HUTCHMED Completes Rolling Submission of NDA to U.S. FDA for Fruquintinib for the Treatment of Refractory Metastatic Colorectal Cancer

On March 31, 2023 HUTCHMED (China) Limited ("HUTCHMED") (Nasdaq/AIM:​HCM, HKEX:​13) reported that it completed the rolling submission of a New Drug Application ("NDA") to the U.S. Food and Drug Administration ("FDA") for fruquintinib, its highly selective and potent oral inhibitor of VEGFR-1, -2 and -3, for the treatment of refractory metastatic colorectal cancer ("CRC") (Press release, Hutchison China MediTech, MAR 31, 2023, View Source [SID1234629657]).

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"This FDA submission is a significant milestone for patients in the U.S. with metastatic CRC, one of the most common and deadly cancers in the U.S. and worldwide. Fruquintinib is an important treatment option for patients with metastatic CRC in China, where it has been available to patients since 2018. We look forward to working with our partner Takeda to commercialize fruquintinib outside China, and we remain on track to submit regulatory filings in Europe and Japan later this year," said Dr. Michael Shi, Head of R&D and Chief Medical Officer of HUTCHMED.

The NDA is supported by the global Phase III multi-regional clinical trial ("MRCT") FRESCO-2 study conducted in the U.S., Europe, Japan and Australia that investigated fruquintinib plus best supportive care ("BSC") vs placebo plus BSC in patients with refractory metastatic CRC, along with data from the FRESCO study conducted in China. Filing of a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) and an NDA to the Japan Pharmaceuticals and Medical Devices Agency (PMDA) are planned in 2023.

In March 2023, HUTCHMED and Takeda Pharmaceutical Company Limited (TSE:4502, NYSE:TAK) closed an exclusive license agreement to further the global development, commercialization and manufacture of fruquintinib outside China. In China, fruquintinib is approved under the brand name ELUNATE and is included in the China National Reimbursement Drug List ("NRDL"). HUTCHMED markets fruquintinib in China in partnership with Eli Lilly and Company.

About CRC

CRC is a cancer that starts in either the colon or rectum. According to the International Agency for Research on Cancer, CRC is the third most prevalent cancer worldwide, associated with more than 935,000 deaths in 2020.1 In the U.S., an estimated 153,000 patients were diagnosed with CRC and there were 53,000 deaths from the disease in 2023.2 In Europe, CRC was the second most common cancer in 2020, with approximately 520,000 new cases and 245,000 deaths. In Japan, CRC is the most common cancer, with an estimated 148,000 new cases and 60,000 deaths in 2020.1 Although early stage CRC can be surgically resected, metastatic CRC remains an area of high unmet need with poor outcomes and limited treatment options.

About Fruquintinib

Fruquintinib is a highly selective and potent oral inhibitor of VEGFR-1, -2 and -3. VEGFR inhibitors play a pivotal role in blocking tumor angiogenesis. Fruquintinib was designed to improve kinase selectivity with the intention of minimizing off-target toxicities, improving tolerability and providing more consistent target coverage. Fruquintinib has been generally well tolerated in patients to date, and is being investigated in combinations with other anti-cancer therapies.

About Fruquintinib Approval in CRC in China

Fruquintinib was approved for marketing by the China National Medical Products Administration (NMPA) in September 2018 and commercially launched in China in November 2018 under the brand name ELUNATE. It has been included in the NRDL since January 2020. ELUNATE is indicated for the treatment of patients with metastatic CRC who have been previously treated with fluoropyrimidine, oxaliplatin and irinotecan, including those who have previously received anti-VEGF therapy and/or anti-epidermal growth factor receptor (EGFR) therapy (RAS wild type). Results of the FRESCO study3, a Phase III pivotal registration trial of fruquintinib in 416 patients with metastatic CRC in China, were published in The Journal of the American Medical Association, JAMA, in June 2018 (NCT02314819). The primary endpoint of the study, overall survival ("OS"), was achieved with a hazard ratio ("HR") of 0.65 (95% confidence interval ["CI"] 0.51–0.83; p<0.001)

The safety and efficacy of fruquintinib for the following investigational uses have not been established and there is no guarantee that it will receive health authority approval or become commercially available in any country for the uses being investigated.

About the FRESCO-2 Phase III Trial in CRC Outside China

The FRESCO-2 study is a MRCT conducted in the U.S., Europe, Japan and Australia that investigated fruquintinib plus BSC vs placebo plus BSC in patients with refractory metastatic CRC (NCT04322539). The results were presented at European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) congress in September 2022.4 The MRCT FRESCO-2 study demonstrated that treatment with fruquintinib resulted in a statistically significant and clinically meaningful increase in the primary OS endpoint and key secondary progression free survival ("PFS") endpoint compared to treatment with placebo.

Specifically, the median OS was 7.4 months for the 461 patients treated with fruquintinib compared to 4.8 months for the 230 patients in the placebo group (HR 0.66; 95% CI 0.55–0.80; p<0.001). The median PFS was 3.7 months for patients treated with fruquintinib compared to 1.8 months for patients in the placebo group (HR 0.32; 95% CI 0.27–0.39; p<0.001). The disease control rate ("DCR") was 55.5% in the fruquintinib group compared to 16.1% for patients in the placebo group. Median duration of follow-up was approximately 11 months for patients in both groups.

The safety profile of fruquintinib in FRESCO-2 was consistent with previously reported fruquintinib studies. Grade 3 or above adverse events occurred in 62.7% of patients who received fruquintinib, compared to 50.4% of patients who received placebo. Grade 3 or above adverse events that occurred in more than 5% of patients who received fruquintinib were hypertension (13.6% vs 0.9% in the placebo group), asthenia (7.7% vs 3.9% in the placebo group) and hand-foot syndrome (6.4% vs 0% in the placebo group). Treatment related adverse events leading to discontinuation occurred in 20.4% of patients who received fruquintinib, compared to 21.1% of patients who received placebo.

About Other Fruquintinib Developments

Gastric Cancer in China: The FRUTIGA study is a randomized, double-blind, Phase III study in China to evaluate fruquintinib combined with paclitaxel compared with paclitaxel monotherapy, for second-line treatment of advanced gastric cancer or gastroesophageal junction adenocarcinoma (NCT03223376). Topline results were announced in November 2022. The trial met one of the primary endpoints of statistically significant improvement in PFS, which is clinically meaningful. The other primary endpoint of OS was not statistically significant per the pre-specified statistical plan, although there was a numerical improvement in median OS. Fruquintinib also demonstrated a statistically significant improvement in secondary endpoints including objective response rate (ORR), DCR, and improved duration of response (DoR). The safety profile of fruquintinib in FRUTIGA was consistent with previously reported studies. Results are expected to be disclosed at an upcoming scientific meeting.

HUTCHMED is also developing fruquintinib for the treatment of multiple solid tumor cancers in combination with PD-1 monoclonal antibodies for the treatment of endometrial and other solid tumors.

