On September 22, 2025 Fierce biotech reported that from advancing radically new therapies to refining existing modalities, this year’s Fierce 15 companies are pushing the envelope and giving us a reason for optimism (Press release, Alterome Therapeutics, SEP 22, 2025, View Source [SID1234656136]).

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This year has been chock-full of challenges, ranging from a seemingly never-ending biotech bear market to deep uncertainty surrounding regulatory and international policies. Yet, unmet need still fuels biotech, with companies risking it all in hopes of bringing new medicines to patients.

Welcome to this year’s best in biotech. These biotechs were carefully selected from hundreds of nominees and represent the most innovative and visionary companies leading the pack—even, or maybe especially, through unpredictable conditions.

This year, the Fierce 15 recognizes biotechs across continents and indications, including companies working to battle cancer, neurodegeneration, rare diseases, autoimmune conditions and more.

This is the crème de la crème working on both next-generation drugs and never-before-seen modalities. While the organizations differ across methods and therapeutic areas, there’s one main common thread: They’re all challenging old ways of working.

The 2025 class is defined by resilience, diversity in both strategy and leadership, and treatments that hold life-changing potential for underserved patients around the world.

Read on to meet the companies—and leaders—redefining biotech. We are pleased to present Fierce Biotech’s 2025 Fierce 15.

Alterome Therapeutics

Targeting the genetic alterations that cause cancer while sparing healthy cells

CEO: Jung Choi
Founded: 2021
Based: San Diego
Clinical focus: Breast and endometrial cancers, colorectal cancer, pancreatic ductal adenocarcinoma, non-small cell lung cancer, solid tumors

What makes Alterome fierce: Alterome Therapeutics was founded with a mission to discover precision medicines that could potentially treat what CEO Jung Choi describes as "some of the scariest cancers out there," including cancers of the pancreas, colon and lungs.

As its name suggests, Alterome’s approach is centered on developing drugs that aim to attack the genetic mutations that cause cancer, while trying to minimize side effects to the body’s healthy cells.

The company’s work is driven by three main factors, Choi said in an interview with Fierce Biotech: "a very deep understanding of the cellular pathways that drive cancer," a fast-paced drug development approach rooted in advanced chemical structure and physics-based design—powered by its Kraken computational chemistry platform—and a team of "relentless" scientists at the core of it all.

"So, that’s how we’ve been able to go from idea to clinic in just three and a half years, with two potentially best-of-their-kind cancer medications," she said.

Those two candidates are now in phase 1 trials. The first is a KRAS selective inhibitor that Choi described as "the Goldilocks of KRAS," because it aims to bridge the gap between KRAS inhibitors that only target specific mutations and those that take aim at all forms of RAS, leading to unwanted toxicities.

Alterome’s take on the approach, then, is an attempt at "hitting KRAS very selectively, but also inhibiting nearly all, if not all, of the KRAS mutations potently and durably," she said, while also inhibiting KRAS whether active or inactive and boasting "very good druglike properties."

The company believes ALTA3263 is "the best KRAS inhibitor that hits all four characteristics," according to Choi. It’s being studied in colorectal, pancreatic and non-small cell lung cancers.

The other candidate, ALTA2618, is a covalent AKT1 E17K mutation-selective inhibitor that Alterome has developed to target only the mutant form of AKT that drives cancer, while leaving the benign form of the protein alone.

"What’s exciting to us is that, as far as we know, we are the first investigational therapy that’s in the clinic with this approach," Choi said, adding that ALTA2618 is being studied in patients with hormone-positive breast cancer as well as endometrial, ovarian and other AKT1-driven cancers.

Alterome is hoping to keep up the fast pace of development. The company plans first to generate monotherapy data for both candidates in the "not-too-distant future," per Choi, before "moving very quickly" into testing them as part of combination therapies, then taking those results to the FDA for the go-ahead to start registrational studies.

The company’s current and future plans are being helped along by VC funding that most recently included a series B round led by Goldman Sachs Alternatives and closed in the spring of 2024 with $132 million. Like any biotech startup, Choi said Alterome will "do more financing as time goes on," drawing in new backers based on "very meaningful clinical milestones."

