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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.

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"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.

Gritstone Announces Private Placement Financing of $55.0 Million

On September 16, 2021 Gritstone bio, Inc. (Nasdaq: GRTS), a clinical-stage biotechnology company developing next generation cancer and infectious disease immunotherapies and vaccines, reported a $55.0 million private investment in public equity (PIPE) financing from the sale of 5,000,000 shares of its common stock at a price per share of $11.00 (Press release, Gritstone Oncology, SEP 16, 2021, View Source [SID1234592013]). Gross proceeds from the PIPE financings total $55.0 million, before deducting placement agent fees and offering expenses. The PIPE is being led by Frazier Life Sciences Public Fund, with additional participation from Redmile Group and Gilead Sciences.

"As long-term backers of Gritstone, we continue to be impressed by the company’s progress and emergence as a leader in development of next generation immunotherapies and vaccines for cancer and infectious diseases," said Jamie Brush, M.D., General Partner and Portfolio Manager of the Frazier Life Sciences Public Fund. "We believe Gritstone’s EDGE platform and integrated vaccine manufacturing capabilities uniquely position the company to rapidly expand into infectious disease vaccine development with a potentially refrigerator stable self-amplifying mRNA vaccine platform. This financing will help ensure Gritstone has the resources to move quickly in this exciting new area, and we are excited to support the company in its next phase of growth."

The closing of the PIPE financing is subject to customary closing conditions and is expected to close by September 17, 2021. Cowen served as the sole placement agent for the PIPE financing.

The securities sold in this private placement have not been registered under the Securities Act of 1933, as amended, and may not be offered or sold in the U.S. except pursuant to an effective registration statement or an applicable exemption from the registration requirements. Gritstone bio has agreed to file a registration statement with the Securities and Exchange Commission registering the resale of the shares of common stock issued in this private placement.

This press release shall not constitute an offer to sell or a solicitation of an offer to buy these securities, nor shall there be any sale of these securities in any state or other jurisdiction in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of any such state or other jurisdiction.

ALX Oncology Announces Initiation of Investigator-Sponsored Trial of Evorpacept (ALX148) in Patients with Indolent and Aggressive Non-Hodgkin Lymphoma

On September 16, 2021 ALX Oncology Holdings Inc., ("ALX Oncology") (Nasdaq: ALXO), a clinical-stage immuno-oncology company developing therapies that block the CD47 checkpoint pathway, reported the initiation of a Phase 1/2 investigator-sponsored trial of evorpacept (also known as ALX148), a next generation CD47 blocker, in combination with rituximab and lenalidomide for the treatment of patients with indolent and aggressive non-Hodgkin lymphoma ("NHL") (Press release, ALX Oncology, SEP 16, 2021, View Source [SID1234591864]). This study is being led by Dr. Paolo Strati at The University of Texas M.D. Anderson Cancer Center ("MDACC"), one of the largest multidisciplinary programs in the U.S. for treating NHL.

"We are excited to launch this study that builds upon the promising anti-tumor activity and tolerability observed from ASPEN-01, ALX Oncology’s Phase 1b study to investigate the combination of evorpacept and rituximab in patients with advanced relapsed and refractory NHL," said Paolo Strati, M.D., Assistant Professor, Department of Lymphoma-Myeloma and Department of Translational Molecular Pathology, MDACC. "NHL remains a difficult-to-treat cancer and patients are in desperate need for more therapeutic options to help improve disease outcomes. From a mechanistic perspective, the combination of a CD47 blocker and rituximab, as well as the combination of lenalidomide and rituximab, have demonstrated clinical activity against NHL. As these doublet combinations act through different but synergistic mechanisms, and have non-overlapping individual toxicity profiles, we anticipate the triplet combination of evorpacept, rituximab and lenalidomide will positively impact efficacy without increasing toxicity."

About Non-Hodgkin Lymphoma

Approximately 500,000 people worldwide are diagnosed with NHL each year. In the U.S., NHL is the seventh most common type of cancer, and over 80,000 newly diagnosed cases of NHL are estimated in 2021. Treatment options are currently limited and resistance to existing therapies or relapse following treatment is common. The most prevalent form of NHL, accounting for about 40% of newly diagnosed NHL cases, is an aggressive form called diffuse large B-cell lymphoma ("DLBCL"). Patients with relapsed or refractory DLBCL have an extremely poor prognosis with a median survival of approximately 6 months. Indolent lymphomas comprise another common form of NHL, especially among elderly individuals, where safe and effective chemotherapy-free options for these patients are urgently needed.