Benlysta May Lead Wave Of New Approvals For Lupus Drugs

The looming approval of Benlysta may create an easier pathway to approval for other lupus candidates, while leaving a potentially broad opportunity for other drugs to fill gaps in its label. Start-Up profiles three emerging lupus drug developers: Azano Pharmaceuticals, Resolve Therapeutics and SuppreMol

The looming approval of Benlysta may create an easier pathway to approval for other lupus candidates, while leaving a potentially broad opportunity for other drugs to fill gaps in its label.

The end of a 50-year drought for new drugs to treat lupus should come on March 11, 2011, with the widely anticipated approval of Benlysta (belimumab). The antibody drug, developed by Human Genome Sciences Inc. (HGS) and optioned by GlaxoSmithKline PLC under a long-term collaboration between the companies, will determine how segmented an estimated multibillion-dollar market for lupus therapies will become. [See Deal] [See Deal] [See Deal]

In early December, the Food and Drug Administration announced that it would extend its review period for Benlysta by 90 days, giving more time to write an appropriate label for the drug to reflect that significant portions of the lupus patient base were not represented in HGS' pivotal clinical trials. ( See "Benlysta Decision Likely To Be Delayed By Negotiations On Labeling," "The Pink Sheet ," November 22, 2010 (Also see "Benlysta Decision Likely To Be Delayed By Negotiations On Labeling" - Pink Sheet, 22 Nov, 2010.).) That the agency chose to extend its review rather than issue a "complete response" letter was almost cause for celebration among analysts and other industry watchers.

If Benlysta obtains FDA approval, the drug is expected to achieve blockbuster status in just a few years. Such is the pent-up demand for a new therapy in a disease setting that has seen no new drug approvals in decades. Treated traditionally with anti-malarials and corticosteroids, more severe cases of lupus recently have come to be treated with chemotherapy agents like Baxter International Inc.'s Baxter Healthcare Corp.'s Cytoxan (cyclophosphamide) and biologics like Roche's CellCept (mycophenylate motefil) and Biogen Inc./Roche's anti-CD20 antibody Rituxan (rituximab). ( See "Market Snapshot: After Benlysta Breakthrough, How High Is The Sky In Lupus?," "The Pink Sheet," October 12, 2009 (Also see "Market Snapshot: After Benlysta Breakthrough, How High The Sky In Lupus?" - Pink Sheet, 12 Oct, 2009.).) Off-label use of CellCept and Rituxan accounted for about 75% of lupus prescriptions in 2008.

Lupus is a chronic, systemic autoimmune disease characterized by the formation of autoantibodies that attack and inflame healthy tissue. There is no widespread agreement on patient totals, although the Lupus Foundation of America says about 1.5 million Americans and five million people worldwide suffer from the disease. The fact that lupus is a very heterogeneous disease has created problems for new drug development: its potential effects on multiple organ systems have made clinical trial design and the selection of appropriate endpoints extremely difficult.

About 70% of lupus patients are thought to have systemic lupus erythematosus (SLE), a form of the disease in which an internal organ is involved. However, 25 to 30% suffer from a more severe version of the disease called lupus nephritis (LN, an inflammation of the kidney) or central nervous system lupus, both of which are refractory to current treatment methods. Health care consulting firm Decision Resources estimates that the global market for SLE therapies will increase nearly fivefold in the next decade, from about $404 million in 2009 to $1.985 billion in 2019. The consulting firm projects Benlysta sales exceeding $900 million by 2019, while Rituxan will remain second in the market, largely as the therapy of choice for patients with more severe manifestations of lupus – those left out of Benlysta's anticipated initial labeling.

HGS' development program for Benlysta, which targets B lymphocyte stimulator, also known as B cell activation factor (BAFF), a contributor to the production of autoantibodies in lupus and other autoimmune diseases, is intended to obtain approval for SLE, defined as patients suffering from moderate to severe lupus. The company also plans to perform a trial of the drug in LN. According to the company, patients with this condition were excluded from the Phase III program due to inexperience with the background therapies for treating the condition. Now that more experience has been gained with therapies like CellCept, a study is more appropriate, HGS says.

Benlysta's likely approval for SLE would leave the door open for new therapies for LN but also should provide a demonstrated pathway for other SLE candidates to follow in proving efficacy. That barrier could be high, however, as Benlysta might need to serve as a comparator in pivotal trials: in recent guidance, FDA has cited a preference for randomized superiority trials, using either placebo or active control with the investigational therapy as an add-on to standard of care, as a gold standard in study design for SLE. ( See "Late-Stage Lupus Therapies Glow In Halo Of Benlysta Spotlight," "Pharmaceutical Approvals Monthly," July 2010 (Also see "Late-Stage Lupus Therapies Glow In Halo Of Benlysta Spotlight" - Pink Sheet, 1 Jul, 2010.).)

