On June 17, 2024 TME Pharma N.V. (Euronext Growth Paris: ALTME), a clinical-stage biotechnology company focused on developing novel therapies for treatment of cancer by targeting the tumor microenvironment (TME), reported the launch of a capital increase through issuance of new shares for a minimum of €2.2 million gross proceeds (Press release, TME Pharma, JUN 17, 2024, View Source [SID1234644409]). Guaranteed net proceeds will allow the company to reach key strategic partnering and financing milestones in 2024.

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The operation is open to professional investors and is also open to the retail investors in France via the PrimaryBid platform for up to €390,000, representing up to 15% of the total capital increase. A separate guarantee agreement has been put in place to ensure the company will have received €2.2 million gross by June 28, 2024. Guaranteed net proceeds will extend cash runway from July 20241 into December 2024, past targeted strategic partnering and financing milestones in Q4-2024.

"NOX-A12 has delivered exceptional data in chemotherapy-resistant patients with the aggressive brain cancer, glioblastoma, in combination with radiotherapy and the anti-VEGF antibody bevacizumab: a 10-fold increase in the rate of survival at 21 months when compared to a reference cohort receiving standard of care (50% vs 5%) and a near-doubling of the median overall survival (19.9 vs. 10.5 months)2. This strong clinical data enabled TME Pharma to fulfill its promises to: 1) obtain FDA approval for the Phase 2 trial design in brain cancer, 2) obtain Fast Track designation and access to the accelerated regulatory pathway from the FDA, 3) raise funds to eliminate convertible debt from the capital structure of the company, and 4) generate a high-profile scientific publication around NOX-A12 such as Nature Communications article announced earlier today," said Aram Mangasarian, CEO of TME Pharma. The guaranteed capital injection announced today will provide TME Pharma with financing into December 2024, with the possibility of extending our cash runway even further should the outstanding Warrants Z be exercised between July 1 and the end of 2024. This increased financial visibility will allow us to focus on achievement of our next targeted strategic partnering and financing milestones for 2024, which include: cooperation with a pharma partner on drug supply of the anti-VEGF antibody combination drug for the Phase 2, monetization of the NOX-E36 asset (e.g. via a spinout) and additional transactions sufficient to secure financing of the upcoming Phase 2 NOX-A12 brain cancer trial via a combination of non-dilutive grant funding, a strategic alliance and/or investment from expert institutional investors. In summary, our goal for this financing is to allow a significant transformation of the company’s profile in the remainder of 2024."

Key Financing details and timetable

Capital increases as part of a transaction comprise:
a public offering in France only through the French PrimaryBid platform for up to €390,000, or up to 15% of the total capital increase for retail investors (and not in any other jurisdiction including without being exclusive the Netherlands or any other EU/EEA Member State, the United Kingdom, the United States of America, Australia, Canada or Japan) under the exemption and subject to the applicable publication requirement listed in the French Code monétaire et financier and the General Regulation of the Autorité des marchés financiers (AMF) and falling within one or more of the exemptions from any requirement for the company to publish a prospectus pursuant to the prospectus regulation within the meaning of Regulation (EU)2017/1129 of the European Parliament and of the Council of June 14, 2017, as amended (the PrimaryBid Offering); and
a reserved offering to professional investors within the European Union by way of private placement with an accelerated book-build (the Reserved Offering) with the minimum of €2.2 million excluding the PrimaryBid Offering.
The price of €0.1798 per new share, representing a discount of 10% to the closing price on June 17, 2024.
The PrimaryBid Offering will close on June 17, 2024, at 10.00 p.m. Paris time and the Reserved Offering will close on June 18, 2024, before start of trading (subject to early closure).
A group of guarantors are contractually committed guarantee €2.2 million in gross proceeds by June 28, 2024, by purchasing new shares at the same price of €0.1798 per share, in exchange for a 10% fee on the guaranteed amount. This ensures that even if today’s capital increase does not reach its targeted amount, net proceeds from the guarantors will extend cash runway into December 2024, past targeted strategic partnering and financing milestones in Q4-2024.
The company will announce the results of the transaction as soon as possible following the closing of the order book for the Reserved Offering in a press release, which will present the final number of new ordinary shares issued.
Settlement of the new shares and their admission to trading on Euronext Growth Paris multilateral trading facility are expected to occur on June 20, 2024. The new shares will be of the same class and fungible with the existing shares, will carry all rights attached to the shares, and will be admitted to trading under the same ISIN code NL0015000YE1.
Use of Proceeds

