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Lynparza plus abiraterone approved in Japan for the treatment of BRCA-mutated metastatic castration-resistant prostate cancer

On August 24, 2023 AstraZeneca and MSD reported that Lynparza (olaparib) in combination with abiraterone and prednisolone has been approved in Japan for the treatment of adult patients with BRCA-mutated (BRCAm) castration-resistant prostate cancer with distant metastasis (mCRPC) (Press release, AstraZeneca, AUG 24, 2023, View Source [SID1234634653]).

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This approval by the Japanese Ministry of Health, Labour and Welfare was based on a subgroup analysis of the PROpel Phase III trial which showed that Lynparza plus abiraterone demonstrated highly clinically meaningful improvements in both radiographic progression-free survival (rPFS) and overall survival (OS) versus abiraterone alone in patients with BRCA mutations.

Prostate cancer is the most common cancer in men in Japan and the sixth leading cause of cancer death in the region.1 Despite various treatment options available, the prognosis for mCRPC remains poor, with limited options for patients whose cancer progresses following initial treatment.1,2

Mototsugu Oya, Professor and Chairman, Department of Urology, Keio University School of Medicine, Japan, said: "The PROpel trial showed that the combination of Lynparza plus abiraterone delivered clinically meaningful improvements in outcomes for patients with BRCA-mutated metastatic castration-resistant prostate cancer. With this approval, patients in Japan will now have the opportunity to benefit from this new treatment combination which has the potential to become the new standard of care for patients with BRCA mutations."

Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: "This Lynparza combination has been shown to reduce the risk of disease progression or death compared to standard of care and underscores the critical importance of BRCA testing at metastatic diagnosis. Today’s approval is a major step forward for patients in Japan with BRCA-mutated metastatic castration-resistant prostate cancer who urgently need new first-line treatment options."

Eliav Barr, Senior Vice President, Head of Global Clinical Development and Chief Medical Officer, MSD Research Laboratories, said: "Prostate cancer impacts thousands of patients in Japan each year, and currently there are limited options available to those with metastatic disease. It is very important to develop and deliver novel treatment combinations to patients with BRCA-mutated metastatic castration-resistant prostate cancer that improve on the current standard of care."

In the subgroup analysis of PROpel, results showed that Lynparza plus abiraterone reduced the risk of disease progression or death by 77% (based on a hazard ratio [HR] of 0.23; 95% confidence interval [CI] 0.12-0.43) and reduced the risk of death by 61% (based on a HR of 0.39; 95% CI 0.16-0.86) versus abiraterone alone in patients with BRCAm mCRPC. Median rPFS and median OS were not reached for patients treated with Lynparza plus abiraterone versus a median of 8.4 months and 23.6 months, respectively, for those treated with abiraterone alone.

The safety and tolerability of Lynparza plus abiraterone in PROpel was in line with that observed in prior clinical trials and the known profiles of the individual medicines.

Lynparza in combination with abiraterone and prednisone or prednisolone is approved in the European Union (EU) and several other countries for the treatment of adult patients with mCRPC in whom chemotherapy is not clinically indicated, based on the PROpel trial. This combination is also approved in the US for the treatment of adult patients with deleterious or suspected deleterious BRCAm mCRPC.

Lynparza monotherapy is also approved in Japan for patients with BRCAm mCRPC based on results from the PROfound Phase III trial. It is approved in the EU and China for the same indication, as well as in the US for patients with homologous recombination repair (HRR) gene-mutated mCRPC (BRCA and other HRR gene mutations) who have progressed following prior treatment with enzalutamide or abiraterone.

Notes

Prostate cancer
Prostate cancer is the second most commonly diagnosed cancer in men and the fifth leading cause of cancer death in men globally, with an incidence of 1.4 million and 375,000 deaths in 2020.3,4 In Japan, there are an estimated 96,400 new cases and 13,300 deaths in 2022.2,5 Overall survival for patients with mCRPC is approximately three years in clinical trial settings, and even shorter in the real-world.6 Approximately half of patients with mCRPC may receive only one line of active treatment, and those that go on to receive further treatment often have diminishing benefit of subsequent therapies.7-12

Metastatic castration-resistant prostate cancer
Metastatic prostate cancer is associated with a significant mortality rate.13 Development of prostate cancer is often driven by male sex hormones called androgens, including testosterone.14

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.15 Approximately 10-20% of men with advanced prostate cancer will develop castration-resistant prostate cancer (CRPC) within five years, and at least 84% of these men will have metastases at the time of CRPC diagnosis.16 Of patients with no metastases at CRPC diagnosis, 33% are likely to develop metastases within two years.16

Despite the advances in mCRPC treatment in the past decade with taxane and new hormonal agent (NHA) treatment, there is a high unmet need in this population.15-18

PROpel
PROpel is a randomised, double-blind, multi-centre Phase III trial testing the efficacy, safety, and tolerability of Lynparza versus placebo when given in combination with abiraterone, as well as prednisone or prednisolone, in men with mCRPC who had not received prior chemotherapy or NHAs in the mCRPC setting.

