The U.S. Food and Drug Administration (FDA) held an advisory committee meeting May 27 in regard to the new drug application for tesamorelin (proposed brand name: Egrifta). AIDS Beacon associate publisher Courtney McQueen attended and reported on the meeting via liveblog.

During its meeting, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee reviewed data related to the efficacy and safety of tesamorelin. The Committee, which consisted of non-FDA medical experts, also voted on whether it believed tesamorelin should be approved by the FDA. The FDA is under no obligation to follow recommendations made by its advisory committees, but it generally does.

The FDA report prepared for the meeting has been made public and can be viewed on the FDA’s website. In the report, the FDA states that tesamorelin does appear to reduce excess abdominal fat, but the fat generally returns once patients stop taking tesamorelin. In addition, the report notes that there appears to be an increased risk of diabetes among patients who have taken tesamorelin.

The liveblog from the event can be found below.

8:10 am: The meeting gets underway, with the FDA introducing tesamorelin and the questions at hand. The presentation from Theratechnologies will be first, followed by a presentation by the FDA.

8:25 am: Theratechnologies has started off explaining why tesamorelin is necessary.

Dr. Steven Grinspoon, principal investigator of the Phase 3 clinical trials in the United States, explains that about 30 percent of people living with HIV show evidence of lipodystrophy.

Lipodystrophy has been associated with metabolic changes (such as high cholesterol and changes in glucose, which is associated with increased risk for diabetes). Since more people living with HIV are dying from heart problems, this is a concern. Dr. Grinspoon shows that at all ages, people with HIV are at higher risk of heart attack than people without HIV.

8:35 am: Dr. Grinspoon finishes his portion of the presentation by pointing out that there are no currently approved treatments for lipodystrophy. Other attempts to treat the condition have included lifestyle changes (such as diet and exercise), changes in ART regimens, and drug treatments. All of these have yielded either inconsistent results or, in some cases, have raised serious safety questions.

The next speaker from Theratechnologies is Christian Marsolais, the Vice President of Clinical Research and Medical Affairs. He will be describing the results of the Phase 3 clinical trials for tesamorelin.

9:00 am: Dr. Marsolais describes the two Phase 3 clinical trials on tesamorelin as being essentially identical. The studies revealed that tesamorelin successfully reduced visceral (belly) fat compared to the placebo.

Theratechnologies reports that 57.4 percent of patients taking tesamorelin experienced an 8 percent or greater reduction in visceral fat over the course of the trial, versus 29.3 percent of the placebo group.

They also report a decrease in triglycerides and inflammatory factors, and better overall self-reported body image in patients taking tesamorelin. However, these changes did not last when tesamorelin was stopped: visceral fat returned, and other indicators returned to their initial values.

9:25 am: Dr. Graziella Soulban, Director of Clinical Research at Theratechnologies, discusses the safety profile of tesamorelin. The main safety issues that have come up are increases in a protein called IGF-1, or insuline-like growth factor 1, and elevated risk of diabetes and pre-diabetes.

IGF-1 can have tumor-promoting activities, and since people with HIV are already prone to cancers of various types, this is a concern. Dr. Soulban shows that the increases in IGF-1 were not associated with increased risk of cancer in their study; however, she states that Theratechnologies will need to run a long-term observational study to be sure.

Additionally, people taking tesamorelin had a higher incidence of pre-diabetes and diabetes by the 26th week of the clinical trial. By 52 weeks, the incidence of pre-diabetes was still higher, but the number of people with diabetes had dropped. In both cases, about 2 percent to 4 percent of participants were affected.

9:30 am: Dr. Morris Schambelan, a professor emeritus at University of California San Francisco, discusses the benefit/risk analysis of taking tesamorelin. He starts by stating that current methods to treat lipodystrophy have not been effective; they give either inconsistent results, did not work at all, or had safety issues (primarily with glucose metabolism). Dr. Schambelan argues that tesamorelin is an improvement over these because it does reduce visceral fat and improves body image in patients taking the drug.