Still, even if FDA sought superiority data, an approved Benlysta could light the way for other approvals in SLE because it would be a standard of care with a known efficacy range, compared with the current standard of care, which consists of off-label use of several drugs whose therapeutic effect for lupus has not been established in clinical trials.

A host of Big Pharma, specialty pharma and biotech companies are competing with HGS to launch new therapies for lupus. As expected, there have been casualties in trying to treat a disease with multiple and fairly poorly understood underlying biological triggers. Roche and Biogen have abandoned efforts to demonstrate Rituxan's efficacy in lupus and, more recently, Roche also pulled the plug on another anti-CD20 antibody, ocrelizumab, which it was studying in rheumatoid arthritis as well as lupus, when it halted its BELONG study in LN due to serious and opportunistic infection signals. A separate study in SLE was abandoned in 2008.

Roche remains in the game, however, with CellCept, an immunosuppressant that inhibits inosine monophosphate dehydrogenase, in Phase III in LN. In June, Roche and partner Vifor Pharma Inc. (a division of Galencia Group) unveiled top-line data showing that CellCept achieved the primary endpoint in the ALMS study, demonstrating superiority to azathioprine, an immunosuppressant used in rheumatoid arthritis and the organ transplant setting, in delaying treatment failure in LN patients.

The Swiss pharma also hopes to find a success route to addressing SLE through the development of antibodies to interferon alpha. It has advanced rontalizumab (RG7415, developed by its Genentech Inc. unit), into Phase II for SLE. Nor is Roche alone on that path, as AstraZeneca PLC and partner Bristol-Myers Squibb Co. have brought their own anti-interferon alpha candidate, sifalimumab (MEDI-545), into Phase II as well.

Seeking to show efficacy in both SLE and LN is Merck KGAA unit Merck Serono SA's atacicept, a recombinant TACI receptor-ligand fusion protein that binds BlyS and APRIL receptors. Like Benlysta, it would work largely by inhibiting B cell maturation. Atacicept is in Phase III for both lupus indications, and also is being investigated in multiple sclerosis and rheumatoid arthritis.

UCB Group and partner Immunomedics Inc. have anti-CD22 antibody epratuzumab, another inhibitor of B cell maturation, in Phase III in SLE. [See Deal] In December, the companies launched a pair of Phase III studies in moderate to severe SLE after producing Phase IIb data that showed their antibody reduced disease activity over a 12-week treatment period. Also in Phase III is BristolMyers' Orencia (abatacept), a T-cell co-stimulation modulator already approved in both RA and juvenile idiopathic arthritis, for lupus nephritis. Orencia is a fusion protein CTLA-4 ligand that binds to the CD80 and CD86 proteins. Nine other candidates are in early-stage clinical development. ( See Exhibit 1.)

But the search for new lupus drugs is not limited to large, deep-pocketed pharmas. Start-ups have also gotten into the game, with several either in or poised to enter clinical trials with their compounds.

SuppreMol GMBH, (Also see "SuppreMol GMBH" - Scrip, 1 Jan, 2011.) profiled in this issue, for example, is developing SM101, a recombinant version of human Fcγ receptor Fc γRIIb, now in Phase IIa for SLE. This candidate competes with membrane-bound Fcγ receptors on immune cells, preventing binding of immune complexes containing autoantigens and inhibiting re-stimulation of immune cells.

Resolve Therapeutics LLC, (Also see "Resolve Therapeutics LLC" - Scrip, 1 Jan, 2011.) also profiled here, has a protein that targets the interferon pathway, RSLV-125, about to begin IND-enabling studies for SLE. [Azano Pharmaceuticals Inc.] (Also see "Azano Pharmaceuticals Inc." - Scrip, 1 Jan, 2011.) has a C-reactive protein, Az 121, and a CRP mutant, Az 175, in preclinical study in lupus nephritis.

Resolve's compound is intended to act in the same pathways as Roche/Genentech's rontalizumab and AstraZeneca's sifalimumab, but upstream of interferon alpha. The idea is not to block production of interferon itself, but rather to block events that usually trigger alpha-interferon production in lupus patients. The drug candidate RSLV-125 is a protein that company founders believe will eliminate pieces of cellular debris that accumulate in lupus patients.

Although significant work remains before Azano's compounds can enter clinical development, the company already has an eye on the structure of its clinical program, which it says will be in line with guidelines issued last year by FDA calling for lupus nephritis drugs that are less toxic than current therapies and better at reducing inflammation. – Joseph Haas