Choi joined Alterome earlier this year, fresh off a stint as entrepreneur in residence at Third Rock Ventures and following various roles leading corporate development at Gilead Sciences, Chimerix, InterMune—until it was purchased by Roche in 2014—and Global Blood Therapeutics, through its own 2022 acquisition by Pfizer.

On September 20, 2025 Immutep Limited (ASX: IMM; NASDAQ: IMMP) ("Immutep" or "the Company"), a late-stage immunotherapy company targeting cancer and autoimmune diseases, reported the initiation of an investigator-initiated Phase II trial evaluating neoadjuvant eftilagimod alfa (efti) administered subcutaneously as monotherapy and then in combination with standard-of-care chemotherapy prior to surgery in patients with early-stage HR+/HER2-negative breast cancer (Press release, Immutep, SEP 20, 2025, View Source [SID1234656122]).

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The study will treat up to 50 evaluable patients in a two-stage design and will be primarily funded by grants and The George Washington (GW) University Cancer Center. Immutep will provide efti at no cost, technical support, and limited funding that falls within its existing budget. The trial will be led by Principal Investigator, Pavani Chalasani, MD, MPH, Division Director of Hematology and Medical Oncology at the GW Cancer Center and a leader of the GW Cancer Center Breast Cancer clinical research team.

Dr. Chalasani stated, "Given my clinical experience with efti in the AIPAC-003 study coupled with promising data from additional trials evaluating efti in metastatic breast cancer settings, we look forward to evaluating this unique immunotherapy at earlier stage disease in patients with HR+/HER2 -ve breast cancer. As a novel neoadjuvant immunotherapy option, efti’s powerful and safe activation of a broad anti-cancer immune response in combination with chemotherapy may lead to high rates of pathologic complete responses, the primary endpoint of this study. Additionally, we are hopeful that efti’s immune activation in these patients with early stage cancer who have stronger immune systems may lead to improved disease free survival."

Efti’s targeting and unique activation of powerful antigen-presenting cells via MHC Class II leads to a broad anti-cancer immune response. This includes the activation and proliferation of cytotoxic CD8+ T cells that can be armed in vivo with chemotherapy-induced tumour antigens, as well as numerous other immune cells and cytokines enhancing the immune system’s ability to fight cancer. This novel immunotherapy has yielded encouraging clinical results in metastatic disease and earlier stage disease in its initial trial as a neoadjuvant treatment in soft tissue sarcoma.

Immutep CEO, Marc Voigt added, "We are thankful for the interest and investment by academia in the United States and elsewhere to evaluate the promise of efti at earlier-stage disease. This trial helps us cost-efficiently expand our clinical pipeline for neoadjuvant efti in areas of high unmet need. Our belief is this novel immune system activator can play a meaningful role in metastatic settings and in the ongoing expansion of immunotherapy into neoadjuvant settings to fight cancer."

The goal of this multi-center study led by the GW Cancer Center is to determine pathological complete response (pCR) after neoadjuvant efti treatment and neoadjuvant chemotherapy (NAC). This is a single-arm interventional trial in patients with early-stage HR+/HER2 -ve breast cancer (Stage I-III) who are eligible for NAC. Enrolled patients will be treated with efti monotherapy for three weeks and then start NAC in combination with efti. For more information, visit clinicaltrials.gov (NCT07102940).

About Eftilagimod Alfa (efti)
Efti is Immutep’s proprietary soluble LAG-3 protein and MHC Class II agonist that stimulates both innate and adaptive immunity for the treatment of cancer. As a first-in-class antigen presenting cell (APC) activator, efti binds to MHC (major histocompatibility complex) Class II molecules on APC leading to activation and proliferation of CD8+ cytotoxic T cells, CD4+ helper T cells, dendritic cells, NK cells, and monocytes. It also upregulates the expression of key biological molecules like IFN-ƴ and CXCL10 that further boost the immune system’s ability to fight cancer.

Efti is under evaluation for a variety of solid tumours including non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), and metastatic breast cancer. Its favourable safety profile enables various combinations, including with anti-PD-[L]1 immunotherapy and/or chemotherapy. Efti has received Fast Track designation in first line HNSCC and in first line NSCLC from the United States Food and Drug Administration (FDA).

