On September 16, 2021 Translational Drug Development (TD2), a leading precision oncology contract research organization (CRO), and Deep Lens reported a strategic partnership that will enhance access to tailored oncology treatments and novel clinical studies for patients receiving care in community oncology practices (Press release, TD2, SEP 16, 2021, View Source [SID1234587862]). The partnership will enable TD2 to offer Deep Lens’ proprietary clinical trial matching solution, VIPER, as well as other research coordination services, to its drug development clients, thereby improving the ability for hospitals, trial coordinators, investigators, and patients to promote, collaborate, participate in and manage oncology clinical trials.

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There has been tremendous growth in precision oncology, or the development of treatments that target the molecular profile of a patient’s tumor. The number of approved novel immunotherapy and targeted agents for different cancer indications has increased dramatically over the past five years, as has the number of clinical trials studying their safety and efficacy1. However, identifying and recruiting eligible patients for precision medicine trials can be challenging. Complex eligibility criteria coupled with very narrow timelines for enrollment can be difficult and labor intensive for study sites and sponsors. The blending of TD2 expertise in precision oncology with the Deep Lens’ clinical trial matching solution platform will improve efficiencies in trial recruitment and enrollment, increase patient access to trials, specifically at community oncology sites, where the majority of patients are diagnosed, and facilitate enhanced access to the right care, for the right patient, at the right time.

The Deep Lens VIPER platform automates the study screening process from time of patient diagnosis to qualified enrollment through the ingestion of genomic data, EMR, pathology, radiology and other patient data. VIPER provides rich data and interactive reporting capabilities to aggregate site and study-level patient data, making it easier for sites to achieve study objectives.

"The highest priority for TD2 is to ensure every patient that participates in a TD2 clinical trial has the opportunity of achieving clinical benefit," said Stephen Gately, President and CEO at TD2. "Working with the Deep Lens platform and coordinators, TD2 can match cutting edge science and molecular testing results with clinical protocol inclusion/exclusion criterion to ensure patients get access to clinical trials where there is an increased likelihood of benefit. We are truly excited that this partnership has the potential to change the way early phase oncology trials are run and enrolled, taking the pressure off the sites to find the next patient and putting the focus on the right patient."

"The drug development process has expanded significantly as our knowledge and understanding of cancer has evolved, and this has resulted in an increase in the number of precision medicine trials studying targeted therapies. While this is a positive step in our battle against cancer, unfortunately, the large majority of these trials fail to enroll enough patients to progress," said Dave Billiter, co-founder and chief executive officer of Deep Lens. "Our approach is to reach more patients by working in the community oncology setting, where the majority of these patients are diagnosed and treated. The partnership with TD2 will allow us to support drug developers to identify and enroll patients into trials for which they are eligible – through our AI-based platform, we can do this right at the time of a patient’s diagnosis. This means more patients have access to life-changing therapies sooner, and drug developers can more effectively test the safety and efficacy of new therapies in more diverse populations."

On September 16, 2021 BWX Technologies, Inc. (NYSE: BWXT) reported that its BWXT Medical Ltd. subsidiary (BWXT Medical) has entered into an agreement with Bayer AG (Bayer) to develop Actinium-225 (Ac-225) supply and further partnering opportunities on finished products as both companies broaden their respective commercialization strategies for targeted radionuclide therapies (TRTs) and other innovative products (Press release, Bayer, SEP 16, 2021, View Source [SID1234587861]).

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Ac-225 is a highly powerful radioisotope used in targeted alpha therapies (TATs), an emerging class of radionuclide therapy for various tumors with a high unmet medical need, delivering alpha radiation directly to tumors either via its bone-seeking properties (radium-223) or by combining alpha radionuclides such as Ac-225 with specific tumor-seeking targeting vectors.

BWXT Medical is a global supplier of medical isotopes and radiopharmaceuticals. Bayer is a global enterprise with core competencies in the life science fields of health care and nutrition. The oncology franchise at Bayer includes six marketed products including Xofigo (radium-223 dichloride, the first and only approved TAT) and several other TATs in different stages of development, including an investigational Ac-225 labeled differentiated prostate-specific membrane antigen (PSMA) small molecule for the treatment of prostate cancer.

