On October 23, 2023 Ayala Pharmaceuticals, Inc. (OTCQX: ADXS), a clinical-stage oncology company, reported that new data from the RINGSIDE study evaluating its lead investigational candidate AL102 for the treatment of desmoid tumors (DT) reported presentation at the European Society for Molecular Oncology (ESMO) (Free ESMO Whitepaper) Congress 2023, taking place October 20th to 24th in Madrid, Spain (Press release, Ayala Pharmaceuticals, OCT 23, 2023, View Source [SID1234636237]). The data are from Phase 2 (Part A) of the study and from the Open Label Extension (OLE). The results are featured in a poster being presented by Professor Robin Jones, Team Leader in Sarcoma Clinical Trials at The Institute of Cancer Research and Consultant Medical Oncologist at The Royal Marsden, UK.

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"The RINGSIDE results continue to improve over time, with more patients in this latest Phase 2 and OLE data cut demonstrating responses to treatment with AL102," said Kenneth Berlin, President and CEO of Ayala. "We are seeing impressive anti-tumor activity across multiple parameters and are particularly encouraged by the high response rates, including 83% in the 1.2 mg once daily arm, the dose being used in our Phase 3 study, and 64% across all three doses combined. Furthermore, in two other important efficacy parameters, patients receiving 1.2 mg daily dose experienced an 88% reduction in tumor volume and 85% reduction in T2W signal intensity in median best change from baseline. We are pleased to note that 29 of the 42 patients who participated in Phase 2 of RINGSIDE entered the OLE and that we are seeing new responses in some of the patients who were receiving dosing twice a week and are now receiving 1.2 mg once daily. The Phase 3 registration segment (Part B) of RINGSIDE continues to enroll patients globally at a good pace with greater than 70% of the 154 patients we aim to enroll already dosed. These latest results from Phase 2 and OLE reinforce our belief that AL102 has the potential to be a best-in-class gamma secretase inhibitor and may offer a promising new treatment option to patients with unresectable, recurrent or progressive desmoid tumors."

Professor Robin Jones commented, "The outlook for patients with desmoid tumors appears to be improving, with one gamma secretase inhibitor already in registration with FDA, as an important new class of agents. These latest results on AL102 are unprecedented, showing meaningful clinical benefits across three key efficacy measures in a large proportion of treated patients as well as a manageable safety profile."

Andres Gutierrez MD PhD., Executive VP and Chief Medical Officer of Ayala, added, "The data from the Phase 2 segment of RINGSIDE continue to show efficacy across all dose cohorts with the earliest and deepest responses observed in the 1.2 mg once daily arm, the dose being evaluated in the ongoing Phase 3 segment. The large reductions in T2 signal intensity, as measured by MRI, are noteworthy as they have been correlated with loss of tumor cellularity and symptom control in patients undergoing treatment for DT. AL102 continues to be generally well tolerated and has a manageable safety profile as seen in all three dose arms. The safety results appear consistent with the GSI class."

RINGSIDE Study Phase 2 and OLE Highlights

The ongoing Phase 2/3 RINGSIDE clinical trial is a randomized, global multi-center study evaluating AL102 in patients with progressing desmoid tumors. The study consists of two parts: Phase 2 (Part A) is an open-label, dose regimen finding study, and Phase 3 (Part B) is a double blind, placebo-controlled study and Open Label Extension utilizing the 1.2 mg once daily dose regimen selected based on data from Phase 2. Patients in Phase 2 were randomized to one of three dose regimens of AL102 (n=14 each), including 1.2 mg once daily (QD), 4 mg twice a week (BIW) or 2 mg BIW. Patients in the intermittent dosing arms were allowed to rollover to the Open Label Extension to receive 1.2 mg once daily after evaluations were completed in the Phase 2 part.

The results presented at ESMO (Free ESMO Whitepaper) reflect a cut-off date as of July 5, 2023.

Efficacy Results

1.2 mg once daily achieved ORR of 83% per RECIST in the evaluable population as assessed by MRI BICR (Blinded Independent Central Review)
ORR per RECIST was 64% in evaluable patients across the 3 dose arms (n=36)
Efficacy results continue to demonstrate a dose-response pattern favoring the 1.2 mg once daily arm
First Partial Responses (PRs) observed at 16 weeks and 21 additional PRs and 1 Complete Response across all dose arms
Early and deep volume (-52%) and T2 signal intensity (-58%) reductions within 16 weeks after starting 1.2 mg once daily
Best overall median reductions of 88% and 85% in volume and T2 signal intensity, respectively, in the 1.2 mg once daily arm at 16.6 months of median time on treatment
Reductions in volume and T2 signal intensity were also observed across biweekly dose arms
29 patients rolled over to the OLE between Oct 2022 and May 2023, with 27 still on study
Three patients from the 4 mg BIW arm achieved PR after rolling over to the OLE where they received 1.2 mg once daily
Best overall responses for the three dose arms in the evaluable population of Part A and OLE, as determined by blinded independent central review (BICR), are summarized in the table below:

Evaluable population

1.2 mg QD 4 mg BIW 2 mg BIW All
(n=12) (n=13) (n=11) (n=36)
ORR (CR + PR), n (%) 10 (83) 8 (62) 5 (45) 23 (64)
Complete Response (CR) 0 0 1 (9) 1 (3)
Partial Response (PR) 10 (83) 8 (62) 4 (36) 22 (61)
Stable Disease (SD) 2 (17) 5 (38) 5 (45) 12 (33)
Progressive Disease (PD) 0 0 1 (9) 1 (3)
Disease Control Rate 100% 100% 91% 97%
Time to objective response (months), median (range)

8.1 12 9.2 9.4
(3.8-15) (9.0-18) (6.4-9.2) (3.8-18)
The second table shows tumor responses as measured by volume reduction, T2W signal intensity and RECIST:

Best median change from baseline across all dose groups as measured on MRI by BICR

1.2 mg QD 4 mg BIW 2 mg BIW Overall
(n=12) (n=13) (n=11) (n=36)
Tumor Volume -88 -70 -481 -832
T2W Signal Intensity (cellularity) -85 -77 -53 -76
Central RECIST v1.1 -54 -36 -29 -38
1 n=10 for tumor volume in the 2 mg BIW arm
2 n=35 for tumor volume in the overall population

Safety

AL102 was generally well tolerated with a manageable safety profile across all dose arms
Adverse events (AEs) were consistent with gamma secretase inhibitors’ (GSI) mechanism of action. The most frequent treatment-related AEs with 1.2 mg once daily included diarrhea (92.8%), nausea (57.1%), fatigue (50%), dry skin (50%), alopecia (50%), stomatitis (50%), dermatitis acneiform (42.9%), dry mouth (42.9%), hypophosphatemia (42.9%), rash maculopapular (37.7%) and aspartate aminotransferase increased (28.6%)
Regardless of dose regimen, AEs were Grade 1 or Grade 2 in >95% of the cases
There was one Grade 4 unrelated AE and no Grade 5 AEs. There were no treatment-related serious AEs
Ovarian dysfunction was reported in 56% of pre-menopausal women in the 1.2 mg once daily arm and 61% of pre-menopausal women across all dose arms
The registration-enabling Phase 3 segment of RINGSIDE is now enrolling patients globally. Patients are receiving AL102 1.2mg once daily or placebo. For more information on RINGSIDE, please visit ClinicalTrials.gov and reference Identifier NCT04871282 (RINGSIDE).

A copy of the poster will be available on the Ayala corporate website, following the ESMO (Free ESMO Whitepaper) congress.

About Desmoid Tumors

Desmoid tumors, also called aggressive fibromatosis or desmoid-type fibromatosis, are rare connective tissue tumors that typically arise in the upper and lower extremities, abdominal wall, head and neck area, mesenteric root, and chest wall, or other parts of the body. Desmoid tumors do not metastasize, but often aggressively infiltrate neurovascular structures and vital organs. People living with desmoid tumors are often limited in their daily life due to chronic pain, functional deficits, general decrease in their quality of life and organ dysfunction. Desmoid tumors have an annual incidence of approximately 1,700 patients in the United States and typically occur in patients between the ages of 15 and 60 years. They are most commonly diagnosed in young adults between 30-40 years of age and are more prevalent in females. Today, surgery is no longer regarded as the cornerstone treatment of desmoid tumors due to surgical morbidity and a high rate of recurrence post-surgery. There are currently no FDA-approved systemic therapies for the treatment of unresectable, recurrent or progressive desmoid tumors.

About AL102

AL102 is an investigational small molecule Gamma Secretase Inhibitor (GSI) that is designed to potently and selectively inhibit Notch 1, 2, 3 and 4, and is currently being evaluated in the Phase 2/3 RINGSIDE clinical studies in patients with progressing desmoid tumors. AL102 is designed to inhibit the expression of Notch gene targets by blocking the final cleavage step by the gamma secretase required for Notch activation. Ayala obtained an exclusive, worldwide license to develop and commercialize AL102 from Bristol-Myers Squibb Company in November 2017. AL102 was granted U.S. FDA Fast Track Designation for the treatment of DT.