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TILT Biotherapeutics Announces Data at ESMO on Its Oncolytic Immunotherapy Platform

On September 17, 2021 TILT Biotherapeutics, a clinical-stage biotechnology company developing cancer immunotherapeutics, reported that the company presented yesterday clinical study results at the annual congress of the European Society of Molecular Oncology (ESMO) (Free ESMO Whitepaper) (Press release, TILT Biotherapeutics, SEP 17, 2021, View Source [SID1234587847]).

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The ESMO (Free ESMO Whitepaper) poster (1), presented by TILT with collaborators at the National Center for Cancer Immune Therapy Herlev Hospital, Copenhagen University, and CHU Nantes, provided an update on the company’s progress with its TILT-123 oncolytic immunotherapy asset designed to stimulate T-cells, currently in clinical trials in Denmark and France for metastatic melanoma.

Interim data from six patients shows that TILT-123 monotherapy or a combination of TILT-123 and tumor-infiltrating lymphocytes (TILs) is deemed safe with the lowest two dose levels of TILT-123. Also, the company’s engineered oncolytic virus appears to be highly tumor specific, as extended replication in tumors was seen even at the lowest dose level, without quantifiable shedding into saliva or urine.

TILT Biotherapeutics’ CEO, Akseli Hemminki, a biotech entrepreneur and oncologist who has personally treated 300 patients with eleven different oncolytic viruses, said, "The annual ESMO (Free ESMO Whitepaper) congress is one of the world’s most prestigious oncology events, and I am delighted we were able to present there about recent progress with our oncolytic immunotherapy platform. We have now proceeded to the third dose level in our T215 and T115 trials, with patients in France, Denmark, and Finland."

(1) Poster title and link: "A phase I, first-in-human, study of TILT-123, a tumor-selective oncolytic adenovirus encoding TNFa and IL-2, in participants with advanced melanoma receiving adoptive T-cell therapy with tumor-infiltrating lymphocytes." The clinical trial details are here.

Novartis reports positive health-related quality of life data for 177Lu-PSMA-617 radioligand therapy in patients with advanced prostate cancer at ESMO 2021

On September 17, 2021 Novartis reported positive health-related quality of life (HRQoL) data from its Phase III VISION study evaluating 177Lu-PSMA-617, an investigational targeted radioligand therapy, plus standard of care for metastatic castration-resistant prostate cancer (mCRPC) versus standard of care alone. Many patients with mCRPC live with reduced physical functioning as well as significant pain2,3 (Press release, Novartis, SEP 17, 2021, View Source [SID1234587822]). This data from a quality of life assessment of the VISION trial, referred to as HRQoL, showed delayed worsening of these difficult to bear symptoms in the 177Lu-PSMA-617 plus standard of care arm compared to standard of care alone arm. No new or unexpected safety concerns, including changes in creatinine clearance, were noted1. These results will be presented at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress, 17-21 September 2021.

HRQoL ad hoc analysis showed that the 177Lu-PSMA-617 plus standard of care arm resulted in an estimated 54% risk reduction in the worsening of HRQoL (measured by Functional Assessment of Cancer Therapy – Prostate (FACT-P) scale) from baseline (hazard ratio: 0.46 with 95% confidence interval (CI): (0.35, 0.61)) compared to the standard of care only arm1. In addition, 177Lu-PSMA-617 plus standard of care also resulted in an estimated 55% risk reduction of worsening of pain intensity (measured by Brief Pain Inventory – Short Form (BPI-SF) scale) from baseline (hazard ratio: 0.45 with 95% (CI): (0.33, 0.60)) compared to the standard of care only arm1.

"Patients with mCRPC suffer from many complications associated with advanced disease that can impact their quality of life2,3," said Jeff Legos, Global Head of Oncology Development, Novartis. "These new data emphasize the potential impact on quality of life that investigational 177Lu-PSMA-617 may provide as a potential new treatment option, beyond previously reported improvements in overall survival and radiographic progression-free survival4."

Two additional studies with 177Lu-PSMA-617 radioligand therapy in earlier lines of treatment for metastatic prostate cancer are ongoing, investigating potential clinical utility in the mCRPC pre-taxane setting (PSMAfore) and in the metastatic hormone-sensitive setting (PSMAddition). Novartis is also evaluating opportunities to investigate 177Lu-PSMA-617 radioligand therapy in earlier stages of prostate cancer.

About Advanced Prostate Cancer
Prostate cancer is a form of cancer that develops in the prostate gland, a small walnut shaped gland in the pelvis of men. In castration resistant prostate cancer (CRPC), the tumor shows signs of growth, such as rising Prostate Specific Antigen (PSA) levels, despite the use of hormone treatments that lower testosterone5. In metastatic CRPC (mCRPC), the tumor spreads to other parts of the body, such as neighboring organs or bones and remains unresponsive to hormone treatment5. The five-year survival rate for patients with metastatic prostate cancer is approximately 30%6.

