On March 11, 2024 Cellworks Group Inc., a leader in Personalized Therapy Decision Support and Precision Drug Development, reported the results from a real-world study of gastroesophageal cancer which found that Therapy Response Index (TRI) scores generated using the Cellworks Biosimulation Platform predicted overall survival (OS) above and beyond standard clinical factors, including patient age, sex, and tumor-node-metastasis (TNM) staging (Press release, Cellworks, MAR 11, 2024, View Source [SID1234641037]). The study also showed a significant association between a patient’s TRI score and disease-free survival (DFS) and tumor regression grade (TRG).

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The peer-reviewed paper, ‘Integration of genomic aberrations to predict clinical outcomes for patients with gastroesophageal adenocarcinoma receiving neoadjuvant chemotherapy,’ is available at ESMO (Free ESMO Whitepaper) Gastrointestinal Oncology.

Despite progress in gastroesophageal cancer therapy, only a small proportion of patients attain long-term survival. Previous precision-based strategies have been constrained by focusing on single biomarker–drug associations. This oversimplified approach to the disease has resulted in a wide spectrum of patient outcomes, with long-term survival rates spanning from 25% to 75% using multi-modality therapy — a combination of chemotherapy, radiation, surgical resection, and adjuvant nivolumab, which has become the standard of care.

"The focus for guiding treatment decisions for gastroesophageal patients has centered on specific biomarkers such as HER2, MSI, PD-L1 and CLD18.2," said Dr. Elizabeth Smyth, Oxford University Hospitals NHS Foundation Trust; and Co-Principal Investigator of the study. "However, further refinement of treatment selection using computational biomarkers might be possible. This study highlights the unique value that Cellworks computational biosimulation can bring to the treatment decision process by utilizing a patient’s comprehensive genomic profile and biosimulating all possible therapy combinations. This approach could offer a promising avenue for recommending a treatment strategy at an individual level, thereby improving patient outcomes."

"The size and complexity of comprehensive genomic panels pose a formidable challenge, making it difficult for oncologists to translate the intricate biology into actionable clinical decisions," said Dr. Rebecca Fitzgerald, MD, Professor of Cancer Prevention at the University of Cambridge; Director of the Early Cancer Institute; and Co-Principal Investigator of the study. "This study demonstrates that utilizing whole genome sequencing of a patient’s gastroesophageal cancer along with Cellworks personalized biosimulation approach has the potential to highlight when alternative treatment strategies such as fluoropyrimidines, taxanes, anthracyclines or platinum compounds may yield superior outcomes for a specific patient."

"The transition from small panel NGS to whole exome and whole genome sequencing brings new insights about each cancer’s complex proteogenomic network," said Dr. Michael Castro M.D., Oncologist at Beverly Hills Cancer Center; and Chief Medical Officer at Cellworks, Group Inc. "These insights reveal the basis for drug sensitivity and resistance that allows oncologists to select the optimal combination therapy for individual patients and creates the possibility of targeting the sources of therapeutic resistance. The view that genomic information is ‘unactionable’ is transformed by artificial intelligence (AI)-level molecular diagnosis provided by Cellworks’ biosimulation. Most genomic information that can be measured is highly relevant to tumor biology and treatment response but is beyond the grasp of busy clinicians. With Cellworks biosimulation, the oncogene-only approach to precision medicine is already obsolete."

Clinical Study

Methods
The performance of Cellworks in silico biosimulation and Therapy Response Index (TRI) scores were studied in patients with gastroesophageal adenocarcinoma (OGA) with operable cancers from the UK Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) International Cancer Genome Consortium study. A total of 270 patients with OGA were selected who had 50x whole genome sequencing carried out on tissue derived from either biopsy or resection within 12 months of treatment. Patients were treated with chemotherapy drugs or regimes according to UK clinical guidelines.

Biosimulation was carried out utilizing the Cellworks computational biology model (CBM), which uses both mechanistic and statistical approaches to integrate a patient’s genomic aberrations, revealing signaling pathway dysregulation and variable drug response. Using patient-specific predictions derived from the CBM, a TRI score was used to predict therapeutic overall survival (OS), disease-free survival (DFS) and tumor regression grade (TRG).

