On December 9, 2025 Moleculin Biotech, Inc., (Nasdaq: MBRX) ("Moleculin" or the "Company"), reported an update on enrollment from its November report with an increase to 78% of the target number of subjects for the first planned interim unblinding of data having consented to its pivotal Phase 2B/3 "MIRACLE" study of Annamycin in combination with cytarabine for the treatment of adult patients with acute myeloid leukemia (AML) who are refractory to or relapsed (R/R) after induction therapy (R/R AML). This is up from 60% in its report in November. The targeted number for the first unblinding of data is 45 subjects. Additional subjects beyond the 78% mark continue to be identified by site investigators. This update is as of December 3, 2025, as identification and recruitment are ongoing. The Company expects to complete treatment of the first 45 subjects in the first quarter of 2026.

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Walter Klemp, Chairman and CEO of Moleculin, commented, "We continue to see blinded clinical activity tracking within our expected range, based on historical responses of the trial arm equivalents. With this update, we are quickly approaching the 45th subject, which we expect to be in the first quarter of 2026, to be treated and support the first unblinding in Part A of the MIRACLE trial shortly thereafter. This increase in subjects consented in one month is highly encouraging and demonstrates the enthusiasm of investigators around Europe and the US. Although we saw early enrollment at some sites in Europe being impacted by bed shortages, we are now seeing this situation improve in certain EU countries. Moving toward our first unblinding milestone, we are excited about Annamycin’s potential to fill a major gap in AML treatment. We believe we’re well on our way to determining if Annamycin has the potential to offer a much-needed, safer, and more effective option for patients facing this devastating disease."

Mr. Klemp continued, "While the 45 subject data is not designed to hold statistical significance, we expect to see that at least one of the two arms of Annamycin (at two different dosages) plus cytarabine outperforms cytarabine plus placebo, the control arm. That could be a strong indicator that the MIRACLE trial is on track to support approval of Annamycin. We will continue to recruit the remaining 45 subjects for the full 90 subjects of Part A while we are unblinding the first 45 subjects. The second unblinding should provide enough data to decide on which dose of Annamycin to proceed with into Part B of the MIRACLE trial."

MIRACLE Trial Progress and Next Steps

The MIRACLE study (derived from Moleculin R/R AML AnnAraC Clinical Evaluation) is a Phase 2B/3, global multi-center, randomized, double-blind, placebo-controlled, adaptive designed clinical trial whereby data from the 2B (Part A) portion will be combined with the Phase 3 (Part B) portion for purposes of measuring its primary efficacy endpoint. The protocol for the MIRACLE trial allows for the unblinding of preliminary primary efficacy data (Complete Remission or CR) and safety/tolerability of the three arms at 45 subjects, in addition to the conclusion of Part A (90 subjects). The first early unblinding will yield 30 subjects treated with Annamycin (190mg/m2 and 230 mg/m2) in combination with HiDAC and 15 subjects treated with just HiDAC plus placebo. Before each unblinding, trial data will be subject to audit, database lock and review.

The currently consented subjects are from sites across seven countries, providing a diverse base of patient population. Subjects are identified, consented, screened, enrolled, treated and then evaluated in that order with subjects possibly withdrawing from the trial at any point of this process. The Company expects to reach the recruitment and treatment of the first 45 subjects in the first quarter of 2026 and to complete Part A of the MIRACLE trial with up to 90 patients within the first half of 2026.

For more information about the MIRACLE trial, visit clinicaltrials.gov and reference identifier NCT06788756. Additionally, the clinical trial in the EU is on euclinicaltrials.eu and the reference identifier there is 2024-518359-47-00.

Annamycin, also known by its non-proprietary name of naxtarubicin, currently has Fast Track Status and Orphan Drug Designation from the FDA for the treatment of relapsed or refractory acute myeloid leukemia, in addition to Orphan Drug Designation for the treatment of soft tissue sarcoma. Annamycin also benefits from composition of matter patent protection through 2040 with the potential to extend that protection as far as 2045. Furthermore, Annamycin has Orphan Drug Designation for the treatment of relapsed or refractory acute myeloid leukemia from the EMA.

