Tuesday's FDA Panel Review for Human Genome Science's Benlysta

Walking In Purple For Lupus Awareness In Honou...
Purple Walk for Lupus Awareness

Everything you need to know about Tuesday's FDA panel recommendation for Human Genome Sciences therapy for Lupus, Benlysta.  If approved Benlysta would be the first approved therapy in 50 years for Lupus.  Friday the FDA released the notes for the upcoming panel review Tuesday, November 16th.  Concerns for the panel Tuesday were an increased risk of suicide, risk of infection, and decreased efficacy in African-American patients, who are more prone to Lupus.  Forbes' The Medicine Show Blog with Matthew Herper highlighted some of these concerns.  Benlysta is teamed up with Glaxo SmithKline and if approved Human Genome Sciences will share marketing costs and profits.  The expected market is anywhere between 1-3 Billion.

I think the benefits for the drug outweigh any concerns and it could be approved December 9th by the FDA.  With that being said though, the FDA has rejected a lot of drugs this year and is very conservative.  There are some concerns and more clinical trials could be advised before approval.  We will have to see.  Today's FDA review notes had concerns with the drug's suicide rate and it's efficacy for African-Americans, who are more likely to have Lupus.  The concerns dropped the stock and has investors spooked, but I still think that it will be recommended.  I hope I am not wrong on this one. 

Wikinvest--Glaxo (GSK)
Yahoo Finance--HGSI
Yahoo Finance--GSK

For more on Tuesday's Decision

Investors Spooked; HGSI Shares Fall

Benlysta's Modest Benefit vs. Risks Poses Dilemma

By Donna Young
Washington Editor

WASHINGTON – Shares of Human Genome Sciences Inc. tumbled 10.9 percent Friday after FDA drug reviewers questioned whether the modest benefit of Benlysta (belimumab) in treating some lupus patients is worth the potential increased risk of death, infection or adverse neuropsychiatric effects, including suicide.

Regulators also noted that patients with serious systemic lupus erythematosus (SLE) manifestations, such as renal and central nervous system (CNS) lupus, in whom immunosuppressives and other biologics likely will be needed, were excluded from HGSI's Phase III studies, leaving it unclear about the safety of combining Benlysta with other lupus treatments in populations with more serious disease.

Those questions, drug reviewers said in briefing documents released ahead of Tuesday's meeting of the FDA's Arthritis Advisory Committee, have created "dilemmas" for HGSI's biologic license application for Benlysta, which was submitted in June. (See BioWorld Today, June 11, 2010.)

Shares of Rockville, Md.-based HGSI (NASDAQ:HGSI) lost $2.88 Friday, to close at $23.60.

The FDA's reviewers acknowledged that Benlysta demonstrated a statistically significant difference in the proportion of responders in Phase III testing. But they also pointed to the fact that the results in HGSI's BLISS-76 trial (study 1056) were less robust than in its BLISS-52 study (study 1057), and both studies' data from other endpoints and subgroup analyses "were not consistently supportive." (See BioWorld Today, July 21, 2009, and Nov 3, 2009.)

A second post-hoc analysis of racial subgroups suggested there may be reversal in the direction of treatment effect in patients of African-American or African heritage, compared with other races, regulators said.

"This is of concern because patients of African-American or African heritage are known to have more aggressive SLE, often leading to worse outcomes," FDA reviewers stated. In addition, they noted that Benlysta's data demonstrated an inconsistent efficacy trend across different geographical regions of the world, with numerically smaller separation of efficacy measures between Benlysta vs. placebo in patients from the U.S. and Canada, compared with other regions.

"In light of this somewhat marginal efficacy, the relative safety profile of the product must be weighed," regulators said. Whether Benlysta's benefits sufficiently outweigh its risks "is the crux of the issue," they added.

Increased risk of serious infection is "almost a given" with biologic immunosuppressives, so the risk of infection with Benlysta is "expected," the FDA reviewers said.

But "somewhat unexpectedly" – though perhaps not unusual given the underlying characteristics of the SLE population – there may be an increase in the risk for adverse neuropsychiatric events with Benlysta, regulators said. The FDA drug reviewers noted that there were three completed suicides in patients taking Benlysta in HGSI's trials.

JP Morgan analyst Cory Kasimov said the suicidality risk likely was what had investors spooked Friday, noting that the FDA's concern came as somewhat of a surprise to Wall Street. But, he said, "we consider it unlikely that a targeted biologic is increasing suicidality in a patient population already known to be at increased risk."

Nevertheless, given that SLE patients already have a higher documented rate of depression, "it was enough" for the FDA to bring the issue to its panel, Kasimov said.

In separate documents posted online Friday by the FDA, HGSI noted that there is a fivefold increase of suicides in the SLE population.