BWXT Medical plans to utilize its deep relationships with strategic partners in irradiation services and development of Ac-225. Much like BWXT Medical’s other products, processing and manufacturing would then be conducted at BWXT Medical facilities. Bayer and BWXT Medical have structured the evolution of their relationship to progress over stages, and the complete terms of the commercial agreements will be finalized at a later date.

"Bayer has long been a leader in targeted alpha therapies with Xofigo, and we share their aspiration of making a significant difference in the lives of people suffering from cancer," said Martyn Coombs, president of BWXT Medical. "Targeted radionuclide therapies are anticipated to be a significant growth market in the future, and we plan to leverage our differential strengths in nuclear medicine to be a strong partner to Bayer for Ac-225-based products and other opportunities."

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 [SID1234587860]). 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.

On September 16, 2021 Nouscom, a clinical stage immuno-oncology company developing off-the-shelf and personalized cancer neoantigen vaccines, reported initial results from the Phase 1 trial of NOUS-209, the first clinical results for the company. NOUS-209, an off-the-shelf cancer vaccine based on shared neoantigens, in combination with the anti-PD-1 checkpoint inhibitor pembrolizumab, was shown to be safe, highly immunogenic, and demonstrated promising early signs of clinical efficacy with no dose-limiting toxicities, in the treatment of Microsatellite Instable High (MSI-H) gastric, colorectal and gastro-esophageal junction solid tumors (Press release, NousCom, SEP 16, 2021, View Source [SID1234587857]).

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The results were presented in an e-poster (#1004P) at the European Society of Molecular Oncology (ESMO) (Free ESMO Whitepaper) congress which is taking place September 16 to 21, 2021. The primary author of the poster is Dr Michael Overman, Principal Investigator (PI) of the trial and Professor in the Department of Gastrointestinal Medicine at the University of Texas MD Anderson Cancer Center.

Dr Michael Overman, PI of the trial, said: "There is still a significant unmet need in the treatment of MSI-H tumors, with many patients not responding to a single agent immunotherapy. The technology developed by Nouscom is innovative and looks to address this issue – the Phase 1 results are very encouraging, and this data provides exciting early validation of the multi-neoantigen approach in humans, supporting the compelling preclinical data seen previously. I look forward to reporting on the fully enrolled Phase 1 results.”

The Phase 1 study (NCT04041310) is a multicenter, open label, multiple cohorts, first-in-human clinical study of NOUS-209 in combination with pembrolizumab, designed to evaluate safety, tolerability and immunogenicity and to detect preliminary evidence of anti-tumor activity. The trial enrolled 21 patients in the US.

Furthermore, the trial was designed to define the recommended Phase 2 dose (RP2D), with dose level 2 selected as RP2D, based on safety and tolerability, and supportive data gained from infectious disease studies.

"Presenting the first clinical dataset from our lead candidate NOUS-209 for the treatment of MSI-H solid tumors at ESMO (Free ESMO Whitepaper), a major oncology conference, is an important milestone for Nouscom." Dr Marina Udier, Chief Executive Officer of Nouscom added. "We are very pleased to have demonstrated NOUS-209 is safe, highly immunogenic and shows early signs of clinical efficacy. NOUS-209 leverages a core strength of the company’s platform, namely the capacity of its proprietary viral vectors to encode a large number of neoantigens."

MSI-H tumors are characterized by a defective DNA mismatch repair system, which generates highly immunogenic frame shift peptides (FSPs) that are not found on healthy tissue. NOUS-209 encodes 209 FSP cancer neoantigens, selected by Nouscom’s proprietary GENESIS (GE(netic)NE(oantigen)S(election)I(n)S(ilico)) algorithm, so that each patient’s tumor will express, on average, 50 of these neoantigens.

NOUS-209 is Nouscom’s lead candidate and has been developed from its proprietary heterologous prime/boost viral vector platform, which combines viral vector vaccines based on neoantigens, with other immunomodulators to harness the full power of the immune response. The vaccine is composed of four Great Ape Adenoviral (GAd) and four Modified Vaccinia Ankara (MVA) vectors.

The poster is available to registered congress participants, speakers and viewers on the ESMO (Free ESMO Whitepaper) website (View Source).

