Parabilis Medicines, Inc.

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Investment Snapshot

S-1/A All Filings

Symbol

PBLS

Offer Range

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Shares Offered

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Total Shares Post-IPO

213.2M

Market Cap

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Target Price

$00.00

Implied Upside vs Midpoint

$00.00

Use of Proceeds

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Company Description (Source)

We are a clinical-stage biopharmaceutical company built to develop transformative medicines addressing some of the most consequential, yet historically undruggable, protein targets driving human disease. We leverage our proprietary platform to pioneer a novel therapeutic modality, Helicons, which are stabilized helical peptides engineered to bind and precisely modulate proteins that have long been beyond the reach of conventional medicines. To our knowledge, our lead product candidate, zolucatetide, is the first-ever drug to directly target the interaction between b-catenin and the T-cell factor (“TCF”) family of transcription factors. This is the central node in the Wnt/b-catenin cell signaling pathway, which regulates cell proliferation and differentiation and whose hyperactivation is a driver of millions of cancer cases annually across many tumor types. Drugging this critical node eluded three decades of intensive efforts to do so across the pharmaceutical industry. Zolucatetide has been evaluated in over 150 patients to date and has generated promising clinical data in a range of solid tumors driven by alterations in the Wnt/ß-catenin pathway. In our lead indication, desmoid tumors, we have observed tumor reductions in 100% of patients with a 74% objective response rate (“ORR”) in patients who have had at least two post-baseline scans. Objective responses have been observed across patients who have failed g-secretase inhibitors (“GSIs”) and those who have never taken GSIs. Importantly, zolucatetide has been able to generate this rate of response with a tolerability profile that we believe is more favorable than that of currently available drug therapy. We plan to initiate a global registrational Phase 3 trial for zolucatetide in patients with desmoid tumors in the first half of 2027. We believe zolucatetide provides clinical validation of our first-in-industry Helicon approach and represents an expansive opportunity for medical and commercial impact. Our preclinical pipeline provides additional examples of the repeatability of our Helicon approach and includes programs targeting two key drivers of prostate cancer, the ETS-related gene (“ERG”) and the androgen receptor (“AR”) in its active state (“ARON”). Our current pipeline is focused on various cancers and tumor types; however, we believe Helicons could also have broad applicability against targets in many diseases with substantial unmet need outside oncology, and we plan to evaluate other therapeutic areas in the future. An estimated 80% of biologically validated disease targets are considered undruggable, largely because the majority reside inside cells and present flat interaction surfaces. Small molecules can enter cells but cannot bind flat surfaces, and antibodies and other highly-selective biologics can selectively bind flat protein surfaces but cannot enter cells to access these targets. To our knowledge, Helicons are the only modality to date with the potential to consistently solve this problem as they are engineered for cell penetration and capable of binding to flat intracellular protein target surfaces with high specificity. Helicons combine the precision of antibodies and biologics with the intracellular access and tunability of small molecules in a single modality, enabling direct engagement of historically inaccessible protein targets. Our proprietary Helicon discovery platform allows us to integrate ligands and additional functionalities at multiple positions to precisely tune potency, selectivity, and pharmacologic properties. While our initial programs are focused on disrupting protein-protein interactions and inducing targeted protein degradation, we believe our platform can incorporate other advances in small molecule drug design and extend them to targets that are likely to remain out of reach for other modalities. Our Helicon discovery platform integrates advanced artificial intelligence (“AI”)- and physics-based computational modeling with high-throughput peptide synthesis and experimental screening to discover and develop drug candidates. Since our founding, we have advanced computational models as well as custom design, synthesis, handling and manufacturing know-how to position us to produce Helicons reliably and at scale. A decade of applying these capabilities to Helicon drug discovery has generated vast proprietary datasets, comprising millions of data points for hundreds of thousands of Helicons across dozens of drug-like properties. These data power a continuous learning loop that refines our models from target selection through lead optimization, enhancing our speed, precision, and ability to generate high quality molecules against difficult targets. As a result, our platform produces unique complex synthetic molecules at scale and a compounding advantage that we believe is difficult to replicate. We are advancing a wholly-owned pipeline of Helicon-based product candidates against high-value targets. --- Our lead product candidate, zolucatetide, is, to our knowledge, the first and only investigational therapy that inhibits the ß-catenin:TCF interaction, the critical downstream node of the Wnt/ß-catenin pathway. Activating mutations in this pathway, gain of function b-catenin mutations, or loss of function Adenomatous Polyposis Coli (“APC”) mutations, are present in over 10% of all cancers and span a broad range of tumor types. We are evaluating zolucatetide in ongoing clinical trials across multiple solid tumor indications, with more than 150 patients dosed to date. Zolucatetide has been observed to be well tolerated across the therapeutic dose range. We believe the data generated to date, along with our understanding of the