On May 16, 2023 AstraZeneca reported that it will present new clinical and real-world data in multiple haematological conditions, further demonstrating its ambition to redefine care in haematology at the European Hematology Association (EHA) (Free EHA Whitepaper) 2023 Hybrid Congress, 8 to 11 June 2023 (Press release, AstraZeneca, MAY 16, 2023, View Source [SID1234631756]).

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A total of 29 abstracts will feature 10 approved and potential new medicines across the Company’s haematology portfolio and pipeline spanning more than 10 types of haematological conditions and rare diseases.

This includes a presentation from Alexion, AstraZeneca’s Rare Disease group, reporting positive results from the pivotal ALPHA Phase III trial evaluating the investigational first-in-class oral Factor D inhibitor danicopan (ALXN2040) as an add-on to standard of care C5 inhibitor therapy Ultomiris (ravulizumab) or Soliris (eculizumab).1 Data show add-on treatment with danicopan significantly improved signs and symptoms of clinically significant extravascular haemolysis (EVH) in the small subset of patients with paroxysmal nocturnal haemoglobinuria (PNH) treated with C5 inhibition who are affected, allowing them to maintain treatment with standard of care and disease control.1 PNH is a rare and severe blood disorder characterised by the destruction of red blood cells, known as intravascular haemolysis (IVH), and white blood cell and platelet activation that can cause thrombosis (blood clots) and result in organ damage and potentially premature death.2-4

Gianluca Pirozzi, Senior Vice President, Head of Development, Regulatory and Safety, Alexion, said: "We look forward to presenting results at EHA (Free EHA Whitepaper) from the ALPHA Phase III trial showing the potential for danicopan, as an add-on to Ultomiris or Soliris, to address clinically significant EVH, which can impact approximately 10% to 20% of PNH patients treated with C5 inhibitors, while allowing them to maintain treatment with standard of care. Additional presentations will highlight our momentum in expanding our pipeline beyond complement to address the needs of more people living with rare diseases."

Additionally, AstraZeneca will present new data analyses, external collaborations and real-world data that will continue to display the long-term safety and efficacy of Calquence (acalabrutinib) in patients with chronic lymphocytic leukaemia (CLL), including a matching-adjusted indirect comparison (MAIC) of the efficacy and safety of Calquence versus zanubrutinib in relapsed or refractory CLL, demonstrating Calquence’s meaningfully differentiated profile.5 New tolerability and efficacy data showing the activity of Calquence in combination with bendamustine and rituximab for the treatment of mantle cell lymphoma(MCL) will also be presented.6

The Company will present data on AZD0486, a CD19/CD3 next-generation T-cell engager for patients with relapsed or refractory follicular lymphoma (FL).7 New clinical data demonstrating the emerging potential of capivasertib, an AKT inhibitor, in the treatment of relapsed or refractory non-Hodgkin lymphoma (NHL), and AZD4573, a CDK9 inhibitor, in the treatment of peripheral T-cell lymphoma (PTCL) will also be presented.8,9

Anas Younes, Senior Vice President, Haematology R&D, AstraZeneca, said: "Our data at EHA (Free EHA Whitepaper) will showcase the promise of our growing haematology pipeline, reinforcing our dedication to patients with haematologic conditions. We are excited to share new Calquence analyses that will further build on our medicine’s differentiated long-term efficacy and safety profile in chronic lymphocytic leukaemia and mantle cell lymphoma. Positive clinical data on our CD19/CD3 T-cell engager and our oral AKT inhibitor, capivasertib, will showcase their potential as treatments for patients with lymphoma."

Advancing the treatment landscape to improve outcomes for more patients with PNH

A prespecified interim efficacy analysis from the ALPHA Phase III trial of danicopan as an add-on to Ultomiris or Soliris will show its potential to improve haemoglobin levels and reduce the need for transfusions in the small subset of people living with PNH who experience clinically significant EVH, while on standard of care.1
Real-world and clinical trial data will estimate that the prevalence of clinically significant EVH in patients with PNH who are receiving C5 inhibitor therapy ranges from 7% to 21%. Additionally, the data will offer insights into disease control and treatment satisfaction among patients and physicians.10
An analysis of outcomes up to four years from the pivotal, Phase III trial and open-label extension of Ultomiris in C5 inhibitor-experienced adults with PNH will further support its long-term use in PNH management. The analysis will show Ultomiris maintained effective control of intravascular haemolysis with a low incidence of major adverse vascular events and demonstrated a 98.4% survival rate throughout the four-year study period.11
An analysis of Korean registry data in patients with PNH will outline lactate dehydrogenase (LDH) levels, and not haemoglobin levels, as a predictor of thromboembolism, and thromboembolism as a predictor of death, reinforcing the importance of controlling terminal complement activation and intravascular haemolysis in the treatment of PNH.12
Further analyses demonstrate continued efficacy and safety for Calquence