Approximately 30% of net proceeds from the capital increase will be used on research and development (R&D) activities including ongoing NOX-A12 GLORIA Phase 1/2 trial in brain cancer, regulatory interactions in Europe for the next brain cancer trial and intellectual property activities. Another approximately 30% of net proceeds will be used for outreach to potential industry partners and investors, the pursuit of government or charitable grants and preparation for the targeted monetization of the NOX-E36 program. The remaining 40% of net proceeds will be used for general corporate purposes including accounting, auditing, legal advice and maintenance of the listing.

Guarantee

Gross proceeds of €2.2 million is guaranteed by a group of investors, whose individual commitment is not representing a concerted action towards the potential control of the company. None of them individually would cross threshold of 50% ownership even if the guarantee was required in full.

Shareholder and Corporate Authorizations

The issuance of shares in this transaction relies upon the authorizations granted to the Issuer by its shareholders in the annual general meeting (AGM) on June 29, 2023, under agenda items 5 and 6. Issuer has completed and obtained all necessary corporate approvals for the transaction. In particular, at the AGM held on June 29, 2023, the company’s shareholders approved the transitional provision which came into effect in February 2024, as a result the authorized capital amounts to €900,000 divided into 80,000,000 ordinary shares and 10,000,000 preference shares, each share with a nominal value of €0.01.

Dilutive Potential

Shareholders residing in France have the option to participate via the PrimaryBid platform to reduce dilution from this transaction if they are able to purchase sufficient number of shares. If they do not participate in the PrimaryBid Offering they will be diluted as outlined in the table below.

Table: Dilutive Potential from Transaction

Description

Shares to be issued
(max)

Total shares
outstanding

Dilution (max)

Shareholder
starting with 1%
would then hold

Prior to announcement of capital increase

–

28,453,373

–

1%

Up to €2,590,000 capital increase at €0.1798 per share

14,404,894

42,858,267

33.61%

0.66%

Financial Intermediaries

ALLinvest is the global coordinator – lead manager and bookrunner for the Reserved Offering.
For the PrimaryBid Offering, retail investors will be able to subscribe exclusively through the PrimaryBid partners indicated on the PrimaryBid website (www.PrimaryBid.fr). The PrimaryBid Offering is not covered by an underwriting agreement. For further details, please refer to the PrimaryBid website at www.PrimaryBid.fr.

Risk Factors

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

the market price of the company’s shares may fluctuate and fall below the subscription price of the new shares, resulting in a loss for investors;
the volatility and liquidity of the company’s shares may fluctuate significantly;
existing shareholders will see their stake in the company’s share capital diluted;
the placement is not subject to a performance guarantee and investors who have acquired shares could sustain a loss equal to the price of acquiring these shares if the company is not able to continue its operations due to strategic, operational or financial factors;
the company expects to incur losses for the foreseeable future and will need substantial additional funding from industrial partners, financial investors, and/or governmental or charitable institutions in order to complete the development and commercialization of its product candidates, which may not be available on acceptable terms when needed, if at all.
Before deciding to invest, investors are asked to familiarise themselves with the risks described in the company’s 2023 annual financial report available on the company website.

Potential Conflict of Interest

Part of the variable remuneration of management relates to corporate goals for advancing the development pipeline of TME Pharma as well as securing the respective funding. Management also holds shares, warrants and options in the company.