underlying Wnt/ß-catenin pathway, support zolucatetide’s potential to benefit patients across multiple tumor types driven by ß-catenin or APC alterations and its advancement into a Phase 3 registrational trial. Our target indications include: • Desmoid Tumors: Our lead indication for zolucatetide is desmoid tumors, which are rare, locally invasive soft tissue tumors driven by somatic or germline b-catenin pathway mutations. We estimate that approximately 11,000 desmoid tumor patients in the United States are actively managed under physician care. Desmoid tumors impose substantial and long-term morbidity, including pain, functional and mobility impairment, and the potential for life-threatening complications depending on tumor location. Given the chronic nature of the disease and onset in a predominantly young patient demographic with a near-normal life expectancy, prolonged or lifelong management is typically required. The only existing U.S. Food and Drug Administration (“ FDA”) approved therapy for desmoid tumors, a GSI, does not address the underlying Wnt/ß-catenin-driven disease biology. In our ongoing clinical trials, as of February 16, 2026, 38 desmoid patients have been enrolled and treated with zolucatetide, of which 25 had sufficient follow up to be response-evaluable, and all 25 patients showed tumor reductions (disease control rate (“DCR”) of 100%). Of the 19 patients with at least two post-baseline scans, 74% (14/19) had an objective response per RECIST 1.1. We have observed responses in patients naive to GSI therapy, those who had progressed on GSI therapy, as well as patients that discontinued GSI therapy due to tolerability issues. To date, we have observed a tolerability profile that we believe compares favorably to the tolerability profile associated with GSIs and other off-label therapies, and supports continued development. We believe a medicine for the treatment of desmoid tumors with a superior efficacy and safety profile, compared to the existing systemic therapy, could significantly improve patient outcomes and expand the desmoid tumor commercial opportunity. We plan to initiate a registrational Phase 3 trial for zolucatetide in patients with desmoid tumors in the first half of 2027. • Familial Adenomatous Polyposis (“FAP”): We are evaluating zolucatetide’s potential in FAP, an orphan disease that impacts an estimated 34,000 people in the United States. FAP is characterized by extensive precancerous polyps in the gastrointestinal tract, with a near-inevitable risk of polyp progression to colorectal cancer in the absence of life-altering colon-removal surgery. There is currently no approved treatment for FAP. Desmoid tumors and FAP share common ß-catenin biology, and approximately 10% of desmoid tumor patients also have underlying FAP. In the desmoid tumor cohort of our ongoing Phase 1/2 clinical trial, administration of zolucatetide in two patients with FAP and an associated desmoid tumor demonstrated significant improvement in duodenal polyposis burden at 10 and 60 weeks, respectively, following initiation of treatment. As of February 16, 2026, we have enrolled six desmoid tumor patients with FAP in our ongoing clinical trial and are also planning to enroll a separate dedicated cohort of patients with FAP beginning in the second half of 2026. • Hepatocellular Carcinoma (“HCC”): We are evaluating zolucatetide’s potential in HCC, the most common type of primary liver cancer. HCC accounts for approximately 80-90% of liver cancer cases globally, with an estimated 38,000 new HCC cases annually in the United States and approximately 700,000–800,000 new cases worldwide. Approximately 30% of HCC tumors harbor ß-catenin mutations and are otherwise relatively low in mutational burden. In a heavily pre-treated patient with CTNNB1-mutant HCC treated with zolucatetide, we observed a confirmed partial response for nine months. Based on this observation, we began enrolling an HCC-specific cohort in our ongoing Phase 1/2 clinical trial. • Additional Rare Tumors: There are over 70 different cancer types with documented APC or ß-catenin mutations, equating to approximately 10% of all tumors and a prevalence in the United States of approximately 1.8 million patients. In pursuit of this significant opportunity, we are evaluating zolucatetide in additional rare Wnt/ß-catenin-driven tumors that harbor APC loss or activating b-catenin mutations, including adamantinomatous craniopharyngioma (“ACP”), solid pseudopapillary neoplasm, salivary gland tumors, and ameloblastoma where we have observed partial responses to date. For these and potentially other rare tumor types, we are evaluating various regulatory strategies, including potentially accelerated development approaches based on a shared genomic signature of Wnt/ß-catenin pathway activation or, where appropriate, histologic characteristic clustering. Tumor-agnostic or molecularly defined approval pathways have been used selectively in oncology, and we believe targeting the root genetic cause of Wnt/ß-catenin pathway activation-driven disease may support a similar approach. • Colorectal Cancer (“CRC”): We are also evaluating the potential for zolucatetide in CRC, the third most commonly diagnosed cancer globally with approximately two million new cases annually. APC mutations, which drive aberrant ß-catenin activation, occur in more than 80% of microsatellite stable CRC patients, representing the most prevalent mutations observed in this tumor type. In our ongoing clinical trials, we have observed disease stabilization and ctDNA reductions in a subset of CRC patients treated with zolucatetide monotherapy, and we are currently evaluating multiple rational combination regimens, based on the results of paired tumor biopsies showing tumor differentiation and a dose responsive functional pathway inhibition. Our ongoing rational combination regimen includes anti-Vascular Endothelial Growth Factor (“VEGF”), DNA-damaging chemotherapy, and anti-programmed cell death protein 1 (“PD-1”) agents, as supported by preclinical and early translational data. We have also generated preclinical evidence for a rational combination with a RAS inhibitor. Taken together, we believe the breadth of clinical