HPT/Axis, Inc. Awarded “Most Promising Life Science Technology Company” at 2010 Rice Alliance Life Science Venture Forum

This company is seeking to get approval of a drug protocol that will speed up the normalization of the Hypothalamus-Pituitary-Gonadal  (HPG) Axis after long term use of anabolic steroids or testosterone for medical or non medical uses.  Cessation of anabolics or testosterone replacement causes androgen -induced hypogonadism that can negatively impact someone’s health if the HPG axis does not stabilize soon after these compounds are stopped.  Depression, fatigue, sexual dysfunction, lack of motivation, and other health related problems can occur.
FOR IMMEDIATE RELEASE
 June 24, 2010 — 
HOUSTON – HPT/Axis, Inc. was named one of the most promising Life Science companies at the 9th Annual Rice Alliance for Technology &Entrepreneurship Life Science Venture Forum in Houston last week. Life Science companies showcased their new ventures for an audience of more than 400 attendees, including investors, venture capitalists, industry representatives, business leaders, advisors/mentors, service providers, and entrepreneurs. 

Cynthia A. Doerr, M.D., partner, Essex Woodlands Health Ventures said of the presenters, “This is one of the most mature groups of healthcare-related company presentations that I have reviewed in Houston, and I intend to follow their progress closely.” 

HPT/Axis, Inc., a Delaware C Corporation, seeks to profit from developing a treatment for the adverse effects that occur from the condition androgen-induced hypogonadism (AIH), a condition that occurs 100% of the time after stopping androgen or anabolic steroid use, both prescription and nonprescription, the only variables being the duration and severity. The effects of AIH include decreased sex drive,impotence, infertility, depression, obesity, decreased muscle strength and mass, cognitive impairment, and more. 

The Federal and State government have taken special notice for the period after androgen cessation. In 2005, the U.S. House of Representatives held a committee hearing, “Restoring Faith in America’s Pastime: Evaluating Major League Baseball’s Efforts to Eradicate Steroid Use,” that took special notice of the adverse effects after stopping anabolic steroids, particularly depression and suicide. The Committee received testimony from several parents whose sons had committed suicide after stopping androgen use. Testimony from Kirk J. Brower, M.D., University of Michigan, stated, “[d]epressive episodes and suicide attempts are most likely to occur within three months of stopping [androgen] use.” In that same year, Texas HB 3563, “Use Of Anabolic Steroids By Public School Students”, was passed and signed into law. Of particular importance is the bill’s analysis citing the problem of “clinical depression when steroid use is stopped.” 

HPT/Axis’ drug candidate will be first-in-class, the standard of care treatment. Our treatments have intellectual property protection by pending novel method-of-use patents. HPT/Axis’ lead drug candidate, enclomiphene, is a repositioning of the current FDA approved generic drug clomiphene. Repositioning allows for an expedited path to FDA approval. The company recently completed a successful FDA pre-IND meeting, which gave a preliminary approval for the initiation of clinical trials. 

Michael Scally (mscally@hptaxis.com), HPT/Axis’ President & CEO, stated, “Combining the number of men who stop using anabolic steroids, both prescription and nonprescription, there is a substantial current market for this indication, increasing by double-digits annually. We believe HPT/Axis is on a timeline for a FDA NDA within three to five years.” 

The one-day event culminated in an announcement of the Most Promising Life Science Companies chosen from nearly 40 competitors and judged by the Rice Alliance Information Technology Advisory Board, based on the companies’ elevator pitch presentations. The exercise simulates meeting an investor on an elevator and having only 90 seconds to convince them to invest in your company. 

Rice Alliance Director Brad Burke, announced the winners of the Most Promising Life Science Company awards at the event. “Every year the quality of companies improves. Many of the companies at this year’s event have developed prototypes, obtained proven results and are on their second round of funding. This makes them more appealing to investors, who have also expressed appreciation for the quality of the companies.” 

