Seismic Therapeutics investment analysis

December 4, 2023

This is not investment advice. We used AI and automated software tools for most of this research. A human formatted the charts based on data / analysis from the software, prompted the AI to do some editing, and did some light manual editing. We did some fact checking but cannot guarantee the accuracy of everything in the article. We do not have a position in or a relationship with the company.

Overview

Seismic Therapeutics is a private biotechnology firm developing immunology therapies for autoimmune diseases. Employing its proprietary machine learning platform IMPACT, the company streamlines the drug discovery and development process. Seismic recently completed a $121 million Series B funding round, raising its total capital to $222 million. The round was led by Bessemer Venture Partners, with additional investments from both new and existing shareholders.

Seismic's two lead programs are: S-1117, a pan-immunoglobulin G protease designed for reduced immunogenicity, and S-4321, a PD-1 agonist targeting dual-cell populations.

Their IMPACT platform integrates protein engineering, structural biology, and translational immunology to optimize biologics' function, immunogenicity, and development to overcome traditional challenges in biologics development, such as the complexity of immune interactions. The platform optimizes biological function and minimizes immunogenic responses, positioning Seismic as an innovator in developing therapies for dysregulated adaptive immunity.

Pipeline overview

Product name	Modality	Target	Indication	Discovery	Preclinical	Phase 1	Phase 2	Phase 3	FDA submission	Commercial
S-1117	Protease	IgG	Autoimmune diseases
Other IgSc Programs	Protease	IgG	Autoimmune diseases
S-4321	Bispecific antibody	PD-1, FcγRIIb Engager	Autoimmune diseases
Other DcB Programs	Bispecific antibody	Engager	Autoimmune diseases

Highlights and risks

Valuation

Given the early stage of the company and limited information about its programs, we did not conduct a valuation analysis.

S-1117

Scientific thesis

The therapeutic rationale for a Pan-IgG protease in autoimmune diseases is based on the understanding that many of these diseases are driven by autoantibodies—misguided antibodies that target an individual's own body tissues. These pathogenic autoantibodies can cause a diverse set of autoimmune diseases by various mechanisms, including direct tissue damage, formation of immune complexes that deposit in tissues, or by interfering with normal cellular functions.

Pan-IgG proteases are enzymes that can cleave all subclasses of IgG, the predominant type of autoantibody implicated in many autoimmune disorders. The cleavage of IgG antibodies by these proteases neutralizes their ability to cause harm by several mechanisms:

1. Reduction of IgG Levels: The enzyme reduces the overall levels of circulating IgG and immune complexes, which can alleviate the burden on the immune system and reduce inflammation.

2. Elimination of Antibody Effector Functions: By cleaving IgG antibodies, these proteases disrupt their structure, rendering them unable to mediate effector functions such as complement fixation. This can prevent the recruitment of inflammatory cells and further immune-mediated damage.

3. Cleavage of B Cell Antigen Receptors: The protease can cleave the antigen receptors on self-reactive memory B cells. These are cells that have participated in an immune response and can quickly respond upon re-exposure to the antigen. By cleaving these receptors, the enzyme hampers the B cells' ability to perpetuate the autoimmune response.

Seismic Therapeutics is using its IMPACT platform, which integrates machine learning with biologics drug discovery, to generate these novel Pan-IgG proteases. The platform can identify and design enzymes with reduced immunogenicity—that is, lower likelihood of being recognized by the immune system as foreign, which reduces the chance of anti-drug antibody development. By employing machine learning, the platform can predict and remove potential T and B cell epitopes to minimize immunogenicity while maintaining enzyme activity and stability.

The company's research and development strategy includes:

• Identifying and generating Ig specific proteases: These enzymes, identified through the IMPACT platform, are tested for their ability to cleave specific subclasses and isotypes of IgG, thus providing tailored therapies for various autoimmune conditions.

• Developing in vitro assays: These assays assess the removal of T and B cell epitopes to ensure that the modified enzymes still function as intended without eliciting unwanted immune responses.

• Evaluating PK/PD relationships in vivo: Pharmacokinetics and pharmacodynamics studies assess how long the protease stays active in the body and the relationship to its efficacy in cleaving IgG, including autoantibodies.

• Assessment through high-throughput methods: Techniques such as Western Blot are optimized to quickly and accurately evaluate the efficacy of different IgG cleaving proteases.

In summary, the development of a Pan-IgG protease for treating autoimmune diseases is a promising therapeutic approach that targets the abnormal adaptive immune response seen in such conditions. By cleaving pathogenic autoantibodies, these proteases can disable the harmful mechanisms that cause tissue damage and inflammation, potentially improving outcomes for patients with autoimmune diseases.