Hamlet Pharma and SelectImmune Pharma merge to create an innovative pharmaceutical company with a broad and strong portfolio of projects for the treatment of cancer and infections

On March 31, 2023 Hamlet Pharma AB and SelectImmune Pharma AB, listed on the Spotlight Stock Market, reported to merge and create a powerful pharmaceutical company for drug development for the treatment of cancer and infectious diseases (Press release, HAMLET Pharma, MAR 31, 2023, View Source;utm_medium=rss&utm_campaign=hamlet-pharma-and-selectimmune-pharma-merge-to-create-an-innovative-pharmaceutical-company-with-a-broad-and-strong-portfolio-of-projects-for-the-treatment-of-cancer-and-infections [SID1234629656]). The merged company (Hamlet Biopharma) gets a portfolio with a total of ten pharmaceutical projects, of which three projects are in phase II, where two of the projects already have positive results in clinical studies. The portfolio includes a total of eleven patent families for cancer, infections and tuberculosis with more than 60 patents. Hamlet Biopharma is now building a focused commercial organization with access to a technology platform and university-based scientist as well as an extensive network of international specialists for drug development and clinical studies. A larger listed company will become more cost-effective and attract talents to the company as well as to the network. Hamlet Biopharma has secured funding for at least twelve months.

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The board of directors of Hamlet Pharma AB (publ) ("Hamlet Pharma") and SelectImmune Pharma AB (publ) ("SelectImmune") (together the "Companies") have today adopted a merger plan (the "Merger plan") to carry out a merger of Hamlet Pharma and SelectImmune Pharma ("Hamlet BioPharma") through a corporate merger (the "Merger"). The Merger is subject to, inter alia, approvals by the extraordinary general meetings of the two Companies. As merger consideration, shareholders in SelectImmune will receive 0.8 shares in Hamlet Pharma for each share in SelectImmune, for each class of shares.

Furthermore, Hamlet Biopharma has entered into an agreement with Linnane Pharma AB ("Linnane Pharma") regarding the acquisition of the company that owns rights to a project for the treatment of tuberculosis (the "Project").

Background and reason

The long-term goal of the company group consisting of Hamlet Pharma, SelectImmune Pharma and Linnane Pharma is to commercialize a broad portfolio of innovative pharmaceutical projects and to create an agile organization where the commercial leadership in Hamlet Biopharma, which is a merger of Hamlet Pharma and SelectImmune, focuses on establishing partnerships, licensing or selling rights, running clinical studies and protecting patents and IP rights. The board of directors of Hamlet Pharma and SelectImmune (collectively the "Board of Directors") now see positive clinical results in Hamlet Pharma and SelectImmune, and therefore believe that the time is right to take this step. The main shareholder of the companies looks positively on the merger to create a powerful company to effectively run the pharmaceutical projects in the long term. Hamlet Biopharma has secured funding for at least twelve months.

The Board of Directors have investigated the consequences of a merger between the Companies and see a convincing strategic and operational advantage of the merger. The purpose of the Merger is to create a broader portfolio of pharmaceutical projects in two major clinical areas, cancer and infections. The need for new, more selective cancer drugs is great, as is the need for alternatives to antibiotics, which increasingly lose their effects due to antibiotic resistance and leave the patient without treatment options. Furthermore, the Companies project portfolio is supplemented by the acquisition of drug projects and patents for the treatment of tuberculosis with the company Linnane Projects AB (the "Acquisition"), which holds rights to the Project.

Merger of two supplementary businesses

Through the Acquisition and the Merger, a combined powerful company is created with a broad portfolio of pharmaceutical projects for the treatment and prevention of cancer and infectious diseases.
The Acquisition entails that Hamlet Biopharma obtains the rights to patents and access to developed know-how to commercialize the tuberculosis project.
Overall, the Board of Directors consider that there are clear logical and rational reasons for the Merger and the Acquisition as the businesses complement each other well. The Board of Directors thus assess that the Merger and Acquisition are beneficial for Hamlet Pharma’s and SelectImmune’s shareholders.
The Merger creates a larger company that takes care of the promising projects in Hamlet Pharma and SelectImmune. Through the Merger and Acquisition of Linnane Projects AB ("Linnane Projects"), the various sub-projects are established in an organization that can effectively drive them further towards market approval within important clinical indications. This includes the most advanced pharmaceutical projects within the respective companies: Alpha1H for the treatment of bladder cancer, which is in clinical phase II, and KineretR for the treatment of acute cystitis and bladder pain syndrome which is in phase II. Furthermore, the Companies see a great potential for synergies in the form of strengthened know-how.

Portfolio pharmaceutical projects and patents

Project/company For treatment Phase
Alpha 1HHamlet Pharma Bladder cancer Phase II clinical trials
Alpha 1HHamlet Pharma Brain tumor Positive data in animal model, development of technology
Hamlet Hamlet Pharma Colon and rectal cancer Preclinical evaluation
Hamlet Hamlet Pharma Oral cavity cancer Preclinical evaluation
IL1-beta receptor antagonistSelectImmune Pharma Infection and inflammation Preclinical evaluation Phase II – clinical trialsa) Bladder pain syndromeb) Recurrent acute cystitis
NK1R receptor antagonistSelectimmune Pharma Inhibitor of pain and nerve activation Positive data in animal model, development of technology.Development of substance for clinical studies
RNA Pol II inhibitorsSelectImmune Pharma Preventive inflammation inhibitor Positive data in animal model, development of technology Development of substance for clinical studies
RNA Pol II bacteriotherapySelectImmune Pharma Prevention of inflammation and treatment of infection Positive data in animal model, development of technology
IRF7 inhibitor, siRNASelectImmune Pharma Inhibits severe bacterial infections Positive data in animal model, development of technologyData to support the development of drugs for clinical studies
Project tuberculosis Plectasin Lung tuberculosis Positive data in animal model, development of technology for drug production
The pharmaceutical projects are based on a total of eleven patent families and applications for a further four patent families, a total of more than 60 patents and patent applications, see the table below.

Indication Patent Group Description Countries
Cancer ALL-ALA This case relates to αLactalbumin complexes that have been engineered to optimize production DE, DK, FI, FR, UK, NL, SE, AU, CA, IN, JPUSA
Cancer Alpha1 and Alpha2 fragment complexes This case relates to the αLA fragment complexes – comprising the human Alpha1 or Alpha2 sequences. CH, DE, DK, ES, FI, FR, UK, HU, IE, IT, NL, NO, PL, SEUSAUSA divisional
Cancer PAPILLOMA This case relates to αLA complexes (including HAMLET and BAMLET) for treatment of skin papillomas. USAUSA divisional
Cancer PROPHYLACTIC THERAPY This case relates to αLA complexes for prophylactic treatment of cancer. CH, DE, DK, ES, FI, FR, UK, HU, IE, IT, NL, NO, PL, SE,USA divisional
Cancer NUTRACEUTICAL This case relates to milk-based nutraceuticals that contain αLA-complexes. CH, DE, DK, ES, FI, FR, UK, IE, IT, NL, NO, SE, HKUSA
Cancer 39-MER COMPLEX This case relates to the Alpha1H 39mer complex. CH, DE, DK, ES, FI, FR, UK, IE, IT, NL, NO, PL, SE, HK, AU, CA, CN, IN, JP, KP, SG, USA
Cancer MIXING METHOD This case relates to a simplified production method. Europe divisionalHong KongUSA continuation
Cancer SYNERGISTIC COMBINATION CANCER THERAPY This case relates to anticancer protein-fatty acid complexes plus other chemotherapeutic agents as a combination for use in anticancer therapy. EuropeUSAJapan
Infection/Immunotherapy IL-1 RECEPTOR ANTAGONISTS IL-1 receptor antagonists for the treatment of cystitis. AustraliaEurope (CH, DE, DK, FI, FR, NL, SE, GB)USA
Infection/Immunotherapy MMP7 INHIBITORS MMP-7 inhibitors for the treatment of cystitis. AustraliaEurope (CH, DE, DK, FI, FR, NL, SE, GB)
Infection/Immunotherapy ASC / NLRP-3 ASC or NLRP-3 proteins for the treatment of cystitis. EuropeUSA
Infection/Immunotherapy IRF7 INHIBITORS IRF-7 inhibitors for the treatment of Enterobacteriaceae infections. AustraliaEurope (CH, DE, DK, FI, FR, NL, SE, GB)USA
Infection/Immunotherapy NK1 ANTAGONISTS NK1 antagonists for treating bacterial infection or management of pain caused by bacterial infections. EuropeHong KongUSA
Infection/Immunotherapy POL II INHIBITORS Inhibitors of polymerase II, which can be used for immunosuppression, anti-inflammation, and/or anti-infection. AustraliaEurope (CH, DE, DK, FI, FR, NL, SE, GB)Hong KongIndiaSingaporeUSA
Infection/Immunotherapy BLADDER PAIN IL-1 receptor antagonists for the treatment of bladder pain. EuropeUSAAustraliaChinaJapan
Infection/Immunotherapy PYELONEPHRITIS Treatment or prevention of acute pyelonephritis and/or urosepsis. Great Britain, initial filing
Tuberculosis TUBERCULOSIS TREATMENT Bactericidal peptide Plectasin for the treatment of M. tuberculosis. CH, DE, DK, FI, FR, NL, SE, UK, AU, CA, HK, IN, US
The Merger and Acquisition also creates strategic advantages for the shareholders. By broadening the business, the shareholders’ risk is reduced and the possibility of future income increases. This increases the likelihood of attracting stronger ownership groups. The Board of Directors expect that the shareholders will benefit from more robust trading of shares in Hamlet Biopharma than in the trading of shares in the Companies individually. In addition, Hamlet Biopharma will have a greater ability to raise capital than SelectImmune on its own.