(Press release, Moleculin, DEC 9, 2025, View Source [SID1234661315])

On December 9, 2025 Immix Biopharma, Inc. ("ImmixBio", "Company", "We" or "Us" or "IMMX"), a global leader in relapsed/refractory AL Amyloidosis, reported the closing of its previously announced underwritten registered offering of 19,117,646 shares of its common stock at a price to the public of $5.10 per share, and to certain investors in lieu of common stock, pre-funded warrants to purchase 490,196 shares of common stock at a price to the public of $5.09 per pre-funded warrant, which represents the per share public offering price for the common stock, less the $0.01 per share exercise price for each such pre-funded warrant. The net proceeds to Immix from the offering, after deducting the underwriting discounts, commissions and other offering expenses, were approximately $93.7 million.

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The financing includes leading U.S. biotechnology institutional investors and mutual funds.

Morgan Stanley acted as the sole book-running manager for the offering. Citizens Capital Markets and Mizuho acted as co-managers for the offering.

The securities in the registered offering were offered and sold pursuant to a "shelf" registration statement on Form S-3 (File No. 333-269100), including a base prospectus, filed with the U.S. Securities and Exchange Commission (the "SEC") on January 3, 2023, and declared effective on January 11, 2023. A prospectus supplement and accompanying prospectus describing the terms of the registered offering was filed with the SEC and is available on its website at www.sec.gov. Copies of the prospectus supplement and the accompanying prospectus relating to the offering may also be obtained from: Morgan Stanley & Co. LLC, attention: Prospectus Department, 180 Varick Street, 2nd Floor, New York, New York 10014, by phone: 1-866-718-1649 or by email: [email protected].

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

(Press release, Immix Biopharma, DEC 9, 2025, View Source [SID1234661314])

On December 9, 2025 Fennec Pharmaceuticals Inc. (NASDAQ:FENC; TSX: FRX), a specialty pharmaceutical company, reported the planned initiation of an investigator-sponsored study (IST) by City of Hope, a U.S. cancer research and treatment organization, to evaluate PEDMARK (sodium thiosulfate injection) for the prevention of cisplatin-induced ototoxicity (CIO) in adult men with stage II-III metastatic testicular germ cell tumors.

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"Cisplatin has transformed outcomes for patients with germ cell tumors, turning what was once a highly fatal disease into one of oncology’s true success stories. However, as many as four out of five survivors are left with permanent hearing loss that impacts their quality of life long after treatment ends.i Through this investigator-initiated study, City of Hope aims to better understand how protecting hearing can become an integral part of comprehensive cancer care," said Alexander Chehrazi-Raffle, M.D., City of Hope assistant professor, Department of Medical Oncology & Therapeutics Research, and principal investigator of the study.

PEDMARK is currently approved for pediatric patients one month of age and older with localized, non-metastatic solid tumors, and is also recognized by the National Comprehensive Cancer Network with a 2A recommendation for use in adolescent and young adult patients.

"Initiation of this study by City of Hope reflects the growing clinical interest in addressing the burden of hearing loss among patients receiving cisplatin-based chemotherapy, an indispensable treatment with high survival rates but significant long-term quality-of-life consequences," said Pierre S. Sayad, PhD, M.S., chief medical officer of Fennec Pharmaceuticals. "With cancer rates rising, especially among younger populations, the future of oncological care needs to focus on both survival and survivorship. Fennec is proud to see independent investigators driving important research that not only has the potential to change the standard of care for their patients today but also expand the evidence base for PEDMARK into metastatic disease, where cisplatin is widely used but hearing protection options remain limited."

Study Details:

City of Hope: Duarte, California:

Principal Investigator: Alexander Chehrazi-Raffle, M.D.

Title:

Testing the Addition of PEDMARK to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors.

Overview:

Phase I study (NCT07218913) to evaluate whether adding PEDMARK to standard of care cisplatin-based chemotherapy reduces drug-induced ear damage (ototoxicity) in men with stage II-III testicular germ cell tumors that have spread from where they first started (primary site) to other places in the body (metastatic).

Multiple other investigator-initiated studies have already been submitted to Fennec and are currently under review, with several others in advanced contracting or evaluation stages. These collaborations are expected to further strengthen Fennec’s clinical and commercial foundation. Additional details will be shared as these programs progress.

