NEW YORK – Maia Biotechnology is seeking new development partners for its telomerase inhibitor THIO following a strong interim data readout for the drug combined with a PD-1 inhibitor in the second-line advanced non-small cell lung cancer setting.
About 85 percent of cancers are characterized by telomerase expression. Early in life, telomerase extends the telomere, a protective region of DNA at the end of the chromosome, but then becomes inactive. Telomeres naturally become shorter as people age, and this shortening leads to cell senescence and death. However, in rapidly dividing cancer cells, telomerase can become reactivated, extending the telomeres and the life of the malignant cell.
Drugmakers have long pursued this class of drugs, but thus far, other than THIO, Geron's imetelstat is the only other telomerase inhibitor to progress to late-stage clinical trials.
Unlike imetelstat and other compounds designed to directly inhibit telomerase, Maia's THIO (6-thio-2′-deoxyguanosine) is rapidly converted inside the cell to the telomerase substrate 6-thio-2′-deoxyguanosine-5′-triphosphate and is incorporated into the telomere by telomerase. This results in uncapping of telomeres and subsequent degradation and cell death. The activity of telomerase is detectable using a confocal microscope to visualize Telomere dysfunction Induced Foci (TIF) formations.
According to Maia, this approach has the advantage of producing an anticancer effect faster than is possible with direct inhibition of telomerase. The latter drugs block telomerase without directly shortening telomeres, creating a lag between treatment and tumor cell death. In patients with longer telomeres, this lag could allow enough time for the cancer to spread to the extent that there's no survival advantage for the patient.
In preclinical studies, Maia found that THIO's effects on normal cells were minimal, and mice treated for up to a month with therapeutic doses of the drug did not lose weight and had no hematological, liver, or kidney abnormalities. In vitro, THIO killed most cancer cells, while normal cells were unaffected, and in xenograft models of lung cancer, treatment with THIO led to telomere dysfunction and a significant reduction in tumor size.
Chicago-based Maia is now advancing THIO in the THIO-101 Phase II trial in combination with Regeneron's PD-1 inhibitor Libtayo (cemiplimab) in 182 patients with locally advanced or metastatic NSCLC who have PD-L1 expression in 50 percent or more tumor cells.
The company has hypothesized that THIO will be able to restore advanced NSCLC patients' ability to respond to a PD-1 inhibitor after they have developed resistance to or relapsed on a first-line immune checkpoint inhibitor. In the Phase II trial, investigators are testing several doses of THIO with a 350 mg dose of Libtayo and tracking safety, toxicity, overall response rate, and disease control rate. Researchers will also evaluate patients' duration of response, progression-free response, and overall survival as secondary endpoints. As an exploratory biomarker, they will measure THIO's on-target activity via the TIF confocal microscopy assay and genomic DNA damage in circulating tumor cells via a gamma-H2AX induction assay.
In an interim data readout earlier this month, Maia reported that 42 patients had completed at least one post-baseline assessment. In the second-line setting, all patients achieved disease control on THIO plus Libtayo, while 88 percent of third-line patients achieved the same.
"The level of efficacy that has been observed with THIO is absolutely astounding," said Maia CEO Vlad Vitoc, noting that such high rates of disease control have not been seen before in the second- and third-line advanced NSCLC setting. For patients who have received chemotherapy and immunotherapy as first-line treatment, second-line therapy usually comprises a chemotherapy agent such as docetaxel and an EGFR inhibitor or other targeted therapy.
According to Vitoc, disease control rates for those second-line regimens top out at 50 percent to 60 percent. And he said that in the third-line setting, where chemotherapy is typically used, disease control rates are around 25 percent to 35 percent. In comparison, the 88 percent disease control rate observed thus far in Maia's Phase II trial is about three times what is achievable with standard therapy.
Vitoc said that THIO is designed to work in any cell that is telomerase positive, which accounts for 85 percent of cancer cells overall, but telomerase expression can vary by tumor type. For example, telomerase is expressed in around 40 percent of neuroblastomas or soft tissue sarcomas but occurs in nearly all small cell lung cancers.
Maia plans to study THIO initially in cancers that have very high telomerase expression by nature, so initially they are only measuring telomerase activity as an exploratory endpoint using the TIF assay. However, as the company expands to other cancer types, Vitoc expects that testing for telomerase activity will be more important for selecting patients for clinical trials and treatment.
"[Telomerase] is a very interesting biomarker because it has such a high prevalence," Vitoc said. "Most companies are struggling to find targets that are one, two, or three percent of patients. This is 85 percent of patients."
THIO has also shown promising activity in glioma, diffuse intrinsic pontine glioma, hepatocellular carcinoma, and small cell lung cancer. The US Food and Drug Administration has also granted THIO orphan drug designation as a treatment for glioblastoma, small cell lung cancer, and hepatocellular carcinoma.
Maia is developing other second-generation, discovery-stage compounds that are designed to target telomerase activity like THIO that have potential for improved specificity for cancer cells compared to normal cells and increased anticancer activity.
Vitoc sees a two- to three-year commercialization timeline for THIO, which means the drug could hit the market as soon as the end of 2025 or early 2026. The company is advancing THIO under a partnership agreement with Regeneron signed in 2021. Under the terms of their original agreement, Maia is sponsoring the Phase II clinical trial and Regeneron is supplying Libtayo. Maia retains global development and commercial rights to THIO and is free to develop it in combination with other agents outside of NSCLC.
The firm wants to study THIO with other compounds and currently is negotiating co-development and licensing arrangements with multiple pharmaceutical companies.
Vitoc said Maia, which is publicly traded on the New York Stock Exchange, has enough funds to carry it through THIO's regulatory approval and has means of accessing additional financing. In November, the firm raised $4 million in a registered direct offering of common stock to fund R&D activities and general corporate purposes. In Q3 2023, Maia reported a net loss of $4.9 million, or $0.36 per share, and as of Sept. 30, 2023, it had $6.1 million in cash.