On November 28, 2023 AstraZeneca reported that it will present new clinical and real-world data in multiple haematological conditions at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition in San Diego, CA, 9 to 12 December 2023 (Press release, AstraZeneca, NOV 28, 2023, View Source [SID1234638029]).

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A total of 63 abstracts will feature 14 approved and potential new medicines across the Company’s portfolio and pipeline including from Alexion, AstraZeneca’s Rare Disease group, in chronic lymphocytic leukaemia (CLL) and several types of lymphoma, paroxysmal nocturnal haemoglobinuria (PNH), atypical haemolytic uraemic syndrome (aHUS) and amyloid light-chain (AL) amyloidosis.

Anas Younes, Senior Vice President, Haematology R&D, AstraZeneca, said: "Our data at ASH (Free ASH Whitepaper) will exemplify how we are advancing a range of innovative modalities including antibody drug conjugates, next-generation immunotherapies and T-cell engagers in haematology. Updated clinical data for AZD0486, our CD19/CD3 T-cell engager, reinforce our belief in this approach as a potential new treatment for lymphoma, and new Calquence data continue to demonstrate long-term efficacy and safety in chronic lymphocytic leukaemia with further follow up."

Gianluca Pirozzi, Senior Vice President, Head of Development, Regulatory and Safety, Alexion, said: "Alexion has transformed the treatment landscape and redefined care for the paroxysmal nocturnal haemoglobinuria patient community over the past two decades. At the ASH (Free ASH Whitepaper) Annual Meeting, new results from our pivotal ALPHA trial will demonstrate the promise of Factor D inhibition to advance care for the small subset of patients with paroxysmal nocturnal haemoglobinuria who experience clinically significant extravascular haemolysis. We are proud to further our leadership in rare disease by sharing data from our robust haematology pipeline, reflecting our commitment to innovation and improving outcomes for the patients and families we serve."

Calquence continues to demonstrate long-term benefits in CLL

Six-year follow-up data from the pivotal ELEVATE-TN Phase III trial will further support the continued efficacy, safety and tolerability of Calquence for long-term use in patients with treatment-naïve CLL.1

Data from a Phase II trial will show the safety and efficacy of Calquence and rituximab followed by chemotherapy and autologous stem cell transplantation in fit patients with treatment-naïve mantle cell lymphoma (MCL).2

An analysis of five prospective Calquence trials, including three randomised, controlled Phase III trials and two non-randomised trials, will show acceptable safety outcomes based on rates of nonfatal and fatal ventricular arrhythmias and sudden death in patients with CLL.3

Novel early assets show potential to improve outcomes for blood cancer patients

Data from our early portfolio will demonstrate how the Company is advancing multiple modalities across several scientific platforms, including Immuno-Oncology, Immune-Engagers, Antibody Drug Conjugates (ADCs) and Epigenetics as part of its strategy to attack cancer from multiple angles.

Updated Phase I data for AstraZeneca’s CD19/CD3 T-cell engager, AZD0486, will further demonstrate the acceptable safety profile and high response rate of this treatment in relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL).4 We will also present the first clinical data on sabestomig, a PD-1/TIM-3 targeting bispecific antibody, in R/R Hodgkin lymphoma, showing encouraging early signals of activity.5

The first preclinical data for AZD9829, a novel CD123-targeting ADC, using AstraZeneca’s proprietary linker technology to deliver a topoisomerase I inhibitor warhead, will demonstrate promising anti-tumour activity in acute myeloid leukaemia.6 In addition, preclinical data will demonstrate anti-tumour activity of AstraZeneca’s novel PRMT5 inhibitor in MTAP silenced Hodgkin lymphoma models.7

Showcasing advances to bolster our leadership in PNH with new data on Factor D inhibition and impact of C5 inhibition in long-term disease control

New results from the 24-week and long-term extension period from the pivotal ALPHA Phase III trial will reinforce the potential for danicopan add-on therapy to address clinically significant extravascular haemolysis (EVH) in the small subset of PNH patients who experience this condition while treated with C5 inhibitor therapy, allowing them to maintain control of intravascular haemolysis (IVH) through standard-of-care treatment with Ultomiris (ravulizumab) or Soliris (eculizumab).8

Further, patient-reported outcomes from the ALPHA trial will suggest danicopan as an add-on to Ultomiris or Soliris improved quality of life compared to C5 inhibitor therapy alone in patients with PNH who experience clinically significant EVH.9

Additionally, Alexion will present an analysis of six-year outcomes from the Phase III clinical trial evaluating the safety and efficacy of Ultomiris in patients with PNH who did not have previous treatment with a C5 inhibitor.10 The analysis compared survival against untreated patients in the International PNH Registry, the largest global real-world database of patients with PNH. Results will suggest Ultomiris improved survival and maintained effective long-term control of IVH, the most significant contributor to morbidity and premature mortality in PNH.10

Improving diagnosis and management of life-threatening rare diseases, including amyloidosis

24-month results of a Phase II trial will demonstrate the safety and tolerability of CAEL-101 in combination with cyclophosphamide-bortezomib-dexamethasone with or without daratumumab for the treatment of AL amyloidosis.11

Real-world analyses across AL amyloidosis, aHUS and haematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA) will also be presented, advancing the scientific understanding of these rare, haematological conditions.12-16