Data will be shared from a MAIC of the efficacy and safety of Calquence versus zanubrutinib in relapsed or refractory CLL, based on data from the ASCEND and ALPINE Phase III trials.5
An interim safety analysis will display the safety and treatment adherence with Calquence in patients more than 80 years old or frail patients with CLL in an ongoing investigator-initiated Phase II trial.13
A Phase Ib trial will show the safety and efficacy of Calquence, bendamustine and rituximab in patients with treatment-naïve or relapsed or refractory MCL, and support further investigation to determine if this could be an alternative treatment option for patients with MCL.6
Emerging pipeline molecules and treatment strategies show therapeutic potential

Interim results for AZD0486 (TNB-486), a CD19/CD3 next-generation T-cell engager, will display a high complete response (CR) in patients with relapsed or refractory FL with a manageable safety profile in an ongoing Phase I trial.7
A Phase II, open-label, multicentre trial (CAPITAL) of capivasertib, a potent, oral AKT inhibitor in patients with relapsed or refractory B-cell NHL will show the molecule had single-agent activity and a manageable safety profile in patients with heavily pretreated relapsed or refractory FL and could be a potential treatment option in NHLs more broadly.8
Efficacy and safety results from a Phase IIa study looking at the CDK9 inhibitor, AZD4573, in patients with relapsed or refractory PTCL will show encouraging clinical activity as a monotherapy, including three CRs and one complete metabolic response after initial progressive disease.9
Preliminary ongoing Phase I/II safety and tolerability results of AZD0466, a Bcl-2/Bcl-xl inhibitor, will show it is tolerated as a monotherapy for patients with relapsed or refractory acute leukaemia.14
Improving understanding and management of debilitating rare diseases

Results through eighteen months on safety, tolerability and biomarker data will be presented from a Phase II trial evaluating CAEL-101, a potentially first-in-class monoclonal antibody, in adults with light-chain (AL) amyloidosis.15
An encore presentation will highlight the design and methodology of two Phase III trials evaluating the efficacy and safety of CAEL-101 compared to placebo to reduce amyloid burden in treatment-naive patients with AL-amyloidosis with cardiac involvement.16
Results from a double-blind survey of healthcare providers in Europe, North America and Australia will offer insight into factors influencing treatment discontinuation with C5 inhibitors for patients with atypical haemolytic uraemic syndrome (aHUS), including thrombotic microangiopathy response, haemolysis and kidney function.17
Key AstraZeneca presentations during EHA (Free EHA Whitepaper) 2023

Lead author

Abstract title

Presentation details

Danicopan (ALXN2040)

Lee, JW

Patients with paroxysmal nocturnal hemoglobinuria and clinically significant extravascular hemolysis on ravulizumab/eculizumab showed hemoglobin response superiority with add-on danicopan vs placebo

Abstract # P771

Poster Presentation

Poster Session

9 June 2023

18:00 – 19:00 CEST

Ultomiris (ravulizumab) and Soliris (eculizumab)

Kulasekararaj, A

Prevalence of clinically significant extravascular hemolysis in stable C5 inhibitor-treated patients with PNH and its association with disease control, quality of life and treatment satisfaction

Abstract # PB2056

e-Publication

Online Only

Kulasekararaj, A

Long-term ravulizumab treatment in complement inhibitor-experienced patients with PNH provides durable control of intravascular hemolysis with low incidence of major adverse vascular events and death

Abstract # P772

Poster Presentation

Poster Session

9 June 2023

18:00 – 19:00 CEST

CAEL-101

Wechalekar, A

Cardiac amyloid reaching for extended survival (CARES) trials: 2 placebo-controlled, double-blind, randomized, Phase 3 trials assessing CAEL-101 in patients with mayo stages IIIA/IIIB AL amyloidosis