On September 20, 2025 C4 Therapeutics, Inc. (C4T) (Nasdaq: CCCC), a clinical-stage biopharmaceutical company dedicated to advancing targeted protein degradation science, reported data from the Phase 1 clinical trial of cemsidomide, an orally bioavailable IKZF1/3 degrader, in combination with dexamethasone for the treatment of relapsed/refractory multiple myeloma (RRMM) (Press release, C4 Therapeutics, SEP 20, 2025, View Source [SID1234656121]). With enrollment in the Phase 1 trial complete, data continue to show cemsidomide’s differentiated safety and tolerability profile and potentially class-leading anti-myeloma activity, supporting clear development paths for second line and later patient populations.

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"Cemsidomide’s clinical trial results to date have shown compelling anti-myeloma activity, a differentiated safety and tolerability profile and immunomodulatory effects across all dose levels, which have allowed us to create a derisked development plan that we are prepared to rapidly execute to potentially bring cemsidomide to patients, caregivers and hematologist-oncologists," said Len Reyno, M.D., chief medical officer of C4 Therapeutics. "As we prepare to initiate the Phase 2 study in Q1 2026 to evaluate cemsidomide in combination with dexamethasone and the Phase 1b study in Q2 2026 to evaluate cemsidomide and dexamethasone in combination with a BCMA BiTE—both development pathways that have the potential for accelerated approval—we are excited to further differentiate cemsidomide as the IKZF1/3 degrader of choice among approved medicines in this class, which are used across lines of therapy and in various combination regimens. We look forward to generating data in the future that further demonstrates cemsidomide’s potential to become a class-leading IKZF1/3 degrader across the growing populations of relapsed/refractory multiple myeloma patients."

Approved IKZF1/3 degraders remain backbone therapy across lines of multiple myeloma treatment, even as novel therapeutic approaches enter the treatment landscape. Recent advances in treatment, including immune-directed therapies, are not cures and the majority of patients ultimately relapse, creating a need for new medicines targeted at these heavily pretreated patients. This need for therapeutic options in later lines of therapy, which continue to incorporate IKZF1/3 degradation into the treatment regimen to promote myeloma cell death and T-cell activation, is expected to grow as patients live longer on newer treatments but still ultimately progress.

"The clinical data presented today for this potent Cereblon-based IKZF1/3 degrader shows a potentially class-leading safety profile and impressive evidence of anti-myeloma activity in a population of patients with extensive prior therapies—including 75% of patients who have progressed despite having received prior immune-based therapies, including BiTEs or CAR-Ts," said Binod Dhakal, M.D., M.S., associate professor of medicine, Medical College of Wisconsin, Division of Hematology. "Cemsidomide in combination with dexamethasone is well positioned both as a potential therapeutic option for patients with multi-refractory disease, and as the potential combination regimen of choice with immune-directed therapies due to its ability to enhance the immune response and add additional direct anti-myeloma effects via IKZF1/3 degradation."

Phase 1 Results
At the IMS Annual Meeting, C4T presented data from the Phase 1 dose escalation trial, for which enrollment is now complete. These data demonstrate cemsidomide’s potential to have a class-leading profile based on both its anti-myeloma activity and safety and tolerability profile, which positions the investigational medicine to become the IKZF1/3 degrader of choice across lines of therapy.

As of the July 23, 2025 data cutoff, a total of 72 patients received cemsidomide in combination with dexamethasone across five dose levels (50 µg dosed Monday, Wednesday, Friday [MWF]; 37.5 µg dosed once daily [QD]; 62.5 µg QD; 75 µg QD; 100 µg QD). The trial enrolled a heavily pretreated relapsed/refractory patient population that had received a median of seven prior therapies. Fifty-four patients (75%) received prior BCMA-targeted therapy, and 54 patients (75%) received prior CAR-T or T-cell engager therapy.

Safety: Cemsidomide in combination with dexamethasone was generally well tolerated over the range of doses tested.