He repeats the safety data, including the fact that there appeared to be no serious side effects except for the slight increase in people with diabetes and pre-diabetes, and the raised IGF-1 levels. He concludes that the benefits of tesamorelin outweigh the risks, and that Theratechnologies will continue to closely monitor patients to make sure these safety issues are not prohibitive.

9:45 am: At the conclusion of the Theratechnologies presentation, the FDA advisory panel begins asking questions. Dr. Mark Molitch begins by asking if Theratechnologies thinks tesamorelin will really have beneficial effects on cardiovascular risk in people taking it, given the potential problems with diabetes and glucose metabolism.

Dr. Grinspoon replies that while there was an increase in pre-diabetes and diabetes, this seemed to decrease over time. He suggests that in the long run, tesamorelin may have a neutral or even good effect on glucose metabolism. He also points out that triglycerides went down as visceral fat decreased, and that triglycerides went down even more in people who started out with high triglyceride levels.

These things, combined with the reductions in waist size and decrease in inflammatory factors, he feels will contribute to reduced cardiovascular risk over time. But Dr. Grinspoon also acknowledges that this is speculative.

9:50 am: Additional questions from the FDA Advisory Committee. Dr. Victoria Cargill notes that women on estrogen therapy were excluded from the clinical trial, and would like to know if this also included women on estrogen-containing contraceptives.

Theratechnologies indicates they do not have that information with them, but can retrieve it.

Dr. Adrian Dobs asks about lipodystrophy: how consistent is it? Do people go in and out of a lipodystrophy diagnosis? And where does the 8 percent reduction in visceral fat, used as a benchmark in the clinical trials, come from?

Dr. Grinspoon responds that patients with lipodystrophy tend to see increases in abdominal fat over time. He states that the 8 percent cutoff was somewhat arbitrary, but that Theratechnologies and the FDA thought a 5 to 10 percent reduction in visceral fat would be of medical benefit, and 8 percent was a good compromise. He notes that tesamorelin easily met the 8 percent requirement, and probably could have met a higher bar for percent reduction in visceral fat.

9:55 am: Dr. Abraham Thomas of the Advisory Committee asks how often people on tesamorelin changed classifications from diabetic to normal, and vice versa – are these rates similar to what occurs in the normal population? He also asks about family history being a possible factor, and asks if retinopathy – a possible effect of growth hormone, which is stimulated by tesamorelin – was observed during the clinical trial.

Dr. Soulban says that fluctuation between a diabetes versus normal diagnosis does occur over time, and the rates did not appear to be different for tesamorelin versus the placebo group.

Ms. Tracy Swan of the Committee asks how quickly visceral fat returned in patients who stopped taking tesamorelin, and wants to know if these patients returned to their initial state, or whether they gained additional visceral fat?

Theratechnologies states that the visceral fat return happens quickly, within 13 weeks after discontinuing tesamorelin. They did not bring data on individuals, but on average, people returned to their baseline visceral fat values; they did not put on additional fat.

10:00 am: Some final questions from the Committee before the morning break. There is a fairly technical discussion about lipid proteins, inflammation markers, and IGF-1 numbers in the study. Theratechnologies promises to provide the FDA with some further data, particularly on the IGF-1 values.

A question from Dr. Clifford Rosen of the Committee addresses the question of ART adherence. If lipodystrophy is a cause of non-adherence to ART, did Theratechnologies see an increase in adherence in people taking tesamorelin?

Dr. Grinspoon says that adherence was generally very high during the clinical trial, so they can’t say whether tesamorelin improved ART adherence or not.

There are more questions, but they will be addressed after the FDA presentation.

10:15 am: The FDA presentation begins. After introducing tesamorelin and the clinical trials, Dr. Dragos Roman from the FDA notes that visceral fat reduction has never been used as a primary efficacy endpoint in a clinical trial; in other words, it has never been the primary measurement used to determine whether a drug is approved or not.

Dr. Roman reviews the clinical trial results and safety issues with tesamorelin, and emphasizes two issues the FDA is concerned with: the worsening of glucose profiles, i.e. the development of pre-diabetes and diabetes; and the higher IGF-1 levels, which could be a cancer concern in the long run.