About Cisplatin-Induced Ototoxicity

Cisplatin and other platinum-based chemotherapies are widely used to treat solid tumors and have been vital in improving survival rates. Unfortunately, these life-saving treatments often result in permanent, irreversible hearing loss, also known as ototoxicity.ii

Hearing loss from cisplatin treatment is not rare. Studies show that between 60-90% of patients treated with cisplatin may develop hearing loss, depending upon the dose and duration of chemotherapyiii. Many of those treated with cisplatin will require lifelong hearing aids or cochlear implants, which can be helpful for some, but do not reverse the hearing loss and can be costly over time.iv Treatment-induced hearing loss can reduce quality of survivorship as it impacts many aspects of life, such as speech and language skills, academic performance, social-emotional development, career potential and the ability to live independently.v,vi While audiologic monitoring is recommended to help manage ototoxicity, it is currently underutilized in certain cancer patient populations.

PEDMARK (sodium thiosulfate injection)

PEDMARK is the first and only U.S. Food and Drug Administration (FDA) approved therapy indicated to reduce the risk of ototoxicity associated with cisplatin treatment in pediatric patients 1 month of age and older with localized, non-metastatic, solid tumors. It is a unique formulation of sodium thiosulfate in single-dose, ready-to-use vials for intravenous use in pediatric patients. PEDMARK is also the first and only therapeutic agent with proven efficacy and safety data with an established dosing regimen, across two open-label, randomized Phase 3 clinical studies, the Children’s Oncology Group (COG) Protocol ACCL0431 and SIOPEL 6.

Additionally, PEDMARK is recommended for the adolescent and young adult (AYA) population by the National Comprehensive Cancer Network, or NCCN, with a 2A endorsement.

Approximately 500,000 patients in the U.S. are diagnosed annually with cancers that could be treated with a platinum-based chemotherapy.vii,viii The incidence of ototoxicity depends upon the dose and duration of chemotherapy, and many of those treated will require lifelong hearing aids. Until the FDA approval of PEDMARK, there were no preventative agents for this hearing loss. Patients with hearing loss resulting from cancer treatment have a statistically significant worse quality of life compared with peers who have no hearing loss.ixx

PEDMARK has been studied by co-operative groups in two Phase 3 clinical studies of survival and reduction of ototoxicity, COG ACCL0431 and SIOPEL 6. Both studies have been completed. The COG ACCL0431 protocol enrolled childhood cancers typically treated with intensive cisplatin therapy for localized and disseminated disease, including newly diagnosed hepatoblastoma, germ cell tumor, osteosarcoma, neuroblastoma, medulloblastoma, and other solid tumors. SIOPEL 6 enrolled only hepatoblastoma patients with localized tumors.

Indications and Usage

PEDMARK (sodium thiosulfate injection) is indicated to reduce the risk of ototoxicity associated with cisplatin in pediatric patients 1 month of age and older with localized, non-metastatic solid tumors.

Limitations of Use

The safety and efficacy of PEDMARK have not been established when administered following cisplatin infusions longer than 6 hours. PEDMARK may not reduce the risk of ototoxicity when administered following longer cisplatin infusions, because irreversible ototoxicity may have already occurred.

Important Safety Information

PEDMARK is contraindicated in patients with history of a severe hypersensitivity to sodium thiosulfate or any of its components.

Hypersensitivity reactions occurred in 8% to 13% of patients in clinical trials. Monitor patients for hypersensitivity reactions. Immediately discontinue PEDMARK and institute appropriate care if a hypersensitivity reaction occurs. Administer antihistamines or glucocorticoids (if appropriate) before each subsequent administration of PEDMARK. PEDMARK may contain sodium sulfite; patients with sulfite sensitivity may have hypersensitivity reactions, including anaphylactic symptoms and life-threatening or severe asthma episodes. Sulfite sensitivity is seen more frequently in people with asthma.

PEDMARK is not indicated for use in pediatric patients less than 1 month of age due to the increased risk of hypernatremia or in pediatric patients with metastatic cancers.

Hypernatremia occurred in 12% to 26% of patients in clinical trials, including a single Grade 3 case. Hypokalemia occurred in 15% to 27% of patients in clinical trials, with Grade 3 or 4 occurring in 9% to 27% of patients. Monitor serum sodium and potassium levels at baseline and as clinically indicated. Withhold PEDMARK in patients with baseline serum sodium greater than 145 mmol/L.

Monitor for signs and symptoms of hypernatremia and hypokalemia more closely if the glomerular filtration rate (GFR) falls below 60 mL/min/1.73m2.

