On December 13, 2022 RemedyBio, an immune therapy discovery and development biotech company, combining the power of functional immune mapping through its proprietary Nanoreactor platform for the discovery of new immune oncology therapies, reported a research and evaluation agreement with Glaxo Smith Kline (GSK) to identify and analyse certain rare immune cells and their function within tumours (Press release, Remedy Biologics, DEC 13, 2022, View Source [SID1234644120]).

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The outputs from this evaluation may allow GSK to address certain biological questions that are difficult or impossible to answer via other methods.

"We are excited to collaborate closely with the immune oncology team at GSK.", said Dan Crowley, CEO and co-founder of RemedyBio. "Our work in immune cell function, with the scale and speed offered by our unique platform, has allowed us to decipher and understand the complexities associated with rare cell to cell interactions in the TME and tumour, directly exploring complex scientific questions in this GSK collaboration."

In addition to its collaborations with Pharma and oncology focussed institutions, RemedyBio continues to develop its own pipeline in the immune oncology space, through functional discovery of therapies directly from patient biology.

On December 13, 2022 Erasca, Inc. (Nasdaq: ERAS), a clinical-stage precision oncology company singularly focused on discovering, developing, and commercializing therapies for patients with RAS/MAPK pathway-driven cancers, reported the United States Food and Drug Administration (FDA) has cleared an investigational new drug (IND) application for ERAS-3490, an orally available small molecule KRAS G12C inhibitor designed to have high central nervous system (CNS) penetration for the treatment of KRAS G12C-mutated solid tumors, including non-small cell lung cancer (NSCLC) (Press release, Erasca, DEC 13, 2022, View Source [SID1234639368]).

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"KRAS G12C is a prevalent oncogenic mutation that was historically considered undruggable. While first generation inhibitors have made great progress against this mutation, we believe that they do not sufficiently penetrate the blood-brain barrier which can lead to poor disease control, particularly in NSCLC, where up to 40% of patients may develop CNS metastases," said Jonathan E. Lim, M.D., Erasca’s chairman, CEO, and co-founder. "ERAS-3490, our first homegrown development candidate, was selected for its robust CNS and systemic activity. We are pleased the FDA has cleared our IND for ERAS-3490."

In April, Erasca presented nonclinical data for ERAS-3490 at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting showing robust anti-tumor activity in KRAS G12C mutant MIA PaCa-2, NCI-H1373, and NCI-H2122 CDX subcutaneous models. ERAS-3490 also demonstrated robust anti-tumor activity and dose-dependent survival benefit in the KRAS G12C NSCLC intracranial model NCI-H1373-luc, a nonclinical model of NSCLC CNS metastases.

On December 13, 2022 BIOASIS TECHNOLOGIES INC. (OTCQB:BIOAF; TSX.V:BTI) (the "Company" or "Bioasis"), a multi-asset rare and orphan disease biopharmaceutical company developing clinical stage programs based on epidermal growth factors and a differentiated, proprietary xB3 platform for delivering therapeutics across the blood-brain barrier ("BBB") and the treatment of central nervous system ("CNS") disorders in areas of high unmet medical need, reported that it has entered into a definitive agreement dated December 13, 2022 with Midatech Pharma plc (NASDAQ:MTP; AIM:MTPH) ("Midatech"), a company focused on the research and development of medicines that would benefit from improved bio-delivery or bio-distributions using proprietary drug delivery technologies, pursuant to which Midatech will acquire 100% of the issued and outstanding common shares in the capital of Bioasis from Bioasis’ shareholders in exchange for ordinary shares of Midatech in the form of American depositary shares ("ADSs") (Press release, Bioasis Technologies, DEC 13, 2022, View Source [SID1234625695]).