Hamlet Pharma and SelectImmune have developed their projects with the support of Linnane Pharma. As part of the Acquisition and Hamlet Biopharma, the current agreements between Linnane Pharma and Hamlet Pharma and SelectImmune, respectively, will be replaced by a new collaboration agreement, which includes HAMLET, Alpha1H, the tuberculosis project and all projects operated by SelectImmune (the "Collaboration Agreement"). Hamlet Pharma is currently conducting a technical evaluation of BAMLET. BAMLET is therefore not covered by the collaboration agreement with Linnane Pharma.

Cancer and infections are among the greatest challenges for humanity, with high mortality and limited efficacy of the drugs and traditional treatments currently used. The vision for Hamlet Biopharma is to develop new drug concepts with great potential to improve people’s health, increase the quality of life and reduce the suffering of those who become ill and need new treatments.

Summary of the Merger

The merger will be carried out by Hamlet Pharma absorbing SelectImmune which will then be dissolved.
As merger consideration, new shares in Hamlet Pharma will be issued to SelectImmunes shareholders in proportion to their existing shareholdings in SelectImmune. One (1) class A share in SelectImmune entitles the holder to receive 0.8 class A shares in Hamlet Pharma and one (1) class B share in SelectImmune entitles the holder to receive 0.8 class B shares in Hamlet Pharma (the "Merger consideration").
The Merger consideration is based, among other things, on the volume-weighted average price paid for SelectImmune’s B share and Hamlet Pharma’s B share 30 trading days before the day of the announcement and on the Companies’ prospects after the implementation of planned measures.
Based on the volume-weighted average price paid over the last thirty trading days of Hamlet Pharma’s B share, the offer values ​​SelectImmune at SEK 3.06 per share, which means a premium of approximately 63.25 percent compared to the volume-weighted average price paid of SelectImmune’s B share over the past thirty trading days and a premium of approximately 36.07 percent compared to the closing price of SelectImmune’s B share on March 30, 2023.
The merger requires, among other things, approvals at extraordinary general meetings in both Companies.
The Merger is conditional on approval of the Acquisition and the Collaboration Agreement at an extraordinary general meeting of Hamlet Pharma.
A merger document is expected to be published on or around May 3, 2023.
The acquisition, etc.

Through the Acquisition, Hamlet Pharma acquires all shares in Linnane Projects. The company is newly started and holds ownership rights to patents and access to know-how for commercialization of the Project. The purchase price amounts to a total of SEK 10 million, of which SEK 5 million is paid upon closing and the remainder is paid in two equal installments during 2024 and 2025. In addition, Linnane Pharma, as the seller, is entitled to an ongoing cash compensation corresponding to three percent of future net revenues attributable to the Project.

A total of 1.5 million deaths from tuberculosis occurred ("TB") in 2018 (including a quarter of a million with HIV). Worldwide, TB is one of the top ten causes of death and the most common cause from a single infectious agent. Current treatment protocols require a cocktail of antibiotics given by skilled medical staff over six months but there is a growing problem of drug resistance, which reduces the options for this patient group.

The acquired Project (patent and right to know-how) offers a new therapeutic concept to fight TB through treatment with bactericidal peptide drug candidates that show efficacy in animal models. In terms of research and development, the project fits very well into Hamlet Biopharma’s operations and the already established collaboration with the researchers.

Hamlet Pharma and SelectImmune have a multi-year collaboration with Linnane Pharma, which ensures Hamlet’s and SelectImmune’s access to advanced science and cutting-edge technology for drug development. The collaboration means that Linnane Pharma’s technology platform and other resources are available to Hamlet Pharma and SelectImmune respectively.

Hamlet Biopharma has a great need for continued collaboration with Linnane Pharma. Hamlet Biopharma will therefore replace the previous collaboration agreements with the Collaboration Agreement with Linnane Pharma, which in the cancer area includes HAMLET and Alpha1H and in the infection area includes all projects run by SelectImmune regarding immunotherapy with inhibitors of inflammation and pain such as IL1-RA (KineretR) NKR1 inhibitors against pain, RNA POL II inhibitors against inflammation and infection and IRF7 inhibitors against kidney infection and sepsis. Furthermore, the tuberculosis project acquired from Linnane Pharma is added.

Linnane Pharma has unique competence that is of direct benefit to the projects run in Hamlet Biopharma. In addition, Hamlet Biopharma will not have to develop its own resources as they are provided by Linnane Pharma in a more efficient, less expensive and flexible way. Hamlet Biopharma will pay an annual fixed fee for these services.

Linnane Pharma is Hamlet Pharma’s largest shareholder with a holding of approximately 49,33 percent of the shares and 83,52 percent of the vote. Both the Acquisition and the Collaboration Agreement are related party transactions that require approval at a general meeting in Hamlet Pharma. Linnane Pharma does not have the right to vote for its shares in the general meeting’s decision on approval.

Hamlet Pharma’s board of directors believes that the Acquisition is beneficial for Hamlet Pharma and its shareholders. The board believes that the purchase price paid in the Acquisition is reasonable from a financial point of view for Hamlet Pharma’s shareholders and this opinion is supported by a valuation from an independent third party, Xplico ApS, that Hamlet Pharma’s board has obtained based on and subject to the assumptions and limitations stated therein.

The preliminary timetable for the Acquisition, etc. is in accordance with below.

19 May 2023 Extraordinary general meeting of Hamlet Pharma for the approval of:Implementation of the AcquisitionEntering into the Collaboration Agreement with Linnane Pharma
23 Maj 2023 Closing date of the Acquisition
Hamlet Biopharma

After Completion of the Merger, Catharina Svanborg, Carl-Johan Wachtmeister, Helena Lomberg, Bill Hansson, Ulla Trägårdh and Magnus Nylén are expected to be members of the board and Martin Erixon to be the CEO of Hamlet Biopharma.

In addition, there are currently no decisions regarding significant changes to Hamlet Pharma’s or SelectImmune’s employees or to the current organization and operations, including the terms of employment and the locations where the Companies conduct their business.