activity and tolerability profile observed to date reinforce zolucatetide’s potential as a pipeline-in-a-product with the ability to address significant unmet need across multiple tumor types. We expect to generate substantial additional clinical data as we advance zolucatetide into registrational development in desmoid tumors and continue to expand our understanding of its therapeutic potential across additional indications. Beyond zolucatetide, we are advancing two preclinical stage Helicon programs in prostate cancer: an ERG degrader and an allosteric ARON degrader. Both programs seek to leverage the unique properties of Helicons to address areas of unmet need in prostate cancer treatment by targeting degradation of the historically undruggable ERG protein, an oncogenic driver present in approximately 40-50% of prostate cancer patients, and of AR via a novel AR binding site that seeks to overcome the primary drivers of resistance to AR targeted therapies. • ERG: We have identified novel peptide binding sites on ERG and developed bifunctional degraders that have been observed to drive potent, selective ERG degradation in cells and in vivo tumor models. We have observed that patient-derived tumor models are dependent on ERG protein expression and activity for growth, which we believe supports the clinical therapeutic potential of our ERG degrader in ERG fusion-positive prostate cancer. We are now testing our lead Helicon in Investigational New Drug (“IND”)-enabling studies and continue to advance additional Helicons for optionality. • ARON: Our ARON degrader is designed to overcome resistance driven by AR mutations and amplification, both of which limit the effectiveness of current AR-targeted therapies. In approximately 80% of patients, resistance to AR-targeted therapies is associated with amplification of the AR gene and point mutations at the drug binding site of AR. Approved AR antagonists and clinical-stage AR degraders of which we are aware target the same ligand binding pocket, making them non-combinable and vulnerable to the same resistance mechanisms. Our AR degrader binds to a historically undruggable allosteric co-activator protein binding site that is accessible only when androgen is bound to the receptor. As we are binding to this allosteric site and are not competitive with the binding site of all approved AR antagonists, we believe we will avoid the frequent mutations that occur within the ligand binding domain. By selectively targeting this active pool of AR, we believe our ARON degrader can more effectively address AR amplification, which we consider the most clinically significant driver of resistance in metastatic castration-resistant prostate cancer (“mCRPC”). Importantly, because it binds at the allosteric co-activator protein binding site, our ARON degrader is uniquely suited for combination with existing AR antagonists. These therapies all bind the androgen-binding pocket and are not currently combinable with one another. We believe that such a combination therapy approach could slow the development of resistance, improve efficacy, and meaningfully extend treatment duration. Our ARON degrader program is in late lead optimization and advancing toward IND-enabling studies. In addition to pursuing additional targets, we are continuing to develop novel approaches to target b-catenin, building on the foundational biology established with zolucatetide within Parabilis. • β-catenin Degrader: Two avenues have emerged from our efforts to maximize the clinical potential of β-catenin targeting agents. First, we have identified multiple binding sites on β-catenin beyond the site leveraged by zolucatetide and are exploring how b-catenin target engagement at these sites may impact different aspects of tumor biology. The downstream biology affected by Helicon binding to these sites is dependent on the multitude of intracellular protein complexes in which b-catenin resides within the tumor cell. Second, we have successfully applied our bifunctional degrader technology to develop b-catenin degraders using both zolucatetide and the additional binding site Helicons as the anchor for this approach. The degrader functionality has the potential for improved potency via a catalytic mechanism of action and has the potential to drive unique biology by virtue of removing b-catenin protein rather than inhibiting protein-protein interactions. We intend to advance multiple additional discovery-stage programs that target genetically validated, historically undruggable proteins where we believe Helicons may offer a meaningful advantage over existing modalities. We apply a rigorous framework to evaluate and prioritize programs that may result in substantial therapeutic and commercial opportunities before committing substantial resources toward those that we believe have the highest probability of clinical and commercial success. Given the versatility of the Helicon platform, we also believe there may be opportunities to selectively explore additional therapeutic approaches on our own and through strategic collaborations where a partner’s complementary expertise could be leveraged. We recently entered into a collaboration with Regeneron with a focus on evaluating Antibody-Helicon Conjugates (“AHCs”), a potentially novel approach that combines antibody targeting capabilities with Helicon payloads designed to modulate intracellular proteins. We view this collaboration as an opportunity to explore the broader applicability of Helicons in a focused and capital-efficient manner alongside a leading partner. --- We were incorporated under the laws of the State of Delaware in July 2015 under the name FOG Pharmaceuticals, Inc. We changed our name to Parabilis Medicines, Inc. in October 2024. Our principal executive offices are located at 30 Acorn Park Drive, Cambridge, MA 02140, and our telephone number is (617) 945-9510. Our website address is www.parabilismed.com. We have two subsidiaries, Parabilis Security Corporation, formed in December 2018 under the laws of the Commonwealth of Massachusetts, and Parabilis Medicines (Shanghai) Ltd Co, formed in March 2026 under the laws of Shanghai, China.

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