Administer antiemetics prior to each PEDMARK administration. Provide additional antiemetics and supportive care as appropriate.

The most common adverse reactions (≥25% with difference between arms of >5% compared to cisplatin alone) in SIOPEL 6 were vomiting, nausea, decreased hemoglobin, and hypernatremia. The most common adverse reaction (≥25% with difference between arms of >5% compared to cisplatin alone) in COG ACCL0431 was hypokalemia.

Please see full Prescribing Information for PEDMARK at: www.PEDMARK.com.

(Press release, Fennec Pharmaceuticals, DEC 9, 2025, View Source [SID1234661313])

On December 9, 2025 Enterome, a clinical-stage company pioneering OncoMimics, a new class of off-the-shelf, multi-targeted in vivo immune therapies that induce a fast and potent expansion of memory T-cells to fight cancer, reported highly encouraging updated interim data from two cohorts of patients with low tumor-burden follicular lymphoma in the ongoing SIDNEY Phase 2 trial of its lead OncoMimics immunotherapy EO2463. The data were presented at the 67th meeting of the American Society for Hematology (ASH) (Free ASH Whitepaper) in Orlando, Florida.

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In Cohort 3, 100% (6/6) ORR was achieved with EO2463 plus rituximab as first-line treatment for previously untreated patients with low tumor-burden follicular lymphoma in need of treatment. In this feasibility assessment among the 6 patients, 5 had a complete response, and one a partial response. The median time to OR was 17 weeks, and to CR 18 weeks. These results marked an improvement over preliminary data submitted in the abstract for ASH (Free ASH Whitepaper).

"These new results are encouraging, despite the limited number of patients. The potent and rapid expansion of specific CD8 T-cells induced by EO2463 supports our understanding that OncoMimics trigger memory T-cells to generate sustained immune responses. The data suggest that the combination therapy given as a first-line treatment in patients with low-tumor burden follicular lymphoma should be evaluated in further studies," said Dr Stephen Smith, principal study investigator at the Fred Hutchinson Cancer Center, University of Washington, Seattle, WA, USA, who presented the data.

Data from Cohort 2 continue to show that EO2463 monotherapy produces excellent response rates when offered to patients with newly diagnosed follicular lymphoma or marginal zone lymphoma as an alternative to the standard watch-and-wait regime. Previously undisclosed data from 19 evaluable patients with follicular lymphoma showed a 52.6% ORR as of October. The ORR in the total group of 21 patients with follicular lymphoma or marginal zone lymphoma was 47.6% (14.3% CR and 33.3% PR). Current standard of practice is that, while patients often have visibly swollen lymph nodes, no treatment other than watchful waiting is suggested, as long as they do not show troublesome symptoms. Nevertheless, these patients often are understandably anxious about their disease, which progresses in the majority of cases, and then leads to a decreased quality of life.

"These new data with EO2463 contribute more compelling evidence and further strengthen our belief in the potential of our OncoMimics multi-targeted in vivo immune therapies for blood cancers. I’m looking forward to initiating Phase 3 testing of EO2463 in patients in the watch-and-wait setting in 2026," said Pierre Belichard, CEO of Enterome.

Follicular Lymphoma, one of several types of indolent Non-Hodgkin Lymphoma, is a difficult to treat chronic condition with relapses, characterized by slow progression and few symptoms, and reduced life expectancy. It is usually diagnosed by the appearance of swollen lymph nodes, and the early stages of the disease can be characterized by a lack of troublesome symptoms such as night sweats, fever or weight loss. There is a widespread consensus among leading investigators on the need for a well-tolerated and effective monotherapy to stop or slow progression for patients in the watch-and-wait setting.

EO2463 is an innovative, off-the-shelf OncoMimics active immunotherapy that combines four synthetic peptides. These non-self, microbial-derived peptides correspond to CD8 HLA-A2 epitopes that exhibit molecular mimicry with the B lymphocyte-specific lineage markers CD20, CD22, CD37, and CD268 (BAFF receptor). It also includes the helper peptide (CD4+ epitope) universal cancer peptide 2 (UCP2). The unique ability of EO2463 to selectively target multiple B cell markers enables the destruction of malignant B lymphocytes. By ensuring broad target coverage across malignant B cells, this novel approach aims to simultaneously improve safety and maximize efficacy, reducing the tumor cells’ capacity to develop immune-resistance mechanisms such as antigen escape.