The primary endpoint is rPFS and secondary endpoints include OS, time to secondary progression or death, and time to first subsequent therapy. In September 2021, at a planned interim analysis, the Independent Data Monitoring Committee concluded that the PROpel trial met the primary endpoint of rPFS.

For more information about the trial please visit ClinicalTrials.gov.

Lynparza
Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in HRR, such as those with mutations in BRCA1 and/or BRCA2, or those where deficiency is induced by other agents (such as NHAs).

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 currently approved in a number of countries across multiple tumour types including maintenance treatment of platinum-sensitive relapsed ovarian cancer and as both monotherapy and in combination with bevacizumab for the 1st-line maintenance treatment of BRCA-mutated (BRCAm) and homologous recombination repair deficient (HRD)-positive advanced ovarian cancer, respectively; for germline BRCA mutation (gBRCAm), HER2-negative metastatic breast cancer (in the EU and Japan this includes locally advanced breast cancer); for gBRCAm, HER2-negative high-risk early breast cancer (in Japan this includes all BRCAm HER2-negative high-risk early breast cancer); for gBRCAm metastatic pancreatic cancer; in combination with abiraterone for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in whom chemotherapy is not clinically indicated (EU) and for BRCAm mCRPC (US); and as monotherapy for HRR gene-mutated mCRPC in patients who have progressed on prior NHA treatment (BRCAm only in the EU and Japan). In China, Lynparza is approved for the treatment of BRCAm mCRPC as well as a 1st-line maintenance treatment with bevacizumab for HRD-positive advanced ovarian cancer.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, has been used to treat over 75,000 patients worldwide. Lynparza has a broad clinical trial development programme, and AstraZeneca and MSD are working together to understand how it may affect multiple PARP-dependent tumours as a monotherapy and in combination across multiple cancer types. Lynparza is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.

The AstraZeneca and MSD strategic oncology collaboration
In July 2017, AstraZeneca and Merck & Co., Inc., Kenilworth, NJ, US, known as MSD outside the US and Canada, announced a global strategic oncology collaboration to co-develop and co-commercialise Lynparza, the world’s first PARP inhibitor, and Koselugo (selumetinib), a mitogen-activated protein kinase inhibitor, for multiple cancer types.

Working together, the companies will develop Lynparza and Koselugo and other potential new medicines as monotherapies and as combinations. The companies will also develop Lynparza and Koselugo in combination with their respective PD-L1 and PD-1 medicines independently.

Royalty Pharma and Ferring Pharmaceuticals enter into US $500 million royalty agreement for new intravesical gene therapy Adstiladrin® (nadofaragene firadenovec-vncg)

On August 24, 2023 Royalty Pharma plc (Nasdaq: RPRX) and Ferring Pharmaceuticals reported that Royalty Pharma has acquired a synthetic royalty on US net sales of Ferring’s Adstiladrin (nadofaragene firadenovec-vncg) for up to US $500 million comprised of an upfront payment of US $300 million and a US $200 million milestone payment (Press release, Ferring, AUG 24, 2023, View Source [SID1234634647]). The milestone payment is contingent on certain manufacturing goals that are expected to be achieved in 2025 for the FDA-approved intravesical gene therapy that Ferring will make available next month through an early experience program for the treatment of adult patients with high-risk, Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors.

Under the terms of the agreement, Royalty Pharma is acquiring a 5.1% percentage royalty on net sales of Adstiladrin in the United States, which will increase to 8.0% upon payment of the manufacturing-related milestone. The royalty is expected to end in the early to mid-2030s.

"This major investment by Royalty Pharma, the largest buyer of biopharmaceutical royalties and a leading funder of innovation, is yet another demonstration of the value and confidence in our gene therapy Adstiladrin to address significant unmet medical needs for patients. It also highlights its significant potential as a key growth driver for Ferring, and our commitment to Uro-Oncology," said Jean-Frédéric Paulsen, Executive Chairman of Ferring Pharmaceuticals.