As of the data cutoff date, 72 patients were evaluable for safety.
Cemsidomide was generally well tolerated with manageable incidents of on-target neutropenia across all dose levels; there were low rates of febrile neutropenia across all dose levels: three patients (4%) at Grade 3, one patient (1%) at Grade 4 and no patients at Grade 5.
There were low rates of thrombocytopenia across all dose levels: five patients (7%) at Grade 3, three patients (4%) at Grade 4 and no patients at Grade 5.
All treatment emergent adverse events were manageable; there were minimal dose reductions (four patients; 6%) and no discontinuations related to cemsidomide treatment.
The maximum administered dose is 100 µg QD.

Pharmacodynamics: Cemsidomide in combination with dexamethasone leads to robust IKZF1/3 degradation and T-cell activation, reinforcing its potential to be administered with dexamethasone, and with dexamethasone in combination with a B-cell maturation antigen bispecific T-cell engager (BCMA BiTE).

Cemsidomide achieved >50% degradation of IKZF1 and > 80% degradation of IKZF3, as assessed by mass spectrometry in human peripheral blood mononuclear cells (PBMCs).
Across all dose levels, cemsidomide in combination with dexamethasone led to significant T-cell activation associated with an enhancement of cytokine production, including IL-2.

Anti-myeloma activity: Cemsidomide in combination with dexamethasone demonstrates the potential for class-leading anti-myeloma activity.

As of the data cutoff, 67 patients were evaluable for anti-myeloma activity.
Across all dose levels, 23 patients (34%) achieved a partial response (PR) or better, with a median duration of response of 9.3 months.
At the 100 μg dose level, seven patients (50%) achieved a PR or better.
One patient achieved a minimal residual disease (MRD) negative complete response.
After the data cutoff and as of September 5, 2025, one patient who had achieved a very good partial response (VGPR) converted to a complete response (CR).
After the data cutoff and as of September 5, 2025, one patient who became efficacy evaluable achieved a PR; this PR is not included in the ORR reported above.
At the 75 μg dose level, eight patients (40%) achieved a PR or better.
Ten of the 15 efficacy evaluable patients (67%) who achieved a PR or better at the 75 µg and 100 µg dose levels remain on treatment; median duration of response has not yet been reached at 100 μg and 75 μg.

Cemsidomide’s Regulatory Path
Based on the Phase 1 trial results supporting cemsidomide’s differentiated safety profile and anti-myeloma activity, as well as insights gathered in the June 2025 Type C Meeting with the U.S. Food & Drug Administration (FDA), C4T plans to advance cemsidomide through two clinical trials that will position the investigational medicine for two distinct potential accelerated approvals.

Fourth line of therapy or later: C4T expects to initiate a Phase 2 single-arm registrational trial in the first quarter of 2026 to evaluate cemsidomide in combination with dexamethasone; initial ORR data is expected in the second half of 2027. If the data are supportive, C4T will pursue accelerated approval. In this setting, cemsidomide has the potential to provide a safe, tolerable and efficacious treatment option for highly refractory patients, including those who have received anti-BCMA therapies.
Second line of therapy or later: C4T plans to initiate a Phase 1b trial in the second quarter of 2026 to evaluate the safety and tolerability of cemsidomide and dexamethasone in combination with a BCMA BiTE; data are expected by mid-2027. If the data are supportive, C4T will advance this combination regimen directly into a single, randomized controlled Phase 3 study. This Phase 3 study will be designed to support the full approval for both the cemsidomide and dexamethasone pathway, as described above, and the cemsidomide and dexamethasone in combination with a BCMA BiTE pathway. In preclinical studies, the combination of cemsidomide with a BCMA BiTE exhibits a strong immunomodulatory effect and enhances T-cell dependent cellular cytotoxicity of multiple myeloma cells while continuing to demonstrate anti-myeloma activity.

Expected Upcoming Milestones:

Formally align with FDA on the recommended Phase 2 dose of cemsidomide for the Phase 2 trial by the end of 2025.
Initiate a Phase 2 single-arm registrational trial in the first quarter of 2026 to evaluate cemsidomide in combination with dexamethasone.
Initiate a Phase 1b trial in the second quarter of 2026 to evaluate the safety and tolerability of cemsidomide and dexamethasone in combination with a BCMA BiTE.

C4T Webcast for Analysts and Investors
C4T will host an investor webcast today, Saturday, September 20, 2025, at 3 pm ET. To join the webcast, please visit this link or the "Events & Presentations" page of the Investors section on the company’s website at www.c4therapeutics.com. A replay of the webcast will be archived and available following the event.