OncoMimics consist of bacteria-derived peptide antigens that closely mimic tumor-associated antigens (TAAs) of solid tumors, or cell linage markers as for B cell lymphomas. These antigens induce a fast and potent in vivo expansion of cytotoxic memory CD8+ T cells that were primed by gut bacteria, and are cross-reactive with TAAs/B cell markers. Because the peptides are "non-self", OncoMimics avoid the self-tolerance that limits many cancer immunotherapies to enable rapid, potent, and durable responses to tumors. The synthetically produced peptides are designed in silico, mining Enterome’s proprietary database of 23 million commensal bacteria genes. Each product combines multiple high-affinity peptides to broaden target coverage and mitigate tumor heterogeneity.

OncoMimics are easy to manufacture, store, distribute and administer as an "off-the-shelf" subcutaneous injection. OncoMimics have achieved rapid and potent responses in clinical testing in over 230 patients to date, with a benign safety profile.

(Press release, Enterome, DEC 9, 2025, View Source [SID1234661312])

On December 9, 2025 Eli Lilly and Company (NYSE: LLY) reported results from the Phase 3 BRUIN CLL-313 clinical trial of Jaypirca (pirtobrutinib), a non-covalent Bruton tyrosine kinase (BTK) inhibitor, versus bendamustine plus rituximab (BR), in treatment-naïve patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) without 17p deletions. Pirtobrutinib met its primary endpoint demonstrating a reduction in the risk of disease progression or death by 80% (HR=0.20 [95% CI, 0.11-0.37]; p<0.0001).

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These data will be highlighted in a late-breaking oral presentation at the 67th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition taking place in Orlando, Florida and simultaneously published in the Journal of Clinical Oncology.

"The results from BRUIN CLL-313 show a significant effect size, among the most pronounced ever observed for a single agent BTK inhibitor in a front-line CLL study," said Wojciech Jurczak, MD, PhD, Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland. "The magnitude of the progression-free survival benefit, early overall survival trend and safety profile observed in BRUIN CLL-313 offer highly compelling evidence for the potential role of pirtobrutinib in treatment-naïve CLL."

BRUIN CLL-313 is the first prospective, randomized Phase 3 study examining the efficacy and safety of a non-covalent BTK inhibitor, pirtobrutinib, exclusively in patients with treatment-naïve CLL/SLL. BRUIN CLL-313 enrolled 282 patients with previously untreated CLL/SLL without del(17p), who were randomized 1:1 to receive continuous pirtobrutinib monotherapy (n=141) or BR (n=141). Crossover to the pirtobrutinib arm was allowed after independent review committee (IRC)-confirmed disease progression. The efficacy results are based on a July 11, 2025, data cutoff.

At a median follow-up of 28.1 months, the primary endpoint of IRC-assessed progression-free survival (PFS) was significantly improved with pirtobrutinib compared to BR (HR=0.20 [95% CI, 0.11–0.37]; p<0.0001). PFS results favored pirtobrutinib across all pre‑specified subgroups, including those with high-risk molecular features such as TP53 mutations, complex karyotype, and unmutated IGHV, and was consistently observed among investigator assessments.

Overall survival (OS), a key secondary endpoint, remains immature, but a trend favoring pirtobrutinib was observed (HR=0.257 [95% CI, 0.070–0.934]; p=0.0261) despite over half (52.9%) of patients treated with BR crossing over to receive pirtobrutinib after IRC-confirmed disease progression. Final testing of OS superiority is planned at a future date.

The overall safety profile of patients treated with pirtobrutinib in BRUIN CLL-313 was similar to previously reported trials. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 40.0% of patients who received pirtobrutinib versus 67.4% with BR. Fewer adverse event-related dose reductions (3.6% versus 31.1%) and TEAE-related discontinuations (4.3% versus 15.2%) were seen with pirtobrutinib versus BR. The incidence of all-grade and high-grade atrial fibrillation/flutter were similar between pirtobrutinib and BR, a notable finding as BR is not a regimen associated with increased risk of this side effect (1.4% versus 1.5% and 0.7% versus 0.8%, respectively).

