HONG KONG – Singaporean drugmaker Aslan Pharmaceuticals Ltd. announced top-line data from its pivotal phase III TreeTopp (treatment opportunity with varlitinib (ASLAN-001) in biliary tract cancer) study in second-line biliary tract cancer patients, which failed to meet co-primary endpoints of progression-free survival (PFS) and overall response rate (ORR). The study enrolled 127 patients from the U.S., Europe, Australia, and Japan and other Asian countries.

Varlitinib is a small-molecule pan-HER inhibitor that targets human epidermal growth factor receptor (HER)1, HER2 and HER4. By inhibiting the activation of the HER receptors, varlitinib aims to inhibit proliferation and control tumor growth.

Data from TreeTopp show the median PFS was 2.83 months for varlitinib in combination with capecitabine vs. median PFS of 2.79 in the control arm. ORR was 9.4% in the varlitinib arm vs. 4.8% in the control arm. The trial did not reach statistical significance; however, preplanned exploratory analyses identified a subgroup which appeared to show efficacy improvement. That finding has been supported by a retrospective review of the JADETREE study, which tested varlitinib in combination with capecitabine in second-line biliary tract cancer (BTC) patients in China.

"We are currently investigating a subgroup that we identified in the study that appeared to show a benefit to varlitinib," Aslan CEO Carl Firth told BioWorld. "At some stage we may decide to initiate a clinical study if the hypothesis warrants further clinical investigation. Besides biliary tract cancer, we have an ongoing study in second-line gastric cancer being run by K-MASTER, Korea's leading precision medicine research group."

Aslan's (NASDAQ:ASLN) stock price plummeted from $2.08 on Nov. 8 to 67 cents on Nov. 11. Shares dropped further this week, closing Wednesday at 37 cents.

"Despite our hesitation, we had previously assigned a 35% probability of success (POS) to the TreeTopp study, reflecting the relatively low bar in the second-line BTC setting where currently approved regimens demonstrate single-digit response rates," Jonathan Chang, managing director at SVB Leerink, said in a note.

"The control arm ORR of 4.8% in TreeTopp was consistent with recently reported [second-line] data, specifically the ABC-06 study (presented American Society of Clinical Oncology 2019) in which patients treated with doublet chemotherapy (modified FOLFOX) demonstrated a 5% ORR (33% disease control rate)," Chang added.

Edward Tenthoff, senior research analyst at Piper Jaffray, removed all value for varlitinib and continues to evaluate early stage ASLAN-004 in atopic dermatitis and ASLAN-003 in acute myeloid leukemia (AML).

"With TreeTopp failure and focus now on early stage pipeline assets, we are downgrading Aslan to Neutral from Overweight and lowering our price target to $1 from $7," he said in a note.

ASLAN-003 is an inhibitor of dihydroorotate dehydrogenase (DHODH) that has the potential to be first-in-class drug in AML. The Singaporean company licensed it from Barcelona, Spain-based Almirall SA in 2012. Aslan has global rights for all nontopical and nondermatological indications.

The drug is in a phase II AML trial, and the company is also exploring other solid tumor indications where DHODH may be relevant, such as triple-negative breast cancer and hepatocellular carcinoma.

ASLAN-004 is a fully human monoclonal antibody that targets the interleukin (IL)-13 receptor α1 subunit (IL-13Rα1). By targeting IL-13Rα1, ASLAN-004 aims to inhibit the signaling of both IL-4 and IL-13. Those two proteins are central to triggering allergy symptoms in atopic dermatitis such as itching, as well as asthma symptoms like shortness of breath, wheezing and coughing.

In June, Aslan acquired worldwide rights to ASLAN-004 from Melbourne, Australian-based CSL Pharmaceuticals Ltd. for a $30 million payment upon phase III trial start and $750 million in potential milestones with mid-single-digit to 10% royalties. The candidate is in a phase I multiple ascending-dose study enrolling 50 atopic dermatitis patients, with interim data expected in early 2020.

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