Alumis investment analysis

March 7, 2024

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 an ongoing business relationship with the company.

Overview

Alumis Inc., a clinical-stage biopharmaceutical company focusing on developing oral therapies for immune-mediated diseases, recently announced a $259M Series C funding round led by Foresite Capital, Samsara BioCapital, and venBio Partners, supported by a consortium of new and returning investors. The funding aims to advance Alumis' leading drug candidates, including ESK-001, a highly selective allosteric tyrosine kinase 2 (TYK2) inhibitor showing promise as a best-in-class oral therapy. ESK-001 is entering pivotal Phase 3 clinical trials for moderate to severe plaque psoriasis in the latter half of 2024 and undergoing Phase 2 trials for systemic lupus erythematosus (SLE) and non-infectious uveitis. Additionally, Alumis is developing A-005, another TYK2 inhibitor targeting neuroinflammatory and neurodegenerative diseases, with a Phase 1 clinical trial expected to begin in the first half of 2024.

Product name	Modality	Target	Indication	Discovery	Preclinical	Phase 1	Phase 2	Phase 3	FDA submission	Commercial
ESK-001	Small molecule	TYK2 Inhibitor	Psoriasis
ESK-001	Small molecule	TYK2 Inhibitor	Systemic Lupus Erythematosus
ESK-001	Small molecule	TYK2 Inhibitor	Uveitis
A-005	Small molecule	TYK2 Inhibitor	Neuro-inflammation

Highlights and risks

Scientific background

The therapeutic rationale for targeting TYK2 with an allosteric inhibitor for the treatment of psoriasis, systemic lupus erythematosus (SLE), and uveitis is founded on the crucial role TYK2 plays in the pathophysiology of these inflammatory and autoimmune conditions.

• TYK2 in Immune Signaling: TYK2 (Tyrosine Kinase 2) is a member of the Janus kinase (JAK) family, which is integral to cytokine signaling pathways. These pathways involve the activation of Signal Transducer and Activator of Transcription (STAT) proteins, leading to the transcription of genes critical for immune cell function. TYK2 specifically mediates signaling for several cytokines implicated in autoimmunity and inflammation, including interleukin (IL)-12, IL-23, and type I interferons.

• In Psoriasis: Psoriasis is characterized by hyperproliferation of keratinocytes and an inflammatory infiltrate of T cells, dendritic cells, and other immune cells in the skin. IL-23, which signals through TYK2, is central to the pathogenesis of psoriasis as it promotes the differentiation and survival of Th17 cells, a subtype of T cells that produce inflammatory cytokines such as IL-17. By inhibiting TYK2, the IL-23/Th17 axis is downregulated, reducing inflammation and the hyperproliferation of keratinocytes.

• In Systemic Lupus Erythematosus (SLE): SLE is an autoimmune disease characterized by the production of autoantibodies that form immune complexes, leading to inflammation and damage in multiple organs. Type I interferons, signaling through TYK2, play a pivotal role in SLE by promoting the differentiation of B cells (which produce antibodies) and the activation of T cells. An allosteric inhibitor of TYK2 could dampen the type I interferon response, potentially reducing autoantibody production and the subsequent inflammatory damage.

• In Uveitis: Uveitis refers to inflammation of the uvea, the middle layer of the eye, which can lead to vision loss if untreated. Similar to psoriasis and SLE, cytokines such as IL-12 and IL-23 are involved in the pathogenesis of uveitis, impacting the migration and activation of inflammatory cells within the eye. Targeting TYK2 could, therefore, reduce ocular inflammation by modulating these cytokine pathways.

• Advantages of Allosteric Inhibition: Allosteric inhibitors target sites distinct from the ATP-binding active site utilized by most kinase inhibitors. This can provide several advantages, including improved selectivity, which may reduce off-target effects and associated toxicity. Allosteric inhibition of TYK2 could allow for finer control of its kinase activity, potentially translating into a safer and more effective treatment for patients.

In conclusion, targeting TYK2 with an allosteric inhibitor presents a compelling therapeutic strategy for psoriasis, SLE, and uveitis. It exploits a central node in the inflammatory signaling network, with the promise of disrupting disease processes while minimizing unintended effects on the immune system. Further clinical evaluation will elucidate the full potential of TYK2 allosteric inhibitors in these complex diseases.

The scientific rationale for targeting TYK2 in autoimmune and inflammatory diseases is well-founded on a substantial body of preclinical and some clinical evidence. However, as with any emerging therapeutic strategy, several aspects are still under investigation or debate. Here’s a breakdown of how established the science is, the uncertainties, and the overall level of evidence:

• Established Science:

  • Role of TYK2 in Immune Signaling: The role of TYK2 in cytokine signaling, especially its involvement in the pathways of IL-12, IL-23, and type I interferons, is well-documented.

  • Pathogenesis of Conditions: The involvement of the IL-23/Th17 axis in psoriasis and the role of type I interferons in SLE are supported by a wealth of scientific evidence, including genetic, biochemical, and clinical data. Likewise, the contribution of cytokines to the pathophysiology of uveitis is recognized, albeit to a lesser extent.

  • Approval of deucravacitinib: Deucravacitinib (brand name Sotyktu), a highly selective allosteric inhibitor of TYK2, was approved in late 2022 for treatment of moderate-to-severe plaque psoriasis.

• Uncertainties and Debate:

  • Specificity of the Allosteric Site: The specificity and the potential for off-target effects of allosteric inhibitors, given their novel mechanism of action, remain subjects of investigation. The interaction between the allosteric site and the broader kinase domain in the context of different physiological conditions is not fully understood.

  • Long-term Outcomes: The long-term impact of modulating TYK2 activity on the immune system has yet to be comprehensively assessed. There is debate over whether sustained inhibition could lead to unforeseen immune dysregulation or susceptibilities.

• Overall Level of Evidence:

  • Preclinical studies provide a strong foundation for the role of TYK2 in disease pathogenesis and the potential benefits of its inhibition. These studies include genetic models demonstrating the impact of TYK2 manipulation on disease phenotypes.

  • Early-phase clinical trials and some later-stage trials have begun to furnish promising results supporting the efficacy and safety of TYK2 inhibitors in psoriasis and, to a lesser extent, SLE and uveitis. However, the breadth of clinical data is not as extensive as for more established treatments.

  • The mounting evidence from translational research and early clinical studies is highly suggestive of the potential of TYK2 inhibitors, but more robust clinical data are needed to fully validate their therapeutic value.

In summary, while the scientific basis for targeting TYK2 in autoimmune and inflammatory diseases is strong, certain aspects of the therapeutic use of allosteric TYK2 inhibitors necessitate further clarification and validation. Continued research, including more comprehensive clinical trials, is crucial to address these uncertainties and to accurately define the place of TYK2 inhibitors in the treatment landscape of these complex conditions.

There is a notable body of literature supporting the role of TYK2 in the pathogenesis of psoriasis, systemic lupus erythematosus (SLE), and uveitis. Below are highlights from the scientific literature supporting TYK2's role in these conditions:

• Psoriasis:

  • A key study identified polymorphisms in the TYK2 gene that were associated with susceptibility to psoriasis, suggesting a genetic link between TYK2 and the disease (International Psoriasis Genetics Consortium). Furthermore, preclinical models have demonstrated the efficacy of TYK2 inhibitors in reducing psoriatic symptoms, reflecting TYK2's role in mediating pro-inflammatory cytokine signaling, especially through the IL-23/Th17 axis considered pivotal in psoriasis pathogenesis.

• Systemic Lupus Erythematosus (SLE):

  • Genetic studies have found associations between TYK2 gene polymorphisms and the risk of developing SLE, indicating TYK2's involvement in the disease's genetic susceptibility (Sigurdsson et al., 2005). Experimental models of lupus have demonstrated the importance of interfering with the signaling pathways mediated by TYK2, such as those activated by type I interferons, which are key drivers of the disease's pathophysiology. The effectiveness of TYK2 inhibition in these models supports the therapeutic potential of this approach in SLE.

• Uveitis:

  • While direct genetic evidence linking TYK2 to uveitis is less robust than for SLE and psoriasis, the role of TYK2 in mediating signaling of cytokines implicated in uveitis pathogenesis (such as IL-23 and IL-12) provides a strong rationale for targeting TYK2 in this condition. Research in animal models of autoimmune uveitis supports the potential therapeutic benefits of modulating these cytokine pathways through TYK2 inhibition.

• General:

  • Across these diseases, TYK2 is implicated in the signaling pathways of key cytokines driving the immune dysregulation and inflammatory responses characteristic of these conditions. The development and clinical testing of TYK2 inhibitors, such as BMS-986165 (Deucravacitinib), which has shown promising results in phase 2 and phase 3 trials for psoriasis and is being explored for SLE and other autoimmune diseases, provide practical evidence supporting TYK2's therapeutic targeting. These inhibitors offer a new class of drugs with a mechanism of action distinct from traditional non-selective JAK inhibitors, potentially offering improved safety and efficacy profiles.