"These findings support the potential use of pirtobrutinib in certain treatment-naïve patients and underscore its unique position as the only BTK inhibitor to show promise in treating both newly diagnosed patients with CLL or SLL and those who have progressed on a covalent BTK inhibitor," said Jacob Van Naarden, executive vice president and president, Lilly Oncology. "Alongside the recently presented BRUIN-CLL 314 results, we are excited about how collectively these data may advance the therapeutic landscape in treatment-naïve CLL and are hopeful we will receive regulatory approvals for pirtobrutinib in earlier disease settings sometime next year, further expanding treatment options for patients."

Lilly has begun submitting results from BRUIN CLL-313 and BRUIN CLL-314 studies to regulatory authorities with the goal of further expanding Jaypirca’s label into earlier lines of therapy.

Lilly is studying Jaypirca in CLL/SLL in multiple Phase 3 studies. Details on the trials can be found by visiting clinicaltrials.gov.

About BRUIN CLL-313
BRUIN CLL-313 is a Phase 3, global, randomized, open-label study of pirtobrutinib versus chemoimmunotherapy (bendamustine plus rituximab) in people with CLL/SLL without 17p deletions who have not been previously treated. The trial enrolled 282 patients who were randomized 1:1 to receive pirtobrutinib (200 mg orally, once daily) or bendamustine plus rituximab (BR) per labeled doses. BR is a chemoimmunotherapy regimen used in the treatment of CLL. The primary endpoint is PFS as assessed by blinded IRC. Secondary endpoints include investigator and IRC assessed overall response rate (ORR), duration of response (DoR), and PFS, OS, time to next treatment (TTNT), safety and tolerability and patient-reported outcomes (PRO).

About Jaypirca (pirtobrutinib)
Jaypirca (pirtobrutinib, formerly known as LOXO-305) (pronounced jay-pihr-kaa) is a highly selective (300 times more selective for BTK versus 98% of other kinases tested in preclinical studies), non-covalent (reversible) inhibitor of the enzyme BTK.1 BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL).2,3 Jaypirca is a U.S. FDA-approved oral prescription medicine, 100 mg or 50 mg tablets taken as a once-daily 200 mg dose with or without food until disease progression or unacceptable toxicity.

About Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are forms of slow-growing non-Hodgkin lymphoma that develop from white blood cells known as lymphocytes.4 CLL is one of the most common types of leukemia in adults.4 In the U.S., CLL accounts for about one-quarter of the new cases of leukemia and there will be approximately 23,690 new cases of CLL diagnosed this year.4,5 SLL is identical to CLL from a pathologic and immunophenotypic standpoint, with the main difference between them being the location of the cancer cells.4 In CLL, the cancer cells are present in the blood, and in SLL, the cancer cells are found in the lymph nodes.4

INDICATIONS FOR JAYPIRCA (pirtobrutinib)
Jaypirca is indicated for the treatment of

Adult patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have previously been treated with a covalent BTK inhibitor.
Adult patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor. This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical trial benefit in a confirmatory trial.
IMPORTANT SAFETY INFORMATION FOR JAYPIRCA (pirtobrutinib)

Infections: Fatal and serious infections (including bacterial, viral, fungal) and opportunistic infections occurred in Jaypirca-treated patients. Across clinical trials, Grade ≥3 infections occurred (25%), most commonly pneumonia (20%); fatal infections (5%), sepsis (6%), and febrile neutropenia (3.8%) occurred. In patients with CLL/SLL, Grade ≥3 infections occurred (32%), with fatal infections occurring in 8%. Opportunistic infections included Pneumocystis jirovecii pneumonia and fungal infection. Consider prophylaxis, including vaccinations and antimicrobial prophylaxis, in patients at increased risk for infection, including opportunistic infections. Monitor for signs and symptoms, evaluate, and treat. Based on severity, reduce dose, temporarily withhold, or permanently discontinue Jaypirca.

Hemorrhage: Fatal and serious hemorrhage has occurred with Jaypirca. Across clinical trials, major hemorrhage (Grade ≥3 bleeding or any central nervous system bleeding) occurred (2.6%), including gastrointestinal hemorrhage; fatal hemorrhage occurred (0.3%). Bleeding of any grade, excluding bruising and petechiae, occurred (16%). Major hemorrhage occurred when taking Jaypirca with (2.0%) and without (0.6%) antithrombotic agents. Consider risks/benefits of co-administering antithrombotic agents with Jaypirca. Monitor for signs of bleeding. Based on severity, reduce dose, temporarily withhold, or permanently discontinue Jaypirca. Consider withholding Jaypirca 3-7 days pre- and post-surgery based on surgery type and bleeding risk.