On June 17, 2024 Charles River Laboratories International, Inc. (NYSE: CRL) and Captain T Cell, a spinoff from the renowned Max Delbrück Center Berlin, Germany, reported a plasmid DNA and retrovirus vector production program agreement (Press release, Captain T Cell, JUN 17, 2024, View Source [SID1234644408]). As part of Charles River’s Cell and Gene Therapy (CGT) Accelerator Program (CAP), Captain T Cell will have access to established plasmid and viral vector contract development and manufacturing organization (CDMO) capabilities and advisory services ahead of Captain T Cell’s plan to manufacture a TCR-T cell therapy for solid tumor patients for a Phase I clinical trial.

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An Award-winning Approach to Cancer Immunotherapy
With the goal to give new patient groups access to T cell immunotherapies, Captain T Cell is developing efficacy-enhanced treatment options for solid tumor therapies. Using a toolbox of next-generation technologies, Captain T Cell generates T cells displaying tumor-specific T cell receptors (TCR) as well as enhanced persistence and the capacity to cope with the hostile tumor microenvironment of difficult-to-treat solid tumors. Once infused into a patient’s body, these tumor-specific T cells intend to find and destroy tumor cells. This therapeutic method may provide an option for patients with tumors that no longer respond to other therapies.

Cell and Gene Therapy CDMO Solutions
To bring its gene-modified cell therapy to clinic, Captain T Cell will leverage Charles River’s established plasmid and viral vector production capabilities, finetuned over decades supporting CGT developers from pre-clinical to commercial scale.

In recent years, Charles River has significantly broadened its cell and gene therapy portfolio with several acquisition integrations and expansions to simplify complex supply chains and meet growing demand for plasmid DNA, viral vector, and cell therapy services. Combined with its legacy testing capabilities, Charles River offers a premier "concept-to-cure" advanced therapies solution.

Approved Quotes
"We are thrilled to work with the Captain T Cell team to support the manufacture of its TCR-T cell cancer immunotherapy. Charles River has decades of success reliably manufacturing plasmid DNA, viral vectors, and cell therapies, helping to safeguard our customer programs and bring potential therapies to patients with limited options." – Kerstin Dolph, Corporate Senior Vice President, Global Manufacturing, Charles River

"Captain T Cell is devoted to developing a new generation of toolbox-engineered T cell-based immunotherapies for solid tumor patients. We have the utmost confidence in the expertise of Charles River as we work to bring our lead candidate to the clinic." – Felix Lorenz, CEO, Captain T Cell

On June 17, 2024 Compugen Ltd. (Nasdaq: CGEN) (TASE: CGEN), a clinical-stage cancer immunotherapy company and a pioneer in computational target discovery, reported that Pierre Ferré, Ph.D, SVP, Preclinical Development and Corporate Operations, Compugen will present a case study on clinical dose selection for TIGIT monospecific and bispecific antibodies at the Antibody Industrial Symposium taking place June 20-21, 2024, Montpellier, France (Press release, Compugen, JUN 17, 2024, View Source [SID1234644407]).

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Event: 12th Antibody Industrial Symposium, Montpellier, France
Date: Friday, June 21, 2024
Presenter: Pierre Ferré, Ph.D., SVP, Preclinical Development and Corporate Operations, Compugen
Presentation title: Case study on clinical dose selection for TIGIT monospecific and bispecific antibodies

On June 17, 2024 Johnson & Johnson (NYSE: JNJ) reported the submission of a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for a fixed combination of amivantamab and recombinant human hyaluronidase for subcutaneous administration (SC amivantamab) for all currently approved or submitted indications of intravenous (IV) RYBREVANT (amivantamab-vmjw) in certain patients with non-small cell lung cancer (NSCLC) (Press release, Johnson & Johnson, JUN 17, 2024, View Source [SID1234644406]).

