Triveni Bio investment analysis

October 31, 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

Triveni Bio is a private biotechnology company developing genetics-informed precision medicines, specifically functional antibodies, for the treatment of immunological and inflammatory (I&I) disorders.

The company’s primary antibody program, TRIV-509, targets kallikreins 5 and 7 (KLK5/7) for treating conditions such as atopic dermatitis, asthma, and other I&I disorders.

TRIV-509 functions through a distinctive mechanism that directly addresses barrier dysfunction, inflammation, and itch in atopic dermatitis. Atopic dermatitis is a large market with Dupixent, a novel antibody for atopic dermatitis, generating nearly $9B in 2022 revenue (in atopic dermatitis and other conditions). Many patients experience inadequate responses to Th2-targeted therapies like Dupixent, creating a compelling opportunity for a treatment like TRIV-509.

On October 26, 2023, Triveni Bio announced a $92 million series A financing round co-led by Atlas Venture and Cormorant Asset Management and included participation from notable investors such as OrbiMed, Viking Global Investors' private equity branch, Invus, Polaris Partners, and Alexandria Venture Investments, among others. Triveni Bio was formed as a result of a merger between Amagma Therapeutics, funded by Polaris, and Modify Therapeutics, seeded by Atlas.

Triveni Bio Pipeline Overview

Product name	Modality	Target	Indication	Discovery	Preclinical	Phase 1	Phase 2	Phase 3	FDA submission	Commercial
TRIV-509	Monoclonal antibody	KLK5/7 antibody	Atopic dermatitis

Highlights and risks

Valuation

As the company is preclinical and limited data is available on its programs, we did not conduct a valuation analysis.

Scientific thesis

Triveni Bio employs a "genetics-informed precision medicine approach" to design functional antibodies for treating Immunological and Inflammatory (I&I) disorders. At its core, the company's strategy focuses on:

• Genetically Validated Targets: They emphasize prosecuting targets that are genetically validated, often linked to monogenic diseases. Monogenic diseases are caused by mutations in single genes and often provide a clearer understanding of the direct impact of a particular gene on disease pathology.
• Precision Populations across Multiple Indications: The focus is on designing treatments tailored for specific patient subpopulations, ensuring that the therapies are most effective for the people who are most likely to benefit from them.
• Leveraging Data: Triveni Bio uses both public and private datasets to identify these genetically validated disease nodes, which helps them predict and stratify patient subpopulations and gain insights into disease mechanisms.

The approach adopted by Triveni Bio echoes broader trends in the biotech industry. As our understanding of genetics has deepened, there's been a shift towards more targeted, personalized therapies. This is not unique to Triveni; several other companies are also pursuing genetics-informed approaches, especially in oncology where targeted therapies based on tumor genetics have made significant strides.

Using genetic insights from monogenic diseases to inform drug development for more complex, polygenic diseases has precedent. For example, the discovery of PCSK9 mutations in individuals with familial hypercholesterolemia led to the development of PCSK9 inhibitors, which are now widely used to treat high cholesterol in the broader population.

There are also risks to the precision medicine approach:

• Translatability of Monogenic Insights: While monogenic diseases provide clear genetic insights, complex diseases (like many I&I disorders) might have multiple genetic and environmental factors at play. A target relevant in a monogenic context may not have the same importance or therapeutic relevance in a complex disease setting.
• Patient Stratification: While stratifying patients ensures that the right patient gets the right drug, it also narrows down the market size. If the stratification is too narrow, it could limit the commercial viability of a drug.
• Data Reliability: Leveraging datasets for insights requires that the data be accurate, comprehensive, and representative. Biased or incomplete data can lead to misguided conclusions.
• Genetic Heterogeneity: Even within genetically defined patient subpopulations, there can be significant genetic variability, which might impact drug efficacy.
• Regulatory & Payer Challenges: Regulatory agencies and payers are still adapting to the precision medicine paradigm. While there's enthusiasm for targeted therapies, companies like Triveni might face challenges in clinical trial design, regulatory approval, and reimbursement.

In addition to their lead program in atopic dermatitis, the company expects to have two additional development candidate nominations expected in 2024.

TRIV-509 in atopic dermatitis

Atopic dermatitis (AD), commonly known as eczema, is a chronic inflammatory skin condition characterized by intense itching, redness, and scaling. The pathogenesis of AD is multifactorial, involving a complex interplay of genetic, immunological, and environmental factors. Among these, the role of the skin barrier and the immune system are considered particularly important.

Kallikreins are a subgroup of serine proteases, which are enzymes that break down proteins. In the context of the skin, kallikreins, especially KLK5 and KLK7, have been identified as significant players in skin homeostasis and diseases.

One of the primary features of AD is an impaired skin barrier, which can lead to increased trans-epidermal water loss, facilitating the penetration of allergens and irritants. KLK5 and KLK7 are known to degrade desmoglein 1, a key protein component of desmosomes that play a crucial role in maintaining skin barrier integrity. An overactivity of these kallikreins can therefore compromise the skin barrier, making it more permeable to environmental allergens and pathogens.