Key presentations during the 65th ASH (Free ASH Whitepaper) Annual Meeting and Exposition

Lead author

Abstract title

Presentation details

Calquence (acalabrutinib)
Sharman, JP

Acalabrutinib ± Obinutuzumab vs Obinutuzumab + Chlorambucil in Treatment-naive Chronic Lymphocytic Leukemia: 6-year Follow-up of ELEVATE-TN

Abstract # 636

Oral Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Frontline Treatment with Targeted Agents in Patients with Chronic Lymphocytic Leukemia

10 December 2023

17:45 PST

Location: Seaport Ballroom ABCD (Manchester Grand Hyatt San Diego)

Westin, J

Smart Stop: Lenalidomide, Tafasitamab, Rituximab and Acalabrutinib Alone and with Combination Chemotherapy for the Treatment of Newly Diagnosed Diffuse Large B-cell Lymphoma

Abstract # 856

Oral Session: 626. Aggressive Lymphomas: Prospective Therapeutic Trials: Initial treatment strategies in Aggressive B-Cell Lymphomas

11 December 2023

15:30 PST

Location: Seaport Ballroom ABCD (Manchester Grand Hyatt San Diego)

Hawkes, EA

A Window Study of Acalabrutinib and Rituximab, Followed by Chemotherapy and Autograft (ASCT) in Fit Patients with Treatment-naïve Mantle Cell Lymphoma (MCL): First Report of the Investigator-initiated Australasian Leukaemia and Lymphoma Group NHL33 ‘WAMM’ Trial

Abstract # 735

Oral Session: 623. Mantle Cell, Follicular and Other Indolent B-Cell Lymphomas: Clinical and Epidemiological: Prospective Clinical Trials in Mantle Cell Lymphoma Incorporating Novel Agents

11 December 2023

11:00 PST

Location: Grand Hall B (Manchester Grand Hyatt San Diego)

Hawkes, EA

TrAVeRse: A Phase 2, Open-Label, Randomized Study of Acalabrutinib in Combination with Venetoclax and Rituximab in Patients with Treatment- naïve Mantle Cell Lymphoma

Abstract # 3054

Poster Session: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphomas: Clinical and Epidemiological: Poster II

10 December 2023

18:00 – 20:00 PST

Location: Halls G-H (San Diego Convention Center)

Sharman, J

Analysis of Ventricular Arrhythmias and Sudden Death with Acalabrutinib From 5 Prospective Clinical Trials

Abstract # 4643

Poster Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster III

11 December 2023

18:00 – 20:00 PST

Location: Halls G-H (San Diego Convention Center)

Ferrajoli, A

Cumulative Review of Hypertension in Patients with Chronic Lymphocytic Leukemia (CLL) and Other Hematologic Malignancies Treated with Acalabrutinib: Data from Clinical Trials

Abstract # 1917

Poster Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster I

9 December 2023

17:30 – 19:30 PST

Location: Halls G-H (San Diego Convention Center)

Sun, C

Extended Follow-Up and Resistance Mutations in CLL Patients Treated with Acalabrutinib

Abstract # 1891

Poster Session: 641. Chronic Lymphocytic Leukemias: Basic and Translational: Poster I

9 December 2023

17:30 – 19:30 PST

Location: Halls G-H (San Diego Convention Center)

Jain, P

Acalabrutinib with Rituximab as First-line Therapy for Older Patients with Mantle Cell Lymphoma – A Phase II Clinical Trial

Abstract # 3036

Poster Session: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphomas: Clinical and Epidemiological: Poster II

10 December 2023

18:00 – 20:00 PST

Location: Halls G-H (San Diego Convention Center)

Perini, G

ACRUE: A Phase 2, Open-label Study of Acalabrutinib in Combination with Rituximab in Elderly and/or Frail Patients with Treatment-naïve Diffuse Large B-Cell Lymphoma

e-Publication

Online Only

AZD0486
Gaballa, S

Double Step-Up Dosing (2SUD) Regimen Mitigates Severe ICANS and CRS While Maintaining a High Efficacy in Subjects with Relapsed/Refractory (R/R) B-cell Non-Hodgkin Lymphoma (NHL) Treated with AZD0486, a Novel CD19xCD3 T-cell Engager (TCE): Updated Safety and Efficacy Data from the Ongoing First-in-Human (FIH) Phase I Trial

Abstract # 1662

Poster Session: 623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphomas: Clinical and Epidemiological: Poster I

9 December 2023

17:30 – 19:30 PST

Location: Halls G-H (San Diego Convention Center)

AZD9829

Dutta, D

First Disclosure of AZD9829, a TOP1i-ADC Targeting CD123: Promising Preclinical Activity in AML Models with Minimal Effect on Healthy Progenitors

e-Publication

Online Only

AZD7789

Mei, M

Safety and Preliminary Efficacy of Sabestomig (AZD7789), an Anti-PD-1 and Anti-TIM-3 Bispecific Antibody, in Patients with Relapsed or Refractory Classical Hodgkin Lymphoma Previously Treated with Anti-PD-(L)1 Therapy

Abstract # 4433

Poster Session: 624. Hodgkin Lymphomas and T/NK cell Lymphomas: Clinical and Epidemiological: Poster III

11 December 2023

18:00 – 20:00 PST

Location: Halls G-H (San Diego Convention Center)