About Phenotypic Precision Medicine in Advanced Prostate Cancer
Despite advances in prostate cancer care, there is a high unmet need for new targeted treatment options to improve outcomes for patients with mCRPC. More than 80% of prostate cancer tumors highly express a phenotypic biomarker7 called Prostate Specific Membrane Antigen (PSMA) 8-10,11,12, making it a promising diagnostic (through positron emission tomography (PET) scan imaging) and potential therapeutic target for radioligand therapy13. This differs from ‘genotypic’ precision medicine which targets specific genetic alterations in cancer cells7.

About 177Lu-PSMA-617
177Lu-PSMA-617 is an investigational PSMA-targeted radioligand therapy for metastatic castration-resistant prostate cancer. It is a type of precision cancer treatment combining a targeting compound (ligand) with a therapeutic radioisotope (a radioactive particle)14-16. After administration into the bloodstream, 177Lu-PSMA-617 binds to prostate cancer cells that express PSMA17, a transmembrane protein, with high tumor-to-normal tissue uptake14,18,19. Once bound, emissions from the radioisotope damage tumor cells, disrupting their ability to replicate and/or triggering cell death20-22. The radiation from the radioisotope works over very short distances to limit damage to surrounding cells13,14,18.

About VISION
VISION is an international, prospective, randomized, open-label, multicenter, phase III study to assess the efficacy and safety of 177Lu-PSMA-617 (7.4 GBq administered by intravenous infusion every 6 weeks for a maximum of 6 cycles) plus investigator-chosen standard of care in the investigational arm, versus standard of care in the control arm4. Patients with PSMA PET-scan positive mCRPC, and progression after prior taxane and androgen receptor pathway inhibitors, were randomized in a 2:1 ratio in favor of the investigational arm4. The study met both alternate primary endpoints of radiographic progression free survival and overall survival; secondary endpoints were also met4. The study enrolled 831 patients4.

Disclaimer
This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as "potential," "can," "will," "plan," "may," "could," "would," "expect," "anticipate," "seek," "look forward," "believe," "committed," "investigational," "pipeline," "launch," or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases such as COVID-19; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

Endeavor Biomedicines Licenses ULK1/2 Inhibitor Program From Salk Institute And Sanford Burnham Prebys To Broaden Its Precision Oncology Pipeline

On September 16, 2021 Endeavor BioMedicines, a clinical-stage precision medicine company targeting the core drivers of multiple terminal diseases including oncology and fibrosis, reported the in-licensing of a ULK1/2 inhibitor program from the Salk Institute for Biological Studies and Sanford Burnham Prebys (Press release, Endeavor BioMedicines, SEP 16, 2021, View Source [SID1234606754]). The license agreement provides Endeavor with exclusive worldwide rights to ENV-201, an orally available small molecule inhibitor of ULK1/2, a critical enzyme in a cellular recycling process called autophagy that is often linked to drug resistance in RAS- and LKB1-mutated cancers. Endeavor plans to complete IND-enabling studies and advance the program into the clinic initially in colorectal and lung cancers in the next 18 months.

"The Salk Institute and Sanford Burnham Prebys have pioneered early research on the ULK1/2 pathway in RAS-mutated cancers, including those that have become resistant to current standard of care," said John Hood, Ph.D., Co-Founder, CEO and Chairman of Endeavor. "This powerful ULK1/2 program that we have acquired is synergistic with our growing portfolio of precision medicine treatments and has the potential to be an important new treatment option for patients with life-threatening colorectal and lung cancers."

Mutations in the tumor suppressor LKB1 are found in approximately 15% of all people with non-small cell lung cancer and a significant number of individuals with other cancers, including colorectal carcinoma. LKB1 mutations remove a "brake" preventing oncogenesis and are frequently co-mutated with KRAS oncogenes which stimulates oncogenesis. These patients are generally resistant to the standard of care (chemotherapy or immuno-oncology treatment) and face a very poor prognosis. In preclinical models, the ULK1/2 inhibitor ENV-201 demonstrated single-agent activity against these tumors providing a potential therapeutic option where there is none today. Endeavor intends to advance the orally available, small molecule compound as a single-agent treatment, and the company also plans to explore combination treatment with cancer immunotherapy in refractory patients.

"Since we initially discovered how cancer cells starved of nutrients activate ULK1/2, we focused on finding a drug that could block its activity," said Nicholas Cosford, Ph.D., professor and deputy director of the NCI-designated Cancer Center at Sanford Burnham Prebys. "Using medicinal chemistry, chemical biology and rational drug design, we created compounds that inhibit ULK1/2 and we are hopeful this approach will have an impact as an anti-cancer treatment. This agreement with Endeavor BioMedicines moves our efforts closer to our goal of helping people living with cancer."