About Cemsidomide
Cemsidomide is an investigational, orally bioavailable small-molecule degrader in clinical development for the treatment of relapsed/refractory multiple myeloma. Data from the Phase 1 trial, which has completed enrollment, show cemsidomide’s differentiated safety and tolerability profile and potentially class-leading anti-myeloma activity that support the potential for durable outcomes. Two clinical trials are planned to further evaluate cemsidomide in relapsed/refractory multiple myeloma: a Phase 2 single-arm registrational trial to evaluate cemsidomide in combination with dexamethasone, which is expected to initiate in Q1 2026; and a Phase 1b trial to evaluate the safety and tolerability of cemsidomide and dexamethasone in combination with a BCMA BiTE, which is expected to initiate in Q2 2026.

About Multiple Myeloma
Multiple myeloma (MM) is a rare blood cancer affecting plasma cells. Approximately 36,000 people in the United States are diagnosed with MM each year. Despite advances in treatment, MM remains incurable. Treatment combinations include IKZF1/3 degraders, which are established backbone therapies, across lines of therapy.

On September 19, 2025 Nuvation Bio Inc. (NYSE: NUVB), a global oncology company focused on tackling some of the toughest challenges in cancer treatment, reported that Japan’s Ministry of Health, Labour and Welfare (MHLW) has approved IBTROZITM (taletrectinib) for the treatment of adult patients with ROS1-positive (ROS1+) unresectable, advanced and/or recurrent non-small cell lung cancer (NSCLC) (Press release, Nuvation Bio, SEP 19, 2025, View Source [SID1234656117]). As part of an exclusive license agreement entered in 2023, Nippon Kayaku will commercialize IBTROZI in Japan.

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The approval by Japan’s MHLW was based on data from the pivotal Phase 2 TRUST clinical program evaluating taletrectinib in patients globally, including Japan. Results from a pooled analysis of the TRUST clinical program were published in the Journal of Clinical Oncology in April 2025.

In parallel, the MHLW also approved the AmoyDx PLC Panel as a companion diagnostic to identify patients with locally advanced or metastatic ROS1+ NSCLC who may benefit from treatment with IBTROZI.

"Building on the regulatory approvals for IBTROZI in the U.S. and China, this additional approval by the MHLW further underscores the best-in-class potential and promise that IBTROZI holds for patients living with advanced ROS1-positive non-small cell lung cancer around the globe," said David Hung, M.D., Founder, President, and Chief Executive Officer of Nuvation Bio. "We remain steadfastly committed to bringing forward innovative cancer treatments that can help patients stay ahead of their disease."

On June 11, 2025, the U.S. Food and Drug Administration (FDA) granted full approval to IBTROZI for the treatment of locally advanced or metastatic ROS1+ NSCLC across lines of therapy, following a Priority Review and double Breakthrough Therapy designations. On June 20, the National Comprehensive Cancer Network added taletrectinib (IBTROZI) as a Preferred Agent in the National Comprehensive Cancer Network Clinical Practice Guidelines (NCCN Guidelines) in Oncology for Non-Small Cell Lung Cancers (NSCLC). Specifically, the NCCN Guidelines now include taletrectinib (IBTROZI) as a Preferred Agent for both first-line and subsequent therapy for ROS1+ NSCLC, including specific recommendations for those with brain metastases and resistance mutations.

Prior to this, Nuvation Bio announced on January 6, 2025, that China’s National Medical Products Administration (NMPA) had approved taletrectinib for the treatment of adult patients with locally advanced or metastatic ROS1+ NSCLC who either have or have not been previously treated with ROS1 tyrosine kinase inhibitors (TKI). Taletrectinib is marketed in China by Innovent Biologics under the brand name DOVBLERON.

Upon the first establishment of the reimbursement price in Japan, which is anticipated in the fourth quarter of 2025, Nuvation Bio will receive a USD $25 million milestone payment to go towards continued progression of our pipeline and portfolio.