Cytopenias: Jaypirca can cause cytopenias, including neutropenia, thrombocytopenia, and anemia. Across clinical trials, Grade 3 or 4 cytopenias, including decreased neutrophils (27%), decreased platelets (13%), and decreased hemoglobin (11%), developed. Grade 4 decreased neutrophils (15%) and Grade 4 decreased platelets (6%) developed. Monitor complete blood counts regularly. Based on severity, reduce dose, temporarily withhold, or permanently discontinue Jaypirca.

Cardiac Arrhythmias: Cardiac arrhythmias occurred in patients taking Jaypirca. Across clinical trials, atrial fibrillation or flutter were reported in 3.4% of Jaypirca treated patients, with Grade 3 or 4 atrial fibrillation or flutter in 1.6%. Other serious cardiac arrhythmias such as supraventricular tachycardia and cardiac arrest occurred (0.4%). Cardiac risk factors such as hypertension or previous arrhythmias may increase risk. Monitor and manage signs and symptoms of arrhythmias (e.g., palpitations, dizziness, syncope, dyspnea). Based on severity, reduce dose, temporarily withhold, or permanently discontinue Jaypirca.

Second Primary Malignancies: Across clinical trials, second primary malignancies, including non-skin carcinomas, developed in 9% of Jaypirca-treated patients, most frequently non-melanoma skin cancer (4.4%). Other second primary malignancies included solid tumors (including genitourinary and breast cancers) and melanoma. Advise patients to use sun protection and monitor for development of second primary malignancies.

Hepatotoxicity, Including Drug-Induced Liver Injury (DILI): Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of DILI, has occurred in patients treated with BTK inhibitors, including Jaypirca. Evaluate bilirubin and transaminases at baseline and throughout Jaypirca treatment. For patients who develop abnormal liver tests after Jaypirca, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold Jaypirca. If DILI is confirmed, discontinue Jaypirca.

Embryo-Fetal Toxicity: Jaypirca can cause fetal harm. Administration of pirtobrutinib to pregnant rats caused embryo-fetal toxicity, including embryo-fetal mortality and malformations at maternal exposures (AUC) approximately 3-times the recommended 200 mg/day dose. Advise pregnant women of fetal risk and females of reproductive potential to use effective contraception during treatment and for one week after last dose.

Adverse Reactions (ARs) in Patients Who Received Jaypirca

The most common (≥30%) ARs in the pooled safety population of patients with hematologic malignancies (n=704) were decreased neutrophil count (54%), decreased hemoglobin (43%), decreased leukocytes (32%), fatigue (31%), decreased platelets (31%), decreased lymphocyte count (31%), calcium decreased (30%).

Mantle Cell Lymphoma

Serious ARs occurred in 38% of patients, with pneumonia (14%), COVID-19 (4.7%), musculoskeletal pain (3.9%), hemorrhage (2.3%), pleural effusion (2.3%), and sepsis (2.3%) occurring in ≥2% of patients. Fatal ARs within 28 days of last dose occurred in 7% of patients, most commonly due to infections (4.7%), including COVID-19 (3.1% of all patients).

Dose Modifications and Discontinuations Due to ARs: Dose reductions in 4.7%, treatment interruption in 32%, and permanent discontinuation of Jaypirca in 9% of patients. Permanent discontinuation in >1% of patients included pneumonia.

Most common ARs (≥15%) and Select Laboratory Abnormalities (≥10%) (all Grades %; Grade 3-4 %): hemoglobin decreased (42; 9), platelet count decreased (39; 14), neutrophil count decreased (36; 16), lymphocyte count decreased (32; 15), creatinine increased (30; 1.6), fatigue (29; 1.6), musculoskeletal pain (27; 3.9), calcium decreased (19; 1.6), diarrhea (19; -), edema (18; 0.8), dyspnea (17; 2.3), AST increased (17; 1.6), pneumonia (16; 14), bruising (16; -), potassium decreased (13; 1.6), sodium decreased (13; -), lipase increased (12; 4.4), ALT increased (11; 1.6), potassium increased (11; 0.8), alkaline phosphatase increased (11; -). Grade 4 laboratory abnormalities in >5% of patients included neutrophils decreased (10), platelets decreased (7), lymphocytes decreased (6).

