Egrifta Quality Of Life Deciding Factor In Advisory Panel's Recommendation

Improving patients' quality of life seemed to be more important than an unproven cardiovascular benefit in an FDA advisory panel's unanimous vote to recommend approval of Theratechnologies' Egrifta (tesamorelin), indicated for reduction of visceral adipose tissue in HIV patients receiving antiretroviral therapy.

Up to 800,000 patients in the U.S. who are receiving ART suffer from HIV lipodystrophy, also known as fat redistribution syndrome, which leads to such unpleasant phenomena as the "buffalo hump" at the base of the neck. This is a source of great distress to patients, some of whom may never start treatment or discontinue it as a result, panel members were told. (However, Egrifta would treat abdominal fat, not the "buffalo hump," Theratechnologies spokeswoman Leila Boukassi noted.)

"I voted yes primarily for quality-of-life reasons," Jessica Henderson, Western Oregon University, said at the May 27 meeting of the Endocrinologic and Metabolic Drugs Advisory Committee.

"I think there could be few things more difficult to deal with than feeling like they've lost control of their body, and that their efforts to do things to maintain their own health or improve it, that's not paying off," the panel's consumer representative, Tracy Swan, Treatment Action Group, said.

"Using something that feels like it can be synergistic with your self-care efforts and show you a benefit can't help but help, and that's extremely important," Swan said. "And in a way, that's deeply linked to adherence [to antiviral treatment]. And I can't show you research results, but I can tell you I've talked to a lot of people who say, 'I won't start on those drugs because everyone will look at me and be able to know that I have HIV.' So the issue is not only staying on them when you've started, but even seeking treatment when you need it."

Given the strong vote and passionate patient interest in the product, FDA - which was skeptical of the product in its briefing documents - would face a significant public relations challenge if it did not approve Egrifta by its "action date" (see sidebar: " ¹ Egrifta Misses PDUFA Deadline, On Track For 'Action Date' ").

The meeting was remarkable for the amount of attention panel members paid in their discussion to public comments made by Deborah Sergi-Laws and Lisa Hamilton, HIV patients who had participated in the clinical trials. They testified to the problems HIV lipodystrophy has caused them, both emotionally and in such everyday tasks as bending over, and the relief they had felt when Egrifta appeared to relieve their symptoms.

Advisory committee members referred repeatedly to their remarks during their deliberations. "I think that the compelling data from the public testimony suggested ... there is some clinical relevance to what has been demonstrated," Clifford Rosen, Maine Medical Center Research Institute, said.

"There seemed to be consensus and appreciation of the patient testimony this afternoon that was quite impressive. That perceived benefit seems to be important," committee Chair Kenneth Burman, Washington Hospital Center, said in summarizing the discussion of the patient-perceived benefits.

"The tools that study body perception were used and showed that there was a benefit and this has a potential benefit on daily living and psychiatric outlook of these patients," Burman said.

"There was a discordance between the small quantitative changes in waist circumference and the perceived benefit that was obtained in the questionnaire, and we need further information regarding psychological aspects, such as quality of daily life and psychological profile."

More Patient-Reported Outcomes Sought

The patient-reported outcome measure was a "conceptual framework developed for lipodystrophy impact on body image and health-related quality of life" administered by an outside company called Phase V, Theratechologies' Christian Marsolais said during the sponsor presentation. The "body image impact module" was field-tested in Phase II trials of Egrifta and confirmed in Phase III, with psychometric analyses of reliability, validity and responsiveness.

"I was very pleased to see that at least we had some data on patient perspective," Henderson said.

"However, the belly profile was not enough, and I think it was obvious from Deborah and Lisa's testimony that the belly profile was incomplete in what you're calling 'patient-perceived benefits.' This data didn't address the activities of daily living, or the energy, or the psychological well-being or the social well-being that Deborah and Lisa talked about. And so I'd really, really like to have more quality of life data."

Moreover, Egrifta may not represent a panacea for HIV patients' distress at their physical appearance, Princy Kumar, Georgetown University School of Medicine, said. "When patients complain of how disfiguring treatments or the synergy between treatments and HIV can be, again as a clinician I want to remind myself that there's no data on lipoatrophy. ... So there's nothing in anything that I am seeing here that as a clinician I can say will improve antiretroviral therapy, that will make patients want to start on antiretroviral therapy or stay on antiretroviral therapy."

Phase V's techniques were in accordance with FDA's December 2009 final guidance on patient-reported outcomes, Marsolais said. The guidance says that FDA will only consider credible those PRO measurement instruments that were developed according to patient input, which sponsors should document, and should meet criteria of content validity (² (Also see "FDA's Final PRO Guidance Grounds Policy With More Details" - Pink Sheet, 8 Dec, 2009.)).

VAT Not A Surrogate For CV Benefit

The patient-reported outcomes were only secondary endpoints in the studies. In two pivotal Phase III clinical trials, a subcutaneous daily injection of 2 mg of the drug reduced patients' excess VAT relative to placebo, by an average of 19.6 percent in one trial and 11.7 percent in the other (³ (Also see "The Risks Of Surrogacy: Egrifta Faces Twofold Challenge At Advisory Committee" - Pink Sheet, 25 May, 2010.)). This was statistically significant and far exceeded the 8 percent goal FDA and Theratechnologies agreed on in advance.