Abstract # PB2150

e-Publication

Online Only

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: 18-month results of a Phase 2 study

Abstract # S204

Oral Presentation

11 June 2023

11:30 – 11:45 CEST

Calquence (acalabrutinib)

Skarbnik, A

A matching-adjusted indirect comparison of the efficacy and safety of acalabrutinib versus zanubrutinib in relapsed or refractory chronic lymphocytic leukemia

Abstract # P642

Poster Presentation

9 June 2023

18:00 – 19:00 CEST

Simon, F

Safety and treatment adherence with acalabrutinib in very old (≥80y) and/or frail patients with chronic lymphocytic leukemia (CLL) – interim safety analysis of the ongoing Phase-II CLL-frail trial

Abstract # P630

Poster Presentation

9 June 2023

18:00 – 19:00 CEST

Philips, T

Safety and efficacy of acalabrutinib, bendamustine, and rituximab in patients with treatment-naïve or relapsed/refractory mantle cell lymphoma: Phase Ib trial

Abstract # P1094

Poster Presentation

9 June 2023

18:00 – 19:00 CEST

AZD0486

Jacobs, R

High complete response rate with TNB-486 a Novel CD19xCD3 T-Cell Engager, in relapsed/refractory follicular lymphoma: Interim results from an ongoing Phase 1 study

Abstract # S224

Oral Presentation

9 June 2023

14:45 – 16:00 CEST

AZD0466

Marconi, G

Safety and tolerability of AZD0466 as monotherapy for patients with advanced hematological malignancies – Preliminary results from an ongoing Phase I/II trial

Abstract # P537

Poster Presentation

9 June 2023

18:00 – 19:00 CEST

AZD4573

Shortt, J

Encouraging complete responses (CRs) observed with CDK9 inhibitor AZD4573 in Patients (pts) with Relapsed/Refractory (r/r) Peripheral T-cell Lymphoma (PTCL): Early trial analysis

Abstract # P1141

Poster Presentation

9 June 2023

18:00 – 19:00 CEST

Capivasertib

Hodson, D

A Phase II, open-label, multicenter study of capivasertib, a potent, oral pan-AKT inhibitor, in patients with relapsed or refractory B-Cell non-hodgkin lymphoma (CAPITAL)

Abstract # P1098

Poster Presentation

9 June 2023

18:00 – 19:00 CEST

PNH

Jang, JH

Lactate dehydrogenase is a predictor of thromboembolism, and thromboembolism is a predictor of death, in patients with paroxysmal nocturnal hemoglobinuria (PNH): results from a Korean PNH registry

Abstract # PB2040

e-Publication

Online Only

aHUS

Lo, SH

Real-world clinical practices in treatment discontinuation with complement C5 inhibitors for atypical hemolytic uremic syndrome: a global survey of healthcare professionals

Abstract # P1599

Poster Presentation

9 June 2023

18:00 – 19:00 CEST

Sickle Cell Disease

Patel, A

Epidemiology and treatment of sickle cell disease associated vaso-occlusive crises in inpatient and emergency care settings: a systematic literature review and meta-analysis

Abstract # P1430

Poster Presentation

9 June 2023

18:00 – 19:00 CEST

On May 15, 2023 Sumitomo Dainippon Pharma reported its Summary of Consolidated Financial Results for the Year Ended March 31, 2023 (Press release, Sumitomo Dainippon Pharma, MAY 15, 2023, View Source [SID1234632882]).

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CTI BioPharma has filed a 10-Q – Quarterly report [Sections 13 or 15(d)] with the U.S. Securities and Exchange Commission .

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On May 15, 2023, Emergent BioSolutions Inc. (the "Company") reported to have entered into that certain Fourth Amendment to Amended and Restated Credit Agreement, Waiver and First Amendment to Amended and Restated Collateral Agreement (the "Credit Agreement Amendment"), among the Company, as borrower, certain subsidiaries of the Company, as guarantors, Wells Fargo Bank, National Association, as administrative agent (in such capacity, the "Administrative Agent") and certain lenders party thereto (Filing, 8-K, Emergent BioSolutions, May 15, 2023, View Source [SID1234631842]). The Credit Agreement Amendment amends the Amended and Restated Credit Agreement, dated as of October 15, 2018, among the Company, the lenders party thereto from time to time and the Administrative Agent (as previously amended, modified and supplemented, the "Existing Credit Agreement"), relating to the Company’s senior secured credit facilities consisting of a senior revolving credit facility (the "Revolving Credit Facility") and a senior term loan facility (the "Term Loan Facility" and together with the Revolving Credit Facility, the "Senior Secured Credit Facilities").