Below is a pro forma statement that has been adjusted to reflect the effect of the Merger and Acquisition on Hamlet Pharma’s balance sheet as of December 31, 2022, as if the Merger and Acquisition had been completed at the beginning of the interim period and to reflect the effect of the Merger and Acquisition for the six-month period ended on 31 December 2022, as if the Merger and Acquisition had been completed at the beginning of the interim period. The pro forma statement is presented for information purposes only and reflects estimates and assumptions made by Hamlet Pharma’s management as it deems reasonable, and other so-called forward-looking statements. It does not imply to represent what Hamlet Pharma’s actual results or financial position would have been if the Merger and acquisition of Linnane Projects had occurred on the date indicated and is not necessarily indicative of future results or financial position. For complete information regarding the pro forma accounts, including notes, please refer to the merger document to be published on or around May 3, 2023.

Consolidated pro forma income statement in summary for the six-month period ended December 31, 2022

SEK thousand
Hamlet Pharma Select-Immune Linnane Projects Pro forma adjustments Consolidated income statement pro forma
Net sales 0 0 0 0 0
Other operating income 0 0 0 0 0
Operating expenses -11,929 -2,750 0 1,600 -13,079
Operating results -11,929 -2,750 0 0 -13,079
Financial posts 98 0 0 0 98
Profit before tax -11,831 -2,750 0 0 -12,981
Tax on the period’s results 0 0 0 0 0
Profit after tax -11,831 -2,750 0 0 -12,981
Earnings per share, SEK -0.1070 -0.1575 0 0 -0.1014

Group pro forma balance sheet in summary as of 31 December 2022

SEK thousand
Hamlet Pharma Select-Immune Linnane Projects Pro forma adjustments Consolidated balance sheet pro forma
Assets
Total fixed assets 0 922 0 0 922
Total current assets 29,766 9,306 25 0 39,097
Total assets 29,766 10,228 25 0 40,019
Equity & Liabilities
Total tied up equity 1,125 873 25 0 2,023
Total unrestricted equity 25,057 8,162 0 0 33,219
Total equity 26,183 9,035 25 0 35,243
Total short-term liabilities 3,583 1,193 0 0 4,776
Total equity and liabilities 29,766 10,228 25 0 40,019


Number of shares 110,529,666 17,459,225 25,000 0 128,013,891
The table below illustrates the ownership in Hamlet Biopharma if the Merger had been completed based on the shareholder information from Euroclear Sweden AB as of December 30, 2022.

Shareholder Class A shares Class B shares Percentage of capital Percentage of votes
Catharina Svanborg, privately and through Linnane Pharma 37,946,152 22,976,104 49.93% 82.95%
Avanza Pension 40,576 5,623,009 4.55% 1.24%
Nordnet Pensionsförsäkring 0 5,663,178 4.55% 1.17%
EFG BANK/Geneva, W8IMY 273,538 268,500 0.44% 0.62%
Rolf Karlsson (FV Group) 0 2,903,707 2.33% 0.60%
Hans Nygren 0 2,067,553 1.66% 0.43%
Hazina Ljungman, privately and through companies 74,846 227,126 0.24% 0.20%
Försäkringsaktiebolaget Skandia 3,342 891,042 0.72% 0.19%
Olle Jonsson 0 711,998 0.57% 0.15%
Fredrik Herslow, privately and through companies 0 497,965 0.40% 0.10%
Others 1,732,712 42,595,698 35.61% 12.35%
Total 40,071,166 84,425,880 100% 100%
Merger consideration

The Merger consideration has been determined after negotiations between the parties, whereby representatives of the respective companies have discussed various options to determine the exact distribution of the Merger consideration. The parties have, among other things, considered the volume-weighted average prices paid of the respective Companies during the last 30 trading days as well as Hamlet Pharma’s and SelectImmune’s prospects after the implementation of planned measures. In connection with the signing of the Merger plan, each company has assessed that it can accept an agreement that results in a distribution of the Merger consideration as set out below.

The Merger consideration will consist of newly issued shares in Hamlet Pharma, provided that shareholders in the Companies resolve to approve the Merger at the extraordinary general meetings that will resolve on the Merger plan. One (1) class A share in SelectImmune entitles the holder to 0.8 class A shares in Hamlet Pharma and one (1) class B share in SelectImmune entitles the holder to 0.8 class B shares in Hamlet Pharma.

Based on the volume-weighted average price paid of Hamlet Pharma’s class B share during the last thirty trading days, the Merger consideration represents a premium of approximately 63.25 percent compared to volume-weighted average price paid of SEK 1.88 for SelectImmune’s class B share during the last thirty trading days (prior to the announcement of the Merger) and approximately 36.07 percent compared to the closing price of SEK 2.25 for SelectImmune’s class B share (the day before the announcement of the Merger).

Entitled to receive the Merger consideration will be the shareholders who are recorded in SelectImmune’s share register on the date of registration of the Merger by the Swedish Companies Registration Office. However, the board is entitled to postpone this date if required for practical reasons. Such postponement will be communicated as soon as possible after such decision is made.

The shareholders of SelectImmune will collectively own approximately 11.22 percent of the shares and approximately 5.85 percent of the votes in Hamlet Biopharma (based on a total of 17,459,225 outstanding shares in SelectImmune, of which 2,000,000 class A shares and 15,459,225 class B shares, as of the date of this announcement).

Fractions

Only whole shares of Hamlet Pharma will be paid to shareholders of SelectImmune as Merger consideration. Hamlet Pharma and SelectImmune will therefore assign Aqurat Fondkommission AB ("Aqurat") to combine all fractions of class B shares in Hamlet Pharma ("Fractions") that do not entitle to a whole new class B share in Hamlet Pharma as Merger consideration and the total number of class B shares in Hamlet Pharma corresponding to such Fractions will thereafter be sold by Aqurat on Spotlight Stock Market. The sale shall take place as soon as possible after the registration of the Merger with the Swedish Companies Registration Office (the "Completion"). The proceeds of the sale of Fractions shall be accounted for by Aqurat and thereafter paid to those entitled thereto in proportion to the value of the Fractions held immediately prior to the sale. Such payment shall be made as soon as practicable after such sale of the Fractions. All class A shares in SelectImmune are held by Linnane Pharma and thus no fractions will arise.

Accounting for Merger consideration

To the extent not otherwise stated below, the Merger consideration will be recognized after the Swedish Companies Registration Office has registered the Merger by Euroclear Sweden AB registering the number of Hamlet Pharma shares to which the shareholder is entitled on each beneficiary’s securities account. At the same time, the shareholder’s shareholding in SelectImmune shall be deregistered from the same account. The Merger consideration will thus be distributed automatically, and no action will be required by SelectImmune’s shareholders in this regard. The new shares in Hamlet Pharma issued as Merger consideration entitle the holder to the rights of shareholders from and including the date of registration of the shares with the Swedish Companies Registration Office. The accounting of the sale proceeds for the sale of Fractions shall, as stated above, be done through the agency of Aqurat. The accounting shall take place as soon as practicable after the sale of the Fractions. If the shares in SelectImmune are pledged at the time of accounting of the Merger consideration, accounting shall, as a result, be made to the pledgee. If the shares in SelectImmune are registered in the name of a nominee, the resulting accounting shall be made to the nominee.

Issuance of consideration shares

The issue of shares in Hamlet Pharma for payment of the Merger consideration must be approved by Hamlet Pharma’s shareholders at the extraordinary general meeting that will resolve on the Merger plan. The shares issued in Hamlet Pharma as Merger consideration to the shareholders in SelectImmune shall carry the right to a dividend for the first time on the record date for the dividend that falls closest to the Completion.