Results
The results of the study revealed that the association of TRI value with overall survival (OS) for gastroesophageal adenocarcinoma patients was significant (P = 0.0012) above and beyond standard clinical factors including patient age, sex, tumor-node-metastasis (TNM) stage and neoadjuvant therapy. The association between TRI values and disease-free survival (DFS) was also significant (P = 0.0288). In addition, the TRI values optimized for tumor regression grade (TRG) displayed a significant association (P = 0.0011).

Conclusions
This study concluded that TRI scores for gastroesophageal adenocarcinoma patients predict OS and DFS beyond clinical factors. These results highlight the clinical value of employing Cellworks biosimulation for personalized therapy selection and warrant additional clinical evaluation.

Cellworks Platform and Therapy Response Index (TRI)

The Cellworks Platform biosimulates the impact of specific drug compounds on an individual patient or class of patients using their genomic profile. Multi-omic data from an individual patient or cohort is used as input to the in silico Cellworks Computational Biology Model (CBM) to generate a personalized or cohort-specific disease model. The CBM is a highly curated mechanistic network of 6,000+ human genes, 30,000 molecular species and 600,000 molecular interactions. This model along with associated drug models are used to biosimulate the impact of specific compounds or combinations of drugs on the patient or cohort and produce therapy response predictions, which are statistically modeled to produce a qualitative Therapy Response Index (TRI) score, scaled from 0 (unfavorable outcome) to 100 (favorable outcome) for a specific therapy. The Cellworks CBM has been tested and applied against various clinical datasets with results provided in over 125 presentations and publications with global collaborators.

On March 11, 2024 Synnovation Therapeutics, a precision medicine company developing small molecule therapies optimized to achieve best-in-class pharmacology against highly validated disease targets, reported that the first patient has been dosed in a Phase I trial evaluating SNV1521 in patients with solid tumors (Press release, Synnovation Therapeutics, MAR 11, 2024, View Source [SID1234641036]). SNV1521 is a potentially best-in-class, potent, highly selective and CNS penetrant PARP1 inhibitor.

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The Phase I trial, which is being led by Timothy Yap, M.D., Ph.D., professor of Investigational Cancer Therapeutics at The University of Texas MD Anderson Cancer Center, is designed to assess proof-of-concept with SNV1521 as an oral monotherapy in a dose escalation and preliminary efficacy expansion study. PARP inhibition is clinically validated for homologous recombination deficiency (HRD, a molecular biomarker) driven cancers; however, the safety profile of first generation PARP1 agents limits the potential of the class, particularly in combination with chemotherapy or other novel agents. In preclinical models, selective PARP1 targeting has been shown to improve both the efficacy and safety of the class.

"We believe that a highly potent and selective PARP1 inhibitor – such as SNV1521 – has the potential for both improved efficacy and enhanced safety due to its excellent physicochemical properties," said Kevin O’Hayer, M.D., Ph.D., Senior Vice President, Head of Clinical Development at Synnovation. "Dosing of the first patient in the SNV1521 Phase I trial is a key milestone as Synnovation transitions from a preclinical to clinical stage biotech company. We are excited to collaborate with Dr. Yap and the rest of our SNV1521 study investigators on this program."

On March 11, 2024 Ranok Therapeutics, a clinical-stage biopharmaceutical company that is developing a novel approach to targeted protein degradation for the treatment of cancers, reported the initiation of patient dosing in China for a Phase 1 study of RNK05047, its first protein degrader candidate (Press release, Ranok Therapeutics, MAR 11, 2024, View Source [SID1234641035]). The study, which mirrors an ongoing Phase 1 study in the U.S., will evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of RNK05047 in Chinese patients with advanced solid tumors or lymphomas. Ranok anticipates preliminary data from both the US and China Phase 1 studies by the end of 2024.

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"RNK05047, which has been developed using Ranok’s proprietary CHAMP technology, is the first BRD4-selective protein degrader to have entered clinical testing in China. This extends our ongoing clinical study of RNK05047 in the U.S. to an Asian patient population, which we believe will provide important insights"

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"RNK05047, which has been developed using Ranok’s proprietary CHAMP technology, is the first BRD4-selective protein degrader to have entered clinical testing in China. This extends our ongoing clinical study of RNK05047 in the U.S. to an Asian patient population, which we believe will provide important insights," said Weiwen Ying, Ph.D, Founder and Chief Executive Officer of Ranok. "RNK05047 degrades BRD4 protein preferentially in tumors, which may potentially lead to improved safety and efficacy. We look forward to sharing initial results from both the US and China studies later this year."