About ROS1+ NSCLC
Each year, more than one million people globally are diagnosed with non-small cell lung cancer (NSCLC), the most common form of lung cancer. It is estimated that approximately 2% of patients with NSCLC have ROS1+ disease. About 35% of patients newly diagnosed with metastatic ROS1+ NSCLC have tumors that have spread to their brain. The brain is also the most common site of disease progression, with about 50% of previously treated patients developing central nervous system (CNS) metastases.

About IBTROZI
IBTROZI is an oral, potent, CNS-active, selective, next-generation ROS1 inhibitor therapy. On June 11, following Priority Review and Breakthrough Therapy Designations for both first- and second-line or later, the U.S. Food and Drug Administration (FDA) approved IBTROZI for the treatment of adult patients with locally advanced or metastatic ROS1+ NSCLC. Learn more at IBTROZI.com.

About the TRUST Clinical Program
The TRUST clinical program evaluating IBTROZI for the treatment of adult patients with advanced ROS1+ NSCLC included two Phase 2 single-arm pivotal studies: TRUST-I (NCT04395677) in China, which enrolled 173 patients, and TRUST-II (NCT04919811), a global study, which enrolled 189 patients. The primary endpoint of these registrational studies is confirmed objective response rate (cORR) as assessed by an independent review committee (IRC). Secondary endpoints include intracranial cORR, duration of response, progression-free survival, and safety.

Indication
IBTROZI is indicated for the treatment of adult patients with locally advanced or metastatic ROS1+ non-small cell lung cancer (NSCLC).

IMPORTANT SAFETY INFORMATION FOR IBTROZITM (taletrectinib)

WARNINGS AND PRECAUTIONS

Hepatotoxicity: Hepatotoxicity, including drug-induced liver injury and fatal adverse reactions, can occur. 88% of patients experienced increased AST, including 10% Grade 3/4. 85% of patients experienced increased ALT, including 13% Grade 3/4. Fatal liver events occurred in 0.6% of patients. Median time to first onset of AST or ALT elevation was 15 days (range: 3 days to 20.8 months).

Increased AST or ALT each led to dose interruption in 7% of patients and dose reduction in 5% and 9% of patients, respectively. Permanent discontinuation was caused by increased AST, ALT, or bilirubin each in 0.3% and by hepatotoxicity in 0.6% of patients.

Concurrent elevations in AST or ALT ≥3 times the ULN and total bilirubin ≥2 times the ULN, with normal alkaline phosphatase, occurred in 0.6% of patients.

Interstitial Lung Disease (ILD)/Pneumonitis: Severe, life-threatening, or fatal ILD or pneumonitis can occur. ILD/pneumonitis occurred in 2.3% of patients, including 1.1% Grade 3/4. One fatal ILD case occurred at the 400 mg daily dose. Median time to first onset of ILD/pneumonitis was 3.8 months (range: 12 days to 11.8 months).

ILD/pneumonitis led to dose interruption in 1.1% of patients, dose reduction in 0.6% of patients, and permanent discontinuation in 0.6% of patients.

QTc Interval Prolongation: QTc interval prolongation can occur, which can increase the risk for ventricular tachyarrhythmias (e.g., torsades de pointes) or sudden death. IBTROZI prolongs the QTc interval in a concentration-dependent manner.

In patients who received IBTROZI and underwent at least one post baseline ECG, QTcF increase of >60 msec compared to baseline and QTcF >500 msec occurred in 13% and 2.6% of patients, respectively. 3.4% of patients experienced Grade ≥3. Median time from first dose of IBTROZI to onset of ECG QT prolongation was 22 days (range: 1 day to 38.7 months). Dose interruption and dose reduction each occurred in 2.8% of patients.

Significant QTc interval prolongation may occur when IBTROZI is taken with food, strong and moderate CYP3A inhibitors, and/or drugs with a known potential to prolong QTc. Administer IBTROZI on an empty stomach. Avoid concomitant use with strong and moderate CYP3A inhibitors and/or drugs with a known potential to prolong QTc.​

Hyperuricemia: Hyperuricemia can occur and was reported in 14% of patients, with 16% of these requiring urate-lowering medication without pre-existing gout or hyperuricemia. 0.3% of patients experienced Grade ≥3. Median time to first onset was 2.1 months (range: 7 days to 35.8 months). Dose interruption occurred in 0.3% of patients.

