Metastatic Pancreatic Cancer Program

The incidence of pancreatic cancer is increasing steadily, with an estimated 67,530 new cases and 52,740 deaths in United States for 2026. Pancreatic cancer is predicted to become the second leading cause of cancer-related deaths in the United States by 2030. The survival rate of patients diagnosed with pancreatic cancer is dismal, with median overall survival of 4 months with only ~12.5 % of patients expected to survive 5 years following diagnosis. A significant reason for such poor survival outcomes is the lack of early diagnosis, leading to only 15—20% of patients being eligible for surgery, which is the only curative intent treatment option.

Up to 85 % of patients present with a locally advanced or metastatic disease. Half of pancreatic cancer patients will present with distant metastases, and palliative treatment is provided to reduce cancer-related symptoms and prolong survival.

When compared with other carcinomas, pancreatic cancer is genomically a relatively homogeneous disease. The major genetic event and hallmark in the development of pancreatic ductal adenocarcinoma is the somatic activating KRAS oncogene mutation which is observed in more than 90% of pancreatic tumors. The KRAS mutation remains active during the progression from epithelial cells to invasive cancer, contributing to the processes of proliferation, survival, migration, and invasion. By its effect on the tumor stroma and microenvironment, the KRAS protein plays an important role in the process of metastatic spread and chemotherapy resistance.

Among various tubulins, βIII- and βIV-tubulin isoforms have been primarily implicated in pancreatic cancer progression, metastasis and chemoresistance. However, there are no specific inhibitors of these isoforms that have potent anticancer activity with low toxicity are not readily available.

In carcinogenesis, βIII-tubulin (TUBB3) gene is aberrantly expressed in a range of epithelial tumors and is associated with drug resistance and aggressive disease. In pancreatic cancer, it should be noted that βIII-tubulin protein is NOT expressed in normal ductal epithelium of the pancreas. In contrast, βIII-tubulin overexpression is frequently reported in tumor specimens, particularly in advanced or metastatic specimens. βIII-tubulin aberrant expression has been commonly observed in up to 90% of pancreatic adenocarcinoma cancers. Diverse cancer cell lines have shown that overexpression of βIII-tubulin confers resistance to paclitaxel, docetaxel, and vinca alkaloids as well as DNA damaging agents, such as cisplatin, topoisomerases inhibitors, and doxorubicin. Aberrant βIII-tubulin expression was also associated with poorly differentiated tumors, shorter disease progression, chemoresistance, unfavorable prognosis and worse overall survival — not only in pancreatic cancer, but also in many other types of cancers including lung, ovarian, breast, prostate, urothelial and bladder, gastric, rectal cancers, esophageal squamous cell carcinoma, and thymic carcinoma.

Daraxonrasib is a major recent medical advancement that confirms the importance of targeting and blocking the KRAS signaling pathway in metastatic pancreatic cancer. In the registration Phase 3 RASolute 302 clinical trial (NCT06625320) for the second line treatment of metastatic pancreatic cancer, daraxonrasib treatment demonstrated unprecedented improvement in overall survival with a median of 13.2 months. Unfortunately, pancreatic cancer progression eventually occurs with the median progression-free survival, or time to cancer progression, of 7.2 months as the pancreatic cancer becomes resistant to daraxonrasib. Interestingly, the most common cause (>90%) for resistance to daraxonrasib is the reactivation of KRAS signaling pathway. Consequently, the next rational therapeutic strategy is to target and inhibit the downstream effectors of this reactivated KRAS signaling pathway.

Based on over 12 peer reviewed publications in preclinical cell lines and xenograft cancer models across a broad range of tumor types*, sabizabulin treatment disrupted and fragmented microtubules, inhibited cancer cell proliferation and tumor growth, prevented cancer cell invasion and metastases, and suppressed angiogenesis. Sabizabulin was able to restore chemosensitivity and overcome paclitaxel resistance in a variety of tumor types including taxane resistant lung, prostate, ovarian, and cervical cancers. Sabizabulin arrests the cell cycle in the G2/M halting mitosis in rapidly dividing cells resulting in cell death. Independent of its activities to disrupt the microtubules, sabizabulin preferentially decreases the transcription of βIII- and βIV-tubulin isoforms to restore chemotherapy sensitivity as well as induces apoptosis in nondividing cells by activation of Caspase 3 and 9 and cleaving PARP and modulation of both cell cycle regulatory proteins (Cdc2, Cdc25c, and Cyclin B1) and intrinsic apoptosis-associated proteins (Bax, Bad, Bcl-2, and Bcl-xl) to induce apoptosis. Down regulation of Bcl-2 is particularly interesting as Bcl-2 overexpression protects cancer cell from cell death. Moreover, sabizabulin may overcome other common drug resistance mechanisms since it is not substrate for proteins involved in multidrug resistance including P-glycoprotein, MRP and BCRP so that sabizabulin cannot be effluxed or pumped out of cancer cells.

*Triple negative breast cancer (taxane resistant), cervical cancer, lung cancer (taxane resistant), ovarian cancer (taxane resistant), prostate cancer (taxane resistant), melanoma (BRAF resistant), pancreatic cancer, colon cancer, glioma, and human promyelocytic leukemia (vincristine resistant).

The Company believes the positive efficacy and safety clinical data from Phase 1b/2 first-in-man clinical study of sabizabulin monotherapy conducted in 80 patients with heavily pretreated metastatic castration resistant and taxane resistant prostate cancer support the translational potential of sabizabulin treatment for daraxonrasib resistant metastatic pancreatic cancer.