The Forum was supported by Baker Botts, LLP, Essex Woodlands Health Ventures, Winstead Attorneys and Santé Venture with supporting sponsors Greater Houston Partnership and Houston Technology Center and media sponsors Houston Business Journal and the BusinessMakers Radio Show. Elevator pitches from the competition can be seen at www.alliance.rice.edu beginning July 6, 2010

Pipeline Problems

by David Evans


In the past month, two companies shelved their once-promising experimental HIV drugs, citing the challenging nature of bringing a profitable product to market. Has the overwhelming success of modern-day HIV drugs jeopardized the future of new HIV treatment options?
Since Matt Sharp first learned that he was HIV positive in 1988, life has been about trying to stay one step ahead of the virus. Like many, he started each new HIV drug only to have it eventually fail, followed by a wait for the next one to be available through a clinical trial, expanded access program or U.S. Food and Drug Administration (FDA) approval. That’s just the way it was—trying to outrun HIV and to hold on until science and the pharmaceutical industry developed the next best thing. There were no other options.

The last three years, however, have been kinder to Sharp. In the space of about a year and a half, from June 2006 through January 2008, four new antiretroviral (ARV) treatments were approved, all of them with the potential to work against even the most drug-resistant HIV. After Sharp started a regimen with one of these new treatments, his virus became undetectable for the first time ever. His CD4 cells, which had been depressed for years, started to inch back up, and he continues to do well today.

Sharp is not alone in his Lazarus effect. Thousands of people with multidrug resistant virus, many of whom were once quite sick, have been able to push their viral loads to undetectable levels and restore their health with the newest antiretrovirals, often in combination with each other. But what happens if their HIV accumulates additional mutations and breaks through? Unfortunately, the number of promising agents waiting in the wings for people with drug resistant virus is dwindling.

Two companies, Avexa and Myriad Genetics, suspended development of their experimental ARV treatments over the past month. From press statements, it appears that both companies determined that their drugs—apricitabine (a nucleoside reverse transcriptase inhibitor) and bevirimat (a maturation inhibitor)—could not be brought profitably to market. While neither drug was perfect, or had a certain shot at FDA approval, some activists and researchers see their failure as evidence of a paradox—that today’s highly effective drugs are hurting the development of tomorrow’s promising agents.

“The very incentives that got industry involved to develop HIV drugs are now working against us,” says Jay Lalezari, MD, the director of clinical research at Quest Clinical Research in San Francisco, who specializes in the study of drugs for people with multiple drug resistance. “But, you know, money is a driver, and you don’t expect these companies to do it for nothing,” he laments.

“It’s getting harder and harder to hit a homerun with a new HIV drug,” says Bob Huff, a longtime HIV treatment activist from San Diego. “The current drugs are very good, and most doctors and patients are fairly satisfied…. The incentive for companies to invest in developing new HIV drugs is not strong right now.”

“It’s disconcerting,” Sharp agrees. “In terms of practical issues around drug development, we do need to put our heads together and strategize about fixing the things that are broken.”

Sharp is working with Huff and Nelson Vergel, an activist from Houston, to help identify novel ways for people who’ve run out of treatment options to get their hands on multiple experimental agents at one time. The three are also looking at creative ways for companies to get drugs approved that might only benefit treatment-experienced people, a market that is increasingly small and potentially less profitable than ever before.

Sharp, Huff and Vergel express concern about options for people who have already become resistant to current meds. With apricitabine and bevirimat now out of the picture, it only leaves a couple of drugs in an advanced state of development for people with multi-drug-resistant virus. Given the uncertain nature of drug development, however, those drugs could also tank or be delayed, and it could be quite a while before something new is approved.

Sharp is not hopeless, however, and cautions that, “There’s no reason to panic. I definitely don’t think this is the end of the world.”

Lalezari agrees that things are not so bleak, at least not yet. He points out that a number of his patients are still doing well clinically, despite going for many years with very low CD4 counts and detectable virus. He stresses that it is possible to pick a regimen and stick with it for a long time, even if your viral load remains detectable. He encourages people to sit tight on such a regimen and to “try to keep this détente with the virus, and we’ll see if gene therapies or other immune therapies can be brought to bear in the future.”

