Sanofi would in my opinion be the front runner to take up a license with Starpharma in Dep Cabaxztaxel
Novartis is the company which owns Sandoz
The history with Sandoz creating a generic version of Cabazitaxel has been well documented. Sanofi took Sandoz to court and prevented this generic version going out into the market place
The parent company of Sandoz (Novartis) is heavily involved in looking for novel ways to prevent cancers. FYI they are investigating dendrimers
Alexei Karpov, PhD Co-Mentor: Robert Grotzfeld, PhD
Global Discovery Chemistry
Basel, Switzerland
A priority research area for our New Modalities Group is to evaluate and further develop a variety of techniques for the targeted delivery of novel drug molecules to diseased tissue. The ultimate goal is to apply the most effective and innovative targeting strategies to the next generation of medicines, achieving excellent efficacy and vastly superior safety profiles compared to current treatments, thus bringing the maximum benefit to patients. We have developed expertise in targeted delivery of cytotoxic compounds into tumor tissues in the context of antibody-drug-conjugates (ADCs). Building on this experience, we will now look beyond ADCs and investigate the opportunities and limitations of passive targeted delivery approaches relying on the EPR (enhanced permeability and retention) effect. Drawing from our extensive experience in linker chemistry, we aim at designing the next generation of tissue targeting systems which would release drugs only at the desired site of action, thus maximizing their therapeutic window.
One aspect of this is to evaluate dendrimers as carriers for drug delivery. Dendrimers represent a flexible and modular approach that will enable the exploration of specific drug release mechanisms in combination with tissue-targeting modalities. We aim to develop novel linkers and dendrimer scaffolds and evaluate biological activity of the resulting constructs in vivo.
FYI
Global head of oncology at Novartis is Shiva Malek (since 2o21). Before this she was the vice president for discovery oncology at Genentech. (parent company is Roche and Starpharma has a collaboration with Genentech)
It would not surprise me if Novartis was interested in Dep Cabazitaxel.
To be sure if they are.........there will be a bidding
In regards to the final phase 2 results for Dep Cabazitaxel.......we could not have asked for better data
EFFICACY AND SAFETY ARE SUPERIOR TO THE CURRENT VERSIONS
Remember all the patients are using our product as a last resort. They have all been heavily pre treated
An agreement with upfront fees is just around the corner in my opinion.
Take note the value of Dep Cabazitaxel will not only be for current indications but in the unmet need of indications not using this drug
Take note also, all generic and current Jevtana will become obsolete on registration for use of Dep Cabazitaxel and revenue will be much more than the dollars generated now
Let the auction for our blockbuster begin
Oct 18, 2023 Positive DEP® Cabazitaxel Phase 2 Results in Multiple Cancers (ASX Announcement)
Melbourne, Australia; 18 October 2023: Starpharma (ASX: SPL, OTCQX: SPHRY) today announces the final positive results from its completed Phase 2 open-label clinical trial of DEP® cabazitaxel. The trial met its objectives, with endpoints demonstrating positive anti-tumour efficacy of DEP® cabazitaxel in advanced, metastatic castrate-resistant prostate cancer (mCRPC), as well as other difficult-to-treat cancers, including platinum-resistant ovarian cancer and gastro-oesophageal cancers. The trial results also confirmed the favourable safety and tolerability profile of DEP® cabazitaxel.
Developed by Starpharma, DEP® cabazitaxel is a patented, dendrimer nanoparticle version of cabazitaxel (Jevtana®), which is widely used in the treatment of prostate cancer, with Jevtana® achieving peak sales of €433 million in 20211.
In Starpharma’s Phase 2 trial, DEP® cabazitaxel achieved highly encouraging anti-tumour efficacy in multiple advanced solid cancers, including metastatic castration-resistant prostate cancer, platinum-resistant ovarian cancer, and gastro-oesophageal cancers. Summary of key efficacy results:
Heavily pre-treated, advanced prostate cancer patients (mCRPC) treated with DEP® cabazitaxel achieved a median progression-free survival (PFS) that was more than 50% longer and a median overall survival (OS) that was 10% longer than published data for Jevtana® at the same dose2. These final progression-free survival results improve upon the interim results on DEP® cabazitaxel reported by Starpharma at the ESMO (European Society of Medical Oncology) Congress 20223.