About NOUS-209

Nous-209 is an off-the-shelf immunotherapy for Microsatellite Instable High (MSI-H) tumors. The design of NOUS-209 is based on the neoantigens created by frameshift mutations (frameshift peptides, FSP) and are shared across multiple MSI tumors, not found in healthy tissues. NOUS-209 comprises 209 shared FSP neoantigens, selected by a proprietary algorithm on the basis than an average of 50 neoantigens on any patient’s tumor will be shared with those in NOUS-209. These FSPs were cloned into proprietary Great Ape Adenoviral (GAd) and Modified Vaccinia Ankara (MVA) vectors to generate the viral-vectored vaccine.

NOUS-209 is in Phase 1 clinical trial in combination with the anti-PD-1 checkpoint inhibitor pembrolizumab in US patients with gastric, colorectal and gastro-esophageal junction MSI tumors.

On September 16, 2021 Laekna Therapeutics, an emerging innovative biotech company based in China’s "Zhangjiang Pharma Valley" and New Jersey, USA, focusing on the development of ground-breaking innovative therapies to treat cancer and liver diseases, reported positive results in two clinical studies for the treatment of early and late stages of prostate cancer respectively at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021 today (Press release, Laekna Therapeutics, SEP 16, 2021, View Source [SID1234587856]).

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The first study with LAE001 monotherapy targeting early stage of prostate cancer, and the second study with combination therapy of LAE001 + afuresertib in drug-resistant late stage prostate cancer, demonstrated positive and encouraging results by Laekna Therapeutics.

E-Poster: 597P

A Phase I Dose-Escalation Study of LAE001 In Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Lead author and presenter: Dr. Dingwei Ye (Shanghai, China)

This ClinicalTrials NCT03843918 is a phase I dose-escalation and expansion study of LAE001 monotherapy without steroid, in patients with metastatic castration-resistant prostate cancer (mCRPC). LAE001 is the first CYP17A1/CYP11B2 dual inhibitor globally.

Results:

As of May 25, 2021, 27 pts (16, 5, 3, 3 pts in the 50, 75, 100 and 125 mg BID cohorts, respectively) enrolled in the phase Ia & Ib part and had a median 7.3 months follow up (1-25 months). Based on safety data, 50mg BID of LAE001 was selected as the RP2D; no DLT nor AE leading to discontinuation was reported under the RP2D, and the related serious adverse event (SAE) in the RP2D cohort was 6%.

Out of 15 patients treated in 50mg bid cohort, 11 pts (73%) had a >50% best PSA decline from baseline, among whom 6 pts (40%) had >90% PSA decline from baseline.
2 pts (50mg bid) had a PSA response that sustained for >52 weeks; 81% patients are ongoing treatment at the cut-off date.
Conclusions:

LAE001 monotherapy without steroid co-use is safe and well-tolerated at 50mg BID level (RP2D). The preliminary antitumor activity of LAE001 monotherapy at RP2D level supports the potential clinical benefit of treating patients with mCRPC. Further expansion phase 1b and II[1] study at RP2D is ongoing.

E-Poster: 599P

A Phase I Dose-Escalation Study of LAE001/Prednisone Plus Afuresertib in Patients with Metastatic Castration-Resistant Prostate Cancer (mCRPC) Following Standard of Care (SOC) Treatment

Lead author and presenter: Dr. Alberto Bessudo (Encinitas, CA, United States of America)

This ClinicalTrials NCT04060394 is a phase I dose-escalation study of a combination therapy with LAE001/prednisone plus afuresertib in patients with metastatic castration-resistant prostate cancer (mCRPC) following failed average 3,3 lines of prior SOC treatments. Afuresertib (LAE002) is an oral, small molecule pan-AKT kinase inhibitor. Whereas LAE001 is the first CYP17/CYP11B2 dual inhibitor globally.

Results:

As of 06/29/2021, 14 pts (8 in cohort 1 and 6 in cohort 2) received study treatment with median 12.5 months follow up. The dose of LAE001 75 mg BID/prednisone 5 mg BID and afuresertib 125 mg QD was determined as the RP2D. 2 DLTs were reported in cohort 1 (thrombocytopenia) and cohort 2 (skin rash), respectively, and only one non-DLT grade >= 3 treatment-emergent adverse events (TEAE) (skin rash) in cohort 2 (RP2D).

