If Human Genome Sciences/GlaxoSmithKline's Benlysta (belimumab) succeeds in becoming the first new lupus therapy in half a century to make it through the regulatory gauntlet, it could change not only the commercial outlook in the lupus market, but also the landscape of future lupus clinical trial design.

That's because Benlysta would be in a position to provide something the industry hasn't had for equally as long: a comparator for use in clinical trials that carries approval for lupus.

In recent guidances, FDA sets a randomized superiority trial, using either placebo or active control with the investigational therapy as an add-on to standard of care, as the gold standard study design for both systemic lupus erythematosus - the indication HGS seeks for Benlysta - and lupus nephritis (¹ Also see "FDA Guidances On Lupus Drug Development Call For Superiority Trials" - Pink Sheet, 28 June, 2010.). The agency posted the final guidances on lupus drug development June 21.

The complication is that the standard of care for lupus includes off-label use of drugs approved for other indications. And because the therapeutic effects of commonly prescribed immunosuppressives, such as cyclophosphamide, azathioprine or mycophenolate mofetil (Roche's immune suppressant CellCept ) have not been established for lupus in clinical trials, their impact on treatment effect is difficult to measure.

It could be significantly easier to get through FDA if the comparator in a clinical trial has a known efficacy range.

Another concern highlighted in the new guidances is that the mechanism of action in an experimental drug might be similar to that of the standard of care, again confounding measurements of treatment effect.

Having an approved therapy with which to compare an investigational compound in studies of the notoriously inconsistent disease cuts down on the unknowns or at least provides an extra measure of confidence for regulators.

But, while a Benlysta approval might offer a more stable target for comparisons at the regulatory end of development, it also could introduce new challenges for the already difficult field of lupus drug development.

In the intensifying comparative effectiveness environment, products in development might have to prove superiority over the approved therapy or at least add a comparative arm to the trial design - producing results that will be scrutinized by payers and practitioners.

The approval also might affect clinical trial enrollments for SLE; with an approved drug available, patients might not be as willing as they have been to participate in new studies for experimental agents.

HGS announced June 10 that it had submitted the U.S. Benlysta BLA, while GSK made the European filing June 7. If the drug wins six-month priority review, as most observers believe it will, approval could come by the end of the year, with a fall advisory committee evaluation anticipated. Benlysta's Phase III BLISS program was conducted under a special protocol assessment with FDA.

At least five other lupus candidates are either in or entering Phase III, including Roche's attempt to get an official clearance for CellCept (see chart, ² Lupus Drugs in Clinical Development).

Final BLISS-76 Data Released At EULAR

HGS released final results for BLISS-76, one of the two pivotal Phase III trials submitted in the Benlysta package, June 17 at the European League Against Rheumatism meeting in Rome.

The top-line results of the trial, released in November, confirmed the efficacy seen in BLISS-52, but the full data from BLISS-76 filled out the picture - among other things, providing data on North American patients. BLISS-76 treated 819 patients primarily in North America and Europe, while BLISS-52 treated 865 patients primarily in Asia, South America and Eastern Europe (³ Also see "Outlook BLISSful For HGS' Benlysta After Full Data Released At ACR" - Pink Sheet, 26 October, 2009.).

The primary endpoint of BLISS-76 was patient response at week 52, as measured by the SLE Responder Index (SRI), which defines patient response by an improvement in scores on a two-part disease activity index called the SELENA SLEDAI. Treatment continued for the full 76 weeks, however, so data could be compiled on secondary endpoints. HGS learned from its Phase II program for Benlysta that an individual responder index similar to those used in other autoimmune diseases, such as rheumatoid arthritis, might produce the most accurate data and that a four-point improvement in SELENA SLEDAI was a clinically significant improvement (⁴ Also see "Emerging Phase III Data Validate Clinical Trial Design In Lupus" - Pink Sheet, 1 September, 2009.).

So for BLISS, an SRI score of 4 points or greater with no clinically significant worsening measured by the British Isles Lupus Assessment Group scale (BILAG), and no clinically significant worsening in Physician's Global Assessment (PGA), met the criteria for success. Among the group taking 10 mg/kg Benlysta with standard of care, 43.2 percent had a statistically significant improvement at week 52 compared to 33.5 percent with placebo (p=0.017).

However, though it trended positive, the difference at week 76, a major secondary endpoint, failed to reach statistical significance with 38.5 percent of the treatment group and 32.4 percent of the placebo group improving by 4 or more points.

