Biotech Values

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Benlysta's Modest Benefit vs. Risks Poses Dilemma

By Donna Young

http://www.bioworld.com/servlet/com.accumedia.web.Dispatcher?next=bioWorldHeadlines_article&forceid=56406

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.




Published November 15, 2010