On December 21, 2022 NovaRock Biotherapeutics Limited announced today that the U.S. Food and Drug Administration (FDA) has cleared its investigational new drug (IND) application for NBL-020, a tumor necrosis factor receptor 2 (TNFR2) antibody for the treatment of advanced solid tumors (Press release, NovaRock Biotherapeutics, DEC 21, 2022, View Source [SID1234625494]). The Phase I clinical trials will evaluate safety, tolerability and pharmacokinetics of NBL-020.

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About NBL-020

TNFR2 belongs to the TNF receptor (TNFR) superfamily and promotes tumor progression directly or indirectly by maintaining an immune-suppressed microenvironment for tumor cells via various signaling pathways. It stimulates various immune suppressive cell types, including regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs) and can act as an oncogene. Inhibition of highly suppressive Tregs and MDSCs using TNFR2 antibodies in TME is a promising novel strategy for the treatment of advanced solid tumors.

NBL-020 is a fully human antibody against TNFR2 discovered and developed from NovaRock’s proprietary AFIS platform. Preclinical studies have demonstrated that NBL-020 has an excellent safety profile, high affinity to target cells and potent anti-tumor activity. NBL-020 inhibits tumor growth and prolongs survival as a single agent or in combination with anti-PD1 antibodies in both PD-1 sensitive and PD-1 resistant syngeneic models. Although PD-1/PD-L1 inhibitors have made remarkable breakthroughs in solid tumor treatment. There are still significant unmet medical needs for PD-1/PD-L1 resistant/refractory tumors. NBL-020 offers potential advantages to treat anti-PD-1/PDL1 resistant and PD-1 refractory patients.

NovaRock also filed an IND application to National Medical Products Administration (NMPA) in PRC in November 2022.

On December 21, 2022 NeuBase Therapeutics, Inc. (Nasdaq: NBSE) ("NeuBase" or the "Company"), a biotechnology platform company Drugging the Genome to address disease at the base level using a new class of precision genetic medicines, reported its financial results for the fiscal year ended September 30, 2022, and other recent developments (Press release, NeuBase Therapeutics, DEC 21, 2022, View Source [SID1234625493]).

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"Fiscal year 2022 was a challenging period in our Company’s history as we faced a tightening of the broader capital markets for small biotech companies. To address this reality, we made the decision to reduce internal investments in our gene silencing programs in myotonic dystrophy type 1 (DM1), Huntington’s disease (HD) and cancers driven by common KRAS gene mutations, which were entering more expensive development stages. In order to keep building momentum for these programs as they move into the clinic and beyond, we are pursuing collaborative initiatives, including partnerships. We believe potential collaborators will be attracted by the important new exploratory toxicology data in non-human primates (NHP) and rodents we generated in our DM1 program, and new three-month NHP pharmacokinetic data, illustrating that we can deliver pharmacologically effective amounts of our development candidate to tissues affected in DM1 patients with doses under the maximum tolerated doses, possibly unlocking a path to an Investigational New Drug (IND) filing and human clinical trials," stated Dietrich A. Stephan, Ph.D., Founder and Chief Executive Officer of NeuBase.

"Our technology platform is unique in that it allows us to engage the double stranded genome in a sequence selective manner to modulate machinery that controls gene function. We have now illustrated the capability to silence disease-gene output in various high-value indications. As mentioned, we are focused on moving these programs forward via partnerships. Our technology has also been repeatedly published in journals such as Nature and Science to perform ‘nuclease free’ in vivo gene editing to restore healthy gene function. In the future, we expect to develop the capability to increase gene output to address loss-of-function mutations. It is this ability to address the three major causal mechanisms behind genetic diseases that promises a unified and scalable approach to addressing disease in the future. FY2022 is a turning point as we take the next step in the expansion of the capabilities of the platform and expect to generate an exciting next generation of therapies capable of addressing various high-value genetic mutations."