The evidence base supporting the therapeutic rationale for targeting TYK2 in conditions like psoriasis, systemic lupus erythematosus (SLE), and uveitis has both strengths and weaknesses.

• Strengths:

  • Genetic Associations: There are multiple genetic studies linking variations in the TYK2 gene with an increased risk of auto-immune diseases like psoriasis and SLE. These associations provide a strong biological rationale for targeting TYK2 as these genetic links underscore its role in disease pathogenesis.

  • Biological Plausibility and Preclinical Studies: The involvement of TYK2 in key cytokine signaling pathways (e.g., IL-12, IL-23, and type I IFNs) critical to the immune responses implicated in these diseases is well-understood. Preclinical models have demonstrated that inhibiting TYK2 can lead to reduced disease severity, supporting the therapeutic potential of TYK2 inhibition.

  • Emerging Clinical Data: Early clinical trials, especially in psoriasis with TYK2 inhibitors like Deucravacitinib, have shown promising efficacy and safety profiles. This emerging data strengthens the case for TYK2 inhibitors as a novel therapeutic class.

• Weaknesses:

  • Generalizability and Specificity of Genetic Data: While genetic associations provide compelling evidence for the involvement of TYK2 in disease pathogenesis, these findings do not always directly translate to therapeutic efficacy. For instance, the genetic risk associated with TYK2 might be due to a complex interplay of multiple genes and environmental factors, which might not be fully addressed by targeting TYK2 alone.

  • Lack of Long-Term Safety Data: The newer nature of specific allosteric inhibitors means that there is limited long-term safety data available. The precise modulation of immune pathways without undesirable immunosuppression is a delicate balance, and the long-term implications of TYK2 inhibition need thorough investigation.

  • Clinical Efficacy Data Is Still Emerging: While there are promising results from early-phase trials, comprehensive Phase 3 data and post-marketing surveillance reports are necessary to fully understand the therapeutic value of TYK2 inhibitors. The clinical efficacy and safety profiles, especially compared to existing treatments, are yet to be fully established.

  • Understanding of Mechanism of Allosteric Inhibition: Allosteric inhibitors function differently from traditional kinase inhibitors that target the ATP-binding site. While this may offer selectivity advantages, predicting off-target effects and fully understanding the implications of allosteric inhibition is more challenging due to the complexity of kinase regulation and signaling pathways.

In conclusion, the therapeutic rationale for targeting TYK2 in autoimmune and inflammatory diseases is supported by a solid foundation of genetic, biological, and early clinical evidence. However, the continuation of rigorous clinical trials and the generation of long-term safety and efficacy data are crucial steps to overcome the current weaknesses in the evidence base. These steps are essential not only for confirming the therapeutic potential of TYK2 inhibitors but also for elucidating the broader implications of modulating immune pathways in complex diseases.

Clinical trial overview

Summary of Study Design:

Study Title: A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of ESK-001 in Patients With Moderate to Severe Plaque Psoriasis

Study Sponsor: Alumis Inc

Clinical Trial ID: NCT05600036

Duration: 20 weeks, including a 4-week screening period, a 12-week treatment period, and a 4-week follow-up period.

Participants: Individuals with moderate to severe plaque psoriasis, totalling 228 enrollees.

Methodology: Participants were randomized into either the treatment or placebo group. The treatment group received varying doses of ESK-001 as an oral tablet across different arms (Dose Levels 1 to 5), while the control group received a placebo oral tablet. The study's randomization, allocation, and masking were designed to ensure the trial's integrity by minimizing bias across participant, investigator, and outcome assessor levels.

Primary Objective: To evaluate the efficacy of ESK-001 in comparison to placebo by measuring the proportion of participants achieving at least a 75% reduction in the Psoriasis Area and Severity Index (PASI-75) at 12 weeks.

Secondary Objectives: These included assessing the safety and tolerability of ESK-001, response rate in the static Physician's Global Assessment (sPGA), and characterization of the pharmacokinetics (PK) of ESK-001 in terms of Cmax and Ctrough at week 8.

Critiques of the Study Design:

• Dose Variety: The inclusion of multiple dose levels allows for a comprehensive evaluation of ESK-001's efficacy and safety, but it also complicates data interpretation and increases the complexity of statistical analysis.
• Duration: A 20-week duration including follow-up might not be sufficient to fully assess long-term efficacy and potential late-onset side effects, which is critical for chronic conditions like psoriasis.
• Sample Size: With 228 participants and multiple treatment arms, there may be concerns regarding the power of the study to detect differences between each dose level and the placebo, especially if dropout rates are higher than anticipated.

Operational or Technical Challenges:

• Blinding and Randomization: Maintaining the integrity of double-blinding with multiple doses can be challenging, especially in ensuring that placebo and ESK-001 tablets are indistinguishable in appearance, taste, and packaging.
• Assessment Variability: The primary and secondary outcomes involve subjective assessments (e.g., PASI-75 and sPGA scores), which might introduce variability and bias despite training and standardization efforts.
• Pharmacokinetics Analysis: Conducting PK analysis, including Cmax and Ctrough, requires precise timing in sample collection and sophisticated analytical techniques, which could present logistical and technical challenges, especially in a multi-center setting.
• Patient Retention and Compliance: Ensuring adherence to treatment and follow-up visits over the 20-week period in a condition known for impacting patient quality of life like psoriasis can be challenging. Strategies to enhance participant engagement and compliance are crucial and may introduce additional operational complexities.
• Open Label Extension Study: The mention of an open label extension study for participants who complete the treatment poses additional challenges in terms of regulatory compliance, data handling, and ensuring continuity in participant care without unblinding the initial study phases.

The designed clinical study for ESK-001 aims to provide proof-of-concept for its use in treating psoriasis. A critical component of establishing this proof-of-concept lies in the study’s carefully selected endpoints, alongside the delineation of inclusion and exclusion criteria to ensure the selection of a suitable patient population. Let's examine these components in the context of their appropriateness and the potential reproducibility challenges they might bring.

Appropriateness of Primary and Secondary Endpoints

Primary Endpoint: The use of PASI-75 as a primary outcome metric is appropriate and relevant for psoriasis studies. Achieving a 75% reduction in the Psoriasis Area and Severity Index (PASI) is a well-recognized marker for significant clinical improvement. Considering the disease-specific impact on patients, this endpoint directly assesses the efficacy of ESK-001 in treating moderate to severe plaque psoriasis, and it's a standard benchmarking metric used across psoriasis trials.

Secondary Endpoints: Including safety and tolerability assessments, response rates in static Physician's Global Assessment (sPGA), and pharmacokinetics characterization adds depth to the evaluation of ESK-001. sPGA is a relevant clinical measure for assessing disease severity, and combined with PASI, provides a holistic view of treatment efficacy. The pharmacokinetic measures ensure a comprehensive understanding of ESK-001's absorption and metabolism, which is critical for dose optimization and safety evaluation.

Inclusion / Exclusion Criteria Appropriateness

The Inclusion Criteria are broad enough to encompass a diverse patient population within the age range of 18-75 years and stipulate a necessary minimum body weight, thus ensuring the drug's pharmacodynamics can be evaluated across a wide demographic. The requirement for effective contraception methods reflects a cautious approach to minimizing risks during the study.

Exclusion Criteria are well-thought-out to mitigate potential risks and confounding variables:

• Excluding individuals with a recent history of malignancy, certain infections (HIV, Hepatitis B or C), or tuberculosis reduces the risk of adverse outcomes and complications.
• Excluding patients with specific heart risks (QTcF prolongation) is prudent given the unknown cardiac effects of new drugs.
• The decision to exclude non-plaque forms of psoriasis and those recently vaccinated with live vaccines fine-tunes the study population to those most likely to benefit from the treatment and reduces variability due to different disease mechanisms or immune reactions.

Potential Reproducibility Challenges

While the inclusion and exclusion criteria are designed to ensure a safe and appropriate patient population, they may also introduce challenges in reproducing the study findings across a more general patient population. Specifically:

• Exclusion of Certain Health Conditions: Patients with complex comorbid conditions, a common scenario in real-world clinical settings, are excluded, which might limit the generalizability of study results to all psoriasis patients.
• Contraceptive Requirement: This could impact the willingness of potential participants to join the study, particularly those not currently practicing contraception or who are planning for a family in the near term, arguably skewing the demographic profile of participants.
• Narrow Disease Focus: By focusing solely on plaque psoriasis, findings may not be extrapolable to other forms of the disease, limiting the potential market and usability of ESK-001.
• Age and Weight Criteria: While necessary for safety and pharmacokinetic reasons, these criteria might exclude significant subgroups within the psoriasis population, particularly those under 18, offering less insight into the pediatric use of ESK-001.

Addressing these challenges will be vital for future studies, especially in Phase 3 trials, where demonstrating broader applicability and identifying sub-populations who may benefit differently from ESK-001 will be crucial. Establishing the proof-of-concept with this Phase 2 trial is a significant first step toward these goals, provided the study's endpoints are achieved and the selection criteria are carefully considered.

