Protara Therapeutics Announces Positive Preliminary Data from ADVANCED-1 Phase 1a Dose Escalation Trial of TARA-002 in NMIBC Supporting Advancement into Phase 2 Clinical Development

On April 28, 2023 Protara Therapeutics, Inc. (Nasdaq: TARA), a clinical-stage company developing transformative therapies for the treatment of cancer and rare diseases, reported positive preliminary results from the Phase 1a dose-escalation component of its ongoing ADVANCED-1 clinical trial of TARA-002, the Company’s investigational cell-based therapy, for the treatment of patients with high-grade non-muscle invasive bladder cancer (NMIBC) (Press release, Protara Therapeutics, APR 28, 2023, View Source [SID1234630674]). The clinical data indicate that TARA-002, a novel intravesical monotherapy, was generally well tolerated and showed anti-tumor activity in high-grade NMIBC patients. The data will be featured during a moderated poster session at the American Urological Association (AUA) 2023 Annual Meeting being held in Chicago from April 28, 2023 to May 1, 2023.

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"These promising results suggest TARA-002 may provide meaningful benefit to patients with NMIBC, who currently have limited treatment options," said Neal Shore, M.D., Medical Director, Carolina Urologic Research Center, Chief Medical Officer, GenesisCare US, and study investigator. "These data show favorable tolerability and initial evidence of anti-tumor activity, thus serving as an impetus to advance TARA-002 into larger, later-stage trials."

"We are highly encouraged by preliminary results from the dose-escalation component of ADVANCED-1 and look forward to deepening our understanding of TARA-002’s potential in the ongoing expansion trial, which is currently enrolling NMIBC patients with carcinoma in situ (CIS)," said Jathin Bandari, M.D., Chief Medical Officer of Protara Therapeutics. "We plan to initiate larger clinical trials in NMIBC patients with CIS who are Bacillus Calmette-Guérin (BCG)-naïve and BCG-unresponsive in the second half of this year."

Preliminary Results

TARA-002 was generally well tolerated at all three dose levels evaluated in the trial, and no dose limiting toxicities were observed. A maximum tolerated dose was not determined, and dose escalation remains ongoing in exploratory cohorts. The Company has selected the 40KE1 dose for use in subsequent clinical trials.
The majority of reported adverse events were Grades 1 and 2 across all dose levels, and treatment-related adverse events, as assessed by study investigators, were in line with typical responses to bacterial immunopotentiation, and included fatigue, headache, fever, and chills. The most common urinary symptoms were urinary urgency, urinary frequency, urinary tract pain/burning, incomplete emptying, and bladder spasm. Most bladder irritations resolved soon after administration or in a few hours to a few days.
A total of nine patients were enrolled in the study, including three patients with CIS who reached the three-month efficacy assessment. Of those three patients with CIS, one heavily pre-treated BCG-unresponsive patient achieved a complete response (CR) at the 20KE dose, and tumor regression was observed in the other two patients.
A copy of the AUA poster will be available in the Events and Presentations section of the Company’s website: View Source The Company plans to present complete results from the ADVANCED-1 study at a subsequent medical conference.

Patient enrollment is ongoing in the open-label expansion trial (ADVANCED-1EXP), which is evaluating intravesical TARA-002 at the 40KE dose in 12 CIS patients, including BCG-naïve, BCG-unresponsive, and BCG-inadequately treated patients.

Clinical Development Plan Update

Based on these results, Protara is advancing the clinical development of TARA-002 for the treatment of NMIBC. The Company plans to initiate ADVANCED-2, a Phase 1b/2 open-label trial evaluating intravesical TARA-002 in up to 102 patients with CIS. The Phase 1b trial is expected to enroll 27 patients with CIS (± Ta/T1), BCG-Naïve or BCG-experienced, who have not received intravesical BCG for at least 24 months prior to CIS diagnosis. The Phase 2 trial is expected to enroll 75 patients with BCG-unresponsive CIS (± Ta/T1). ADVANCED-2 is expected to initiate in the second half of 2023.

About ADVANCED-1

ADVANCED-1 is a Phase 1 dose-finding, open-label trial (NCT05085977) evaluating TARA-002 in treatment-naïve and treatment-experienced NMIBC patients with carcinoma in situ (CIS) and high-grade papillary tumors (Ta). In the initial dose escalation phase of the trial, patients received six weekly intravesical doses of TARA-002 evaluating the 10KE, 20KE and 40KE doses. The primary objective of the trial was to evaluate the safety, tolerability and preliminary signs of anti-tumor activity of TARA-002, with the goal of establishing a recommended dose for a future Phase 2 clinical trial.