PRMT5 inhibitor

Urosevic, J

Epigenetic Silencing of MTAP in Hodgkin’s Lymphoma Renders it Sensitive to a 2nd Generation PRMT5 Inhibitor

Abstract # 4185

Poster Session: 605. Molecular Pharmacology and Drug Resistance: Lymphoid Neoplasms: Poster III

11 December 2023

18:00 – 20:00 PST

Location: Halls G-H (San Diego Convention Center)

Danicopan

Kulasekararaj, A

Danicopan as Add-On Therapy to Ravulizumab or Eculizumab Versus Placebo in Patients with Paroxysmal Nocturnal Hemoglobinuria and Clinically Significant Extravascular Hemolysis: Phase 3 Long-term Data

Abstract # 576

Oral Session: 508. Bone Marrow Failure: Acquired: Unraveling the Future of PNH Therapy from Clinical Trials

10 December 2023

17:45 PST

Location: Room 7 (San Diego Convention Center)

Piatek, C

Patient-reported Outcomes: Danicopan as Add-On Therapy to Ravulizumab or Eculizumab Versus Placebo in Patients with Paroxysmal Nocturnal Hemoglobinuria and Clinically Significant Extravascular Hemolysis

Abstract # 1346

Poster Session: 508. Bone Marrow Failure: Acquired: Poster I

9 December 2023

17:30 – 19:30 PST

Location: Halls G-H (San Diego Convention Center)

Ultomiris (ravulizumab)

Kulasekararaj, A

Ravulizumab Provides Durable Control of Intravascular Hemolysis and Improves Survival in Patients with Paroxysmal Nocturnal Hemoglobinuria: Long-Term Follow-Up of Study 301 and Comparisons with Patients of the International PNH Registry

Abstract # 2714

Poster Session: 508. Bone Marrow Failure: Acquired: Poster II

10 December 2023

18:00 – 20:00 PST

Location: Halls G-H (San Diego Convention Center)

Röth, A

Ravulizumab Effectiveness in the Real-world: Evidence from the International PNH Registry

Abstract # 2722

Poster Session: 508. Bone Marrow Failure: Acquired: Poster II

10 December 2023

18:00 – 20:00 PST

Location: Halls G-H (San Diego Convention Center)

Piatek, C

Efficacy and Safety of Subcutaneous Ravulizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria Who Received Prior Intravenous Eculizumab: 2-Year Follow-Up

Abstract # 2713

Poster Session: 508. Bone Marrow Failure: Acquired: Poster II

10 December 2023

18:00 – 20:00 PST

Location: Halls G-H (San Diego Convention Center)

CAEL-101

Valent, J

Safety and Tolerability of CAEL-101, an Anti-Amyloid Monoclonal Antibody, Combined with Anti-Plasma Cell Dyscrasia Therapy in Patients with Light-Chain Amyloidosis: 24-Month Results of a Phase 2 Study

Abstract # 540

Oral Session: 654. MGUS, Amyloidosis and Other Non-Myeloma Plasma Cell Dyscrasias: Clinical and Epidemiological: From Light Chain to Fibril–Novel Diagnostics to Treatments for Amyloidosis

10 December 2023

13:15 PST

Location: Seaport Ballroom EFGH (Manchester Grand Hyatt San Diego)

Costello, M

CAEL-101 Enhances the Clearance of Light Chain Fibrils and Intermediate Aggregates by Phagocytosis

Abstract # 3307

Poster Session: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational: Poster II

10 December 2023

18:00 – 20:00 PST

Location: Halls G-H (San Diego Convention Center)

AL Amyloidosis

Lyons, G

Treatment Patterns and Outcomes for Patients with Light Chain (AL) Amyloidosis: Analysis of a Large US Claims Database

e-Publication

Online Only

Thompson, J

Real-world Treatment Patterns Following Update to National Comprehensive Cancer Network Guidelines for Light-Chain Amyloidosis: Results from a US Administrative Claims Database

e-Publication

Online Only

Laires, P

Prevalence, Incidence, and Characterization of Light Chain Amyloidosis in the USA: A Real-world Analysis Utilizing Electronic Health Records (EHR)

e-Publication

Online Only

aHUS

Wang, Y

Patient Characteristics and Diagnostic Journey of Thrombotic Microangiopathy Associated with a Trigger: A Real-world, Retrospective, Multi-national Study

e-Publication

Online Only

HSCT-TMA

Wang, Y

Real-world Analysis of the Underdiagnosis, Clinical Outcomes and Associated Burden of Hematopoietic Stem Cell Transplantation-Associated Thrombotic Microangiopathy (HSCT-TMA) in the United States of America

Abstract # 491

Oral Session: 904. Outcomes Research – Non-Malignant Conditions: What to Know: Management Costs and Outcomes in Various Non-Malignant Disorders

10 December 2023

10:30 PST

Location: Pacific Ballroom Salons 15-17 (Marriott Marquis San Diego Marina)

PNH

Wagner-Ballon, O

Neutrophil PNH Type II Cells Are Associated with Thrombosis and Bone Marrow Failure Without Hemolysis: Evidence from Analysis of the 5-year French Nation-Wide Multicenter Observational Study

Abstract # 4083

Poster Session: 508. Bone Marrow Failure: Acquired: Poster III

11 December 2023

18:00 – 20:00 PST

Location: Halls G-H (San Diego Convention Center)

On November 28, 2023 TME Pharma N.V. (Euronext Growth Paris: ALTME), a biotechnology company focused on developing novel therapies for treatment of cancer by targeting the tumor microenvironment (TME), reported the launch of a 100% guaranteed capital increase through issuance of new shares for €2.7 million gross proceeds with associated warrants potentially raising up to €2.2 million of additional gross proceeds in order to secure financing to reach key regulatory milestones in 2024 (Press release, TME Pharma, NOV 28, 2023, View Source [SID1234638028]). The guaranteed amount is secured by a group of Dutch investors.