In advanced, platinum-resistant ovarian cancer patients, who were heavily pre-treated with an average of 4 prior lines of chemotherapy, DEP® cabazitaxel achieved a disease control rate (DCR) of 66.7% and an objective response rate (ORR) of 17.6%, which compares favourably to standard-of-care therapies that report ORRs ranging from ~9 to 16%4,5,6.
In advanced gastro-oesophageal cancer patients, DEP® cabazitaxel achieved a median progression-free survival (PFS) and median overall survival (OS) that were 53.1% and 28.5% longer, respectively, than similar patient cohorts treated with standard-of-care paclitaxel7.
These very encouraging DEP® cabazitaxel efficacy results were also clinically significant, given all patients had late-stage, hard-to-treat cancers, and had failed multiple therapies, including closely related taxanes8, prior to entering this trial.
Furthermore, these positive efficacy results in prostate, ovarian, and gastro-oesophageal cancers demonstrate the significant market value and growth potential for DEP® cabazitaxel, not only in the approved prostate cancer indication of Jevtana®, but also in other cancers that have a high unmet medical need.
Importantly, DEP® cabazitaxel was also very well tolerated across the trial in patients who were often elderly, heavily pre-treated and had advanced disease. The overall rate of grade 3 or 4 non-haematological, treatment-related adverse events (AEs) across all DEP® cabazitaxel treated patients (21.3%) was approximately half that reported for Jevtana® (40%)2 at the same dose. Unlike standard cabazitaxel, DEP® cabazitaxel is highly water soluble and does not contain toxic excipients (detergents) that can cause anaphylaxis, so patients do not need to be pre-medicated with steroids or antihistamines when using DEP® cabazitaxel, leading to an improved patient experience.
Commenting on the positive DEP® cabazitaxel Phase 2 results:
Professor James Spicer, FRCP, MBBS, PhD, Pgrofessor of Experimental Cancer Medicine at King’s College London and Consultant in Medical Oncology and the Principal Investigator for the trial at Guy’s Hospital in London, commented:
“In our cancer early phase trials unit at Guy’s Hospital, we conduct many studies of novel oncology therapeutics. The results with DEP® cabazitaxel clearly demonstrate promising and durable anti-cancer activity in very hard-to-treat cancer patients, not only in prostate cancer patients but also platinum-resistant ovarian cancer, and advanced gastro-oesophageal cancers. These advanced patients have few treatment options and we have had many patients who benefited from DEP® cabazitaxel therapy. It was also pleasing to see the limited impact on bone marrow function of this agent given these advanced patients are often at risk of complications of chemotherapy-induced bone marrow toxicity, especially low neutrophil counts.” Dr David Pinato, MD, MRCP (UK), MRes, PhD, Clinical Reader and Consultant Medical Oncologist, Director of Developmental Cancer Therapeutics, and Investigator for the trial at Imperial College London, said:
“I am impressed with the data on Starpharma's novel dendrimer formulation of cabazitaxel, not only in prostate cancer patients, but in patients with other difficult-to-treat diseases such as advanced platinum-resistant ovarian and gastro-oesophageal cancers.
“DEP® cabazitaxel showed very encouraging efficacy signals in these heavily pre-treated patients who have few options remaining.
“For example, in elderly patients with prostate cancer who typically would not tolerate standard cabazitaxel due to low neutrophil counts and other adverse effects, treatment with DEP® cabazitaxel was possible due to its lack of significant effects on the bone marrow and its generally well tolerated safety profile, and achieved some excellent outcomes for these patients.
“Based on the data and my experience with DEP® cabazitaxel, it represents a well-tolerated and promising treatment alternative, not only to standard cabazitaxel for prostate cancer patients, but also for ovarian, gastro-oesophageal and potentially other cancers for which standard cabazitaxel is not indicated.”
DEP® Cabazitaxel Efficacy Results
Prostate Cancer
Prostate cancer is the most commonly diagnosed cancer in Australia, with an estimated one in six males diagnosed by the age of 85; the average age at diagnosis is 70 years9.