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Midatech has also entered into securities purchase agreement with an institutional investor for (i) a registered direct offering of ADSs for gross proceeds of approximately US$400,000 (the "Registered Direct Offering") that is expected to be completed on or about December 15, 2022 and (ii) a private placement equity financing for gross proceeds of approximately US$9.6M that will be completed concurrently with Midatech’s acquisition of Bioasis (the "PIPE", and together with the Registered Direct Offering, the "Midatech Financing").

The combination of Bioasis and Midatech will create a multi-asset rare and orphan disease company that will be renamed Biodexa Pharmaceuticals PLC ("Biodexa"). Bioasis and its shareholders are expected to benefit from Biodexa’s capital markets profile in the United States as a NASDAQ-listed company, as well as increased trading liquidity and broadened appeal to global index and generalist investors relative to Bioasis’ status as a TSXV-listed company. Biodexa is expected to have strengthened balance sheet with pro forma cash of approximately C$17.9 million as at June 30, 2022. Biodexa is also expected to benefit from the collective scientific, technical, and operational expertise of both Midatech and Bioasis as well as cost synergies as a result of the elimination of duplicative salaries, administrative and regulatory costs and other public company expenses. Through their ownership of ADSs, current Bioasis securityholders will maintain exposure to the value that is expected to be unlocked as Bioasis and Midatech’s pipeline programs progress through clinical development and the drug delivery technologies secure additional partnerships.

Bioasis’ Executive Chair, Deborah Rathjen PhD, commented "As shareholders are aware, in December 2021 we indicated that Bioasis would seek value accretive strategic alternatives and pursue opportunities that have the potential to unlock value and liquidity for shareholders. With this transaction and through the formation of Biodexa, it is anticipated that Bioasis’ pipeline will achieve value accretive milestones whilst continuing to monetize the xB3 platform through additional partnerships. Once the transaction is closed, Bioasis shareholders will have access to the benefits of a NASDAQ listing through their ownership of Biodexa. We are very excited by the prospects for this transaction given the evident synergies between Bioasis and Midatech".

Mr Stephen Stamp, Midatech CEO and incoming Biodexa CEO added "By combining the two groups to create Biodexa Pharmaceuticals, we have the opportunity to reposition the enlarged group as an emerging biotech company focused on the development of therapeutics for rare diseases, supported by Midatech and Bioasis’s enabling drug delivery platforms. We continue to believe there is substantial value to be unlocked from Midatech’s MTX110, particularly in glioblastoma, and to leverage our Q-Sphera technology. In combination with Bioasis’s promising development pipeline we have the opportunity to create a much stronger group."

Transaction Details

Bioasis and Midatech have entered into an arrangement agreement (the "Arrangement Agreement") pursuant to which Midatech will acquire all of the issued and outstanding common shares in the capital of Bioasis from Bioasis’ shareholders by way of a statutory plan of arrangement (the "Arrangement") under the Business Corporations Act (British Columbia) in exchange for ordinary shares of Midatech (in the form of ADSs) on the basis of 0.9556 Midatech ordinary shares (or approximately 0.0382 ADSs) for each Bioasis share.

Upon completion of the Arrangement and the Midatech Financing, it is expected that the current Midatech securityholders, the current Bioasis securityholders and the Midatech Financing investor will own approximately 39.8%, 30.7% and 9.9%, respectively, of the issued and outstanding Biodexa shares on a non-diluted diluted basis and 10.5%, 9.3% and, subject to the ownership limitations described below, 66.1%, respectively, of the issued and outstanding Biodexa shares on a fully-diluted diluted basis, with the balance held by Lind (as defined below) and Ladenburg (as defined below) or reserved for issuance to the vendors pursuant to Bioasis’ contingent payment obligations under the terms of the asset purchase agreement dated June 15, 2022 among Bioasis and the owners of Cresence AS (see Bioasis press release dated June 16, 2022 for further details).