He also questions the clinical relevance of visceral fat reduction relative to cardiovascular risk. How will the diabetes issues affect this, and how will the raised IGF-1 levels affect patients who use tesamorelin long-term?

10:30 am: Dr. Ali Mohamadi, a Clinical Reviewer from the FDA, takes over the presentation. After giving background on tesamorelin and the clinical trials, he gives the FDA analysis of the results. Dr. Mohamadi notes that at least 80 percent of patients taking tesamorelin had a decrease in visceral fat, and that there is a clear difference between the tesamorelin group and the placebo group in fat reduction level.

However, he notes that after discontinuing tesamorelin treatment, patients regained visceral fat quickly, and ended with a 0.28 percent increase in visceral fat at the end of the clinical trial. Patients who remained on tesamorelin, in contrast, kept the visceral fat losses.

10:45 am: Dr. Mohamadi disputes Theratechnologies’ analysis that patients experienced a reduction in belly appearance distress. The FDA finds that this result was not significant in one of the two clinical trials, and that there is not much difference between the tesamorelin group versus those taking a placebo. The FDA also finds no difference in patient-reported belly size or belly profile in people taking tesamorelin.

The FDA does confirm a drop in triglyceride levels in patients taking tesamorelin in one of the clinical trials; however, the drop was not significant in the second trial. Dr. Mohamadi also finds that the difference between the tesamorelin group versus placebo is small. The same issue arises with cholesterol measurements: the first clinical trial shows a reduction, but the second does not.

On the other hand, the increases in IGF-1 are significant, and there is a definite difference in both clinical trials between the tesamorelin and placebo groups, with higher IGF-1 levels in the tesamorelin group.

10:55 am: The FDA begins discussing safety issues. Only one death in the tesamorelin patient group was considered to be related to the treatment, and Dr. Mohamadi concludes that there does not appear to be a difference for tesamorelin versus the placebo group.

Minor side effects that led to people discontinuing tesamorelin treatment mostly stemmed from the injections, such as skin irritations and rashes. About 25 percent of people who discontinued tesamorelin did so because of side effects.

Dr. Mohamadi begins to discuss the higher levels of IGF-1 in the tesamorelin group, and notes that up to a third of participants may have had raised IGF-1 levels. These increases were higher in men than in women on average. The trial was approximately 85 percent men and 15 percent women, so more men were represented than women. After treatment was discontinued, IGF-1 levels dropped back to initial levels.

11:15 am: Dr. Mohamadi now begins to go through the glucose- and diabetes-related data. The FDA analysis finds 49.2 percent of patients in the tesamorelin group had no instances of raised blood-glucose levels, which are considered a sign of pre-diabetes or diabetes.

However, 17.3 percent of people taking tesamorelin had three or more increased blood-glucose measurements during the clinical trial, versus only 7.3 percent in the placebo group. Additionally, 25 percent of patients in the tesamorelin group who started off as pre-diabetic became diabetic during the trial.

The FDA finds that the percentage of patients with diabetes in the tesamorelin group is higher than in the placebo group after 26 weeks of treatment.

After 52 weeks, the differences were not as clear. There were still more instances of increased blood-glucose measurements in the tesamorelin group, but other measures of pre-diabetes and diabetes showed no difference between the two groups. The FDA finds this data to be inconclusive.

11:20 am: The FDA finishes by discussing the issue of antibodies to tesamorelin, which could be a problem affecting treatment. However, the FDA found that although about half of patients made antibodies to tesamorelin, this did not seem to interfere with the treatment or affect IGF-1 levels.

The FDA concludes that there do not appear to be a significant number of severe side effects in the tesamorelin group versus the placebo, with most side effects known to be related to growth hormone (which is stimulated by tesamorelin) or having to do with the injection. However, there is concern regarding the diabetes issue. Antibodies did not seem to be a problem.