IgG in autoimmune disease

Immunoglobulin G (IgG) is the most common antibody in human blood circulation, playing a key role in immune defense. It neutralizes pathogens, facilitates their destruction by immune cells, triggers the complement system, and uniquely crosses the placenta to provide fetal immunity. However, IgG can be implicated in immune diseases; it may erroneously attack body tissues in autoimmune diseases, contribute to certain allergic reactions, and its deficiency or overproduction can lead to immunodeficiency disorders or overactive immune responses, respectively. This makes IgG a crucial yet complex component of the human immune system.

The science underlying the therapeutic use of proteases to target pathogenic autoantibodies in autoimmune diseases is evolving. Some aspects of the science are fairly well-established, while others may still be subject to uncertainty or debate. Below are key points regarding the level of evidence and potential areas of uncertainty:

1. Targeting Pathogenic IgG: The role of IgG autoantibodies in many autoimmune diseases is well-established. Therapeutic strategies aimed at reducing or neutralizing these autoantibodies, such as plasmapheresis or immunosuppression, are in clinical use, which supports the rationale for targeting IgG with proteases.

2. IgG Cleaving Enzymes: Enzymes like IdeS (IdeS protease or Imlifidase) from Streptococcus pyogenes can cleave IgG, and IdeS has been used in clinical settings to desensitize patients for kidney transplantation by reducing anti-HLA antibodies. This provides real-world evidence of the feasibility of using IgG-cleaving enzymes in a therapeutic context.

3. Reducing Immunogenicity: Although efforts to reduce the immunogenicity of therapeutic enzymes are ongoing, predicting immunogenicity through computational methods is complex. The immunogenic potential of engineered proteases can vary from one individual to another due to the highly polymorphic nature of immune response genes in humans. Therefore, while machine learning and other computational methods can help design less immunogenic proteins, this aspect of drug development can be challenging and unpredictable.

4. Machine Learning in Drug Development: The application of machine learning in drug discovery, including for biologics like enzymes and antibodies, is a relatively new field. While there is optimism about the potential for machine learning to accelerate drug discovery, its impact is still being evaluated, and the algorithms will require validation in diverse clinical scenarios.

5. Preclinical Evidence: Much of the knowledge of the immunomodulatory effects of proteases comes from preclinical models or in vitro studies. There can be considerable differences between how drugs behave in animal models and human disease due to species-specific immune system differences. Rigorous clinical trials in humans are necessary to establish safety and efficacy.

6. Clinical Use: There is limited clinical experience with the use of pan-IgG proteases across a broad range of autoimmune diseases. While the therapeutic rationale is strong, actual effectiveness, dosing strategies, and long-term outcomes will need to be established in clinical trials.

The role of immunoglobulin G (IgG) in autoimmune diseases is well-documented in the scientific literature. IgG autoantibodies are involved in a variety of pathological processes that result in autoimmune disease. Here are some examples of literature supporting the role of IgG in autoimmune conditions:

• Rheumatoid Arthritis (RA): Autoantibodies to the Fc portion of IgG, known as rheumatoid factors (RF), are a well-known marker of RA and can form immune complexes that contribute to joint inflammation.

• Nienhuis, R. L., & Mandema, E. (1964). A new serum factor in patients with rheumatoid arthritis; the antiperinuclear factor. Annals of the Rheumatic Diseases, 23(4), 302–305. https://doi.org/10.1136/ard.23.4.302

• Systemic Lupus Erythematosus (SLE): In SLE, a wide range of autoantibodies are produced, including those against double-stranded DNA (dsDNA) and other components of the cell nucleus. IgG anti-dsDNA antibodies can cause kidney damage by forming immune complexes.

• Arbuckle, M. R., McClain, M. T., Rubertone, M. V., Scofield, R. H., Dennis, G. J., James, J. A., & Harley, J. B. (2003). Development of autoantibodies before the clinical onset of systemic lupus erythematosus. New England Journal of Medicine, 349(16), 1526–1533. https://doi.org/10.1056/NEJMoa021933

• Myasthenia Gravis (MG): Myasthenia gravis is mediated by autoantibodies against acetylcholine receptors (AChR) at the neuromuscular junction, which result in muscle weakness.