Vergel is another veteran of the treatment wars and knows what it’s like to face uncertainty. He says that if his current drug regimen fails, he’s not sure what he’ll turn to. He’s not despairing, however, because he feels that he and other activists are making progress with the FDA in figuring out how to make new treatment options available, even when the traditional avenues of approval are a challenge.

In the meantime, he distills his own positive outlook for the many hundreds of people with HIV he interacts with each year through his Internet and public speaking activities. As he sums it up: “You have to give them hope.”
A Good News, Bad News Story

“The bigger picture with HIV therapeutics is a good news, bad news story,” says Paul Sax, MD, clinical director of the HIV program at Brigham and Women’s Hospital in Boston. “The good news is that HIV treatment success is so high now. The bad news,” he adds, is that “the motivation to develop new drugs, especially drugs to treat resistant virus, has ironically never been lower. There’s this small group of people who have no options even with those newer drugs, and for them, the situation is very discouraging.”

Treatment success has made developing a new drug targeted toward drug-resistant virus problematic in several ways. First, we can no longer simply pit a new drug against a placebo, with no other active drugs to back it up. A number of studies have found that when people take only one active drug at a time, they quickly develop resistance to that drug. For this reason, federal treatment guidelines recommend waiting to start a new treatment, if possible, until two or three active drugs can be combined into a new regimen.

While combining two or three active agents is good for study participants, it’s a headache for trial designers. This is because the difference between an experimental drug and a placebo are much smaller and more difficult to measure if their impact is masked by the potency of other powerful drugs.

Sax points to the failure of the drug vicriviroc to demonstrate efficacy over a placebo in treatment experienced participants as a perfect example of this dynamic at work. “The vicriviroc study had the old study design,” Sax explains, “which was [a background regimen chosen by drug resistance tests] plus or minus the [vicriviroc], and they didn’t see any benefit, unless you [only looked at people taking] one other active drug.”

To detect such slight differences you have to either recruit only people with one or fewer active treatments available or design trials with twice as many people. The first option goes against the grain of treatment guidelines, and Sax thinks that the challenging and slow recruitment for a number of recent studies targeting treatment-experienced patients makes it quite unattractive to the companies. Even more unattractive, however, is the second option which almost doubles the cost of the trial.

Vergel has been working with Lalezari and Steve Deeks, MD, professor of medicine at the University of California at San Francisco, to estimate the number of people in the United States with resistance to all of the existing drugs—the kind of people that Sax says would be a challenge to recruit.

Vergel estimates that there are at least 1,500 such individuals, but that number is not growing rapidly. While this may be good news from a public health perspective, it is bad news for people with highly drug-resistant HIV who are depending on the pharmaceutical industry to develop new treatment options. Corporate board members and shareholders demand the highest profit possible with the least expense. With clinical trials potentially getting more expensive and harder to recruit, and the market size staying small, it’s getting very difficult to meet those demands.

“We’re up against the fact that drug development is about making a profit,” Sharp says, “and unfortunately that’s what we have to deal with.”
What the Future Holds

Sharp, who works frequently with Vergel on treatment advocacy projects, says that there are promising treatments further back in the pipeline, and that still other more innovative types of treatment are finally reaching the point where they can move in to clinical trials designed to prove efficacy and safety. What’s more, Sharp remains devoted to advocacy related to eradication: the elimination of HIV from the body.

Lynda Dee, a veteran treatment activist and the president of AIDS Action Baltimore, confirms Sharp’s experience: “Activists have met with companies over the last year, and some have said that they have internal programs looking at new drugs and eradication,” she says. “I’m hopeful that this discontinuation of the development of [apricitabine and bevirimat] doesn’t mean that all of the industry has turned tail and left the HIV field.”