Clinical trial overview

This study design is focused on evaluating the long-term safety and efficacy of ESK-001 as a treatment for plaque psoriasis. It is an interventional, phase 2, multi-center, open-label extension (OLE) study with parallel assignment aimed at patients who have previously participated in a prior plaque psoriasis study of ESK-001. These participants are allocated to one of two open-label dose levels of ESK-001, administered as an oral tablet. The primary objective is to assess the safety and tolerability of ESK-001 through the incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) over approximately three years. Secondary objectives include assessing long-term efficacy via changes from baseline in the Psoriasis Area and Severity Index (PASI), changes in quality of life through the Dermatology Life Quality Index (DLQI), and pharmacokinetics (PK) analysis of ESK-001.

Critiques of the Study Design:

• Open-Label Bias: The open-label nature of the study can introduce bias as participants and investigators are aware of the treatment being administered, potentially influencing both subjective (quality of life assessments) and somewhat objective outcomes (reporting of adverse events).
• Selection Bias: Only enrolling patients who have participated in a previous ESK-001 study could introduce selection bias as these individuals may not be representative of the broader population with plaque psoriasis.
• Lack of Control Group: Without a placebo or active comparator group, it's difficult to discern whether changes in PASI scores, DLQI, or safety profiles are attributable to ESK-001 or other external factors.
• Dose Levels: The study examines two open-label dose levels without mentioning if these were determined based on previous studies or if there’s a rationale for expecting different efficacy or safety profiles at these levels.

Operational and Technical Challenges:

• Long-term Follow-up: Maintaining participant engagement and adherence over a three-year study period is challenging. This is particularly relevant for an open-label study where participants may perceive their treatment assignment as less effective or encounter adverse events.
• Safety Monitoring: Continuous and rigorous safety monitoring is required to promptly identify adverse events over the long term, necessitating robust operational mechanisms to collect, analyze, and report data.
• Commercial Availability Impact: As participants are allowed to remain in the study until ESK-001 becomes commercially available, variations in regulatory approval timelines across jurisdictions could affect participant retention and the comparability of long-term data.
• Ensuring Consistent Dosing and Compliance: Given the oral administration of ESK-001, ensuring that participants adhere to the dosing schedule over an extended period, especially outside of a controlled clinical setting, poses a logistical challenge.
• Data Management and Analysis: Managing and analyzing the large volume of data collected over three years, especially for safety, efficacy, and pharmacokinetics, requires sophisticated data management systems and expertise to ensure the integrity and reliability of findings.

In summary, while the study aims to fulfill an important need by assessing the long-term safety and efficacy of ESK-001 in plaque psoriasis, its design has inherent biases and operational challenges that could impact the interpretation and generalizability of the results. Adopting strategies to mitigate these concerns, such as incorporating control arms in future studies or utilizing blinded independent adjudicators for outcome assessment, could enhance the robustness of the study findings.

This study, focusing on the long-term safety and efficacy of ESK-001 in plaque psoriasis, offers an opportunity to further explore the therapeutic potential of ESK-001 beyond initial safety and efficacy demonstrations. The choice of primary and secondary endpoints and the inclusion/exclusion criteria are crucial components in evaluating the study's ability to provide proof-of-concept for ESK-001's use in psoriasis.

Primary and Secondary Endpoints Appropriateness

• Primary Endpoint (Safety and Tolerability): Given that the drug is in a phase 2 study aiming for long-term use, the emphasis on safety and tolerability is appropriate. Chronic conditions like psoriasis require treatments that patients can tolerate over extended periods without significant adverse effects.
• Secondary Endpoints (Efficacy and Quality of Life): Changes from baseline in PASI scores address the clinical efficacy that directly correlates with disease severity, an essential aspect of therapeutic proof-of-concept. Additionally, evaluating quality of life through the DLQI and assessing pharmacokinetics provide a holistic view of the drug’s impact on patients' lives and its behavior in the body over time, which is crucial for chronic administration.

Inclusion / Exclusion Criteria Appropriateness

• Inclusion Criteria: Setting a broad age range (18-75 years) and a minimum total body weight (>40 kg) ensures that the study potentially covers a wide spectrum of the adult population suffering from plaque psoriasis. The requirement for effective contraception addresses safety concerns regarding potential drug effects on pregnancy.
• Exclusion Criteria: Excluding individuals with a history of malignancy, chronic infections (HIV, Hepatitis B or C), tuberculosis, non-plaque forms of psoriasis, and those with significant QTcF prolongation ensures patient safety. These criteria also help in reducing variability in the study's outcomes attributable to complex medical histories or conditions that could interact with the drug's effects or its pharmacokinetics.

The inclusion/exclusion criteria, while necessary for ensuring participant safety and data integrity, might pose challenges to the study's reproducibility and generalizability:

• Narrow Disease Focus: By exclusively focusing on plaque psoriasis, the findings may not be directly applicable to other psoriasis types, potentially limiting the broad applicability of ESK-001 within the psoriasis population.
• Exclusion due to Recent Malignancy or Chronic Infection: These criteria exclude a significant portion of the population that may benefit from ESK-001, particularly since individuals with psoriasis may have co-morbid conditions. This exclusion could influence the reproducibility of the study across a broader, more diverse population.
• QTcF Criteria: The specific exclusion thresholds for QTcF intervals (450 msec for males, 470 msec for females) could exclude patients who are on the borderline of these thresholds but might still safely benefit from the treatment. This exclusion might limit the applicability of the study findings to all potential users.

Overall, while the study design, including its primary and secondary endpoints, generally seems well-suited to provide a proof-of-concept for the use of ESK-001 in plaque psoriasis, the reproducibility and generalizability of the study's findings might be constrained by its narrowly defined inclusion and broad exclusion criteria. Further research could explore the applicability of ESK-001 across a more diverse patient population and in various psoriasis subtypes to fully understand its potential benefits and limitations.

Clinical data update

The Phase 2 clinical trial conducted by Alumis Inc. evaluated the efficacy and safety of ESK-001, an oral allosteric tyrosine kinase 2 (TYK2) inhibitor, in patients with moderate-to-severe plaque psoriasis. This study, presented at the American Academy of Dermatology (AAD) Annual Meeting, showed positive results across several key metrics.

The trial, known as STRIDE, included 228 patients randomized into five dosage groups of ESK-001 or a placebo. The primary endpoint was achieving a 75% improvement in the Psoriasis Area and Severity Score (PASI 75) by week 12 compared to placebo. This goal, along with key secondary efficacy endpoints, was met across all clinically relevant doses tested, indicating a clear dose-dependent response. The highest efficacy and TYK2 inhibition were observed at the top dose of 40 mg twice daily, which was well tolerated across all dose levels.

At week 12, 64.1% of patients on the highest dose of 40 mg twice daily achieved PASI 75, demonstrating a clear advantage over lower doses and placebo. The same high dose also resulted in 38.5% of patients reaching PASI 90 and 15.4% achieving PASI 100, suggesting substantial improvements in skin clearance. For the 20 mg twice daily and 40 mg once daily doses, PASI 75 responses were similar, indicating that frequency of dosing plays a role in the drug's efficacy.

Further insights were provided by the ongoing open-label extension (OLE) study, which examined two dosing regimens of ESK-001 (40 mg once daily and 40 mg twice daily) over 16 weeks. Preliminary data indicated significant improvements over time, with an impressive 90% of patients observed to achieve PASI 75 and 57% reaching PASI 90 at the 40 mg twice-daily dose. When applying non-responder imputation, which is a more conservative analysis method, the results remained robust with 80% achieving PASI 75, underscoring the sustained efficacy of ESK-001.

No treatment-related serious adverse events were reported, and the incidence of treatment-related adverse events was comparable to placebo, with the majority being mild or moderate in nature. Headache, upper respiratory tract infections, and nasopharyngitis were the most common adverse events noted. A discontinuation rate of less than 3% due to adverse events reflects the favorable safety and tolerability profile of ESK-001.

Key insights from the Phase 2 program highlighted ESK-001's potential to safely achieve maximal target inhibition, correlating with significant clinical improvement that continued to grow over time. These findings suggest a promising risk-benefit profile and the potential for ESK-001 to be a best-in-class option for psoriasis treatment.

In addition to psoriasis, ESK-001 is being explored for other autoimmune conditions, including systemic lupus erythematosus (SLE) and non-infectious uveitis, under the LUMUS and OPTYK-1 Phase 2 trials, respectively. Alumis is also developing a once-daily tablet formulation of ESK-001, leveraging precision data analytics and a multi-platform approach to expand its therapeutic applications.

The Phase 2 study's success, particularly in achieving maximum target inhibition and translating this to high clinical efficacy, underscores the potential of ESK-001 as a significant advancement in oral treatments for psoriasis and possibly other immune-mediated diseases. This positions Alumis and ESK-001 favorably as they prepare for Phase 3 trials, aiming to offer a more effective oral treatment option for patients. These outcomes highlight the potential of ESK-001 to offer a meaningful oral treatment option with biologic-like efficacy for patients with moderate-to-severe plaque psoriasis.