"The excitement around our gene editing technology is driven by our ability to achieve precise repair of a diverse set of mutations in the genome without the need to deliver nucleases, such as modified bacterial CRISPR/Cas enzymes. To achieve this, we create platform-derived compounds that target a mutation, without the requirement for a flanking protospacer adjacent motif (PAM) sequence, and recruit the cell’s own DNA repair machinery to correct transition, transversion, insertion and deletion mutations, thus potentially enabling correction of up to 90% of all known pathogenic mutations. The system utilizes four layers of sequence selectivity to dramatically increase fidelity and reduce or eliminate off-target edits. A low immunogenicity profile alongside low toxicity due to a lack of double-stranded breaks enables the potential for repeat dosing to compensate for tissue turnover and achieve requisite editing efficiencies needed for clinical benefit. We plan to use non-viral delivery technologies to further bolster the ability to repeatedly dose without generating an acquired immune response, to ensure durable disease management. This editing approach leverages machinery that is used up to a million times a day, in each of the trillions of cells in the human body, to ensure the fidelity of our hereditary information, speaking to why the fidelity metrics that have been published using our technology significantly outperform the base and prime editors, and position the system favorably for in vivo applications. Our PATrOL editing technology recently attracted a global healthcare company to collaborate with us in a research agreement to evaluate three monogenic genetic diseases."

"As we look ahead to fiscal year 2023, we expect to announce partnerships that move our gene silencing programs forward while ensuring that learnings and validating data are available to the Company so we can continue to improve our platform performance over time. We also expect to announce an expanded pipeline that includes gene editing programs targeting prevalent mutations that cannot be edited by base editors. Throughout calendar year 2023, we anticipate sharing data on ex vivo and in vivo editing results against high-value genetic mutations, together with associated performance metrics such as fidelity and efficiency," concluded Dr. Stephan.

Fourth Quarter of Fiscal Year 2022 and Recent Operating Highlights

R&D Expansion to Include Gene Editing: The Company announced plans to expand its R&D focus to include the advancement of the differentiated gene editing capabilities of the Company’s PATrOL platform; currently identifying and evaluating multiple indications for possible future development; further details expected to be provided during fiscal year 2023 regarding the Company’s gene editing pipeline.
Research Agreement: In line with the expansion of NeuBase’s focus to include the advancement of its platform into gene editing, the Company announced a research agreement with a global healthcare company, pursuant to which the global healthcare company will evaluate the PATrOL platform for three monogenic genetic diseases and collaborate with NeuBase on the evaluation of drug candidates for three undisclosed indications. The global healthcare company will have the exclusive opportunity, subject to certain terms and conditions, to license and develop the drug candidates created under this research evaluation agreement.
Gene Silencing Pipeline Strategy: The Company is actively pursuing collaborative initiatives, including partnerships, for its DM1, HD, and KRAS (G12D and G12V) programs. Preclinical activities for all three of these programs have been deferred, and plans to submit an IND application for DM1 to the U.S. Food and Drug Administration (FDA) are on hold.
Corporate Restructuring: The Company completed a workforce reduction of approximately 60% and implemented other cost reduction plans to extend its cash runway into the second quarter of calendar year 2024 based on current operating plans and estimates.
Board of Directors Update: Dov A. Goldstein, M.D. was appointed Chairperson of the Company’s Board of Directors effective October 14, 2022.
Financial Results for the Fiscal Year Ended September 30, 2022

As of September 30, 2022, the Company had cash and cash equivalents of approximately $23.2 million, compared with approximately $52.9 million as of September 30, 2021.
NeuBase estimates its current cash and cash equivalents are sufficient to fund currently planned operating and capital expenditures into the second quarter of calendar year 2024.
For the fiscal year ended September 30, 2022, the Company reported a net loss of approximately $33.8 million, or a net loss of $1.04 per share, compared with a net loss of approximately $25.4 million, or a net loss of $0.93 per share, for the same period last year.
For the fiscal year ended September 30, 2022, total operating expenses were approximately $33.3 million, consisting of approximately $11.9 million in general and administrative expenses and $21.4 million of research and development expenses. This compares with total operating expenses of approximately $26.6 million for the same period last year, consisting of approximately $12.2 million in general and administrative expenses, $11.5 million in research and development expenses and $2.9 million in research and development expenses related to the acquisition of assets of Vera Therapeutics, Inc.

On December 21, 2022 NANOBIOTIX (Euronext: NANO –– NASDAQ: NBTX – the ‘‘Company’’), a late-clinical stage biotechnology company pioneering physics-based approaches to expand treatment possibilities for patients with cancer, reported that it has ended the liquidity contract signed on October 23, 2012 with Gilbert Dupont (Press release, Nanobiotix, DEC 21, 2022, View Source [SID1234625492]). The termination is effective from December 20th, 2022, after the close of Euronext market.