Pursuant to the terms of the Midatech Financing, the investor in the Midatech Financing may not (i) exercise any of the warrants to be issued to it in the Midatech Financing to the extent that, after giving effect to such exercise, it (together with its affiliates or any person with whom it is acting in concert under the UK Takeover Code) would own more than 9.99% of the outstanding ordinary shares or (ii) at any time (together with its affiliates or any person with whom it is acting in concert under the UK Takeover Code), directly or indirectly own more than 29.9% of the outstanding ordinary shares.

Completion of the Arrangement is subject to the completion of the Midatech Financing and Midatech shareholder approval along with other closing conditions customary for transaction of this nature including, among other things, approval of the Arrangement by the Supreme Court of British Columbia and the approval of at least two-thirds of the votes cast by (i) all Bioasis shareholders, and (ii) Bioasis shareholders together with Bioasis warrantholders and optionholders, voting together as a single class, determined on an as-converted to Bioasis share basis, in each case, present in person or by proxy at the annual and special meeting called for purposes of reviewing and approving the Arrangement (the "Bioasis Meeting"). The Arrangement Agreement includes customary deal protection provisions pursuant to which each party (i) has agreed not to solicit any other acquisition proposal (subject to customary fiduciary out rights and, in the case of Midatech, exceptions required under UK law) and (ii) will pay a termination fee of US$330,000 to the other party (subject, in the case of Midatech, to certain exceptions required under UK law) if the Arrangement Agreement is terminated in certain circumstances. The directors and officers of Bioasis, together with certain other shareholders, who collectively own approximately 8.2% of Bioasis’ issued and outstanding common shares, have entered into transaction support agreements with Midatech pursuant to which they have agreed to vote their Bioasis shares in favour of the Arrangement at the Bioasis Meeting.

Under the Arrangement Agreement, Midatech has agreed to advance a bridge loan in the amount of US$750,000 to Bioasis following the completion of the Registered Direct Offering (the "Midatech Bridge Loan"). The Midatech Bridge Loan will bear interest at the rate of 2.0% per month and is repayable on the earlier to occur of (i) completion of the Arrangement, (ii) the occurrence of an event of default and (iii) June 30, 2023. Bioasis’ obligations under the Midatech Bridge Loan are secured by a second-ranking pledge of all of its assets. Bioasis will use the proceeds of the Midatech Bridge Loan for working capital purposes.

After the completion of the Arrangement and subject to the receipt of any Midatech shareholder approvals required by AIM, Midatech will use its commercially reasonable efforts delist its shares from AIM, change its name to Biodexa Pharmaceuticals PLC and restructure its board of directors and officers with Stephen Parker serving as non-executive chairman, Deborah Rathjen (currently Bioasis’ executive chair and Chief Executive Officer), Mario Saltarelli (currently a Bioasis director) and Simon Turton serving as non-executive directors and Stephen Stamp serving as Chief Executive Officer and director.

The board of directors of Bioasis (the "Board") has unanimously approved the Arrangement Agreement and resolved to recommend that Bioasis securityholders vote in favour of the Arrangement at the Bioasis Meeting. The Board has obtained an opinion from Evans & Evans Inc. that, subject to the assumptions, limitations and qualifications on which such opinion is based, the consideration to be received by Bioasis shareholders in connection with the Arrangement is fair, from a financial point of view, to such shareholders.

Subject to all conditions precedent to completion of the Arrangement being met, the Arrangement is expected to close in the first quarter of 2023. In connection with the closing of the Arrangement, Bioasis will apply to have its shares delisted from the TSX Venture Exchange.

Amendments to Lind Convertible Security Funding Agreement and Bridge Loan

In connection with the execution of the Arrangement Agreement, Bioasis and Lind Global Macro Fund, LP ("Lind") entered into a waiver and amending agreement (the "Lind Amending Agreement") in respect of the convertible security funding agreement between Bioasis and Lind dated June 21, 2021 (the "CSFA").

