First-in-Class FRα-Targeting ADC Elahere Receives Full FDA Approval; Competitive Landscape of Domestic Pipeline Leaders Analyzed

Mar 31, 2024 09:12 CST Updated 09:12

AbbVie

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March 22, 2024AbbVie today announced that the U.S. FDA has fully approvedIts "first-in-class" antibody-drug conjugate (ADC) Elahere (mirvetuximab soravtansine) is used to treat patients with folate receptor alpha (FRα)-positive, platinum-resistant epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer who have previously received up to three systemic treatment regimens. ELAHERE is the first and only antibody-drug conjugate (ADC) approved in the United States for the treatment of this difficult-to-treat malignancy.

ELAHERE received FDA approval for the first time in November 2022.Accelerated Approval, This time, the data from the confirmatory Phase III MIRASOL trial has been converted into full approval. According to the data published so far, the median OS for patients in the Elahere group was 16.46 months, compared to 12.75 months in the IC chemotherapy group,The hazard ratio (HR) was 0.67, p=0.0046. This means that, compared with the IC chemotherapy group, the risk of death in the Elahere group was reduced by 33%.Compared with IC chemotherapy, Elahere demonstrated a statistically and clinically significant improvement in PFS, with a hazard ratio of 0.65 (p<0.0001), which means that the risk of tumor progression or death was reduced by 35% in the Elahere group compared to the IC chemotherapy group.The median PFS in the Elahere group was 5.62 months, compared to 3.98 months in the IC chemotherapy group. The ORR in the Elahere group was 42.3%, including 12 complete responses (CR), while the ORR in the IC chemotherapy group was 15.9%, with no patients achieving CR. Compared with the IC chemotherapy control group, ELAHERE overall showed fewer grade 3 or higher adverse events and a lower proportion of patients discontinuing treatment due to adverse events.

Elahere, as the first FRa ADC, has a toxin of DM4 and a cleavable linker. In terms of expression,FRα is highly expressed in ovarian cancer, followed by lung cancer. In preclinical animal models, ADCs with DXD or exatecan as payloads demonstrated promising efficacy, regardless of high, medium, or low expression levels.

In my ADC development journey, DXD has truly achieved effectiveness—whether observed clinically for targets with medium to low expression or traced back to preclinical efficacy—almost without a doubt, showing promising therapeutic outcomes. DXD has ushered in an era, and currently, the two leading companies in China developing this target are Bio-Thera and Provention, using...exatEcan. Compared with DXD, exatecan has one less hydroxyacetyl group, which results in completely different activities and linkers suitable for their cleavage. It is well known that exatecan is more toxic than DXD. The toxicity of exatecan in its free drug form is 5-20 times higher than that of DXD, with some differences in cytotoxicity depending on the cell type. The key point relates to hydrophilicity.linkerTheTransformation, DXD andexatecanNot compatible with the same set of linkers, useexatecanNeed to explore new linkers. It should be noted that the cytotoxicity of free drug is different from the cytotoxicity of ADC formed by conjugating toxin to an antibody. Different ADC designs, even with the same drug, also have certain distinctions.

Both Pufang and Bio-Thera modified the linker to be more hydrophilic; Pufang added a sugar chain, while Bio-Thera added PEG.

Profound Bio announced the early clinical data of its FRα ADC, excerpted as follows:

Rina-S is an investigational ADC drug that targets folate receptor α (FRα) and uses the topoisomerase 1 inhibitor exatecan as its payload, linked via a novel hydrophilic linker developed by Provention Bio. It is currently in Phase 1/2 clinical development for various solid tumors. The early-stage clinical study of Rina-S enrolled 36 patients, with a dose escalation range of 60 mg/m² to 180 mg/m² administered once every 21 days.

Research Background:

• The patients included in the study encompassed 17 cases of ovarian cancer, 9 cases of endometrial cancer, 3 cases of breast cancer, 5 cases of non-small cell lung cancer, and 2 cases of mesothelioma.

• These patients had previously received multiple lines of treatment, with a median of 4.5 prior treatments, including a median of 6 for ovarian cancer patients and a median of 4 for endometrial cancer patients.

• Responses were observed across a broad dose-escalation range from 60 to 140 mg/m2, and for most patients, the response deepened with longer treatment duration.

• A patient with ovarian cancer who had previously been treated with mirvetuximab soravtansine (Elahere™) achieved complete response (CR) after two doses of Rina-S.

Dose optimization studies are ongoing.

Bio-Thera Solutions also updated the early clinical data of its FRα ADC (BAT8006), excerpted as follows:

BAT8006 is a recombinant humanized anti-FRα antibody developed independently by Bio-Thera Solutions, linked to a cytotoxic small molecule topoisomerase I inhibitor through a cleavable linker. As of July 6, 2023, 29 patients with advanced solid tumors have been enrolled into dose escalation cohorts at 1.2mg/kg, 1.8mg/kg, 2.1mg/kg, and 2.4mg/kg. There was no requirement for FRα expression levels in the enrolled subjects, covering multiple tumor types including ovarian cancer, breast cancer, non-small cell lung cancer, and cervical cancer, with ovarian cancer patients accounting for approximately 60%.

BAT8006 is currently undergoing dose optimization and dose expansion studies across multiple tumor types, with more clinical data to be further presented at upcoming international academic conferences.

It can be seen that the products developed under the ADC platforms of both are still at a lower level than DXD in terms of dose exploration, which generally aligns with the potency of the toxins observed in preclinical studies. Exatecan is more potent, so the dosage is inevitably reduced. Meanwhile, the Fc region of the antibody from Provention has been specially designed to silence its interaction with Fc receptors.

Interstitial pneumonia associated with DS-8201 has been indicated in literature to be related to Fc. However, we have not observed this side effect in ADCs using exatecan as the payload, so it is impossible to discuss whether Fc silencing can reduce the occurrence of interstitial pneumonia. More clinical data is needed for further clarification.

The linker-payload designs of Providence and Bio-Thera are extremely similar. However, when standardized to the same dosing unit, Bio-Thera's dose is 2.4 mg/kg, while Providence’s (potential dose) is 3.4 mg/kg, showing a certain gap between them. Due to differences in both the linker and Fc design, it is impossible to conclusively determine whether the observed effects are due to the linker or the Fc region. Hematological toxicity occurs regardless of whether the Fc function is silenced or not, suggesting that hematological toxicity is mainly caused by free toxins released after cleavage. It can also be confirmed that silencing the Fc does not reduce its efficacy compared to Bio-Thera’s non-specialized Fc design. Mechanistically, silencing the Fc can indeed reduce non-targeted distribution of ADCs, avoid affecting PK, and enhance drug infiltration into tumors. Another point is whether Providence’s design is more hydrophilic compared to Bio-Thera’s.

The design of ADCs by Pufang and Bio-Thera Solutions provides a certain contrast, which is highly referential for the industry. However, whether exatecan has more advantages over DXD toxins still requires further data validation and comparison. The FRα ADCs from Bio-Thera Solutions and Pufang have both demonstrated promising efficacy data.

But whether a good linear PK can be achieved within the dose range of 2-3 still needs to be analyzed with subsequent data release. The lower dose of Bio-Thera may be more difficult to achieve a favorable PK to some extent. The PK limitations of the drug may, to a certain extent, affect the maximum efficacy of the drug. Innovent also...exatecanFor the payload, adopting the DAR4 design, whether it can be more advantageous, we also look forward to the revelation of the answer in the future.

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