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The capital increase is carried out with preferential subscription rights for the company’s shareholders. The preferential subscription rights are detached and their listing begins today, November 28, 2023 (ISIN code of PSR: FR001400M9E2).

The transaction is expected to extend the company’s cash runway from February 20241 into May 2024 with possibility to extend further into July 2024 if the associated warrants expiring in February 2024 are exercised in full, and to September 2024 if both sets of warrants are fully exercised by July 2024. This transaction will reduce the liquidity risk that the company has been facing in recent months. The operation offers current shareholders subscription rights to maintain their holding in the company without being diluted.

"This guaranteed capital injection provides TME Pharma with financing into May 2024, with the possibility of extending our cash runway even further should all the warrants be fully exercised while ensuring minimal dilution to existing shareholders who continue to support our venture," said Aram Mangasarian, CEO of TME Pharma. "This will allow us to achieve our next clinical and regulatory milestones with our lead asset NOX-A12 in newly diagnosed brain cancer patients, including further maturing of the survival data, an Investigational New Drug filing, and potential access to expedited regulatory pathways in the US, such as Fast-Track. We are also announcing the repurchase of almost half our existing outstanding convertible debt, with the remainder locked up until April next year. This is the latest step in our commitment to our shareholders to end the use of convertible bond financing so we can remain focused on our goal of developing novel therapies for cancer patients and bringing them to market."

Key Preferential Rights Issue details2:

Preferential subscription right: 1 preferential subscription right (PSR) will be awarded for 1 ordinary share held on November 27, 2023
Subscription rate: Each 3 PSRs give right to subscribe for 5 ABSA Y (5 new shares with 5 Warrants Y attached)
Subscription price: €0.25 per ABSA Y, representing a 37.5% discount vs. the closing price of EUR 0.4005 of the company’s shares on November 24, 2023
Subscription period: From November 30 to December 11, 2023 (inclusive)
ABSA are shares with warrants attached. There are two types of ABSA: ABSA Y, containing one new share and one Warrant Y, and ABSA Z, containing one new share and one Warrant Z.

Warrants Y:

Each series of 5 Warrants Y entitle a holder to subscribe for 2 ABSA Z (2 new shares with 2 Warrants Z attached)
Warrant Y will have an exercise price of €0.25
Warrant Y maturity: February 16, 2024, with two periods of exercise. Warrants Y that have not been exercised by the end of the exercise period will become null and void. See Warrants Terms & Conditions for further details.
Warrants Z:

Each series of 4 Warrants Z entitle a holder to subscribe for 5 new shares
Warrant Z will have an exercise price of €0.20
Warrant Z maturity: June 30, 2025, with one period of exercise per quarter. Warrants Y that have not been exercised by the end of the exercise period at the latest will become null and void, without value. See Warrants Terms & Conditions for further details.
Illustrative example

A shareholder holding 300 shares of TME Pharma as of November 27, 2023, would be awarded 300 preferential subscription rights (PSRs). Having 300 PSRs entitles the shareholder to acquire 500 ABSA Y, composed of 500 new shares and 500 Warrant Y, for an amount of €125. The 500 Warrant Y entitle them to subscribe for 200 ABSA Z for €50. These 200 ABSA Z are composed of 200 new shares and 200 Warrant Z. The 200 Warrant Z can be exercised for €50 granting 250 new TME Pharma shares. Thus, if this shareholder participates fully in the transaction, they would hold 1250 shares, of which 900 newly acquired for €225.

Timetable of the Rights Issue:

November 17, 2023

Decision of the Board of Directors on the launch of Capital Increase

November 24, 2023

Press release announcing the Capital Increase
Release of the Euronext notice

November 27, 2023

Suspension of the right to exercise dilutive instruments issued by the Company
Accounting day at the end of which the holders of existing shares recorded in their securities accounts will be awarded preferential subscription rights (PSRs)

November 28, 2023

Detachment of PSRs and start of their listing

November 29, 2023

Euronext "Record date"

November 30, 2023

(included)

Opening of the subscription period – Start of the period of PSR exercise

December 07, 2023 (included)

End of PSR listing

December 11, 2023 (included)

Closing of the subscription period – End of the period of PSR exercise

December 13, 2023

Reception of the results of the public offer

December 14, 2023

Decision of the Board of Directors on the issue of the New Shares, and where applicable, the limitation of the Capital Increase, the reallocation of the Capital Increase

December 14, 2023

Distribution of the press release announcing the final amount of Capital Increase

December 18, 2023

Settlement-delivery, listing of New Shares, listing of Warrants Y

December 18, 2023

Resumption of the right to exercise any dilutive instruments issued by the Company, except convertible bonds subject to lock-up until April 1, 2024

Use of Proceeds:

Approximately 1/3rd of the proceeds from the guaranteed part of the capital increase will be used to reach increased data maturity in the ongoing NOX-A12 GLORIA Phase 1/2 trial in glioblastoma, advance the discussions with the US Food and Drug Administration (FDA) past regulatory milestones. Another 1/3rd of proceeds will be used for general corporate purposes including intensifying interactions with investors and potential industry partners. The final 1/3rd will be used to buy back part of the remainder of the convertible debt as described below.