The total number of shares that will be issued to SelectImmune’s shareholders as Merger consideration will be based on the number of SelectImmune shares outstanding at the time of the Completion of the Merger. Assuming that the number of outstanding shares at the time of this press release is unchanged upon the Completion, 1,600,000 class A shares and 12,367,380 class B shares are to be issued by Hamlet Pharma to make up the total of 13,967,380 shares in Hamlet Pharma of which the Merger consideration consists of. At the time of Completion of the Merger, there will be a total of 40,071,166 outstanding class A shares and 84,425,880 class B shares in Hamlet Biopharma based on the number of shares in Hamlet Pharma at the time of this press release.

Commitments prior to the Merger

The Companies undertake, during the period from the approval of the Merger plan by the respective general meetings until the Completion, to take all necessary measures to carry out the Merger on the terms stated herein and to continue to conduct their respective businesses in the usual manner. The Companies shall not take any of the following actions without the prior written consent from the other company:

a) resolve on or pay dividends or make any other value transfer to shareholders, with the exception that the Companies may pay such dividends as follows from Chapter 18 Section 11 of the Swedish Companies Act;

b) issue shares or other securities;

c) enter or amend material contracts or other agreements or raise new material loans, beyond what falls within the company’s normal business operations; or

d) take any other action likely to unreasonably affect the relative value of the Merger consideration in relation to the value of the shares in SelectImmune.

Terms of the Merger

The Completion is conditional on:

that Hamlet Pharma’s shareholders, at a general meeting in Hamlet Pharma, approve the Merger plan and approve the issue of the shares that make up the Merger consideration;
that SelectImmune’s shareholders, at a general meeting in SelectImmune, approve the Merger plan;
that Spotlight Stock Market has decided to admit the class B shares that constitute the Merger consideration to trading on Spotlight Stock Market;
that the Merger is not wholly or partially made impossible or substantially more difficult due to laws, court decisions, authority decisions or the like;
that neither Hamlet Pharma nor SelectImmune has breached the commitments set out under the heading "Commitments prior to the Merger" before the date on which the Merger is registered with the Swedish Companies Registration Office in such a way that would lead to a material adverse effect on the Merger or Hamlet Biopharma;
that no change, circumstance or event or consequence of changes, circumstances or events has occurred which had or could reasonably be expected to have a material adverse effect on the financial position or operations, including SelectImmune’s, Hamlet Pharma’s or Hamlet Biopharma’s turnover, results, liquidity, solvency, equity or assets, and as a result the other party cannot reasonably be expected to complete the Merger;
completion of the Acquisition, including approval of the transaction at a general meeting in Hamlet Pharma; and
approval of the Cooperation Agreement at a general meeting in Hamlet Pharma.
If the conditions stated in this section have not been met and the Completion has not taken place by October 1, 2023, the Merger will not be implemented and the Merger plan will cease to apply, provided that the Merger shall be terminated and the Merger plan will cease to apply only, to the extent permitted by applicable law, if the non-compliance is of material importance to the Merger or to Hamlet Biopharma. The Board of Directors reserve the right to waive, in whole or in part, one, several or all the above conditions by a joint decision.

The boards have, to the extent permitted by applicable law, the right to decide by joint resolution to postpone the latest date for fulfillment of the conditions from October 1, 2023, to a later date.

Recommendation from SelectImmune’s board and valuation statement (so-called fairness opinion)

SelectImmune’s board of directors believes that the Merger is beneficial for SelectImmune and its shareholders. The board of directors considers that the Merger consideration is fair from a financial point of view for SelectImmune’s shareholders and this opinion is supported by a so-called fairness opinion from Hjalmarsson & Partners Corporate Finance AB which SelectImmune obtained in accordance with Section IV.3 of the Swedish Corporate Governance Board’s takeover rules for certain trading platforms (the "Takeover Rules") and which states that, based on and subject to the assumptions and limitations set forth therein, as of March 30, 2023, the Merger consideration to be received in the Merger by SelectImmune’s shareholders is reasonable from a financial standpoint of such shareholders.

SelectImmune’s board of directors has issued a statement pursuant to Section II.19 of the Takeover Rules, according to which SelectImmune’s shareholders are advised to vote in favor of the Merger.

Recommendation from Hamlet Pharma’s board

Hamlet Pharma’s board of directors believes that the Merger is beneficial for Hamlet Pharma and its shareholders. The board of directors considers that the Merger consideration is fair from a financial point of view for Hamlet Pharma. Accordingly, Hamlet Pharma’s board of directors recommends that its shareholders approve the Merger plan and the issuance of the Merger consideration to SelectImmune’s shareholders at the extraordinary general meeting in Hamlet Pharma. As a basis for this view, the board of directors of Hamlet Pharma has considered several factors, including, but not limited to, the volume-weighted average price paid for SelectImmune’s class B share and Hamlet Pharma’s class B share respectively thirty trading days prior to the date of this announcement, as well as the Companies prospects after the implementation of planned actions.

Form of merger and dissolution of SelectImmune

The board of directors consider that the combination of Hamlet Pharma and SelectImmune shall be carried out as a corporate merger of the Companies, whereby the shareholders of both Companies are given the opportunity to approve the Merger at an extraordinary general meeting in each company. All shares in SelectImmune are covered by the Merger.

Provided that the extraordinary general meeting of each company votes in favor of the Merger plan, SelectImmune will be dissolved, and all its assets and liabilities will be transferred to Hamlet Pharma when the Swedish Companies Registration Office registers the Merger. This is expected to take place no earlier than the third quarter of 2023. The Companies will later announce the date on which the Swedish Companies Registration Office is expected to register the Merger.

The last day for trading in SelectImmune’s shares is expected to be the trading day that falls two (2) trading days before the date of the Swedish Companies Registration Office’s registration of the Merger and the first day for trading in the newly issued shares in Hamlet Pharma is expected to fall two (2) trading days after the date of registration of the Merger.

Share ownership between Hamlet Pharma and SelectImmune

Hamlet Pharma does not own or control any shares in SelectImmune, or other financial instruments, which give Hamlet Pharma a financial exposure equivalent to a holding in SelectImmune. SelectImmune does not own or control any shares or other financial instruments in Hamlet Pharma. However, the Companies are associated companies vis-à-vis each other through Linnane Pharma, which is the majority shareholder as well as the parent company of both Companies.

The Merger requires, among other things, approvals at extraordinary general meetings in both Companies. Linnane Pharma is SelectImmune’s largest shareholder with a holding of approximately 34.37 percent of the shares and 67.69 percent of the votes in SelectImmune. Since Linnane Pharma is also the parent company of Hamlet Pharma and thus is part of the same group as Hamlet Pharma, Linnane Pharma does not have the right to vote at SelectImmune’s general meeting. Linnane Pharma has a holding of 49.33 percent of the shares and 83.52 percent of the votes in Hamlet Pharma and has the right to vote at Hamlet Pharma’s general meeting regarding the Merger.

Holders of securities with special rights

There are no outstanding shares, warrants, convertibles or other securities that entitle the holder to special rights in SelectImmune.

There are also no incentive programs for board members, senior executives or other employees who will be affected by the Merger.

Certain related party matters, etc.

Catharina Svanborg and Helena Lomberg are chairpersons in the boards and board members respectively in both Hamlet Pharma and SelectImmune. Furthermore, Catharina Svanborg is, through Linnane Pharma, SelectImmune’s and Hamlet Pharma’s largest shareholder. For this reason, neither Catharina Svanborg nor Helena Lomberg participated in the handling of and decisions regarding the Merger in SelectImmune.