HGS responded to the missed endpoint a week later on June 25 at the International Congress on SLE in Vancouver, with a post hoc analysis that compared the arms for patients that had increases of 5, 6, 7, 8, 9 and 10 points and revealed a statistically significant response at both 52 and 76 weeks (p<0.05). in="" particular,="" at="" week="" 76,="" 21.9="" percent="" of="" patients="" taking="" benlysta="" achieved="" an="" 8="" point="" or="" better="" improvement="" compared="" to="" 12.9="" percent="" on="" placebo=""><0.01) and="" 15.4="" percent="" improved="" 9="" points="" or="" more="" compared="" to="" 4.8="" percent="" for="" placebo=""><>

Why Did A "Good Drug" Squeak By Placebo?

During an analyst day broadcast from EULAR, HGS execs and investigators from the BLISS program fielded questions about the results. Chief among them: what happened to the statistical significance in the last 24 weeks of BLISS-76 and why didn't a drug that has had such rave reviews perform better against placebo?

"The placebo patients do pretty well and [Benlysta] patients do somewhat better. Why isn't there more of a difference?" asked Leerink Swann analyst Joseph Schwartz.

"The truth is, the percentage difference, even though it's statistically significant, is not a huge number," acknowledged investigator Ronald van Vollenhoven, Karolinska Institute, Stockholm, Sweden. Van Vollenhoven was on the steering committee for both BLISS-52 and BLISS-76.

The numbers don't do justice to the "variety between patients," von Vollenhoven said, adding his prediction that it will be found that some patients respond to the drug better than others. Additionally, he said, even with all the work that went into developing the measuring instruments, "these are not great instruments. They are not very refined."

"The signal-to-noise ratio was really the issue here, [and] I think the true effect is probably better than what we're reading out from these instruments," especially at the individual patient level, he argued.

Because the disease is so complex, "we're always going to have to accept high placebo rates in lupus trials," investigator Michelle Petri, Johns Hopkins, added. Petri pointed out that patients were allowed to change medications in their background regimen up until weeks 16 through 24, and those changes opened the door for patients on placebo to "look better, and took away from the possible difference" between the two groups.

Petri added her opinion, however, that the SLEDAI is a tough index, meaning a change on its scale "really is clinically meaningful," and that because of that she expects the drug will "get buy-in from the rheumatology community."

Indeed, according to a survey report from market research firm Decision Resources, initial uptake among rheumatologists should be good, particularly among those with in-office infusions services.

Memory-B Cells Preserved

Benlysta is an antibody that targets the B-lymphocyte stimulator (BLyS), essential for maturation of antibody-producing B cells. Elevated BLyS levels are associated with production of autoantibodies, which attack the body's own tissues in autoimmune diseases like lupus. However, the drug appears to spare the memory-B cells that are important to defense against infection.

HGS also revealed in Vancouver that Benlysta did not significantly affect the ability of SLE patients, whose treatment regimens typically leave them immune compromised, to maintain a protective response to pneumococcal, tetanus and influenza vaccines, a response consistent with preservation of memory B-cells.

While patients on the study drug had significantly greater median percent reductions in levels of B-cell and plasma B-cell subsets compared to placebo, memory B-cells - the immune cells formed in response to an infection or vaccination so the body can mount a faster antibody response if the antigen appears again - were preserved. Increases in CD20+ and CD27+ memory cells were observed at week 8 and increased through weeks 24, 52 and 76.

Also at EULAR, on June 19, HGS reported five-year results from a long-term Phase II continuation trial demonstrating durable sustained improvement and adding to the drug's safety database. Data showed an increase from 46 percent to 59 percent in the SRI response used in the Phase III program (SRI of 4 or greater), a decrease from 62 percent to 22 percent in the overall frequency of disease flares, measured by SELENA SLEDAI, and a decrease from 23 percent to 11 percent in the frequency of patients experiencing a new BILAG A (severe) flare or more than one new BILAG 2 (moderate) flare. An increase from 33 percent to 41 percent from weeks 52-76 in mean percent improvement in physician's global assessment was sustained through the five years.

One question that remains is whether Benlysta has enough of a steroid sparing effect to make the claim, another major secondary endpoint and a goal for lupus therapies identified by FDA in the guidance. Results so far trend positive, but are not statistically significant (⁵ Also see "Benlysta Back In The Spotlight With BLISS-76, But Second Phase III Still May Not Be Enough To Support Some Claims" - Pink Sheet, 2 November, 2009.). A pooled analysis from BLISS-76 and BLISS-52 showing superiority are to be presented at the American College of Rheumatology meeting in November in Atlanta. The combined analysis, however, was not prespecified in the SPA and HGS will have to make its case to regulators.