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The Credit Agreement Amendment amends the Existing Credit Agreement to, among other things, (a) extend the maturity date of the Senior Secured Credit Facilities from October 13, 2023 to May 15, 2025, (b) reduce the available commitments under the Revolving Credit Facility from $600.0 million to $300.0 million, (c) remove the Company’s ability to incur incremental loans and (d) amend certain mandatory prepayment triggers, affirmative covenants, negative covenants and events of default thereunder. In connection with the Credit Agreement Amendment, the Company used the approximately $270.0 million of proceeds from the previously announced sale of its travel health business to Bavarian Nordic, which closed on May 15, 2023, together with approximately $217.2 million of cash on hand, to repay approximately $144.4 million in outstanding principal amount of loans under the Term Loan Facility and $342.8 million outstanding principal amount of loans under the Revolving Credit Facility.

The Credit Agreement Amendment also (w) amends the consolidated debt service coverage ratio financial covenant to require the minimum level to be 2.25 to 1.00 for the fiscal quarters ending March 31, 2024, June 30, 2024, September 30, 2024 and December 31, 2024, and then 2.50 to 1.00 for each fiscal quarter ending thereafter, (x) amends the consolidated leverage ratio to require the maximum level to be 4.50 to 1.00 for the fiscal quarter ending March 31, 2024 and each fiscal quarter ending thereafter, (y) adds minimum Consolidated EBITDA requirements and maximum capital expenditure requirements for each of the months ending April 30, 2023 through February 29, 2024 and a minimum liquidity requirement as of the end of each calendar month and (z) requires the Company to increase its liquidity by April 30, 2024 by raising at least $75.0 million of equity or unsecured indebtedness.

In addition, the Credit Agreement Amendment replaces the interest rate benchmark such that borrowings under the Revolving Credit Facility and the outstanding principal amount of the Term Loan Facility shall bear interest at a rate per annum equal to (a) a rate based on SOFR, EURIBOR or CDOR plus a margin of 6.00% until March 31, 2024 and thereafter, a margin ranging from 2.75% to 4.00% depending on the Company’s consolidated leverage ratio, or (b) a base rate (which is the highest of the prime rate, the federal funds rate plus 0.50%, and a SOFR rate for an interest period of one month plus 1%) plus a margin of 5.00% until March 31, 2024 and thereafter, a margin ranging from 1.75% to 3.00% depending on the Company’s consolidated leverage ratio. In addition, the commitment fee the Company is required to pay in respect of the annual daily unused commitments under the Revolving Credit Facility shall be 0.15% to 0.40% per annum, depending on the Company’s consolidated leverage ratio.

Under the Credit Agreement Amendment, the Company and the other guarantors have also agreed to provide a lien over certain assets as additional collateral for the benefit of the lenders, including owned real property, equity interests of foreign subsidiaries and certain deposit accounts.

The foregoing description of the Credit Agreement Amendment does not purport to be complete and is qualified in its entirety by reference to the full text of the Credit Agreement Amendment, a copy of which is filed herewith as Exhibit 10.1 and is incorporated herein by reference. The Credit Agreement Amendment contains representations, warranties and covenants that were made only for purposes of such agreement and as of specific dates, that are solely for the benefit of the parties to such agreement, and that may be subject to limitations agreed upon by the contracting parties. The Credit Agreement Amendment is not intended to provide investors and the public with factual information about the Company’s current state of affairs. Rather, investors and the public should look to other disclosures contained in the Company’s filings with the U.S. Securities and Exchange Commission (the "SEC").

