On December 14, 2021 Cellworks Group, Inc., a world leader in Personalized Medicine in the key therapeutic areas of Oncology and Immunology, reported the results from two clinical studies using the Cellworks Biosimulation Platform and Computational Omics Biology Model (CBM) to predict therapy response for individual MDS patients were featured in two poster presentations at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition held December 11-14, 2021 in Atlanta, Georgia (Press release, Cellworks, DEC 14, 2021, View Source [SID1234597117]). The complete results from these clinical studies are available online in the ASH (Free ASH Whitepaper) Meeting Library as Abstract 2615 and Abstract 3690.

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In the ASH (Free ASH Whitepaper) Abstract 2615 study, the Cellworks Biosimulation Platform and CBM identified genomic and molecular markers for decitabine (DAC) plus valproic-acid (VPA) treatment response in patients with Myelodysplastic Syndromes (MDS). In the ASH (Free ASH Whitepaper) Abstract 3690 study, the Cellworks Biosimulation Platform and CBM identified immune modulation as a key pathway for predicting azacitidine (AZA) response in MDS.

"There is a need for a predictive clinical approach that can stratify MDS patients according to their chance of a favorable outcome from current therapies, while also identifying and predicting their responses to new and emerging treatment options," said Dr. Michael Castro, MD, Chief Medical Officer at Cellworks. "Ideally, patients predicted to be non-responders could be offered to participate in a clinical trial for a new therapy or combination treatment where they were predicted to have a higher likelihood of response based on their genetic biomarkers. By using Cellworks MDS biomarker identifications and therapy response predictions in advance of participation in a clinical trial, pharmaceutical companies can increase the success rate of trials and accelerate the approval timeframe for new treatments."

The Cellworks Biosimulation Platform simulates how a patient’s personalized genomic disease model will respond to therapies prior to treatment and identifies novel drug combinations for treatment-refractory patients. The platform is powered by the groundbreaking Cellworks Computational Omics Biology Model (CBM), a network of 4,000+ human genes, 30,000+ molecular species and 100+ signaling pathways. By reliably predicting an individual patient’s therapy response prior to receiving the treatment, the Cellworks Platform can guide selection of the optimal treatment, help patients avoid ineffective therapies and improve patient outcomes.

Clinical Study: ASH (Free ASH Whitepaper) Abstract 2615

Biosimulation using the Cellworks Computational Omics Biology Model (CBM) identifies genomic and molecular markers for decitabine (DAC) plus valproic-acid (VPA) treatment response in patients with Myelodysplastic Syndromes (MDS).

Background

DNA methyltransferase inhibition (DNMTi) with hypomethylating agents (HMA), azacitidine (AZA) or decitabine (DAC), remains the mainstay of therapy for most high-risk MDS patients. However, only 40-50% of MDS patients achieve clinical improvement with DNMTi. This study explored the molecular basis of observed clinical response in a group of patients treated with DAC and valproic-acid (VPA). Biosimulations were conducted on each patient-specific disease model to measure the effect of DAC + VPA according to a cell growth score.

Results

In the biosimulation, VPA is a relatively weak HDAC inhibitor, but it also inhibits GSK3B and in turn increases beta-catenin (CTNNB1) levels. Additionally, monosomy 7 associated with loss of CAV1, HIPK2 and TRRAP also caused high CTNNB1, thereby further contributing to drug resistance. Biosimulation correctly identified that 7 of 8 patients with these genomic findings were clinical non-responders to VPA, indicating that CTNNB1 status is likely to predict treatment failure from the VPA + HMA combination in this disease. By contrast, high levels of c-MYC predict response to VPA + HMA combination.

Conclusions

Cellworks Biosimulation Platform found that signaling pathway consequences related to CTNNB1 and c-MYC modulation predict response to DAC + VPA. Although HMA plus HDAC inhibition can be generally beneficial for MDS, variable mechanisms of action among various HDAC inhibitors and unique patient disease characteristics should be considered for optimal treatment selection. Also, CTNNB1 emerged from the Cellworks biosimulations as a therapeutically relevant target in MDS that determines whether VPA synergizes or antagonizes the effect of other agents in this challenging subtype of MDS.