These circumstances also mean that Section IV of the Takeover Rules is applicable to the Merger. This means that, according to Section IV.3 of the Takeover Rules, SelectImmune’s board is obliged to obtain and publish a valuation statement, a so-called fairness opinion, regarding the shares in SelectImmune from independent expertise.

Financing

The execution of the Merger is not dependent on any financing as the Merger consideration consists exclusively of new shares in Hamlet Pharma.

Due Diligence

In connection with the preparations for the Merger, the Companies have conducted customary limited due diligence investigations of a confirmatory nature of certain business-related and legal information regarding Hamlet Pharma and SelectImmune respectively. During the due diligence investigations, no other information that has not previously been made public and that could constitute insider information in relation to Hamlet Pharma and SelectImmune has been disclosed.

Fees due to the Merger etc.

No special fees or benefits, within the meaning of the Swedish Companies Act, will be paid to any of Hamlet Pharma’s or SelectImmune’s board members or CEO in connection with the Merger. Apart from what is stated below, no such fees or benefits will be paid to the Companies’ auditor.

The fees to the auditor of Hamlet Pharma and SelectImmune shall be paid according to approved invoice for, among other things, its opinion on the Merger plan, its review of the Merger plan and other work performed by the auditor in connection with the Merger.

Indicative timetable for the Merger

The preliminary timetable for the Merger is as per below.

31 March 2023 The Merger plan is published and made available to the Company’s shareholders
3 May 2023 Disclosure of the merger document
17 May 2023 Extraordinary general meeting in SelectImmune
19 May 2023 Extraordinary general meeting in Hamlet Pharma
Beginning of August 2023 The Swedish Companies Registration Office grants permission for the Merger. Press release on preliminary timetable for the last day of trading in SelectImmune’s class B share, payment of the Merger consideration, etc.
Beginning of August 2023 The Swedish Companies Registration Office registers the Merger.
The indicative timetable is preliminary and may be subject to change. An exact timetable is not possible to indicate; the timetable is partially dependent on factors within the framework of the regulatory process that are beyond the Companies’ immediate control.

Applicable law and disputes

The Merger shall be governed by and construed in accordance with Swedish law. Through the commitments that follow from the Companies’ listing on Spotlight Stock Market, the Merger and the Companies are subject to the Takeover Rules, the Swedish Securities Council’s statements and advice on the interpretation and application of the Takeover Rules (and, where applicable, the Swedish Securities Council’s previous statements and advice on the interpretation and application of the rules for public offers of the Swedish Industry and Commerce Stock Exchange Committee that were previously applied), as well as the sanctions that Spotlight Stock Market may decide on in case of violation of the Takeover Rules. Disputes relating to, or arising in connection with, the Merger shall be settled by a Swedish court exclusively, with the Stockholm district court as first instance.

Advisor

Hamlet Pharma has engaged Advokatfirman Delphi as legal advisor. SelectImmune has engaged Falkenborn Advokatbyrå as legal advisor.

Please note, this is a translation of the Swedish original. In case of deviations, the Swedish version of the press release available on the company’s website shall prevail.

This is information that Hamlet Pharma AB (publ) and SelectImmune Pharma AB (publ) are obliged to make public pursuant to the EU Market Abuse Regulation. The information was submitted for publication, through the agency of the contact persons set out below, on March 31, 2023, at 08:00.

Checkpoint Therapeutics Announces $6.1 Million Registered Direct Offering Priced At-the-Market Under Nasdaq Rules

On March 31, 2023 Checkpoint Therapeutics, Inc. ("Checkpoint") (Nasdaq: CKPT), a clinical-stage immunotherapy and targeted oncology company, reported that it has entered into definitive agreements for the issuance and sale of an aggregate of 1,700,000 shares of its common stock at a purchase price of $3.60 per share of common stock in a registered direct offering priced at-the-market under Nasdaq rules (Press release, Checkpoint Therapeutics, MAR 31, 2023, View Source [SID1234629654]).

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In addition, in a concurrent private placement, Checkpoint will issue and sell Series A warrants to purchase up to 1,700,000 shares of common stock and Series B warrants to purchase up to 1,700,000 shares of common stock. The Series A warrants will be exercisable immediately upon issuance and will expire five years following the issuance date and have an exercise price of $3.35 per share and the Series B warrants will be exercisable immediately upon issuance and will expire eighteen months following the issuance date and have an exercise price of $3.35 per share.

H.C. Wainwright & Co. is acting as exclusive placement agent for the offering.

The closing of the offering is expected to occur on or about April 4, 2023, subject to the satisfaction of customary closing conditions. The gross proceeds from the offering are expected to be approximately $6.1 million. Checkpoint intends to use the net proceeds of this offering for working capital and general corporate purposes, including the manufacturing of cosibelimab and certain pre-commercial activities in anticipation of potential approval and commercial launch.

The shares of common stock described above (but not the warrants issued in the concurrent private placement or the shares of common stock underlying such warrants) are being offered by Checkpoint pursuant to a shelf registration statement on Form S-3 (File No. 333-251005) that was previously filed with the Securities and Exchange Commission ("SEC") on November 27, 2020, and subsequently declared effective on December 17, 2020. The shares of common stock offered in the registered direct offering are being offered only by means of a prospectus, including a prospectus supplement, forming a part of the effective registration statement. A final prospectus supplement and accompanying base prospectus relating to, and describing the terms of, the registered direct offering will be filed with the SEC and will be available on the SEC’s website at www.sec.gov. Electronic copies of the final prospectus supplement and the accompanying base prospectus relating to the offering, when available, may also be obtained by contacting H.C. Wainwright & Co., LLC, at 430 Park Ave., New York, New York 10022, by telephone at (212) 856-5711, or by email at [email protected].

The warrants described above are being made in a transaction not involving a public offering and have not been registered under Section 4(a)(2) of the Securities Act of 1933, as amended (the "Securities Act") and/or Rule 506(b) of Regulation D promulgated thereunder and, along with the shares of common stock underlying the warrants, have not been registered under the Securities Act or applicable state securities laws. Accordingly, the warrants and underlying shares of common stock may not be reoffered or resold in the United States except pursuant to an effective registration statement with the Securities and Exchange Commission (the "SEC") or an applicable exemption from the registration requirements of the Securities Act and such applicable state securities laws.

This press release does not constitute an offer to sell or a solicitation of an offer to buy the securities in this offering, nor shall there be any sale of these securities in any state or other jurisdiction in which such offer, solicitation or sale would be unlawful prior to the registration or qualification under the securities laws of any such state or other jurisdiction.

Bristol Myers Squibb Receives Positive CHMP Opinion for CAR T Cell Therapy Breyanzi (lisocabtagene maraleucel) for Relapsed or Refractory Large B-cell Lymphoma After One Prior Therapy

On March 31, 2023 Bristol Myers Squibb (NYSE: BMY) reported the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended approval of Breyanzi (lisocabtagene maraleucel) for the treatment of adult patients with diffuse large B-cell lymphoma (DLBCL), high grade B-cell lymphoma (HGBCL), primary mediastinal large B-cell lymphoma (PMBCL) and follicular lymphoma grade 3B (FL3B), who relapsed within 12 months from completion of, or are refractory to, first-line chemoimmunotherapy (Press release, Bristol-Myers Squibb, MAR 31, 2023, View Source [SID1234629651]).