Clinical significance

The clinical findings from the STRIDE trial for ESK-001 demonstrate significant potential in the treatment of moderate-to-severe plaque psoriasis, which is noteworthy for several reasons:

• Efficacy of Oral TYK2 Inhibition: The data show that an oral allosteric TYK2 inhibitor can produce substantial improvements in psoriasis symptoms, as measured by PASI scores. Achieving PASI 75, PASI 90, and PASI 100 represents a 75%, 90%, and 100% reduction in psoriasis severity, respectively, which are critical benchmarks in psoriasis treatment. The high percentages of patients achieving these benchmarks, especially with the 40 mg twice-daily dose, are indicative of strong clinical efficacy. These results are particularly impressive for an oral medication, which historically has lagged behind biologic therapies in terms of efficacy.
• Dose-Dependent Response: The clear dose-dependent response, with the highest dose providing the greatest improvement in PASI scores, suggests that the mechanism of action of ESK-001 is consistent and predictable, which is advantageous for tailoring treatment to individual patient needs.
• Safety Profile: The reported favorable safety profile, with no serious treatment-related adverse events and a low discontinuation rate, is significant. Safety is a critical concern in long-term treatments for chronic diseases like psoriasis, where patients may require ongoing therapy for years. The fact that the safety profile is comparable to placebo is encouraging for the use of ESK-001 as a long-term treatment option.
• Quality of Life Considerations: Psoriasis is not just a physical condition; it has substantial impacts on patients' quality of life, with associated psychosocial comorbidities. Oral treatments that are both efficacious and well-tolerated, like ESK-001, could provide a significant advantage in terms of patient adherence and preference compared to injectable biologic treatments.
• Long-Term Improvement: The continued improvement over time, particularly in the OLE study, suggests that ESK-001 could have a sustained effect with continued use. This is crucial for a chronic condition like psoriasis, where ongoing management is necessary.
• Potential for Best-in-Class Status: Given the high efficacy, favorable safety profile, and oral route of administration, ESK-001 has the potential to become a best-in-class therapy for plaque psoriasis. This is especially relevant when considering that many current leading treatments for moderate-to-severe plaque psoriasis are biologics that require injection or infusion.
• Innovation in Psoriasis Treatment: If the Phase 3 trials confirm the Phase 2 results, ESK-001 could represent a significant innovation in psoriasis treatment by providing a new, highly effective oral medication option that could compete with or potentially replace some biologic therapies, especially for patients who prefer oral medication or have contraindications to biologics.

In conclusion, the clinical significance of the STRIDE trial findings lies in demonstrating that ESK-001 has the potential to address an unmet need in the treatment landscape of plaque psoriasis, offering an oral therapy that does not compromise on efficacy or safety, which could improve patient adherence and outcomes.

Clinical trial overview

The ESK-001 study is a Phase 2, multicenter, multinational, randomized, double-blind, placebo-controlled trial designed to assess the safety, efficacy, and pharmacokinetics (PK) of multiple dose levels of ESK-001 in adults with Systemic Lupus Erythematosus (SLE). The study aims to enroll approximately 388 patients, who will be randomized to receive either ESK-001 at one of three dose levels or placebo in the form of oral tablets for a duration of 48 weeks, followed by a 4-week follow-up period, totaling 57 weeks. This study also promises an open-label extension for participants completing it. The primary outcome measure is to compare the effect on disease activity measured by the proportion of patients achieving a response according to the British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) criteria at Week 48. Secondary outcomes include safety and tolerability assessments, the effect on corticosteroid use, disease activity, quality of life measures, and patient-reported fatigue, among others.

Critiques of the Study Design

• Sample Size: The estimated enrollment of 388 patients may or may not be sufficient to capture the variability in response to treatment across the diverse population affected by SLE, given the heterogeneity of the disease. Power analysis details are not provided, which are crucial to determine whether the sample size is adequate to detect a statistically significant difference between treatment arms.
• Duration: While 48 weeks of treatment with a 4-week follow-up is reasonable to observe the efficacy and safety of the drug, long-term effects beyond this period remain unknown. SLE is a chronic disease, and longer-term studies may be necessary to fully understand the potential benefits and risks of ESK-001.
• Outcome Measures: While the primary and secondary outcome measures are comprehensive, the reliance on BICLA as the primary endpoint could be criticized due to its subjectivity. Additionally, assessing a wide range of secondary outcomes can lead to issues with multiple comparisons, potentially diluting the significance of findings if not properly controlled.

Operational and Technical Challenges

• Recruitment and Retention: Recruiting a sufficient number of eligible patients within the planned timeframe can be challenging, especially considering the specific inclusion criteria and the chronic nature of SLE. Ensuring participant retention throughout the 57-week study period is crucial for minimizing dropouts, which can impact the study's power and validity.
• Blinding and Randomization: Maintaining the double-blind nature of the study is critical for minimizing bias. Operational challenges include ensuring that the placebo and ESK-001 tablets are indistinguishable in appearance and that the randomization code is securely maintained to prevent unblinding.
• Adherence to Treatment: Ensuring participant adherence to the daily oral regimen of ESK-001 or placebo over 48 weeks is another challenge. Non-adherence can affect the study's outcomes and the interpretation of efficacy and safety data.
• Disease Flare Management: Given the fluctuating nature of SLE, managing and accurately recording disease flares during the study is necessary for assessing the drug's efficacy. This requires well-defined flare criteria and prompt reporting and documentation.
• Safety Monitoring: Continuous and rigorous safety monitoring is vital due to the potential for adverse effects, especially considering the immunomodulatory nature of treatments for SLE. Implementing an effective data management system to promptly capture and evaluate adverse event data is essential.

The selection of inclusion and exclusion criteria in the ESK-001 Phase 2 study is tailored to identify adult patients with active Systemic Lupus Erythematosus (SLE) who can safely participate while trying to minimize the heterogeneity often seen in SLE patient populations. This tailoring enhances the potential to demonstrate the proof-of-concept for the use of ESK-001 in SLE, especially considering the primary and secondary endpoints. Let's discuss the potential these criteria have on demonstrating efficacy and address reproducibility challenges.

Potential of Study to Provide Proof-of-Concept:

• Inclusion Criteria Appropriateness: By selecting patients with SLE according to the 2019 EULAR/ACR criteria and requiring active disease manifestation (indicated by a SLEDAI-2K score), the study focuses on those who could significantly benefit from a new therapeutic option. The inclusion of patients already on a stable medication regimen (corticosteroids, antimalarials, or specific DMARDs) underlines an intention to evaluate the efficacy of ESK-001 as both a monotherapy and as part of combination therapy.
• Primary and Secondary Endpoints: The primary endpoint focusing on the BICLA response and secondary endpoints, including SLE Responder Index, corticosteroid use, quality of life measures, and patient-reported outcomes, are well-chosen. They encompass a broad perspective on disease management, from the reduction of disease activity to the improvement of patients' daily living, which is critical for evaluating the comprehensive potential of ESK-001 in SLE treatment.

Reproducibility Challenges Posed by Inclusion/Exclusion Criteria:

• Disease Activity and Medication Requirements: The need for a specific SLEDAI-2K score to demonstrate active disease might limit the pool of eligible patients, potentially slowing recruitment and impacting the generalizability of study results. Additionally, requiring stability in medication (especially corticosteroids and DMARDs) could exclude patients with recently fluctuating or worsening conditions who may seek or require adjustments in their treatment regimen.
• Exclusion Criteria Specificity: While necessary for patient safety, the extensive exclusion criteria, especially regarding neuropsychiatric SLE manifestations and infections, could exclude a significant portion of the SLE population. This might limit the study's applicability to a wider SLE patient population, as those with more complicated SLE manifestations or comorbid conditions may respond differently to ESK-001.
• Operational Complications: Implementing strict inclusion/exclusion criteria can introduce operational complexities, requiring thorough screening processes that may extend recruitment periods and potentially delay timelines. There's also an increased burden on healthcare providers to accurately assess and document eligibility, particularly in distinguishing SLE symptoms from exclusionary conditions like severe fibromyalgia.

To overcome these reproducibility challenges, future studies could consider broader inclusion criteria or stratified analyses that allow for the inclusion of more varied patient populations. Moreover, real-world evidence studies post-approval could provide additional insights into the drug's efficacy across a broader, more diverse patient population.

In summary, the ESK-001 study design showcases a thoughtful approach to assessing the drug’s potential in treating SLE, with well-considered inclusion/exclusion criteria and endpoints. However, addressing the challenges related to patient selection and operational complexities will be crucial for translating the study's findings into broader clinical practice.