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Data from the Phase 3 PALOMA-3 study (NCT05388669) presented at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and published in the Journal of Clinical Oncology showed SC amivantamab had comparable overall response rates to IV administration in patients with NSCLC with epidermal growth factor receptor (EGFR) exon 19 deletion or L858R mutations. SC amivantamab also demonstrated significantly shorter administration time and a five-fold reduction in infusion-related reactions, alongside longer overall survival, progression-free survival and duration of response.1 Efficacy results like these have not been seen before in a study assessing IV and SC comparability. The BLA submission includes data from the Phase 2 PALOMA-2 (NCT05498428) study evaluating SC amivantamab in settings where IV amivantamab has been previously submitted for approval and is intended to support dosing schedules of every two and every three weeks.2

"RYBREVANT administered intravenously is a foundational treatment for patients with EGFR-mutated NSCLC," said Kiran Patel, M.D., Vice President, Clinical Development, Solid Tumors, Johnson & Johnson Innovative Medicine. "This subcutaneous option, administered in approximately five minutes, is a clinically important advancement that could transform the treatment experience for patients, oncologists and nursing staff. We look forward to working with the FDA and global regulators in the review of these applications."

Today’s submission follows two recent milestones for the RYBREVANT IV formulation, including the approval of RYBREVANT in combination with chemotherapy as the first FDA-approved therapy for first-line treatment of patients with NSCLC with EGFR exon 20 insertion mutations supported by the Phase 3 PAPILLON study and a CHMP positive opinion for RYBREVANT in combination with chemotherapy for this indication in Europe.

About PALOMA-3

PALOMA-3 (NCT05388669), which enrolled 418 patients, is a randomized, open-label Phase 3 study evaluating the pharmacokinetics (PK), efficacy and safety of subcutaneous amivantamab (administered via manual injection) combined with lazertinib compared to IV amivantamab and lazertinib in patients with EGFR-mutated advanced or metastatic NSCLC after progression on osimertinib and chemotherapy. The co-primary PK endpoints of the study were trough concentration (Ctrough on Cycle [C] 2 Day [D] 1 or C4D1) and C2 area under the curve (AUCD1-D15). Key secondary endpoints were objective response rate and progression-free survival. Overall survival was a predefined exploratory endpoint. Prophylactic anticoagulation was recommended for the first four months of treatment.1

About the PALOMA-2 Study

PALOMA-2 (NCT05498428) is an open-label Phase 2 study evaluating the efficacy, safety, and PK of first-line SC amivantamab (administered via manual injection) combined with lazertinib and/or chemotherapy in patients with EGFR-mutated advanced or metastatic NSCLC. Sixty-eight and 58 patients were enrolled in Cohorts 1 and 6, respectively. Prophylactic anticoagulation for the first four months of treatment was recommended in Cohort 1 and mandatory in Cohort 6. The primary endpoint was objective response rate (ORR) as assessed by the investigator per RECIST v1.1.2

About RYBREVANT

RYBREVANT (amivantamab-vmjw), a fully-human bispecific antibody targeting EGFR and MET with immune cell-directing activity, is approved in the U.S., Europe, and in other markets around the world as monotherapy for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.3 In the subcutaneous formulation, amivantamab is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s ENHANZE drug delivery technology.

RYBREVANT is also approved in the U.S. in combination with chemotherapy (carboplatin and pemetrexed) for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test. In October 2023, a type II extension of indication application was submitted to the European Medicines Agency (EMA) seeking approval of RYBREVANT for this indication.

In December 2023, Johnson & Johnson submitted a supplemental Biologics License Application (sBLA) together with a New Drug Application (NDA) to the U.S. FDA for RYBREVANT in combination with lazertinib for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or L858R substitution mutations, as detected by an FDA-approved test. This submission is based on the Phase 3 MARIPOSA study and was granted Priority Review in February 2024. A marketing authorization application (MAA) and type II extension of indication application were also submitted to the EMA seeking approval of lazertinib in combination with RYBREVANT based on the MARIPOSA study.