Management believes that the completion of the regulatory milestones with the FDA in Q1-2024 will allow the company to pursue additional non-dilutive and dilutive financing on improved conditions.

Buyback and Lock-up of Convertible Debt key details3:

The company plans to reduce the outstanding convertible debt with part of the guaranteed proceeds from this transaction. As announced on April 18, 2023, the company terminated the agreement with Atlas Special Opportunities, LLC (ASO) other than with regard to already issued convertible bonds (CBs). One of the conditions of the investor group guaranteeing this financing is that TME Pharma repurchase 898 out of 1,898 outstanding convertible bonds for the total amount of €942,900 including 5% premium4 representing approximately 1/3rd of the initial guaranteed part of the funds raised. Furthermore, ASO agrees to a lock-up of the remaining 1,000 convertible bonds until April 1, 2024, in exchange for a flat fee of 100 additional CBs with a nominal value of €100,000. The redemption and lock-up prevent further conversion of CBs to shares and reiterate the company’s commitment to methodically end its reliance on convertible bond financing. The company is evaluating options to repurchase the last part of remaining convertible debt.

Guarantee:

The capital increase of €2.7 million is guaranteed by a group of four investors, whose individual commitment is not representing a concerted action towards the potential control of the company. None of them individually would cross threshold of 50% ownership even if the guarantee was required in full.

Shareholder and Corporate Authorizations:

The issuance of shares in this transaction relies upon the authorizations granted to the Issuer by its shareholders in the annual general meeting (AGM) on June 29, 2023. Issuer has completed and obtained all necessary corporate approvals for the rights issue. In particular, at the AGM held on 29 June 2023, the company’s shareholders approved the authorized capital amounting to € 212,500, divided into 20,000,000 ordinary shares, and 1,250,000 preference shares, each share with a nominal value of € 0.01. In addition, and if and as per the moment the company’s issued and paid-up ordinary share capital will amount to €200,000, comprised 20,000,000 ordinary shares, the transitional provision outlined in article 37 of the company’s articles of association will become effective, according to which the authorized capital of the company amounts to € 900,000 divided into 80,000,000 ordinary shares and 10,000,000 preference shares, each share with a nominal value of € 0.01.

Dilutive Potential:

Shareholders participating fully in the transaction, i.e. purchasing the ABSA Y and exercising Warrants Y and Z will not be diluted, and may increase their percentage shareholding if other investors do not exercise their Warrants.

Table: Dilutive Potential from Transaction Assuming an Existing Shareholder Does NOT Participate in the Transaction

Description

Shares to be issued
(max)

Total shares
outstanding

Dilution (max)

Shareholder
starting with 1%
would then hold

Purchase of ABSA Y

10,825,528

17,320,845

62.50%

0.38%

Exercise of Warrant Y

4,330,211

21,651,057

70.00%

0.30%

Exercise of Warrant Z

5,412,764

27,063,821

76.00%

0.24%

Risk Factors:

The main risk factors relating to the issue are as follows:

the market for preferential subscription rights may offer only limited liquidity and be subject to a high level of volatility;
shareholders who do not exercise their preferential subscription rights would see their stake in the company’s share capital diluted;
the market price of the company’s shares may fluctuate and fall below the subscription price of the New Shares;
the volatility and liquidity of the company’s shares may fluctuate significantly;
if the market price of the company’s shares falls, the value of preferential subscription rights could fall;
the Rights Issue is not subject to a performance guarantee and investors who have acquired preferential subscription rights could sustain a loss equal to the price of acquiring these preferential subscription rights.
The company expects to incur losses for the foreseeable future and will need substantial additional funding in order to complete the development and commercialization of its product candidates, which may not be available on acceptable terms when needed, if at all.
Before deciding to invest, Investors are asked to familiarise themselves with the risks described in the company’s 2022 annual financial report (LINK), and 2023 half-year financial report (LINK), both available on the company website. Key strategic, operational and financial risks are described in the Information Document prepared specifically for this transaction in accordance with the guidelines of the Dutch Authority for the Financial Markets which is available on the company website (LINK).

Potential Conflict of Interest:

Part of the variable remuneration of management relates to corporate goals for advancing the development pipeline of TME Pharma as well as securing the respective funding.

Additional Information:

Additional Information: The characteristics, terms and conditions and dilution resulting from the transaction may be found in the Annex to this press release and in the dedicated Right Issue page on the TME Pharma website: LINK.

On November 28, 2023 Novocure (NASDAQ: NVCR) reported a series of actions to strengthen and optimize business operations to support near-term growth drivers and long-term value creation (Press release, NovoCure, NOV 28, 2023, View Source [SID1234638027]). The plan includes an expected reduction in residual operating expenses of approximately $60 million, enabling the Company to fund future growth priorities without an associated increase in expected forward operating cash burn. Novocure continues to focus resources on its global commercial infrastructure and launch preparation ahead of its anticipated indication in metastatic non-small cell lung cancer and on high-potential research and development programs.