11:45 am: The Advisory Committee poses several questions to the FDA presenters. Most are technical in nature and involve the statistical analysis, but Dr. Princy Kumar raises the issue that ART regimens including protease inhibitors could exacerbate the glucose levels. The FDA replies that it is possible, but they are not sure. Theratechnologies adds that they analyzed the few glucose-related adverse events during the trial, and the numbers were too small to tell if protease inhibitors had any effect.

Another Committee member asks about participants starting diabetic treatments, and wonders if this could be masking some of the effects of tesamorelin on glucose levels. Theratechnologies states that five people started diabetic treatment during the trial. Dr. Grinspoon argues that an initial rise in glucose, followed by a drop, is not uncommon in studies involving growth hormone, which is stimulated by tesamorelin. He also states that it may have been a mistake to allow people with diabetes in the clinical trial, and emphasizes that people with diabetes should not take tesamorelin.

11:50 am: Dr. David Schade on the FDA Advisory Committee asks how effective tesamorelin is in returning people to a “normal” state, before lipodystrophy altered their visceral fat levels. The FDA states that there is no data on the participants in their “normal” state; Dr. Grinspoon of Theratechnologies states that tesamorelin eliminates about half of the excess visceral fat.

There are a few more questions on technical points, then the meeting breaks for lunch. It will resume at 1 pm with the public hearing session, followed by another question and answer session.

1:00 pm: The meeting begins again after lunch with the Open Public Hearing Session. The first speaker is Deborah Sergi-Laws, a registered nurse from Sarasota, FL who is HIV-positive. She mentions her background in educating and mentoring other people with HIV, then discusses her own history of multiple ART regimens and experiences with lipodystrophy. She says she feels she has “a barrel around my midsection.” Her lipodystrophy has made it difficult for her to bend, and causes pain and discomfort. She has had 1.5 lbs of fat removed from her neck region, and faces increased levels of lipids in her blood, which are a risk for cardiovascular problems.

Ms. Sergi-Laws says she has tried exercise and other regimens to treat her lipodystrophy unsuccessfully, and joined the tesamorelin clinical trial as an attempt to treat her condition. She asserts a positive impact on her girth and her blood lipid levels, and says she felt “really good” while in the clinical trial. “One of the positive aspects of the tesamorelin trial, for me, was how well I tolerated the drug,” she says. She has had a lot of side effects with other treatments throughout the years, but none with tesamorelin. She hopes the drug will be approved and made available to herself and others.

She also says reactions from others in the HIV-positive community have been very positive, and thanks Theratechnologies for allowing her the opportunity to be in the clinical trial.

1:15 pm: The next speaker is Dr. Lisa Hamilton, who is also HIV-positive. She discusses how her quality of life has decreased because of the health-risks and discomfort caused by her lipodystrophy. She asked her doctor to keep her in mind for clinical trials involving treatment of lipodystrophy after unsuccessful attempts to eliminate the problem with diet and exercise.

She joined the tesamorelin clinical trial in 2005 and says she “achieved tremendous results.” She says the decrease in fat on her abdomen increased her quality of life and made her more comfortable; she also emphasized the health benefits she received in terms of reduced risk for cardiovascular problems. “If given the opportunity, I would stay on tesamorelin for life,” she says. “This improved my quality of life so much.”

Since the clinical trial ended, she says her discomfort has returned, and is worried that the weight gain will have further serious health effects. She hopes the panel will respond positively to the tesamorelin trial results.

1:20 pm: Jeff Berry, a representative from the AIDS Treatment Activists Coalition’s Drug Development Committee, speaks next. He argues that lipodystrophy is a major unsolved problem faced by people with HIV, and that the tesamorelin results indicating improved body image cannot be underestimated. Lipodystrophy significantly affects the psychological well-being of people with HIV, and their willingness to take their antiretroviral treatments, he says.

Mr. Berry argues the results from the clinical trials clearly show the benefits outweigh the risks, and urges the panel to recommend approval. However, he does want additional trials on the effects of tesamorelin on cardiovascular risks and heart attacks, as well as gallbladder disease, liver disease, arthritis, pulmonary function, and sleep apnea.

