This story has been updated to clarify that Olema is considering only non-dilutive options to support additional clinical programs.
NEW YORK – Olema Oncology is optimistic that a three-year biotech financing drought is finally coming to an end as it looks to raise non-dilutive funding for expanded trials of its selective estrogen receptor degrader (SERD) palazestrant and a KAT6-targeted therapy program.
San Francisco, California-based Olema had a flush year of financing in 2020, raising $54 million in Series B financing and $85 million in a Series C round, and in November that year, it brought in $240 million in gross proceeds through an initial public offering. With these funds, the firm launched palazestrant (OP-1250) into Phase I/II clinical development. Olema was one of many companies that benefitted as venture financing and IPO activity soared in the biotech sector during the COVID-19 pandemic in 2020 and 2021. But in the subsequent three years, the flood of cash has slowed to a trickle.
In September 2023, the company sold its stock through a private placement and raised around $130 million. This provided sufficient resources so Olema can continue the Phase III OPERA-01 trial until top-line data reads out in 2026. In that trial, Olema is comparing palazestrant to standard-of-care therapy in second- and third-line estrogen receptor (ER)-positive, HER2-negative advanced breast cancer.
"We were fortunate coming out of our IPO in late 2020 to be well-funded and able to weather the storm, and not have to worry about trying to engage investors or equity markets for funding during most of that period," said Olema President and CEO Sean Bohen.
However, Olema has plans beyond the OPERA-01 readout that will require additional cash. "We are well-funded to execute our current development programs, and we are considering non-dilutive alternatives to fund our potential second pivotal Phase III trial in combination with [Kisqali]," Bohen said.
Olema believes palazestrant's ability to completely block the estrogen receptor will give it an advantage over other compounds in the class, if it can get the product to market. Around 80 percent of breast cancers are ER-positive, and for those patients the standard treatment is endocrine therapy targeting activation of the estrogen receptor. Palazestrant has activity as both a SERD and an estrogen receptor antagonist, which may give it an edge against other SERDS like Menarini's Orserdu (elacestrant), AstraZeneca's camizestrant, and Roche's giredestrant.
In October 2023, interim results from a Phase I/II trial of palazestrant monotherapy showed a 40 percent clinical benefit rate in patients with HR-positive, HER2-negative breast cancer who had received at least one prior hormonal therapy regimen. When broken down by ESR1 mutation status, 52 percent of patients with ESR1 mutations benefitted, while 32 percent of patients with wild-type ESR1 saw a benefit with palazestrant. Further, the median progression-free survival was 7.2 months for a subset of patients receiving palazestrant as a second- or third-line therapy with or without prior chemotherapy. Those results gave Olema the confidence to launch OPERA-01 by the end of 2023.
In OPERA-01, Olema is paying particular attention to patients with ESR1 mutations, who are on their second- or third-line of therapy. The benefit seen in this group in the Phase III EMERALD trial led to the US Food and Drug Administration's approval of Orserdu.
"The FDA, in their analysis, set a precedent that they will look at the subgroups,ESR1 wild-type and ESR1 mutant, and since Orserdu showed no [progression-free survival] benefit over the control arm in ESR1 wild-types, the [agency] approved it only for ESR1 mutant [patients]," Bohen said. "We believe that this is the way the FDA will assess other endocrine therapies, and why our OPERA-01 trial design stratifies these subgroups."'
The company is also investigating combination strategies for palazestrant. Olema researchers evaluated the safety and pharmacokinetics of palazestrant in combination with Pfizer's CDK4/6 inhibitor Ibrance (palbociclib) in patients with ER-positive, HER2-negative advanced or metastatic breast cancer in a Phase Ib/II study. Results from that trial, reported in December 2022, established that palazestrant-Ibrance was well-tolerated and caused no dose-limiting toxicities and no drug-drug interactions.
Olema is also studying palazestrant with other drugs in Phase I/II trials, including with Novartis' CDK4/6 inhibitor Kisqali (ribociclib) in patients with advanced or metastatic HR-positive, HER2-negative breast cancer. As of a March 13 data cut-off, the clinical benefit rate was 85 percent among evaluable patients receiving palazestrant-Kisqali and both ESR1-mutant and ESR1-wild-type patients responded, according to Olema.
Olema now aims to advance the palazestrant-Kisqali combo into registrational studies and is looking at non-dilutive options to support that program. In its decision, the company closely tracked emerging data from studies combining CDK4/6 inhibitors like Kisqali and Ibrance with aromatase inhibitors. In the MONALEESA-2, MONALEESA-3, and MONALEESA-7 trials of Kisqali combined with letrozole, fulvestrant, and a tamoxifen-aromatase inhibitor compound, respectively, the Kisqali-based regimens showed an overall survival benefit compared to controls. However, in the PALOMA 2 trial of Ibrance plus letrozole and the PALOMA 3 trial of Ibrance plus fulvestrant, there were no statistically significant improvements in overall survival compared to controls.
"The CDK4/6 landscape in the first-line metastatic or advanced setting has really evolved," Bohen said. "It has gone from Ibrance being the leader to Kisqali taking over."
Olema is still planning the palazestrant-Kisqali registration trial, Bohen said, and if the company can raise funds for it, it will compare first-line therapy with palazestrant-Kisqali to letrozole-Kisqali in patients with advanced or metastatic ER-positive, HER2-negative breast cancer. Although the design of the trial must be finalized with regulatory authorities, the company will propose progression-free survival as the primary endpoint, according to Bohen.
Outside of palazestrant, the firm is also working on a KAT6-targeted treatment program. KAT6, a histone lysine acetyltransferase, has emerged as a potentially significant target in breast and other cancers. In June, researchers from Pfizer and academic institutions around the world published a study demonstrating that Pfizer's KAT6A/6B inhibitor PF-07248144 had a tolerable safety profile and durable antitumor activity in heavily pretreated patients with ER-positive, HER2-negative metastatic breast cancer. The study validated KAT6 as a druggable target in cancer.
Olema released preclinical data on several investigational KAT6 inhibitors at a medical conference last year, which suggested these compounds have efficacy and may work synergistically when combined with Ibrance or palazestrant. Bohen said the company will release more preclinical data later this year, around the time it files an investigational new drug application with the FDA for its lead KAT6 inhibitor candidate, OP-3136.
Olema hopes to investigate OP-3136 in ER-positive, HER2-positive metastatic breast cancer and castrate-resistant prostate cancer but has not yet decided if it will pursue a biomarker strategy to identify subgroups of patients within those categories most likely to benefit. The data from initial trials will inform Olema's decision in this regard.
Bohen is optimistic that Olema will land the funds it needs to accomplish all of its goals, although he underscored again that the company has enough resources to complete ongoing trials like OPERA-01. "The funding environment has become more difficult in recent years," Bohen acknowledged. "But we believe it is beginning to shift toward more investor willingness to fund companies with promising projects."