In November 2023, Johnson & Johnson submitted an sBLA to the U.S. FDA for RYBREVANT in combination with chemotherapy for the treatment of patients with EGFR-mutated NSCLC who progressed on or after osimertinib based on the MARIPOSA-2 study. A type II extension of indication application was also submitted to the EMA seeking approval of RYBREVANT for this indication.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for NSCLC§ prefer next-generation sequencing–based strategies over polymerase chain reaction–based approaches for the detection of EGFR exon 20 insertion variants. The NCCN Guidelines include:

Amivantamab-vmjw (RYBREVANT) plus carboplatin and pemetrexed as a preferred (Category 1 recommendation) first-line therapy in treatment-naive patients with newly diagnosed advanced or metastatic EGFR exon 20 insertion mutation-positive advanced NSCLC, or as a subsequent therapy option (Category 2A recommendation) for patients that have progressed on or after platinum-based chemotherapy with or without immunotherapy and have EGFR exon 20 insertion mutation-positive advanced NSCLC.4 †‡

Amivantamab-vmjw (RYBREVANT) plus chemotherapy as a preferred (Category 1 recommendation) subsequent therapy for patients with locally advanced or metastatic NCSLC with EGFR exon 19 deletions or exon 21 L858R mutations who experienced disease progression after treatment with osimertinib.4 †‡

Amivantamab-vmjw (RYBREVANT) as a subsequent therapy option (Category 2A recommendation) for patients that have progressed on or after platinum-based chemotherapy with or without an immunotherapy and have EGFR exon 20 insertion mutation-positive NSCLC.4 †‡
RYBREVANT is being studied in multiple clinical trials in NSCLC, including:

The Phase 1 PALOMA (NCT04606381) study assessing the feasibility of subcutaneous administration of amivantamab based on safety and pharmacokinetics and to determine a dose, dose regimen and formulation for amivantamab subcutaneous delivery.5

The Phase 2 PALOMA-2 (NCT05498428) study assessing subcutaneous amivantamab in patients with advanced or metastatic solid tumors including EGFR-mutated NSCLC.2

The Phase 3 PALOMA-3 (NCT05388669) study assessing lazertinib with subcutaneous amivantamab compared to intravenous amivantamab in patients with EGFR-mutated advanced or metastatic NSCLC.1

The Phase 3 PAPILLON (NCT04538664) study assessing RYBREVANT in combination with carboplatin-pemetrexed versus chemotherapy alone in the first-line treatment of patients with advanced or metastatic NSCLC with EGFR exon 20 insertion mutations.6

The Phase 3 MARIPOSA-2 (NCT04988295) study assessing the efficacy of RYBREVANT (with or without lazertinib) and carboplatin-pemetrexed versus carboplatin-pemetrexed alone in patients with locally advanced or metastatic EGFR ex19del or L858R substitution NSCLC after disease progression on or after osimertinib.7

The Phase 3 MARIPOSA (NCT04487080) study assessing RYBREVANT in combination with lazertinib versus osimertinib and versus lazertinib alone in the first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR ex19del or L858R substitution mutations.8

The Phase 1 CHRYSALIS (NCT02609776) study evaluating RYBREVANT in patients with advanced NSCLC.9

The Phase 1/1b CHRYSALIS-2 (NCT04077463) study evaluating RYBREVANT in combination with lazertinib and lazertinib as a monotherapy in patients with advanced NSCLC with EGFR mutations.10

The Phase 1/2 METalmark (NCT05488314) study assessing RYBREVANT and capmatinib combination therapy in locally advanced or metastatic NSCLC.11

The Phase 1/2 PolyDamas (NCT05908734) study assessing RYBREVANT and cetrelimab combination therapy in locally advanced or metastatic NSCLC.12

The Phase 2 SKIPPirr study (NCT05663866) exploring how to decrease the incidence and/or severity of first-dose infusion-related reactions with RYBREVANT in combination with lazertinib in relapsed or refractory EGFR-mutated advanced or metastatic NSCLC.13
For more information, visit: View Source

About Lazertinib

Lazertinib is an oral, third-generation, brain-penetrant EGFR tyrosine kinase inhibitor (TKI) that targets both the T790M mutation and activating EGFR mutations while sparing wild type-EGFR. An analysis of the efficacy and safety of lazertinib from the Phase 3 study was published in The Journal of Clinical Oncology in 2023. In 2018, Janssen Biotech, Inc., entered into a license and collaboration agreement with Yuhan Corporation for the development of lazertinib.14