Clinical Study: ASH (Free ASH Whitepaper) Abstract 3690

Biosimulation using the Cellworks Computational Omics Biology Model (CBM) identifies immune modulation as a key pathway for predicting azacitidine (AZA) response in MDS.

Background

Only 40-50% of MDS patients achieve clinical improvement with DNMTi, the mainstay of therapy for the majority of high-risk MDS patients. Recently, a discovery of immune modulation by HMA has emerged. Although the PD-L1/PD1 blockade plus HMA has been recognized as a beneficial combination, there are no established markers to guide decision-making. This study analyzed the utility of immunomic profiling of chromosome 9 copy number status as a significant mechanism of immune evasion and HMA resistance.

Results

Although AZA treatment increased tumor associated antigens and interferon signaling, it also increased PD-L1 expression to inactivate cytotoxic CD8(+) T cells. Copy number alternations of the chromosome 9p region were found to significantly drive PD-L1 expression with multiple genes such as CD274, IFNA1, JAK2, PDCD1LG and KDM4C playing a role in PD-L1 regulation further increasing immune suppression.

Conclusion

Based on the results from the Cellworks Biosimulation Platform and Computational Biology Model (CBM), copy number variants of chromosome 9p and 16 can be used as biomarkers for selecting patients that may achieve high clinical benefit from addition of immune checkpoint inhibitors to HMA regimen.

On December 14, 2021 Numab Therapeutics AG (Numab) and 3SBio Inc. ("3SBio", HKEX:1530) reported that 3SBio’s subsidiary Sunshine Guojian Pharmaceutical (Shanghai) Co., Ltd. ("Sunshine Guojian") exercised its option for an exclusive regional license for the development and commercialization of NM28, a potential best-in-class bivalent mesothelin (MSLN)-targeting CD3 T cell engager (Press release, Numab, DEC 14, 2021, View Source [SID1234597111]).

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Under the terms of this collaboration, which builds on the existing relationship between the two parties established in 2019, Sunshine Guojian will have exclusive rights to develop and commercialize NM28 in the Greater China area, including mainland China, Hong Kong, Macao and Taiwan. Numab retains NM28 rights for the rest of the world.

"We are very pleased to enter into this agreement with Sunshine Guojian, which illustrates our global development strategy to form regional partnerships in Asia for our proprietary assets," said David Urech, Ph.D., Founder and Chief Executive Officer of Numab Therapeutics. "NM28 is a next generation T cell engager for the therapy of mesothelin-expressing tumors based on our MATCHTM-4 platform that allows for bivalent interaction with mesothelin and therefore holds the potential for a larger therapeutic window over conventional T cell engagers."

"Collaborating with the world’s leading technology platforms and biotech companies to develop high-quality drug candidates is a central pillar of our growth strategy. We are looking forward to working with Numab on this very exciting cancer therapy targeting difficult to treat tumors. This alliance is in line with our goal to expand our pipeline with a diverse set of first-in-class multispecific antibodies," said Dr. Jing Lou, Chairman and Chief Executive Officer of 3SBio.

About NM28
NM28 consists of four stabilized and humanized antibody variable domain fragments directed against MSLN, CD3 and human serum albumin (HSA). MSLN is commonly expressed in a variety of tumor cells, including mesothelioma, lung, biliary, ovarian, breast and pancreatic cancer. NM28 is designed to be resistant to the scavenging effect of soluble MSLN shed from tumor cells to improve efficacy, and to discriminate between tumor cells and MSLN-expressing normal cells to improve safety when compared to monovalent T cell engaging approaches targeting MSLN.

On December 14, 2021 Oncotelic Therapeutics, Inc. ("Oncotelic" or the "Company") (OTCQB:OTLC), a leading developer of TGF-β therapeutics for oncology and virology, reported that the Company’s Chief Clinical Officer and Board Director, Dr. Anthony Maida, will present at the upcoming 2nd Annual TGF-β for Immuno-Oncology Drug Development Summit (tgf-beta-summit.com), which will take place virtually from January 25, 2022 to January 27, 2022 (Press release, Oncotelic, DEC 14, 2021, View Source [SID1234597108]).