Although the FDA has a specific suicidality question on its agenda for Tuesday's meeting, it is not a voting question.

"We would be surprised if this issue prevents the ultimate approval of Benlysta," Kasimov said.

Baird & Co. analyst Christopher Raymond noted that, as is customary, the FDA's briefing docs showed Benlysta in the "worst light possible," putting the drug's risks and benefits "under a microscope with the aim of encouraging vigorous debate. These documents always aim to air dirty laundry," Raymond said.

As expected, he added, the agency "appears determined to pressure test its approval decision for Benlysta."

Nonetheless, Raymond said he expected timely approval next month for Benlysta, a recombinant, fully human, IgG1-lambda monoclonal antibody that binds and inhibits the biological activity of soluble B lymphocyte stimulator protein, which plays a critical role in the normal regulation of B cell homeostasis.

The FDA acknowledged that "clearly there is a need for effective therapies" in SLE, a chronic debilitating autoimmune disease that primarily affects young women of childbearing age, although men, children and teenagers also can develop lupus.

There are about 1.5 million people in the U.S. and an estimated 5 million or more around the world with lupus, said Sandra Raymond, CEO of the Lupus Foundation of America (LFA).

The manifestations of lupus include arthritis, pleuritis, pericarditis, stroke, seizure, nephritis, vasculitis, anemia, thrombocytopenia, alopecia, photosensitivity and malar rash. Over time, patients with lupus accrue irreversible organ damage, which contributes to an increased mortality rate in these patients. LFA's Raymond noted there are few products approved for the disease.

The current standard-of-care treatment for mild-to-moderate manifestations of SLE includes nonsteroidal anti-inflammatory drugs, antimalarials, such as Plaquenil (hydroxychloroquine), and corticosteroids.

Life-threatening manifestations of SLE, such as those involving the kidneys, CNS or blood vessels, are treated more aggressively with high-dose corticosteroids or immunosuppressive agents, such as cyclophosphamide and azathioprine.

But none of those products were specifically designed to treat lupus, and no new therapies against the disease have entered the U.S. market in 52 years, Raymond told BioWorld Today.

That's why it is a "pretty exciting event" to have a drug like Benlysta, which she noted was "specifically aimed" at the disease, so close to approval.

And while Benlysta is "not a miracle cure," Raymond said it is a "beacon of hope to all people in the lupus community."

When "slicing and dicing" Benlysta's data, she said, the FDA needs to not only weigh its safety concerns about the drug, but also must measure the cost of morbidity associated with lupus – something Raymond insisted often is ignored when "ranking" diseases.


Human Genome: FDA Reviews Lupus Drug

Adam Feuerstein The Street
WASHINGTON, D.C. (TheStreet) -- U.S. regulators posed some tough questions about the efficacy and safety of Human Genome Sciences'(HGSI) experimental lupus drug Benlysta in a review posted ahead of next Tuesday's advisory panel meeting.
Investors largely expect Human Genome Sciences and partner GlaxoSmithKline(GSK) to receive approval for Benlysta, which would be the first new treatment for the autoimmune disease lupus in about 50 years. To achieve the goal, however, Benlysta must first pass muster from a panel of outside experts and then receive final approval from the U.S. Food and Drug Administration.

Friday's medical review of Benlysta, posted on the FDA's web site, is the first step in this process. The FDA tends to take a prosecutorial role in its drug reviews ahead of advisory panel meeting, so investors largely anticipated the questions and concerns raised about Benlysta.

Across two large clinical trials, FDA acknowledged that two large clinical trials demonstrated a statistically significant difference in the number of lupus patients who responded to treatment with Benlysta compared to placebo. However, FDA said the results from the Benlysta studies produced "somewhat marginal efficacy" in part because the drug's biggest positive effect was on organ systems in patients that are not life threatening. The FDA also found that the study conducted outside the U.S. also produced stronger results than the study conducted here and African-Americans lupus patients underperformed relative to non-African Americans.

The FDA also raised some concerns about Benlysta's safety, including risk for infections and neuropsychiatric adverse events including suicide. The specter of an increased risk of suicide was probably the most surprising revelation in the FDA material.

"Clearly there is a need for effective therapies in SLE [lupus]," FDA concludes. "However whether belimumab's [Benlysta's] benefits sufficiently outweigh its risks is the crux of the issue... If belimumab only has a modest effect for some patients and manifestations, is a possible increased risk of death, infection, or neuropsychiatric adverse effects worth the potential benefit?"

That's the question which will be answered Tuesday when the FDA's panel of outside experts convene and decide whether to recommend Benlysta for approval, or not.

