On September 14, 2024 Bicycle Therapeutics plc (NASDAQ: BCYC), a pharmaceutical company pioneering a new and differentiated class of therapeutics based on its proprietary bicyclic peptide (Bicycle) technology, reported updated Phase 1/2 clinical results for Bicycle Toxin Conjugate (BTC) zelenectide pevedotin (formerly BT8009) in metastatic urothelial cancer (mUC); BTC molecule BT5528 in advanced solid tumors, such as mUC and ovarian; and Bicycle Tumor-Targeted Immune Cell Agonist (Bicycle TICA) BT7480 in advanced solid tumors (Press release, Bicycle Therapeutics, SEP 14, 2024, View Source [SID1234646566]). The company also shared an analysis of peripheral neuropathy, a key adverse event of interest associated with monomethyl auristatin E (MMAE)-based drug conjugates, in patients treated with BTC molecules. These data will be presented during a poster session at the European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress 2024 in Barcelona today.

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"We are pleased that the data presented at ESMO (Free ESMO Whitepaper) continue to support the promising response and differentiated safety profiles of our Bicycle molecules. Importantly, our lead investigational therapy zelenectide pevedotin continues to demonstrate an overall response rate that is in line with other drug conjugates used to treat metastatic urothelial cancer, but with a marked improvement in tolerability. Overall, we believe the data continue to demonstrate the potential of our Bicycle technology platform to create differentiated medicines designed to help patients not only to live longer but also to live well," said Kevin Lee, Ph.D., CEO of Bicycle Therapeutics. "These clinical data are just the first set of updates that we have guided to delivering this year. In the coming months, we look forward to sharing initial imaging data from our growing radiopharmaceutical pipeline and additional data for zelenectide pevedotin in bladder, breast and lung cancer."

ESMO 2024 Data Highlights

Zelenectide pevedotin is a BTC molecule targeting Nectin-4, a well-validated tumor antigen, designed to overcome the significant toxicity associated with other drug conjugate approaches. Updated results from the ongoing Phase 1/2 Duravelo-1 trial evaluating 5 mg/m2 weekly of zelenectide pevedotin monotherapy in 45 mUC patients who had not previously been treated with enfortumab vedotin showed:

Among 38 efficacy-evaluable patients, a 45% overall response rate (ORR), including 1 confirmed complete response and 16 partial responses (13 confirmed). Stable disease was maintained in 9 patients, and 12 patients experienced progressive disease.
A median duration of response of 11.1 months among the 14 patients with confirmed responses.
An emerging differentiated safety profile, particularly around adverse events of interest such as peripheral neuropathy, skin reactions and eye disorders. Notably, there were no Grade ≥3 treatment-related adverse events (TRAEs) of peripheral neuropathy (any kind), skin reactions or eye disorders, and patients with pre-existing peripheral neuropathy were unlikely to develop worsening peripheral neuropathy during treatment with zelenectide pevedotin.
The global Phase 2/3 Duravelo-2 registrational trial of zelenectide pevedotin in patients with mUC is currently enrolling. Additional data updates for zelenectide pevedotin in combination with pembrolizumab in first line mUC and monotherapy in late line triple-negative breast cancer and non-small cell lung cancer (NSCLC) are planned for later this year.

BT5528 is a BTC molecule targeting EphA2, a tumor antigen that is widely expressed in many cancers and has historically been difficult to target using other drug conjugate approaches. Updated results from the ongoing Phase 1/2 trial evaluating 6.5 mg/m2 every two weeks and 5 mg/m2 weekly of BT5528 monotherapy in patients with advanced solid tumors showed:

Among 113 efficacy-evaluable patients, a 12% ORR in patients with advanced solid tumors.
The highest anti-tumor activity in mUC, with a 34% ORR in all efficacy-evaluable patients enrolled in the dose escalation and expansion cohorts. Among patients receiving 6.5 mg/m2 every two weeks, a 31% ORR was observed in the dose escalation and expansion cohort and a 45% ORR was observed in the expansion cohort only. A lower but acceptable ORR of 27% was observed in patients receiving 5 mg/m2 weekly.
No objective responses in patients with ovarian cancer who received 5 mg/m2 weekly. However, 5 patients maintained stable disease.
A suggested correlation between EphA2 expression and response. Among 14 patients with mUC who had available immunohistochemistry and response data, a 43% ORR was observed in EphA2-positive patients compared to a 20% ORR in EphA2-negative patients.
A clearly differentiated emerging safety profile, with none of the hemorrhage events or hematological toxicities that have been associated with other EphA2-targeting drug conjugates.
The company has begun assessing BT5528 at 6.5 mg/m2 every two weeks in combination with nivolumab. Results from this cohort are expected in 2025.