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On the termination date of this contract, the following assets appeared on the liquidity account:

22,118 shares
€71,489.96 in cash
As a reminder, for the latest half-year statement as of June 30, 2022, the following assets appeared on the liquidity account:

25,706 shares
€ 60,051.07 in cash
And between July 1, 2022, and December 20, 2022, included:

Buy side Traded volume:
303,404 shares € 1,157,145.04 1,274 transactions
Sell side Traded volume:
306,992 shares € 1,168,583.92 990 transactions
Upon initiation of the liquidity contract, the following assets were made available:

0 share
€ 300,000.00 in cash

On December 21, 2022 Moleculin Biotech, Inc., (Nasdaq: MBRX) (Moleculin or the Company), a clinical stage pharmaceutical company with a broad portfolio of drug candidates targeting highly resistant tumors and viruses, reported that it has received approval from the Agenzia Italiana del Farmaco (AIFA, the Italian Medicines Agency competent authority) and the Istituto Superiore di Sanità (ISS, the Italian National Institute of Health) for its Phase 1/2 trial evaluating Annamycin in combination with Cytarabine (Ara-C) in the treatment of subjects with AML who are refractory to or relapsed after induction therapy (MB-106) (Press release, Moleculin, DEC 21, 2022, View Source [SID1234625491]). This adds to the approval the Company already has in Poland where three sites are currently open and recruiting subjects. Additionally, the Company has ongoing efforts to open additional clinical sites in Poland and Italy and gain approval to proceed in other European countries for the MB-106 clinical trial to potentially improve recruitment rates.

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"We are pleased to receive authorization to expand our MB-106 trial into Italy. This marks an important milestone in the global expansion of our AML development program. Based on the encouraging data seen to date from the successfully concluded single agent trials, we remain very optimistic in Annamycin’s potential to treat refractory or relapsed AML in combination with Cytarabine. We are committed to driving enrollment and our team is working diligently to bring additional sites online and enroll subjects for the study," commented Walter Klemp, Chairman and CEO of Moleculin. He continued, "In Poland we expect the first subject to be treated in MB-106 to be in the near term."

Annamycin is the Company’s next-generation anthracycline that has been designed to be non-cardiotoxic and has been shown in animal models to accumulate in the lungs at up to 30-fold the level of doxorubicin (a commonly prescribed anthracycline), as well as demonstrating the ability to avoid the multidrug resistance mechanisms that typically limit the efficacy of doxorubicin and other currently prescribed anthracyclines. Annamycin is currently in development for the treatment of relapsed or refractory AML and STS lung metastases and the Company believes it may have the potential to treat additional indications.

The Phase 1/2 MB-106 trial is an open label trial that builds on the safety and dosage data from the two successfully concluded single agent Annamycin AML Phase 1 trials (MB-104 and MB-105) conducted in the U.S. and Europe. Additionally, the preclinical animal data from sponsored research demonstrated Annamycin in combination with Cytarabine had a 68% improvement in the median overall survival (OS) compared to Annamycin as a single agent and a 241% increase in OS compared to Cytarabine alone.1 Subject enrollment and screening for the MB-106 trial is underway and the Company expects to initiate subject treatment in the near term and the first subject to be treated in Italy in the first quarter of 2023.

1 Zal T, Zielinski R, Grela K, Cardenas-Zuniga R, Skora S, Fokt I, Zal A, Andreeff M, Gil L Shephard R, Priebe W, High Efficacy of Liposomal Annamycin (L-ANN) in Combination with Cytarabine in Syngeneic p53-Null AML Mouse Model, Blood (2020) 136 (Supplement 1): 6-7. View Source

Annamycin currently has Fast Track Status and Orphan Drug Designation from the US Food and Drug Administration (FDA) for the treatment of STS lung metastases and the treatment of relapsed or refractory AML. For more information about the MB-106 Phase 1/2 trial, visit clinicaltrialsregister.eu and reference EudraCT 2020-005493-10 or clinicaltrials.gov and reference NCT05319587.

