MyVisionTest News Archive
Jan 25, 2010
As-needed Lucentis therapy for AMD
A flexible, individualized visual acuity-guided regimen after the three initial injections may sustain vision improvement with Lucentis (ranibizumab) and could improve cost-effectiveness and convenience and reduce drug administration–associated risks, according to a new study.
In two phase 3 clinical trials, the time course of mean visual acuity (VA) changes seen with monthly Lucentis injections showed a biphasic pattern. Rapid visual acuity (VA) improvement was seen in most patients during the initial 3 months, followed by a 9-month phase, in which only small further changes in mean VA of approximately 2 letters occurred, compared with the level achieved at the end of the 3-month initiation phase (Figure 1).
The VA improvements seen during the first three consecutive monthly Lucentis injections in the MARINA, ANCHOR, and PIER3 trials — and the differences between monthly and quarterly treatment during the following 9 months of these trials — demonstrate the relevance of the initiation phase, but prompt two key questions for the period after the initiation phase:
After the three monthly injections in the initiation phase, the monthly regimen used in MARINA and ANCHOR appeared to be superior to the quarterly regimen used in PIER, in terms of the observed mean VA changes. However, analysis of the data from the PIER trial showed that 40% of patients treated with 0.5 mg Lucentis maintained their initial gain in VA with the quarterly regimen, providing proof of the principle that initial VA gains can be sustained in some patients with injections given less frequently than monthly (Figure 2).
To answer the second question, the researchers constructed a drug and disease model of neovascular AMD treated with intravitreal Lucentis to explore an individualized, flexible regimen after an initiation phase of three once-monthly injections.
Methods and Results
For visual acuity (VA), a model was developed on the 12-month data from ANCHOR, MARINA, and PIER. Data from untreated patients were used to model patient-specific disease progression in terms of VA loss. Data from treated patients from the period after the three initial injections were used to model the effect of predicted ranibizumab vitreous concentration on VA loss. The model was checked by comparing simulations of VA outcomes after monthly and quarterly injections during this period with trial data. A flexible VA-guided regimen (after the three initial injections) in which treatment is initiated by loss of >5 letters from best previously observed VA scores was simulated.
Simulated monthly and quarterly VA-guided regimens showed good agreement with trial data. Simulation of VA-driven individualized treatment suggests that this regimen, on average, sustains the initial gains in VA seen in clinical trials at month 3. The model predicted that, on average, to maintain initial VA gains, an estimated 5.1 ranibizumab injections are needed during the 9 months after the three initial monthly injections, which amounts to a total of 8.1 injections during the first year.
Discussion and Conclusions
The concept of an individualized dosage regimen for the treatment of neovascular AMD with Lucentis was initially formed based on subgroup analysis of the PIER study results. This analysis demonstrated that some patients can maintain initial improvement in VA with injections given on a quarterly basis (Figure 2). However, a comparison of data from the ANCHOR, MARINA, and PIER studies shows that, on average, monthly Lucentis is more efficacious than quarterly treatment. Therefore, the Lucentis treatment schedule requires optimization to an individualized approach, as the combined results of these three trials suggest that, in some patients, monthly injections would lead to overtreatment and, therefore, unnecessary exposure to treatment risks.
The drug and disease model reported herein for the treatment of neovascular AMD with ranibizumab was designed to evaluate whether an individualized, flexible VA-guided treatment regimen could obtain efficacy comparable to that observed with monthly doses, while at the same time considerably reducing the number of retreatment injections. Together with its corresponding simulations, this approach can be considered as a proof of concept (i.e., a first indication of relevant efficacy) for such an individualized treatment regimen.
The results from the drug and disease model suggest that it is feasible and effective to individualize Lucentis treatment based on monthly monitoring of VA. The simulation predicts that during a year of VA-guided therapy, mean VA results over time closely mirror those seen in previous clinical trials with monthly injections, even though the simulation resulted in substantially fewer intravitreal injections. The difference between the monthly regimen and the VA-guided regimen can be estimated to be approximately 3 to 4 letters after 1 year of treatment after the initiation phase. This difference can be mainly explained by the retreatment guidance that requires a patient to experience a loss of at least 5 letters before retreatment.