About TARA-002

TARA-002 is an investigational cell therapy in development for the treatment of NMIBC and of LMs for which it has been granted Rare Pediatric Disease Designation by the U.S. Food and Drug Administration. TARA-002 was developed from the same master cell bank of genetically distinct group A Streptococcus pyogenes as OK-432, a broad immunopotentiator marketed as Picibanil in Japan and approved in Taiwan by Chugai Pharmaceutical Co., Ltd. Protara has successfully shown manufacturing comparability between TARA-002 and OK-432.

When TARA-002 is administered, it is hypothesized that innate and adaptive immune cells within the cyst or tumor are activated and produce a strong immune cascade. Neutrophils, monocytes and lymphocytes infiltrate the abnormal cells and various cytokines, including interleukins IL-2, IL-6, IL-8, IL-10, IL-12, interferon (IFN)-gamma, and tumor necrosis factor (TNF)-alpha are secreted by immune cells to induce a strong inflammatory reaction and destroy the abnormal cells.

About Non-Muscle Invasive Bladder Cancer

Bladder cancer is the 6th most common cancer in the United States, with NMIBC representing approximately 80% of bladder cancer diagnoses. Approximately 65,000 patients are diagnosed with NMIBC in the United States each year. NMIBC is cancer found in the tissue that lines the inner surface of the bladder that has not spread into the bladder muscle.

Update on FDA Advisory Committee Vote on LYNPARZA® (olaparib) Plus Abiraterone and Prednisone or Prednisolone in First-Line Metastatic Castration-Resistant Prostate Cancer

On April 28, 2023 Merck (NYSE: MRK), known as MSD outside of the United States and Canada, reported that the U.S. Food and Drug Administration’s (FDA) Oncologic Drugs Advisory Committee (ODAC), by a vote of 11 to 1 with one abstention, supported FDA approval of LYNPARZA plus abiraterone and prednisone or prednisolone (abi/pred) for the first-line treatment of adult patients with BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC) (Press release, Merck & Co, APR 28, 2023, View Source [SID1234630673]). The committee voted that FDA should restrict use of LYNPARZA plus abi/pred to these BRCAm mCRPC patients, recommending against approval beyond this patient population.

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In August 2022, the FDA accepted the supplemental New Drug Application for LYNPARZA plus abi/pred for priority review based on positive results from the pivotal Phase 3 PROpel trial, which were also published in NEJM Evidence. The ODAC provides the FDA with independent, expert advice and recommendations on marketed and investigational medicines for use in the treatment of cancer. The FDA is not bound by the committee’s guidance but takes its advice into consideration. AstraZeneca and Merck will continue to work with the FDA as the agency completes its review of the application.

Neal Shore, chief medical officer of urology and surgical oncology for GenesisCare, US and PROpel trial investigator, said, "Today’s recommendation by the ODAC is disappointing news for clinicians and prostate cancer patients alike. Preventing or delaying radiographic progression is an important clinical endpoint in assessing oncologic treatment and is very relevant to patients, their caregivers and their families. It is essential that physicians and their patients have an opportunity to choose treatment with the goal of optimizing cancer care outcomes."

Susan Galbraith, executive vice president, oncology R&D, AstraZeneca, said, "Novel treatments are urgently needed for patients with metastatic castration-resistant prostate cancer. While we are pleased with the recognition of the benefit of LYNPARZA plus abiraterone for patients with BRCA-mutated metastatic castration-resistant prostate cancer, we are disappointed with the outcome of today’s ODAC meeting. We strongly believe in the results of the PROpel trial, which demonstrated a clinically meaningful benefit for this combination in a broad population of patients regardless of biomarker status."

Eliav Barr, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories, said, "With the incidence and mortality of prostate cancer set to double in the coming decades, it is critical that we bring new treatment options with the potential to reduce the risk of disease progression or death to patients at the earliest possible moment in their care. Though we are pleased that the ODAC recommended LYNPARZA for patients with mCRPC who have BRCA mutations, we believe in the potential of LYNPARZA plus abi/pred for a broad range of patients with mCRPC, based on the results of PROpel. We look forward to the outcome of the FDA’s review of the application."

Results from the PROpel trial showed a statistically significant and clinically meaningful 34% reduction in the risk of radiographic disease progression or death with LYNPARZA plus abi/pred (HR=0.66 [95% CI, 0.54-0.81]; p<0.001) versus placebo plus abi/pred in patients with mCRPC. Median radiographic progression-free survival (rPFS) was 24.8 months versus 16.6 months, respectively.