Low rates of treatment-related peripheral neuropathy (TRPN) following monotherapy treatment with BTC molecules zelenectide pevedotin or BT5528. In 149 patients treated with zelenectide pevedotin and 74 patients treated with BT5528 from ongoing Phase 1/2 studies, results showed:

TRPN in 28% of patients treated with zelenectide pevedotin and 19% of patients treated with BT5528, nearly all of which were low grade (1-2). One Grade 3 event (neuralgia) was reported in a patient treated with zelenectide pevedotin following prior therapy with enfortumab vedotin. No Grade 3-4 events were observed for BT5528.
Among zelenectide pevedotin-treated patients with peripheral neuropathy at baseline, 80% did not develop TRPN during treatment.
TRPN resulted in few dose modifications across the overall patient populations for zelenectide pevedotin and BT5528, and no drug withdrawals were necessary for either BTC molecule.
TRPN had completely resolved in 14% (zelenectide pevedotin) and 21% (BT5528) of patients, and 26% and 21%, respectively, had some resolution or improvement at time of reporting, though post-treatment follow-up was limited. Median time to resolution or improvement of TRPN was 2.2 weeks for zelenectide pevedotin and 1.7 weeks for BT5528.
The data support the hypothesis that the antibody-drug construct may be a primary driver of peripheral neuropathy rather than MMAE toxicity as was previously believed.

BT7480 is a Nectin-4 targeted CD137 agonist designed to overcome immune agonist toxicities and activate the immune system in Nectin-4 expressing tumors. Initial data from the Phase 1/2 dose escalation trial evaluating BT7480 in patients with advanced solid tumors showed:

Among 39 patients assigned to receive one of 10 different doses (0.002-3.5 mg/kg weekly) of BT7480, an emerging differentiated safety and tolerability profile with a low number of severe adverse events. Low rates of Grade ≥3 TRAEs (5%) and of treatment-related severe adverse events (TRSAEs) (8%) were reported, with no such events among those receiving the highest dose of 3.5 mg/kg.
Best overall response of stable disease in 13 patients, 5 of whom had NSCLC. Stable disease was prolonged (>8 months) in 3 patients, 2 with NSCLC and 1 with anal cancer. There were 2 unconfirmed partial responses, both in patients with cervical cancer.
Preliminary biomarker analyses that support BT7480 dual targeting of CD137 and Nectin-4 as demonstrated by enhanced immune cell activation, aligned with the proposed mechanism of action of BT7480.
As the maximum tolerated dose for BT7480 has not yet been reached, the company is continuing dose exploration in combination studies, starting with nivolumab.

The posters are available in the Publications section of the Bicycle Therapeutics website.

On October 10, 2024 Nona Biosciences, a global biotechnology company providing a total solution from "Idea to IND" (I to ITM), reported that it has entered into a multi-target antibody discovery collaboration with Umoja Biopharma, a transformative immunotherapy company creating off-the-shelf treatments that aim to extend the reach and effectiveness of CAR-T cell therapies in oncology and autoimmunity (Press release, Nona Biosciences, SEP 13, 2024, View Source [SID1234647140]). This collaboration leverages Nona’s proprietary fully human heavy chain only antibody (HCAb) technology to produce novel in vivo generated CAR-T cell therapy drug candidates.

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Fully human HCAbs have the potential to significantly reduce immunogenicity and offer versatility in CAR design due to their compact size, simplified structure, and precisely calibrated binding properties. This partnership aims to combine Nona’s HCAb Harbour Mice platform and direct CAR-function-based HCAb library screening platform (NonaCarFx) with Umoja’s VivoVec platform to develop novel in vivo CAR-T cell therapies and expand the potential reach of this innovative delivery technology.