Best Benefit When Added To CellCept

Patients on immunosuppressants who added Benlysta to a regimen containing CellCept had had the highest response compared to standard of care in the BLISS program. That finding led some to speculate that Benlysta can't have added benefit to mycophenolate, and "that isn't the case," William Freimuth, HGS' VP for immunology, rheumatology and infectious diseases clinical research, stressed during the firm's analyst day.

The protocol allowed virtually all immunosuppressants except biologicals and I.V. cyclophosphamide, but azathioprine, methotrexate and mycophenolate had the top three positive responses, he said.

Roche and Vifor Pharma (formerly Aspreva) are exploring the efficacy of CellCept against lupus nephritis, which affects approximately 25 percent to 30 percent of lupus patients. On June 3, the companies announced top-line data from the maintenance phase of the Aspreva Lupus Management Study showing CellCept had successfully achieved its primary endpoint of superiority over azathioprine as maintenance treatment in delaying treatment failure in patients with LN. In the ALMS study, patients who had been successfully put into remission with either cyclophosphamide or CellCept received either CellCept or azathioprine for maintenance for up to three years. The study may enable Roche to register CellCept in LN, for which it is widely used off-label.

But the ALMS trial may also draw HGS into the lupus kidney disease indication it has hesitated to consider because Benlysta can take 18 months to show its positive effect; LN is a more acute disease than SLE. In a July 2 research note, Barclays Capital analyst Jim Birchenough predicts that HGS will be drawn into that arena, initiating a trial comparing the efficacy and safety of Benlysta with and without CellCept in LN maintenance.

New Data For Anti-CD22 Drug Epratuzumab

Shortly after Benlysta emerged last year as a clear affirmation of BLyS as a target for lupus drug development, Immunomedica/UCB released data on the humanized anti-CD22 antibody epratuzumab that also became a trail-blazing event.

At both EULAR and the Vancouver lupus meeting, UCB presented data from the Phase IIb EMBLEM study showing epratuzumab had a clinically meaningful and statistically significant effect on SLE disease activity at 12 weeks, with responder rates twice as high as for placebo at 43.2 percent for the 74 patients on epratuzumab and 21.1 percent for the 38 on placebo.

Unlike the Benlysta program, the epratuzumab program emphasizes BILAG, which measures disease activity in all affected body systems. The goal is a reduction in all baseline BILAG measures with no deterioration in SLEDAI, no increase in use of corticosteroids and/or immunosuppressive agents over baseline and no change in physicians' global disease activity assessments.

In its newly final SLE guidance, FDA notes a preference for BILAG to measure reduction in disease activity in clinical trials. Because BILAG scores patients based on their need for therapy, "the clinical interpretation of a change in score is apparent," regulators assert. The agency, however, acknowledges that other indexes, such as SELENA SLEDAI, have been shown to be valid in some treatment settings.

UCB is set to launch the Phase III program for epratuzumab, licensed from Immunomedica, in the second half.

Affirmation Is BLyS

Buoyed by HGI's perseverance and success, other companies are forging ahead with their BLyS programs.

Merck Serono's atacicept is a dual-action anti-BLyS molecule that also inhibits the lupus-related APRIL ligand, potentially blocking production of autoantibodies in two ways. Merck KGaA licensed the fusion protein from Zymogenetics.

After the drug failed in lupus nephritis because of severe infection and sharp drops in immunoglobulin levels in some early patients, Merck dropped it in LN. But, according to Barclays' Birchenough, the company was heartened by HGS' success with Benlysta and persisted with atacicept in SLE. Data from the ongoing Phase II/III study are expected in 2011.

Thinking ahead, Anthera Pharmaceuticals is already differentiating its Phase II BLyS inhibitor from others in the growing field. A fusion peptide protein, or peptibody, as opposed to an antibody, A-623 offers potential partners dosing flexibility - with both subcutaneous and I.V. delivery - and distinctive intellectual property.

Based on encouraging Phase Ia and Ib results, as well as the validation of BLyS as a target in lupus, the company is planning a Phase IIb study testing A-623 administered subcutaneously against standard of care or placebo plus standard of care in serologically active lupus patients.

- Shirley Haley ( ⁶ s.haley@elsevier.com )

Late-Stage Lupus Therapies Glow In Halo Of Benlysta Spotlight

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