Summary Basis of Decision for Egrifta

Clinical Pharmacology

Human immunodeficiency virus (HIV)-associated lipodystrophy is a poorly defined condition associated with antiretroviral therapy and HIV infection itself. Lipodystrophy is characterised by abnormalities in body composition and metabolism, including increased loss of subcutaneous fat (lipoatrophy), especially in the legs, arms and face, visceral adiposity (lipohypertrophy), glucose intolerance, and lipid abnormalities, including hypercholesterolemia. There is currently no approved therapy for excess abdominal fat in patients with HIV lipodystrophy, although evidence exists for benefit from exercise in the reduction of truncal fat in HIV infected patients with increased abdominal girth.

In vitro, tesamorelin binds and stimulates human Growth Hormone-Releasing Factor (hGRF) receptors with similar potency as the natural GRF. Growth Hormone-Releasing Factor, also known as Growth Hormone-Releasing Hormone (GHRH), is a hypothalamic peptide that acts on the pituitary somatotroph cells to stimulate the synthesis and pulsatile release of endogenous Growth Hormone (GH). Growth hormone has been shown to be anabolic and lipolytic. It exerts its effects by interacting with specific receptors on a variety of target cells, including chondrocytes, osteoblasts, myocytes, hepatocytes, and adipocytes, resulting in a host of pharmacodynamic effects. Some, but not all these effects, are primarily mediated by IGF-1 produced in the liver and in peripheral tissues.

The absolute bioavailability of subcutaneous tesamorelin 2 mg dose was <4% in healthy subjects. In HIV patients, the area under the curve (AUC), maximum concentration (C_max), median of time to maximum plasma concentration (t_max), volume of distribution (VD), and half-life (t_1/2) of subcutaneous 2 mg tesamorelin were 852.8 pg.h/mL, 2,822.3 pg/mL, 0.15 h, 10.5 L/kg and 38 minutes, respectively. Tesamorelin pharmacokinetics were not characterized in renal or hepatic impaired subjects as well as special populations (pediatrics, geriatrics, race and gender).

From the perspective of drug-drug interactions, tesamorelin does not significantly affect CYP3A activity. Pharmacokinetics of the CYP3A substrate simvastatin or CYP3A4 inhibitor ritonavir were not altered when co-administered with multiple dose 2 mg tesamorelin in healthy subjects.

For further details, please refer to the Egrifta Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

Evidence for the efficacy and safety of (Egrifta) tesamorelin was based on two pivotal Phase III clinical studies: study LIPO-010 (Main and Extension Phase) and the second study, which was subdivided into studies CTR-1011 and CTR-1012 (corresponding to the Main and Extension Phases of study LIPO-010), but which can be considered a single pivotal trial essentially identical to study LIPO-010. Patients were randomized 2:1 between tesamorelin and control treatments; in the combined studies a total of 543 patients were randomized to the tesamorelin group and 263 to the placebo group. At Week 26, patients willing to continue to Week 52 (the Extension Phase) were re-randomized so that patients who had received tesamorelin received either tesamorelin or switched to placebo, and patients who had received placebo were switched to tesamorelin.

The primary efficacy endpoint of the pivotal studies was a reduction of visceral adipose tissue (VAT), as measured by cross-sectional computed tomography (CT) scan at the L4-5 level after 26 weeks of tesamorelin therapy. A reduction in VAT of ≥ 8% was deemed clinically relevant. This cut-off was based on an arbitrary figure determined in a 2005 HIV Forum on lipodystrophy, which included participants from industry, academia and regulators, including the United States Food & Drug Administration.

In the tesamorelin pivotal studies, after 26 weeks of daily tesamorelin 2 mg intramuscular injections, VAT losses in the tesamorelin treated patients compared to placebo were 20% and 10%, for studies LIPO-010 and CTR-1011, respectively, yielding a pooled placebo-adjusted mean decrease of 15.4% (p<0.001). These results exceeded the pre-specified cut-off of 8% for clinical significance. Anthropometrically, at 26 weeks, a placebo-adjusted decrease in mean waist circumference of 1.6 cm was seen, from a baseline mean waist circumference of 105 cm.

Patients who continued on tesamorelin from Weeks 26-52 maintained their VAT loss, with no further significant VAT decrease, and the majority of VAT loss was evident by Week 13. Patients who discontinued tesamorelin at Week 26 experienced a return of VAT to baseline levels by Week 39 of treatment.

Secondary endpoints assessed in the pivotal studies included several Patient Reported Outcomes (PROs), with the key PRO consisting of the Belly Appearance Distress (BAD) score. Changes from baseline in lipid parameters [triglycerides, total cholesterol:high density lipoprotein (HDL) ratio, non-HDL cholesterol] were also determined, as well as changes in levels of insulin-like growth factor-1 (IGF-1), which was considered a surrogate endpoint of response to tesamorelin.

Results for the secondary efficacy endpoints were inconsistent between studies. For BAD, in Study LIPO-010 at Week 26 the difference between the tesamorelin and placebo groups did not achieve statistical significance, by the protocol-specified analysis. In Study CTR-1011, the improvement in the tesamorelin group was significantly greater than in the placebo group, and the combined result for the studies was statistically significant.

Changes from baseline in lipid parameters were also inconsistent between the pivotal studies. The differences between the tesamorelin group and placebo failed to achieve statistical significance for any lipid endpoint in study CTR-1011, while the differences compared to placebo were statistically significant for study LIPO-010. The improvements in lipid indices were relatively modest, with decreases in triglycerides, non-HDL cholesterol and total cholesterol:HDL ratio in the tesamorelin group compared to placebo of 12.3%, 3.9% and 7.2%, respectively.