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"There is significant worldwide interest in the clinical application of anti-TGF-β inhibitors, in combination with checkpoint inhibitors, as well as other immuno-oncology and chemotherapeutic options. We look forward to sharing the clinical promise of OT-101 in this setting." noted Dr. Anthony Maida, Chief Clinical Office – Translational Medicine.

TGF-β has been recognized by drug developers, for many years, as holding vast therapeutic potential due to its vital role in cell functioning and signaling. But its complex nature and its ability to be both tumor promoting and tumor suppressing has presented many obstacles for the industry. However, the field appears to be at a tipping point at present, with more candidates moving through clinical evaluation, pointing to an explosion of new data on the way.

"I am excited that we have the opportunity to join other professionals in the field in January to explore novel insights into targeting TGF-β from discovery through clinical testing, and to learn from fellow colleagues such as Genentech, AbbVie, Takeda, and Mestag Therapeutics." noted Dr. Vuong Trieu, CEO and Chairman of Oncotelic.

OT-101 is a first-in-class anti-TGF-β ribonucleic acid ("RNA") therapeutic that has exhibited single agent activity in relapsed/refractory cancer patients in multiple clinical trials. OT-101 has also demonstrated activity against the SARS-CoV-2 virus, the virus that causes COVID-19, and is currently being evaluated in the Company’s C001 clinical trial against hospitalized severe COVID-19 patients. Both tumor cells and SARS-Cov-2 induce TGF-β as part of their immune evasion mechanism.

Consequently, inhibiting TGF-β through therapeutic use of OT-101 carries significant potential to help both cancer and COVID patients in the future.

Recent analyst report for Oncotelic can be accessed here: View Source

Recent Dr. Anthony Maida interview on our clinical program can be accessed here: View Source

On December 14, 2021 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) ("Actinium" or the "Company"), a leader in the development of targeted radiotherapies for patients with unmet needs reported that updated data from the recently complete Actimab-A and CLAG-M Phase 1 combination trial being conducted at the Medical College of Wisconsin (MCW) was presented at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (ASH) (Free ASH Whitepaper) that is being held December 11 – 14, 2021 in Atlanta, Georgia and virtually (Press release, Actinium Pharmaceuticals, DEC 14, 2021, View Source [SID1234597107]). This Phase 1 trial was a dose escalation study that evaluated Actimab-A, a CD33 targeting antibody radiation conjugate (ARC) armed with the alpha-emitting radioisotope Actinum-225, combined with CLAG-M (Cladribine, Cytarabine, G-CSF and Mitoxantrone), a salvage chemotherapy regimen for patients fit for intensive therapy.

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Actimab-A + CLAG-M Phase 1 Results:

Complete remissions (CR/CRp) in all dose cohorts
80% overall response rate (CR/CRp/MLFS) in patients receiving less than 4 lines of prior therapy with a total of 10 complete remissions across all four dose cohorts
72% MRD negativity rate determined by flow cytometry compares favorably to 39% MRD negativity rate with CLAG-M alone in MCW’s institutional experience1
60% response rate in patients receiving prior venetoclax therapy including 4 patients that achieved a complete remission
75% of patients proceeded to a bone marrow transplant, excluding patients with prior transplant experience
Median time to best response was 40 days
No 30-day mortality
0.75uCi/kg of Actimab-A identified as recommended Phase 2 dose
Dr. Sameem Abedin, Assistant Professor of Medicine, Medical College of Wisconsin, Division of Hematology and Oncology and Principal Investigator of the study, commented, "We are excited to have completed dose escalation and to report the Phase 1 results of this novel combination of CLAG-M with Actimab-A. AML is known to be highly radio-sensitive, but we cannot treat AML effectively with external radiation sources. Actimab-A solves this issue by directing the potent alpha-emitting radioisotope Actinium-225 at the cellular level inside the body to CD33, which is expressed in virtually all AML patients. Based on our experience with Actimab-A as a single agent, we believed that in combination with CLAG-M it would improve remission rates and the depth of remissions while being safe, given the non-overlapping mechanisms of action. We are very encouraged by the high rates of remissions with MRD negativity, indicating deep responses, and the high number responses seen in patients that had previously failed venetoclax, which is becoming an increasingly larger portion of the AML patient population. Also of note is the high number of patients able to proceed to bone marrow transplant on the study. We look forward to continuing to study this novel combination."