Pursuant to the Lind Amending Agreement, among other things, Lind agreed to (i) waive Bioasis’ repayment obligations under the CSFA until December 31, 2022, (ii) consent to the completion of the Arrangement and (iii) advance a C$350,000 bridge loan to Bioasis (the "Lind Bridge Loan"), net of amounts payable to Lind in respect of its legal fees and expenses. In consideration of the foregoing, Bioasis agreed to issue a promissory note to Lind in the amount of C$510,000 (the "Holiday Note") along with a promissory note in the principal amount of the Lind Bridge Loan. The Holiday Note and the Lind Bridge Loan bear interest at the rate of 2.0% per month and are repayable on the earlier to occur of (i) completion of the Arrangement, (ii) the occurrence of an event of default and (iii) June 30, 2023. Bioasis’ obligations under the Holiday Note and the Lind Bridge Loan are secured by a first-ranking pledge of all of its assets. Bioasis will use the proceeds of the Lind Bridge Loan to fund transaction expenses related to the Arrangement.

Concurrently with the execution of the Lind Amending Agreement, Bioasis, Midatech and Lind entered into a tripartite agreement (the "Tripartite Agreement") pursuant to which, among other things, Midatech agreed to (i) assume Bioasis’ obligations under the CSFA concurrently with the completion of the Arrangement, (ii) repay to Lind, upon completion of the Arrangement, 50% of the outstanding principal and 100% of the accrued pre-paid interest under the CSFA and all amounts owing under the Lind Bridge Loan and the Holiday Note. Lind agreed that the remaining 50% of the principal owing under the CSFA will be satisfied by way of the issuance to Lind by Midatech of the securities issuable under the PIPE at the same price at which such securities are issued in the PIPE.

Additional Information

Full details of the Arrangement are set out in the Arrangement Agreement, which will be filed by Bioasis, along with copies of the Lind Amending Agreement and the Tripartite Agreement, under its profile on SEDAR at www.sedar.com. In addition, further information regarding the Arrangement will be contained in a management information circular of the Company to be prepared in connection with the Meeting. All securityholders of Bioasis are urged to read the management information circular once it becomes available, as it will contain additional important information concerning the Arrangement.

Advisors

Goodmans LLP and Lawson Lundell LLP are Bioasis’ Canadian legal advisors. Ladenburg Thalmann & Co. Inc. ("Ladenburg") is Bioasis’ financial advisor. Pursuant to the terms of Ladenburg’s engagement by Bioasis, Ladenburg is entitled to receive a fee upon the completion of the Arrangement in the form of Midatech securities.

On December 13, 2022 BeiGene (NASDAQ: BGNE; HKEX: 06160; SSE: 688235) a global biotechnology company, reported the final progression-free survival (PFS) analysis of the ALPINE trial demonstrating superior efficacy and a favorable cardiac safety profile for patients receiving BRUKINSA as compared to IMBRUVICA in a global phase 3 trial in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic leukemia (SLL) (Press release, BeiGene, DEC 13, 2022, View Source [SID1234625394]). These data will be presented (Abstract #LBA-6) during the late-breaking session at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in New Orleans and simultaneously published in The New England Journal of Medicine. The paper’s lead author Jennifer Brown, M.D., Ph.D., Director, CLL Center at Dana-Farber Cancer Institute will present these data.

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Dr. Brown noted that "PFS is the gold standard for measuring efficacy in CLL clinical trials. The ALPINE data showing superior efficacy and consistent benefit across patient subgroups including patients with high-risk del(17p)/TP53, along with a favorable cardiovascular safety profile, provide compelling evidence for BRUKINSA as a practice-changing Bruton’s tyrosine kinase (BTK) inhibitor for patients with CLL."

"BRUKINSA was specifically designed to maximize BTK occupancy and minimize off-target effects. Our clinical development programs were intended to test for a differentiated efficacy and safety profile," said Mehrdad Mobasher, M.D., M.P.H., Chief Medical Officer, Hematology at BeiGene. "We believe the ALPINE PFS data and cardiac safety results for BRUKINSA, including an absence of cardiac death, demonstrate a meaningful advance in outcomes for patients with CLL."