The individualized, flexible retreatment regimen, based on monthly VA assessment and treatment when the VA declines by more than 5 letters, should provide an approach to further optimize Lucentis treatment in AMD by specifically addressing over-treatment and its associated risks.
The drug and disease model was developed using simplified assumptions and was fitted to the patients in the MARINA, ANCHOR, and PIER trials, who fulfilled the respective inclusion/exclusion criteria; correspondingly, the conclusions derived from this model are limited to the patient population of these studies. Underlying assumptions, such as an absence of between-patient variability in the intravitreal concentration of ranibizumab in response to a dedined dose as well as stable individual natural progression disease rate, mean that the model has a tendency to underestimate variability in the need for retreatment and, therefore, also underestimates the benefit of an individualized flexible treatment regimen. Even with these conservative assumptions regarding between-patient variability, the model predicted considerable variability in the number of injections required during the VA-guided phase, providing strong justification for an individualized treatment regimen with the potential to substantially avoid overtreatment.
The advantages of flexible dose regimen reported herein is likely to be even greater in clinical practice if the guidance for retreatment could be extended to other disease status assessments, particularly optical coherence tomography (OCT), using both quantitative and qualitative criteria.
In conclusion, VA outcomes data from Lucentis phase 3 clinical trials, together with the drug and disease modeling results reported herein, support an individualized Lucentis treatment regimen of three initial once-monthly injections of 0.5 mg Lucentis followed by monthly monitoring of VA, and retreatment if a VA loss of more than 5 letters occurs. The simulations predict that using an individualized treatment approach in the clinic would have the potential to reduce overtreatment and its associated risks.
Read more...
Invest Ophthalmol Vis Sci. 2010 Jan;51(1):405-12
Tags: dosing strategy, clinical trial, wet AMD
A flexible, individualized visual acuity-guided regimen after the three initial injections may sustain vision improvement with Lucentis (ranibizumab) and could improve cost-effectiveness and convenience and reduce drug administration–associated risks, according to a new study.In two phase 3 clinical trials, the time course of mean visual acuity (VA) changes seen with monthly Lucentis injections showed a biphasic pattern. Rapid visual acuity (VA) improvement was seen in most patients during the initial 3 months, followed by a 9-month phase, in which only small further changes in mean VA of approximately 2 letters occurred, compared with the level achieved at the end of the 3-month initiation phase (Figure 1).
- Do the available data support the concept of an individualized treatment regimen, based on individual differences in the need for retreatment?
- If this is the case, can a VA-guided treatment regimen obtain efficacy comparable to that observed with a monthly dose (i.e., on average maintaining the initial VA gain achieved at month 3)?
After the three monthly injections in the initiation phase, the monthly regimen used in MARINA and ANCHOR appeared to be superior to the quarterly regimen used in PIER, in terms of the observed mean VA changes. However, analysis of the data from the PIER trial showed that 40% of patients treated with 0.5 mg Lucentis maintained their initial gain in VA with the quarterly regimen, providing proof of the principle that initial VA gains can be sustained in some patients with injections given less frequently than monthly (Figure 2).
To answer the second question, the researchers constructed a drug and disease model of neovascular AMD treated with intravitreal Lucentis to explore an individualized, flexible regimen after an initiation phase of three once-monthly injections.
Methods and Results
For visual acuity (VA), a model was developed on the 12-month data from ANCHOR, MARINA, and PIER. Data from untreated patients were used to model patient-specific disease progression in terms of VA loss. Data from treated patients from the period after the three initial injections were used to model the effect of predicted ranibizumab vitreous concentration on VA loss. The model was checked by comparing simulations of VA outcomes after monthly and quarterly injections during this period with trial data. A flexible VA-guided regimen (after the three initial injections) in which treatment is initiated by loss of >5 letters from best previously observed VA scores was simulated.
