Why Novartis Rejected Access Consortium In Favor Of Direct Uk Radioligand Filing
Executive Summary
A direct marketing authorization application to the UK medicines regulator offered a quicker route to approval for Novartis prostate cancer treatment Pluvicto than following the international Access Consortium process, because of the novel nature of the therapy, according to the company.
decided against using the international Access Consortium work-sharing procedure to obtain a marketing authorization for its radioligand therapy Pluvicto in Great Britain because it felt that a direct application to the UK regulator, the MHRA, would be faster.
The Access Consortium had not yet assessed a radioligand therapy , which is an emerging treatment approach, so it was felt that the consortium process would have been slower to deliver an approval than going direct to MHRA, Novartis told the Pink Sheet.
In August, the MHRA became the first regulator in Europe to authorize Pluvicto vipivotide tetraxetan). The product is for adults with prostate-specific membrane antigen -positive metastatic castration-resistant prostate cancer who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy or who are not medically suitable for taxanes.
The authorization is valid in England, Scotland and Wales, but not Northern Ireland, which is subject to EU medicines regulations. The applicant for the product was the Novartis company, Advanced Accelerator Applications SA.
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Determination Of Psa Levels
PSA levels were determined using blood samples prior to the first RLT and on the admission days for the following cycles. For the present analysis, we included PSA values up to cycle 4, day 0. Following the recommendations of the Prostate Cancer Clinical Trials Working Group 3 , patients were allocated to different categories . In this regard, response was defined as PSA decrease50%, progressive disease as PSA increase that is25% and2 ng/mL above the nadir as well as stable disease which is neither response nor PD. Categories were then as follows: sustained response response followed by SD SD response followed by PD SD followed by PD and PD.
Independent of PCWG3 criteria, we also calculated relative changes in PSA levels compared to baseline levels, and categorized them as initial and sustained decrease in PSA levels, or initial and sustained increase in PSA levels , or PSA fluctuations during follow-up, characterized by change after initial decrease or increase . For the subgroup , late responders were characterized by an initial increase followed by a decrease in PSA levels.
We then compared survival between all subgroups. OS was defined as the time between first cycle of RLT and date of death.
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Targeted Radioligand Therapy Viable For Certain Men With Advanced Prostate Cancer
Hofman MS, et al. Abstract 5000. Presented at: ASCO Annual Meeting June 3-7, 2022 Chicago.
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CHICAGO Lutetium Lu 177 vipivotide tetraxetan is a viable option for certain men with advanced prostate cancer, according to study results presented at ASCO Annual Meeting.
Lutetium Lu 177 vipivotide tetraxetan appeared associated with a higher response rate, greater PFS benefit and better patient-reported outcomes than cabazitaxel for men with metastatic castration-resistant, prostate-specific membrane antigen-positive prostate cancer whose disease progressed after docetaxel and an androgen receptor pathway inhibitor.
OS appeared comparable between the two therapies, results of the TheraP ANZUP 1603 trial showed.
Background and methods
Lutetium Lu 177 vipivotide tetraxetan formerly called 177Lu-PSMA-617 is the first targeted radioligand therapy for treatment of progressive, prostate-specific membrane antigen -positive metastatic castration-resistant prostate cancer. PSMA is highly expressed in more than 80% of men with prostate cancer.
The TheraP trial included 200 men with metastatic castration-resistant prostate cancer whose disease progressed after docetaxel.
Eligibility criteria included high PSMA expression defined as at least one site with standard uptake valuemax of 20 or higher and 18F-FDA demonstrating no discordant disease .
Results
Convergent Therapeutics Point Biopharma Pair Antibody Radioligand Therapy In Prostate Cancer Study
NEW YORK Convergent Therapeutics on Tuesday said it will evaluate CONV 01-alpha, a prostate-specific membrane antigen-directed antibody paired with the alpha particle emitter actinium-225, in combination with Point Biopharmas PSMA radioligand PNT2002 linked to a beta particle emitter lutetium-177 in advanced castration-resistant prostate cancer patients.