On December 21, 2022 AstraZeneca and Merck (NYSE: MRK), known as MSD outside of the United States and Canada, reported that LYNPARZA has been approved in the European Union (EU) in combination with abiraterone and prednisone or prednisolone for the treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC) in whom chemotherapy is not clinically indicated (Press release, Merck & Co, DEC 21, 2022, View Source [SID1234625490]).

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This approval by the European Commission follows the positive recommendation from the Committee for Medicinal Products for Human Use received in November this year and was based on the Phase 3 PROpel trial, results of which were published in NEJM Evidence in June 2022.

In PROpel, LYNPARZA in combination with abiraterone and prednisone or prednisolone reduced the risk of disease progression or death by 34% (HR=0.66 [95% CI, 0.54-0.81]; p<0.0001) versus placebo plus abiraterone and prednisone or prednisolone, based on investigator assessment. Median radiographic progression-free survival (rPFS) was 24.8 months for the LYNPARZA plus abiraterone arm (95% CI, 20.5, 27.6) versus 16.6 months for the placebo plus abiraterone arm (95% CI, 13.9, 19.2). A planned sensitivity analysis by blinded independent central review was consistent with the investigator-based analysis, with a median rPFS of 27.6 months for the LYNPARZA plus abiraterone arm compared to 16.4 months for the placebo plus abiraterone arm.

Interim results for the key secondary efficacy endpoint of overall survival (OS) did not reach statistical significance, with an event rate of 37.1% in the LYNPARZA plus abiraterone arm versus 43.1% in the placebo plus abiraterone arm at the time of the analysis (HR=0.83 [95% CI, 0.66-1.03]).

The safety and tolerability of LYNPARZA in combination with abiraterone and prednisone or prednisolone was generally consistent with that of the individual medicines. Approximately 16% of patients who received LYNPARZA in combination with abiraterone and prednisone or prednisolone discontinued treatment due to an adverse event (AE). As previously reported, based on an analysis from the PROpel trial presented earlier this year at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary Cancers Symposium, the most common AEs (≥20%) were anemia (46%), fatigue (37%) and nausea (28%). Grade ≥3 AEs were anemia (15%), hypertension (4%), urinary tract infection (2%), fatigue (2%), decreased appetite (1%), vomiting (1%), back pain (1%), diarrhea (1%) and nausea (0.3%).

Prostate cancer is the most commonly diagnosed cancer in men in Europe, with an estimated 473,000 cases and 108,000 deaths in 2020. Approximately 10-20% of patients with prostate cancer are estimated to develop castration-resistant prostate cancer (CRPC) within five years, with at least 84% of these patients presenting with metastases at the time of CRPC diagnosis. Patients diagnosed with advanced prostate cancer have a particularly poor prognosis, with a five-year relative survival rate of about 30%, compared to patients diagnosed with earlier stages of the disease, with a five-year relative survival rate of more than 99%.

Noel Clarke, urological surgeon and professor of urological oncology at Manchester’s Christie/Salford Royal Hospitals and Manchester University, a senior investigator of the PROpel trial, said, "The results of the PROpel Phase 3 trial of olaparib in combination with abiraterone as a first-line treatment show that this therapeutic combination can provide significant clinical benefit to patients with mCRPC. Patients with this condition in the EU will now, for the first time, have the opportunity to benefit from this new treatment combination."

Dave Fredrickson, executive vice president, oncology business unit, AstraZeneca, said, "Many patients with mCRPC are only able to receive one line of active therapy, as the disease can progress quickly. LYNPARZA in combination with abiraterone has been shown to reduce the risk of disease progression by 34% versus the standard of care treatment in the PROpel trial. Moreover, the combination of LYNPARZA with abiraterone as a first-line treatment expands the use of LYNPARZA to a broader group of mCRPC patients than those treated with LYNPARZA alone in the second-line setting in the PROfound trial. Today’s approval marks a significant advance toward addressing the unmet need of patients with mCRPC in the EU."

Dr. Eliav Barr, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories, said, "Merck is committed to developing new treatment options for patients with mCRPC, a complex disease that urgently needs more therapies. This approval by the European Commission marks another step toward delivering on that commitment, and we look forward to extending the benefits of LYNPARZA to more patients with mCRPC in the EU."