In this final analysis, BRUKINSA achieved superior PFS over ibrutinib (HR: 0.65 [95% CI, 0.49-0.86] p=0.0024, for both Independent Review Committee [IRC] and investigator). At 24 months, the investigator-assessed PFS rates were 78.4% for BRUKINSA compared to 65.9% with ibrutinib. The PFS benefit was observed across all major subgroups, including high-risk del(17p)/TP53 (HR: 0.52; [95% CI, 0.30-0.88]), as assessed by IRC. BRUKINSA also demonstrated higher overall response rate (ORR), with a response rate of 80.4% versus 72.9% (two-sided p=0.0264), as assessed by IRC.

BRUKINSA was generally well-tolerated with fewer adverse events leading to treatment discontinuation compared with ibrutinib (15.4% vs. 22.2%). There was a lower rate of cardiac disorders for BRUKINSA compared with ibrutinib (21.3% vs 29.6%), and cardiac disorders leading to treatment discontinuation occurred in one BRUKINSA patient versus 14 ibrutinib patients (0.3% vs. 4.3%). No patient receiving BRUKINSA died due to a cardiac adverse event; six patients receiving ibrutinib experienced a fatal cardiac adverse event (0% vs. 1.9%). The most commonly reported treatment emergent adverse events (≥20%) with BRUKINSA and ibrutinib were diarrhea (16.0% vs. 24.1%), hypertension (14.8% vs. 11.1%), neutropenia (22.8% vs. 18.2%), COVID-19 (23.1% vs. 17.9%), and upper respiratory tract infection (21.0% vs. 14.2%).

CLL is the most common type of leukemia in adults, accounting for about one-quarter of new cases of leukemia in the United States.1 The condition is characterized by consecutive relapses, with response to therapy ultimately determining clinical benefit, including survival.

BeiGene’s sNDA for BRUKINSA in CLL is currently under review with the FDA and has a target action date of January 20, 2023.

Investor Events

•Tuesday, December 13, 2022 – BeiGene will host a webcast and conference call following the ALPINE late-breaker presentation at 2:00 p.m. CST. BeiGene senior management along with invited medical experts will review the presented data and join for a Q&A panel.
oDial in: 855-303-0072; Passcode: 306575

•Tuesday, December 13, 2022 – BeiGene will host a webcast in Chinese at 6:00 p.m. CST/December 14, 2022 8:00 a.m. China time to capture company presentations at ASH (Free ASH Whitepaper). BeiGene senior management will review highlights of the presented data.
oDial in: +86 10 8783 3177 or +86 10 5387 6330; Passcode: 03233799

These events can be accessed live from the Investors section of BeiGene’s website at View Source, View Source or View Source Archived replays will be posted for 90 days following both events.

About ALPINE

ALPINE is a randomized, global Phase 3 trial (NCT03734016) comparing BRUKINSA against ibrutinib in previously treated patients with relapsed or refractory chronic lymphocytic leukemia CLL or SLL. In the trial, a total of 652 patients across Europe (60%), the United States (17%), China (14%), New Zealand and Australia (9%) were randomized into two arms, with the first receiving BRUKINSA (160 mg orally twice daily) and the second receiving ibrutinib (420 mg orally once daily) until disease progression or unacceptable toxicity.

The primary endpoint of overall response rate (ORR), defined by pre-specified non-inferiority of BRUKINSA versus ibrutinib, was assessed by investigator and IRC using the modified 2008 iwCLL guidelines, with modification for treatment-related lymphocytosis for patients with CLL, and per Lugano Classification for non-Hodgkin’s lymphoma for patients with SLL. There was pre-specified hierarchical testing of non-inferiority followed by superiority in ORR as assessed by investigator and IRC. Key secondary endpoints include PFS and event rate of atrial fibrillation or flutter; other secondary endpoints include duration of response, overall survival, and incidence of adverse events.