The drugmakers are evaluating CONV 01-alpha and PNT2002 in a Phase I/II trial that has already begun enrolling patients at Weill Cornell Medicine. Investigators will enroll up to 33 patients with metastatic castration-resistant prostate cancer that is PSMA-positive by PET imaging. Patients must have progressive disease despite prior treatment with an androgen receptor signaling inhibitor and taxane chemotherapy.
In the Phase I dose-escalation portion, researchers will establish the maximum tolerated dose for CONV 01-alpha, which patients will receive in combination with a dose of PNT2002 that Point established in another ongoing trial, called SPLASH. Then, in the Phase II expansion portion, researchers will track the number of patients who after receiving the combination regimen experience more than a 50 percent decline in prostate-specific antigen levels.
The strategy to couple an antibody with ligand-targeted treatments evolved from research conducted at Weill Cornell Medicine and patented by Cornell University, which Cambridge, Massachusetts-based Convergent exclusively licensed.
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Why Are Readiness Assessment Frameworks Needed
To create a health system that is ready to adapt to change, we must take a rigorous approach that allows for evidence-based decision-making and proactive policy action.
Frameworks are tools that can be used to help understand and solve complex problems, allowing us to proactively prepare for the future of healthcare. A framework enables us to assess the operations of a health system in a standardised and objective way. It can also help to ensure that people are asking the right questions in regard to health system improvement.
Data generated by applying frameworks can also be used to identify gaps in the provision of care. As the same framework can be applied in different settings, it can also enable comparison and learning within and between countries.
The Health Policy Partnership has developed the Readiness Assessment Framework to evaluate current integration of and readiness for innovative approaches to care across a health system. The framework covers five key domains: governance, regulation and reimbursement, identified need, service provision and health information. Before it is applied, the framework should be adapted to a particular care approach to ensure that the data generated are specific, relevant and useful.
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Survival In Men With Psa Fluctuations Is Comparable To Those With Maintained Psa Decrease
Median OS of patients with sustained decrease in PSA levels was significantly longer when compared to patients with sustained increase of PSA levels . Patients with PSA fluctuations showed a significantly longer median OS compared to patients with sustained increase of PSA levels , but were comparable to those patients with sustained decrease in PSA levels .
a Median overall survival of patients with sustained decrease in PSA levels was significantly longer when compared to men with sustained increase of PSA levels . Median OS of patients with PSA fluctuations was significantly longer compared to patients with sustained increase of PSA levels . However, there was no significant difference in OS between patients with PSA fluctuations to patients with sustained decrease in PSA levels , thereby indicating that patients with tumor marker oscillations should continue treatment. b In the subgroup of patients with PSA fluctuations , the median OS did not differ significantly between patients with initial decrease or initial increase of PSA levels
In the subgroup of patients experiencing PSA fluctuations during follow-up, median OS did not differ significantly between patients with initial decrease or late responders .
Similar findings were also observed for a subgroup analysis investigating patients treated with either Lu-PSMA I& T or Lu-PSMA-617 .
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Patients With Pd Had Shorter Overall Survival Compared To All Other Patients
According to our six predefined categories following PCWG3 criteria , 47/176 patients were allocated to category 1, 8/176 to category 2, 20/176 to category 3, 20/176 to category 4, 18/176 to category 5, and 61/176 to category 6. Two patients had to be excluded due to classification, which did not fall into one of the predefined categories. OS was significantly shorter for patients in category 6 compared to all other categories . No significant differences in OS were found when comparing patients within the categories 15 .
Following the recommendations of the Prostate Cancer Clinical Trials Working Group 3 , patients were allocated to different categories , which also took PSA values during follow-up into account. The derived categories were as follows: sustained response, response followed by SD, SD, response followed by PD, SD followed by PD, PD. Median overall survival was significantly shorter for patients in category 6 compared to all other categories . There were no significant differences within the categories 15 . cat., category SD, stable disease PD, progressive disease
What Is Health System Readiness
Health system readiness is the ability of a health system to promptly and sustainably adapt its policies, infrastructure and processes to support the integration of innovative approaches to care.