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"Decisions like these are deeply personal and challenging, because of the impact on our employees and their families," said Novocure’s Chief Executive Officer, Asaf Danziger. "To those departing Novocure, I want to express my sincere gratitude for your hard work. Your contributions have influenced the lives of many cancer patients and your legacy will forever be intertwined with Novocure."

"The initiatives announced today prioritize growth and maintain financial health and flexibility as we position our company for future profitability," said Novocure’s Chief Financial Officer, Ashley Cordova. "These decisions were difficult, yet essential. With a more focused organization, we are confident that these initiatives will bolster Novocure’s position, enabling us to unlock our long-term potential and fulfill our mission."

Key elements of the plan include:

Portfolio prioritization
Novocure has taken a holistic review of operating expenses and has focused resources on the areas of greatest anticipated value creation, intended to balance near-term and long-term growth opportunities.

Novocure continues to invest in launch readiness, including field-based commercial and field-based medical team hiring, for the anticipated approval of Tumor Treating Fields therapy for the treatment of metastatic non-small cell lung cancer following progression on or after platinum-based therapies.
Novocure will deliver two phase 3 randomized clinical trial readouts in brain metastases from non-small cell lung cancer (METIS) and locally advanced pancreatic cancer (PANOVA-3) anticipated in 2024.
Novocure has prioritized development investments on a sharply focused list of randomized clinical trials – TRIDENT, KEYNOTE D58 and LUNAR-2 – which have the potential to drive the greatest value in solid tumors where Tumor Treating Fields therapy has established efficacy.
Strategic restructuring
In conjunction with its portfolio prioritization, Novocure is streamlining its operational expenses.

Novocure’s plan to reduce residual operating expenses by approximately $60 million includes a planned reduction in headcount of approximately 200 colleagues, 13% of its current workforce. Field-based commercial and field-based medical employees are minimally affected. Novocure expects to incur one-time costs related to the workforce reduction of approximately $7 million in the fourth quarter of 2023.
The anticipated cost savings are expected to offset growth investments and accelerate Novocure’s path to profitability.

On November 28, 2023 Blue Earth Diagnostics, a Bracco company and recognized leader in the development and commercialization of innovative PET radiopharmaceuticals, reported the publication of results of a post-hoc analysis assessing the impact of urinary activity on the interpretation of POSLUMA (flotufolastat F 18) injection (formerly known as 18F-rhPSMA-7.3) PET/CT in prostate cancer (Press release, Blue Earth Diagnostics, NOV 28, 2023, View Source [SID1234638026]). The analysis was based on data from Blue Earth Diagnostics’ prospective Phase 3 LIGHTHOUSE1 and SPOTLIGHT2 studies that evaluated the diagnostic performance and safety of POSLUMA in newly diagnosed and recurrent prostate cancer. Majority read results from 3 blinded readers assessing 712 evaluable POSLUMA scans showed that urinary activity in the bladder and ureters did not influence disease assessment for the vast majority (96%, 682/712) of patients. Halo artifacts, which can inhibit image assessment, were very rare, and were absent in 99.7% (710/712) of patients by majority read. Ureteric activity, which can also limit assessment of lymph nodes distant to the bladder, was also absent in a majority of patients (56%, 401/712). FDA-approved POSLUMA is indicated for positron emission tomography (PET) of prostate-specific membrane antigen (PSMA) positive lesions in men with prostate cancer with suspected metastasis who are candidates for initial definitive therapy or with suspected recurrence based on elevated serum prostate-specific antigen (PSA) level.

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The results, "Quantitative and qualitative assessment of urinary activity of 18F-flotufolastat-PET/CT in patients with prostate cancer: A post-hoc analysis of the LIGHTHOUSE and SPOTLIGHT studies," were published online in Molecular Imaging and Biology (2023), View Source and will also appear in an upcoming print issue. Authors are Phillip H. Kuo, Departments of Medical Imaging, Medicine, and Biomedical Engineering, University of Arizona, Tucson, AZ, USA, and Southern Arizona Veterans Administration Healthcare System; Rick Hermsen, Department of Nuclear Medicine, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands; Ross Penny and Ernst J. Postema, Blue Earth Diagnostics Ltd, Oxford, UK.

"The ability to gather actionable information from PSMA PET scans is important for physicians to make informed decisions about patient management for men with prostate cancer," said Phillip Kuo, MD, Ph.D., Departments of Medical Imaging, Medicine, and Biomedical Engineering. "Activity in the urinary bladder and ureters is a common feature of PSMA-PET radiopharmaceuticals. It can potentially obscure tumors and lymph nodes in the prostate region – the most common site of recurrence – as well as pelvic and retroperitoneal lymph nodes distant to the prostate region, interfering with accurate image interpretation. In early clinical experience, POSLUMA demonstrated a high binding affinity for PSMA, with low urinary activity, providing enhanced image evaluation in the prostate and regions near the ureters for patients with prostate cancer. Results from this large dataset, based on images from two Phase 3 prospective trials, build on that experience and demonstrate that POSLUMA urinary activity is low and rarely impacts disease assessment."