Interim study results from ALPINE were published online in Journal of Clinical Oncology in November 2022 (DOI: 10.1200/JCO.22.00510).

About BRUKINSA

BRUKINSA is a small-molecule inhibitor of Bruton’s tyrosine kinase (BTK) discovered by BeiGene scientists that is currently being evaluated globally in a broad clinical program as a monotherapy and in combination with other therapies to treat various B-cell malignancies. BRUKINSA was specifically designed to deliver targeted and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity. With differentiated pharmacokinetics compared to other approved BTK inhibitors, BRUKINSA has been demonstrated to inhibit the proliferation of malignant B cells within a number of disease-relevant tissues.

BRUKINSA is supported by a broad clinical program which includes more than 4,700 subjects in 35 trials in more than 30 geographies. To date, BRUKINSA is approved in more than 60 markets, including the United States, China, the European Union, Great Britain, Canada, Australia, South Korea, Switzerland, and additional international markets.

On December 13, 2022 Novartis reported detailed results from the pivotal Phase III APPLY-PNH trial1 (Press release, Novartis, DEC 13, 2022, https://www.novartis.com/news/media-releases/novartis-presents-pivotal-phase-iii-apply-pnh-data-ash-demonstrating-investigational-oral-monotherapy-iptacopan-superiority-over-anti-c5 [SID1234625240]). The results showed a vast majority of patients with paroxysmal nocturnal hemoglobinuria (PNH) who received the investigational oral monotherapy iptacopan achieved clinically meaningful increases in hemoglobin levels compared to anti-C5 therapy1. The study met both primary endpoints and most secondary endpoints, with iptacopan demonstrating superiority over anti-C5 therapy in adult patients with PNH experiencing residual anemia despite prior treatment with anti-C5 therapy1.

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In the study, the safety profile of iptacopan monotherapy was consistent with previously reported data, with no serious infections caused by encapsulated bacteria1,3,4. The results, from the APPLY-PNH 24-week randomized treatment period, were featured as an oral presentation during the late-breaking abstract session and in a press briefing at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition (ASH) (Free ASH Whitepaper).

"More than half of patients with PNH experience residual anemia despite treatment with anti-C5 therapy and many remain dependent on blood transfusions during treatment, largely due to unaddressed destruction of red blood cells in the spleen and the liver – called extravascular hemolysis," said study principal co-investigator Prof Régis Peffault de Latour, MD, PhD of Saint-Louis Hospital, Greater Paris University Hospital. "The Phase III APPLY-PNH results show oral iptacopan was superior in resolving extravascular hemolysis and maintaining intravascular hemolysis control compared to intravenous anti-C5 therapies – a potentially groundbreaking benefit for those living with this chronic blood disorder."

The study met both primary endpoints, showing superiority for iptacopan vs. anti-C51. For the first, an estimated 82.3%* (95% CI: 73.4, 90.2) of iptacopan-treated patients achieved hemoglobin-level increases of 2 g/dL or more from baseline without the need for red blood cell transfusions, compared to an estimated 2.0%* (95% CI: 1.1, 4.1) of anti-C5-treated patients: an estimated 80.3%* (95% CI: 71.3, 87.6; P<0.0001) difference in favor of iptacopan1. The observed number of patients achieving this primary endpoint was 51/60# for iptacopan vs. 0/35 for anti-C51.

For the second primary endpoint, an estimated 68.8%* (95% CI: 58.3, 78.9) of iptacopan-treated patients achieved hemoglobin levels of 12 g/dL or more without the need for blood transfusions, compared to an estimated 1.8%* (95% CI: 0.9, 4.0) of anti-C5-treated patients: an estimated 67.0%* (95% CI: 56.3, 76.9; P<0.0001) difference in favor of iptacopan1. The observed number of patients achieving this primary endpoint was 42/60# for iptacopan vs. 0/35 for anti-C51.

