Context Therapeutics — R&D webinar highlights CTIM-76’s potential

CLDN6 is a member of the claudin family of tight junction proteins (27 members exist in humans), which play an important role in cell polarity, permeability and adhesion, and participate in the regulation of cell proliferation and differentiation. A unique aspect of CLDN6 is that it has been found to be upregulated in several malignant tumors such as endometrial, ovarian, lung and gastric cancers, but is rarely expressed in adult healthy tissue. However, expression appears to be heterogeneous across cancer subtypes and seems directly related to tumor grade (the higher the grade, the higher the CLDN6 enrichment). According to data presented by Context in its R&D webinar, CLDN6 expression can range from 2% to 95% across indications, with testicular and ovarian cancer reported to have the highest expression (95% and 54–55%, respectively). Importantly, studies have indicated that a higher level of CLDN6 expression leads to poorer prognosis in terms of overall survival and progression-free survival (Exhibit 1). A 2020 study assessing CLDN6 expression in endometrial cancer tissue resected from patients concluded that the five-year survival rate in the high CLDN6 expression group was 30%, compared to 90% for the low expression group. This makes CLDN6 an attractive therapeutic target for these indications, in our view.

While several pharmaceutical companies are developing CLDN6-targeting antibodies, most candidates are in early-stage clinical or preclinical development (Exhibit 2). Historically, development has been hampered by challenges in accurate selectivity due to CLDN6’s close resemblance to other claudins (such as CLDN9, CLDN4 and CLDN6), which are present in healthy cells. In particular, CLDN9, which differs from CLDN6 by only three amino acids in the extracellular domain, is crucial to maintaining normal hearing and a healthy gut, highlighting the importance of accurate targeting.

As previously noted, Context’s partner Integral Molecular had tested a library of 54 CLDN6xCD3 bispecific formats and combinations with high CLDN6 specificity, of which four lead candidates were shortlisted for further testing, comprising two one-by-one formats, including CTIM-76 (one binding site each with CLDN6 and CD3), one two-by-two format (two binding sites each with CLDN6 and CD3) and one BiTE platform developed by Amgen (one binding site each with CLDN6 and CD3 but without the typical IgG scaffold), see Exhibit 3.

CTIM-76 was selected as the final candidate for future development, based on higher potency and lower levels of cytokine release versus other tested bispecific constructs. CTIM-76 demonstrated higher or similar activity versus the other bispecific formats in both high CLDN6 expressing (K562 CLDN6) and medium CLDN6 expressing (OV90) cell lines (Exhibit 4).

Importantly, data presented by Context demonstrated that this level of activity can be achieved at extremely low concentrations (picomolar) based on CNDL6 expression levels (tEC50 value of 0.0004nM for the high CNDL6 expressing line). This meant that in a cytokine release profiling test (Exhibit 5), CTIM-76 was able to induce cytotoxic T-cell activation without drastically increasing cytokine production compared to a BiTE molecule with identical binder arms, indicating a potentially broad therapeutic window. Cytokine release syndrome (CRS) is an adverse side-effect experienced in some patients in response to immunotherapy. Therefore, in our view, the lower selected therapeutic dose may potentially reduce the risk of CRS, although this will need to be confirmed in clinical trials.

As highlighted previously, development of CLDN6-targeting therapies has been hampered due to CLDN6’s strong resemblance to other claudins, resulting in off-target effects and toxicities (Astellas’ ASAP1650/Ganymed’s IMAB027 is a case in point where Phase II development was terminated due to the drug’s high affinity for CLDN9). In contrast, CTIM-76 has shown meaningfully high specificity and cytotoxicity for CLDN6 at various doses in cell lines expressing different claudins (Exhibit 6). Management had earlier indicated that CTIM-76 is more than 1,000x more selective for CLDN6 than CLDN9. To our knowledge, this is higher than other drugs under development and should provide Context with a key competitive advantage if the results are reproduced in larger studies.

In September 2022, BioNTech, which we believe is the current leader in this category, presented encouraging follow-up data on its CLDN6 CAR-T asset BNT211 from its ongoing Phase I/II study, in patients with relapsed or refractory advanced solid tumors. Data were presented for 21 evaluable patients (testicular, ovarian and endometrial, as well as sarcoma, fallopian tube and gastric cancer), who were treated across two dose levels (dose 1: 1x107 CAR-T cells, n=7; and dose 2: 1x108 CAR-T cells, n=15) alone or combined with CARVac (a vaccine designed to enhance T-cell activity and persistence through periodic infusions following CAR-T treatment). The overall response rate (ORR) for the cohort was 33%, with a disease control rate (DCR) of 67%, with one complete response, six partial responses and seven patients with stable disease. The results in patients with testicular cancer treated with dose 2 following lymphodepletion (n=7) were even more pronounced: an ORR of 57% and DCR of 85%, with one complete response, three partial responses and two with stable disease. More importantly, adverse events, including CRS and dose-limiting toxicities were manageable, a key issue in the development of this class of therapeutics in the past. We believe that the promising efficacy data, particularly in patients with testicular cancer (and an acceptable safety profile) presented by BioNTech have increased market interest in this novel therapeutic target, which bodes well for new and potentially improved assets under development. Context asserts that CTIM-76’s easier manufacturability and administration versus CAR-Ts also offers a competitive advantage.

A key indicator of rising market interest in CLDN6 was the recent $158m fund-raising by TORL BioTherapeutics to advance its development pipeline, including the Phase I asset TORL-1-23, an ADC targeting CLDN6. Interestingly, Bristol Myers Squibb is one of the investors in the Series B financing, potentially indicating big pharma interest in the target.

Context has initiated IND-enabling studies with CTIM-76 and has indicated that it is on track for an IND application in Q124. Lonza is undertaking manufacturing of the drug substance and drug product following an agreement signed in November 2022. While target indications for clinical studies have not been officially communicated, we expect the initial areas of interest will be ovarian cancer, testicular cancer and non-small cell lung cancer, all indications with high CLDN6 prevalence (Exhibit 7). We note that there are more clinically advanced CLDN6xCD3 bispecific antibodies in development, notably BioNTech’s BNT142 and Amgen’s AMG 794, which are currently undergoing Phase I studies. However, Context argues that the structure and design of its candidate allows superior activity and binding to CLDN6 (more than 1,000x versus c 7x and c 630x for BNT142 and AMG 794, respectively) which, if proved in clinical studies, could offer market differentiation.

The discontinuation of the ONA-XR program, as per management guidance should allow Context to extend its cash runway late FY24 (FY22 cash burn of $14.2m; y/e cash balance of $35.5m), which we expect to be sufficient to initiate the Phase I clinical trial for CTIM-76. However, additional funding would be required to progress the asset further through the clinic and management has communicated that it will explore all options, including external fund raising, partnership(s) or asset sale.

Our forecast and valuation for Context are currently on hold, following the company’s recent decision to cease development of its ONA-XR program and focus exclusively on CTIM-76. We will present our revised forecasts and valuation in due course.