AIDS Activists Support the Approval of Egrifta- But With Some Conditions for Theratecnologies and Serono
Posted Jun 10 2010 12:00am
17 May 2010
Paul Tran, BS Pharrn, RPh Advisors and Consultants Staff
Center for Drug Evaluation and Research Food and Drug Administration
5630 Fishers Lane, HFD-21
Rockville, MD 20857
Dear Mr. Tran:
On behalf ofthe Drug Development Committee (DDC) ofthe AIDS Treatment Activists Coalition (ATAC), I am writing to urge members ofthe Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) to recommend approval of Egrifta (tesamorelin) for the treatment of HIV-associated lipohypertrophy (NDA 22-505). This letter of support is submitted free of influence, financial or otherwise, from the NDA's sponsor, Theratechnologies, or Egrifta's planned U.S. distributor, EMD Serono.
Though the exact prevalence of lipohypertrophy among HIV -positive patients is not well established-the prevalence of the broader lipodystrophy syndrome is believed to be between 18 and 81 percent of people living with HIV-it has been an established comorbidity in the HIV patient population since the mid-1990s. Indeed, it is one of the only clinically significant HIV-related manifestations for which there is no proven treatment modality approved for use.
After review of the published data, we firmly believe that Egrifta, with its moderate efficacy profile and minimal adverse effects, should receive an EMDAC approval recommendation and cleared for marketing by the Food and Drug Administration (FDA). However, we remain sensitive to the fact that there are lingering concerns and questions regarding Egrifta's long-term efficacy and safety. Thus, our support for approval hinges on the establishment of post-marketing safety and efficacy features, clearly written into the product's labeling, along with a commitment to conduct additional safety and efficacy evaluations.
Interpretation of Efficacy Evaluations
Our initial optimism began with the successful completion of seven Phase II studies showing clear benefits-with minimal adverse events, notably a statistically significant increase in rates of glucose intolerance and diabetes mellitus-associated with 2 mg daily dosing of Egrifta.
The 26- and 52-week efficacy data from Theratechnologies' two Phase III studies, LIPO-Ol0 and CTR-l0lljCTR-l012, solidify our encouragement. The 15 percent and 11 percent reductions in visceral adipose tissue (VAT), respectively, after 26 weeks (and maintained reductions among patients treated for 52 weeks) and the differences in the intent-to-treat and per-protocol analyses with respect to the primary endpoint (a VAT reduction of ~8 percent) are proof-positive of Egrifta's potential for HIV-infected patients with lipohypertrophy. We are also heartened by Egrifta's secondary benefits, compared with placebo, including decreases in waist circumference, increases in lean body mass, preservation of subcutaneous adipose tissue (SAT) and significant improvements in triglyceride levels and other CVD-related biochemical indices.
It is disappointing that the Phase III studies lacked the design and resources needed to validate decreases in VAT as a surrogate marker for reduced cardiovascular disease (CVD) risk, in light of data indicating that VAT and increased waist circumference is a predictor of clinical and subclinical CVD in both HIV-positive and HIV-negative individuals. There is undoubtedly a need for observational and randomized, controlled studies exploring the effects of VAT -reducing agents, including Egrifta, on the absolute and relative risks of serious cardiovascular and cerebrovascular events, as well as other clinical manifestations such as sleep apnea and pancreatic, liver, pulmonary and vascular functioning.
There is, however, much to be said for patient reported outcomes of both studies. These data cannot be overstated given the disfiguring and stigmatizing effects of lipodystrophy. Increases in VAT have clearly been shown to be associated with psychological distress, impaired quality of life measurements, reduced willingness to commence antiretroviral (ARV) therapy and poorer adherence among those on ARV treatment.
As is clearly documented in the published data, Egrifta treatment is associated with significant improvements in patient ratings of belly and body appearance distress, along with improvements in physician ratings of belly profile. These comprehensive data are unmatched by any other lipohypertrophy-reversing strategy explored thus far.
Interpretation of Safety Evaluations
Unlike the last hormonal agent (Serostim; recombinant human growth hormone) reviewed and ultimately rejected by the FDA for the treatment of lipohypertrophy, the 52-week data from Egrifta's two Phase III studies are encouraging with respect to safety. Indeed, they establish that Egrifta's moderate efficacy outweighs Egrifta's minimal adverse effects.
Rates of injection site reactions, including localized hypersensitivity, appear to be more common among Egrifta-treated patients compared with placebo recipients. These rates, however, are dwarfed by those associated with another injectable agent, Fuzeon (enfuvirtide), used by people living with HIV.