Lalezari thinks that an entry inhibitor from TaiMed Biologics, an integrase inhibitor from ViiV Healthcare, and an attachment inhibitor from Bristol-Myers Squibb might have a shot further down the road. He’s less sanguine than Sharp or Dee about the prospects for antiretroviral drug development in general, given the challenges involved. “I think we could enter a period where there’s an abrupt end to HIV drug development,” he asserts. “That’s not to say that there aren’t new modalities of interest…but in terms of new direct-acting antivirals, it’s going to be very difficult,” he predicts.
Protecting Your Options

Are we on the verge of returning to the days when the best that a long-term survivor could do was guard against opportunistic infections and pray to survive long enough to benefit from the next drugs to come out of the pipeline?

Perhaps not, according to Lalezari. “The thing about the treatment-experienced population, which is astonishing, is that I have a whole bunch of people that I have been following for a number of years now, who are doing just fine. They have detectable virus, and their [CD4] cells are less than 20, but their health is just great, which is not explained in my understanding of the universe.”

Sax stresses that going off treatment would be a lot worse than staying on a failing regimen. “You know, all attempts of treatment interruptions of people with drug resistant virus met with bad outcomes,” he says, “So one thing for sure, is that people should stay on something. The question of what is more difficult. It’s never been well studied.”

In the end, what’s at stake is whether new drug development can stay ahead of HIV-positive people’s needs for new treatment options. Vergel points out that those who’ve yet to develop drug resistance can preserve their future options by finding a tolerable effective treatment and adhering to it religiously. In this regard, the possibility of a dry spell in new drug approvals could encourage people not to take for granted that new options will inevitably keep coming down the pike. “Fear,” Vergel says, “can be a good motivator” by way of emphasizing the importance of treatment adherence.

For people who’ve run out of new options, there is still reason for hope. It is possible to stay clinically healthy despite a failing ARV regimen, as Sax and Lalezari point out, and there are ways to minimize the risk of developing resistance to the experimental agents that might come later. Vergel tries to remind people of that and tells them “to not come from a place of despair.”

Sax thinks it will be helpful for researchers and health care providers to pool together their knowledge and resources to figure out the best care models for people who’ve run out of treatment options, arguing that since few providers have large numbers of such individuals it is difficult to become an “expert” in treating them. He thinks that activists and groups such as the Forum for Collaborative HIV Research in Washington, DC, can aid in that process.

Despite the challenges involved in developing the next generation of HIV therapies, Sax believes in remaining optimistic, especially with his patients who’ve run out of options. He tells them: “Press on. Drug development has helped us in the past. We hope it does again in the future.”