Use of LYNPARZA in combination with abiraterone and prednisone or prednisolone is currently under review by the U.S. FDA for the treatment of adult patients with mCRPC. LYNPARZA is approved in the U.S. as monotherapy for patients with homologous recombination repair (HRR) gene-mutated mCRPC (BRCA-mutated and other HRR gene mutations) who have progressed following prior treatment with enzalutamide or abiraterone and in the EU, Japan and China for patients with BRCA-mutated mCRPC who have progressed following prior therapy that included a new hormonal agent (NHA). These approvals were based on the data from the Phase 3 PROfound trial.

About PROpel
PROpel is a randomized, double-blind Phase 3 trial testing the efficacy, safety and tolerability of LYNPARZA versus placebo when given in addition to abiraterone and prednisone or prednisolone in patients with mCRPC who had not received prior chemotherapy or NHAs in the mCRPC setting. The major efficacy outcome was rPFS as assessed by investigator per RECIST v1.1 and Prostate Cancer Working Group (bone) criteria. OS was an additional efficacy outcome measure.

IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
There are no contraindications for LYNPARZA.

WARNINGS AND PRECAUTIONS
Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in approximately 1.5% of patients exposed to LYNPARZA monotherapy, and the majority of events had a fatal outcome. The median duration of therapy in patients who developed MDS/AML was 2 years (range: <6 months to >10 years). All of these patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy.

Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood count weekly until recovery.

If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Discontinue LYNPARZA if MDS/AML is confirmed.

Pneumonitis: Occurred in 0.8% of patients exposed to LYNPARZA monotherapy, and some cases were fatal. If patients present with new or worsening respiratory symptoms such as dyspnea, cough, and fever, or a radiological abnormality occurs, interrupt LYNPARZA treatment and initiate prompt investigation. Discontinue LYNPARZA if pneumonitis is confirmed and treat patient appropriately.

Venous Thromboembolic Events (VTE): Including severe or fatal pulmonary embolism (PE) occurred in patients treated with LYNPARZA. VTE occurred in 7% of patients with metastatic castration-resistant prostate cancer who received LYNPARZA plus androgen deprivation therapy (ADT) compared to 3.1% of patients receiving enzalutamide or abiraterone plus ADT in the PROfound study. Patients receiving LYNPARZA and ADT had a 6% incidence of pulmonary embolism compared to 0.8% of patients treated with ADT plus either enzalutamide or abiraterone. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism, and treat as medically appropriate, which may include long-term anticoagulation as clinically indicated.

Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, LYNPARZA can cause fetal harm. A pregnancy test is recommended for females of reproductive potential prior to initiating treatment.

Females
Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months following the last dose.

Males
Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of LYNPARZA and to not donate sperm during this time.

ADVERSE REACTIONS—First-Line Maintenance BRCAm Advanced Ovarian Cancer
Most common adverse reactions (Grades 1-4) in ≥10% of patients who received LYNPARZA in the first-line maintenance setting for SOLO-1 were: nausea (77%), fatigue (67%), abdominal pain (45%), vomiting (40%), anemia (38%), diarrhea (37%), constipation (28%), upper respiratory tract infection/influenza/nasopharyngitis/bronchitis (28%), dysgeusia (26%), decreased appetite (20%), dizziness (20%), neutropenia (17%), dyspepsia (17%), dyspnea (15%), leukopenia (13%), urinary tract infection (13%), thrombocytopenia (11%), and stomatitis (11%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients who received LYNPARZA in the first-line maintenance setting for SOLO-1 were: decrease in hemoglobin (87%), increase in mean corpuscular volume (87%), decrease in leukocytes (70%), decrease in lymphocytes (67%), decrease in absolute neutrophil count (51%), decrease in platelets (35%), and increase in serum creatinine (34%).

ADVERSE REACTIONS—First-Line Maintenance Advanced Ovarian Cancer in Combination with Bevacizumab
Most common adverse reactions (Grades 1-4) in ≥10% of patients treated with LYNPARZA/bevacizumab and at a ≥5% frequency compared to placebo/bevacizumab in the first-line maintenance setting for PAOLA-1 were: nausea (53%), fatigue (including asthenia) (53%), anemia (41%), lymphopenia (24%), vomiting (22%), and leukopenia (18%). In addition, the most common adverse reactions (≥10%) for patients receiving LYNPARZA/bevacizumab irrespective of the frequency compared with the placebo/bevacizumab arm were: diarrhea (18%), neutropenia (18%), urinary tract infection (15%), and headache (14%).

