Regulatory Decision Summary for INVEGA TRINZA

Invega Sustenna, a product which contains the medicinal ingredient paliperidone palmitate, is a long-acting formulation designed to be administered once every 4 weeks in maintenance treatment of schizophrenia. Invega Sustenna has been approved and available in Canada since 2010, and is widely prescribed. The current SNDS is for Invega Trinza, an ultra-long-acting formulation of paliperdone palmitate, designed to be given once every 3 months in maintenance treatment of schizophrenia. Invega Trinzas longer duration of action compared to Invega Sustenna results from the use of a larger paliperidone palmitate particle size and a higher suspension concentration. Injection volumes are also larger. It is important to note that Invega Trinza is only to be used after patients have been stabilized on Invega Sustenna for at least four months. Clinical efficacy and safety of Invega Trinza has only been evaluated for use under this condition.

The filed SNDS consisted of three studies, a Phase I pharmacokinetic study (PSY 1005) and two Phase III studies (PSY 3012 and PSY 3011). The aim of the PSY 1005 study was to determine the choice of the dosing conversion between Invega Sustenna and Invega Trinza which would then be used in the Phase III studies. As patients need to be stabilized on Invega Sustenna prior to being switched to Invega Trinza, it is important to ensure that paliperidone palmitate exposures will be as similar as possible between the two formulations. Since Invega Sustenna is administered every 4 weeks and Invega Trinza every 3 months, the use of a 3-fold dosage conversion between Invega Sustenna and Invega Trinza was first explored. In study PSY-1005, it was determined that a 3-fold conversion factor was not sufficient, and that a 3.5-fold conversion factor would produce more similar exposures between the two formulations. A 3.5-fold conversion factor was then used in the Phase III studies. Recommended maintenance doses for Invega Sustenna are 50 mg, 75 mg, 100 mg, and 150 mg. Therefore, 3.5 times these doses were used for Invega Trinza.

In the two Phase III studies, patients were first administered Invega Sustenna during open-label stabilization, and investigators were permitted to adjust the dose as needed within the recommended dosage range. However, for the last two doses, they were to remain constant. The transition over to Invega Trinza was based on the final Invega Sustenna dose in the open-label study. Patients were administered their doses either in gluteal or deltoid muscle depending on their preference. Previous Invega Sustenna data had indicated that at steady state use of these two injection sites resulted in similar Invega Sustenna exposures, and injections at either site were generally well tolerated.

Study PSY-3012 was a randomized, double-blind withdrawal study That is, during the double-blind phase, patients were randomized to either continue on Invega Trinza or they were switched to placebo. The Primary outcome measure for this study was the time to relapse. Results from the study demonstrated a clinically and statistically significant shorter time to relapse in the placebo group. These results however, do not provide information about comparative efficacy of Invega Trinza versus Invega Sustenna using a 3.5-fold dosage conversion.

The PSY-3011 study enabled a direct comparison of efficacy and safety between Invega Trinza and Invega Sustenna, under conditions of use previously discussed. The PSY-3011 study was a non-inferiority study comparing patients randomized to Invega Trinza or continuing on Invega Sustenna after 4 months of open-label stabilization with Invega Sustenna. The switch from Invega Sustenna to Invega Trinza used a 3.5 fold conversion factor, thus allowing direct comparison of Invega Sustenna dosing to Invega Trinza dosing using this conversion factor. Time to relapse was the primary outcome. Survival curves for the two formulations were essentially identical, as was time to relapse, demonstrating the non-inferiority of Invega Trinza to Invega Sustenna. It must be noted however that as with PSY-3012 study, investigators prescribed the two higher paliperidone palmitate doses to most of the patients (~90%). Therefore, the data reflect efficacy at the higher paliperidone palmitate doses. However, efficacy at the two lower paliperidone palmitate doses is unclear.