Healthcare is rapidly changing, so it is important that health systems are flexible and able to adapt effectively. Looking at one area of a health system in isolation is not sufficient we must take a holistic approach to ensure that innovative diagnostics and treatments can be integrated into care in a timely manner, and that all people can access the services that could benefit them most.
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Fda Grants Priority Review To Targeted Radioligand Therapy For Advanced Prostate Cancer
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The FDA granted priority review to 177Lu-PSMA-617 for treatment of certain men with advanced prostate cancer.
The designation applies to use of 177Lu-PSMA-617 , an investigational targeted radioligand therapy, by men with metastatic castration-resistant disease who received androgen receptor pathway inhibition and taxane-based chemotherapy.
The FDA is expected to make a decision on approval in the first half of 2022.
The agency based the priority review designation on results of the randomized phase 3 VISION study.
As Healio previously reported, results presented during the plenary session of this years virtual ASCO Annual Meeting showed the addition of 177Lu-PSMA-617 to standard care significantly extended OS and radiographic PFS among men with progressive prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer.
The FDA previously granted breakthrough therapy designation to 177Lu-PSMA-617 for metastatic castration-resistant prostate cancer.
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Fda Grants Priority Review For Investigational Targeted Radioligand Therapy 177lu
- Priority Review is based on positive data from the pivotal, Phase III VISION study showing 177Lu-PSMA-617 plus standard of care , significantly improved overall survival and radiographic progression-free survival for men with progressive PSMA-positive mCRPC compared to SOC alone2
- Two additional studies with 177Lu-PSMA-617 in earlier lines of treatment for metastatic prostate cancer are ongoing, investigating clinical utility in the pre-taxane setting and in the metastatic hormone-sensitive setting 3,4
The FDA previously granted Breakthrough Therapy designation for 177Lu-PSMA-617 for the treatment of mCRPC. Data from the VISION study were published in The New England Journal of Medicine 2. Novartis is also evaluating additional opportunities to investigate 177Lu-PSMA-617 in earlier stages of prostate cancer.
Disclaimer
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Health Canada Approves Pluvicto As First Targeted Radioligand Therapy For Progressive Psma Positive Metastatic Castration
- Prostate cancer is the most diagnosed cancer among men2 new approaches are needed to treat patients with advanced forms of the disease
- Advanced Accelerator Applications is committed to reimagining medicine and cancer care with targeted radioligand therapy, a precision cancer treatment
Mississauga, Ontario, September 7, 2022 – Advanced Accelerator Applications Canada Inc. is pleased to announce that Health Canada has approved PLUVICTOTM vipivotide tetraxetan injection) for the treatment of adult patients with prostate-specific membrane antigen -positive metastatic castration-resistant prostate cancer who have received at least one androgen receptor pathway inhibitor and taxane-based chemotherapy1.
Psa Fluctuations Occur Frequently But Rate Of Late Responders Is Low
For the entire cohort, 61/176 patients showed a sustained increase in PSA levels and 86/176 a sustained decrease in PSA levels. The remaining 29 out of 176 men showed PSA fluctuations. Twenty-two out of twenty-nine of those patients showed an initial decrease followed by an increase during follow-up, while the remaining 7 patients were classified as late responders. As such, among the entire cohort, only 4% demonstrated late response.
Similar results were achieved when analyzing patients that received either Lu-PSMA-617 or -I& T, with patients characteristics demonstrating no significant differences between both groups .1). For individuals treated with the latter radiopharmaceutical, 34/89 patients showed a sustained increase in PSA levels and 44/89 a sustained decrease in PSA levels. The remaining 11/89 showed PSA fluctuations. Of those patients, 8/11 showed an initial decrease followed by increase during follow-up, while 3/11 were late responders. Detailed PSA courses over all treatment cycles for patients treated with Lu-PSMA I& T are shown in Fig. 2 .
