On November 6, 2023 Ayala Pharmaceuticals, Inc. (OTCQX: ADXS), a clinical-stage oncology company, reported that the U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to AL102, a Gamma Secretase Inhibitor (GSI), for the treatment of desmoid tumors (DT). AL102 is an investigational small molecule GSI, currently being evaluated in the Phase 3 RINGSIDE study in DT (Press release, Ayala Pharmaceuticals, NOV 6, 2023, View Source [SID1234637009]). Orphan drug designation is granted by the FDA to drugs and biologics intended for treatment, prevention or diagnosis of a rare disease or condition that affects fewer than 200,000 people in the U.S. at the time of designation.

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Desmoid tumors 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. They do not metastasize, but often aggressively infiltrate neurovascular structures and vital organs. 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. 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. There are currently no FDA-approved systemic therapies for the treatment of unresectable, recurrent or progressive desmoid tumors.

Under the FDA’s Orphan Drug Act, orphan drug status provides incentives, including tax credits, grants and waiver of certain administrative fees for clinical trials, and seven years of market exclusivity following drug approval.

"Receiving FDA orphan drug status for AL102 underscores the significant unmet need for novel treatment options for people living with desmoid tumors. We look forward to continuing to work closely with regulators, clinical investigators, patients and their families to advance this potentially important medicine and make it available to those who may benefit from it," said Kenneth Berlin, President and CEO of Ayala.

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.

On November 6, 2023 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) (Actinium or the Company), a leader in the development of targeted radiotherapies, reported data was presented at Society of Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) 38th Annual Meeting on Saturday, November 4, 2023, further supporting Actimab-A, the Company’s clinical stage targeted radiotherapeutic comprised of the CD33 targeting antibody lintuzumab and the Actinium-225 (Ac-225) alpha-particle emitting payload (Press release, Actinium Pharmaceuticals, NOV 6, 2023, View Source [SID1234637008]).

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The poster highlighted Actimab-A’s ability to target and deplete myeloid-derived suppressor cells (MDSCs), which uniformly express CD33. MDSCs are a cell population of interest as they remodel the tumor environment and promote immune evasion. Actinium believes Actimab-A has the potential to be used in combination with immunotherapy, including immune checkpoint inhibitors, to enhance antitumor immunity via targeted MDSC depletion. Supportive data from the SITC (Free SITC Whitepaper) presentation includes:

Actimab-A reduced cancer patient-derived MDSCs in a dose-dependent manner ex vivo and decreased MDSC viability approximately two-fold greater than a non-radiolabeled CD33 antibody
MDSC suppression of activated T cell proliferation and cytokine effector function ex vivo was restored following treatment with Actimab-A

Actimab-A significantly depleted MDSCs in peripheral blood of tumor-bearing humanized mice compared to non-radiolabeled CD33 antibody in vivo

SPECT/CT imaging confirmed uptake of lintuzumab in humanized mice at the sites of non-small cell lung cancer tumor indicating enrichment of CD33+ MDSCs in the tumor microenvironment
Sandesh Seth, Actinium’s Chairman and CEO, commented, "These data further increase our enthusiasm for Actimab-A’s potential in solid tumor indications. Immunotherapy has had a profound impact on patient outcomes across multiple solid tumor indications, however, there are still several indications with high unmet needs and significant room to further improve patient outcomes. By depleting MDSCs in a targeted manner, we are excited by the prospect of Actimab-A synergizing with immunotherapy to enhance antitumor immunity. We look forward to continuing to advance this initiative in continuing our goal to address high unmet patient needs with our targeted radiotherapeutics."

On November 6, 2023 Aclaris Therapeutics, Inc. (NASDAQ: ACRS), a clinical-stage biopharmaceutical company focused on developing novel drug candidates for immuno-inflammatory diseases, reported its financial results for the third quarter of 2023 and provided a corporate update (Press release, Aclaris Therapeutics, NOV 6, 2023, View Source [SID1234637007]).

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"Throughout the first three quarters of this year, I believe our company has performed remarkably well in terms of executing across our clinical development programs," stated Doug Manion, M.D., Chief Executive Officer of Aclaris. "Most importantly, we are rapidly approaching the topline data read-outs for our two most advanced clinical programs, zunsemetinib in rheumatoid arthritis this month and ATI-1777 in atopic dermatitis around the end of this year. This level of high-quality execution is further exemplified as we advance ATI-2138 in patients with ulcerative colitis, and we’re pleased to collaborate with Washington University as they advance ATI-2231 in patients with advanced solid tumor malignancies."