Bladder cancer is the sixth most common cancer in the United States, with NMIBC representing approximately 75% of all new bladder cancer cases.[i] Adstiladrin is a non-replicating adenovirus vector-based gene therapy for the treatment of adult patients with high-risk BCG-unresponsive NMIBC. Although BCG remains the first-line standard of care for people living with high-grade NMIBC, more than 50% of patients who receive initial treatment with BCG will experience disease recurrence and progression within one year, with many developing BCG-unresponsive disease.[ii] In April 2023, the FDA approved a Prior-Approval Supplement (PAS) to the Biologics License Application (BLA) for the therapy which enabled the scale-up of drug substance manufacturing process.

"After several decades of little progress in the field, Adstiladrin brings a major innovation to patients with high-risk NMIBC who no longer respond to current first-line treatment and have few other good options. Our ambition is for Adstiladrin to become the new standard of care and the backbone therapy for these patients and to drive research in other urothelial cancers. This agreement positions us well for continued significant and sustained investment to further advance Adstiladrin as the foundation of our leadership drive in Uro-Oncology," said Bipin Dalmia, Global Head, Uro-Oncology Franchise of Ferring Pharmaceuticals.

"We are delighted to partner with Ferring, a research-driven, global specialty biopharmaceutical company. This investment is consistent with our strategy of acquiring royalties on innovative therapies in areas of high unmet patient need," said Pablo Legorreta, founder and Chief Executive Officer of Royalty Pharma. "Adstiladrin is the first gene therapy in our diversified royalty portfolio. We believe it has blockbuster potential and we are pleased to provide funding to support the launch of Adstiladrin and help Ferring reach as many patients as possible with this important therapy in the United States."

About Adstiladrin
Adstiladrin (nadofaragene firadenovec-vncg) is a gene therapy developed as a treatment for adult patients with BCG-unresponsive NMIBC. It is a non-replicating adenovirus vector-based gene therapy containing the gene encoding interferon alfa-2b protein, administered by catheter into the bladder once every three months. The vector enters the cells of the bladder wall, releasing the interferon gene. The internal cell machinery translates the interferon DNA sequence, resulting in the cells secreting high quantities of interferon alfa-2b protein, a recombinant analog of the naturally occurring protein the body uses to fight cancer. This novel gene therapy approach thereby turns the patient’s own bladder wall cells into interferon microfactories, enhancing the body’s natural defenses against the cancer. Nadofaragene firadenovec-vncg has been studied in a clinical trial program that includes 157 patients with high-grade, BCG-unresponsive NMIBC who had been treated with adequate BCG previously and did not see benefit from additional BCG treatment (full inclusion criteria published on clinicaltrials.gov: NCT02773849).

US FDA approval of Adstiladrin on December 16, 2022 was based on results of the Phase 3 clinical trial, which met its primary endpoint with more than half (51%, n=50 of 98; 95% CI 41 to 61) of patients with carcinoma in situ with or without concomitant high-grade Ta or T1 disease (CIS ± Ta/T1) achieving a complete response (CR) by three months. Of the patients who achieved an initial CR, 46% (n=23 of 50) continued to remain free of high-grade recurrence at 12 months.

INDICATION
Adstiladrin is a non-replicating adenoviral vector-based gene therapy indicated for the treatment of adult patients with high-risk Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors.

IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS: Adstiladrin is contraindicated in patients with hypersensitivity to interferon alfa or any component of the product.

WARNINGS AND PRECAUTIONS:

Risk with delayed cystectomy: Delaying cystectomy in patients with BCG-unresponsive CIS could lead to development of muscle invasive or metastatic bladder cancer, which can be lethal. If patients with CIS do not have a complete response to treatment after 3 months or if CIS recurs, consider cystectomy.
Risk of disseminated adenovirus infection: Persons who are immunocompromised or immunodeficient may be at risk for disseminated infection from ADSTILADRIN due to low levels of replication-competent adenovirus. Avoid ADSTILADRIN exposure to immunocompromised or immunodeficient individuals.
DOSAGE AND ADMINISTRATION: Administer Adstiladrin by intravesical instillation only. Adstiladrin is not for intravenous use, topical use, or oral administration.

USE IN SPECIFIC POPULATIONS: Advise females of reproductive potential to use effective contraception during Adstiladrin treatment and for 6 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during Adstiladrin treatment and for 3 months after the last dose.

ADVERSE REACTIONS: The most common (>10%) adverse reactions, including laboratory abnormalities (>15%), were glucose increased, instillation site discharge, triglycerides increased, fatigue, bladder spasm, micturition (urination urgency), creatinine increased, hematuria (blood in urine), phosphate decreased, chills, pyrexia (fever), and dysuria (painful urination).