• Lindstrom, J. M., Seybold, M. E., Lennon, V. A., Whittingham, S., & Duane, D. D. (1976). Antibody to acetylcholine receptor in myasthenia gravis. Neurology, 26(11), 1054–1059. https://doi.org/10.1212/wnl.26.11.1054

• Immune Thrombocytopenic Purpura (ITP): In ITP, IgG autoantibodies target platelet membrane glycoproteins, leading to platelet destruction and an increased risk of bleeding.

• Zufferey, A., Kapur, R., & Semple, J. W. (2017). Pathogenesis and Therapeutic Mechanisms in Immune Thrombocytopenia (ITP). Journal of Clinical Medicine, 6(2), 16. https://doi.org/10.3390/jcm6020016

• Goodpasture’s Syndrome: Autoantibodies against the alpha-3 chain of type IV collagen (anti-GBM antibodies) target the basement membrane in the kidneys and lungs, leading to Goodpasture’s syndrome.

• Salama, A. D., Levy, J. B., Lightstone, L., & Pusey, C. D. (2001). Goodpasture's disease. The Lancet, 358(9285), 917–920. https://doi.org/10.1016/s0140-6736(01)06077-9

These are just a few examples, and there are many other autoimmune diseases where the role of IgG autoantibodies has been established. The pathogenic role of IgG in such diseases makes it a key target for therapeutic interventions, including the development of treatments that can neutralize these autoantibodies.

It is important to note that IgG autoantibodies can vary widely in their specificity and the mechanisms by which they cause disease, leading to diverse clinical manifestations. Consequently, therapies targeting IgG must be carefully designed to avoid impairing the normal, protective functions of IgG antibodies in immune responses to pathogens.

The therapeutic rationale for targeting IgG in autoimmune diseases is predicated on several lines of evidence, each with its own strengths and weaknesses:

Strengths of the Evidence Base:

1. Pathophysiological Understanding: The role of IgG autoantibodies in the pathophysiology of various autoimmune diseases is well-established. This clear mechanistic link provides a strong rationale for targeting IgG as a therapeutic strategy.

2. Clinical Correlation: In many autoimmune diseases, the presence and levels of specific types of autoantibodies correlate with disease activity and severity, supporting the idea that reducing or neutralizing these autoantibodies could lead to clinical improvement.

3. Empirical Success: There is empirical evidence demonstrating that treatments which reduce autoantibody levels can ameliorate disease symptoms. Plasmapheresis, intravenous immunoglobulin (IVIG), and B cell depletion therapy (e.g., rituximab) are all treatments that, in different ways, reduce the impact of autoantibodies and have shown benefit in various autoimmune diseases.

4. Proof of Concept: IdeS protease (Imlifidase) has been used in desensitizing transplant patients with preformed anti-HLA antibodies, providing a proof of concept for the use of IgG-degrading enzymes in a clinical setting to directly mitigate antibody-mediated pathology.

Weaknesses of the Evidence Base:

1. Generalizability: The efficacy of IgG-targeting therapies may not be uniform across all autoimmune diseases. Autoantibodies can differ in their mechanisms of action and not all are direct causes of pathology, making it challenging to develop universal therapies based on IgG cleavage.

2. Breadth of Clinical Data: While some therapies that impact IgG levels are in use, the direct application of engineered IgG proteases in a wide range of autoimmune diseases is not extensively studied yet. More comprehensive clinical trials are required to establish their safety and efficacy.

3. Complexity of Autoimmunity: The immune system is extremely complex, and autoimmunity often involves a delicate balance of many immune components. Modifying one aspect of the immune response may have unintended consequences on other parts of the system, potentially leading to immunosuppression or other complications.

4. Immunogenicity of Enzymes: Proteases sourced from pathogens can be immunogenic, and the engineering process to reduce immunogenicity has yet to be fully proven in long-term clinical use. The potential for an immune response to these novel enzymes remains a concern.

5. Adverse Effects: Any intervention aimed at modifying the immune system poses a risk of adverse effects. For example, indiscriminate degradation of IgG could potentially compromise the normal immune functions, such as increased susceptibility to infections.

6. Machine Learning Predictions: While machine learning offers the potential to enhance drug development processes, its predictions regarding immunogenicity and other drug properties are still being validated. The extent to which these predictions will hold true in clinical practice is not yet fully established.

7. Regulatory Hurdles: Novel therapies involving proteases acting on IgG will need to navigate the regulatory landscape, where the acceptability of these treatments, their design, and their monitoring will be rigorously scrutinized.

In conclusion, the evidence base supports a strong, rational, and promising approach to treating autoimmune diseases by targeting IgG. However, the translation of this rationale into effective and safe therapies will require more widespread and rigorous clinical testing to understand the long-term implications of these treatments in diverse patient populations.