Further results from the final pre-specified overall survival (OS) analysis were presented at the 2023 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Genitourinary Cancers Symposium (maturity 47.9%, HR=0.81 [95% CI, 0.67-1.00]; p=0.0544). While the observed 7.4-month numerical increase in median OS did not achieve statistical significance, the totality of the efficacy results from PROpel build on the meaningful gains achieved for patients in this setting versus patients treated with abi/pred alone, a current standard of care.

In exploratory analyses of the BRCAm subgroup, patients in the LYNPARZA plus abi/pred arm had fewer rPFS (HR=0.23 [95% CI, 0.12-0.43]) and OS (HR=0.29 [95% CI, 0.14-0.56]) events versus those receiving placebo plus abi/pred. In the subgroup of patients who tested negative for BRCAm by either a tumor tissue-based test or a circulating tumor DNA test, patients in the LYNPARZA plus abi/pred arm also had fewer rPFS events (HR=0.76 [95% CI, 0.61-0.94] versus those receiving placebo plus abi/pred, as well as modestly fewer OS events (HR=0.91 [95% CI, 0.73-1.13]).

The safety and tolerability of LYNPARZA plus abi/pred in PROpel was in line with that observed in prior clinical trials and the known profiles of the individual medicines. The most common adverse events (AEs) (≥20%) were anemia (49.7%), fatigue (38.7%), nausea (30.7%), back pain (21.6%) and diarrhea (20.6%). Grade ≥3 AEs were anemia (16.1%), hypertension (3.8%), urinary tract infection (2.5%), fatigue (2.5%), vomiting (1.5%), diarrhea (1.3%), decreased appetite (1%), back pain (1%) and nausea (0.3%). Approximately 17% of patients who received LYNPARZA in combination with abi/pred discontinued treatment due to an AE.

LYNPARZA in combination with abi/pred is approved in the European Union and several other countries for the treatment of adult patients with mCRPC based on the PROpel trial. In the U.S., LYNPARZA is currently approved for patients with homologous recombination repair gene-mutated mCRPC who have progressed following prior treatment with enzalutamide or abiraterone based on the Phase 3 PROfound trial. For that U.S. indication, patients are selected for therapy based on an FDA-approved companion diagnostic for LYNPARZA.

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 abi/pred in patients with mCRPC who had not received prior chemotherapy or new hormonal agents 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.

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 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. Of patients with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.

Isofol initiates preclinical evaluation of arfolitixorin with Oncosyne AS

On April 28, 2023 Isofol Medical AB (publ), (Nasdaq Stockholm: ISOFOL), reported that the company has initiated a preclinical research collaboration with the Norwegian biotech company Oncosyne AS, to evaluate the effect of the drug candidate arfolitixorin in different doses combined with the cancer drug 5-FU, among others (Press release, Isofol Medical, APR 28, 2023, View Source [SID1234630672]). This is an important step in the company´s previously communicated strategy to re-evaluate possible future tracks for arfolitixorin and to maximize the opportunities to take the drug candidate further toward potential market approval.

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Isofol, together with external experts, is conducting an extensive analysis of the data from the clinical phase III study, AGENT. In the study, arfolitixorin did not meet its goals and the study was terminated in 2022. The initial conclusions from the analysis indicate that the dose of arfolitixorin may have been too low to allow a fair comparison with the control group and that the substance may not have been administrated optimally. Arfolitixorin’s safety profile was a prioritized part of the analysis, and the company has not found any obstacles to proceed with the development of the drug candidate.

Based on the initial analysis of data from the AGENT study, Isofol intends to evaluate several doses of arfolitixorin in combination with 5-FU as well as other possible treatments, within a research collaboration with the Norwegian biotech company Oncosyne.

Oncosyne AS has developed a technology platform for preclinical testing in functional precision oncology, based on drug screening of the patient’s own cancer cells. The technology can be used in several stages of drug development from functional evaluation of drug activity to selection of patients for clinical trials.

" Initial outcomes from the comprehensive analysis of phase III data conducted in collaboration with leading external experts provide support for initiating a preclinical evaluation of the drug candidate. Oncosyne has developed a technology platform that quickly and cost-effectively can provide an answer to whether a different dosage regiment could strengthen the future potential of arfolitixorin," says Thomas Andersson, CEO of Isofol.