In addition, venous thromboembolic events occurred more commonly in patients receiving LYNPARZA/bevacizumab (5%) than in those receiving placebo/bevacizumab (1.9%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients for LYNPARZA in combination with bevacizumab in the first-line maintenance setting for PAOLA-1 were: decrease in hemoglobin (79%), decrease in lymphocytes (63%), increase in serum creatinine (61%), decrease in leukocytes (59%), decrease in absolute neutrophil count (35%), and decrease in platelets (35%).

ADVERSE REACTIONS—Maintenance Recurrent Ovarian Cancer
Most common adverse reactions (Grades 1-4) in ≥20% of patients who received LYNPARZA in the maintenance setting for SOLO-2 were: nausea (76%), fatigue (including asthenia) (66%), anemia (44%), vomiting (37%), nasopharyngitis/upper respiratory tract infection (URI)/influenza (36%), diarrhea (33%), arthralgia/myalgia (30%), dysgeusia (27%), headache (26%), decreased appetite (22%), and stomatitis (20%).

Study 19: nausea (71%), fatigue (including asthenia) (63%), vomiting (35%), diarrhea (28%), anemia (23%), respiratory tract infection (22%), constipation (22%), headache (21%), decreased appetite (21%), and dyspepsia (20%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients who received LYNPARZA in the maintenance setting (SOLO-2/Study 19) were: increase in mean corpuscular volume (89%/82%), decrease in hemoglobin (83%/82%), decrease in leukocytes (69%/58%), decrease in lymphocytes (67%/52%), decrease in absolute neutrophil count (51%/47%), increase in serum creatinine (44%/45%), and decrease in platelets (42%/36%).

ADVERSE REACTIONS—Adjuvant Treatment of gBRCAm, HER2-Negative, High-Risk Early Breast Cancer
Most common adverse reactions (Grades 1-4) in ≥10% of patients who received LYNPARZA in the adjuvant setting for OlympiA were: nausea (57%), fatigue (including asthenia) (42%), anemia (24%), vomiting (23%), headache (20%), diarrhea (18%), leukopenia (17%), neutropenia (16%), decreased appetite (13%), dysgeusia (12%), dizziness (11%), and stomatitis (10%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients who received LYNPARZA in the adjuvant setting for OlympiA were: decrease in lymphocytes (77%), increase in mean corpuscular volume (67%), decrease in hemoglobin (65%), decrease in leukocytes (64%), and decrease in absolute neutrophil count (39%).

ADVERSE REACTIONS—gBRCAm, HER2-Negative Metastatic Breast Cancer
Most common adverse reactions (Grades 1-4) in ≥20% of patients who received LYNPARZA in the metastatic setting for OlympiAD were: nausea (58%), anemia (40%), fatigue (including asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract infection (27%), leukopenia (25%), diarrhea (21%), and headache (20%).

Most common laboratory abnormalities (Grades 1-4) in >25% of patients who received LYNPARZA in the metastatic setting for OlympiAD were: decrease in hemoglobin (82%), decrease in lymphocytes (73%), decrease in leukocytes (71%), increase in mean corpuscular volume (71%), decrease in absolute neutrophil count (46%), and decrease in platelets (33%).

ADVERSE REACTIONS—First-Line Maintenance gBRCAm Metastatic Pancreatic Adenocarcinoma
Most common adverse reactions (Grades 1-4) in ≥10% of patients who received LYNPARZA in the first-line maintenance setting for POLO were: fatigue (60%), nausea (45%), abdominal pain (34%), diarrhea (29%), anemia (27%), decreased appetite (25%), constipation (23%), vomiting (20%), back pain (19%), arthralgia (15%), rash (15%), thrombocytopenia (14%), dyspnea (13%), neutropenia (12%), nasopharyngitis (12%), dysgeusia (11%), and stomatitis (10%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients who received LYNPARZA in the first-line maintenance setting for POLO were: increase in serum creatinine (99%), decrease in hemoglobin (86%), increase in mean corpuscular volume (71%), decrease in lymphocytes (61%), decrease in platelets (56%), decrease in leukocytes (50%), and decrease in absolute neutrophil count (25%).