Simulated monthly and quarterly VA-guided regimens showed good agreement with trial data. Simulation of VA-driven individualized treatment suggests that this regimen, on average, sustains the initial gains in VA seen in clinical trials at month 3. The model predicted that, on average, to maintain initial VA gains, an estimated 5.1 ranibizumab injections are needed during the 9 months after the three initial monthly injections, which amounts to a total of 8.1 injections during the first year.
Discussion and Conclusions
The concept of an individualized dosage regimen for the treatment of neovascular AMD with Lucentis was initially formed based on subgroup analysis of the PIER study results. This analysis demonstrated that some patients can maintain initial improvement in VA with injections given on a quarterly basis (Figure 2). However, a comparison of data from the ANCHOR, MARINA, and PIER studies shows that, on average, monthly Lucentis is more efficacious than quarterly treatment. Therefore, the Lucentis treatment schedule requires optimization to an individualized approach, as the combined results of these three trials suggest that, in some patients, monthly injections would lead to overtreatment and, therefore, unnecessary exposure to treatment risks.The drug and disease model reported herein for the treatment of neovascular AMD with ranibizumab was designed to evaluate whether an individualized, flexible VA-guided treatment regimen could obtain efficacy comparable to that observed with monthly doses, while at the same time considerably reducing the number of retreatment injections. Together with its corresponding simulations, this approach can be considered as a proof of concept (i.e., a first indication of relevant efficacy) for such an individualized treatment regimen.
The results from the drug and disease model suggest that it is feasible and effective to individualize Lucentis treatment based on monthly monitoring of VA. The simulation predicts that during a year of VA-guided therapy, mean VA results over time closely mirror those seen in previous clinical trials with monthly injections, even though the simulation resulted in substantially fewer intravitreal injections. The difference between the monthly regimen and the VA-guided regimen can be estimated to be approximately 3 to 4 letters after 1 year of treatment after the initiation phase. This difference can be mainly explained by the retreatment guidance that requires a patient to experience a loss of at least 5 letters before retreatment.
The individualized, flexible retreatment regimen, based on monthly VA assessment and treatment when the VA declines by more than 5 letters, should provide an approach to further optimize Lucentis treatment in AMD by specifically addressing over-treatment and its associated risks.
The drug and disease model was developed using simplified assumptions and was fitted to the patients in the MARINA, ANCHOR, and PIER trials, who fulfilled the respective inclusion/exclusion criteria; correspondingly, the conclusions derived from this model are limited to the patient population of these studies. Underlying assumptions, such as an absence of between-patient variability in the intravitreal concentration of ranibizumab in response to a dedined dose as well as stable individual natural progression disease rate, mean that the model has a tendency to underestimate variability in the need for retreatment and, therefore, also underestimates the benefit of an individualized flexible treatment regimen. Even with these conservative assumptions regarding between-patient variability, the model predicted considerable variability in the number of injections required during the VA-guided phase, providing strong justification for an individualized treatment regimen with the potential to substantially avoid overtreatment. The advantages of flexible dose regimen reported herein is likely to be even greater in clinical practice if the guidance for retreatment could be extended to other disease status assessments, particularly optical coherence tomography (OCT), using both quantitative and qualitative criteria.
In conclusion, VA outcomes data from Lucentis phase 3 clinical trials, together with the drug and disease modeling results reported herein, support an individualized Lucentis treatment regimen of three initial once-monthly injections of 0.5 mg Lucentis followed by monthly monitoring of VA, and retreatment if a VA loss of more than 5 letters occurs. The simulations predict that using an individualized treatment approach in the clinic would have the potential to reduce overtreatment and its associated risks.
Read more...
Invest Ophthalmol Vis Sci. 2010 Jan;51(1):405-12