"Nearly every patient treated with iptacopan – 60 out of 62 – remained blood-transfusion free after six months of treatment, compared to only 14 out of 35 anti-C5-treated patients – a potentially practice-changing outcome for people with PNH," stated study principal co-investigator Antonio Risitano, M.D., Ph.D., President of the International PNH Interest Group and Head of the Hematology and Hematopoietic Transplant Unit, Reference Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria at the AORN San Giuseppe Moscati, Avellino, Italy. "This outcome, along with the exceptional hemoglobin-level increases of at least 2 g/dL in 51 out of 60 patients, suggests that, if approved, iptacopan could transform treatment and outcomes for patients with PNH."

"With combined Phase III APPLY-PNH and recently announced positive Phase III APPOINT-PNH results, Novartis has a comprehensive data package to support a 2023 regulatory submission, with the possibility of iptacopan becoming the first oral monotherapy for patients with PNH," said David Soergel, M.D., Global Head, Cardiovascular, Renal and Metabolism Development Unit, Novartis.

Iptacopan also showed superiority over anti-C5 therapy across most secondary endpoints, including change from baseline in hemoglobin levels, blood-transfusion independence, patient-reported fatigue (as measured by Functional Assessment of Chronic Illness Therapy – Fatigue [FACIT-F] scores), absolute reticulocyte (immature red blood cells) counts (ARC), and rate of clinical BTH1.

Iptacopan-treated patients achieved a 3.59 (95% CI: 3.32, 3.86) g/dL adjusted average increase in hemoglobin levels from baseline, compared to a 0.04 (95% CI: -0.42, 0.35) g/dL decrease for anti-C5-treated patients: a 3.63 (95% CI: 3.18, 4.08; P<0.0001) g/dL difference in favor of iptacopan1. Average hemoglobin levels irrespective of blood transfusions for iptacopan-treated patients were 12.6 (standard deviation [SD]: 1.4) g/dL, compared to 9.2 (SD: 1.4) g/dL for anti-C5-treated patients1.

In the six months prior to randomization, 57.7% of patients had received blood transfusions1. After 24 weeks of treatment, an estimated 96.4%* (95% CI: 90.7, 100.0) of iptacopan-treated patients remained blood-transfusion free, compared to an estimated 26.1%* (95% CI: 12.4, 42.7) of anti-C5-treated patients: an estimated 70.3%* (95% CI: 52.6, 76.9; P<0.0001) difference in favor of iptacopan1. The observed number of patients achieving this endpoint was 60/62 for iptacopan vs. 14/35 for anti-C51. Iptacopan-treated patients achieved an 8.59 (95% CI: 6.72, 10.47) point adjusted average increase in FACIT-F score from baseline, compared to a 0.31 (95% CI: -2.20, 2.81) point increase for anti-C5-treated patients: an 8.29 (95% CI: 5.28, 11.29; P<0.0001) point difference in favor of iptacopan1.

There was no significant difference between iptacopan monotherapy and anti-C5 for rate of major adverse vascular events or change from baseline in lactate dehydrogenase levels – with the latter showing maintenance of intravascular hemolysis control1.

The most commonly reported adverse events (AEs) with iptacopan were headache (iptacopan: 16.1%; anti-C5: 2.9%) and diarrhea (iptacopan: 14.5%; anti-C5: 5.7%), while the most commonly reported AEs with anti-C5s were COVID-19 (anti-C5: 25.7%; iptacopan: 8.1%) and clinical BTH events (anti-C5: 17.1%; iptacopan: 3.2%)1. Two anti-C5-treated patients had serious AEs of hemolysis, compared with no iptacopan-treated patients1. No patients discontinued iptacopan or anti-C5s because of AEs1.