ADVERSE REACTIONS—HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer
Most common adverse reactions (Grades 1-4) in ≥10% of patients who received LYNPARZA for PROfound were: anemia (46%), fatigue (including asthenia) (41%), nausea (41%), decreased appetite (30%), diarrhea (21%), vomiting (18%), thrombocytopenia (12%), cough (11%), and dyspnea (10%).

Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients who received LYNPARZA for PROfound were: decrease in hemoglobin (98%), decrease in lymphocytes (62%), decrease in leukocytes (53%), and decrease in absolute neutrophil count (34%).

DRUG INTERACTIONS
Anticancer Agents: Clinical studies of LYNPARZA with other myelosuppressive anticancer agents, including DNA-damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.

CYP3A Inhibitors: Avoid coadministration of strong or moderate CYP3A inhibitors when using LYNPARZA. If a strong or moderate CYP3A inhibitor must be coadministered, reduce the dose of LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during LYNPARZA treatment.

CYP3A Inducers: Avoid coadministration of strong or moderate CYP3A inducers when using LYNPARZA.

USE IN SPECIFIC POPULATIONS
Lactation: No data are available regarding the presence of olaparib in human milk, its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise a lactating woman not to breastfeed during treatment with LYNPARZA and for 1 month after receiving the final dose.

Pediatric Use: The safety and efficacy of LYNPARZA have not been established in pediatric patients.

Hepatic Impairment: No adjustment to the starting dose is required in patients with mild or moderate hepatic impairment (Child-Pugh classification A and B). There are no data in patients with severe hepatic impairment (Child-Pugh classification C).

Renal Impairment: No dosage modification is recommended in patients with mild renal impairment (CLcr 51-80 mL/min estimated by Cockcroft-Gault). In patients with moderate renal impairment (CLcr 31-50 mL/min), reduce the dose of LYNPARZA to 200 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min).

INDICATIONS
LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:

First-Line Maintenance BRCAm Advanced Ovarian Cancer
For the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

First-Line Maintenance HRD-Positive Advanced Ovarian Cancer in Combination with Bevacizumab
In combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD)-positive status defined by either:

a deleterious or suspected deleterious BRCA mutation, and/or
genomic instability
Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

Maintenance Recurrent Ovarian Cancer
For the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy.

Adjuvant Treatment of gBRCAm, HER2-Negative, High-Risk Early Breast Cancer
For the adjuvant treatment of adult patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative high-risk early breast cancer who have been treated with neoadjuvant or adjuvant chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

gBRCAm, HER2-Negative Metastatic Breast Cancer
For the treatment of adult patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have been treated with chemotherapy in the neoadjuvant, adjuvant, or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

First-Line Maintenance gBRCAm Metastatic Pancreatic Cancer
For the maintenance treatment of adult patients with deleterious or suspected deleterious gBRCAm metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer
For the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

Please see complete Prescribing Information, including Medication Guide.

Financial considerations
Under the oncology collaboration with AstraZeneca and following this new approval for LYNPARZA, AstraZeneca will receive a $105 million payment from Merck.

About LYNPARZA (olaparib)
LYNPARZA is a first-in-class PARP inhibitor and the first targeted treatment to potentially exploit DNA damage response (DDR) pathway deficiencies, such as BRCA mutations, to preferentially kill cancer cells. Inhibition of PARP with LYNPARZA leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death. LYNPARZA is being tested in a range of tumor types with defects and dependencies in the DDR.

LYNPARZA, which is being jointly developed and commercialized by AstraZeneca and Merck, has a broad clinical trial development program, and AstraZeneca and Merck are working together to understand how it may affect multiple PARP-dependent tumors as a monotherapy and in combination across multiple cancer types.

About metastatic castration-resistant prostate cancer
Prostate cancer is the second most common cancer in male patients globally and is associated with a significant mortality rate. Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone. In patients with mCRPC, their prostate cancer grows and spreads to other parts of the body, despite the use of androgen-deprivation therapy to block the action of male sex hormones. Approximately 10-20% of patients with prostate cancer will develop CRPC within five years, with at least 84% of these patients presenting with metastases at the time of CRPC diagnosis. Of patients with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.