"This analysis of FDA-approved POSLUMA marks the first and only published assessment of urinary activity for a PSMA-targeted PET/CT prostate cancer agent, and we are pleased that the results have been published in Molecular Imaging and Biology where they can be widely shared with the imaging community," said David E. Gauden, D.Phil., Chief Executive Officer of Blue Earth Diagnostics. "POSLUMA represents a new class of PSMA-targeted PET radiopharmaceuticals based on novel radiohybrid technology. It is engineered to advance clinical decision-making by providing clinically precise information for treatment planning in men with prostate cancer, which can lead to changes in patient management. We believe that POSLUMA’s diagnostic performance, high-affinity PSMA binding and low urinary activity characteristics make it a valuable diagnostic tool that is radiolabeled with 18F for high image quality and readily available patient access."

Published results were based on 712 evaluable POSLUMA scans (348 newly diagnosed patients and 364 patients with recurrent prostate cancer from LIGHTHOUSE and SPOTLIGHT, respectively). Of the 718 eligible scans, 6 were excluded on the basis of cystectomy, renal failure or presence of a urinary catheter. Findings included quantitative analyses of activity in the urinary bladder, based on maximum and mean standardized uptake values (SUVmax and SUVmean, respectively). Qualitative analyses conducted by 3 blinded, independent PET readers examined the impact of any urinary activity on the ability to assess the prostate/prostate bed and pelvic lymph nodes using a 3-point scale.

The median bladder SUVmax and SUVmean for POSLUMA were 17.1 and 12.5, respectively. For the qualitative metrics, by majority read, it was possible to distinguish urinary activity from disease uptake in 96% (682/712) of patients. Halo artifacts impacting assessment around the ureters and bladder were only observed in 0.3% (2/712) of patients.

There were several limitations to the study. It was not designed as a head-to-head comparison with other PSMA-PET radiopharmaceuticals and any comparisons with other radiopharmaceuticals reported in the literature should be made with caution. Another limitation was that reader agreement was not formally tested, however the authors noted that patient-level inter-reader agreement has been previously reported as ≥ 95%3 and ≥ 75%4 for LIGHTHOUSE and SPOTLIGHT respectively. Image interpretation errors can occur with POSLUMA PET. A negative image does not rule out the presence of prostate cancer and a positive image does not confirm the presence of prostate cancer.

Blue Earth Diagnostics’ LIGHTHOUSE Phase 3 clinical trial (NC04186819) was a prospective, Phase 3, multi-center, single-arm, imaging study conducted in the United States and Europe to evaluate the safety and diagnostic performance of POSLUMA PET in men with newly diagnosed prostate cancer. Results from the SPOTLIGHT study were published in European Urology DOI.org/10.1016/j.eururo.2023.06.0181. The SPOTLIGHT trial (NCT04186845) was a Phase 3, multi-center, single-arm imaging study conducted in the United States and Europe to evaluate the safety and diagnostic performance of POSLUMA PET imaging in men with suspected prostate cancer recurrence based on elevated PSA following prior therapy. Results from the SPOTLIGHT study were published in the Journal of Urology: DOI: 10.1097/JU.0000000000003493.2

About POSLUMA (flotufolastat F 18)

POSLUMA (flotufolastat F 18) injection (formerly referred to as 18F-rhPSMA-7.3) is an optimized, targeted radiohybrid diagnostic imaging agent indicated for positron emission tomography (PET) of prostate-specific membrane antigen (PSMA) positive lesions in men with prostate cancer with suspected metastasis who are candidates for initial definitive therapy or with suspected recurrence based on elevated serum prostate-specific antigen (PSA) level. Precision PET imaging with POSLUMA can help identify the location and extent of prostate cancer, providing clinically valuable information to guide patient management. POSLUMA represents a new class of high-affinity PSMA-targeted PET radiopharmaceuticals based on novel radiohybrid technology and is labeled with the radioisotope 18F to provide readily available patient access and leverage the high image quality of 18F-labeled PSMA PET imaging to facilitate effective detection of disease. POSLUMA was approved by the U.S. Food and Drug Administration in May 2023.

About Radiohybrid Prostate-Specific Membrane Antigen (rhPSMA)

Radiohybrid Prostate-Specific Membrane Antigen (rhPSMA) compounds consist of a radiohybrid ("rh") Prostate-Specific Membrane Antigen-targeted receptor ligand which attaches to and is internalized by prostate cancer cells, and they may be radiolabeled with imaging isotopes for PET imaging, or with therapeutic isotopes for therapeutic use – providing the potential for creating a true theranostic technology. Radiohybrid technology and rhPSMA originated from the Technical University of Munich, Germany. Blue Earth Diagnostics acquired exclusive, worldwide rights to rhPSMA diagnostic imaging technology from Scintomics GmbH in 2018, and therapeutic rights in 2020, and sublicensed the therapeutic application to its sister company Blue Earth Therapeutics. Blue Earth Diagnostics received U.S. Food and Drug Administration approval for its radiohybrid PET diagnostic imaging product for use in prostate cancer in 2023. rhPSMA compounds for potential therapeutic use are investigational and have not received regulatory approval.