In heavily pre-treated advanced mCRPC patients (N=25) who had received a median of 4 lines and 70 cycles/months of prior anti-cancer treatment, DEP® cabazitaxel achieved a median progression-free survival (PFS) of 4.4 months, which is more than 50% longer than the published median PFS of 2.9 months for standard cabazitaxel (Jevtana®) at the same dose (20 mg/m2)2. It is also more than 25% longer than the median PFS of 3.5 months at a higher dose of Jevtana® (25 mg/m2) (Table 1).
DEP® cabazitaxel also achieved an improved median overall survival (OS)10 of 14.7 months in these heavily pre-treated mCRPC patients, which also compares favourably with the published median OS of 13.4 months for Jevtana® at the same dose (20 mg/m2)2.
These improved and clinically meaningful outcomes were achieved with DEP® cabazitaxel despite these advanced prostate cancer (mCRPC) patients being significantly more heavily pre-treated prior to entry into this trial than patients in published clinical trials of Jevtana®. Notably, these responses were achieved despite 96% of patients in this trial cohort having received closely related taxane therapy, including up to 19 cycles of docetaxel and up to 10 cycles of conventional cabazitaxel (Jevtana®), prior to enrolment in the DEP® cabazitaxel trial.
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Table 1. Longer PFS (median) observed in DEP® cabazitaxel mCRPC patients compared to published data on Jevtana®11
Intent-to-treat (ITT) populations; PFS = Composite endpoint from date of randomisation to date of first tumour progression, PSA progression, or death.
In addition to the abovementioned efficacy outcomes relating to overall survival or progression of disease measured radiologically, 90% of evaluable13 DEP® cabazitaxel patients achieved a reduction in the important cancer biomarker, prostate specific antigen (PSA), and more than half (52.4%) achieved a PSA reduction of at least 50% (PSA50). This PSA50 result compares favourably with published data for Jevtana® at the same dose, where only 29.5% of patients achieved a PSA502.
DEP® cabazitaxel also achieved highly durable anti-tumour responses in 70.6% of prostate cancer (mCRPC) patients with assessable soft tissue lesions. Responses in these patients included partial responses (PR14) maintained for up to 55 weeks (Table 2) and disease control (stable disease, SD) maintained for up to 64 weeks. 100% of evaluable mCRPC patients15 achieved a response to DEP® cabazitaxel in at least one measure of efficacy (soft tissue disease [SD or PR], PSA decrease, and/or no progression in bone disease).
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Table 2. Key efficacy endpoints for DEP® cabazitaxel in prostate cancer
The final DEP® cabazitaxel progressions-free survival results in advanced mCRPC patients reported here improve upon the interim results reported by Starpharma at the ESMO Congress in September 20223. Now that all patient cohorts have completed treatment, and final data analysis has been completed, overall survival (OS) results have also been calculated.
Platinum-resistant Ovarian Cancer
Ovarian cancer is a significant cause of morbidity and mortality worldwide, often diagnosed in an advanced stage where the 5-year survival rate is only 20–41%19.
DEP® cabazitaxel also achieved highly encouraging efficacy results in patients with advanced platinum-resistant ovarian cancer (N=22), including tumour shrinkage of up to 40% and response durations of up to 34 weeks. The ovarian cancer patients in this study were also heavily pre-treated, having received a median of 4 and up to 11 lines (with a median of 25 cycles) of prior anti-cancer treatment. All (100%) patients had received at least one prior taxane, with 45% having previously received 2 or more lines of taxane treatment.
DEP® cabazitaxel achieved a disease control rate (DCR) of 66.7% and an objective response rate (ORR) of 17.6% (Table 3) in evaluable ovarian cancer patients, despite this heavy pre-treatment. This ORR compares favourably to standard-of-care single-agent therapies that report ORRs ranging from ~9 to 16% (paclitaxel [Taxol®], topotecan [Hycamtin®], gemcitabine [Gemzar®] or pegylated liposomal doxorubicin [Caelyx®])4,5,6. DEP® cabazitaxel also achieved reductions of up to 95% in ovarian cancer biomarkers, CA12520, or CEA21, in 75% of evaluable ovarian cancer patients.