S-4321

Scientific thesis

Autoimmune diseases are conditions in which the body's immune system mistakenly attacks its own cells, tissues, and organs, leading to chronic inflammation and tissue damage. Current treatments often involve immunosuppression, which can have broad and sometimes severe side effects due to the indiscriminate dampening of immune function. There is a constant search for therapies that can more selectively target pathological immune responses while preserving normal immune function.

The therapeutic rationale for the use of Dual-cell Bidirectional (DcB) antibody therapies in autoimmune diseases is rooted in a nuanced understanding of the disease pathogenesis, which often involves abnormal interactions between T cells and antigen-presenting cells (APCs), including B cells. The aim is to restore immune homeostasis by engaging two critical points in the immune response pathway:

1. Agonizing PD-1 on T cells: PD-1 is an inhibitory receptor expressed on the surface of T cells. When engaged, it sends a signal to the T cell to reduce its activity, which can diminish the autoimmune response and alleviate inflammation. Agonizing PD-1 effectively 'brakes' these cells from further attacking self-tissues.

2. Engaging FcγRIIb on APCs: FcγRIIb is an inhibitory receptor on B cells and other APCs. Engaging this receptor on B cells can reduce the activation and proliferation of these cells, thereby decreasing the presentation of autoantigens to T cells and the production of autoantibodies, which are often a hallmark of autoimmune responses.

DcB antibodies are engineered to target both PD-1 on T cells and FcγRIIb on B cells/APCs. This creates a more specific and potentially synergistic therapeutic effect by simultaneously down-modulating the activity of both cell types essential to the autoimmune response, with the goal of reducing the pathological immune activity without broadly suppressing the immune system.

Preclinical studies of these therapies have shown promising results, including enhanced PD-1 agonism (which would contribute to T cell inhibition) and reduced pro-inflammatory cytokine production (indicating a reduction in inflammatory immune responses) when using PD-1 DcB antibody candidates with a novel Fc domain that selectively binds FcγRIIb.

This therapeutic rationale promises to selectively restore balance to an overactive immune system, aiming for disease remission with fewer side effects compared to traditional immunosuppressive therapies. By utilizing the IMPACT platform and designing DcB antibody therapies, researchers hope to develop more effective and safer treatments for various autoimmune diseases, such as systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis, where these disease mechanisms are relevant.

The science behind using therapeutics that engage both PD-1 on T cells and FcγRIIb on antigen-presenting cells is a growing area in immunotherapy with a substantial amount of preclinical evidence and ongoing clinical research to validate its efficacy and safety. The scientific principles supporting this approach are well-founded, as both PD-1 and FcγRIIb are well-characterized immune checkpoints with known roles in regulating immune responses.

Here are some aspects to consider about the level of evidence and uncertainty:

1. Established Science:
• The roles of T cells and B cells in the pathogenesis of autoimmune diseases are well-documented.
• Immune checkpoints such as PD-1 are validated targets in cancer therapy (e.g., using checkpoint inhibitors) and are being explored in autoimmune diseases. PD-1 inhibition has shown that it can activate an immune response in cancer, and theoretically agonizing PD-1 could "turn off" an overactive immune response in autoimmune disease.

• The principle of immune homeostasis and the need to restore balance in autoimmune conditions are established concepts in immunology.

2. Current Uncertainties and Debates:

• Most of the data regarding Dual-cell Bidirectional (DcB) antibody therapies, especially those that agonize PD-1 and engage FcγRIIb, are preclinical. This means there is still a way to go before these findings can be translated into approved treatments.
• The safety profile of DcB therapies is not yet fully understood. While these therapies aim to provide a more targeted immune modulation, there might be unforeseen effects on the immune system that could lead to adverse events or compromised immunity to infections or malignancies.
• The concept of using an agonist to PD-1 in autoimmune diseases is somewhat contrary to cancer therapy, where PD-1 is antagonized to enhance immune responses against cancer cells. The balance between suppressing autoimmunity without inducing immunodeficiency is delicate.
• There might be individual variability in how patients respond to DcB therapy based on genetic and environmental factors, and this personalized response is an active area of research.

Overall, while there is a strong scientific foundation for the mechanisms at work in DcB antibody therapies, key aspects such as clinical efficacy, optimal dosing regimens, long-term safety, and the potential for individualized treatment strategies are still being worked out through ongoing research. The overall level of evidence is strong in terms of the biological mechanisms involved but remains to be fully established in terms of large-scale clinical outcomes. As with any emerging therapeutic approach, the findings from preclinical studies will need to be validated in clinical trials before such treatments become standard care for autoimmune diseases.