Separately, Novartis recently announced the Phase III APPOINT-PNH trial was positive, with iptacopan providing clinically meaningful increases in hemoglobin levels in complement-inhibitor-naïve patients with PNH2,5. Data from APPLY-PNH and APPOINT-PNH will be included as part of global regulatory submissions in 2023.

Following presentation of the APPLY-PNH data at ASH (Free ASH Whitepaper), Novartis will host an investor conference call on December 13, 2022 at 18:30 CET / 12:30 ET. A simultaneous webcast may be accessed by visiting the Novartis website at View Source, and a replay will be available after the call.

*These estimated proportions of patients are marginal proportions, calculated using a pre-specified logistic regression model (this also applies for the differences in marginal proportions and 95% CIs)1. Marginal proportions reflect the population average probability of a patient meeting the endpoint criteria1. The values are adjusted for baseline covariates and missing data have been imputed1.
#Evaluable/non-missing data was available for 60 iptacopan-treated patients (out of the total 62 iptacopan-treated patients in the trial)1.

About the study
APPLY-PNH (NCT04558918) is a Phase III, randomized, multinational, multicenter, active-comparator controlled, open-label trial to evaluate the efficacy and safety of twice-daily, oral iptacopan monotherapy (200 mg) for the treatment of PNH by demonstrating the superiority of iptacopan compared to anti-C5 therapies (eculizumab or ravulizumab) in adult patients presenting with residual anemia (Hb <10 g/dl) despite a stable regimen of anti-C5 treatment in the last six months prior to randomization1,6.

About paroxysmal nocturnal hemoglobinuria (PNH)
PNH is a rare, chronic, and serious complement-mediated blood disorder7. People with PNH have an acquired mutation in some of their hematopoietic stem cells (which are located in the bone marrow and can grow and develop into red blood cells (RBCs), white blood cells and platelets) that causes them to produce RBCs that are susceptible to premature destruction by the complement system7,8. This leads to intravascular hemolysis (destruction of RBCs within blood vessels) and extravascular hemolysis (destruction of RBCs mostly in the spleen and liver), which cause anemia (low levels of circulating RBCs), thrombosis (formation of blood clots), fatigue, and other debilitating symptoms that can impact people’s quality of life7,8.

It is estimated that approx. 10-20 people per million worldwide live with PNH7. Although PNH can develop at any age, it is often diagnosed in people between 30-40 years old9,10.

PNH has a significant unmet need not addressed by anti-C5 therapies (eculizumab or ravulizumab): despite treatment with anti-C5s, a large proportion of people with PNH remain anemic, fatigued, and dependent on blood transfusions7,8,11,12.

About iptacopan
Iptacopan is an investigational first-in-class, orally administered targeted factor B inhibitor of the alternative complement pathway1,3,4,13. It acts upstream of the C5 terminal pathway, preventing not only intravascular but also extravascular hemolysis in PNH1,3,4,13. In doing so, iptacopan targets a key part of the biology responsible for PNH while offering an oral monotherapy option1,3,4,13.

Discovered at the Novartis Institutes for BioMedical Research, iptacopan is currently in development for a number of other complement-mediated diseases (CMDs) where significant unmet needs exist, including kidney diseases C3 glomerulopathy (C3G), IgA nephropathy (IgAN), atypical hemolytic uremic syndrome (aHUS), membranous nephropathy (MN), lupus nephritis (LN), and blood disorders immune thrombocytopenic purpura (ITP) and cold agglutinin disease (CAD). First results for Phase III trials in C3G (APPEAR-C3G) and IgAN (APPLAUSE-IgAN) are expected in 202314,15.

Based on disease prevalence, unmet needs and data from Phase II studies, iptacopan has received FDA Breakthrough Therapy Designation in PNH, orphan drug designations from the FDA and EMA in PNH and C3G, EMA PRIME designation for C3G, and EMA orphan drug designation in IgAN16-19.

Disclaimer
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