About Non-Small Cell Lung Cancer

Worldwide, lung cancer is one of the most common cancers, with NSCLC making up 80 to 85 percent of all lung cancer cases.15,16 The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.17 Among the most common driver mutations in NSCLC are alterations in EGFR, which is a receptor tyrosine kinase controlling cell growth and division.18 EGFR mutations are present in 10 to 15 percent of Western patients with NSCLC with adenocarcinoma histology and occur in 40 to 50 percent of Asian patients.17, 18, 19, 20, 21, 22 EGFR ex19del or EGFR L858R mutations are the most common EGFR mutations.23 The five year survival rate for all people with advanced NSCLC and EGFR mutations treated with EGFR tyrosine kinase inhibitors (TKIs) is less than 20 percent.24, 25 EGFR exon 20 insertion mutations are the third most prevalent activating EGFR mutation.26 Patients with EGFR exon 20 insertion mutations have a real-world five-year overall survival (OS) of eight percent in the frontline setting, which is worse than patients with EGFR ex19del or L858R mutations, who have a real-world five-year OS of 19 percent.27

RYBREVANT IMPORTANT SAFETY INFORMATION3

WARNINGS AND PRECAUTIONS

The safety population of RYBREVANT with carboplatin and pemetrexed described in Warnings and Precautions was based on 151 patients in the PAPILLON study.

The safety population of RYBREVANT as a single agent described in Warnings and Precautions was based on 129 patients in the CHRYSALIS study.

Infusion-Related Reactions

RYBREVANT can cause infusion-related reactions (IRR); signs and symptoms of IRR include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting.

RYBREVANT with Carboplatin and Pemetrexed

RYBREVANT in combination with carboplatin and pemetrexed can cause infusion-related reactions. Based on the safety population, infusion-related reactions occurred in 42% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed, including Grade 3 (1.3%) adverse reactions. The incidence of infusion modifications due to IRR was 40%, and 0.7% of patients permanently discontinued RYBREVANT.

RYBREVANT as a Single Agent

Based on the safety population, IRR occurred in 66% of patients treated with RYBREVANT as a single agent. Among patients receiving treatment on Week 1 Day 1, 65% experienced an IRR, while the incidence of IRR was 3.4% with the Day 2 infusion, 0.4% with the Week 2 infusion, and cumulatively 1.1% with subsequent infusions. Of the reported IRRs, 97% were Grade 1-2, 2.2% were Grade 3, and 0.4% were Grade 4. The median time to onset was 1 hour (range 0.1 to 18 hours) after start of infusion. The incidence of infusion modifications due to IRR was 62%, and 1.3% of patients permanently discontinued RYBREVANT due to IRR.

Premedicate with antihistamines, antipyretics, and, glucocorticoids and infuse RYBREVANT as recommended. Administer RYBREVANT via a peripheral line on Week 1 and Week 2. Monitor patients for any signs and symptoms of infusion reactions during RYBREVANT infusion in a setting where cardiopulmonary resuscitation medication and equipment are available. Interrupt infusion if IRR is suspected. Reduce the infusion rate or permanently discontinue RYBREVANT based on severity.

Interstitial Lung Disease/Pneumonitis

RYBREVANT can cause interstitial lung disease (ILD)/pneumonitis.

RYBREVANT with Carboplatin and Pemetrexed

Based on the safety population, Grade 3 ILD/pneumonitis occurred in 2.6% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed. All patients required permanent discontinuation.

RYBREVANT as a Single Agent

Based on the safety population, ILD/pneumonitis occurred in 3.3% of patients treated with RYBREVANT, with 0.7% of patients experiencing Grade 3 ILD/pneumonitis. Three patients (1%) discontinued RYBREVANT due to ILD/pneumonitis.

Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold RYBREVANT in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed.

Dermatologic Adverse Reactions

RYBREVANT can cause rash (including dermatitis acneiform), pruritus, and dry skin.

RYBREVANT with Carboplatin and Pemetrexed

RYBREVANT in combination with carboplatin and pemetrexed can cause dermatologic adverse reactions. Based on the safety population, rash occurred in 89% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed, including Grade 3 (19%) adverse reactions. Rash leading to dose reductions occurred in 19% of patients; and 2% permanently discontinued RYBREVANT, and 1.3% discontinued pemetrexed.