Research and Development Highlights:

Zunsemetinib, an investigational oral small molecule MK2 inhibitor:
Currently being developed as a potential treatment for immuno-inflammatory diseases
Rheumatoid Arthritis (ATI-450-RA-202): This Phase 2b placebo-controlled dose ranging trial to investigate the efficacy, safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of multiple doses (20 mg and 50 mg twice daily) of zunsemetinib in combination with methotrexate in patients with moderate to severe rheumatoid arthritis (RA) completed enrollment in June 2023. Aclaris continues to expect topline data this month.
Psoriatic Arthritis (ATI-450-PsA-201): This Phase 2a placebo-controlled trial to investigate the efficacy, safety, tolerability, PK and PD of zunsemetinib (50 mg twice daily) in patients with moderate to severe psoriatic arthritis (PsA) is ongoing. Aclaris continues to expect topline data in the first half of 2024.
ATI-1777, an investigational topical "soft" Janus kinase (JAK) 1/3 inhibitor:
Currently being developed as a potential treatment for mild to severe atopic dermatitis (AD)
Atopic Dermatitis (ATI-1777-AD-202): This Phase 2b vehicle-controlled trial to determine the efficacy, safety, tolerability, and PK of multiple doses and application regimens of ATI-1777 in patients with mild to severe AD completed enrollment in September 2023. Aclaris continues to expect topline data around the end of 2023.
ATI-2138, an investigational oral covalent ITK/JAK3 inhibitor:
Currently being developed as a potential treatment for ulcerative colitis; Aclaris is also exploring additional indications for other T cell-mediated autoimmune diseases
Healthy Volunteers (ATI-2138-PKPD-102): This two-week Phase 1 MAD (multiple ascending dose) trial to investigate the safety, tolerability, PK and PD of ATI-2138 in healthy volunteers has been completed. Based on analysis of the PK, PD and safety, Aclaris is progressing ATI-2138 into Phase 2a clinical development in ulcerative colitis, which it expects to initiate in early 2024. Aclaris reported the data in September 2023.
Preliminary data from the MAD trial demonstrated:
ATI-2138 was generally well tolerated at all doses tested in the trial;
ATI-2138 had dose proportional PK; and
a dose-dependent inhibition of both ITK and JAK3 exploratory PD biomarkers, with near maximal inhibition achieved at the 30 mg total daily dose.
ATI-2231, an investigational oral MK2 inhibitor compound:
Currently being explored as a potential treatment for pancreatic cancer and metastatic breast cancer as well as in preventing bone loss in patients with metastatic breast cancer. Aclaris is also currently exploring options to use ATI-2231 as a potential treatment for immuno-inflammatory diseases.
This is the second MK2 inhibitor generated from Aclaris’ proprietary KINect drug discovery platform and is designed to have a long plasma half-life.
Aclaris is supporting Washington University in a first-in-human investigator-initiated Phase 1a trial of ATI-2231 in patients with advanced solid tumor malignancies. Aclaris expects clinical development activities to be initiated in the second half of 2023.
Financial Highlights:

Liquidity and Capital Resources

As of September 30, 2023, Aclaris had aggregate cash, cash equivalents and marketable securities of $187.0 million compared to $229.8 million as of December 31, 2022.

Aclaris continues to anticipate that its cash, cash equivalents and marketable securities as of September 30, 2023 will be sufficient to fund its operations through the end of 2025, without giving effect to any potential business development transactions or financing activities.

Financial Results

Third Quarter 2023

Net loss was $29.3 million for the third quarter of 2023 compared to $20.0 million for the third quarter of 2022.
Total revenue was $9.3 million for the third quarter of 2023 compared to $19.0 million for the third quarter of 2022. The decrease was primarily driven by a one-time upfront payment under the non-exclusive patent license agreement with Eli Lilly and Company (Lilly) received in the third quarter of 2022.
Research and development (R&D) expenses were $23.9 million for the quarter ended September 30, 2023 compared to $23.7 million for the prior year period.
The $0.2 million increase was primarily the result of:
An increase in ATI-2138 development expenses, including costs associated with a Phase 1 MAD trial and other preclinical activities; and
An increase in compensation-related expenses due to an increase in headcount.
The increases were partially offset by a decrease in zunsemetinib costs associated with the completion of the Phase 2a trial in patients with hidradenitis suppurativa.
General and administrative (G&A) expenses were $7.1 million for the quarter ended September 30, 2023 compared to $5.8 million for the corresponding prior year period. The increase was primarily due to increased compensation-related expenses due to an increase in headcount.
Licensing expenses were $7.3 million for each of the quarters ended September 30, 2023 and September 30, 2022, resulting from separate third-party contractual obligations related to the non-exclusive patent license agreement with Lilly.
Revaluation of contingent consideration resulted in a $1.7 million charge for the quarter ended September 30, 2023 compared to a charge of $2.2 million for the prior year period.
Year-to-date 2023