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"This positive CHMP opinion is an important milestone towards introducing a potential new standard of care for people in the European Union living with relapsed or refractory large B-cell lymphoma after first-line treatment, an area of critical unmet need where few patients are able to undergo or derive long-term clinical benefit from stem cell transplant," said Anne Kerber, senior vice president, Cell Therapy Development, Bristol Myers Squibb. "We look forward to continuing to work with the European Medicines Agency with the goal of bringing our cell therapy, Breyanzi, and the potential for cure to more people."

The CHMP adopted a positive opinion based on results from the pivotal Phase 3 TRANSFORM study evaluating Breyanzi as a second-line treatment in adults with relapsed or refractory LBCL compared to the standard of care consisting of salvage chemotherapy followed by high-dose chemotherapy plus hematopoietic stem cell transplant (HSCT).

In the European Union (EU), the European Commission delivers its final decision within approximately two months following receipt of the CHMP opinion. The decision will be applicable to all EU member states and Iceland, Norway and Liechtenstein.*

Bristol Myers Squibb thanks the patients and investigators involved in the TRANSFORM study.

*Centralized Marketing Authorization does not include approval in Great Britain (England, Scotland and Wales).

About TRANSFORM

TRANSFORM (NCT03575351) is a pivotal, global, randomized, multicenter Phase 3 trial evaluating Breyanzi compared to the current standard of care (platinum-based salvage chemotherapy followed by high-dose chemotherapy and hematopoietic stem cell transplant [HSCT] in patients responding to salvage chemotherapy) in patients with large B-cell lymphoma that was primary refractory or relapsed within 12 months after CD20-antibody and anthracycline containing first-line therapy. Patients were randomized to receive Breyanzi or standard of care salvage therapy, including rituximab plus dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP), rituximab plus ifosfamide, carboplatin and etoposide (R-ICE), or rituximab plus gemcitabine, dexamethasone and cisplatin (R-GDP) per the investigators’ choice before proceeding to high-dose chemotherapy (HDCT) and HSCT. The primary endpoint of the study was event-free survival, defined as time from randomization to death from any cause, progressive disease, failure to achieve complete response or partial response, or start of new antineoplastic therapy due to efficacy concerns, whichever occurs first. Complete response rate was a key secondary endpoint. Other efficacy endpoints included progression-free survival, overall survival, overall response rate and duration of response.

About Breyanzi

Breyanzi is a CD19-directed CAR T cell therapy with a 4-1BB costimulatory domain, which enhances the expansion and persistence of the CAR T cells. Breyanzi is approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal LBCL, and follicular lymphoma grade 3B who have refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy, or refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant due to comorbidities or age, or relapsed or refractory disease after two or more lines of systemic therapy. Breyanzi is not indicated for the treatment of patients with primary central nervous system lymphoma. Please see the Important Safety Information section below, including Boxed WARNINGS for Breyanzi regarding cytokine release syndrome and neurotoxicity.

Breyanzi is also approved in Japan for the second-line treatment of relapsed or refractory LBCL, and in Japan, Europe, Switzerland and Canada for relapsed or refractory LBCL after two or more lines of systemic therapy. Bristol Myers Squibb’s clinical development program for Breyanzi includes clinical studies in earlier lines of treatment for patients with relapsed or refractory LBCL and other types of lymphomas and leukemia. For more information, visit clinicaltrials.gov.

Full European Summary of Product Characteristics for Breyanzi is available from the EMA website at www.ema.europa.eu .

U.S. Important Safety Information

BOXED WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES

Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving BREYANZI. Do not administer BREYANZI to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab with or without corticosteroids.
Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving BREYANZI, including concurrently with CRS, after CRS resolution or in the absence of CRS. Monitor for neurologic events after treatment with BREYANZI. Provide supportive care and/or corticosteroids as needed.
BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS.
Cytokine Release Syndrome (CRS)

CRS, including fatal or life-threatening reactions, occurred following treatment with BREYANZI. CRS occurred in 46% (122/268) of patients receiving BREYANZI, including ≥ Grade 3 (Lee grading system) CRS in 4% (11/268) of patients. One patient had fatal CRS and 2 had ongoing CRS at time of death. The median time to onset was 5 days (range: 1 to 15 days). CRS resolved in 119 of 122 patients (98%) with a median duration of 5 days (range: 1 to 17 days). Median duration of CRS was 5 days (range 1 to 30 days) in all patients, including those who died or had CRS ongoing at time of death.

Among patients with CRS, the most common manifestations of CRS include fever (93%), hypotension (49%), tachycardia (39%), chills (28%), and hypoxia (21%). Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, diffuse alveolar damage, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).

Ensure that 2 doses of tocilizumab are available prior to infusion of BREYANZI. Sixty-one of 268 (23%) patients received tocilizumab and/or a corticosteroid for CRS after infusion of BREYANZI. Twenty-seven (10%) patients received tocilizumab only, 25 (9%) received tocilizumab and a corticosteroid, and 9 (3%) received corticosteroids only.

Neurologic Toxicities

Neurologic toxicities that were fatal or life-threatening, occurred following treatment with BREYANZI. CAR T cell-associated neurologic toxicities occurred in 35% (95/268) of patients receiving BREYANZI, including ≥ Grade 3 in 12% (31/268) of patients. Three patients had fatal neurologic toxicity and 7 had ongoing neurologic toxicity at time of death. The median time to onset of the first event was 8 days (range: 1 to 46 days). The onset of all neurologic events occurred within the first 8 weeks following BREYANZI infusion. Neurologic toxicities resolved in 81 of 95 patients (85%) with a median duration of 12 days (range: 1 to 87 days). Three of four patients with ongoing neurologic toxicity at data cutoff had tremor and one subject had encephalopathy. Median duration of neurologic toxicity was 15 days (range: 1 to 785 days) in all patients, including those with ongoing neurologic events at the time of death or at data cutoff.

Seventy-eight (78) of 95 (82%) patients with neurologic toxicity experienced CRS. Neurologic toxicity overlapped with CRS in 57 patients. The onset of neurologic toxicity was after onset of CRS in 30 patients, before CRS onset in 13 patients, same day as CRS onset in 7 patients, and same day as CRS resolution in 7 patients. Neurologic toxicity resolved in three patients before the onset of CRS. Eighteen patients experienced neurologic toxicity after resolution of CRS.

The most common neurologic toxicities included encephalopathy (24%), tremor (14%), aphasia (9%), delirium (7%), headache (7%), dizziness (6%), and ataxia (6%). Serious events including cerebral edema and seizures occurred with BREYANZI. Fatal and serious cases of leukoencephalopathy, some attributable to fludarabine, have occurred in patients treated with BREYANZI.

CRS and Neurologic Toxicities Monitoring

Monitor patients daily at a certified healthcare facility during the first week following infusion, for signs and symptoms of CRS and neurologic toxicities. Monitor patients for signs and symptoms of CRS and neurologic toxicities for at least 4 weeks after infusion; evaluate and treat promptly. Counsel patients to seek immediate medical attention should signs or symptoms of CRS or neurologic toxicity occur at any time. At the first sign of CRS, institute treatment with supportive care, tocilizumab or tocilizumab and corticosteroids as indicated.

BREYANZI REMS

Because of the risk of CRS and neurologic toxicities, BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS. The required components of the BREYANZI REMS are:

Healthcare facilities that dispense and administer BREYANZI must be enrolled and comply with the REMS requirements.
Certified healthcare facilities must have on-site, immediate access to tocilizumab.
Ensure that a minimum of 2 doses of tocilizumab are available for each patient for infusion within 2 hours after BREYANZI infusion, if needed for treatment of CRS.
Certified healthcare facilities must ensure that healthcare providers who prescribe, dispense, or administer BREYANZI are trained on the management of CRS and neurologic toxicities.
Further information is available at www.BreyanziREMS.com, or contact Bristol Myers Squibb at 1-888-423-5436.

