Bolt Therapeutics Conference Call - BOLT BIOTHERAPEUTICS INC

Good morning and welcome to the Bolt Biotherapeutics conference call and webcast. Please note that this call is being recorded and will be available for replay on boltbio.com. All participants are in a listen-only mode. I will now turn the call over to Willie Queen, President and Chief Executive Officer of Bolt Biotherapetics. Sir, please go ahead. Thank you and good morning. Before we begin, I'd like to direct you to the forward-looking statements on slide two. Our remarks today will include forward-thinking statements, including statements concerning the transaction, financing, anticipated clinical development, and future milestones that are subject to risks and uncertainties described in Bolt's SEC filings and in our press release and presentation. The press release and this presentation are available on the investor relations section of Bolt's website. We'll start with an overview of the transaction on slide three. Last Friday, October 23rd, Bolt announced that it has acquired Prana Therapies in a sign and close, stock for stock, reverse merger, and entered into an agreement for a concurrent private placement financing of $120 million in upfront proceeds and up to an additional $60 million in gross proceeds upon exercise of accompanying warrants. Following the transaction, Prana's pipeline is expected to become the primary development focus of the company. The financing is expected the support the advancement of Prana clinical stage programs through multiple important milestones, including Phase 2 proof of concept data for PRA216 expected in 2027. Subject to stockholder approval, the non-voting convertible preferred stock issued in connection with the transaction and financing is expected to convert into BOLT common stock following the planned stockholder vote. In connection with the transaction, Dr. Sheila Gujarati, co-founder and chief executive officer of Prana Therapies, has been appointed chief strategy officer of Bolt and has joined the Bolt board of directors. We are pleased to welcome Sheila and the broader Prana team and believe the combination creates a compelling path forward for Bolt and its stockholders. With that, I'll turn the call over to Sheila to introduce Prana's programs and the opportunity ahead for the company. Thank you, Willie, and thank you to everyone joining us this morning. Starting on slide four, this transaction and financing provide the capital and public company foundation to advance the programs we built at Prana through a very data-rich period ahead. The $120 million in upfront gross proceeds from the private placement is expected to fund operations into 2020E, which we expect to take us through multiple clinical and preclinical milestones. The company will be focused on advancing Prana's pipeline of next-generation, half-life-extended multispecific antibodies, led by PRA216, which is in Phase II development for multiple high-value inflammatory indications, including asthma, chronic obstructive pulmonary disease, or COPD, and atopic dermatitis, or eczema, with an additional Phase II study planned in eosinophilic esophagitis, of EOE. Over the next few minutes, I'll introduce Prana's programs, the homegrown INSPIRE multispecific antibody platform behind these programs, and the exciting clinical and preclinical milestones that lie ahead for our programs and discovery pipeline moving to slide five we are building a new generation of half-life extended multi-specific antibodies with our inspire platform designed to deliver potentially best in disease therapies initially focused on immunology and inflammation we built the inspire platform at prana to solve for the whole product profile our key focus is on improving clinical outcomes by combining the right complementary clinically validated targets to overcome monotherapy efficacy feelings in addition to better efficacy we understand the need to deliver convenient patient-friendly medicines the inspire platform was designed for exposure and target coverage to enable durable efficacy for chronic diseases with infrequent at-home dosing with an auto-injector. In designing INSPIRE, we tasked ourselves with solving the additional challenges encountered by other bispecific formats. The INSPIR platform was built on a fully human IgG-based architecture, which has enabled meaningful improvements in stability, manufacturability, high concentration and subcutaneous formulation, and decreased immunogenicity risk. Our lead program has now provided clinical validation of our platform, and we continue to generate new, wholly-owned programs and expand our INSPIRE pipeline into additional indications. On slide 6 now, complementing the thesis and strategy I just outlined is a team with deep experience and expertise across complex biologics drug discovery and immunology drug development. My background spans immunology development and company building, including Genentech, Bristol-Myers Squibb, Receptos, and Gossamer Bio. Ryan Sullivan, Prana's Chief Scientific Officer, brings extensive experience in complex biologic discovery and early development. Hector Ortega, Prana's chief medical officer, has led development programs across several of the mechanisms central to type 2 inflammatory disease. Tina Trout leads corporate development and brings both large pharma and biotech transaction experience. Miguel San Juan, Pranas co-founder and strategic scientific advisor, has spent more than 25 years developing biologics, including work on half-life extension technology. Together, we