INOVIO to Report First Quarter 2023 Financial Results on May 10, 2023

On April 28, 2023 INOVIO (NASDAQ: INO), a biotechnology company focused on developing and commercializing DNA medicines to help treat and protect people from HPV-associated diseases, cancer, and infectious diseases, reported that first quarter 2023 financial results will be released after the market close on May 10, 2023 (Press release, Inovio, APR 28, 2023, View Source [SID1234630671]). Following the release, INOVIO will host a live conference call and webcast at 4:30 p.m. ET to discuss financial results and provide a general business update.

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A live and archived version of the audio presentation will be available online at View Source This is a listen-only event but will include a live Q&A with analysts.

Immutep Quarterly Activities Report & Appendix 4C Q3 FY23

On April 28, 2023 Immutep Limited (ASX: IMM; NASDAQ: IMMP) ("Immutep" or "the Company"), a biotechnology company developing novel LAG-3 related immunotherapy treatments for cancer and autoimmune diseases, reported an update on the ongoing development of its product candidates, eftilagimod alpha (efti) and IMP761 for the quarter ended 31 March 2023 (Q3 FY23) (Press release, Immutep, APR 28, 2023, View Source [SID1234630668]).

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EFTI DEVELOPMENT PROGRAM FOR CANCER

Immutep made strong progress during the quarter to advance its clinical development strategy to position the company, or a potential partner, to fully exploit efti’s broad potential.

AIPAC-003 — Phase II/III trial in Metastatic Breast Cancer (MBC)

In March, Immutep initiated AIPAC-003 (Active Immunotherapy PAClitaxel), its integrated Phase II/III trial evaluating efti in combination with paclitaxel for the treatment of HER2-neg/low metastatic breast cancer and triple-negative breast cancer. These two indications account for ~78% of breast cancer cases. The trial commenced following the regulatory approval in the United States and Institutional Review Board (IRB) approval in Spain. Immutep anticipates enrolling the first patient in Q2 CY2023.

As a first-in-class soluble LAG-3 protein targeting MHC Class II ligands on antigen-presenting cells (APC), efti is well positioned to improve clinical outcomes from standard-of-care chemotherapy due to its unique mechanism of action. Its activation of APC triggers a broad immune response that includes significant increases in cytotoxic CD8+ T cells armed with chemo-induced tumour antigens to target cancer.

The AIPAC-003 trial employs an integrated clinical design agreed to with the FDA to help inform a potential Biologics License Application (a request for permission to sell a biologic product) and a potential Marketing Authorisation Application with the European Medicines Agency (EMA). This trial design also allows for a risk-balanced approach with the Phase III portion dependent on the Phase II results, among other items.

TACTI-002 (also designated KEYNOTE-PN798) Phase II clinical trial

Positive final data on safety and efficacy was reported from Part B of the TACTI-002 trial in patients with 2nd line non-small cell lung cancer (NSCLC) refractory to anti-PD-(L)1 therapies in a Mini Oral presentation at ESMO (Free ESMO Whitepaper)’s European Lung Cancer Congress (ELCC) 2023. These patients have few therapeutic options, and the addition of efti to pembrolizumab may help these patients by reverting the confirmed anti-PD-(L)1 therapy resistance.

The Company reported encouraging clinical results, including an Overall Survival (OS) rate of 39% at 21 months. In addition, 83% of patients studied for Tumour Growth Kinetics showed deceleration (50%) in tumour growth or shrinkage (33%) of target lesions. Responses were confirmed and durable with responders participating in the study for more than 19 months.

The ORR, PFS, and OS were more pronounced in patients with high PD-L1 expression (N=6) or who were secondary resistant (N=25). For patients with ≥50% PD-L1 TPS expression, median OS was not yet reached, overall response rate (ORR) was 33.3%, and 6-month progression-free survival (PFS) was 50%. Efti plus pembrolizumab was well tolerated without any new safety signals, and there was no treatment discontinuation due to adverse reactions.

TACTI-003 – Phase IIb clinical trial in 1st line HNSCC

In early 2023 Immutep announced it has successfully enrolled over 50% of the planned 154 patients into the randomised Phase IIb TACTI-003 trial. Subsequent to quarter end TACTI-003 has reached 75% enrolment, and Immutep expects to complete enrolment by mid-year positioning the Company to report top-line results in H2 of CY2023.

Planned late-stage trial in 1st line NSCLC

Immutep is continuing its preparations for a late-stage trial evaluating efti in 1st line NSCLC in combination with anti-PD-1 therapy. The NSCLC program will be shaped by the maturing data from the Company’s ongoing TACTI-002 and INSIGHT-003 trials. Current activity is focused on trial design and engagement with regulatory authorities and other stakeholders. The Company obtained US FDA Fast Track designation late last year for this indication.