Net loss was $87.0 million for the nine months ended September 30, 2023 compared to $59.3 million for the nine months ended September 30, 2022.
Total revenue was $13.7 million for the nine months ended September 30, 2023 compared to $22.0 million for the nine months ended September 30, 2022. The decrease was primarily driven by a one-time upfront payment under the non-exclusive patent license agreement with Lilly received in the nine months ended September 30, 2022.
R&D expenses were $71.7 million for the nine months ended September 30, 2023 compared to $56.7 million for the corresponding prior year period.
The $15.0 million increase was primarily the result of higher:
Zunsemetinib development expenses, including costs associated with clinical activities for a Phase 2b trial for RA and a Phase 2a trial for PsA;
ATI-2138 development expenses, including costs associated with a Phase 1 MAD trial and other preclinical activities; and
Compensation-related expenses due to an increase in headcount.
G&A expenses were $24.2 million for the nine months ended September 30, 2023 compared to $18.0 million for the prior year period.
The $6.2 million increase was primarily the result of higher compensation-related costs, including stock-based compensation, due to increased headcount and the impact of equity awards granted during the nine months ended September 30, 2023. Bad debt expense recorded from Aclaris’ determination that collection of amounts due from EPI Health are uncertain as a result of their filing for Chapter 11 bankruptcy protection also contributed to the increase.
Revaluation of contingent consideration resulted in a $0.6 million gain for the nine months ended September 30, 2023 compared to a gain of $2.4 million for the corresponding prior year period.

On November 6, 2023 – Immutep Limited (ASX: IMM; NASDAQ: IMMP) ("Immutep" or "the Company"), a clinical-stage biotechnology company developing novel LAG-3 immunotherapiesfor cancer and autoimmune disease, reported the open-label safety lead-in of its integrated AIPAC-003 Phase II/III trial evaluating for the very first time 90mg of eftilagimod alpha (efti) in combination with paclitaxel has been completed with no safety or tolerability issues (Press release, Immutep, NOV 6, 2023, View Source [SID1234636977]).

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Six patients with metastatic breast cancer receiving this immuno-oncology chemotherapy (IO-chemo) combination, after exhaustion of all endocrine/CDK4/6 based therapies, tolerated the therapy very well and there were no dose limiting toxicities, as confirmed by the independent Data Monitoring Committee (IDMC) appointed for the trial. The IDMC recommended proceeding to the randomised Phase II portion of the trial.

The randomised (1:1) Phase II portion of the study will now open to include up to 58 evaluable patients with metastatic breast cancer receiving either 30mg efti or 90mg efti to determine the optimal biological dose. The evaluation of 90mg efti dosing in combination with paclitaxel is driven by efti’s excellent safety profile, along with the FDA’s Project Optimus initiative in oncology. Importantly the determination of the optimal biological dose is relevant for the whole efti program across all disease indications.

The integrated Phase II/III AIPAC-003 trial is evaluating efti, Immutep’s soluble LAG-3 protein and first-in-class MHC Class II agonist, in combination with standard-of-care paclitaxel for the treatment of metastatic hormone receptor positive (HR+), HER2-negative or HER2-low breast cancer and triple-negative breast cancer. It will take place at approximately 17 clinical sites across Europe and the United States of America. For more information on the trial, please visit clinicaltrials.gov (NCT05747794).

About Eftilagimod Alpha (Efti)

Efti is Immutep’s proprietary soluble LAG-3 protein and MHC Class II agonist that stimulates both innate and adaptive immunity for the treatment of cancer. As a first-in-class antigen presenting cell (APC) activator, efti binds to MHC (major histocompatibility complex) Class II molecules on APC leading to activation and proliferation of CD8+ cytotoxic T cells, CD4+ helper T cells, dendritic cells, NK cells, and monocytes. It also upregulates the expression of key biological molecules like IFN-ƴ and CXCL10 that further boost the immune system’s ability to fight cancer.