believe this team is well-equipped to efficiently execute on our clinical development programs and propel our exciting discovery platform. On slide 7, I'll provide an overview of our programs. PRA216 is our lead program and our first clinical validation for the platform. PRA216 targets IO4 receptor alpha and TSLP and is now in Phase II development in asthma, COPD, and atopic dermatitis, with an EOE study planned. Patient proof-of-concept data across all four studies are expected beginning in the second quarter of 2027. Our second program is an IL-31 containing bispecific being developed initially for atopic dermatitis. We expect to move that program into the clinic and generate initial clinical data in the second half of 2027. Behind those programs, the INSPIRE platform continues to generate additional wholly owned candidates with programs three and four expected to advance through IND-enabling development in the second half of 2027. We are excited for a potentially catalyst-rich 2027 and beyond. Turning to slide eight, we are developing PRA216 for large, clinically validated markets where biologics have already changed the standard of care, yet where substantial unmet need remains. Asthma, COPD, and atopic dermatitis each represent large global markets with hundreds of millions of patients worldwide. Importantly, these are also markets where validated biologics have established the value of targeting type 2 inflammation. But there is still substantial room to improve outcomes. As shown here on the right, even highly effective monotherapies leave meaningful room for improvement in reducing asthma and COPD exacerbation rates. Similar unmet need exists in additional indications. That is the opportunity PRA216 is designed to address. Moving beyond the efficacy ceiling of a single mechanism by combining two of the most clinically validated targets in atopic and inflammatory diseases, PSLP and IO4 receptor alpha. Turning to slide 9, the target combination is central to the PRA216 profile. IL-4 receptor alpha blocks signaling from both IL-41, IL-40, and IL-13, giving us broad downstream type 2 pathway coverage. We've deliberately chosen to target IL-44 receptor alpha rather than IL-14 alone because we believe that inhibiting both IL-4 and IL-13 signaling is critical to fully realizing the therapeutic potential of this biology, particularly in respiratory diseases. However, effective targeting of IL-5 receptor alpha requires an architecture optimized for durable exposure. Our INSPIRE platform was designed for exactly that, enabling us to pursue this approach without compromising exposure or durability. And as you'll see from our clinical data, we believe we've been able to deliver on that promise. TSLP is complementary to IO4 receptor alpha. It sits upstream at the epithelial interface and influences multiple inflammatory pathways with the potential to broaden activity across heterogeneous patient populations. Together, targeting these pathways provides both upstream and downstream inhibition of type 2 inflammation. Our optimized target product profile is the following. First, the potential for deeper and more durable efficacy by combining these complementary mechanisms. Second, broader disease coverage, including heterogeneous type 2 patient populations and a significant proportion of patients living with multiple type 2 inflammatory conditions, where PRA216 has the potential to treat not just a patient's primary disease, but also their comorbid atopic conditions. And third, a convenient maintenance profile, potentially offering patients an every 8 to 12-week dosing regimen with a convenient single at-home auto-injector. Ryan will now take you through how we designed PRA216 to achieve this intended profile and the Phase I data we have generated to date. Thanks, Sheila. Moving to slide 10 now. Here we show how we think about differentiation for PRA 216. For a multispecific and chronic inflammatory disease, we believe you need to deliver both the right biology, and sustained exposure. Either one in isolation is insufficient. PRA-216 combines IL-4 receptor alpha and TSLP blockade to provide that broad inflammatory pathway suppression, and INSPIRE is designed to enable that sustained exposure and target coverage over an extended maintenance interval. That combination is what we are aiming to achieve. differentiated biology, durable exposure, and a practical subcutaneous product profile, with phase two trials now evaluating every eight-week maintenance dosing with the potential to evaluate every 12-week dosing in future trials. On slide 11 now, the preclinical work demonstrates part of the data set that helped us select the INSPIRE format. We evaluated several bispecific architectures using the same binders and the same yte modified fc which allowed us to look at the contribution of format itself in non-human primates the inspire construct showed a substantially longer half-life than the comparator by specific formats which included alternative formats like scfc fusions all evaluated in the same study those findings informed an important design principle for us. Improved FCRN binding via YTE is necessary but not sufficient for durable half-life extension in a bispecific. The underlying architecture is also a critical factor for realizing extended exposure in vivo. We believe INSPIRE is a scaffold that is sufficiently stable to deliver that robust in vivo half-Life extension, and the clinical data we will show next are consistent with the extended exposure profile we observed preclinically. I'll now