Indication and Important Safety Information About POSLUMA

INDICATION

POSLUMA (flotufolastat F 18) injection is indicated for positron emission tomography (PET) of prostate-specific membrane antigen (PSMA) positive lesions in men with prostate cancer

with suspected metastasis who are candidates for initial definitive therapy
with suspected recurrence based on elevated serum prostate-specific antigen (PSA) level
IMPORTANT SAFETY INFORMATION

Image interpretation errors can occur with POSLUMA PET. A negative image does not rule out the presence of prostate cancer and a positive image does not confirm the presence of prostate cancer. The performance of POSLUMA for imaging metastatic pelvic lymph nodes in patients prior to initial definitive therapy seems to be affected by serum PSA levels and risk grouping. The performance of POSLUMA for imaging patients with biochemical evidence of recurrence of prostate cancer seems to be affected by serum PSA levels. Flotufolastat F 18 uptake is not specific for prostate cancer and may occur in other types of cancer, in non-malignant processes, and in normal tissues. Clinical correlation, which may include histopathological evaluation, is recommended.
Risk of Image Misinterpretation in Patients with Suspected Prostate Cancer Recurrence: The interpretation of POSLUMA PET may differ depending on imaging readers, particularly in the prostate/prostate bed region. Because of the associated risk of false positive interpretation, consider multidisciplinary consultation and histopathological confirmation when clinical decision-making hinges on flotufolastat F 18 uptake only in the prostate/prostate bed region or only on uptake interpreted as borderline.
POSLUMA use contributes to a patient’s overall long-term cumulative radiation exposure. Long-term cumulative radiation exposure is associated with an increased risk for cancer. Advise patients to hydrate before and after administration and to void frequently after administration. Ensure safe handling to minimize radiation exposure to the patient and health care providers.
The adverse reactions reported in ≥0.4% of patients in clinical studies were diarrhea, blood pressure increase and injection site pain.
Drug Interactions: androgen deprivation therapy (ADT) and other therapies targeting the androgen pathway, such as androgen receptor antagonists, may result in changes in uptake of flotufolastat F 18 in prostate cancer. The effect of these therapies on performance of POSLUMA PET has not been established.
To report suspected adverse reactions to POSLUMA, call 1-844-POSLUMA (1-844-767-5862) or contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Full POSLUMA prescribing information is available at www.posluma.com/prescribing-information.pdf.

On November 28, 2023 Carisma Therapeutics Inc. (Nasdaq: CARM) ("Carisma" or the "Company"), a clinical stage biopharmaceutical company focused on discovering and developing innovative immunotherapies, reported the clearance of its Investigational New Drug application (IND) by the U.S. Food and Drug Administration (FDA) for CT-0525, an ex vivo gene-modified autologous chimeric antigen receptor-monocyte (CAR-Monocyte) cellular therapy intended to treat solid tumors that overexpress human epidermal growth factor receptor 2 (HER2) (Press release, Carisma Therapeutics, NOV 28, 2023, View Source [SID1234638025]). Having received a Study May Proceed notification from the FDA, Carisma expects to initiate a Phase 1 study in the coming months and to treat the first patient in the first half of 2024.

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"Clearance of the IND for CT-0525 is a significant milestone in Carisma’s mission to develop innovative myeloid cell therapies for metastatic solid tumors," said Steven Kelly, President and Chief Executive Officer of Carisma. "Through this Phase 1 study, we aim to advance our understanding of safety, tolerability, manufacturing feasibility and mechanism of action of CT-0525."

Monocytes are the precursor cells to macrophages, and there are numerous potential benefits to a CAR-Monocyte approach to help overcome certain challenges of treating solid tumors. The CAR-Monocyte manufacturing platform enables the ability to manufacture up to 10 billion cells from a single apheresis and utilizes a rapid, single-day manufacturing process. This manufacturing process holds the potential to significantly reduce the future cost of goods and manufacturing turnaround time associated with this autologous cell therapy. Pre-clinical data presented at The Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s Annual Meeting in November 2022 demonstrate that CT-0525 therapy reduced tumor growth in multiple pre-clinical solid tumor models.

"CT-0525 is the first CAR-Monocyte to be evaluated in the solid tumor setting. With a CAR-Monocyte’s in vivo persistence, ability to differentiate into pro-inflammatory CAR macrophages, and multi-modal anti-tumor mechanism of action, along with its high cell yield, CT-0525 has the potential to improve the treatment paradigm for patients with HER2 overexpressing metastatic solid tumors," said Michael Klichinsky, PharmD, PhD, Co-Founder and Chief Scientific Officer at Carisma. "We look forward to the clinical development of CT-0525."

The Phase 1 study for CT-0525 is designed to assess the safety, tolerability, and the manufacturing feasibility of CT-0525. This study will enroll participants with locally advanced (unresectable) or metastatic solid tumors overexpressing HER2 whose disease has progressed on standard approved therapies. The study will consist of two cohorts: Cohort 1 will receive IV administration of up to 3 billion CAR-positive cells, while Cohort 2 will receive IV administration of CT-0525 of up to 10 billion CAR-positive cells.

About CT-0525

CT-0525 is an ex vivo gene-modified autologous chimeric antigen receptor-monocyte (CAR-Monocyte) cellular therapy intended to treat solid tumors that overexpress human epidermal growth factor receptor 2 (HER2). The CAR-Monocyte approach has the potential to address the challenges of treating solid tumors with cell therapies, including tumor infiltration, immunosuppression within the tumor microenvironment, and antigen heterogeneity.