The therapeutic targets of PD-1 and FcγRIIb have been extensively studied within the context of autoimmune diseases, and their roles have been supported by a variety of research studies. Below are some key points from the literature supporting their involvement in autoimmune pathophysiology:

• PD-1 in Autoimmune Diseases:
• PD-1, or Programmed cell death protein 1, is an immune checkpoint that negatively regulates immune responses. It is expressed on T cells and, upon binding to its ligands (PD-L1 and PD-L2), can inhibit T cell proliferation and cytokine production. This is a natural mechanism to prevent autoimmunity.
• In autoimmune settings, decreased PD-1 expression or function can contribute to the breakdown of self-tolerance, leading to unabated autoimmune responses. For example, PD-1 knockout mice develop lupus-like arthritis and cardiomyopathy, highlighting the critical role of PD-1 in maintaining immune tolerance (Nishimura et al., Science, 1999).

• Therapeutics that target PD-1 have been proposed to help reinstill immune tolerance in autoimmune diseases by mimicking the natural inhibitory signals that prevent autoimmune attack (Sharpe et al., Annual Review of Immunology, 2007).

• FcγRIIb in Autoimmune Diseases:

• FcγRIIb is the only inhibitory Fc gamma receptor and plays a critical role in downregulating immune complex-mediated responses, primarily by binding the Fc portion of IgG antibodies and exerting an inhibitory effect on B cell activity and antigen-presenting cell function.
• The role of FcγRIIb in autoimmunity has been implicated in several ways. For instance, genetic polymorphisms in the FCGR2B gene, which decrease the expression or function of FcγRIIb, are associated with increased susceptibility to systemic lupus erythematosus (SLE) and other autoimmune diseases (Kyogoku et al., Nature Genetics, 2002).
• Therapeutically targeting FcγRIIb is hypothesized to reduce pathological B cell activation and the production of autoantibodies, thus attenuating the autoimmune response (Smith & Clatworthy, Nature Reviews Immunology, 2010).

There is a growing body of preclinical and some clinical evidence indicating that enhancing the signals through these pathways has therapeutic potential in reducing aberrant immune responses characteristic of autoimmune diseases. The studies cited here and others in the literature provide a scientific basis for the development of therapies that might leverage the regulatory functions of PD-1 and FcγRIIb to treat autoimmune conditions. However, the precise applications and efficacy of such treatments in humans will require extensive further study through clinical trials.

The strengths and weaknesses of the evidence base supporting the therapeutic rationale for using Dual-cell Bidirectional (DcB) antibody therapies, focusing on the engagement of PD-1 and FcγRIIb in autoimmune diseases, encompass various aspects of the preclinical and clinical research landscape.

Strengths of the Evidence Base:

• Molecular Understanding:

• The roles of PD-1 and FcγRIIb as immune checkpoints are well-characterized, with numerous studies detailing their structure, signaling pathways, and effects on immune cell regulation. This strong molecular understanding underpins the rationale for targeting these receptors.

• Genetic Associations: Genetic studies have identified associations between polymorphisms in PD-1 and FcγRIIb and susceptibility to autoimmune diseases, suggesting these receptors play a role in the pathogenesis of autoimmune conditions.

• Animal Models: Animal models, particularly those with genetic modifications to PD-1 or FcγRIIb, have elucidated the functions of these molecules in immune regulation and have shown that alterations in these pathways can lead to autoimmune phenotypes.

• Preclinical Studies: Preclinical research with DcB antibodies targeting PD-1 and FcγRIIb has shown promising results in terms of modulating immune responses toward a more controlled state, providing a logical step towards clinical development.

• Clinical Precedents: The clinical use of checkpoint inhibitors in oncology, although with a different therapeutic aim, demonstrates the ability of therapies targeting immune checkpoints to elicit significant biological responses, boding well for their potential in autoimmune diseases.

Weaknesses of the Evidence Base:

• Translation to Humans: The transition from preclinical to clinical efficacy often represents a significant hurdle. Responses seen in animal models and in vitro studies do not always predict human clinical outcomes due to species differences and the complexity of human immune systems.

• Safety Concerns: Potential safety issues may arise when targeting immune checkpoints as these pathways are also crucial for the prevention of infections and malignancies. In cancer treatment, PD-1 inhibition has been associated with immune-related adverse events, and such risks need to be evaluated in the context of treating autoimmune diseases.