RYBREVANT as a Single Agent

Based on the safety population, rash occurred in 74% of patients treated with RYBREVANT, including Grade 3 rash in 3.3% of patients. The median time to onset of rash was 14 days (range: 1 to 276 days). Rash leading to dose reduction occurred in 5% of patients, and RYBREVANT was permanently discontinued due to rash in 0.7% of patients.

Toxic epidermal necrolysis occurred in one patient (0.3%) treated with RYBREVANT as a single agent.

Instruct patients to limit sun exposure during and for 2 months after treatment with RYBREVANT. Advise patients to wear protective clothing and use broad-spectrum UVA/UVB sunscreen. Alcohol-free emollient cream is recommended for dry skin.

If skin reactions develop, start topical corticosteroids and topical and/or oral antibiotics. For Grade 3 reactions, add oral steroids and consider dermatologic consultation. Promptly refer patients presenting with severe rash, atypical appearance or distribution, or lack of improvement within 2 weeks to a dermatologist. Withhold, dose reduce, or permanently discontinue RYBREVANT based on severity.

Ocular Toxicity

RYBREVANT can cause ocular toxicity including keratitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, and uveitis.

RYBREVANT with Carboplatin and Pemetrexed

Based on the safety population, RYBREVANT in combination with carboplatin and pemetrexed can cause ocular toxicity including blepharitis, dry eye, conjunctival redness, blurred vision, and eye pruritus. All events were Grade 1-2.

RYBREVANT as a Single Agent

Based on the safety population, keratitis occurred in 0.7% and uveitis occurred in 0.3% of patients treated with RYBREVANT. All events were Grade 1-2. Promptly refer patients presenting with eye symptoms to an ophthalmologist. Withhold, dose reduce, or permanently discontinue RYBREVANT based on severity.

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal models, RYBREVANT can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of RYBREVANT.

Adverse Reactions

RYBREVANT with Carboplatin and Pemetrexed

For the 151 patients in the PAPILLON clinical trial who received RYBREVANT in combination with carboplatin and pemetrexed, the most common adverse reactions (≥20%) were rash (90%), nail toxicity (62%), stomatitis (43%), infusion-related reaction (42%), fatigue (42%), edema (40%), constipation (40%), decreased appetite (36%), nausea (36%), COVID-19 (24%), diarrhea (21%), and vomiting (21%). The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased albumin (7%), increased alanine aminotransferase (4%), increased gamma-glutamyl transferase (4%), decreased sodium (7%), decreased potassium (11%), decreased magnesium (2%), and decreases in white blood cells (17%), hemoglobin (11%), neutrophils (36%), platelets (10%), and lymphocytes (11%).

Serious adverse reactions occurred in 37% of patients who received RYBREVANT in combination with carboplatin and pemetrexed. Serious adverse reactions in ≥2% of patients included rash, pneumonia, ILD, pulmonary embolism, vomiting, and COVID-19. Fatal adverse reactions occurred in 7 patients (4.6%) due to pneumonia, cerebrovascular accident, cardio-respiratory arrest, COVID-19, sepsis, and death not otherwise specified.

RYBREVANT as a Single Agent

For the 129 patients in the CHRYSALIS clinical trial who received RYBREVANT as a single agent the most common adverse reactions (≥20%) were rash (84%), IRR (64%), paronychia (50%), musculoskeletal pain (47%), dyspnea (37%), nausea (36%), fatigue (33%), edema (27%), stomatitis (26%), cough (25%), constipation (23%), and vomiting (22%). The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased lymphocytes (8%), decreased albumin (8%), decreased phosphate (8%), decreased potassium (6%), increased alkaline phosphatase (4.8%), increased glucose (4%), increased gamma-glutamyl transferase (4%), and decreased sodium (4%).