"Overall, we still think the panel is likely to vote for approval and see nothing in here surprising, other than suicide," said ISI Group biotech analyst Mark Schoenebaum, in an Friday email to clients. "Of course, panels are -- in the end -- impossible to predict. But we are sticking with this one and would recommend adding to positions on what is likely to be a bit of weakness this morning after the stock's recent run."
Human Genome shares dipped about 5% in early trading but are now down 1% to $26.14. The stock closed Thursday at $26.48.

Lupus is a chronic disease in which the body's immune system creates auto-antibodies that attack connective tissue, resulting in inflammation and tissue damage, often to the heart, joints, lungs and kidneys. Women are more often diagnosed with lupus than men, and the disease goes through periods where it flares up then goes into remission.

Benlysta is a human monoclonal antibody designed to recognize and tamp down the biological activity of B-lymphocyte stimulator, or BLyS, a substance that was discovered by Human Genome. High levels of BLyS plays a role in the development of abnormal B cells (B cells are a component of the immune system), and abnormal B cells lead to increased auto-antibody formation.

Benlysta appears to lower levels of BLyS and therefore stop young B cells from growing abnormally. One advantage to treating lupus with this approach is that Benlysta doesn't appear to affect more mature B cells, which are an important part of a patient's immune system.

--Written by Adam Feuerstein in Boston.


Human Genome: Benlysta FDA Panel Preview

BETHESDA, Md. (TheStreet) -- Human Genome Sciences (HGSI) can take a big step towards marketing its first blockbuster product next week when a panel of independent experts convenes to review the lupus drug Benlysta.
The U.S. Food and Drug Administration advisory panel meets Nov. 16 and will vote whether or not to recommend Benlysta's approval as a treatment for lupus, an autoimmune disease that has gone 50 years without a new, effective therapy for affected patients.  The FDA is expected to post online its own review of Benlysta on Friday, Nov. 12, in advance of the FDA panel meeting. That review will be available for FDA web site.

I(Adam Feuerstein) will be live-blogging the Benlysta FDA panel on Nov. 16. You can register below for an email reminder.

Here's what you need to know about this important upcoming event:

Will the FDA panel recommend Benlysta's approval? Yes or No?

Wow, you're not wasting any time getting to the meat of the matter. Do you mind if I offer a nuanced answer? Yes, investor sentiment strongly favors a recommendation for approval. The risk is that FDA advisory panels often go off script. That's never been more apparent than in recent months so don't for a second consider Benlysta a sure thing.

Lupus has proven intractable to treatment with new drugs for years, yet Human Genome Sciences managed to conduct two, large phase III studies of Benlysta, each with positive results. Lupus patients are desperate for a new drug. How can Benlysta's approval be in doubt?

Benlysta's approval is probably not in doubt, but FDA advisory panels aren't coronation ceremonies. The FDA and the experts on the panel are likely to raise questions about just how much patients benefit from Benlysta treatment and for how long; they may quibble over the results from the two studies, the second of which wasn't as successful as the first; and they'll closely examine Benlysta's safety because advisory panels, especially recent iterations, have been obsessed with drug safety.

Human Genome Sciences devised a unique way to measure the clinical benefit of Benlysta in lupus patients. Will this work for the company or against it at the FDA panel?

The SLE Responder Index (SRI) devised by Human Genome Sciences isn't so much a brand new way of measuring clinical benefit in lupus patients as it is a composite of three existing measures of disease activity. Most importantly, FDA agreed that Human Genome could use the SRI as the primary endpoint in its phase III clinical trials.

If FDA told Human Genome that it was okay with the SRI, then no problem, right?

Right, except that the experts on the panel aren't the FDA, so it will be interesting to hear how they react to the data. The SRI sets a relatively high bar for response and includes tests of organ involvement (the BILAG score) and overall disease activity (SELENA SLEDAI) that FDA favors in lupus clinical trials.

You said that one of the Benlysta clinical trials was more positive than the other. Can you explain?

The first phase III study, known as BLISS-52, was conducted outside the U.S. and produced the most positive results. Lupus patients treated with a high dose of Benlysta for one year demonstrated a 14% improvement in the SRI, adjusted for the benefit shown by patients treated with placebo. The result was statistically significant. [A lower dose of Benlysta also demonstrated a statistically significant benefit over placebo.]

The second phase III study known as BLISS-76 enrolled mostly U.S. patients. The primary endpoint of the study measured response at one year like in BLISS-52, but as the study title implies, Benlysta's effect was also measured out to 76 weeks. BLISS-76's results were mixed.

At 52 weeks, the high dose of Benlysta demonstrated a 9.4% improvement in the SRI adjusted for placebo -- lower than the benefit seen in BLISS-52 but still statistically significant. The placebo-adjusted benefit for the low dose of Benlysta was only 6.8% and was not statistically significant.

When BLISS-76 was analyzed at 76 weeks, neither Benlysta dose demonstrated a statistically significant improvement over placebo as measured by SRI response.