"We are excited that Endeavor BioMedicines will be advancing the ULK1/2 program into clinical development – a program that has the potential to be an extraordinary therapeutic option for patients who have certain genetically defined, life-threatening cancers," said Reuben Shaw, Ph.D., professor, Molecular and Cell Biology Laboratory, William R. Brody Chair, Salk Institute for Biological Studies. "It is the right time to pass the baton to Endeavor for late preclinical and clinical development, and it underscores the strength of San Diego’s biotech ecosystem for the benefit of patients who have significant unmet medical need."

Targeting a Cellular Recycling Progress in Cancer Biology

The laboratories of Shaw and Cosford collaborated to develop a portfolio of small molecule inhibitors of ULK1/2, a critical enzyme in a cellular recycling process called autophagy. Tumor cells use this cellular recycling process to supply much-needed nutrients and metabolites when there are not enough nutrients in the available blood supply. Tumors with high levels of autophagy are resistant to standard therapies and those patients generally have a very poor prognosis. Researchers have also found that specific genetic mutations frequently found in lung, colorectal and pancreatic cancer make those tumors highly dependent on this recycling pathway. The combined research suggests that drugs targeting ULK1/2 to inhibit autophagy should work well in genetically defined cancers alone or in combination with existing chemo-, targeted- and immuno-therapeutics.

Aravive to Participate in Fireside Chat at Cantor Fitzgerald Virtual Global Healthcare Conference

On September 16, 2021 Aravive, Inc. (Nasdaq: ARAV), a clinical-stage oncology company developing innovative therapeutics to treat life-threatening diseases, reported that Gail McIntyre, Ph.D., DABT, Chief Executive Officer of Aravive, and Reshma Rangwala, M.D., Ph.D., Chief Medical Officer of Aravive, will participate in a virtual fireside chat at the Cantor Fitzgerald Virtual Global Healthcare Conference on September 30, 2021 at 9:20 AM ET (Press release, Aravive, SEP 16, 2021, View Source [SID1234594064]). Aravive will also participate in one-on-one meetings at the conference.

This conference is being held virtually, and a live webcast will be accessible on the Events & Presentations page of www.aravive.com. An archived replay of the webcast will be available for 90 days following the webcast.

Ayala Pharmaceuticals Presents Preliminary Clinical Data from the Ongoing Phase 2 ACCURACY Trial and Announces Pre-Clinical Proof of Concept Data for Enhanced Activity of AL101 in Combination with Approved Cancer Therapies in ACC

On September 16, 2021 Ayala Pharmaceuticals, Inc. (NASDAQ: AYLA), a clinical-stage oncology company focused on developing and commercializing small molecule therapeutics for patients suffering from rare and aggressive cancers, reported new preliminary clinical data from the 6mg cohort of its ongoing Phase 2 ACCURACY trial of AL101 for the treatment of recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC) harboring Notch-activating mutations (Press release, Ayala Pharmaceuticals, SEP 16, 2021, View Source [SID1234593999]). The data is being presented at the 2021 ESMO (Free ESMO Whitepaper) Virtual Congress as an ePoster. In a separate ePoster presentation, Ayala presented new preclinical results evaluating the potential of AL101 in combination with approved cancer therapies for dual targeting of ACC tumours.

"ACC is an orphan disease with no approved therapies and patients with Notch mutations have a more aggressive disease course and poorer survival outcomes as compared to patients with Notch wild-type. R/M ACC remains a significant area of unmet need, and I am encouraged by the preliminary results that AL101 monotherapy has demonstrated to-date. Coupled with new preclinical data showing that AL101 in combination with approved targeted therapies could potentially treat a greater proportion of ACC tumors, regardless of Notch mutations, it will be exciting to see how AL101 may be developed as a viable treatment option for R/M ACC patients," said Alan L. Ho, M.D., Ph.D., Medical Oncology, Memorial Sloan Kettering Cancer Center and Lead Investigator in The ACCURACY Trial. "While these results are still preliminary, the safety profile of AL101 and the disease control rate of 70% are promising indicators in this incredibly difficult to treat patient population."

"The preliminary safety and efficacy data from the 6mg cohort of our ongoing ACCURACY trial of AL101 highlights a favourable profile. We are pleased to see that AL101’s safety profile continues to be tolerable and manageable, providing us with potential dosing flexibility as we continue to advance our development plans," said Gary Gordon, M.D., Ph.D., Chief Medical Officer of Ayala. "We continue to see strong potential for AL101 to transform the treatment landscape for R/M ACC patients with Notch mutations and we look forward to reporting additional clinical data in 2022."