Clinical trial overview

Summary of the Study Design

The clinical trial for ESK-001 in the treatment of active Noninfectious Uveitis (NIU) provides a rigorous framework for assessing the drug's efficacy and safety. Spanning an estimated total duration of 55 weeks, this Proof-of-Concept (POC) trial has been structured into several critical phases:

• 2-week screening period (+7 days buffer)
• 24-week treatment period
• 24-week extension period
• 4-week follow-up period

Participants in the study are randomized to receive one of two doses of the oral tablet ESK-001 daily for the initial 24-week treatment phase. Those who do not meet the criteria for treatment failure by Week 24 may progress to the extension period.

The outcomes measured include comparing the efficacy between the two treatment groups by the proportion of patients meeting treatment failure criteria by Week 24, time to treatment failure after Week 24, safety and tolerability, and pharmacokinetics (PK) characterized by maximum observed concentration (Cmax) and trough observed plasma concentration (Ctrough) assessments.

Critiques of the Study Design

• Sample Size: With an estimated enrollment of 30 participants, the sample size might be on the smaller side for yielding statistically significant results that are generalizable across the broader population suffering from NIU. This small sample size could limit the power of the study to detect meaningful differences between the two dose levels.
• Blinding and Randomization: The study benefits from a quadruple blinding process (including participant, care provider, investigator, and outcomes assessor), minimizing bias. However, the effectiveness of blinding and randomization methods is not detailed, which are critical for ensuring the internal validity of the study.
• Longitudinal Design: While the phased approach of the study allows for a comprehensive assessment over time, it may also introduce challenges related to participant retention and adherence over the extended period of 55 weeks. Longitudinal designs also face threats from external factors influencing health that are unrelated to the intervention.

Operational and Technical Challenges

1. Participant Recruitment and Retention: Keeping participants engaged for over a year is a significant challenge. The trial's success largely depends on achieving and maintaining high participation levels throughout the study duration.
2. Dose Determination: Determining the optimal dosing levels for efficacy without breaching safety thresholds requires meticulous planning and continuous monitoring. The study might face challenges in adjusting dosing if unexpected safety concerns arise.
3. Pharmacokinetics Analysis: Thoroughly characterizing the drug's pharmacokinetics involves complex analytical protocols and methodologies. This may involve technical challenges in accurately measuring plasma concentrations and interpreting these data in the context of efficacy and safety profiles.
4. Data Analysis and Interpretation: Given the study's design, the data analysis may become complex, especially when measuring time-to-event outcomes like treatment failure. Potential complexities in handling and interpreting longitudinal data may also present technical challenges.

In conclusion, while the study design for evaluating ESK-001 in patients with NIU is comprehensive and robust, addressing the critiques and operational challenges will be crucial for ensuring the reliability and applicability of the study outcomes.

Potential of the Study for Proof-of-Concept for ESK-001 in Uveitis

This study is well-positioned to provide proof-of-concept for the use of ESK-001 in Uveitis, focusing on active noninfectious intermediate, posterior, or panuveitis:

• Appropriateness of Primary and Secondary Endpoints: The primary endpoint, comparing the efficacy between two ESK-001 treatment groups by the proportion of patients failing treatment by Week 24, is highly appropriate for assessing the drug's efficacy short-term. Secondary endpoints, including time to treatment failure after Week 24, safety and tolerability assessments, and pharmacokinetic characterization, comprehensively evaluate the drug's long-term efficacy, safety profile, and dose-response relationship. These endpoints are crucial for establishing the potential therapeutic benefits and risks of ESK-001.
• Inclusion/Exclusion Criteria: The selection criteria are thoughtfully designed to ensure the study population is representative of patients with active noninfectious uveitis while excluding conditions that could confound the efficacy or safety assessments (e.g., infectious uveitis, elevated intraocular pressures, or severe glaucoma). This helps in homogenizing the study population to better attribute observed effects to ESK-001. The requirement for participants to have active uveitis as defined by specific clinical criteria (active inflammatory lesions or ≥ 2+ vitreous haze (VH)) is critical for ensuring that the study addresses the drug's effect in active disease states.

Potential Reproducibility Challenges Posed by Inclusion/Exclusion Criteria

While the eligibility criteria are designed to select a representative and appropriate cohort for assessing ESK-001's efficacy and safety in noninfectious uveitis, they may also introduce challenges in patient recruitment and generalizability of findings, including:

• Narrow Age Range and Specific Disease States: While the age range of 18 to 70 years encompasses a significant portion of the patient population, it excludes younger and much older individuals who may also suffer from uveitis. This could limit the generalizability of findings across all age groups.
• Exclusion of Infectious Uveitis Patients: By focusing on noninfectious uveitis, the study does not address the potential efficacy of ESK-001 in infectious uveitis, which may be considered a missed opportunity to explore the drug's broader anti-inflammatory or immunomodulatory effects.
• Requirement for Active Disease: The requirement for active disease as per specific criteria ensures that the drug is tested in a relevant patient population. However, this specificity may reduce the number of eligible participants, extending recruitment periods and potentially impacting the study timeline and costs.
• Health Conditions and Medication Restrictions: Exclusion criteria related to other health conditions (e.g., malignancies, chronic infections) and restrictions against certain medications or vaccines might limit the enrollment of patients with comorbid conditions, which could again affect the reproducibility and applicability of study results in a real-world setting.

These inclusion/exclusion criteria, while necessary for the integrity and focus of the study, may introduce some challenges in patient recruitment and the applicability of the study results to a broader patient population. Addressing such challenges would involve ensuring a sufficient recruitment pool through wider multicenter participation and potentially adjusting study criteria based on interim analyses and evolving scientific understanding.

Market Overview

Psoriasis

Psoriasis is a chronic autoimmune condition that affects the skin and, in some cases, the joints. It is characterized by the rapid growth of skin cells, leading to the formation of thick, scaly patches that can be red, itchy, and painful. The exact cause of psoriasis is not fully understood but is believed to involve a combination of genetic predisposition and environmental factors. Triggers such as stress, infections, certain medications, and injury to the skin can precipitate or exacerbate the condition.

Pathology

In psoriasis, the immune system mistakes normal skin cells as pathogens and reacts by accelerating the skin cell cycle. Normally, skin cells take about a month to grow and shed, but in psoriasis, this process is dramatically reduced to just a few days. This results in the accumulation of immature skin cells on the surface, forming the characteristic plaques.

Symptoms

• Plaques: Thick, red patches of skin covered with silvery scales. These can appear anywhere but are most common on the knees, elbows, scalp, and back.
• Itching and Soreness: The affected areas can be itchy, tender, and painful.
• Dry, Cracked Skin: That may bleed.
• Nail Changes: Pitting, discoloration, and thickening of the nails.
• Joint Pain and Stiffness: Indicative of psoriatic arthritis, a related condition.

Types

• Plaque Psoriasis: The most common form, characterized by plaques and scales.
• Guttate Psoriasis: Presents as small, dot-like lesions, often following a streptococcal infection.
• Inverse Psoriasis: Affects folds of the skin, such as under the breasts or in the groin.
• Pustular Psoriasis: Characterized by white blisters surrounded by red skin.
• Erythrodermic Psoriasis: A rare, severe form causing widespread redness and scaling that can be life-threatening.

Prognosis

Psoriasis is a chronic condition with no definitive cure. Management focuses on controlling symptoms and preventing flare-ups. Treatment options vary depending on the severity and type of psoriasis and may include topical treatments (creams and ointments), phototherapy (light therapy), systemic medications (oral or injected medications that affect the whole body), and biologic drugs (target specific parts of the immune system).

Lifestyle adjustments, such as stress management, quitting smoking, and maintaining a healthy weight, can also help manage the condition. Regular monitoring and treatment adjustments are often necessary to manage symptoms effectively over time.

Despite its physical manifestations, psoriasis can also have a significant psychological impact, affecting self-esteem and social interactions. Comprehensive treatment, therefore, also often includes support for mental well-being.

Conclusion

Psoriasis is a complex, chronic autoimmune condition requiring a multifaceted treatment approach. While it can significantly impact quality of life, advancements in treatment options have greatly improved the prognosis for many patients, enabling better disease management and a higher quality of life.

Given the information available and leveraging the current understanding of psoriasis, its treatment landscape, and ongoing challenges, we can estimate the market opportunity for a hypothetical drug named ESK-001 intended for psoriasis. It's important to consider various facets of the psoriasis treatment market, including the current standard of care, competitive landscape, and unmet medical needs.

Current Standard of Care

The standard of care for psoriasis varies based on the severity and type of psoriasis. Mild to moderate psoriasis is often managed with topical agents (corticosteroids, vitamin D analogs) and phototherapy. More severe cases may require systemic treatments, including traditional systemics (methotrexate, cyclosporine) and biologics targeting specific immune system molecules implicated in psoriasis (TNF inhibitors, IL-17 inhibitors, IL-23 inhibitors).