AIDS activists ask AVEXA not to leave patients behind

June 17, 2010
Dr. Susan Cox
Former Senior Vice President, Drug Development at Avexa
Cc: Nathan Drona, Chairman of the Board at Avexa
     Stephen Kerr, Board Secretary
We, the undersigned, are asking the decision makers at Avexa to reconsider the decision to stop the development of apricitabine, a nucleoside analog that has shown good efficacy in patients with the most common nucleoside mutation, M184V.  Physicians and a growing number of patients with limited treatment options have been counting on the approval of this drug to enable the construction of effective regimens. Apricitabine can mean the tipping point between success and failure of a salvage regimen – between life and death.
It is well known that the management of multidrug resistant HIV has improved dramatically with the recent approval of a number of highly effective antiretroviral drugs, including raltegravir, maraviroc, darunavir, and etravirine. Despite the impressive effectiveness of these drugs in clinical trials, a growing subset of patients continues to exhibit virologic failure in clinical practice – even when adherence is good. Most of these treatment failures likely occur because of an inability to construct a regimen containing two to three fully effective agents for individuals with extensive prior exposure to antiretroviral drugs. Some of these patients acquired drug resistance while participating in clinical trials. Failure rates in recent phase III studies such as DUET (etravirine and darunavir), MOTIVATE (maraviroc), and BENCHMRK (raltegravir) were in the 27-40% range. Many of the patients who experienced virologic failure while participating in these studies were subsequently unable to construct suppressive regimens.
The prevalence of multidrug failure in clinical practice is not well documented, however there are signs that the number of patients in need of new options is growing. Deeks and colleagues at UCSF/SFGH have an ongoing observational cohort of patients who have developed drug resistant HIV (the SCOPE cohort).  Most of these patients have been able to construct a fully suppressive regimen and are currently doing well.  However, of the original 300 patients, approximately 40 now have evidence of having failed all six therapeutic drug classes. These 40 patients have a GSS of either zero or one, and have no clear options for suppressing HIV replication. Many have advanced disease (CD4 < 100) and hence may not be able to wait for the development and approval of multiple new options.
A 2009 survey of 94 responding HIV clinicians in the United States found approximately 250 patients unable to construct a viable regimen due to resistance. In contrast to a common assessment heard in 2009, several key clinicians now recognize that the latest generation of drugs has not proven as durable as they had hoped, and that resistance is slowly reemerging as a problem for some patients. Although the number of multidrug resistant patients with no treatment options may be relatively small, there is concern that this may be the tip of the iceberg and that the industry will not be prepared to meet the need for newer drugs with unique resistance profiles.   
The options for constructing a three-active agent regimen for this growing population during the next four years appears to be few, which means that the chances for survival for those with lower CD4 cells counts are diminishing. Consequently, an early expanded access program that makes available current investigational agents that have progressed beyond phase II could help improve the outlook for survival for these patients in need. But the drugs must remain in development. 
Other small companies developing new HIV drugs, such as TaiMed and Myriad have faced the same difficulties in finding partners that Avexa has. Of these companies’ drugs, though, apricitabine stands out as a member of a well-understood class, the one nearest to approval, and as an agent addressing one of the most common forms of drug resistance among all people with HIV (including those still naïve to treatment). For the salvage population, convenience in dosing is not the issue: activity is! In our recent meeting with the major HIV drug makers we have been raising awareness about the growing unmet need for new salvage options, and as they hear this message from community and clinicians, they have begun to pay attention. Researchers and statisticians are also working on creative ways to conduct registrational clinical trials in an environment when there are many effective options and a relatively small subject pool (the Forum for Collaborative HIV Research is holding a workshop on this issue in October 2010). Finally, the FDA has said it recognizes the need for new salvage therapies and appears willing to work with companies to bring new products to market in this difficult environment. The tide is turning; this is not the time to abandon apricitabine.
We the undersigned believe that apricitabine is a potentially important drug, and one of the few products currently in the pipeline that could help patients with multidrug resistance tip the balance in favor of viral suppression, health, and, for many, life itself.  We ask that Avexa reconsider its decision not only based on potential sales but also on the survival of patients at risk.
Sincerely,
The Members of the AIDS Treatment Activists Coalition- New York, New York
The Members of the European AIDS Treatment Group- Brussels, Belgium

HIV Salvage Patients Are Concerned About Recent Pharma Decisions

I am scared that companies are dropping new HIV medications
Jun 17, 2010

Nelson, I emailed you before and you told me there were a few medications in research for people with resistance to all meds. But I just heard that two companies abandoned their research. What does that mean for someone like me who is waiting for new medications? I am so concerned.
Response from Mr. Vergel