KLK5 has been shown to activate protease-activated receptor-2 (PAR-2) on keratinocytes. Activation of PAR-2 can promote the release of pro-inflammatory cytokines, contributing to the inflammation observed in AD.

Itching is a hallmark symptom of AD and has a significant impact on the quality of life of patients. KLKs, through their activity and subsequent cascades, can contribute to the sensation of itch. This happens via mechanisms such as the activation of PAR-2, which can amplify itch sensations.

Given the roles of KLK5 and KLK7 in skin barrier dysfunction, inflammation, and itch, it's logical to hypothesize that inhibiting their activity could offer therapeutic benefits for AD patients:

• Restoring Skin Barrier: By inhibiting KLK5 and KLK7, it might be possible to prevent the degradation of critical skin barrier proteins, thereby strengthening the barrier and reducing the infiltration of allergens and irritants.
• Reducing Inflammation: Neutralizing the activities of KLK5 and KLK7 could mitigate the PAR-2 mediated release of pro-inflammatory cytokines, thereby alleviating skin inflammation.
• Alleviating Itch: Given the role of KLKs in promoting itch, an effective antibody against KLK5 and KLK7 might alleviate this distressing symptom, improving the overall quality of life for AD patients.

Market opportunity

Atopic dermatitis (AD) is a chronic, inflammatory skin condition characterized by itching and recurrent eczematous lesions. It is one of the most common inflammatory skin disorders, affecting both children and adults.

Globally, AD affects approximately 15-20% of children and 1-3% of adults. The prevalence varies by region but has generally been on the rise in industrialized countries over the past decades.

The disease significantly impacts quality of life, leading to sleep disturbances, pain, and social stigmatization. The economic burden includes both direct costs (medical care, medications) and indirect costs (lost productivity).

Current standard of care and unmet need

Here is a summary of the current standard of care:

• Topical Therapies: Mild to moderate AD is primarily managed with emollients and topical corticosteroids (TCS). While effective, prolonged TCS use can lead to side effects like skin thinning.
• Topical Calcineurin Inhibitors: Tacrolimus and pimecrolimus are alternatives to TCS but come with concerns about potential cancer risks.
• Systemic Therapies: Severe AD might require systemic treatments, such as cyclosporine, methotrexate, or azathioprine. However, these can have significant side effects.
• Dupilumab (Dupixent): Developed by Sanofi and Regeneron, Dupixent is an IL-4 and IL-13 inhibitor and was the first biologic approved for moderate-to-severe AD. It has shown significant efficacy in reducing AD symptoms and improving quality of life. Dupixent generated almost $9B in global sales in 2022.
• JAK inhibitors: Several Janus kinase (JAK) inhibitors are under investigation or have been approved for AD. These drugs have shown promise in clinical trials, offering oral administration, which can be preferable to injections for some patients.

While the above treatments offer relief, not all patients respond, and some only achieve partial symptom control. There's a need for more effective therapies. Long-term use of many current treatments can lead to side effects. Drugs with better safety profiles, especially for chronic use, are needed. Given the variability in patient response, having a range of therapeutic options to suit individual patient needs is crucial.

Considering the prevalence of AD, the limitations of current treatments, and the unmet needs, the market potential for innovative AD treatments is significant. The success of Dupixent and the interest in JAK inhibitors highlight the lucrative nature of this market. Drugs that can offer improved efficacy, better safety profiles, or cater to patients unresponsive to current therapies could capture a substantial market share.

Triveni seems to be focused on atopic dermatitis patients who generally have an inadequate response to Th2-targeted therapies. The Th2 (T-helper 2) pathway is central to the pathogenesis of atopic dermatitis. Th2 cells produce cytokines like IL-4, IL-5, and IL-13, which play crucial roles in promoting and maintaining the inflammation associated with AD.

Given the role of the Th2 pathway in AD, it's not surprising that therapies targeting this pathway have been developed and marketed. As mentioned previously, Dupilumab (Dupixent) is a classic example. It inhibits the signaling of IL-4 and IL-13, both of which are Th2 cytokines.

While many patients benefit from Th2-targeted therapies, not all achieve full symptom control, and some may not respond at all. A significant portion of AD patients might have an inadequate response to such treatments, which underscores an unmet need. This could be due to various reasons:

• Complex Pathogenesis: AD is a heterogeneous disease with multiple underlying pathways, not just Th2. There's also the Th1, Th17, and Th22 pathways, among others. Therefore, targeting only Th2 might not be sufficient for all patients.
• Variability in Patient Response: Like all treatments, individual variability in response is expected due to genetic factors, the severity of the disease, and other unknown variables.
• Possible Tachyphylaxis: Some patients might initially respond to a treatment but develop resistance or reduced efficacy over time.