with our now clinical development molecule, HST-1011, impacts a range of immune cell types to enhance immunologic responsiveness. Inhibition of CBL-B 1) makes it easier to turn on effector immune cell populations; 2) makes those cells more active; and 3) enhances their durability by making them less responsive to typical immunosuppressive mechanisms. The net result of CBL-B inhibition is that it ultimately promotes a more pro-inflammatory tumor microenvironment. Importantly, these collective attributes of CBL-B inhibition address several of the common challenges of patients’ tumors that do not respond to existing immunotherapy, or respond initially and then wane.

A New Approach to Drugging the ‘Undruggable’

In many respects, there was not a question of ‘if’ scientists should target CBL-B but more a question of ’how’ best to do so. Augustin et al summarized how novel platforms have more recently been applied to try to solve this question including CRISPR genome editing combined with adoptive cell therapy, siRNA knockdown, DNA encoded library approaches and machine learning algorithms. At HotSpot Therapeutics, we have developed a proprietary platform called Smart Allostery that combines computational approaches and AI-driven data mining of large and highly diverse datasets to identify functional pockets – or natural hotspots, as they are commonly called – and then target those natural hotspots with small molecules to control protein function as nature routinely does. HST-1011 is an orally bioavailable, small molecule allosteric inhibitor of CBL-B discovered via this approach, and a molecule that we hope will show the therapeutic power of targeting CBL-B for cancer patients in need of new therapies.

Thinking Smarter to Identify the Right Patients

Even with its more diverse array of biological effects, CBL-B inhibition is still not a magic bullet. Cancer is infinitely more complicated, with huge biological heterogeneity from early- to late-stage disease, between different tumor histologies and from individual patient to individual patient. Bringing the potential benefits of CBL-B inhibition to cancer patients requires us to think smarter around which patients are best suited for this approach and why.

At HotSpot, this is something we debate on a daily basis. How can we target the right patients, or at least exclude those patients unlikely to reap benefit, and thus confound early clinical data? Is there a constellation of transcriptional, protein and/or cellular markers that can be used to enrich the population towards those most likely to respond? Early insights from such an approach can  be used to further refine those markers and more precisely identify the ideal patient population.

The review by Augustin et al rightly gives credence to this essential part of the debate. They even put forward a hypothesis that patients whose tumors have low to moderate inflammatory cell signatures, low to moderate antigen levels (measured by tumor mutational burden) and high CBL-B expression, might be a high unmet need population that is more likely to benefit.  Only time will tell if these and other markers can enrich the population, but it is essential that biomarker-defined strategies be implemented from the earliest days of clinical study. That means partnering closely with engaged clinical investigators to recruit the right patients and to collect the right samples (including pre- and on-treatment biopsies) from the earliest days, and then integrating those complex datasets on an individual patient level to find predictors of response.

The timing could not better for this review put forward by the UPMC team. By spotlighting the challenges and the unique opportunities we have with this novel mechanism of action, Augustin et al have landed on what we believe to be the most exciting new frontier in cancer research. From our perspective at HotSpot, of course, we believe we’ve built the right type of molecule to target CBL-B therapeutically, and we are excited to see who will come along with us on this journey. As the review makes clear, there are many great minds and innovative companies exploring several aspects of CBL-B inhibition using allosteric methods. As the field continues to mature rapidly, we hope to see major breakthroughs gain momentum quickly.  

The post Build It and They Will Come – New Review Spotlights the Scientific Momentum Building for CBL-B Inhibition appeared first on HotSpot Therapeutics.

We believe HST-1011 is differentiated, both in terms of how it functions and – importantly – how we’ve developed this selective molecule by deploying our Smart Allostery platform, which uses proprietary computer algorithms to identify functional pockets on proteins. We believe our approach offers a diversity of advantages for developing novel and differentiated orally bioavailable medicines.

Building a More Aggressive Immune Response

In scientific terms, HST-1011 is an orally bioavailable, selective, small molecule allosteric inhibitor of CBL-B, an E3 ubiquitin protein ligase critically involved in immune cell response. What that means is that HST-1011 is able to bind to and inhibit a natural hotspot on CBL-B, which is a master regulator of immune cell function, yielding the activation and propagation of a targeted anti-tumor immune response. By inhibiting CBL-B in this manner, it is easier for effector immune cells to be activated and to be less susceptible to being suppressed in the tumor microenvironment. That targeted function is what we believe will be the key to addressing the central limitation of existing I-O therapies: treating tumors that do not respond to immunotherapy and those that respond initially but eventually bounce back.

We’ve recently presented research that illustrates how this process works. The research shows how, in the mixed lymphocyte reaction (MLR) assay, which is a strong predictive correlate of the clinical activity of I-O therapies, the HotSpot CBL-B inhibitor demonstrated robust effects on cytokine release and T cell proliferation as monotherapy. Additionally, CBL-B inhibition demonstrated synergistic activity in the MLR assay when combined with existing checkpoint inhibitor-type anti-PD1 therapies. The result has been a more aggressive immune response in vitro and in vivo, and we are excited about the potential for our approach as we embark on the clinical trial phase of this journey.

Allosteric Drug Development Goes Mainstream

The other big breakthrough behind this milestone is the differentiated process we’ve used to develop HST-1011. The therapy was discovered using our proprietary Smart Allostery platform which uses computer algorithms to identify functional pockets on proteins that control their function. These functional pockets, which we refer to as “natural hotspots,” serve as molecular on/off switches and can be used to transform protein activity with innate selectivity. To date, we’ve been able to identify 1,500 proteins containing natural hotspots that control protein function outside of traditional active site cellular function.

From there, it becomes possible to understand how specific pockets drive the behaviors of the protein and thereby design pharmacological modulators that impact cellular function beyond the limitations of existing active site small molecule approaches to drug development.

Ultimately, what this first IND for HotSpot Therapeutics represents is not just one exciting potential new therapy, but the recognition of a breakout approach to clinical discovery that taps the power of machine learning along with innovative biology, chemistry and biophysics to unlock new frontiers.  

We believe those attributes are key to a more targeted, durable immune response that has the potential to usher in the next wave of immuno-oncology innovation. Together, as we initiate our Phase 1/2 study of HST-1011 in the first quarter of this year, we look forward to continuing to break down barriers in I-O innovation for this therapy and the others we expect to follow its lead.

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