INSIGHT-003 – Phase I in 1st line NSCLC

In February, the investigator-initiated INSIGHT-003 trial reached its enrolment target of 20 patients with 1st line NSCLC for this first triple combination therapy study of efti with standard-of-care combination of anti-PD-1 therapy and chemotherapy. INSIGHT-003 has been now extended to include a total of 50 patients. The expansion of INSIGHT-003 will further inform planning for registrational studies.

IMP761 DEVELOPMENT PROGRAM FOR AUTOIMMUNE DISEASES

During the first quarter, our preclinical development continued for IMP761, including preparations to begin the toxicology study. As the first immunosuppressive agonist antibody to LAG-3 acting upstream on activated T cells to target the root cause of self-antigen-specific T cell induced disease, IMP761 is a potential game-changer in how autoimmune diseases are treated. The Company currently anticipates that clinical development will begin in the first half of CY2024.

INTELLECTUAL PROPERTY

During the quarter, Immutep was granted three new patents directed to efti. The first is a United States patent drawn to methods of treating cancer with a combination of efti and chemotherapy, where the efti is administered in a dose of more than 6 mg. This is the third United States patent granted from this family.

The second patent is an Indian patent that protects Immutep’s intellectual property relating to combined preparations of efti with a PD-1/PD-L1 therapy for the treatment of cancer or infection. The third patent is an Australian patent which relates to a potency assay for release testing of efti. The assay is used in Immutep’s commercial-scale (2,000L) manufacturing process. This new Australian patent follows the grant of a similar patent in South Korea in 2022.

BOARD AND MANAGEMENT CHANGES

On 11 April, Lis Boyce was appointed as Non-Executive Director replacing Lucy Turnbull, who re-joined the board after the sudden and untimely death of Grant Chamberlain in January 2022. The Board is grateful to Lucy for stepping in under such tragic circumstances and for her boundless energy and valued insights.

Ms Boyce is a highly experienced corporate lawyer and currently a partner at Piper Alderman. She has extensive experience in the Life Sciences and Healthcare sectors as well as in capital raisings, strategic collaborations, commercial contracts and mergers and acquisitions. Lis is currently deputy chair of AusBiotech’s AusMedtech Advisory Group and a member of AusBiotech’s State Committee for NSW.

On 26 April, Immutep announced that it expanded its leadership team with the appointment of Florian D. Vogl, M.D., Ph.D., MSc., as Chief Medical Officer (CMO) with effect from 1 May 2023. Dr. Vogl has over a decade of experience in the biopharmaceutical industry with extensive clinical development expertise in the field of oncology. Most recently, he was CMO of Cellestia Biotech where he focused on delivering new treatments to patients with cancer and autoimmune disorders that had limited therapeutic options. Prior to Cellestia, Dr. Vogl held senior management roles in Europe and the United States, including Head of Clinical Development Europe at Rainier Therapeutics, Senior Global Medical Leader, Oncology Development at Novartis, and as Early Development Leader, Oncology Pipeline at Amgen.

Dr. Vogl assumes the CMO role from Frédéric Triebel, M.D., Ph.D., who previously acted as both Chief Scientific Officer (CSO) and CMO of Immutep. Dr. Triebel’s foremost focus will be on his responsibilities as CSO and as a member of Immutep’s Board.

FINANCIAL SUMMARY

Immutep continued to focus on prudent cash management during the past quarter (Q3 FY23). The Company remains well funded with a cash runway extending to the end of FY24.

Cash receipts from customers in the quarter increased to $30k, compared to $8k in Q2 FY23. The net cash used in G&A activities in the quarter was $1.12million compared to $734k in Q2 FY23. Payments to Related Parties, detailed in Item 6 of the Appendix 4C cash flow report for the quarter, includes $257k in payments for Non-Executive Director’s fees and Executive Director’s remuneration.

The net cash used in R&D activities in the quarter was $11.52 million, compared to $5.87 million in Q2 FY23. The increase was mainly due to the increased clinical trial and manufacturing activities.

Total net cash outflows used in operating activities in the quarter were $14.17 million compared to $7.02 million in Q2 FY23.

Immutep’s cash and cash equivalent balance at 31 March 2023 was approximately $55.2 million, giving the Company an expected cash reach based on current estimates to June 2024. Immutep will continue to manage its solid cash balance carefully as it pursues its overall clinical development strategy.

A copy of the Appendix 4C — Quarterly Cash Flow Report for the quarter is attached.