Efti is under evaluation for a variety of solid tumours including non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), and metastatic breast cancer. Its favourable safety profile enables various combinations, including with anti-PD-[L]1 immunotherapy and/or chemotherapy.

Efti has received Fast Track Designation in 1st line HNSCC and in 1st line NSCLC from the United States Food and Drug Administration (FDA).

On November 6, 2023 Imugene Limited (ASX: IMU), a clinical stage immuno-oncology company, reported a clinical trial update of its Phase 1 MAST (Metastatic Advanced Solid Tumours) trial evaluating the safety and efficacy of novel cancer-killing virus CF33-hNIS (VAXINIA) (Press release, Imugene, NOV 6, 2023, https://mcusercontent.com/e38c43331936a9627acb6427c/files/44c8291a-171d-e510-504e-2691967778cb/Phase_1_CF33_VAXINIA_Study_Update_Positive_Early_Signals.pdf [SID1234636976]).

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As announced last week, the trial has now cleared cohort 4 of the intravenous (IV) arm of the monotherapy dose escalation study, as well as IV cohort 2 of the combination study where VAXINIA is administered with checkpoint inhibitor drug pembrolizumab (KEYTRUDA). Cohort 5 of the IV arm for the monotherapy dose escalation is now open as is IV cohort 3 of the combination study.

As of 31 October 2023, 34 patients have been dosed with VAXINIA during the continuing dose escalation phase comprised of 16 patients intratumorally and 18 patients intravenously as either monotherapy or in combination with pembrolizumab. Twenty-five patients were evaluable (received at least their first scan at day 42) and seven patients have their first scan still pending. Of the evaluable patients the BOR (best overall response) are 1 Complete Response (CR), 1 Partial Response (PR), 16 Stable Disease (SD), showing patients had control and stability of their cancer and 8 progressive disease (PD) as measured by iRECIST and RECIST criteria
Importantly early results from 6 patients with gastrointestinal cancers who received CF33-hNIS alone including 2 colorectal cancer, 2 bile duct, 1 pancreatic and 1 liver cancer showed positive treatment effects, with a disease control rate (all CR, PR and SD) of 75%
Trial expansion is planned for 10 patients with bile duct cancers

Imugene MD & CEO Leslie Chong said: "Phase 1 trials are generally designed to look for safety, tolerability and early response signals to determine the optimal dose for further development. The early positive response data we are seeing at the mid-dose level in hard-to-treat bile duct cancer suggests that VAXINIA may be a potent anti-cancer drug as we interrogate higher dose levels. With no adverse safety signals, thus allowing us to dose higher, VAXINIA will have a very high therapeutic window which is valuable in oncology drug development."

Notably one patient with bile duct cancer, treated IT with mid-dose level displayed pseudoprogression (see below) with a 49% increase in tumour burden after two cycles of therapy. However, by the 4th cycle they achieved a Complete Response (iCR) with no known recurrence in over 200 days. A second patient with bile duct cancer, who previously progressed on prior drug therapies, achieved Stable Disease (SD) for > 4 months upon receiving IV-administered CF33-hNIS.

Bile duct cancers are difficult to treat and typically respond poorly to immunotherapy drugs. Pseudoprogression is a phenomenon in which the cancer initially appears to be growing, largely due to the cancer cells being infected by the virus then followed by infiltration of cancer fighting immune cells. However, it is usually followed by a decrease in tumour burden when the therapy takes effect. This phenomenon can benefit patients receiving immunotherapy but often leads to premature discontinuation of treatment owing to the false impression the cancer is growing.

The multicenter Phase 1 MAST trial commenced by delivering a low dose of VAXINIA to patients with metastatic or advanced solid tumours who have had at least two prior lines of standard of care treatment. The City of Hope-developed oncolytic virus has been shown to shrink colon, lung, breast, ovarian and pancreatic cancer tumours in preclinical laboratory and animal models. Overall, the study aims to recruit cancer patients across approximately 10 trial sites in the United States and Australia.

The clinical trial is titled "A Phase I, Dose Escalation Safety and Tolerability Study of VAXINIA (CF33- hNIS), Administered Intratumorally or Intravenously as a Monotherapy or in Combination with Pembrolizumab in Adult Patients with Metastatic or Advanced Solid Tumours (MAST)." The trial commenced in May 2022 and is anticipated to run for approximately 24 months while being funded from existing budgets and resources.

Full study details can also be found on clinicaltrials.gov under study ID: NCT05346484.