At-the-Market Equity Offering Facility

On May 17, 2023, the Company entered into an Equity Distribution Agreement (the "Distribution Agreement") with Evercore Group L.L.C. and RBC Capital Markets, LLC (together, the "Managers"), as sales agents, under which the Company may offer and sell its common stock, par value $0.001 per share, from time to time having an aggregate offering price of up to $150,000,000 (the "Shares") during the term of the Distribution Agreement through the Managers. The Company will file a prospectus supplement relating to the offer and sale of the Shares pursuant to the Distribution Agreement, which will form a part of the Company’s Registration Statement on Form S-3 (File No. 333-258634), which was initially filed with the SEC and became automatically effective on August 9, 2021.

Under the Distribution Agreement, the Company will set the parameters for the sale of the Shares, including the number of shares to be issued, the time period during which sales are requested to be made and any minimum price below which sales may not be made. Subject to the terms and conditions of the Distribution Agreement, the Managers will use commercially reasonable efforts to sell

the Shares by methods deemed to be an "at the market offering" as defined in Rule 415 under the Securities Act of 1933, as amended, including sales made directly on the New York Stock Exchange or any other trading market for the Company’s stock. The Company will pay the Managers a commission of up to 3.0% of the aggregate gross proceeds of any Shares sold by the Managers, if any.

The Company is not obligated to sell any Shares pursuant to the Distribution Agreement. The Distribution Agreement contains customary representations, warrantees and agreements between the Company and the Managers, including customary indemnification rights, including for liabilities under the Securities Act. The offering of Shares pursuant to the Distribution Agreement will terminate upon the termination of the Distribution Agreement in accordance with its terms. The Company and the Managers may terminate the Distribution Agreement at any time by providing each other with written notice.

The foregoing summary of the Distribution Agreement does not purport to be complete and is qualified in its entirety by reference to the full text of the Distribution Agreement, a copy of which is filed as Exhibit 10.1 hereto and is incorporated herein by reference. The Distribution Agreement contains representations, warranties and covenants that were made only for purposes of such agreement and as of specific dates, that are solely for the benefit of the parties to such agreement, and that may be subject to limitations agreed upon by the contracting parties. The Distribution Agreement is not intended to provide investors and the public with factual information about the Company’s current state of affairs. Rather, investors and the public should look to other disclosures contained in the Company’s filings with the SEC.

The legal opinion of Covington & Burling LLP relating to the Shares is filed herewith as Exhibit 5.1.

On May 15, 2023 Therapeutic Solutions International (TSOI) spin-off Res Nova Bio announced today a collaboration with Cure Stat Rx, a premiere compounding Pharmacy in the manufacture of initiate doses of FloraStilbene for a planned 12 patient Phase I/II trial aimed at assessing immunomodulatory activity of the drug candidate in advanced breast cancer patients (Press release, Therapeutics Solutions International, MAY 15, 2023, View Source [SID1234631761]).

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The Company previously announced Institutional Review Board clearance to initiate the clinical trial. As part of the collaboration, Ramesh Chigurupati, President of Cure Stat Rx has joined the Advisory Board of Res Nova.

"I am honored to partner with Chigurupati and the team at Cure Stat Rx who have second-to-none expertise in compounding and drug formulation across a range of therapeutic indications," said Famela Ramos, President, and CEO of Res Nova Bio. "Based on our preclinical and pilot clinical data, we are confident that our proposed Phase I/II trial will support the use of FloraStilbene as an immune enhancer in general and specifically a stimulator of natural killer cell activity in advanced cancer patients."

"I have worked with Chigurupati for many years in delivering personalized medicine to patients," said Dr. James Veltmeyer, Chief Medical Officer of Res Nova. "Having seen first-hand the potent therapeutic effects of the Res Nova immunotherapy product ValloVax, I look forward to working with Cure Stat Rx to translate FloraStilbene into the clinical domain."

Cure Stat Rx is an accredited compounding pharmacy specializing in cancer treatments. Cure Stat Rx clinical and compounding staff is knowledgeable and well trained in immuno-oncology.

"Despite significant advances in cancer immunotherapy, many approaches do not induce responses because patients have low immune responses to begin with. By leveraging the significant body of work developed by TSOI in the area of pterostilbene and immuno-oncology, it is exciting to watch how rapidly Famela Ramos and her team are moving towards treating patients with this first in class approach," said Timothy Dixon, President, and CEO of Therapeutic Solutions International and Chairman of Res Nova Bio.