• Complex Disease Pathogenesis: Autoimmune diseases are exceptionally heterogeneous in terms of their pathology and patient presentation. Targeting one or two immune checkpoints may not suffice to manage the disease effectively due to this complexity.

• Long-Term Consequences: The long-term effects of modulating immune checkpoints for autoimmune conditions are not known. Chronic use may have different implications for immune function compared to the shorter courses often used in cancer treatment.

• Clinical Trial Data: There is an absence of large-scale, randomized clinical trial data for DcB therapies in autoimmune diseases, which is the gold standard for establishing clinical efficacy and safety. Such data are needed to solidify the therapeutic rationale.

Before the therapeutic approach of targeting PD-1 and FcγRIIb can be fully validated for autoimmune diseases, it will be important to address these weaknesses through continuing research, particularly controlled human clinical trials designed to assess efficacy, safety, and long-term outcomes.

Market overview

Autoimmune diseases

Autoimmune diseases comprise a broad category of ailments where the immune system attacks healthy cells of the body, mistaking them for harmful invaders. This category includes diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), type 1 diabetes, and psoriasis, among others. The market opportunity in the autoimmune disease sector is significant due to the chronic nature of these diseases, often requiring lifelong treatment, the lack of curative therapies, and the general rise in prevalence of autoimmune disorders globally.

Some successful drugs in various autoimmune indications include:

1. Adalimumab (Humira): Used for RA, psoriasis, and inflammatory bowel disease (IBD), among others. It is one of the best-selling drugs in the world.

2. Etanercept (Enbrel): Prescribed for RA and other autoimmune conditions, such as psoriatic arthritis.

3. Infliximab (Remicade): Besides RA, used for Crohn's disease and ulcerative colitis.

4. Interferon beta-1a and interferon beta-1b: Used for multiple sclerosis to decelerate the progression of the disease.

5. Fingolimod (Gilenya) and Natalizumab (Tysabri): Are newer drugs for MS that have shown benefits in treating relapsing-remitting forms of the disease.

6. Secukinumab (Cosentyx) and ixekizumab (Taltz): These are IL-17 inhibitors used in psoriasis and psoriatic arthritis, indicating the expansion into targeting specific cytokine pathways.

The standard of care for autoimmune diseases often starts with nonsteroidal anti-inflammatory drugs (NSAIDs) and progresses to disease-modifying antirheumatic drugs (DMARDs), biologics, and targeted synthetic DMARDs as necessary. Corticosteroids are often prescribed for acute flare-ups or moderate to severe cases.

The unmet medical needs in autoimmune diseases include:

1. Effective therapies: There's a constant need for more effective treatments with fewer side effects. Many current treatments are not universally effective or lose efficacy over time.

2. Biomarkers for disease progression: The development of biomarkers to track disease progression and response to treatment is necessary for more tailored treatments.

3. Preventive treatments: Treatments that can prevent the autoimmune response from happening initially or alter the disease course rather than just control symptoms are highly sought after.

4. Cure: The ultimate unmet need for any chronic disease is a cure, and autoimmune diseases are no exception.

Pharmaceutical and biotech companies acknowledge the size and growth of the autoimmune disease market and invest significantly in R&D to develop novel therapies. The continued understanding of the underlying immunological mechanisms also drives the emergence of new treatment approaches, such as gene therapy, personalized medicine, and cell-based therapies.

There are multiple promising treatments in various stages of development for autoimmune diseases. The goal of these treatments is typically to better control the immune system without broad immunosuppression, which can lead to increased risks of infections and cancer. Here are a few categories and examples of these treatments:

1. Selective Immunomodulators: New treatments aim to modulate the immune system more selectively to reduce harmful side effects. For example, JAK inhibitors like upadacitinib and filgotinib are designed to block specific pathways involved in the immune response. However, JAK inhibitors have recently been found to exhibit serious side effects including thrombosis, leading FDA to require addition of a black-box warning.

2. Biologic DMARDs: These drugs are often antibodies or fusion proteins designed to target specific components of the immune system. Examples of biologic DMARDs under development include those targeting IL-17, IL-23, and other cytokines beyond the already successful TNF-alpha inhibitors.

3. Tolerogenic Vaccines: This innovative approach aims to re-educate the immune system to tolerate specific antigens (proteins from the body mistaken as foreign) rather than attacking them. This strategy could potentially lead to a state of 'tolerance' and thus halt the autoimmune process.