The Phase 1b portion utilized a 3+3 dose escalation design with escalating daily oral doses of 4.5 mg – 81 mg (7 days on drug/14 days off per 21-day cycle, which was then expanded to daily dosing). The Phase 1b portion included 39 metastatic castration resistant cancer patients that were treated with one or more novel androgen receptor targeting agents. Most patients had bone-only disease (55%) with an additional 21% having both lymph node and bone involvement with 23% of patients with prior taxane-based chemotherapy. The Phase 2 portion tested a daily dose of 63 mg in 41 heavily pretreated similar patient population, but with no prior chemotherapy. Efficacy was assessed using PCWG3 and RECIST 1.1 criteria.

The maximum tolerated dose was not defined in the Phase 1b as all doses tested were well tolerated. The recommended Phase 2 dose was set at 63 mg/day. The most common adverse events (>10% frequency) at the 63 mg oral daily dosing (combined Phase 1b/2 safety data) were predominantly Grade 1-2 events. Grade ≥3 events included diarrhea (7.4%), fatigue (5.6%) and ALT/AST elevations (5.6% and 3.7%, respectively). Neurotoxicity and neutropenia were not observed at these dosage levels.

Efficacy data in patients treated with ≥1 continuous cycle (21 days) of 63 mg or higher had a Kaplan-Meier median radiographic progression-free survival that was estimated to be 11.4 months with durable responses lasting greater than 12 months, occurring in 14.5% (n=55) patients. The objective response rate was 20.7% in patients with measurable disease and durable responses lasting greater than 2.75 years were observed. Compared to historical controls, the radiographic progression-free survival in similar patients was only 3.6 months and objective response rate was 2% with an alternative androgen receptor blocking agent (deBono J NEJM 382:2091, 2020). This Phase 1b/2 clinical trial had a favorable safety profile with promising preliminary antitumor activity and demonstrated that chronic oral daily dosing of sabizabulin was feasible up to 3 years.

KRAS drives a complex network of downstream signaling effectors, including RAF, MAPK/ERK, PI3K/AKT, and aberrant expression of TUBB3 to support cancer. TUBB3 encodes for βIII-tubulin subunit which becomes part of the microtubule and weakens the binding affinity of microtubules to cytotoxic drugs leading to drug resistance to drugs commonly used in combination to treat pancreatic cancer including taxanes and vinca alkaloids as well as DNA damaging agents, such as cisplatin, etoposide, and doxorubicin. Aberrant βIII-tubulin expression is detected in up to 93% of pancreatic cancer specimens and has the strongest association with KRAS-driven pancreatic cancer progression, poorly differentiated tumors, shorter disease progression, chemoresistance, unfavorable prognosis and worse overall survival.

Sabizabulin demonstrated potent low nanomolar anticancer activity in human KRAS-driven pancreatic cancer cell lines and xenograft models including AsPC-1, Panc-1, and HPAF-II (KRAS oncogenic mutation G12D) (Kashrup V et al. J Exp Clin Cancer Res 38:29, 2019). G12D is one of the most common activating mutations of KRAS in human pancreatic cancer. Sabizabulin treatment also preferentially inhibited the expression of TUBB3 (βIII-tubulin) which allowed sabizabulin to overcome chemoresistance. Further, sabizabulin inhibited the expression of other downstream effectors of the KRAS signaling pathway including RAF, ERK, AKT, TUBB3 as well as and PTK2-FAK signaling pathways in a wide range of cancer types. TUBB3 is not only a biomarker for poor prognosis and chemoresistance, but also a potential therapeutic target for the next generation precision medicine approaches.

It was confirmed that the reason for daraxonrasib resistance was the reactivation of the KRAS signaling pathway in both pancreatic and colon daraxonrasib resistant cell lines. The resistance index (RI) was calculated, which is the ratio of drug concentration required to inhibit 50% cell growth in resistant cell line compared to its parental (sensitive) cell line. The resistance index represents the fold-change in drug tolerance of the resistant cell line compared to its sensitive, parental cell line. An RI greater than 1 indicates resistance, while an RI below 1 indicates increased sensitivity to the drug.

Like daraxonrasib, sabizabulin had potent anticancer activity for both pancreatic cancer and colon cancer parental cell lines regardless of the type of KRAS mutation. As expected, the daraxonrasib resistant cell lines were resistant to daraxonrasib with a RI of 68 for pancreatic cancer cell line and RI of >128 for colon cancer cell line. In contrast, daraxonrasib resistant pancreatic cancer cell lines became more sensitive (collateral sensitivity) to sabizabulin with a RI of 0.25 and daraxonrasib resistant colon cell line retained sensitivity to sabizabulin with a RI of 1. In summary, sabizabulin retained highly potent anticancer efficacy in daraxonrasib resistant pancreatic and colon cancer cell lines that had reactivation of KRAS signaling pathway as the mechanism for drug resistance to daraxonrasib. These preclinical data may also support sabizabulin as a treatment of daraxonrasib resistant cancer types beyond pancreatic cancer.

In several previous and current preclinical studies in human cancer models, sabizabulin demonstrated that is has significant anticancer activity and can overcome chemoresistance supporting the potential for sabizabulin for the treatment of metastatic pancreatic cancer that has become resistant to multi-selective KRAS inhibitors like daraxonrasib. Sabizabulin targets and inhibits downstream effectors, RAF/ERK/TUBB3, PI3Kα/AKT, and FAK-PTK2 of the KRAS signaling pathway to suppress cancer cell proliferation, inhibit cell motility, invasion, and metastasis, and overcome chemoresistance.