These durable efficacy responses (disease control, objective responses) in advanced ovarian cancer are highly encouraging, especially given these patients were so heavily pre-treated. Advanced platinum-resistant ovarian cancer represents a significant unmet clinical need and expanded market opportunity for DEP® cabazitaxel.
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Table 3. Key efficacy endpoints for DEP® cabazitaxel in platinum-resistant ovarian cancer
1
Cancer Type
Patients’ Prior Anti-Cancer Therapy (Median)16
Disease Control Rate (DCR13,17)
Objective Response Rate(ORR13,18)
Median PFS
2
Platinum-Resistant Ovarian
4 lines, 25 cycles
66.7%
17.6%
3.1 months
Gastro-oesophageal Cancers
Advanced gastro-oesophageal cancers22 are a significant unmet medical need with a very poor prognosis and limited treatments. These cancers progress rapidly and have a one-year survival rate of only 20%23,24.
In advanced gastro-oesophageal cancer patients, DEP® cabazitaxel achieved excellent efficacy responses, including a median progression-free survival (PFS) of 4.0 months and a median overall survival (OS) of 8.6 months (N=15). These results compare very favourably to standard-of-care paclitaxel treatment in patients with oesophageal or gastro-oesophageal junction cancers, with DEP® cabazitaxel achieving a more than 50% longer median PFS and a 29% longer median OS than paclitaxel administered weekly as a second-line treatment7.
The majority of these gastro-oesophageal cancer patients were refractory to first-line therapy. Despite this refractory disease, DEP® cabazitaxel achieved a disease control rate (DCR) of 80.0%, and an objective response rate (ORR) of 30.0%, including stable disease (SD) for up to 27 weeks and partial responses (PR) for up to 17 weeks in evaluable gastro-oesophageal cancer patients (Table 4).
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Table 4. Key efficacy endpoints for DEP® cabazitaxel in gastro-oesophageal cancers
1
Cancer Type
Patients’ Prior Anti-Cancer Therapy (Median)16
Disease Control Rate (DCR13,17)
Objective Response Rate (ORR13,18)
Median PFS
2
Gastro-oesophageal
1 line, 6 cycles
80.0%
30.0%
4.0 months
Other Cancers
DEP® cabazitaxel also demonstrated promising efficacy responses in patients with a range of other cancer types, including head and neck cancer, cholangiocarcinoma and thymic carcinoma (total N=13). These responses included stable disease and tumour shrinkage of up to more than 30% (partial response, PR).
Standard cabazitaxel is currently only indicated for metastatic castrate-resistant prostate cancer. The efficacy responses of DEP® cabazitaxel in a broad range of cancer types, as demonstrated in the current study, demonstrate the potential clinical utility of DEP® cabazitaxel in additional indications, especially platinum-resistant ovarian cancer and advanced gastro-oesophageal cancers. DEP® Cabazitaxel Safety and Tolerability
In the Phase 2 study, a total of 75 patients were treated with DEP® cabazitaxel at 20 mg/m2 cabazitaxel administered intravenously (IV), once every 3 weeks, for up to 12 cycles. DEP® cabazitaxel was very well tolerated in patients enrolled in the study. Almost 90% of adverse events (AEs) deemed treatment-related were mild (grade 1, 63.9%) or moderate (grade 2, 24.8%), with very few severe (grade 3/4, 11.3%) events. Notably, the percentage of DEP® cabazitaxel-treated patients with grade 3 or 4 non-haematological, treatment-related AEs (21.3%) was approximately half that reported for Jevtana® (40%) at the same dose2.
Importantly, both the incidence and severity of bone marrow toxicity with DEP® cabazitaxel were markedly reduced compared to published data for Jevtana®. Only 16.0% of DEP® cabazitaxel treated prostate cancer patients experienced laboratory-detected grade 3 or 4 neutropenia, compared to 41.8% reported for Jevtana® at the same dose in prostate cancer patients2.
DEP® cabazitaxel treated patients experienced especially low rates or absence of severe, dose-limiting neutropenia, febrile neutropenia and thrombocytopenia, events which are particularly problematic in older patients or patients with poorer health (Table 5). Given the older age of many patients with prostate cancer, this reduced bone marrow toxicity is an important benefit of DEP® cabazitaxel.