4. Cell Therapy: Techniques such as CAR T-cell therapy, which has been successful in treating certain cancers, are being adapted to potentially treat autoimmune diseases by targeting and eliminating specific immune cell subsets that drive the autoimmune process.

5. Regulatory T cells (Tregs): These cells are crucial for maintaining immune tolerance. Researchers are exploring ways to expand or induce Tregs as a potential therapeutic strategy for conditions like type 1 diabetes.

6. B-Cell Modulation: After the success of B cell-depletion therapy with rituximab in certain autoimmune diseases, there is a push toward developing more selective B-cell modulators that can affect disease progression with reduced side effects.

7. Interferonopathies Treatment: Designed to target diseases caused by systemic overproduction of type I interferon, new treatments are looking to inhibit these pathways selectively.

8. Janus Kinase (JAK) Inhibitors: Small molecule drugs that inhibit the JAK-STAT pathway and have shown promise for autoimmune diseases due to their target specificity. They are being actively researched for conditions such as RA, psoriasis, and IBD.

9. Microbiome Modulation: Understanding that the gut microbiome plays a role in the immune system, there is research into how altering the microbiome can potentially treat or prevent autoimmune diseases.

10. Stem Cell Transplantation: Hematopoietic stem cell transplantation (HSCT) is being researched for its potential to 'reset' the immune system in autoimmune diseases such as multiple sclerosis.

The development pipeline for novel treatments in autoimmune disorders is vast and complex due to the range of diseases and underlying mechanisms at play. Each potential therapy requires extensive clinical trials to establish its safety and efficacy before it can be considered for approval and standard clinical use. Recent notable approvals include:

1. Upadacitinib (Rinvoq) - Approved in 2019, this JAK inhibitor is used for moderate to severe rheumatoid arthritis for patients who have had an inadequate response to methotrexate. It has been further approved for other conditions such as psoriatic arthritis and ankylosing spondylitis.

2. Belimumab (Benlysta) - It's a BLyS-specific inhibitor approved for systemic lupus erythematosus (SLE) and is the first drug that was specifically developed and approved for SLE in several decades.

3. Secukinumab (Cosentyx) - An IL-17 inhibitor approved for the treatment of psoriasis, psoriatic arthritis, and ankylosing spondylitis. It was first approved in 2015 and marked a significant advance in the treatment of these conditions.

4. Ocrelizumab (Ocrevus) - The first drug approved to treat primary progressive multiple sclerosis (PPMS) in addition to relapsing-remitting multiple sclerosis (RRMS). It is a monoclonal antibody that targets CD20-positive B cells.

5. Ixekizumab (Taltz) - Approved for the treatment of moderate to severe plaque psoriasis and active psoriatic arthritis.

6. Guselkumab (Tremfya) - Approved in 2017, it's an IL-23 blocker indicated for the treatment of moderate to severe plaque psoriasis.

7. Tocilizumab (Actemra) - An IL-6 receptor antagonist used for RA, giant cell arteritis, and cytokine release syndrome, it has been noteworthy, especially during the COVID-19 pandemic, for its role in treating severe cases.

8. Voclosporin (Lupkynis) - Approved in January 2021, voclosporin is used in combination with a background immunosuppressive therapy regimen for the treatment of adult patients with active lupus nephritis, which is a complication of systemic lupus erythematosus.

This list is not exhaustive, and the pharmaceutical landscape for autoimmune diseases is constantly evolving with new drugs and targets.

Potential role for S-1117 in autoimmune disease

The use of proteases to degrade antibodies is not entirely new in the field. IdeS (Imlifidase) from Streptococcus pyogenes has been used to cleave IgG antibodies to prevent antibody-mediated rejection in organ transplantation. However, S-1117 seems different because it is described as 'invisibilized'—it has been engineered to have reduced immunogenicity, meaning patients' immune systems are less likely to generate neutralizing antibodies against the protease itself. This feature could potentially allow for repeated dosing, which is important for the chronic management of autoimmune diseases, unlike IdeS which is primarily used as a single dose prior to transplantation due to its immunogenic nature.

S-1117 might address several challenges in the standard of care for autoimmune diseases:

1. Broader Applicability: If it can be administered chronically, it may be used in a wider range of autoimmune diseases beyond acute settings.

2. Reduced Side Effects: By selectively targeting autoantibodies while potentially sparing normal immune function, it may have fewer side effects compared to general immunosuppressants.

3. Convenience: If it has been engineered for increased stability and a longer half-life (as the fusion with an Fc region suggests), it could reduce the treatment burden with less frequent dosing.