PSA levels over time in patients undergoing radioligand therapy with Lu-PSMA I& T. Patients with sustained decrease of PSA levels are marked in green. Patients with sustained increase of PSA levels are marked in red. Patients with PSA fluctuations were defined as changes over time after initial increase or decrease and thus, are crossing zero line
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Under Assessment By Nice
Meanwhile, back in Great Britain, an assessment by NICE, the health technology appraisal body for England and Wales, is underway. An appraisal committee meeting is scheduled to take place on 15 September, according to the NICE website. The company has also made a submission to the SMC, the Scottish HTA body, it said.
Currently, 22 specialist centers in the UK can administer RLT, Novartis is committed to working with the NHS to support healthcare system readiness and reduce healthcare inequalities for eligible patients to lutetium vipivotide tetraxetan.
A See It Treat It Approach
Nuclear medicine has both diagnostic imaging and therapeutic components, which we call radioligand imaging and radioligand therapy. Both use the same targeting approach. The diagnostic imaging component delivers radioactive atoms that have the potential to reveal tumor locations, while the therapeutic component delivers radioactive particles that have the potential to damage cells.
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Uk Grants Marketing Authorization For Novartis Radioligand Therapy For Advanced Prostate Cancer
The UKs MHRA has granted marketing authorization for Novartis radioligand therapy, Pluvicto, for the treatment of advanced prostate cancer in Great Britain.
An emerging therapy approach, radioligand therapy may offer an alternative treatment option for some cancer patients, by combining a targeting compound with a therapeutic radioisotope . It is administered via the bloodstream and delivers targeted radiation to cancer cells in the body while aiming to limit damage to surrounding tissue.
Far too many people are still dying each year from prostate cancer. Tragically, those diagnosed with metastatic prostate cancer will only have about a 1 in 2 chance of surviving 5 years, said Steve Allen, acting chair of Tackle Prostate Cancer, in a company press release. Todays announcement of marketing authorization for lutetium treatment is another positive milestone for eligible patients and their families. There continues to be a real and pressing need for better treatments for people with advanced prostate cancer. This new approach is very welcome.
What Are Prostate Cancer Survival Rates
Prostate cancer can either be localized , regional , or advanced .3
Incidence and mortality rates for prostate cancer vary greatly, with more developed nations generally having higher incidence of prostate cancer but lower mortality. For example, the lifetime risk of prostate cancer in the United States is nearly 4 times greater than the global risk.4
Approximately 74% of patients with prostate cancer in the US have localized prostate cancer at diagnosis, while approximately 13% have regional prostate cancer. For people with localized prostate cancer, the 5-year survival rate is nearly 100%.5
However, for the approximately 7% of patients who have advanced prostate cancer when theyre diagnosed, the 5-year survival rate is around 30%.5
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Predictors Of The Response
Ferdinandus et al. evaluated the prognostic value of various pre-therapeutic parameters on therapy response, based on changes in PSA after the first cycle of RLT. Their multivariate analysis of these parameters, which considered any decrease in PSA after 2 months, showed that patients with a high platelet count or a regular need for analgesics had a significantly worse response to the first RLT cycle. When a PSA decline of 50% was considered, patients with a regular need for analgesics showed a worse response in the multivariate analysis however, other pre-therapeutic parameters had no impact on the response to RLT. In this study, the standard uptake value maximum of 68Ga-PSMA-11 was not a significant predictor of the response to RLT. One explanation for this could be that more aggressive tumours may express higher PSMA levels. However, despite the better uptake of 177Lu-PSMA-617 due to the rapid growth of metastases, the response rate did not correlate with the uptake, which could be due to different washout times of 177Lu-PSMA-617 in the respective metastases .