Janux Phase 1 results

March 1, 2024

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Phase 1 results

The Janux Therapeutics announced the interim clinical data from ongoing Phase 1 trials of two novel immunotherapies, JANX007 and JANX008, for the treatment of solid tumors. Here's a detailed summary:

• JANX007 (PSMA x CD3 T cell engager) for mCRPC (metastatic castration-resistant prostate cancer)
  • Trial Phase: Phase 1a, dose escalation in subjects with advanced or metastatic prostate cancer.
  • Patient Population: Heavily pretreated, with a median of 4+ lines of therapy prior to enrollment.
  • Efficacy Results: At a dose ≥ 0.1 mg, 78% (14/18) of subjects achieved PSA30 declines, and 56% (10/18) achieved PSA50 declines. At a higher dose ≥ 0.2 mg, 100% (6/6) achieved PSA30 declines, and 83% (5/6) achieved PSA50 declines. Notably, higher doses led to deeper and more durable PSA responses, including a PSA90 decline in one subject.
  • Safety Results: Low-grade Cytokine Release Syndrome (CRS) (Grade 1 or 2) was observed, mainly during the first treatment cycle, with no further occurrences in subsequent cycles. Most treatment-related adverse events (TRAEs) were of low severity (Grade 1 or 2), with a low incidence of Grade 3 TRAEs and no Grade 4 or 5 events. The treatment has been administered at doses up to 3mg without reaching the maximum tolerable dose.
  • Future Directions: Continuation of dose optimization to deepen PSA responses while maintaining a favorable safety profile. An update on doses for expansion is expected in the second half of 2024.
• JANX008 (EGFR x CD3 T cell engager) for Solid Tumors
  • Trial Phase: Phase 1a, dose escalation in subjects with advanced or metastatic solid tumors expressing high levels of EGFR, including colorectal cancer (CRC), squamous cell carcinoma of the head and neck (SCCHN), non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC).
  • Patient Population: Heavily pretreated, late-stage subjects across all four tumor types.
  • Efficacy Results: Notable responses included a subject with NSCLC achieving a confirmed partial response (PR) with 100% reduction of the target lung lesion and elimination of liver metastasis, and a subject with RCC experiencing a 12% reduction in tumor size and significant clinical benefit.
  • Safety Results: Favorable safety profile with Grade 1 CRS observed in only two subjects and no higher-grade CRS. Most non-CRS TRAEs were low-grade (Grade 1 or 2), primarily occurring in the first treatment cycle. No treatment-related serious adverse events (SAEs) or dose-limiting toxicities (DLTs) were observed.
  • Future Directions: Continuation of the dose escalation and optimization part of the trial.

Clinical significance

The clinical significance of the changes in Prostate-Specific Antigen (PSA) observed with Janux's drug, JANX007, in the context of metastatic castration-resistant prostate cancer (mCRPC) can be substantial for several reasons:

• High PSA Response Rates: The observed PSA50 decline rates of 56% at doses ≥ 0.1 mg and 83% at doses ≥ 0.2 mg indicate a strong antitumor activity in a population of heavily pretreated mCRPC patients. PSA50 decline (a reduction of PSA levels by 50% or more from baseline) is a widely recognized marker of therapeutic efficacy in prostate cancer. High rates of PSA50 decline are often associated with improved outcomes, including longer progression-free survival (PFS) and potentially overall survival (OS), although the latter requires longer follow-up and validation in larger, randomized trials.
• Depth of Response: The data suggests an increasing depth of PSA response with higher doses. Specifically, 100% of subjects achieved PSA30 declines at doses ≥ 0.2 mg, and there was mention of a PSA90 decline, indicating a 90% reduction in PSA levels for at least one subject. Such deep responses may correlate with a more durable clinical benefit, offering hope for prolonged disease control in a setting where treatment options are limited.
• Safety Profile: The favorable safety profile, with no Cytokine Release Syndrome (CRS) greater than Grade 2 observed, and most treatment-related adverse events (TRAEs) being low-grade, enhances the clinical significance of these PSA declines. In the context of cancer immunotherapy, balancing efficacy with tolerability is crucial. A therapy that can induce significant tumor responses without causing severe toxicity is highly desirable, particularly in the mCRPC setting where patients have often undergone multiple lines of therapy and may have a diminished capacity to tolerate adverse effects.
• Potential Best-in-Class Profile: The combination of promising efficacy and a favorable safety profile positions JANX007 as a potential best-in-class therapy within the landscape of treatments for mCRPC. The observed PSA declines are particularly noteworthy given that the study population consists of heavily pretreated subjects with late-stage disease, indicating a significant unmet medical need.
• Proof of Concept for the Platform: The results serve as a compelling proof-of-concept for Janux's Tumor Activated T Cell Engager (TRACTr) platform, suggesting its potential applicability across multiple solid tumor indications. The ability to elicit strong PSA responses without significant toxicity could differentiate JANX007 from other therapies and support the development of additional TRACTr-based therapies for other cancers.

In summary, the changes in PSA observed with JANX007 are clinically significant, offering evidence of its potential efficacy and safety in treating heavily pretreated mCRPC. These results warrant further investigation in larger, controlled clinical trials to fully assess the drug's impact on survival outcomes and quality of life for patients with mCRPC.

Market opportunity

The market potential for new therapies in heavily pretreated metastatic castration-resistant prostate cancer (mCRPC) is substantial, driven by several key factors including the standard of care, the significant unmet need, and the size of the patient population.

• Standard of Care

  The current standard of care for mCRPC includes hormonal therapies (e.g., abiraterone, enzalutamide), chemotherapy (e.g., docetaxel, cabazitaxel), immunotherapy (e.g., sipuleucel-T), radiopharmaceuticals (e.g., radium-223), and PARP inhibitors (e.g., olaparib for patients with certain genetic mutations). While these therapies have significantly improved outcomes, mCRPC remains incurable, and most patients eventually progress after treatment, underscoring the need for novel therapeutic options.

• Unmet Need

  Despite advances, the treatment of heavily pretreated mCRPC presents several challenges, including drug resistance, toxicity management, and maintaining patient quality of life. The high relapse rate after initial therapies highlights a substantial unmet need for treatments that can offer durable responses, minimal adverse effects, and improved survival outcomes. Treatments that can target tumor cells with high specificity, such as Janux's TRACTr platform therapies (e.g., JANX007), potentially offer a new avenue to address these needs.

• Patient Population Size

  Prostate cancer is one of the most common cancers among men globally, with significant morbidity and mortality. According to the American Cancer Society, an estimated 268,490 new cases of prostate cancer were expected in the United States in 2023, with about 34,500 deaths. A subset of these patients will develop mCRPC, and within this group, a fraction becomes "heavily pretreated," having exhausted most standard treatments. While specific numbers for the heavily pretreated population are more challenging to pinpoint, this group represents a significant and growing patient population due to longer overall survival with current therapies.

• Market Potential

  Given the high incidence of prostate cancer, the transition of a notable percentage of these cases to mCRPC, and the eventual progression to heavily pretreated disease status, the market potential for new therapies like JANX007 is significant. The ability of JANX007 to induce deep PSA declines with a favorable safety profile in a heavily pretreated population not only addresses a critical unmet need but also positions it as a potentially valuable addition to the treatment landscape. If further clinical trials confirm its efficacy and safety, JANX007 could capture a meaningful share of the mCRPC treatment market, especially considering the ongoing need for therapies that can provide durable responses with manageable toxicity profiles.

In conclusion, the development of new therapies targeting heavily pretreated mCRPC holds considerable market potential, driven by a large and growing patient population, significant unmet medical needs, and the limitations of current treatment options. As research progresses and more data becomes available, novel treatments like JANX007 could play a crucial role in advancing the standard of care for this challenging condition.