Yes, I am also concerned about what is happening to drug development and its implications for those of use who are living with 3 or 4 medication class resistance who are waiting for more options. There is a belief that everyone treated with HAART has undetectable viral load, and only those who do not adhere to medications are the ones failing HIV therapy. I hear this a lot coming from doctors and researchers in meetings. People in salvage therapy have become the silent minority and if we do not speak up, our lives will be at risk. Salvage therapy advocacy is almost non-existent in this country, so we need to work together to remind companies that we are still here, and that new medications to treat new HIV targets are needed.
Several small companies working in HIV are running out of money since investors do not see HIV as a money making disease anymore.
An Australian company called AVEXA abandoned its apricitabine (a new nucleoside inhibitor) after spending years and millions on its development since their board does not think they can make money in HIV anymore (read the link “Avexa closes apricitabine program” here : http://www.avexa.com.au/news). Their drug could have helped some of us with Epivir/Emtriva resistance. A few activists and myself have sent the company a letter to ask them to reconsider their decision. I am still hopeful.
MYRIAD, a company in Utah, also abandoned their maturation inhibitor this month. The drug has had a lot of ups and downs. It may only work in 50% of naive patients and it may not work in patients like you and me who have multidrug resistance since we may have gag mutations that render this drug ineffective. So, I am not sure I blame them for putting their efforts somewhere else, but still think that other maturation inhibitors should still be explored.
GSK-ViiV is testing two second generation integrase inhibitors in people like you and me who have failed raltegravir. But it is too early to tell if this drug will help us. We will know by early 2011.
TAIMED, a Taiwanese company, have the only drug in a new class which can help people in salvage. The company is small and having problems finding sponsors that would fund their phase III study. Of course, like any new drug, it requires at least one other active medication in combination with it for it to work. But I am hopeful that its drug (ibalizumab, a CD4 monoclonal antibody provided every two weeks) combined with other drugs like GSK’s integrase or non nucleoside could help us if found to work after the current studies are done.
PROGENICS (http://www.progenics.com/prod_pro140.cfm ), also a small company, also has a drug in a new class but in early stages of development (PRO 140, an entry inhibitor). I certainly hope they do not follow AVEXA and MYRIAD !
KORONIS ( http://www.koronispharma.com/KP1461forHIV.html ) also has a very interesting drug that makes the HIV develop mutations that may make it weaker when exposed to HIV medications, but the research on this drug has a long way to go before we think it can help people in salvage.
Hang in there and try to remain as stable as you can while you wait for options. Make sure that you and your doctor find the best “holding pattern” HIV regimen for you as you also take prophylaxis for PCP, herpes, and other potential OIs and co-factors that may affect your health.
Stay tuned. I am still hopeful, but I also need to do a lot of work n activism to ensure that small companies have the support they need from the FDA and community while they search for funding to get their drugs approved. At the same time, we must closely follow the work being done in immune based gene therapies that may provide another avenue to survival to some of us.
Please touch base with me periodically so that I can keep you abreast of new developments in the search for new drugs to help people in salvage therapy.
Nelson
Shorten Response 

AIDS Activists Support the Approval of Egrifta- But Some Conditions for Theratecnologies and Serono

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.
Further Recommendations
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.
Respectfully submitted,
Tim Horn
Drug Development Committee AIDS Treatment Activists Coalition
cc:
Mary Parks, MD
Director, Division of Metabolism and Endocrinology Products
Richard Klein
Office of Special Health Concerns
Kimberly Struble, PharmD
Division of Antiviral Drug Products
ATAC. 611 Broadway, #308 . New York, NY 10012.646/284-3801. admin@atac-usa.org
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AIDS Activists Support the Approval of Egrifta- But With Some Conditions for Theratecnologies and Serono

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.
ATAC. 611 Broadway, #308 . New York, NY 10012.646/284-3801. admin@atac-usa.org
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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.
ATAC. 611 Broadway, #308 . New York, NY 10012.646/284-3801. admin@atac-usa.org
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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
ATAC. 611 Broadway, #308 . New York, NY 10012.646/284-3801. admin@atac-usa.org
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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.
Further Recommendations
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.
ATAC. 611 Broadway, #308 . New York, NY 10012.646/284-3801. admin@atac-usa.org
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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.
Respectfully submitted,
Tim Horn
Drug Development Committee AIDS Treatment Activists Coalition
cc:
Mary Parks, MD
Director, Division of Metabolism and Endocrinology Products
Richard Klein
Office of Special Health Concerns
Kimberly Struble, PharmD
Division of Antiviral Drug Products
ATAC. 611 Broadway, #308 . New York, NY 10012.646/284-3801. admin@atac-usa.org
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