Successful Drugs in the Indication

• TNF inhibitors: Etanercept (Enbrel), Adalimumab (Humira)
• IL-17 inhibitors: Secukinumab (Cosentyx), Ixekizumab (Taltz)
• IL-23 inhibitors: Guselkumab (Tremfya), Risankizumab (Skyrizi)

These drugs generally offer superior efficacy over traditional systemic treatments, with a more favorable safety profile than earlier treatments.

Market Opportunity for ESK-001

To accurately assess the market opportunity for ESK-001, we would need to consider its potential advantages over the current treatments, such as:- Efficacy Improvement: If ESK-001 demonstrates superior efficacy, particularly in patients who have not responded well to existing therapies, it would have a significant market opportunity.- Safety and Tolerability: A better safety profile or fewer adverse effects could position ESK-001 favorably in the market.- Route of Administration: An oral medication or a less frequent dosing schedule may offer a convenience benefit over existing treatments, which are mostly injectable and require regular dosing.

Unmet Medical Needs

Despite advancements, there remain significant unmet needs in psoriasis treatment:- Long-Term Safety: Concerns persist around the long-term use of systemic treatments and biologics.- Cost: High costs of biologic treatments are a barrier for many patients.- Treatment-Resistant Psoriasis: A proportion of patients are unresponsive or lose response over time to current treatments.

Conclusion

The market opportunity for ESK-001 in psoriasis will largely depend on its ability to address these unmet needs and how it compares with existing therapies in terms of efficacy, safety, and patient convenience. An ideal profile would offer improved efficacy, particularly for treatment-resistant cases, with a safer and more patient-friendly administration route.

Given the chronic nature of psoriasis, the evolving patient needs, and the high costs associated with long-term treatment, there is a continuous demand for innovative therapies that can offer better outcomes and improved quality of life. ESK-001's success will be contingent upon its clinical data, positioning within the treatment algorithm, pricing strategy, and its ability to fulfill these currently unmet patient and clinician needs.

Given the competitive landscape of psoriasis treatment, several promising treatments are currently in development which could potentially compete with the hypothetical drug ESK-001. These treatments range from next-generation biologics to novel small molecules and approaches designed to offer improved efficacy, safety, and patient convenience. While the specifics of ESK-001 are not provided, exploring these emerging therapies can shed light on the competitive environment and the innovation trends within the psoriasis treatment domain.

Next-Generation Biologics

• New IL-23 Inhibitors: Since IL-23 plays a crucial role in the pathogenesis of psoriasis, new inhibitors targeting this interleukin are in development. These offer the potential for even greater specificity and fewer side effects.
• Dual-Action Biologics: Therapeutics that can target multiple pathways involved in psoriasis, such as bimekizumab, which inhibits both IL-17A and IL-17F, are showing promise in clinical trials. These dual-action drugs might offer superior efficacy by blocking more than one inflammatory signal.

Tyrosine Kinase 2 (TYK2) Inhibitors

TYK2 inhibitors represent a novel oral treatment option that modulates the immune response by inhibiting the Janus kinase (JAK)-STAT pathway, which is implicated in psoriasis. By offering an oral route of administration with the potential for high efficacy and a favorable safety profile, TYK2 inhibitors could provide a significant advantage over some of the current treatments, including injectable biologics.- An example is deucravacitinib, which has been showing promise in clinical trials and could become a leading treatment option upon approval.

PDE4 Inhibitors

Though not entirely new, the development and optimization of phosphodiesterase 4 (PDE4) inhibitors continue. These drugs work by reducing inflammation. Oral PDE4 inhibitors offer a non-biologic, systemically acting treatment option with an emphasis on safety and convenience.- Apremilast (Otezla) is currently available, but next-generation PDE4 inhibitors may offer improved efficacy and safety profiles.

Small Molecule Inhibitors

Small molecule drugs that can be administered orally and target specific inflammatory pathways in psoriasis are under intensive research. These could compete directly with ESK-001 if they offer comparable or superior efficacy with the convenience of oral dosing and a better safety profile.

IL-1β Inhibitors

Given the role of the interleukin-1 family in inflammation, IL-1β inhibitors are also being explored as potential treatments for psoriasis. These could offer new mechanisms of action compared to currently available treatments.

There are several notable drugs used in the treatment of psoriasis, ranging from well-established biologics to more recently approved therapies that reflect the ongoing evolution in our understanding and management of this complex autoimmune condition. Psoriasis treatment strategies have increasingly become more targeted, aiming for higher efficacy rates, better safety profiles, and improved patient quality of life. Below, we explore some of the key drugs from different classes, including recent approvals:

Drug Name	Name of Notable Phase 3 Studies	PASI-75	PASI-90	PASI-100	Time Point Measured	Patient Population Summary	Notable Side Effects	Mechanism of Action	Route of Administration
ESK-001 (Alumis)	STRIDE (Phase 2; Phase 3 planned)	64.1% (40 mg BID)	38.5% (40 mg BID)	15.4% (40 mg BID)	Week 12	Moderate to severe plaque psoriasis	Well-tolerated; specific side effects profile pending	TYK2 inhibitor	Oral
Methotrexate	-	34-49%	-	-	Variable, often 16 weeks	Moderate to severe plaque psoriasis	Nausea, hepatotoxicity, myelosuppression	Antimetabolite	Oral, Injectable
Cyclosporine	-	50-70%	-	-	Variable, often 12-16 weeks	Moderate to severe plaque psoriasis	Nephrotoxicity, hypertension, increased risk of infections	Calcineurin inhibitor	Oral
Acitretin	-	Varies	-	-	Variable, often 12-24 weeks	Moderate to severe plaque psoriasis, often used for pustular or erythrodermic forms	Teratogenicity, dry skin, hyperlipidemia	Retinoid	Oral
Infliximab (Remicade)	EXPRESS, EXPRESS II	80%	57%	26%	Week 10	Moderate to severe plaque psoriasis	Infusion reactions, increased risk of infections	TNF-alpha inhibitor	Intravenous
Etanercept (Enbrel)	CLEAR, CRYSTEL, CHAMPION	49-59%	25-49%	13-22%	Week 12-24	Moderate to severe plaque psoriasis	Injection site reactions, infections	TNF-alpha inhibitor	Subcutaneous
Adalimumab (Humira)	REVEAL, CHAMPION	71%	59%	-	Week 16	Moderate to severe plaque psoriasis	Injection site reactions, increased risk of infections	TNF-alpha inhibitor	Subcutaneous
Ustekinumab (Stelara)	PHOENIX 1, PHOENIX 2	67-76%	42-51%	-	Week 12	Moderate to severe plaque psoriasis	Nasopharyngitis, upper respiratory tract infections	IL-12 and IL-23 inhibitor	Subcutaneous, Intravenous
Secukinumab (Cosentyx)	ERASURE, FIXTURE	77-81%	59-70%	40-44%	Week 12	Moderate to severe plaque psoriasis	Nasopharyngitis, diarrhea, upper respiratory tract infections	IL-17A inhibitor	Subcutaneous
Ixekizumab (Taltz)	UNCOVER-1, UNCOVER-2, UNCOVER-3	>80%	>70%	>40%	Week 12	Moderate to severe plaque psoriasis	Injection site reactions, upper respiratory tract infections	IL-17A inhibitor	Subcutaneous
Guselkumab (Tremfya)	VOYAGE 1, VOYAGE 2	85%	73%	49%	Week 16	Moderate to severe plaque psoriasis	Upper respiratory infections, headache, injection site reactions	IL-23 inhibitor	Subcutaneous
Tildrakizumab (Ilumya)	reSURFACE 1, reSURFACE 2	58-64%	29-41%	-	Week 12	Moderate to severe plaque psoriasis	Upper respiratory infections, diarrhea, injection site pain	IL-23 inhibitor	Subcutaneous
Risankizumab (Skyrizi)	UltIMMa-1, UltIMMa-2	>80%	70-75%	>50%	Week 16	Moderate to severe plaque psoriasis	Upper respiratory infections, headache	IL-23 inhibitor	Subcutaneous
Apremilast (Otezla)	ESTEEM 1, ESTEEM 2	33%	21%	10%	Week 16	Moderate to severe plaque psoriasis	Diarrhea, nausea, upper respiratory tract infection	PDE4 inhibitor	Oral
Tofacitinib (Xeljanz)	OPT Pivotal 1, OPT Pivotal 2	Varies	-	-	Week 12-16	Moderate to severe plaque psoriasis	Upper respiratory tract infections, headache, diarrhea	JAK inhibitor	Oral
Baricitinib (Olumiant)	-	-	-	-	-	-	-	JAK inhibitor	Oral
Upadacitinib (Rinvoq)	-	-	-	-	-	-	-	JAK inhibitor	Oral
Deucravacitinib (BMS-986165)	POETYK PSO-1, POETYK PSO-2	>50%	>35%	-	Week 12	Moderate to severe plaque psoriasis	Upper respiratory tract infections, headache, nausea	TYK2 inhibitor	Oral
PF-06826647	-	-	-	-	-	-	-	TYK2 inhibitor	Oral
Tapinarof	PSOARING 1, PSOARING 2	-	-	-	Week 12	Moderate to severe plaque psoriasis	Folliculitis, contact dermatitis	Aryl hydrocarbon receptor modulating agent	Topical
Brepocitinib (PF-06700841)	-	-	-	-	-	-	-	Dual JAK1/TYK2 inhibitor	Oral
JNJ-2113	FRONTIER 1 (Phase 2; Phase 3 planned)	Up to 78.6% (100 mg twice daily)	Up to 59.5% (100 mg twice daily)	Up to 40.5% (100 mg twice daily)	Week 16	Adults with moderate-to-severe plaque psoriasis	Generally well tolerated; most frequent AEs were infections and infestations including COVID-19, nasopharyngitis, and upper respiratory tract infection	IL-23 receptor antagonist peptide	Oral