Serious adverse reactions occurred in 30% of patients who received RYBREVANT. Serious adverse reactions in ≥2% of patients included pulmonary embolism, pneumonitis/ILD, dyspnea, musculoskeletal pain, pneumonia, and muscular weakness. Fatal adverse reactions occurred in 2 patients (1.5%) due to pneumonia and 1 patient (0.8%) due to sudden death.

Please read full Prescribing Information for RYBREVANT.

On June 17, 2024 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) (Actinium or the Company), a leader in the development of Antibody Radiation Conjugates (ARCs) and other targeted radiotherapies, reported that an abstract detailing the first ever preclinical data from the combination of menin inhibitors with Actinium’s ARC Actimab-A in acute myeloid leukemia (AML) models was presented at the 2024 European Hematology Association (EHA) (Free EHA Whitepaper) Congress held June 13 – 16, 2024, in Madrid, Spain (Press release, Actinium Pharmaceuticals, JUN 17, 2024, View Source [SID1234644403]). Actinium studied Actimab-A in combination with the leading menin inhibitors, revumenib (Syndax Pharmaceuticals, Inc.) and ziftomenib (Kura Oncology, Inc.), which are being developed for patients with KMT2A rearrangements and NMP1 mutations, which are present in approximately 10% and 30% of AML patients, respectively.

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Actimab-A + Menin inhibitor combination results include:

Actimab-A as a single agent showed potent in vitro AML cell killing activity in both MV-4-11 and MOLM-13 KMT2A mutant cell lines, compared to the non-radio conjugated CD33 antibody lintuzumab (p<0.0001)

Actimab-A enhanced AML cell death when combined with both revumenib and ziftomenib at all dose levels in difficult to treat KMT2A mutant AML

The combination of Actimab-A with leading menin inhibitors triggered an acute increase in AML necrosis and cell death in vivo relative to single agent therapy within 72 hours of dosing

Anti-tumor effect was significantly potentiated and prolonged when combining Actimab-A with a leading menin inhibitor compared to monotherapies in xenograft leukemia models in vivo (p<0.0024 Actimab-A + menin) as shown in the exhibit below
The Actimab-A + Menin Inhibitor combination presentation can be accessed on the investor relations page of Actinium’s website here.

Actimab-A targets CD33, a marker expressed ubiquitously in patients with AML, and is conjugated with the alpha-partible payload Actinium-225. The broad expression of CD33 and the differentiated mutation agnostic cell-killing mechanism of targeted radiotherapy make Actimab-A broadly applicable for combinations with chemotherapy, targeted agents including venetoclax, FLT3 and menin inhibitors, immunotherapies and cellular therapies supporting its potential backbone therapy profile across the AML patient treatment journey.

Sandesh Seth, Actinium’s Chairman and CEO, said, "Combining with menin inhibitors is an exciting expansion of the already broad potential of Actimab-A in AML. Across single agent and combination studies, Actimab-A has produced high rates of response, MRD negativity and improved survival in high-risk, relapsed and refractory patients including those with a TP53 mutation and venetoclax failures. The broad expression of CD33 in AML coupled with the potency of Actinium-225 make Actimab-A an ideal agent for treating radiation sensitive AML. We are encouraged by this highly promising initial data and the synergistic potential of Actimab-A with menin inhibitors, which has broad potential across the AML treatment continuum including frontline, maintenance and relapsed/refractory settings. We are eager to continue to study this combination and generate additional data that could support advancing into clinical studies of Actimab-A with menin inhibitors."

Menin inhibitors are a class of drug candidates being developed for patients with AML that have a rearrangement of the KMT2A gene, previously known as the mixed-lineage leukemia (MLL) or mutation of the NPM1 gene. There are multiple menin inhibitors in development for these patients with revumenib (Syndax Pharmaceuticals, Inc.) being most advanced having a PDUFA data of September 2024 and ziftomenib (Kura Oncology, Inc.) enrolling patients in a registration Phase 2 trial. Multiple menin inhibitors are being studied in Phase 1 clinical trials by companies including Johnson & Johnson, Sumitomo Pharma Co., Ltd., Hutchmed, Biomea Fusion, Inc. and BioNova Pharmaceuticals Pvt Ltd.