You are encouraged to report negative side effects of prescription drugs to FDA. Visit www.FDA.gov/medwatch or call 1-800-332-1088. You may also contact Ferring Pharmaceuticals at 1-888-FERRING.

Circio Holding ASA: First half 2023 results

On August 24, 2023 Circio Holding ASA (OSE: CRNA), a biotechnology company developing novel circular RNA and immunotherapy medicines, reported its first half 2023 results (Press release, Circio, AUG 24, 2023, View Source [SID1234634644]).

Members of Circio’s executive management team will give an online presentation to investors, analysts and the press at 10:00 CET today (details below).

FIRST HALF 2023 HIGHLIGHTS
Corporate
The company was rebranded as Circio, an innovator in next generation circular RNA therapeutics
A convertible bond facility with Atlas Special Opportunities was established, securing up to NOK 300 million in financing over three years
The organization was restructured to reflect the new strategic focus on circRNA, which will lead to significant payroll savings
Circular RNA
Technical proof-of-concept was established for novel circVec vector types and designs, including demonstrating 15X extended half-life vs. mRNA in vitro
A patent application was filed for the circAde concept
Two circRNA posters were presented at the major oncology and gene therapy conferences AACR (Free AACR Whitepaper) and ASGCT (Free ASGCT Whitepaper)
Mutant KRAS
The first patient was dosed with TG01 in the multiple myeloma study at Oslo University Hospital
The first patient was dosed with TG01 in the anti-PD-1 combination study in pancreatic cancer at Kansas University, USA
Erik Digman Wiklund, CEO commented: "Circular RNA is a powerful new format for RNA therapeutics, and with our differentiated circVec platform we have a unique opportunity to take a leading role in this emerging space. We are rapidly building our technical capabilities to demonstrate the versatility and broad potential of our technology and put Circio in position to capture the significant potential of vector-delivered circRNA."

Key figures
Amounts in NOK thousands 1H 2023 1H 2022 FY 2022
Total operating revenues 10 002
Total operating expenses -72 519 -59 786 -503 593
Operating profit/loss -72 519 -59 786 -493 591
Net financial items -3 443 164 -1 737
Income tax – 21 62 430
Net profit/loss -75 962 -59 601 -432 898
Basic and diluted EPS (NOK/share) -0.40 -0.32 -2.30
Net change in cash -34 652 -55 884 -115 667
Cash and cash equivalents start of period 66 015 181 682 181 682
Cash and cash equivalents end of period 31 363 125 798 66 015
The interim financial information has not been subject to audit

Presentation
We invite to a live webcast today at 10.00 CET. You can join the webcast here. It will be possible to submit questions during the presentation.

Positive Preclinical Results Unveiled for DPH001

On August 23, 2023 Disruptive Pharma reported positive results from its recent preclinical study for DPH001 (Press release, Disruptive Pharma, AUG 23, 2023, View Source [SID1234649944]). With its innovative MMC technology, researchers at Disruptive Pharma have engineered an improved sorafenib formulation intended for the treatment of hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). DPH001, confirms its bioequivalent exposure profile at 50% API dose compared to NEXAVAR Our data show that the MMC sorafenib formulation of DPH001 achieved the 2X absorption and reduced inter-animal variability which was the goal of the PK study. The animals were given MMC sorafenib formulation, at 50% API dose, and NEXAVARat standard API dose. CEO Peter Åsberg: "we look forward to continue developing DPH001 which will bring an important improvement for patients with HCC/RCC. We believe it can have a major impact on the market and have a positive impact for the patients in terms of an improved side-effect profile undergoing sorafenib treatment. We’re really excited about our upcoming work and the commercial opportunities we see that DPH001 can bring as well as being a demonstrator on how the patented MMC technology may be utilized to create improved versions of marketed products."

Furthermore, Åsberg highlighted the broader potential of Disruptive Pharma’s MMC technology, which could pave the way for enhanced versions of existing products, stating, "DPH001 serves as a prime example of how our patented MMC technology can be harnessed to create superior iterations of marketed products. This not only demonstrates our commitment to innovation but also underscores our dedication to improving patients’ lives."

Interim results announcement for the six months ended June 30, 2023

On August 23, 2023 WuXi Biologics reported its Interim results for the six months ended June 30, 2023 (Filing, 3 mnth, JUN 30, WuXi Biologics, 2023, AUG 23, 2023, View Source [SID1234634973]).