Hypersensitivity Reactions

Allergic reactions may occur with the infusion of BREYANZI. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO).

Serious Infections

Severe infections, including life-threatening or fatal infections, have occurred in patients after BREYANZI infusion. Infections (all grades) occurred in 45% (121/268) of patients. Grade 3 or higher infections occurred in 19% of patients. Grade 3 or higher infections with an unspecified pathogen occurred in 16% of patients, bacterial infections occurred in 5%, and viral and fungal infections occurred in 1.5% and 0.4% of patients, respectively. Monitor patients for signs and symptoms of infection before and after BREYANZI administration and treat appropriately. Administer prophylactic antimicrobials according to standard institutional guidelines.

Febrile neutropenia has been observed in 9% (24/268) of patients after BREYANZI infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad spectrum antibiotics, fluids, and other supportive care as medically indicated.

Avoid administration of BREYANZI in patients with clinically significant active systemic infections.

Viral reactivation: Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against B cells. Ten of the 11 patients in the TRANSCEND study with a prior history of HBV were treated with concurrent antiviral suppressive therapy to prevent HBV reactivation during and after treatment with BREYANZI. Perform screening for HBV, HCV, and HIV in accordance with clinical guidelines before collection of cells for manufacturing.

Prolonged Cytopenias

Patients may exhibit cytopenias not resolved for several weeks following lymphodepleting chemotherapy and BREYANZI infusion. Grade 3 or higher cytopenias persisted at Day 29 following BREYANZI infusion in 31% (84/268) of patients, and included thrombocytopenia (26%), neutropenia (14%), and anemia (3%). Monitor complete blood counts prior to and after BREYANZI administration.

Hypogammaglobulinemia

B-cell aplasia and hypogammaglobulinemia can occur in patients receiving treatment with BREYANZI. The adverse event of hypogammaglobulinemia was reported as an adverse reaction in 14% (37/268) of patients; laboratory IgG levels fell below 500 mg/dL after infusion in 21% (56/268) of patients. Hypogammaglobulinemia, either as an adverse reaction or laboratory IgG level below 500 mg/dL after infusion, was reported in 32% (85/268) of patients. Monitor immunoglobulin levels after treatment with BREYANZI and manage using infection precautions, antibiotic prophylaxis, and immunoglobulin replacement as clinically indicated.

Live vaccines: The safety of immunization with live viral vaccines during or following BREYANZI treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during BREYANZI treatment, and until immune recovery following treatment with BREYANZI.

Secondary Malignancies

Patients treated with BREYANZI may develop secondary malignancies. Monitor lifelong for secondary malignancies. In the event that a secondary malignancy occurs, contact Bristol Myers Squibb at 1-888-805-4555 for reporting and to obtain instructions on collection of patient samples for testing.

Effects on Ability to Drive and Use Machines

Due to the potential for neurologic events, including altered mental status or seizures, patients receiving BREYANZI are at risk for altered or decreased consciousness or impaired coordination in the 8 weeks following BREYANZI administration. Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

Adverse Reactions

Serious adverse reactions occurred in 46% of patients. The most common nonlaboratory, serious adverse reactions (> 2%) were CRS, encephalopathy, sepsis, febrile neutropenia, aphasia, pneumonia, fever, hypotension, dizziness, and delirium. Fatal adverse reactions occurred in 4% of patients.

The most common nonlaboratory adverse reactions of any grade (≥ 20%) were fatigue, CRS, musculoskeletal pain, nausea, headache, encephalopathy, infections (pathogen unspecified), decreased appetite, diarrhea, hypotension, tachycardia, dizziness, cough, constipation, abdominal pain, vomiting, and edema.

BIO-PATH HOLDINGS REPORTS FULL YEAR 2022 FINANCIAL RESULTS

On March 31, 2023 – Bio-Path Holdings, Inc., (NASDAQ:BPTH), a biotechnology company leveraging its proprietary DNAbilize liposomal delivery and antisense technology to develop a portfolio of targeted nucleic acid cancer drugs, reported its financial results for the year ended December 31, 2022 and provided an update on recent corporate developments (Press release, Bio-Path Holdings, MAR 31, 2023, View Source [SID1234629650]).

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"We entered 2023 from a position of strength and will continue to build on the momentum generated last year to advance our important clinical programs in hard-to-treat cancers," said Peter Nielsen, President and Chief Executive Officer of Bio-Path Holdings. "We see continued enthusiasm from clinical investigators and patients alike and hope to make even more progress toward completing these key studies. We have an exciting year ahead as we look forward to reporting data from a number of clinical trials evaluating our DNAbilize platform across solid tumors and acute myeloid leukemia, all cancers with limited treatment options."

Recent Corporate Highlights

• Announced First Patient Dosed in Phase 1/1b Clinical Trial of BP1001-A in Solid Tumors. In December, Bio-Path announced the enrollment and dosing of the first patient in a Phase 1/1b clinical trial of BP1001-A (liposomal Grb2) in patients with solid tumors, including ovarian, endometrial, pancreatic and breast cancer.

Important Near-Term Clinical Milestones

BP1001-A Phase 1/1b Clinical Trial in Solid Tumors • Important trial with advanced or recurrent solid tumors, including ovarian and uterine, pancreatic and breast cancer with initial cohort completion and data readout expected before mid-year.

BP1002 Phase 1/1b Clinical Trial in Relapsed/Refractory AML • Focus on patients who relapsed on venetoclax treatment with initial cohort completion and readout expected in the second quarter of 2023.

Prexigebersen (BP1001) Phase 2 Clinical Trial in AML

• Two of the three cohorts in the clinical trial already exceed the minimum efficacy required for enrollment expansion. • Assess safety and efficacy of each cohort treatment combination therapy with potential to qualify for expedited program status after cohort’s initial interim analysis, which are expected to commence by cohort in the second quarter of 2023.

Financial Results for the Year Ended December 31, 2022

• The Company reported a net loss of $13.9 million, or $1.91 per share, for the year ended December 31, 2022, compared to a net loss of $10.4 million, or $1.55 per share, for the year ended December 31, 2021.

• Research and development expense for the year ended December 31, 2022, increased to $9.2 million, compared to $5.9 million for the year ended December 31, 2021, primarily due to manufacturing expenses related to drug product releases in 2022, increased enrollment in our Phase 2 clinical trial for prexigebersen in AML and start-up costs related to our Phase 1 clinical trial for BP1002 in refractory/relapsed AML patients.

• General and administrative expense for the year ended December 31, 2022, increased to $4.7 million, compared to $4.5 million for the year ended December 31, 2021, primarily due to increased legal fees.

• As of December 31, 2022, the Company had cash of $10.4 million, compared to $23.8 million at December 31, 2021. Net cash used in operating activities for the year ended December 31, 2022, was $15.1 million compared to $9.9 million for the comparable period in 2021.

Net cash provided by financing activities for the year ended December 31, 2022, was $1.7 million.

Conference Call and Webcast Information

Bio-Path Holdings will host a conference call and webcast today at 8:30 a.m. ET to review these full-year 2022 financial results and to provide a general update on the Company. To access the conference call please dial (833) 630-1956 (domestic) or (412) 317-1837 (international). A live audio webcast of the call and the archived webcast will be available in the Media section of the Company’s website at www.biopathholdings.com.