“This is no different than breast reconstruction following mastectomy,” he says with regard to the psychological benefits of an improved body image. “We firmly believe that [tesamorelin] should be approved.”

1:25 pm: The Public Hearing Session concludes, and the question and answer session begins with additional technical discussion on statistics and calculations. Dr. Kumar asks how exercise was incorporated into the program; Theratechnologies says patients were encouraged to maintain their current exercise regimen.

Dr. Kumar follows-up with a question on how they encouraged women to participate in the trial; Theratechnologies says the number is similar to the percentages in other clinical trials, and that getting women to participate is very difficult. Dr. Grinspoon says the number was sufficient to show that tesamorelin is effective in women as well, but they will continue to try to get more information on women.

Ms. Tracy Swan asks how Theratechnologies will monitor the efficacy of tesamorelin in people who are prescribed the drug. Dr. Grinspoon says they will likely use waist circumference, since it is easy to measure and correlated very well with visceral fat loss in their study. He says if patients see no reduction in waist circumference after 26 weeks, they should probably not continue tesamorelin.

1:45 pm: Dr. Michael Proschan from the Advisory Committee notes that there seem to be large drops in triglyceride levels for patients that perhaps most needed it: those who started out with high triglycerides.

Dr. Adrian Dobs asks how long patients on tesamorelin should be monitored before deciding whether the treatment should continue or not. Theratechnologies says that a long-term observational study would determine this, but that observation for a year is reasonable given the risks and benefits in that time frame.

Dr. Kenneth Burman asks for clarification: Theratechnologies has no information on raised IGF-1 levels past one year of treatment? Theratechnologies confirms that they do not, but that this will be addressed by the long-term study.

2:00 pm: The panel begins to discuss the Questions to the Advisory Committee. This is where the members of the Advisory Committee are asked to discuss various points. The first question is about the glucose intolerance and diabetes associated with tesamorelin, and their impact on long-term cardiovascular risk.

Ms. Swan says she’s concerned about the prevalence of HIV among African-Americans and Latinos, who are also more prone to diabetes, and the fact that they were underrepresented in the trial.

Dr. Victoria Cargill agrees, and again brings up the issue of family history of diabetes. Theratechnologies says they have no information on this.

Dr. Schade says he is unclear about the relationship between treatment and diabetes. If patients treat their diabetes and get it under control, should they still halt tesamorelin treatment? Dr. Grinspoon says if patients can control their diabetes, he sees no reason not to continue tesamorelin treatment, and urges more study of the issue.

2:15 pm: Dr. Burman asks about the markers for cardiovascular health, such as triglycerides and cholesterol, and how much is known about how these correlate to poor health effects. Dr. Dobs and Dr. Mark Molitch state that the links are complicated and not well understood; Dr. Molitch is concerned about the fact that many of the markers did not improve in people taking tesamorelin even though the amount of visceral fat decreased.

Dr. Allison Goldfine says previous small studies have shown that surgical removals of fat tissue have also failed to improve these markers.

Dr. Abraham Thomas says he finds the diabetes data from both Theratechnologies and the FDA confusing, but thinks it needs to be monitored more closely in a clinical trial, not an observational study. He feels a placebo-controlled trial is necessary to determine the risk of diabetes over time, including factors such as family history that were not measured by Theratechnologies in the present clinical trials. He also thinks there should be a proper study of retinopathy, damage to the eye that can arise from diabetes, in people taking tesamorelin.

Dr. Molitch feels the retinopathy problem is not an issue. Dr. Burman feels that while the data is somewhat confusing with regard to diabetes, people who are close to being diabetic are probably at increased risk of being diagnosed with diabetes.

2:25 pm: Dr. Schade argues that the threshold levels for diagnosing diabetes are somewhat arbitrary, and that the diabetes does not concern him as much because it can be treated. He does wonder if continued stimulation of the pituitary gland (which produces the growth hormone stimulated by tesamorelin) could have negative effects.

Dr. Molitch says this is not a problem.