Biologics

• Secukinumab (Cosentyx): Targets IL-17A, a key cytokine involved in the development of psoriasis. Approved in 2015, it was the first IL-17 inhibitor for psoriasis.
• Ixekizumab (Taltz): Another IL-17A inhibitor approved in 2016, showing high efficacy in plaque psoriasis.
• Guselkumab (Tremfya): Approved in 2017, this drug targets IL-23, a cytokine implicated in chronic inflammation and autoimmune diseases, and offers a promising option for moderate to severe plaque psoriasis.
• Risankizumab (Skyrizi): An IL-23 inhibitor approved in 2019, offering high efficacy with quarterly dosing.
• Bimekizumab (Bimzelx): A recent entrant targeting both IL-17A and IL-17F, approved in Europe and other regions as of 2021, offering a novel approach by blocking two key cytokines involved in psoriatic inflammation.

Small Molecule Inhibitors

Small molecule treatments provide an oral option for psoriasis management, broadening the range of treatment modalities available beyond topicals and injectables.

• Apremilast (Otezla): Approved in 2014, this PDE4 inhibitor works by modulating the immune response to reduce plaque psoriasis symptoms and psoriatic arthritis.
• Deucravacitinib: A novel oral TYK2 inhibitor showing promise in clinical trials for its efficacy and safety profile. The drug was recently approved, offering a new oral mechanism of action in psoriasis treatment.

Topicals

• Calcipotriene and Betamethasone Dipropionate (Taclonex): A combination product offering both a vitamin D analog and corticosteroid, widely used for topical treatment.
• Tazarotene (Tazorac): A topical retinoid that can help normalize skin cell growth.
• Roflumilast (Zoryve): A recently approved PDE4 inhibitor cream for plaque psoriasis, including on sensitive areas like the face and intertriginous areas, offering a novel topical mechanism of action as of 2022.

ESK-001 Competitive Positioning

Considering the above data and the current landscape of psoriasis treatments, ESK-001 has a number of characteristics that suggest it could have significant market potential:

• Efficacy: ESK-001's Phase 2 trial results are promising, with 64.1% of patients achieving PASI 75 at the highest dose. While this is somewhat lower than the efficacy seen with some biologics, it's important to note that ESK-001 is an oral medication, which can be a strong market differentiator. Many patients may prefer oral treatments due to convenience and ease of administration compared to injectables.
• Safety and Tolerability: The STRIDE trial indicates ESK-001 was well tolerated with no serious treatment-related adverse events reported. A favorable safety profile is a critical factor in patient and physician drug selection, particularly for a chronic disease like psoriasis, which requires long-term management.
• Convenience: As an oral treatment, ESK-001 could offer greater convenience over injectable biologics, potentially leading to better adherence and patient satisfaction. Convenience is a powerful factor influencing prescription decisions, especially for patients who are needle-averse or require more flexibility due to their lifestyle or travel commitments.
• Potential for Best-in-Class Profile: The drug's potential for a best-in-class profile within the oral treatment options for psoriasis could position it favorably against competitors, assuming the Phase 3 trials confirm its efficacy and safety.
• Treatment Landscape Positioning: If ESK-001 enters the market, it will be compared not only to other oral treatments but also to topicals and biologics. Its positioning will depend on a combination of efficacy, safety, cost, patient preference, and insurance coverage.
• Market Size and Growth: The global psoriasis treatment market is large and continues to grow. An effective new oral therapy could capture a significant market share, particularly if it is positioned as having similar efficacy to biologics with the convenience of an oral drug.
• Pricing Strategy: The success of ESK-001 will also depend on Alumis's pricing strategy. If the drug is priced competitively with current treatments, it could be favored by both prescribers and payers, particularly if it offers cost advantages over expensive biologic treatments.
• Payer Coverage: Insurance coverage and reimbursement will be crucial. Favorable coverage could significantly boost the adoption of ESK-001, especially if it is positioned as a cost-effective alternative to biologics with comparable efficacy.
• Expanded Indications: If ESK-001 shows potential for treating other immune-mediated diseases, as suggested by ongoing studies, this could further increase its market potential.
• Market Entry Timing: The timing of market entry relative to patent expirations of existing biologics and the introduction of biosimilars will affect ESK-001's market potential. Early entry can establish market share before biosimilars become widely adopted.
• Physician and Patient Education: Successful marketing strategies that educate healthcare providers and patients on the benefits and proper use of ESK-001 will be key to its uptake.
• Competitive Landscape: The TYK2 inhibitor space is competitive, with other candidates like deucravacitinib (BMS-986165) also showing promise. The first-to-market advantage or superior efficacy and safety profiles will be crucial.

In conclusion, ESK-001 has substantial market potential due to its efficacy, safety, and the convenience of an oral formulation. However, its success will also depend on Phase 3 results, the competitive landscape, pricing, reimbursement strategies, and how well Alumis can market the drug to both physicians and patients.

Lupus

Lupus involves the immune system producing autoantibodies that attack the body's own cells, particularly affecting the connective tissues of various organs. Genetic predisposition, environmental factors (such as sunlight exposure), hormonal changes, and certain medications are known to contribute to its development, but the exact cause remains unclear.

Lupus symptoms vary widely and can include:

• Fatigue: A pervasive sense of tiredness not relieved by rest.
• Joint pain and swelling: Affecting several joints with arthritis-like symptoms.
• Skin lesions: Including a butterfly-shaped rash across the cheeks and nose and skin lesions that worsen with sun exposure.
• Kidney problems: Potentially leading to kidney failure in severe cases.
• Neurological symptoms: Such as headaches, dizziness, and memory problems.
• Heart and lung involvement: Leading to chest pain and shortness of breath.
• Blood disorders: Such as anemia and leukopenia.

Diagnosing lupus can be challenging, involving patient history, clinical examination, and laboratory tests to check for specific autoantibodies.

The prognosis has improved significantly with advances in medical knowledge and treatment, allowing many with lupus to lead fulfilling lives, despite the disease's variability.

There is no cure for lupus, but symptoms can often be managed through medications and lifestyle modifications such as:

• NSAIDs: For pain and swelling.
• Antimalarial drugs: To manage skin and joint symptoms.
• Corticosteroids and immunosuppressants: To reduce immune system activity.
• Biologics: For patients with more severe disease.

Lifestyle modifications, including sun protection and stress management, play a crucial role in managing lupus.

The standard of care in SLE includes NSAIDs, antimalarials, corticosteroids, and immunosuppressive drugs, with belimumab being the only FDA-approved biologic specifically for SLE as of the last update.

Significant unmet medical needs remain, including the need for safer long-term treatment options, more personalized treatments, and better management of flares.

ESK-001 could capture market share by offering a novel mechanism, demonstrating broad or specific efficacy, reducing the need for steroids, having a favorable safety profile, and improving patient quality of life. However, recent clinical failures of drugs with similar mechansisms (such as brepocitinib) highlight the challenges of lupus drug development.

Emerging Therapies

• Anifrolumab (Saphnelo): An interferon receptor antagonist approved for moderate to severe SLE.
• Voclosporin (Lupkynis): A calcineurin inhibitor approved for lupus nephritis.
• BTK Inhibitors: Being explored for SLE, offering a novel approach to managing the disease.
• IL-6 Inhibitors and JAK Inhibitors: Tested in SLE for their potential benefits in controlling disease activity.
• Deucravacitinib (TYK2 inhibitor): Currently in Phase 3 for lupus.

The development of therapies like anifrolumab and voclosporin marks a shift towards more personalized treatment options for SLE patients. ESK-001 will need to demonstrate distinct advantages to compete effectively.

Despite advancements, significant unmet needs remain, such as developing treatments that offer complete remission, reducing steroid dependence, and addressing severe manifestations of lupus.

Ongoing research is essential for addressing these needs, with the potential for high efficacy and fewer side effects.

Convenience in administration can significantly impact patient adherence and quality of life. If ESK-001 offers an oral option with efficacy comparable to injectable biologics, it might be preferred by patients desiring easier or less invasive treatment methods.