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Table 5.Comparativebone marrow toxicity in prostate cancer patients treated with DEP® cabazitaxel vs published data on Jevtana®
1
Bone Marrow Toxicity
DEP® Cabazitaxel (20 mg/m2) (N=25†)
Jevtana®2(20 mg/m2) (N=580†)
2
Neutropenia* ≥ grade 3
16.0%
41.8%
3
Febrile neutropenia ≥ grade 3
0%
2.1%
4
Thrombocytopenia* ≥ grade 3
0%
2.6%
5
Neutropenic infection / sepsis
0%
2.1%
6
* Lab detected neutropenia or thrombocytopenia, regardless of whether event was reported as an adverse event † Safety population (received at least 1 dose)
AEs observed for DEP® cabazitaxel are all reported with conventional cabazitaxel (Jevtana®). Patients treated with DEP® cabazitaxel had significantly fewer grade 3/4 non-haematologic treatment related AEs25 compared to published data on Jevtana®2. AEs observed in ≥10% of DEP® cabazitaxel patients in Phase 2 included fatigue, neutropenia, anaemia, platelet count decrease, white blood cell decrease, constipation, diarrhoea, nausea, vomiting, peripheral neuropathy (PN) and decreased appetite. These AEs were generally well tolerated and manageable. Patients in the DEP® cabazitaxel study were heavily pre-treated with prior anti-cancer therapies, including taxanes, that have significant toxicities and can pre-dispose patients to toxicities such as myelosuppression (neutropenia) and PN, with subsequent treatments.
For many prostate cancer patients over 65 years old receiving Jevtana®, the recommendation is to receive prophylaxis with G-CSF26 from the first cycle (primary prophylaxis) to prevent severe/life-threatening neutropenia. Despite the high mean age (73 years) of prostate cancer patients in this study, there was no need to give any patients receiving DEP® cabazitaxel, primary G-CSF prophylaxis, including patients over 65. Furthermore, less than 10% of patients required any G-CSF therapy following an event of neutropenia.
Unlike Jevtana®, severe hypersensitivity reactions and anaphylaxis were not observed following DEP® cabazitaxel treatment. In addition, patients treated with DEP® cabazitaxel did not require routine pretreatment with steroids or antihistamines due to the absence of the detergent polysorbate-80 in Starpharma’s DEP® cabazitaxel formulation. Daily treatment with oral corticosteroids was also not required with DEP® cabazitaxel. Avoidance of long-term steroid use is beneficial, particularly for patients with prostate cancer whose bone health can be a significant issue. Dr Jackie Fairley, CEO, Starpharma, commented: “Starpharma is delighted to report positive final results from our Phase 2 clinical trial of DEP® cabazitaxel, which showed both efficacy and tolerability benefits in advanced prostate cancer patients, compared with the published data for Jevtana®. DEP® cabazitaxel also achieved impressive efficacy responses in advanced platinum-resistant ovarian cancer and advanced gastro-oesophageal cancer patients. These outcomes illustrate the ability of the DEP® platform to expand the potential market of an already successful cancer treatment and offer new options for patients.
“These very positive results for DEP® cabazitaxel in three common and hard-to-treat cancers demonstrate its therapeutic and commercial value as well as its ability to address significant unmet medical needs. Many of the patients who participated in the trial had no or very few options, and DEP® cabazitaxel delivered clinically meaningful outcomes. We are deeply grateful to the patients who participated in this trial and to the clinical investigators and their site teams who contributed to the study.”
Commerical Opportunity for DEP® cabazitaxel
The global prostate cancer drugs market was valued at more than US$12 billion in 2022 and is forecast to expand at a compound annual growth rate (CAGR) of 8.4% from 2023 to 203027. Globally, prostate cancer cases reached more than 1.4 million diagnosed in 202028.
The global ovarian cancer drugs market was valued at an estimated US$3.4 billion in 2022 and is anticipated to grow at a CAGR of 6.6% from 2023 to 203029. In 2020, a total of 313,959 new cases of ovarian cancer were recorded globally30.