Dr. Avinash Desai, Actinium’s Chief Medical Officer, said, "This study will prove invaluable to our future development of Actimab-A. There are several positive findings from this study including high rates of MRD negativity, strong responses in patients failing venetoclax therapy and high rates of transplant, which all represent future development opportunities. With these data and the recommended Phase 2 dose level determined, we look forward to finalizing our future development strategy for Actimab-A and CLAG-M for patients with relapsed or refractory AML. In addition, these results support our broader strategy of leveraging the differentiated mechanism of targeted radiotherapy utilizing Actimab-A as a backbone in combination with other therapeutic modalities to improve patient outcomes."

Sources:

1)Mushtaq et al. Leukemia & Lymphoma 2020

On December 14, 2021 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) ("Actinium" or the "Company"), a leader in the development of targeted radiotherapies for patients with unmet needs reported that data from the Phase 1 portion of its Actimab-A and venetoclax combination trial in patients with relapsed or refractory acute myeloid leukemia (AML) was presented at the 63rd American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition (ASH) (Free ASH Whitepaper) that is being held December 11 – 14, 2021 in Atlanta, Georgia and virtually (Press release, Actinium Pharmaceuticals, DEC 14, 2021, View Source [SID1234597105]).

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Patients enrolled in the study to date have been a median age of 64, with 75% of patients having adverse cytogenetics and 50% of patients having received and failed prior venetoclax and hypomethylating agent (HMA) therapy. The trial will continue to dose escalate to a fourth dose cohort of 1.5 μCi/kg to determine the dose for the Phase 2 portion of the study. Key findings from the study to date include:

67% overall response rate (ORR) with 2 remissions in patients with a TP53 mutation
One patient achieving remission has been on study for over 230 days and remains in follow-up after previously failing venetoclax HMA therapy before enrolling on Actimab-A study
No early mortality (< 30 days) in the study to date
"Venetoclax has become a staple therapy for patients with AML, however, patients with relapsed or refractory disease continue to represent a major unmet medical need with median overall survival reported to be 5.5 months and only 3 months in patients that do not respond to venetoclax therapy. After confirming a mechanistic synergy between Actimab-A and venetoclax, we were eager to begin this combination clinical trial. This initial data is highly encouraging thus far, particularly the 2 remissions in patients with a TP53 mutation, which is associated with very poor clinical outcomes. These data support advancing to the Phase 2 portion of the study and based on the high response rates in TP53 patients, we will actively explore a development strategy with this patient population. We look forward to completing the Phase 1 dose escalation portion of this study, to determine the recommended Phase 2 dose so we can continue to advance this novel combination given the high unmet need of the patient population," said Avinash Desai, Actinium’s Chief Medical Officer.

Venetoclax is a targeted therapy for patients with AML that targets Bcl-2, a protein that is overexpressed in certain cancers that enables cancer cells to evade apoptosis or programmed cell death. Actinium evaluated this novel combination after identifying that Actimab-A, via its targeted radiotherapy mechanism, could deplete Mcl-1, a protein that is upregulated in refractory AML cells and mediates resistance to venetoclax. In preclinical studies, Actinium showed that Actimab-A combined with venetoclax, resulted in greater AML cell killing than either Actimab-A or venetoclax alone and resulted in enhanced tumor regression and survival in venetoclax-resistance AML tumor models. The Phase 1/2 trial is a multi-center clinical trial that will enroll up to 38 patients with the Phase 2 portion of the trial to evaluate for safety, minimal residual disease status, disease free survival and overall survival.

Source:

Tenold et al. (2021) Outcomes of Adults with Relapsed/Refractory Acute Myeloid Leukemia Treated With Venetoclax Plus Hypomethylating Agents at a Comprehensive Cancer Center. Front. Oncol. 11:649209. doi: 10.3389/fonc.2021.649209