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

Mar 23, 2024 17:16 CST Updated 17:16

AbbVie

Innovative Drug Developer

▎Traceability

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 to full approval. According to the currently published data, 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 discontinuations 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 demonstrated efficacy—whether observed clinically for targets with medium to low expression or traced back to preclinical effectiveness—almost without question, showing promising results. DXD has ushered in a new era. Currently, the two leading companies in China developing this target are Bio-Thera and Provention Bio.exatEcan. Compared with DXD, exatecan has one less hydroxyacetyl group, which results in completely different activities and linkers suitable for their cleavage. As known, exatecan is more toxic than DXD. The toxicity of the free drug form is 5-20 times higher than that of DXD, varying across different cells. The key point is 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 antibody. Different ADC designs, even with the same drug, also have certain differences.

Pufang and Bio-Thera both modified the linker to be more hydrophilic, with Pufang adding a sugar chain and Bio-Thera adding 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 independently developed by Protheon Biotech. 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 continued treatment.

• 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 by Bio-Thera Solutions, linked to a cytotoxic small molecule topoisomerase I inhibitor via 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 in multiple tumor types, and more clinical data will 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 corresponds to 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 Bio 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, in our ADCs using exatecan as the payload, no such side effect of interstitial pneumonia was observed, so there is no basis to discuss whether Fc silencing could reduce this effect. More clinical data is needed for further clarification.

The linker-payload designs of Pufang and Bio-Thera are extremely similar. However, when standardized to the same dosing unit, Bio-Thera's dose is 2.4 mg/kg, while Pufang's (potential dose) is 3.4 mg/kg, indicating a certain gap. Due to differences in both the linker and Fc design, it is impossible to definitively conclude whether the observed effects are due to the linker or the Fc region. Hematological toxicity occurs regardless of whether the Fc is silenced or not, suggesting that such 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, thereby enhancing drug infiltration into tumors. Another point is whether Pufang’s design is more hydrophilic compared to Bio-Thera’s.

The design of ADCs by Pufang and Bio-Thera Solutions provides an interesting contrast, offering significant reference value to the industry. However, whether exatecan holds greater advantages over DXD toxins still requires further data for verification and comparison. Both Bio-Thera Solutions' and Pufang's FRα ADCs have demonstrated promising efficacy data so far.

But whether a good linear PK can be achieved within the dose range of 2-3 still requires further data release for analysis. The lower dose of Bio-Thera's drug is, to a certain extent, more challenging to achieve favorable PK. 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 unveiling of future answers.

The official account has established a real-name discussion WeChat group for readers. You can join the group by adding WeChat (zhuisu2210). When adding, please actively indicate your name, company, and position.