7. Mersana Therapeutics

Mersana Therapeutics' lead antibody-drug conjugate program, upifitamab rilsodotin, or UpRi, has shown some efficacy in ovarian cancer. (Getty Images)

Number of ADCs in pipeline: 4
Estimated sales: N/A
Expected milestones: Updated phase 1 data for lead candidate, upifitamab rilsodotin (UpRi), in ovarian cancer is expected later this year. Top-line phase 1 data for UpRi and XMT-1592 in non-small cell lung cancer are anticipated in the fourth quarter of 2021 and around the end of the year, respectively, and a phase 1 for XMT-1660 and XMT-2056 is expected to start in early 2022.

Mersana Therapeutics has two antibody-drug conjugates locking in on ovarian cancer and non-small cell lung cancer. Its lead candidate, upifitamab rilsodotin, or UpRi, and second-in-line project, XMT-1592, are both targeting NaPi2b, which is widely expressed in those two cancers.

Both ADCs utilize the proprietary DolaLock payload, which contains an auristatin cytotoxic drug. But their ADC platforms are slightly different.

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For UpRi, Mersana uses a platform called Dolaflexin. Unlike most other ADCs in which the toxic drug is directly conjugated to an antibody, Dolafelxin attaches the drug molecules to a proprietary biodegradable polymer scaffold, which is then conjugated to the antibody. This increases the number of drug molecules each ADC can carry, which Mersana hopes will lead to better efficacy.

By comparison, XMT-1592 is designed with the Dolasynthen platform, which uses a synthetic scaffold for more precise control of the number of drugs that are tagged onto the antibody, offering more consistent delivery of drugs to cancer cells.

UpRi has shown some effect in ovarian cancer. In a January update of the dose expansion stage of a phase 1 trial, UpRi shrunk tumors in 28% of previously treated patients, and its response rate reached 32% in NaPi2b-high patients. But investors sent the company’s stock price south after the response rates decreased from a previous readout in September 2020. Furthermore, the duration of response was unimpressive at a median of about five months for 10 NaPi2b-high patients. Finally, there was one treatment-related patient death from pneumonitis.

But analysts came to Mersana’s defense. In a note following the data update, BTIG analyst Tom Shrader reminded investors that response durations in heavily pretreated patients are generally short. Both Shrader and SVB Leerink analyst Janathan Chang viewed UpRi’s performance in NaPi2b-high patients as better than the 12% overall response rate historically seen with current standard-of-care chemotherapy.

Mersana has launched Uplift, a single-arm registration trial in platinum-resistant ovarian cancer. For this trial, the company changed how it defines NaPi2b high expression to a TPS score of at least 75. Using the TPS marker, UpRi’s ORR in NaPi2b-high patients in the phase 1 trial improved to 39%.

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Roche once had a UpRi candidate called lifastuzumab vedotin (LIFA), which carried a MMAE payload. In a recent note, Evercore ISI pointed out that the now discontinued LIFA showed higher responses when combined with carboplatin, but the neutropenia side effect posed a problem. UpRi showed no grade 3 or higher neutropenia in its own trial, “leaving the opportunity open to combine the drug with platinum-based chemotherapies in earlier line patients,” BTIG’s Shrader wrote in the January note.

For that strategy, Mersana recently launched Upgrade, a phase 1 combination umbrella study. It is initially testing the ADC alongside carboplatin, but other therapies like Avastin, PARP inhibitors or immuno-oncology agents are also on the table, Shrader noted in a report in May.

Later this year, Mersana is expected to provide updated data from UpRi’s phase 1 from the ovarian cancer cohort and plans to report top-line dose expansion results for the NSCLC group.

For XMT-1592, investigators were exploring the right dose in a phase 1 trial as of August. An early NSCLC data readout around the end of the year is possible, Mersana recently said.

Once those data are out, the company will determine which of the two ADCs will move into later-stage NSCLC trials. As Evercore ISI noted in its recent report, XMT-1592 has shown better tumor shrinkage ability than UpRi in animal studies.

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During a July conversation with SVB Leerink, Mersana execs acknowledged that NSCLC represents a highly competitive space compared with ovarian cancer and requires setting the response rate bar in a way that’s “future proof,” Chang wrote in a note.

In addition to those two ADCs, Mersana expects to move two preclinical assets into clinical trials in 2022. XMT-1660 is a potential first-in-class ADC against B7-H4. There’s also XMT-2056, developed with Mersana’s Immunosynthen platform. The company plans to disclose XMT-2056’s target later this year.

7. Mersana Therapeutics