The global gastro-oesophageal cancer drugs market was valued at approximately US$4.6 billion in 2021 and is expected to expand at a CAGR of 4.58% from 2022 to 203031. The number of cases globally is expected to grow from almost 1.7 million in 2020 to approximately 2.5 million by 203532.
These promising efficacy results for DEP® cabazitaxel in multiple common cancers demonstrate the significant market potential for DEP® cabazitaxel, not only in the approved prostate cancer indication of Jevtana®, but also in other cancers that have high unmet medical need.
Starpharma is engaged in ongoing commercial/licensing discussions with potential partners for DEP® cabazitaxel, and these final results form part of these discussions.
Additional Study Information
The study was a multi-centre, open-label, Phase 1/2 trial designed to assess the safety and preliminary efficacy of DEP® cabazitaxel in patients with advanced, metastatic solid tumour cancers. DEP® cabazitaxel was administered intravenously (IV) once every three weeks (Q3W) at a dose of 20 mg/m2 cabazitaxel. The objectives of the Phase 2 component of the trial were to further explore the anti-tumour efficacy in selected patient cohorts, and to further characterize the safety and tolerability of DEP® cabazitaxel.
Efficacy was assessed by radiographic imaging (CT [computerized tomography] scans) of tumours evaluated according to the Response Evaluation Criteria in Solid Tumours (RECIST) (version 1.1). The applicable aspects of the internationally recognised Prostate Cancer Working Group (PCWG3)33 guidelines were also applied for the prostate cancer cohort. Tumour biomarkers, such as prostate specific antigen (PSA), CA12521, and CEA22 were also assessed as a measure of anti-tumour activity, where applicable for a selected cancer type. Adverse events were assessed and graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03.
Treatment of patients with DEP® cabazitaxel continued until their disease progressed or worsened, or withdrawal for other reasons (e.g., COVID-19). However, if the treating investigator determined that clinical benefits, such as reduced pain or improved symptoms, were being derived from the treatment, patients had the option to continue treatment beyond disease progression.
A total of 75 patients with advanced solid tumours were recruited into and received DEP® cabazitaxel in the Phase 2 part of this trial. Patients were enrolled across 5 trial sites in the UK and Australia, including Guy’s Hospital, Imperial College and University College London Hospital (UCLH) in London, Velindre Cancer Centre in Cardiff, and the Kinghorn Cancer Centre at St Vincent’s Hospital in Sydney.
Patients were enrolled into three main patient cohorts: metastatic castrate-resistant (Stage IV) prostate cancer (mCRPC) (N=25), advanced platinum-resistant ovarian cancer (N=22) and advanced gastro-oesophageal cancers (N=15). The remaining Phase 2 patients had advanced disease that could potentially benefit from a taxane such as cabazitaxel: head and neck cancer (N=7), cholangiocarcinoma (N=4), non-small cell lung cancer (NSCLC) (N=1) and thymic carcinoma (N=1).
The ages of patients in the three main cancer cohorts are shown in Table 6.
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Table 6. Patient age by cancer type
1
Age (years)
Prostate
Ovarian
Gastro-oesophageal
2
Mean
73
62
59
3
Range
57 - 83
43 - 76
25 - 73
AEs observed for DEP® cabazitaxel are all reported with conventional cabazitaxel (Jevtana®). These AEs were generally well tolerated and manageable. AEs observed (all grades) in ≥10% of all DEP® cabazitaxel treated patients in Phase 2 include constipation (14.7%), diarrhoea (29.3%), nausea (48.0%), vomiting (29.3%), fatigue (60.0%), neutropenia (37.7%), anaemia (42.7%), platelet count decrease (17.3%), white blood cell decrease (13.3.%), peripheral neuropathy (PN, 60.0%), elevated liver enzymes (alanine aminotransferase, ALT 12.0%; aspartate aminotransferase, AST 18.7%), and decreased appetite (21.3%). Patients in this study were heavily pre-treated with anti-cancer therapies including cisplatin, oxaliplatin and taxanes that cause myelosuppression (neutropenia) and residual neurological toxicity (PN) and predispose patients to recurrence of these AEs with future treatments. The overall rate of laboratory-detected grade 3 or 4 neutropenia was 22.7%. View or download the ASX Announcement, here.
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