Thus, while tesamorelin met its primary efficacy endpoint in the two pivotal studies, there were no consistent, definitive improvements in the secondary efficacy endpoints of patient perception of body image or lipid abnormalities. It also remains unclear what clinical benefit the observed reduction in VAT confers in HIV-infected patients, for example with respect to cardiovascular risk reduction, particularly considering the impaired glucose tolerance that may result from tesamorelin use.

A Notice of Non-Compliance Withdrawal (NON-W) letter was issued since the long-term effects of tesamorelin, notably on cardiovascular risk, are unknown. Clinical safety data from studies with more than one year of tesamorelin use are lacking, despite the fact that tesamorelin is intended for chronic use; data to support long-term safety are therefore considered inadequate.

Data from the two Phase III clinical studies were reviewed by the Reconsideration Panel and they considered that the data from the two phase III clinical studies provide sufficient evidence to support efficacy for the proposed indication.

Following consideration of the recommendations of the Reconsideration Panel, risk mitigation measures were sought in the form of changes to the Egrifta Product Monograph. The proposed conditions of use for Egrifta were modified to address the potential risks of elevated IGF-1 levels by requiring monitoring of IGF-1 levels, and discontinuation of therapy if levels exceed the normal range (an SDS >2) following 26 weeks of tesamorelin use. These parameters are consistent with the conditions of use of other approved IGF-1 related therapeutics. An addition of limitations to the Indications and Clinical Use section of the Product Monograph restricting use of tesamorelin to patients who had failed to reduce VAT using diet and exercise was required. Text was also included stating that tesamorelin is not to be used for weight loss management (weight neutral effect), and that tesamorelin has not been shown to improve compliance with anti-retroviral therapy.

However, uncertainties remain regarding the long-term safety of tesamorelin, particularly regarding its diabetogenic properties and the overall cardiovascular risk associated with its long-term use. These uncertainties are clearly and appropriately reflected in the Product Monograph.

Long-term safety will be established through routine pharmacovigilance, and a Risk Management Plan was submitted, reviewed and approved by Health Canada.

For more information, refer to the Egrifta Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The studies in support of the clinical safety section are the same as described in the previous section, clinical efficacy.

Safety concerns were the main reason for issuance of a Notice of Non-Compliance for the Egrifta New Drug Submission (NDS).

The most common adverse reactions seen with tesamorelin use were those expected from an injected peptide which stimulates growth-hormone release, namely arthralgia, headache, extremity pain, peripheral edema, carpal tunnel syndrome, injection site reactions, and hypersensitivity reactions. Half of the patients receiving tesamorelin developed anti-tesamorelin antibodies, which predisposed to hypersensitivity reactions but did not appear to adversely affect efficacy.

In the pivotal studies tesamorelin therapy resulted in impaired glucose tolerance in some patients, consistent with its growth hormone mediated mechanism of action. New onset of laboratory-diagnosed diabetes occurred more frequently with tesamorelin therapy: 28 (5.3%) tesamorelin-treated patients had at least 1 post-baseline HbA1c (glycated haemoglobin) value ≥6.5% compared to 6 (2.4%) patients on placebo at Week 26 of therapy, which represent a greater than two-fold increase in incidence. A total of 6 (1.1%) tesamorelin-treated patients had at least 1 post-baseline HbA1c value ≥7%, compared to no placebo patients. Mean HbA1c was increased by statistically significant 0.12% compared to placebo, but remained within the normal range (5.26% at baseline and 5.39% at Week 26).

In response to questions posed by the Office of Science (TPD), the Reconsideration Panel suggested that the glycemic changes associated with tesamorelin treatment were not clinically relevant, and could be managed clinically.

Health Canada's review bureau considered that the main safety concern associated with the use of tesamorelin is the substantial increases in plasma levels of insulin-like growth factor 1 (IGF-1). In the pivotal studies, 47.4% of tesamorelin-treated patients had IGF-1 levels more than 2 standard deviations above the mean (Standard Deviation Score [SDS] >2) after 26 weeks of tesamorelin treatment, and amongst those who continued to 52 weeks, 33.7% had IGF-1 levels >2 SDS. Furthermore, 35.6% of patients had IGF-1 levels >3 SDS at 26 weeks, and in those continuing to 52 weeks, 22.6% had IGF-1 levels >3 SDS. In a population with normally distributed IGF-1 levels, 2.3% of patients would be expected to have an SDS >2 and 0.1% of patients would have values >3 SDS.

IGF-1 is tumorigenic in animals at human exposure levels, and prospective epidemiologic studies have demonstrated that high normal range IGF-1 levels are associated with substantially increased risks of breast, prostate and colorectal cancer.

The Reconsideration Panel stated that IGF-1 levels alone cannot be the sole determinants for assessing efficacy and safety, especially in regards to carcinogenic risk, and that there was a need for a more complete clinical assessment. Health Canada agreed with the need for complete assessment of carcinogenic risk, however expert opinion submitted by the sponsor clearly endorses regular monitoring of IGF-1 levels for IGF-related therapeutics, and maintenance of levels within the normal range. Moreover, such recommendations are already included in the product monographs for two Canadian approved growth hormone products. Accordingly, in order to address the safety concerns regarding IGF-1 elevations and mitigate potential risk, the Product Monograph was modified to recommend regular monitoring of IGF-1 levels, and discontinuation of therapy if IGF-1 levels exceed a SDS of 2, determined at Week 26 of therapy.

Appropriate warnings and precautions are in place in the approved Egrifta Product Monograph to address the identified safety concerns.

For more information, refer to the Egrifta Product Monograph, approved by Health Canada and available through the Drug Product Database.