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma from Single-Arm and Randomized Controlled Clinical Trials

Serious ARs occurred in 47-56% of patients across clinical trials. Serious ARs in ≥5% of patients in the single-arm trial were pneumonia (18%), COVID-19 (9%), sepsis (7%), febrile neutropenia (7%). Serious ARs in ≥3% of patients in the randomized controlled trial were pneumonia (21%), COVID-19 (5%), sepsis (3.4%). Fatal ARs within 28-30 days of last Jaypirca dose occurred in 8-11% of patients, most commonly due to infections (7-10%), including sepsis (5%), COVID-19 (2.7-5%), and pneumonia (3.4%).

Dose Modifications and Discontinuations Due to ARs: Dose reductions in 3.6-10%, treatment interruption in 42-51%, and permanent discontinuation of Jaypirca in 9-17% of patients. Permanent discontinuation in >1% of patients included second primary malignancy, pneumonia, COVID-19, neutropenia, sepsis, anemia, and cardiac arrythmias.

Most common ARs and Select Laboratory Abnormalities (≥20%) (all Grades %, Grade 3-4 %)–in a randomized controlled trial: neutrophil count decreased (54; 26), hemoglobin decreased (45; 10), platelet count decreased (37; 17), pneumonia (28; 16), ALT increased (25; 1.8), creatinine increased (25; -), calcium decreased (23; 0.9), sodium decreased (22; 0.9), bilirubin increased (21; 0.9), upper respiratory tract infections (21; 0.9); in a single-arm trial: neutrophil count decreased (63; 45), hemoglobin decreased (48; 19), calcium decreased (40; 2.8), fatigue (36; 2.7), bruising (36; -), cough (33; -), musculoskeletal pain (32; 0.9), platelet count decreased (30; 15), sodium decreased (30; -), COVID-19 (28; 7), pneumonia (27; 16), diarrhea (26; -), abdominal pain (25; 2.7), lymphocyte count decreased (23; 8), ALT increased (23; 2.8), AST increased (23; 1.9), creatinine increased (23; -), dyspnea (22; 2.7), hemorrhage (22; 2.7), lipase increased (21; 7), alkaline phosphatase increased (21; -), edema (21; -), nausea (21; -), pyrexia (20; 2.7), headache (20; 0.9). Grade 4 laboratory abnormalities in >5% of patients included neutrophils decreased (23).

Drug Interactions

Strong CYP3A Inhibitors: Concomitant use increased pirtobrutinib systemic exposure, which may increase risk of Jaypirca ARs. Avoid using strong CYP3A inhibitors with Jaypirca. If concomitant use is unavoidable, reduce Jaypirca dose according to approved labeling.

Strong or Moderate CYP3A Inducers: Concomitant use decreased pirtobrutinib systemic exposure, which may reduce Jaypirca efficacy. Avoid using Jaypirca with strong or moderate CYP3A inducers. If concomitant use with moderate CYP3A inducers is unavoidable, increase Jaypirca dose according to approved labeling.

Sensitive CYP2C8, CYP2C19, CYP3A, P-gp, or BCRP Substrates: Use with Jaypirca increased their plasma concentrations, which may increase risk of ARs related to these substrates for drugs sensitive to minimal concentration changes. Follow recommendations for these sensitive substrates in their approved labeling.

Use in Specific Populations

Pregnancy and Lactation: Due to potential for Jaypirca to cause fetal harm, verify pregnancy status in females of reproductive potential prior to starting Jaypirca. Presence of pirtobrutinib in human milk is unknown. Advise women to use effective contraception and to not breastfeed while taking Jaypirca and for one week after last dose.

Geriatric Use: In the pooled safety population of patients with hematologic malignancies, patients aged ≥65 years experienced higher rates of Grade ≥3 ARs and serious ARs compared to patients <65 years of age.

Renal Impairment: Because severe renal impairment increases pirtobrutinib exposure, reduce Jaypirca dose in these patients according to approved labeling.

PT HCP ISI MCL_CLL Q42025

Please see Prescribing Information and Patient Information for Jaypirca.

(Press release, Eli Lilly, DEC 9, 2025, View Source [SID1234661311])