Dr. Jingsong Wang, MD, PhD, Chairman of Nona Biosciences, commented, "We are excited to collaborate with Umoja Biopharma, a pioneer in cell and gene therapy. We believe that our HCAb Harbour Mice technology and NonaCarFxTM platform, alongside with our extensive experience in oncology and immunology, will empower Umoja to generate novel CAR-T cell therapies that benefit patients worldwide."

Byoung Ryu, PhD, Umoja’s Executive Vice President of Discovery Research and Vector Biology added, "Nona is a great partner for Umoja as we continue to move the CAR-T cell field towards directly administrated in vivo CAR therapeutics. Nona has demonstrated capabilities for generating highly functional CAR candidates, and we look forward to developing multiple in vivo drug candidates through this partnership and ultimately, helping change outcomes for these patients."

On September 13, 2024 Krystal Biotech, a commercial-stage biotechnology company, reported that the Company will participate in the 2024 Cantor Global Healthcare Conference on September 18, 2024, in New York. Krish S. Krishnan, Chairman and Chief Executive Officer, will take part in a fireside chat scheduled at 1:20 pm ET and host investor meetings throughout the day (Press release, Krystal Biotech, SEP 13, 2024, View Source [SID1234646621]).

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A webcast of the presentation will be available here beginning at 1:20 pm ET on Wednesday, September 18, 2024 and will be posted on the Investors section of the Company’s website.

On September 13, 2024 Nxera Pharma and Cancer Research UK reported an upcoming presentation on the ongoing Phase 1/2a clinical trial (NCT05944237) of Nxera’s immunotherapy drug HTL0039732 (also known as NXE0039732) at the European Society for Medical Oncology Congress (ESMO) (Free ESMO Whitepaper) 2024, taking place on 13–17 September in Barcelona, Spain (Press release, Nxera Pharma, SEP 13, 2024, View Source [SID1234646620]).

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The trial’s co-chief investigator, Dr. Debashis Sarker from Guy’s and St Thomas’ NHS Foundation Trust, will present a "Trial in Progress 1 " poster at ESMO (Free ESMO Whitepaper) 2024 on Saturday 14 September (presentation 679TiP, available on the ESMO (Free ESMO Whitepaper) website here).

The first-in-human trial is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics and anti-tumor activity of HTL0039732 as a monotherapy and in combination with the checkpoint inhibitor atezolizumab, in patients with advanced solid tumors.

HTL0039732 is an oral small molecule drug candidate that was rationally designed using Nxera’s NxWave platform and evaluated through rigorous translational and preclinical studies. HTL0039732 works by blocking signaling through a specific type of prostaglandin receptor, the prostaglandin E2 (PGE2)-type prostanoid receptor 4 (EP4). PGE2 acts in the tumor microenvironment to trigger cancer cells to evade the immune system. Targeting EP4 to block the effects of PGE2 increases the ability of the immune system to detect and control cancer cells and makes HTL0039732 a potential candidate to treat patients with cancers that generally do not respond well to current immunotherapies.

Cancer Research UK’s Centre for Drug Development is sponsoring and managing the trial, which is led by chief investigator Dr Bristi Basu, University of Cambridge, and Dr Sarker. The first patient was dosed in August 2023 and the trial is currently open for recruitment at Addenbrooke’s Hospital in Cambridge, Guy’s Hospital in London, and the Christie Hospital in Manchester

Dr. Debashis Sarker says: "We are excited to present this ‘Trials in Progress’ poster at ESMO (Free ESMO Whitepaper), outlining the
scientific rationale and design of the clinical trial of HTL0039732, given alone and in combination with immunotherapy for patients with advanced solid cancers. HTL0039732 targets an important protein within the tumor immune microenvironment called EP4, triggering cancer cells to evade the immune system. Targeting EP4 potentially increases the ability of the immune system to detect and control cancer cells. Enrolment to the trial began in the UK in August 2023 and is ongoing across multiple cancer types.

"We are hopeful that this trial will identify a novel way to target the immune system and improve treatment
options for patients with a range of different solid cancers."

On September 13, 2024 Celyad Oncology (Euronext: CYAD) (the "Company"), reported its financial results for the first half year 2024 ended June 30, 2024, and provides a business update (Press release, Celyad, SEP 13, 2024, View Source [SID1234646603]).