Comparative pharmacokinetic data derived from the PSY 3011 study generally support similar exposures for Invega Sustenna and Invega Trinza when administered in the deltoid using the 3.5 conversion factor. However, when Invega Trinza is administered in the gluteal muscle, exposures were 25%-40% lower than Invega Sustenna gluteal administration, as well as Invega Trinza deltoid administration. These differences were statistically significant. Therefore Invega Trinza administration in the gluteal muscle, on average, produces lower exposures of paliperidone than Invega Sustenna injections (deltoid or gluteal) or Invega Trinza deltoid injections, when the 3.5-fold conversion factor is used. The sponsor has stated that these differences in exposure are not clinically relevant, and they do support this with clinical efficacy data from Study 3011. That is, when deltoid and gluteal injection groups are analyzed separately on efficacy outcome, Invega Sustenna and Invega Trinza survival curves still remain essentially identical. Most patients were treated at the two highest dose levels. At these higher doses, somewhat lower exposure in the gluteal with Invega Trinza may not be an issue. However at lower doses of the drug, it is possible that this difference may have more impact.

This SNDS, as with the Invega Sustenna submission, uses a population pharmacokinetic model (but a different one) as a basis to describe pharmacokinetic values, and to compare the pharmacokinetic profile of Invega Sustenna to Invega Trinza. In addition, the model is used to predict the effect of missed or delayed doses of Invega Trinza, and provides the basis for detailed recommendations with respect to dosing in varied missed or delayed dose scenarios. There were concerns regarding the validity of this model. Therefore, no information derived from the model was included in the Product Monograph; information included was from actual clinical trial data.

One further concern is the use of population pharmacokinetic model simulations to make a recommendation regarding late or missed doses, given the uncertainty of the models validity. Extrapolating from pharmacokinetic data of Study PSY3011, we would expect that the recommendations could result in initial exposures 27-50% higher than at steady state. However, the data suggest that these Invega Trinza exposures would not be as high as those which could occur using the approved regimen for the missed doses of Invega Sustenna. Understanding that it may be best to have higher exposures acutely rather than lower exposures and understanding that the product appears to be well tolerated at higher doses, the proposed dosing recommendations are determined to be adequate.

It should also be noted that Invega Trinza requires 15 seconds of vigorous shaking immediately prior to injection, to ensure homogeneity, and complete injection of dose. Despite these instructions, in the pivotal studies there were a few cases where the product was not sufficiently shaken. Given this issue could potentially result in a substantial reduction in efficacy, the Invega Trinza Product Monograph must adequately highlight this issue, so that healthcare providers always follow the shaking instructions, and that syringes with unusual or lumpy not be injected.

Overall, Invega Trinza offers the benefit of being the longest acting injectable antipsychotic requiring injections only every 3 months. Therefore, use of Invega Trinza for the treatment of schizophrenia in adult patients would require outpatient clinic visits for an injection only 4 times a year, rather than the every 2 or 4 weeks, currently required. In addition, with injections every 3 months, the patient is covered by medication for longer periods of time and so the use of Invega Trinza will delay relapse when treatment is suddenly interrupted (for example [e.g.] as a result of poor adherence or limited access to healthcare resources), and allow more time to attempt to manage non-adherence, compared to currently available products. On the other hand, Invega Trinzas longer duration of action makes it more problematic to manage with dose reduction emergent drug-induced adverse events, or break-through psychosis with dosage escalation. Drug-induced adverse events should be minimized by following the dosage and administration recommendations, establishing tolerance with the monthly formulation for at least 4 months prior to beginning treatment with Invega Trinza.

At a dose of 3.5 times that of Invega Sustenna, Invega Trinza demonstrated similar efficacy with respect to relapse prevention. The safety profile of Invega Trinza is similar to Invega Sustenna. Due to larger particle size and higher suspension concentration of Invega Trinza, it is more difficult to ensure a homogeneous suspension, running the risk of incomplete injection if the syringe is not shaken sufficiently vigorously and for sufficient time. Given the higher suspension concentration and injection volume, one might also expect more injection site reactions with Invega Trinza compared to Invega Sustenna. Clinical data show however, that the injections were generally well tolerated in both the gluteal and deltoid muscle. Exposure with gluteal injection was somewhat lower than with deltoid injections, but this difference in exposure did not result in any observed difference in efficacy between the two injection sites.