"BRD4 is an epigenetic target of great interest for the treatment of many different cancer types," said Ning Li, M.D., Professor and Vice President of the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) in Beijing China, as well as Lead Principal Investigator for this study. "The Cancer Hospital is the first and largest cancer hospital in China for the diagnosis and treatment of cancer. We are excited to be participating in this study and are hopeful that RNK05047 will provide an important new therapeutic option for cancer patients."

Additional information can be found at www.chinadrugtrials.org.cn (CTR20233943) and www.clinicaltrials.gov (NCT05487170).

About Ranok’s CHAMP platform

Ranok’s proprietary Chaperone-mediated Protein Degradation (CHAMP) platform takes advantage of the cellular chaperone network, which regulates the folding and stability of proteins, distinguishing it from other targeted protein degradation approaches. CHAMPs have a number of unique advantages, such as the evasion of mechanisms of drug resistance, and are designed to improve safety and efficacy due to the selective targeting of disease tissues.

About RNK05047

RNK05047 is a first-in-class, small-molecule, tumor- and BRD4-selective protein degrader that was discovered and developed using Ranok’s proprietary approach to targeted protein degradation, CHAMP. The bromodomain transcription factor BRD4 is a key epigenetic regulator of oncogenes such as MYC and BCL2 and is involved in diverse cancer types. Phase 1 trials of RNK05047 are currently underway in both the U.S. and China to assess its safety, tolerability and pharmacokinetics, and also include measures of anti-tumor activity and pharmacodynamic readouts as secondary endpoints. Initial results are expected by the end of 2024.

On March 11, 2024 The Catalan biopharmaceutical company Ability Pharmaceuticals, SA (AbilityPharma), focused on the development of innovative oral autophagy-inducing anticancer compounds, reported a €7M investment from a European-Canadian syndicate of life sciences investors, including CTI Life Sciences Fund, Inveready, the EIC Fund, Fitalent and CDTI Innvierte (Press release, Ability Pharmaceuticals, MAR 11, 2024, View Source;7-million-financing-round-to-advance-development-of-its-clinical-phase-2b-autophagy-inducer-abtl0812-in-metastatic-pancreatic-cancer-302085276.html [SID1234641034]). The funding will allow the Company to fully finance its phase 2b clinical study of antitumor compound ABTL0812 in patients with pancreatic cancer.

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AbilityPharma is completing a Phase 2b clinical trial with ABTL0812 in metastatic pancreatic cancer (all 140 patients recruited) with the aim of demonstrating greater efficacy than standard treatment FOLFIRINOX. The double-blind, placebo-controlled, first-line study in combination with FOLFIRINOX is ongoing in 23 hospitals in Spain, USA, France, and Israel. Efficacy results are expected by year-end.

Significant superior efficacy results will allow AbilityPharma to obtain financing for final development of ABTL0812 or to license it to a multinational pharmaceutical or biotechnology company, with the goal of making ABTL0812 available to pancreatic cancer patients in 2028.

"We are very pleased to complete this financing round and welcome CTI Life Sciences Fund’s Shermaine Tilley to our board of directors, which will enable us to accelerate the development of ABTL0812 in the short term", stated Carles Domènech, PhD, Executive Chairman and CEO at AbilityPharma. "We are thankful to CTI Life Sciences, Inveready and the EIC Fund for completing this financing round, and to all our new and existing investors for their confidence in our team and for their support to our goals. This investment will allow us to continue working tirelessly on taking ABTL0812 to patients with pancreatic cancer".

Shermaine Tilley, PhD, MBA, Managing Partner at CTI Life Sciences Fund, said "We are delighted to provide financing for late-stage development of Ability Pharma’s innovative and highly promising treatment for pancreatic cancer. I am pleased to assume a position on their board of directors and will work with management and the board to optimize the value of ABTL0812 for patients and for investors".

Sara Secall, MSc, MBA, General Partner Inveready, said "We are excited to bring in savvy investors that can help move forward AbilityPharma’s treatment for cancer patients".

Svetoslava Georgieva, Chair of the EIC Fund Board, said: "The EIC Fund has become a strong player in EU deep-tech investments. The unique financing approach through the EIC, combining grants and equity, is attracting significant interest from Europe’s most promising start-ups and provides them with the means to develop and scale their businesses in Europe. Our investment will help Ability Pharma with the development of their product for patients with metastatic pancreatic cancer."