While there also appeared to be slightly larger rates of growth hormone-related adverse events, such as arthralgia and edema, among patients receiving Egrifta compared with placebo, the reported percentages do not compare with the high rates of growth hormonerelated events seen in Phase III clinical trials of Serostim.
Phase II and Phase III studies have consistently documented that Egrifta has an extremely limited effect on glycemic measures and did not appear to significantly increase the risk of glucose intolerance or diabetes mellitus. In fact, as is documented in the available data, patients with diet-controlled diabetes can receive Egrifta without an increased risk of untoward effects. Though an increased risk of glucose intolerance or diabetes cannot be ruled out completely and should be studied further, the risk-at least over 52 weeks of treatment-is minimal when balanced against the drug's moderate efficacy.
Egrifta's highly variable effect on insulin-like growth factor 1 (IGF-l) in a significant number of patents is not without potential concern. While we understand that these variations have not been associated with any clinically meaningful adverse effects, we believe that additional, long-term data are necessary to confirm these initial findings.
Another concern is the development of anti-tesamorelin IgG antibodies in a sizeable number of study participants. Though we are aware of data concluding that antibody production to this peptide is not associated with any clinically meaningful decreases in efficacy or increased rates of adverse events, we have not yet seen research exploring whether anti-tesamorelin IgG antibodies have an effect on endogenous growth hormone production after drug cessation. We are also unaware of data exploring the potential of these antibodies to shunt treatment responses to Egrifta in the event the drug is stopped and then restarted. These data, if not already compiled and analyzed, are necessary.
As with virtually every agent that has been considered by the FDA for an HIV indication, we are not without concerns regarding the long-terms safety of Egrifta. Knowing that the drug
will need to be continued-perhaps indefinitely-to maintain reductions in VAT, we firmly believe that the product's labeling should feature prominent safety-related instructions for clinicians and patients, notably the need for regular glycemic and IGF -1 testing, along with cancer screenings, with recommendations to terminate Egrifta therapy when appropriate.
We also believe that a recommendation for Egrifta's approval be met with a commitment from the sponsor to conduct a long-term post-marketing study-either observational or randomized in design, following patients for at least three to four years-to collect data regarding the long-term safety of Egrifta.
In addition to our request for long-term safety data via a post-marketing study, we advocate for the following:
1)Phase IV evaluations of Egrifta-associated VAT reductions on the risk of CVD.
Though Theratechnologies should not be required to evaluate Egrifta in studies employing myocardial infarction or ischemic stroke as endpoints as a condition for approval, we believe that post-marketing studies exploring associations between VAT reductions and softer measures ofCVD-such as vascular function-should be required.
2)Required Phase IV studies exploring the effects of Egrifta-associated VAT reductions on other clinical outcomes, including fatigue, gallbladder disease, liver disease, osteoarthritis, pulmonary function and sleep apnea.
3)Required Phase IV studies exploring Egrifta in combination with exercise and/or diet modification to determine if VAT can be synergistically decreased.
4)A required Phase IV gender-balanced clinical trial evaluating the safety and efficacy of Egrifta in HIV-positive women with lipohypertrophy compared with men.
5) The approved labeling should spell out the indication for Egrifta treatment, along with indicators of effectiveness while receiving therapy, to ensure that the riskbenefit ratio is maintained for each patient. Though slice CT scans were used to measure VAT reductions in the Phase III clinical trials, these will not likely be practical in the clinical setting. Waist circumference, waist-to-hip ratio and basic psychological/body image assessments are much more feasible and should be employed by clinicians when considering patients for Egrifta and while monitoring their progress (or lack thereof), at regular time points, for as long as treatment is continued.
6)Approve Egrifta as a medical/reconstructive modality. We strongly urge against reviewing, approving, or labeling Egrifta as a cosmetic treatment. Though Egriftaassociated VAT reductions have not yet been established as a marker of reduced CVD risk, its effects on patients' body-image perceptions, sense of well being and quality of life is substantial. This is no different than breast reconstruction following a mastectomy-an unquestioned medical approach to minimize the negative psychological effects stemming from vital but disfiguring treatment.
In conclusion, we sincerely hope that EMDAC panelists will appreciate that the approval of Egrifta, with its favorable efficacy and safety profiles, is supported by this coalition of AIDS treatment activists that has closely followed the development of this agent, carefully scrutinized the published data and-perhaps most importantly-remains eager to see this option made available to address this long-standing unmet medical need.
Drug Development Committee AIDS Treatment Activists Coalition
Mary Parks, MD
Director, Division of Metabolism and Endocrinology Products