2 pts had a PSA response (2/10, 20%). Among 5 pts who have measurable lesions, 1 PR and 2 SDs were reported.
The 10 evaluable pts on average had failed 3.3 lines of SOC.
Conclusions:

The combination therapy of LAE001 75mg BID/prednisone 5mg BID and afuresertib 125mg QD was determined as the RP2D. The preliminary antitumor activity under the RP2D supports the potential clinical benefit for treating drug-resistant mCRPC and moves forward this study to phase II stage.

Encouraging results for patients with prostate cancer to soon benefit from LAE001 and afuresertib

"As an emerging innovative biotech company, Laekna Therapeutics is proud to make its debut at the ESMO (Free ESMO Whitepaper) Congress. We are very pleased to present the results from two clinical studies at this influential academic conference," said Dr Yue Yong, Chief Medical Officer of Laekna Therapeutics.

Prostate cancer is the most common cancer occurring in men world-wide. The monotherapy trial of LAE001 showed that the drug can be used without prednisone, and still demonstrate a tolerable safety profile and strong anticancer efficacy. Laekna plans to further develop LAE001 for patients with mHSPC who require a much longer treatment duration, and would benefit more from the ability to use LAE001 without prednisone.

Currently there is limited treatment options for NAAR drug-resistant mCRPC patients. The combination therapy of LAE001 and afuresertib is intended to benefit patients with PTEN/PIK3CA/AKT alterations.

"The topline data reported by Laekna Therapeutics at the ESMO (Free ESMO Whitepaper) Congress, a top international academic conference marks significant progress for Laekna’s clinical programs," Dr Yue Yong remarked. "With the continued advancement of the above two studies, we have seen more encouraging results in the enrolled patients in the past three months. We hope patients with both early- and late-stage prostate cancer can soon benefit from these two new innovative medicines."

[1] Patient enrollment of the Phase II trial is expected to start between the fourth quarter of 2021 and the first quarter of 2022

About European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2021

The ESMO (Free ESMO Whitepaper) Congress is one of the most influential oncology forums, where participants present the latest advances in the treatment of cancer and have cross-discipline exchanges and discussions. In response to the COVID-19 pandemic, the congress will be held virtually September 16-21, 2021.

About CYP17A1/CYP11B2 dual inhibitor (LAE001)

LAE001 is the first CYP17/CYP11B2 dual inhibitor globally. It is a novel, potent, non-steroidal, reversible dual inhibitor of CYP17 and CYP11B2 (aldosterone synthase) that blocks both androgen and aldosterone synthesis. It will be used as a treatment option for metastatic prostate cancer.

Compared to Abiraterone acetate, a CYP17 enzyme inhibitor that causes hyperaldosteronism, which requires long-term use of corticosteroids and may cause serious side effects, LAE001 has demonstrated similar therapeutic efficacy and improved safety profile in patients with drug-resistant mCRPC. Due to its dual inhibition of both CYP17 and CYP11B2, two critical enzymes for testosterone and aldosterone synthesis, LAE001 does not increase aldosterone level, therefore reduces the risk of cardiovascular toxicity and hepatotoxicity related to long-term prednisone use.

About Afuresertib (LAE002)

Afuresertib (LAE002) is a differentiated oral, small molecule pan-AKT kinase inhibitor that has been investigated in over 10 Phase 1/2 clinical trials, including ovarian cancer, gastric cancer, multiple myeloma, and melanoma. These studies have demonstrated that afuresertib has strong anti-cancer activities and a tolerable safety profile. The global randomized, open-label, multi-center Phase 2 PROFECTA-II clinical trial of afuresertib is the world’s first registration-directed clinical study of a pan-AKT kinase inhibitor to treat platinum-resistant ovarian cancer.

In recent years, AKT (a serine/threonine-protein kinase) has emerged as an important mechanism in oncology, as it plays an important role in regulating various cell functions such as metabolism, survival, proliferation, tissue invasion, and chemotherapy resistance. PTEN deletion and AKT/PIK3CA alteration may lead to excessive activation of the AKT signaling pathways, which is one of the key drivers for cancer growth. The increased activation of the AKT signaling pathway is particularly common in recurrent ovarian cancer, breast cancer, and prostate cancer.