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Roche Buying Seragon to Strengthen its Breast Cancer Pipeline, Improve Upon Standard Hormone Therapy

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NEW YORK (GenomeWeb) – Roche this week announced plans to acquire Seragon Pharmaceuticals, aiming to bolster its own breast cancer pipeline and improve the standard of care for hormone receptor-positive breast cancer.

As part of the deal, Roche subsidiary Genentech will gain access to Seragon's entire portfolio of next-generation, oral selective estrogen receptor degraders (SERDs) for the treatment of HR-positive breast cancer. Seragon's lead product, ARN-810, is undergoing Phase I trials for HR-positive breast cancer patients who haven't responded well to standard hormonal agents. Genentech is hoping to file an investigational new drug application for another SERD, SRN-927, with the US Food and Drug Administration by year end.

Under the terms of the deal, Genentech will acquire Seragon for $725 million in cash. The owners of privately held Seragon can also receive up to $1 billion if certain milestones are reached. The acquisition is awaiting antitrust clearance and is slated to close in the third quarter of this year.

San Diego-based Seragon was founded in 2013 specifically with a focus on developing SERDs for HR-positive cancers. Once the transaction with Roche closes, Seragon’s pipeline of products will become a part of Genentech's research and early development portfolio.

SERDs offer a novel approach to tackling HR-positive breast cancer. If SERDs are successfully developed, they will be indicated for patients with cancer driven by the estrogen receptor. As such, the ER status of patients' tumors will need to be established with standard lab tests ahead of receiving a SERD.

Although there aren't plans to develop a companion diagnostic kit and get it FDA approved alongside the investigational SERDs, the development of these new agents is very much in line with the principles of personalized medicine, James Sabry, senior VP and global head of Genentech partnering, told PGx Reporter.

"You can argue that estrogen receptor testing in many ways was the first companion diagnostic that the industry used in cancer," he said. "We'll look to see whether there are [biomarkers] other than estrogen receptor-positivity that are important to [patients deriving benefit from] these SERDs."

Sabry noted that the incorporation of Seragon's SERDs into Genentech's pipeline will complement the firm's existing strengths as the leading developer of HER2-positive breast cancer therapies, with Herceptin (trastuzumab), Perjeta (pertuzumab), and Kadcyla (trastuzumab emtansine). The company is planning to study in the future whether subsets of HER2-postive breast cancer patients who are also ER-positive benefit from treatment with SERDs.

It is estimated that approximately 40,000 women in the US will die of breast cancer this year, many of whom have disease that is driven by estrogen receptors. It is estimated that 60 percent of breast cancer patients overexpress ER. Life sciences experts believe that ER overexpression leads to cancer in many women because when the estrogen hormone binds to the estrogen receptor it leads to increases in mammary cells, as well as in other chemicals, that can give rise to oncogenic mutations.

The standard treatments for ER-positive breast cancers are anti-hormone agents, such as tamoxifen or aromatase inhibitors. These drugs hinder the body's ability to produce estrogen or the ability of the receptor to bind to the hormone. However, even after treatment with these agents, many patients experience cancer recurrence.

Recently updated treatment guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network recommend that HR-positive breast cancer patients receive a decade of endocrine therapy with tamoxifen or aromatase inhibitors, or the combination of the two. Previously, guidelines recommended five years of adjuvant hormone therapy.

These recommendations are supported by data from two large randomized studies showing that breast cancer patients who took tamoxifen for two years had lower late recurrences than those who took the drug for five years. Still, many women experience adverse events with tamoxifen that make them unable to take it for extended periods of time, and others experience recurrence.

Although HR-positive breast cancer patients respond to standard hormone therapy, "the tumors have a nasty way of becoming resistant," Sabry said, noting that 20 percent of patients treated with traditional anti-hormone agents develop resistance. "The resistance mechanism is actually a mutation in the estrogen receptor-alpha itself," he explained. "The receptor mutates and will signal independently of the estrogen."

So, for resistant patients, estrogen-blocking drugs such as tamoxifen stop working because their cancer cells have figured out a way to proliferate without the help of the estrogen hormone but are still feeding off of receptor signaling. For patients who have become resistant to standard hormonal therapies, such as tamoxifen, aromatase inhibitors, or fulvestrant, "there is very little in the way of … options," Sabry reflected.

The idea behind next-generation SERDs is that they block the interaction of the hormone estradiol at ER so that the receptor becomes degraded, which in turn stops receptor signaling. As Genentech describes it, SERDs change the shape of ER "in a manner that targets it for elimination by the cell."

Genentech is betting that a drug that can break down the receptor itself might prove to be an effective attack against cancer progression. "If we were to degrade the receptor and degrade it fully, which we believe these [SERDs] may do in man, it would be an effective treatment to breast cancer in patients resistant to [standard treatments]," Sabry said.

He further emphasized that while first-generation drugs, such as tamoxifen, also inhibit the interaction between ER and estradiol, a key sex hormone in women, the novel aspect of SERDs is "the way they effectively degrade the receptor itself, not simply block the binding of estradiol to the estrogen receptor."

To date, in in vivo studies, Seragon has been able to show that SERDs appear to have activity against tumor cells that are sensitive and resistant to tamoxifen. Although Genentech is exploring the development of ARN-810 initially in advanced breast cancer patients who don’t respond to standard hormonal agents, Seragon believes that early data suggest its agents have therapeutic potential in early-stage breast cancer, as well as in other ER-driven diseases, such as endometrial and ovarian cancers.

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