On March 11, 2024 enGene Holdings Inc. (Nasdaq: ENGN or "enGene" or the "Company"), a clinical-stage genetic medicines company whose non-viral, intravesical lead product candidate, EG-70, is in a pivotal study for BCG-unresponsive non-muscle invasive bladder cancer (NMIBC), reported its financial results for the first quarter ended January 31, 2024 (Press release, enGene, MAR 11, 2024, https://www.prnewswire.com/news-releases/engene-reports-first-quarter-2024-financial-results-and-recent-corporate-progress-302085823.html [SID1234641033]).

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"This is an exciting time for the Company as we move closer to realizing our vision of mainstreaming genetic medicines to address diseases with high unmet clinical needs. EG-70 was designed from the ground up to achieve this vision as a readily scalable, easy to use product candidate without the onerous storage and handling requirements typical of viral approaches. Our previously announced Phase 1 data for EG-70 in BCG-unresponsive NMIBC demonstrated an encouraging safety profile and a 73% complete response rate at any time, which has garnered significant enthusiasm from patients, the urology community, and investors," said Jason Hanson, Chief Executive Officer of enGene. "We are proud to enter our second quarter as a public company with significant momentum, having raised $200 million from top tier investors in a private financing in February. With existing cash and cash equivalents expected to fund the current operating plan into 2027, we believe enGene is well-positioned to complete the ongoing pivotal-stage LEGEND study of EG-70 in BCG-unresponsive NMIBC, execute on our plan to file our BLA in the first quarter of 2026, and pursue pipeline expansion via additional EG-70 development opportunities and potential new R&D programs."

Recent Business Highlights:

Completed $200 Million Oversubscribed Private Placement: On February 20, 2024, enGene completed the private placement of 20 million common shares at a price per share of $10.00, representing a 31% premium over the closing price prior to pricing the transaction (the "February 2024 PIPE Financing"). The financing included participation from new and existing investors.
Expanded Hercules Capital Debt Facility: On December 22, 2023, enGene announced the expansion of its existing debt facility with Hercules to up to $50 million, subject to certain milestones, with $22.5 million advanced at closing, of which approximately $8.6 million was applied to refinance in full the term loans outstanding under the prior loan agreement with Hercules.
Key Leadership Hires, Board Additions and Succession Planning: enGene continued to build out its executive leadership with the appointment of Ryan Daws as Chief Financial Officer and Lee Giguere as Chief Legal Officer and Corporate Secretary. Additionally, Lota Zoth, CPA, was appointed to the Company’s Board of Directors and serves as the Company’s Audit Committee Chair.
On February 14, 2024, enGene announced that due to personal family and health reasons, Jason Hanson intends to resign from his role as Chief Executive Officer and a member of the Board of Directors upon the appointment of a successor CEO. The Board of Directors is conducting a search for his successor. Following the hiring of a new CEO, Mr. Hanson will support the Company and the new CEO as a strategic advisor.

Anticipated Milestones and Corporate Updates

Announce a new indication and development plans for EG-70 in the first half of 2024.
Interim data readout from the ongoing pivotal Phase 2 LEGEND study of EG-70 in BCG-unresponsive NMIBC with carcinoma-in-situ (Cis) in mid-2024.
Initial efficacy data from the ongoing Phase 2 LEGEND study in a BCG-naive NMIBC cohort in the second half of 2024.
First Quarter 2024 Financial Results

Cash and cash equivalents, as of January 31, 2024, were $85.6 million, compared to $81.5 million as of October 31, 2023. The Company expects that its existing cash and cash equivalents together with the recent net proceeds of $187.5 million from its February 2024 PIPE Financing will fund operating expenses and capital expenditures into 2027.

Three Months ended January 31, 2024

Total operating expenses were $10.8 million for the three months ended January 31, 2024, compared to $4.6 million for the three months ended January 31, 2023. Research and development expenses increased by $2.0 million, mainly due to increasing CMC and clinical costs related to our pivotal EG-70 study. General and administrative expenses increased by $4.2 million, primarily driven by headcount costs and professional fees such as legal, accounting and audit as the Company scales its G&A function to support the operation of a public company.
For the three months ended January 31, 2024, net loss attributable to common shareholders was $10.7 million, or $0.46 per share, compared to $8.6 million, or $13.29 per share, for the same period for the three months ended January 31, 2023. The increase in net loss is mainly attributed to the increase in operating expenses partially offset by net interest income earned during the period.