The primary endpoint for BLISS-76 was measured at 52 weeks where the high dose of Benlysta was effective and statistically significant. Isn't that good enough?

It should be but expect some debate at the panel. The results of BLISS-76 suggest Benlysta's benefit wanes over time. At the more effective high dose, for instance, Benlysta's SRI-measured improvement fell from 9.4% at 52 weeks to 6.1% at 76 weeks. Benlysta also failed to hit a bunch of the key secondary endpoints, including the percentage of patients with decreased steroid use, in the study.

You're quite handy with all these Benlysta data.

Thanks, but credit must go to ISI Group biotech analyst Mark Schoenebaum and a very handy Human Genome Sciences slide deck he assembled for his clients to prep them for next week's FDA panel.

Can I assume that Human Genome will be prepared to argue in favor of Benlysta's approval?

Absolutely. Remember, drugs are approved when the totality of the data demonstrate a clinically meaningful benefit to patients that outweigh the risks. In this case, lupus is a disease that affects patients differently, making it difficult for a single measure of benefit to accurately capture all patients in a single clinical trial.

This is why Human Genome came up with the SRI to assess Benlysta's benefit. The primary endpoint was met in both phase III studies and all the data, when pooled together, further demonstrate the drug's benefit. Human Genome performed an analysis using a more stringent definition of SRI which demonstrated Benlysta's efficacy even out to 76 weeks. While post-hoc, it does bolster the argument in favor of the drug's approval.
And don't forget the context of lupus, as well. We're talking about a disease in which no new drug has been approved for 50 years. Until Benlysta came along, lupus was a disease in which good drugs came to die.

You haven't mentioned anything about safety. Is Benlysta safe?

The two BLISS studies failed to uncover any significant safety concerns associated with use of Benlysta. With that said, the FDA panel may examine what appears to be an increased cancer risk tied to Benlysta, although the numbers are very small. The rate of malignancy in Benlysta patients was 0.53% compared to .018% in placebo patients.

Um… That's a three-fold increase in malignancies! How is that not a big deal?

Only one cancer death in the Benlysta trials was reported and that patient died after just 21 days of treatment. The long-term follow-up from phase II studies of Benlysta doesn't indicate a cancer risk increase after 5 years; and other drugs used to treated autoimmune diseases carry cancer risk warnings in their labels but are still widely used.

Any other safety risks or potential worries?

Benlysta may be responsible for an increased risk of infections, according to pooled data from the BLISS studies, but again, infection risk is a well-known side effect of drugs used to treat autoimmune diseases.

African-Americans didn't respond as well to Benlysta, which could be brought up by the panel since lupus is 2-3 times more common in African-Americans.

You mentioned before that Benlysta is a potential blockbuster drug. Just how big could it be and what impact will it have on Human Genome's stock price?

Analyst estimates for Benlysta's commercial potential vary but generally speaking range from $2 billion to $4 billion, depending on pricing assumptions and market share gains in U.S. and Europe, where the drug will be marketed by partner GlaxoSmithKline(GSK).

One recent area of post-approval concern for investors has been the trajectory of Benlysta's commercial launch, especially given what is likely to be a tough reimbursement environment. Human Genome has been asking analysts who cover the stock to temper Benlysta sales estimates in 2011 because insurers may be slow to cover the drug, or place obstacles in the way of patients who want to use Benlysta before trying other older and less costly lupus therapies first.

ISI's Schoenebaum has a $32 price target on Human Genome, which assumes a positive FDA advisory panel, FDA approval and sales of about $2.5 billion in 2015.

Sanford Bernstein analyst Geoff Porges likewise carries a $32 price target on Human Genome after downgrading the stock to market perform in September:

"HGSI's stock has been one of the strongest performers in the biotech group over the summer and has been boosted by confirmation of BenLysta's priority review status on August 19, as well as speculation about M&A potential for the company. We now see the company as more or less fully valued in the $30 range, with less upside than other names in the mid cap group at current prices. Our launch revenue and earnings expectations are tempered by what is likely to be a tough reimbursement environment in the US. Therisks associated with near term regulatory events now seem more or less equivalent to the upside from a take-out bid, which seems unlikely to emerge before year end," Porges wrote.

--Written by Adam Feuerstein in Boston.

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Walking in Purple For Lupus Awareness
Alright, here is everything you need to know about Human Genome Science's upcoming FDA panel decision next Tuesday November 16th, 2010 for their Lupus therapy, Benlysta.  This therapy would be the first drug to come to market for Lupus in 50 years.  Currently, Human Genome is partnered with Glaxo SmithKline for marketing the drug and would share profits from the sales of Benlysta if approved.  I am sticking to my guns on this one and thinking that it will be recommended by the FDA this Tuesday. 

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