Uveitis

Uveitis is a form of eye inflammation targeting the uvea, the middle layer of the eye that consists of the iris, ciliary body, and choroid. Uveitis may affect one or both eyes, and its presentation can be acute, chronic, or recurring. The condition is an important cause of visual impairment and blindness, especially when diagnosis and treatment are delayed. Its etiology can be idiopathic or associated with systemic diseases, infections, or injuries.

Pathology

The pathology of uveitis involves inflammation of the uveal tract, but it can also affect adjacent structures including the retina, optic nerve, and vitreous humor. It's classified into four types based on the primary site of inflammation:

• Anterior Uveitis (Iritis): Affects the iris and is the most common form.
• Intermediate Uveitis: Involves the ciliary body.
• Posterior Uveitis: Targets the choroid.
• Panuveitis: Involves all segments of the uvea.

The inflammation may result from an autoimmune reaction, wherein the body's immune system mistakenly attacks the eye tissue, or as a secondary reaction to systemic infections or diseases like rheumatoid arthritis, sarcoidosis, or ankylosing spondylitis. Infectious causes include viruses (e.g., herpes simplex virus), bacteria (e.g., syphilis, tuberculosis), parasites, and fungi.

Symptoms

• Eye redness and irritation
• Blurred vision
• Pain in the eye
• Increased sensitivity to light (photophobia)
• Floating spots in the vision (floaters)

The intensity of symptoms can vary; some patients may experience severe eye pain and redness, while others might only notice mild blurring of vision.

Prognosis

The prognosis of uveitis depends on the type, underlying cause, severity at diagnosis, and response to treatment. While anterior uveitis often has a good prognosis with treatment, intermediate, posterior, and panuveitis can be more challenging to manage and are more likely to cause vision loss. Early diagnosis and proper management are critical to prevent complications such as glaucoma, cataract, and permanent vision damage.

Diagnosis

Diagnosis is based on patient history, clinical symptoms, and a thorough eye examination including slit-lamp examination, funduscopy, and ocular imaging. Laboratory tests and imaging may be conducted to determine any systemic association.

Treatment

Treatment aims to relieve pain, prevent further tissue damage, and restore any loss of vision. Options include:

• Corticosteroids: The mainstay of treatment, used to reduce inflammation, can be administered as eye drops, injections, orally, or intravenously, depending on the uveitis type and severity.
• Immunosuppressive and biologic drugs: For cases unresponsive to corticosteroids or associated with systemic autoimmune diseases, medications like methotrexate, mycophenolate mofetil, or TNF-alpha inhibitors may be used.
• Antibiotic or antiviral therapy: When an infectious cause is identified.

Conclusion

Uveitis represents a significant condition within ophthalmology due to its potential to cause severe eye damage and vision loss if not adequately treated. Its management is complex, often requiring a multidisciplinary approach involving ophthalmologists, rheumatologists, and sometimes infectious disease specialists. Advances in understanding the pathophysiology and treatment of uveitis continue to improve outcomes for affected individuals. Given the current landscape of uveitis treatment and management, the introduction of a hypothetical drug such as ESK-001 presents a unique market opportunity. The assessment of this opportunity requires an understanding of the disease's complexity, the current standard of care, existing successful treatments, and the persistent unmet needs within this therapeutic area.

The route of administration plays a crucial role in patient compliance and quality of life. If ESK-001 offers an innovative administration method that provides convenience (e.g., oral administration, long-acting injectables, or implants) while maintaining or enhancing efficacy, it could become a preferred option for both patients and clinicians, especially for those who require long-term treatment.

To effectively fit into and potentially alter the standard of care for uveitis, ESK-001 needs to address current unmet needs, such as reducing treatment burden, offering options for steroid-sparing, and providing treatments that are effective across the diverse spectrum of uveitis manifestations. Additionally, demonstrating cost-effectiveness and accessibility will also be critical factors for its integration into treatment protocols.

The potential for ESK-001 to fit into the uveitis treatment landscape hinges on its ability to offer differentiated benefits over existing therapies, particularly in terms of efficacy, safety, and patient-centric administration. Filling the gaps in current treatment approaches and addressing unmet needs could establish ESK-001 as a valuable addition to the standard of care, ultimately improving outcomes for patients with uveitis. Clinical trials and real-world evidence will be pivotal in determining its place in the therapeutic arsenal against uveitis.

Neuroinflammation program

Scientific background

The therapeutic rationale for targeting TYK2 (Tyrosine Kinase 2) in neuro-inflammation revolves around its central role in the signaling pathways of various inflammatory and immune responses. TYK2 is a member of the Janus kinase (JAK) family and plays a pivotal role in mediating the effects of certain cytokines on immune regulation and inflammation. These cytokines include members of the interferon family and interleukins (e.g., IL-6, IL-10, and IL-12) that are key players in the pathogenesis of neuro-inflammatory diseases.

Neuro-inflammation is an underlying mechanism in many neurological disorders, including multiple sclerosis (MS), Alzheimer’s disease (AD), Parkinson’s disease (PD), and other neurodegenerative conditions. In these diseases, the dysregulation of cytokine signaling can lead to the activation of glial cells, enhanced production of pro-inflammatory factors, disruption of the blood-brain barrier, neuronal damage, and ultimately, worsening of disease symptoms and progression.

Inhibiting TYK2-mediated signaling pathways holds potential for modulating these aberrant immune responses in the central nervous system (CNS). Specifically, a TYK2 inhibitor could:

• Reduce Pro-inflammatory Cytokine Production: By blocking the signaling pathways that lead to the production of pro-inflammatory cytokines, a TYK2 inhibitor can decrease neuroinflammation and potentially ameliorate symptoms and slow disease progression in disorders like MS and AD.
• Restore Immune Balance: By inhibiting TYK2, the excessive immune responses might be dampened, helping to restore a balance. This might reduce neuronal damage caused by an overactive immune system.
• Promote Neuroprotection: Reducing neuroinflammation may also protect against neuronal loss and support mechanisms of neural repair and regeneration, which are crucial for maintaining neurological function.
• Precision Targeting with Reduced Side Effects: Given the selective role of TYK2 in the cytokine signaling pathways, targeting this kinase might offer a more precise mechanism of action with potentially fewer side effects compared to broad-spectrum immunosuppressants.
• Versatility in Treatment of Neurological Diseases: Since neuro-inflammation is a component of various neurological disorders, TYK2 inhibitors could have broad therapeutic applications, offering a new avenue for the treatment of diseases with limited effective therapies.

In conclusion, a TYK2 inhibitor presents a promising therapeutic strategy for managing neuro-inflammation due to its direct impact on cytokine signaling pathways that drive inflammation and immune dysregulation in the CNS. Ongoing research into the role of TYK2 in neuro-inflammation and the development of specific inhibitors will further elucidate the potential of this approach in clinical applications.

The science underpinning the role of TYK2 in inflammation and the potential therapeutic benefits of TYK2 inhibitors in neuro-inflammation is a growing field, supported by both preclinical and, to a lesser degree, early clinical evidence. However, the field is not without uncertainty or debate, highlighting the need for further research. Here are key points considering the state of the science, areas of uncertainty, and the overall level of evidence:

Established Science:

• TYK2 Role in Immune Signaling: The role of TYK2 in cytokine signaling is well established. Its involvement in mediating the effects of interferons and interleukins has been documented in various studies, making it a validated target in autoimmune and inflammatory diseases.
• Neuro-inflammation Mechanisms: The understanding that neuro-inflammation plays a critical role in the pathology of neurological diseases like MS, AD, and PD is also well accepted. The involvement of cytokines and immune cells in these processes has been extensively studied.

Areas of Uncertainty or Debate:

• TYK2 Specificity in Neurological Diseases: While TYK2's involvement in inflammatory pathways is clear, the specificity of its role within the context of neuro-inflammation is less understood. The CNS has a unique immune environment, and how TYK2 inhibitors interact within this milieu is an active area of research.
• Clinical Efficacy and Safety: The translation of preclinical findings to clinical efficacy in humans remains a significant hurdle. Early-stage clinical trials are underway for various TYK2 inhibitors, but comprehensive data on long-term safety, efficacy, and optimal dosing in neuro-inflammatory conditions are still needed.
• Complexity of Neurological Diseases: Neurological diseases are multifaceted, often involving multiple pathways and cell types. The degree to which inhibition of TYK2 alone can address the complex pathology of these conditions is not fully understood.

Overall Level of Evidence:

• Preclinical Evidence: There is substantial preclinical evidence supporting the role of TYK2 in inflammation and the potential benefits of its inhibition in models of disease. This evidence forms a strong scientific rationale for further investigation.
• Clinical Evidence: The evidence from clinical trials, particularly in neuro-inflammatory conditions, is more limited and preliminary. Initial results from studies targeting TYK2 in autoimmune diseases outside the CNS are promising but need to be extended to neuro-inflammation.
• Translation to Neurological Conditions: The direct translation of these findings to the treatment of neurological diseases presents an additional layer of complexity. The CNS environment, barriers to drug delivery (e.g., blood-brain barrier), and specificity of effect all present challenges that are currently the focus of ongoing research.