Myalgia with Creatine Phosphokinase (CPK) Elevation: Myalgia with or without CPK elevation can occur. Myalgia occurred in 10% of patients. Median time to first onset was 11 days (range: 2 days to 10 months).

Concurrent myalgia with increased CPK within a 7-day time period occurred in 0.9% of patients. Dose interruption occurred in 0.3% of patients with myalgia and concurrent CPK elevation.

Skeletal Fractures: IBTROZI can increase the risk of fractures. ROS1 inhibitors as a class have been associated with skeletal fractures. 3.4% of patients experienced fractures, including 1.4% Grade 3. Some fractures occurred in the setting of a fall or other predisposing factors. Median time to first onset of fracture was 10.7 months (range: 26 days to 29.1 months). Dose interruption occurred in 0.3% of patients.

Embryo-Fetal Toxicity: Based on literature, animal studies, and its mechanism of action, IBTROZI can cause fetal harm when administered to a pregnant woman.

ADVERSE REACTIONS
Among patients who received IBTROZI, the most frequently reported adverse reactions (≥20%) were diarrhea (64%), nausea (47%), vomiting (43%), dizziness (22%), rash (22%), constipation (21%), and fatigue (20%). ​

The most frequently reported Grade 3/4 laboratory abnormalities (≥5%) were increased ALT (13%), increased AST (10%), decreased neutrophils (5%), and increased creatine phosphokinase (5%). ​

DRUG INTERACTIONS

Strong and Moderate CYP3A Inhibitors/CYP3A Inducers and Drugs that Prolong the QTc Interval: Avoid concomitant use.
Gastric Acid Reducing Agents: Avoid concomitant use with PPIs and H2 receptor antagonists. If an acid-reducing agent cannot be avoided, administer locally acting antacids at least 2 hours before or 2 hours after taking IBTROZI.
OTHER CONSIDERATIONS

Pregnancy: Please see important information in Warnings and Precautions under Embryo-Fetal Toxicity. ​
Lactation: Advise women not to breastfeed during treatment and for 3 weeks after the last dose.
Effect on Fertility: Based on findings in animals, IBTROZI may impair fertility in males and females. The effects on animal fertility were reversible.
Pediatric Use: The safety and effectiveness of IBTROZI in pediatric patients has not been established.
Photosensitivity: IBTROZI can cause photosensitivity. Advise patients to minimize sun exposure and to use sun protection, including broad-spectrum sunscreen, during treatment and for at least 5 days after discontinuation.
Please see accompanying full Prescribing Information.

On September 19. 2025 Precision Biologics, Inc. reported that in vitro and in vivo efficacy of the novel ADC, using its anti-core 2 O-glycans anti-human carcinoma mAb PB-223 (PB-vcMMAE-5), against human ovarian cancer expressing truncated core 2 O-glycans will be presented in a poster at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Special Conference in Cancer Research: Advances in Ovarian Cancer Research on September 20th, 2025, Grand Hyatt Denver, Denver, Colorado, USA (Press release, Precision Biologics, SEP 19, 2025, View Source [SID1234656116]).

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Poster title: In vitro and in vivo efficacy of the antibody-drug-conjugate (ADC) PB-vcMMAE-5 against human ovarian cancer expressing truncated core 2 O-glycans

The presentation of the poster will be made in person on the following date and location:

Saturday, September 20, 6:30 p.m. – 8:00 p.m.

Grand Hyatt Denver, Denver, Colorado, USA

Poster Section: B

Abstract Control Number: B068

BACKGROUND:

Ovarian cancers remain largely unresponsive to immune checkpoint inhibitors, in part due to their ability to suppress the cytotoxic activity of immune cells infiltrating the tumor microenvironment. One of the disrupted pathways in these cancers is O-glycosylation, a feature particularly associated with ovarian cancer progression, metastasis and poor prognosis. This underscores the urgent need for alternative therapeutic strategies. We developed an ADC, designated PB-vcMMAE-5, composed of the following:

The mAb: We used PB-223, an innovative mAb developed through affinity maturation of mAb NEO-102 (Ensituximab), a chimeric human IgG1 mAb that targets truncated core 2 O-glycans, specifically expressed by cancer cells and not by healthy tissues. The binding affinity of PB-223 for its target was improved, compared to NEO-102, by optimizing its VH and VL sequences through Fast Screening for Expression Biophysical Properties and Affinity. PB-223 demonstrated a binding affinity (KD) at least 4-fold lower than NEO-102, indicating stronger tumor binding. PB-223 does not bind to normal tissues and it can be internalized into human cancer cell lines expressing its target.