Preliminary Safety and Efficacy Data from 6mg Cohort of ACCURACY Phase 2 Trial:
Ayala presented new preliminary 6mg data from its ongoing ACCURACY Phase 2 clinical trial evaluating the safety and efficacy of AL101 monotherapy for the treatment of patients with R/M ACC harboring Notch-activating mutations. The Phase 2 ACCURACY clinical trial is an open-label, single-arm, multi-center study to assess the clinical activity of AL101 using radiographic assessments of patients with R/M ACC demonstrating disease progression within 6 months prior to dosing.

As of July 9, 2021, all 42 patients enrolled in the 6mg cohort were treated and evaluable for safety and 33 were evaluable for efficacy.

Efficacy:
All evaluable patients were assessed for efficacy for a best response by investigators using RECIST 1.1 criteria.

Disease control rate (DCR) (defined as partial response and stable disease) was 70% (23/33 patients).
Partial responses (PR) were observed in 3 patients (9%).
Stable disease (SD) was observed in 20 patients (61%).
Progressive disease (PD) was observed in 8 patients (24%).
Two patients were determined to be evaluable per protocol but their scans were not available for analyses.
Study is ongoing with several patients remaining on drug as of the cutoff date.
Safety:
AL101 6mg QW treatment in patients with R/M ACC was well tolerated with manageable side effects consistent with those observed in the 4mg QW cohort with no new adverse events (AEs) specific to the 6mg cohort.

Most common treatment-related (TR) AEs of any grade were diarrhea (76%), fatigue (48%), nausea (41%), hypophosphatemia (29%), vomiting (26%) and decreased appetite (26%).
Treatment-related diarrhea was common and occurred in 32 patients (76%) and most were grades 1 and 2. Treatment-related serious diarrhea occurred in 6 patients (14%).
Serious TRAEs were reported in 31% of patients with treatment-emergent AEs leading to discontinuation in 26% of patients.
Two patients experienced a grade 4 TRAE: one patient experienced a seizure and one patient experienced drug-induced liver injury.
Four treatment-emergent patient deaths occurred (10%), one of which was assessed by the investigator to be treatment related.
Ayala plans to report additional data from the ACCURACY study in 2022.

"Our new preclinical study evaluating the potential of improved efficacy of AL101 in combination with approved targeted therapies represents a promising potential approach for additive or synergistic activity of gamma secretase inhibition when combined with various mechanisms of action," said Roni Mamluk, Ph.D., Chief Executive Officer of Ayala. "We observed stronger tumor growth inhibition in ACC PDX models with Notch pathway genes downregulated regardless of mutational status in the combination arm of the study, as compared to AL101 monotherapy. Based on these results, we believe there is a strong rationale for a combination therapy approach to treating ACC, in addition to other cancer indications in which Notch is dysregulated. We look forward to the further development of AL101 in Notch dysregulated tumors, both as monotherapy and in combination."

Preclinical Results of AL101 Combined with Other Drugs for Dual Targeting of Notch Dysregulated Tumors:
In this preclinical study evaluating the potential of combination therapy of AL101 in PDX models of ACC, Ayala compared the differential gene expression of ACC tumors versus normal matched tissue regardless of Notch activation status. Combination compounds were selected based on determination of the pathways that are implicated with approved oncology therapies, including inhibitors of Bcl2, HDAC, FGFR & CDK4/6. Based on a comparison of AL101 alone, each approved drug alone, and the combination of each drug with AL101, Ayala observed additive or synergistic activity of AL101 combined with agents of various mechanisms of action. AL101 in combination demonstrated significant tumor growth inhibition, including regressions, compared to each drug alone, showing significant benefit with dual targeting of Notch and other dysregulated pathways. Additionally, the study indicated that crosstalk between signaling pathways may increase the efficacy of AL101 in R/M ACC regardless of Notch mutational status. These preclinical results demonstrated a compelling rationale for potential expansion to a larger portion of ACC patients and to additional cancer indications.

About Adenoid Cystic Carcinoma (ACC)

ACC is a rare malignancy of the secretory glands including salivary glands, accounting for about 10% of all salivary gland tumors with an annual incidence of 3,400 in the U.S. There is currently no approved standard of care for patients with recurrent/metastatic ACC. Patients with locoregional disease undergo surgery and radiation therapy, with recurring disease treated by chemotherapy. ACC is an immunologically "cold" tumor that is refractory to chemotherapy, with a recurrence rate of about 60% after initial surgery. The Notch pathway has been determined to be an oncogenic driver of ACC and its dysregulation plays a key role in tumorigenesis and correlates with a distinct pattern of metastasis and a poor prognosis.

About AL101

AL101 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 two Phase 2 clinical studies, ACCURACY and TENACITY, in patients with adenoid cystic carcinoma (ACC) and in patients with triple negative breast cancer (TNBC), respectively. AL101 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 AL101 from Bristol-Myers Squibb Company in November 2017. AL101 was granted U.S. FDA Fast Track Designation and Orphan Drug Designation for the treatment of ACC.