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Michel Lussier, interim Chief Executive Officer of Celyad Oncology, commented: "Celyad Oncology continues to make remarkable progress in developing cutting-edge technologies for chimeric antigen receptor (CAR) T-cell therapy. Our groundbreaking multiplex platform is revolutionizing the potential of CAR T-cells, while our pioneering NKG2D-based multispecific CAR T-cell platform is further paving the way to conquer current limitations of this transformative class of immunotherapy."

H1-2024 Business highlights

The Company is pursuing a strategy of continued research and development, with a particular focus on intellectual property (IP). Monetization of its innovative approaches and technologies is a key objective. Celyad Oncology is progressing in this regard and is currently in discussion with potential partners for out-licensing deals;
With its research focus, the Company has made concrete progress by providing proof-of-concept of the multiplex short hairpin RNAs (shRNAs) non-gene edited technology platform and the multispecific NKG2D-based CAR T-cell platform, which provide unique options to tackle the major current limitations of CAR T-cell therapies. Options to further explore or validate these data through strategic partnerships, and/or to incorporate these technologies into clinical CAR-T candidates are actively pursued by the Company;
The Company continues to share and discuss its latest advances at international scientific conferences throughout the first half of 2024 with updated results provided at the 27th ASGCT (Free ASGCT Whitepaper) 1 Annual Meeting and the Recent insights into Immuno-Oncology VIB conference 2.
The Company is also focusing on sharing data and views with the scientific community and has published a review highlighting the interest of non-gene editing technologies for allogeneic CAR T-cell therapies in Cells 3 and another review providing an overview of all engineering strategies to safely drive CAR T-cells into the future in Frontiers in Immunology 4, two well-renowned peer-reviewed scientific journals;
In response to the request expressed by several companies and academic institutions engaged in gene and cell therapies for cardiac applications, the Company has re-initiated the manufacturing and commercialization of C-Cath, an intra-myocardial injection catheter developed and owned by the Company.
H1-2024 operational highlights

Multiplex shRNA non-gene edited technology – The Company developed a chimeric micro-RNA (miRNA) cluster to enable multiplexing of shRNAs, designed for easy, efficient, and tunable downregulation of up to four target genes simultaneously in CAR T-cells.
Data successfully demonstrated the feasibility and effectiveness of the multiplex approach to improve allogeneic CAR T-cell viability by avoiding graft-versus-host disease (GvHD) via knocking down of CD3ζ, avoiding host-versus-graft (HvG) reaction and promoting cell persistence via knocking-down of β2M and CIITA, and avoiding CD95L-induced autophagy via knocking-down of CD95;
Another multiplex cassette focusing on the knock-down of co-inhibitory receptors (PD-1, LAG-3, TIM-3 and CD95) was also developed to decrease the expression of exhaustion markers at the surface of CAR T-cells.
Multispecific NKG2D-based CAR T-cell platform – Different NKG2D-based multispecific CAR T-cells were developed to provide the proof-of-concept that NKG2D ligands (NKG2DL) are valuable targets in a multispecific CAR approach to counteract relapses due to antigen loss or antigen heterogeneity.
PSMA/NKG2DL tandem CAR T-cells, that encompass the extracellular domain of the natural NKG2D receptor fused to an anti-PSMA CAR to overcome antigen heterogeneity and improve anti-tumor efficacy against prostate cancer were developed and demonstrated functionality in vitro against prostate cancer cell lines expressing or not the tumor-associated antigen PSMA;
In vivo proof-of-concept of the company’s CD19/NKG2DL tandem CAR T-cell candidate was also provided in a B-ALL relapse model, showing that this multi-specific CAR T-cell candidate has an enhanced anti-tumor efficacy against heterogeneous lymphoma tumors, or to counteract antigen loss, as compared to currently existing treatment options.
First Half 2024 financial review

As of June 30, 2024, the Company’s Treasury position amounts to €6.2 million.

After due consideration of detailed budgets and estimated cash flow forecasts for the years 2024 and 2025, the Company projects that its existing cash and cash equivalents will be sufficient to fund its estimated operating and capital expenditures into the third quarter of 2025.