4. Immunogenicity: Minimizing the molecule's potential to be recognized by the immune system as foreign could improve safety and efficacy over the treatment course.

5. Potentially Decreased Cost and Complexity over Current Therapies: Treatments like plasma exchange are intensive and expensive; a targeted protease therapy could simplify treatment regimens.

The integration of Seismic's IMPACT platform using machine learning to optimize these properties could mean that S-1117 has been fine-tuned effectively for its function, stability, and immunogenic profile. This represents a cutting-edge approach to developing biologic therapies that could potentially offer superior drug-like properties.

However, the actual fit into the current standard of care will depend on the outcomes of clinical trials. It will need to demonstrate not only efficacy and safety but also how it compares with existing therapies in terms of patient outcomes and cost-effectiveness. Given the current challenges and unmet needs in treating autoimmune diseases, S-1117 could represent a significant advancement if it can achieve the hypothesized benefits. Clinical validation will be essential to determine the real-world impact of this promising therapeutic.

Potential role for S-4321 in autoimmune disease

S-4321 is described as a Dual-cell Bidirectional (DcB) antibody therapy. It operates on two fronts:

1. Agonizing PD-1: PD-1 is an inhibitory checkpoint receptor on T cells, and its activation leads to the suppression of T cell activity. This modulation can help curtail the inappropriate autoimmune response seen in conditions like SLE and RA.

2. Selective Engagement of FcγRIIb: The FcγRIIb receptor is found on B cells and other antigen-presenting cells and acts as an inhibitory signal when engaged. Selective activation of this receptor can potentially lead to reduced B cell activity and a decrease in the generation of autoantibodies.

The strategy behind S-4321 appears to be to enhance the natural regulatory mechanisms of the immune system to restore immune homeostasis. Compared to current treatments, this has the potential to bring about better disease management by specifically targeting the dysregulated elements of the immune response, with the hope of inducing remission or a more durable response while minimizing side effects associated with broad immunosuppression.

If S-4321 can achieve these goals and demonstrate safety and efficacy in clinical trials, it could fit into the standard of care for autoimmune diseases as either a first-line treatment option or as a therapy for patients who are non-responsive or intolerant to current treatments. Additionally, considering the specificity of the actions of S-4321, it might offer advantages over non-selective immunosuppression and serve as an option before more aggressive treatments are considered.

Given Seismic Therapeutic's emphasis on machine learning through its IMPACT platform, this biologic—like others from its pipeline—is designed to be optimized for function, reduced immunogenicity, and developability. This could lead to a faster transition from discovery to clinical application and eventually to market, alongside a potentially better safety profile that would be appealing to both providers and patients.

The recent financing supports the advancement of S-4321 through the critical phases of clinical development. The success of this financing round and the interest from prominent investors underscore the potential Seismic Therapeutic's approach holds for bringing innovative treatments to the market.

As with any new therapeutic, the actual fit into the standard of care for autoimmune diseases will depend on the detailed outcomes of the clinical trials, including efficacy in reducing the burden of disease, safety profile, cost-effectiveness, and where it best synergizes with other treatments in the management algorithm for various autoimmune conditions.

Platform overview

Seismic Therapeutic's platform, named IMPACT, focuses on the discovery and development of biologics for immunology. Here's a summary of its key aspects:

• Machine Learning Integration: The platform uniquely integrates machine learning with structural biology, protein engineering, and translational immunology. This integration allows for the simultaneous optimization of multiple drug-like properties, such as immunogenicity, and accelerates the generation of novel biologics.
• Parallelized Drug Development: Unlike traditional linear and sequential drug development methods, IMPACT enables parallelized multi-property optimization. This approach allows for rapid modulation of key attributes of protein therapeutics, reducing both the number and duration of design/test cycles.
• New Protein Sequences: IMPACT opens up new protein sequence spaces, enabling the discovery of previously unexplored sequences and the design of proteins with optimal drug-like properties.
• Invisibilization: A significant feature of the platform is its ability to modify novel biologic drugs to evade the immune system (invisibilization), removing B and T cell epitopes while retaining the drugs' fitness and function.
• Optimization Techniques: The platform employs various optimization strategies, like removing B and T cell epitopes for increased invisibility, elucidating residue dependencies for optimal drug properties, and enhancing enzymatic activities.
• Comprehensive Disciplinary Integration: The IMPACT platform's success hinges on the integration of different disciplines - machine learning for analyzing and modifying protein sequences, structural biology for 3D modeling of proteins, protein engineering for discovering and optimizing biologics, and translational immunology for developing therapeutics targeting dysregulated immune functions.