Quoting the proposed indication of "induc[ing] and maintain[ing] a reduction of excess abdominal fat in HIV-infected patients with lipodystrophy," Victoria Cargill of NIH's Office of AIDS Research said, "The sponsor clearly met that. There is no question this condition causes a fair amount of psychological suffering. It is associated with depression, which is incontrovertibly associated with poor adherence [to ART] and disease outcomes."

However, panel members were more cautious about whether the VAT reduction signified a cardiovascular benefit. "It's a surrogate, even a surrogate of a surrogate," the committee's non-voting industry representative, Merck Research Laboratories Group Vice President for Cardiovascular and Metabolic Diseases Enrico Veltri, said.

"I always worry about approving things on the basis of a surrogate, because that usually means a small trial where you don't see cardiovascular or cancer risks," Michael Proschan, National Institute of Allergy and Infectious Diseases, said.

On the other hand, such qualms clearly didn't translate into negative votes. "I hate surrogate markers, but the target they were asked to achieve was 8 percent [reduction in VAT relative to placebo], and they did it," Rosen said.

But in commenting on her yes vote, Kumar said it "should not be taken to imply in any way that I believe there are any kinds of cardiovascular benefits associated with the drug. That has not been proven, not been shown."

Post-Marketing Studies Needed To Address Risks

The panel also did not avert its gaze from Egrifta's risks. FDA had asked for comment on the findings of glucose intolerance and development of diabetes associated with Egrifta therapy and its impact on long-term cardiovascular risk. The agency also asked the committee to discuss the increase in the levels of insulin-like growth factor 1 associated with use of the drug and concerns that chronic use could lead to long-term cancer and cardiovascular risks.

Chronic use was an unavoidable question because the clinical trials found that when patients were switched from Egrifta to placebo, they rapidly regained the VAT they had lost.

Indeed, another clinical trial seems well off Theratechnologies' radar screen; at present, Egrifta is being studied only in two investigator-initiated studies (see sidebar: " ⁴ Additional Indications, Geographies May Be In Egrifta's Future ").

During his presentation, Ali Mohamadi, a clinical reviewer with FDA's Division of Metabolism and Endocrinology Products, said that in the trials approximately 25 percent of pre-diabetic patients (as determined by their levels of hemoglobin A1c) developed full-blown diabetes, compared to 11 percent of those on placebo.

However, this drew less concern from committee members with expertise in this area than might have been expected. "You can get complications on a spectrum, a continuum," David Schade, University of New Mexico School of Medicine, said. "To think you're OK because your HbA1c is below 6.5 is a myth. I'm not worried about it as a diabetologist; I treat impaired glucose tolerance and can treat it if it's caused by this."

Not everyone agreed, however. "The risk is real, and it's significant because this [clinical trial population] is not the population we see in clinical practice," Kumar said, echoing a concern several members expressed about underrepresentation of minorities in the pivotal studies, including African Americans, who are prone to diabetes. "One more risk, even if it's small ... would be of great concern to me, especially because HIV patients have a higher risk of cardiovascular disease."

The IGF-1 signal drew more negative attention from panel members. "I'm very concerned about IGF-1 in terms of cancer," Rosen said.

"The risk of cancer is quite low, but it needs long-term surveillance," Mark Molitch, of Northwestern University's Feinberg School Medicine, said. "The cardiovascular risk is a concern, and so is the elevated IGF-1 level, especially with patients with acromegaly."

FDA is in a bind about how these risks should be evaluated if it decides to approve Egrifta, Curtis Rosebraugh, director of FDA's Office of Drug Evaluation II, said. He asked whether advisory committee members would favor another randomized controlled trial. "If it's post-approval, how practical would it be to do one? We heard compelling testimony about how people suffer [from lipodystrophy], so how would they agree to have a 50 percent chance of not getting treated? But if it's not a randomized controlled trial, how do you do the study?"

"I was not thinking of randomized controlled trials," Cargill said. Pointing to the fact that Theratechnologies has proposed a Risk Evaluation and Mitigation Strategy including limiting distribution to an approved network of pharmacies, she suggested that these be used to collect data.

"I want to see an induction maintenance study and a minimum of five years of follow-up," Swan said. Burman said post-approval cardiovascular studies may be necessary.

It's important that physicians be told to stop treatment in patients who aren't responding to it, several committee members said. "As a practicing clinician, I really want criteria on when to stop," Kumar said, adding, "a well-kept registry is the barest minimum of what we need to do."

Labeling is going to be a key concern as well. "My favorite suggestion for labeling is that non-responders be taken off the drug after 28 weeks," Henderson said. Molitch suggested assessing whether the drug is working three months after the treatment begins.

"The company's development plan is very important," Allison Goldfine, Joslin Diabetes Center, said. "They could study non-responders to see if they have a different rate of weight loss."

- Martin Berman-Gorvine ( ⁵ [email protected] )