From The Trenches

By Jonathan Montagu, CEO of HotSpot Therapeutics, as part of the From The Trenches feature of LifeSciVC

HotSpot’s trip to Barcelona for the recent European Society of Medical Oncology (ESMO) Annual Meeting was no ‘European Vacation,’ but it was certainly teeming with excitement. At the congress, we were thrilled to share some of the clinical data emerging from our Phase 1 program, an ongoing study evaluating our potent and selective investigational CBL-B inhibitor, HST-1011, in patients with advanced solid tumors. This presentation marked the most significant clinical disclosure of any CBL-B inhibitor to date, an important moment not only for industry, but for us at HotSpot.

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.

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By Ivana Magovčević-Liebisch, CEO of Vigil Neuroscience, as part of the From The Trenches feature of LifeSciVC

In an industry where boom and bust cycles occur regularly and 90 percent of drug candidates fail to reach the market, an outstanding Board of Directors can be a key differentiator for life sciences and biotech companies.

As the CEO of a clinical stage biotech, I am intimately familiar with the advantages of an experienced board, but in many ways, I have learned more in my role as an independent BOD member than in my years in the C-Suite.

In biotech, there is often a need to bridge the gap between the science and the business. As a JD and Ph.D., I see my role as one of providing perspective and professional experience from both sides of the table. I welcome opportunities that allow for exploration of science coupled with the nuance of balancing an organization’s business needs in a highly regulated industry.

Overcoming the Inevitable: Common Hurdles to Avoid

As an independent BOD member, my role is to provide strategic insight and effective governance with the goal of encouraging sustainable, long-term success. Each organization is different, with different goals, opportunities, and challenges.

While not all challenges are avoidable, there are some that – if identified and managed well, can improve the way larger problems are handled. In my experience, there are two predictable forms of deadly dysfunction that can disrupt the performance of even the highest performing management teams or BODs. As with most problems, these are the result of poor communication, misalignment, and unclear expectations.

The first, “black box leadership,” occurs when a CEO is not sharing clear, consistent information with the board. It should be obvious, but when a company’s management team and strategy are obfuscated, the BOD is unable to fulfill their duties and properly advise and guide.

In a “black box leadership” style, board meetings are littered with surprises and provide only a cursory glimpse into the company’s management, operations, and strategy. While board meetings are important milestones on a CEO’s calendar, they should not be the only point when board management is top of mind.

One of the key responsibilities of any CEO is board management, and understanding your board is key to success. Knowing the strengths of each members ensures that when facing a hurdle, the CEO knows who to consult and when. Ideally, a board meeting is a review of the progress the entire team – BOD, management, and staff – has made since the last meeting. Surprises are a symptom of dysfunction which can only be cured with consistent, candid communication.

The second common dysfunction is when the board crosses the line – becoming too operational and involved in the details. As I noted above, the role of the board is to provide strategic insight and effective governance. When a board dictates next steps or strays too far into the minutiae of the company’s operations, it is indicative of larger problems, typically stemming from a misalignment of roles and responsibilities, a misunderstanding of management accountability and ownership, or mix of both.

Fortunately, these two deadly dysfunctions are two sides of the same coin: a board may overstep when kept in the dark, and when a board oversteps, a CEO may withhold information for fear of micromanagement.

Bringing up problems early is a critical step for building trust and transparent communication. As a CEO, I know that sharing a problem can feel intimidating and vulnerable, but bringing issues to the board quickly helps establish an open dialogue that will only improve the outcome.

Key Considerations for Thoughtful BOD Relations

While every CEO and board member will bring their own expertise and style to the relationship, I have found that there are some general recommendations that can be applied across experiences and groups.

As a board member, it is important to come in without any preconceived notions. Boards, like everything else, have their own dynamics. New board members, in an effort to hit the ground running, may make the mistake of stepping in before understanding the subtlety or the history of a given situation. Once you understand the dynamic and your new role within it, then you can thoughtfully offer your insights.

As a CEO creating and managing a BOD, that group dynamic is something I want to manage in a way that is best for the organization. To that end, I seek out specific people with different elements of expertise. If your BOD is stacked with academics with no operational experience, you might struggle to get actionable advice on how to motivate a team or manage a P&L.

Similarly, diversity of opinion is crucial to success. Too often, CEOs seek out marquee names or seasoned board advisors without considering how they might fill the gaps in the management team’s experience. Ensuring that your board’s expertise compliments the strengths and limitations of your management team will undoubtedly do more for the company’s long-term success than the short-term attention generated by a high-profile board appointment.

Finally, in an industry plagued by a persistent diversity problem, a thoughtful approach to recruitment for all positions, including the BOD is critically important. At Vigil, our Board of Directors is comprised of >60% women. A metric much higher than the life sciences industry average, which exemplifies our company’s commitment to diversity and promoting women in leadership in the life sciences industry.

When I talk about Vigil’s commitment to board diversity, I often hear the push back, “but there just aren’t enough seasoned BOD members out there.” While the statistics tell us this is certainly true, it is not an excuse for perpetuating BODs with limited representation. Every seasoned BOD advisor had their “first” board appointment. To expand the talent pool for board members, we must welcome new people to the table. The prerequisite for consideration should be a willingness to share relevant expertise, not prior appointments.

The data show that diverse boards create more value, which, ultimately is the goal of any board. A diverse board with defined roles and consistent and clear communication can help improve company performance and achieve goals. In an industry focused on creating transformational treatment options for patients, every advantage helps, and the importance of proper board management cannot be overstated.

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