The payload: Monomethyl auristatin E (MMAE) was used as payload. MMAE is a potent antimitotic agent that inhibits cell division by blocking the polymerization of tubulin and is the most common ADC payload used to be linked to antibodies in clinical development for oncologic applications.

The linker: mc-vc-PABc was used as a cleavable linker. PB-223 was conjugated to the linker-payload through a cysteine-based conjugation method.
STUDY PRESENTED AT AACR (Free AACR Whitepaper) Special Conference in Cancer Research: Advances in Ovarian Cancer Research, 2025

After development of the ADC PB-vcMMAE-5, we evaluated its efficacy in vitro and in vivo

In vitro efficacy: The in vitro cytotoxicity of PB-vc-MMAE-5 was tested in four human cancer cell lines: triple-negative breast cancer (HCC1937, MDA-MB-231), ER+/PR+/HER2+ breast cancer (BT474), and ovarian cancer (OV-90). Cells were treated with varying ADC concentrations for 5 days.
This study shows that PB-vcMMAE-5 effectively killed all cell lines tested.
At the highest concentration, the percentage of cell killing for PB-vcMMAE-5 was 52.72% in HCC1937 and 88.36% in MDA-MB-231.
At the highest concentration, the percentage of cell killing for PB-vcMMAE-5 was 92.51% in OV-90 and 83.22% in BT474.
In contrast, naked PB-223 mAb showed no killing in all cell lines tested

In vivo safety: In a study presented in April 2025, at AACR (Free AACR Whitepaper) Annual Meeting 2025, we showed that PB-vcMMAE-5 was well tolerated in rats. No sign of distress nor loss of body weight were observed after administration. In this study we confirm the same pattern in mice. NOD-SCID mice bearing OV-90 xenografts were treated with weekly doses of PBS, MMAE alone, or PB-vc-MMAE-5 (1, 3, 6, or 9 mg/kg) for five weeks. Animal body weight was monitored regularly, twice a week, as an indirect measure of toxicity. The ADC PB-vcMMAE-5 was well tolerated in mice. No sign of distress and loss of body weight were observed

No significant hematological or pathological changes were detected in the liver, spleen, brain, or heart of mice treated with efficacious doses of the ADC compared with controls.

In vivo efficacy: The efficacy of the ADC PB-vcMMAE-5 was assessed in OV-90 subcutaneous xenograft model established in NOD-SCID mice. The ADC PB-vcMMAE-5 was administered intravenously at doses 1, 3, 6 or 9 mg/kg, once per week for five weeks.

On day 31 from first ADC infusion, most alive mice were sacrificed, and tumors were excised for histological analysis using Ki-67 staining to assess proliferating viable tumor cells. To further assess systemic toxicity and prolonged efficacy, three mice each from the 6 and 9 mg/kg groups were followed to day 45.

Data presented in this study show that PB-vcMMAE-5 at 1 mg/kg did not significantly reduce tumor volume compared with PBS, whereas PB-vcMMAE-5 at 6 and 9 mg/kg induced robust reduction of tumor volume.

In addition, analysis of tumor viability at day 45 (Ki67 H-score) showed no tumor activity in mice treated with PB-vcMMAE-5 at 9 mg/kg
Findings from this study showed that PB-vcMMAE-5 can kill human cancer cells expressing PB-223’s target, is not toxic in vivo in mice and is highly effective in vivo at 9 mg/kg in NOD-SCID mice bearing human ovarian cancer. In addition, in a poster presented at AACR (Free AACR Whitepaper) Annual Meeting 2025 we reported that PB-vcMMAE-5 is stable in human plasma.

All these data suggest that PB-vcMMAE-5 has promising potential as a therapeutic option for human ovarian tumors and for a range of human malignancies expressing core 2 O-glycans.