turn it over to Hector to discuss our phase one study design and safety profile. Thanks, Ryan. On slide 12 now. Our phase one is study enrolled 57 healthy volunteers in a randomized, double-blind, placebo-controlled, single, and multiple ascending dose design. We evaluated both intravenous and subcutaneous administration across a range of doses. In the multiple-dose cohort, participants received three doses at weeks 0, 2, and 4, which established the induction regimen we are now using in phase 2. array 216 was well tolerated. As of the September 1st data cut-off shown here, there were no serious adverse events or adverse events of special interest, no grade three or greater treatment emerging adverse events, no injections at reactions or local pain, and no conjunctivitis. This safety profile supported our decision to advance rapidly into phase two. I will turn it back to Ryan now. Thanks, Hector. Moving to slide 13 now. The pharmacokinetic results were a particularly important part of the phase one study. During a single intravenous dose, we observed over 16 weeks of exposure. With a single subcutaneous dose, PRA216 demonstrated 85% bioavailability. And following the three-dose subcutaneus induction regimen, exposure extended beyond 20 weeks. We also observed very low immunogenicity. a single subject of the 43 PRA216-treated participants developed a low titer anti-drug antibody response, representing a 2.3 percent total incidence across the study, in line with the human IgG-based design of the INSPIRE platform. These data show sustained exposure following subcutaneous administration and support the the every-eight-week maintenance regimen now being evaluated in Phase 2. Moving to slide 14. Using those Phase 1 PK data, we modeled the planned clinical dosing regimen for our Phase 2 trials. Our simulations support a 600-milligram dose every eight weeks during maintenance, with modeled exposure remaining above our target thresholds for both mechanisms. Importantly, the model is intentionally conservative. It treats each pathway independently and assumes no additional pharmacologic benefit from simultaneously inhibiting IL-4 receptor alpha and TSLP. Our phase two study is evaluating this every eight-week regimen. As we generate patient PK, PD, and efficacy data, we expect to be able to characterize the contribution of the dual-target biology more fully and determine whether longer maintenance intervals may be appropriate to evaluate in the future. On slide 15 now, we also saw clear and durable pharmacodynamic activity at the 600-milligram multiple-dose regimen. Serum TARC, a marker of IL-4 and IL-13 signaling, declined by a median of approximately 50 percent through week 12. Blood eosinophils declined rapidly and remained suppressed through week twelve, consistent with activity on the TSLP pathway. And serum IgE declined by approximately 25 percent, consistent with sustained suppression of type 2 inflammatory signaling. These biomarker data are consistent with engagement of both components of PRA216 and show durable, pharmacodynamic activity through at least the end of the first maintenance interval. Notably, this healthy volunteer data broadly compares very favorably with available monotherapy data and other bispecific assets in development. As we move further into patient populations, we expect the depth of activity to potentially increase further, and we look forward to seeing that potential translate into meaningful clinical benefit in our upcoming Phase 2 readouts. And with that, I will turn it back to Sheila. Thanks, Ryan. Now on slide 16. To summarize the Phase 1 program, PRA216 met or exceeded the objectives we set for the study. We established a favorable safety and tolerability profile in healthy volunteers. We demonstrated sustained exposure, strong subcutaneous bioavailability, and very low observed immunogenicity. And we saw rapid and durable pharmacodynamic activity across multiple type 2 biomarkers. These findings support the optimized product profile we designed PRA216 to achieve. And we have moved quickly into Phase II studies in asthma, COPD, and atopic dermatitis, with a study in EOE being planned. Importantly, we believe these are robust, adequately sized studies designed to evaluate key clinical and pharmacodynamic endpoints, with longer-term follow-up to assess durability of response and inform the potential for less frequent dosing. We expect data readouts on all four programs beginning in the second quarter of 2027 and continuing through the fourth quarter. These studies are designed to inform our Phase III trial design, and Phase III enabling activities are already progressing in parallel, positioning PRA216 to move efficiently into pivotal trials in early 2028. On slide 17, looking ahead, we believe the company is well positioned for an exciting period of growth and value creation with a potentially best in disease lead program, a differentiated multi-specific antibody platform, and a strong balance sheet to advance our clinical development strategy and broader pipeline. With multiple important catalysts expected over the next 12 to 18 months, we look forward to demonstrating the potential of PRA216 while further validating our Inspire platform and its potential to enable a new generation of differentiated therapies. Thank you to the Bolt team and our investors for their support, and thank you all for joining us this morning. I'll turn the call back to the operator. That concludes today's call. Thank you for joining, and you may now disconnect. Everyone, have a great day.