Dr. Eric Felner points out that children who are prescribed growth hormone for several years do not appear to suffer long-term effects. He does not feel that the changes in diabetes markers are a big issue.

Dr. Burman asks Dr. Felner about whether children who are prescribed growth hormone for many years are at risk for increased cancer or cardiovascular problems. Dr. Felner says he knows of no such studies; some of the children he has treated have had brain tumors prior to treatment, and they have not seen increased risk of more tumors in these children.

2:30 pm: The panel agrees in general that the risk of diabetes is probably small but real. Most members seem to feel the problem is manageable, and not a major issue, since diabetes can be treated if it develops.

Dr. Kumar does feel the issue is significant, since the demographics of the trial are different than the general HIV-positive population and minorities, who have a higher diabetes risk, were underrepresented. Also, she feels that even a small increased risk of diabetes is an issue since people with HIV are already at increased risk of cardiovascular disease.

Dr. Cargill agrees with Dr. Kumar as well, and urges additional studies.

2:45 pm: The panel begins to discuss the second question: whether the increased IGF-1 levels are a concern with respect to long-term cancer and cardiovascular risk. All of the members agree that there is not enough data yet to comment on the long-term effects of the increased IGF-1 levels, and more study is needed. However, several panel members express concern about the raised IGF-1 levels.

Dr. Curtis Rosebraugh from the FDA asks for clarification on the type of studies recommended by the panel, and whether they would be randomized, placebo-controlled studies (like the previous clinical trials, but long-term) or observational studies of people prescribed the drug over time.

3:00 pm: There is some disagreement on how to implement follow-up studies. Many members would prefer a placebo-controlled trial, but worry that this would not be practical after the drug is approved because no one would want to receive a placebo. Several members support long-term observational studies, others support a registry (where side effects would be reported). Others argue that a regular placebo-controlled trial would be possible.

Dr. Thomas asks Dr. Rosebraugh to give his opinion on what would be feasible with regard to further studies. Dr. Rosebraugh raises concerns with the practicalities of doing a placebo-controlled trial for a condition in which only one treatment is available. However, he points out that while these are things to think about, the committee has to make its own decision.

The next three questions, regarding clinical relevance of visceral fat reduction with respect to cardiovascular risk, patient-perceived benefits, and adherence to ART, will be combined for the sake of time.

Discussion on the final voting question, on whether the panel recommends approval of tesamorelin, will begin around 4 pm.

3:30 pm: Discussion on the next three questions begins. The committee members seem to agree that there is not enough evidence that reduction in visceral fat decreases cardiovascular risk, and that further study would be needed.

With regard to patient body-image benefits, the committee is divided. Several members are impressed by the testimony during the Public Hearing Session, which emphasized the suffering and reduced quality of life for people living with lipodystrophy. However, there is also some concern that the surveys from the clinical trial do not show as much improvement as perhaps anticipated.

Most members agree that there is not enough evidence to say whether tesamorelin would affect adherence to ART. A few panel members have suggested that some patients may be delaying initiation of treatment for fear of lipodystrophy, and that tesamorelin could help persuade those patients to begin ART earlier.

3:45 pm: Voting begins on the final question: does the risk-benefit assessment support approval for tesamorelin?

The final vote is as follows:

Yes: 16
No: 0
Abstain: 0

4:00 pm: The panel agrees that the evidence supports approval for tesamorelin to treat lipodystrophy, although further study is needed with regard to the safety issues. Panel members felt Theratechnologies showed sufficient evidence that tesamorelin reduced visceral fat, although there was no evidence that this would reduce cardiovascular risk.

Most members emphasize that the suffering caused by lipodsytrophy, and the fact that there is no currently approved treatment, played a large role in their decision.

All the members again state the need for additional follow-up studies, either placebo-controlled trials or long-term observational studies and registries.

4:20 pm: The FDA thanks the panel for their recommendations and acknowledges that there is still quite a bit of work to do with the company. The FDA also thanks Theratechnologies and the speakers. Dr. Burman adjourns the meeting.