Therapeutic focus – Late stage lupus pipeline sparse but potentially valuable

Analysis

Despite claiming numerous drug candidates over the years and a disappointing reception to the first new treatment for fifty years, lupus remains a huge unmet need and continues to attract research attention. However, the challenges the condition throws at developers means lupus remains only for the very brave – only three novel candidates are currently in late-stage studies (see table).

Anthera’s blisibimod could make that four if the company can find the funds, although disappointing phase II results released last week make that a tough ask. Phase IIb data is due from Merck KGaA’s dual acting agent atacicept later this year, while the next registration-stage candidate, Eli Lilly’s tabalumab, will yield data in 2013. Meanwhile GlaxoSmithKline’s attempts to buy partner Human Genome Sciences for access to struggling Benlysta suggest that many still see commercial potential in this market – any further clinical progress made by these late-stage candidates chould be valuable for both patients and the companies involved.

Chronic disease

Systemic lupus erythematosus (SLE), the most common form of lupus, is a chronic severe automimmune disease. The body’s own antibodies, produced by immune B cells, attack organs and tissues including the heart, lungs, skin, joints, kidneys and brain.

Symptoms include fatigue, swollen joints, fever, skin rash and kidney problems, which can flare up unpredictably. About 10-20% of SLE patients have severe lupus nephritis, which a serious complication that affects the kidneys, or CNS lupus, which can also be fatal.

According to the Lupus Foundation of America approximately 1.4 million people in the US, 2 million in Europe and 5 million people worldwide are affected by SLE. However, patients can often manifest different symptoms meaning the disease is not only hard to treat, it is also hard to diagnose and presents challenges to researchers attempting to measure disease progression.

Troubled start

Lupus is still largely treated by primary care physicians with generic drugs such as steroids or immune suppressants. Rheumatologists will treat the more severe patients with very active disease – the population that Benlysta is approved to treat.

The antibody, generically called belimumab, inhibits the B-lymphocyte stimulator (BLyS), sometimes called the B-cell activating factor (BAFF). Its approval not only validated this target in lupus, it also helped establish a regulatory pathway for others. Human Genome designed the SLE Responder Index (SRI) for its pivotal studies, a composite index of measures established by the American College of Rheumatology to assist the development of new lupus therapies. Other developers are already incorporating the SRI into clinical study plans.

However, Benlysta has disappointed since launch and analysts’ sales forecasts have come down dramatically. On approval in March 2011 consensus was for sales to hit $2bn by 2016, a figure that now sits at $933m, according to EvaluatePharma data.

A number of factors have been posited for the slow launch, including fear of biologics, particularly in a patient group not accustomed to intravenously administered therapies. The drug’s high cost and a lack of data confirming its efficacy across the many different lupus subtypes, plus an uphill battle to educate doctors, have not helped drive new prescriptions, Human Genome has said.

A subcutaneous formulation in phase III development could answer a number of those drawbacks; the product could also help attract less severe patients who would not be prepared to undergo intravenous therapy. Results from an 816-patient phase III study of the formulation are unlikely to emerge before 2014. However, the product has the potential to give an important boost to the Benlysta franchise – something that could well have driven Glaxo to take advantage now of Human Genome’s currently weakened state.

Making life easier

Many believe that Benlysta will actually make life easier for any drug that manages to follow it onto the market, in terms of priming patients and doctors for what is a huge step forward in the treatment of this disease.

Most likely to seek approval next, assuming results are positive, is Eli Lilly with LY2127399 or tabalumab. Like Benlysta, tabalumab is an anti-BAFF antibody; however it targets both forms of the activating factor.

BAFF occurs in both cell surface and soluble forms; Benlysta only targets the soluble form. By binding to both forms of BAFF, Lilly believes the agent may further reduce the activity, survival and proliferation of B cells and therefore control disease symptoms more effectively. Currently the drug is in two phase III trials for SLE, which are expected to yield results in early to mid 2013.

Eli Lilly did not complete phase II trials in SLE, choosing the risky path of going straight into pivotal studies, likely buoyed by tabalumab’s similarity to Benlysta. The company is also only testing one dose, administered once or twice monthly; the drug is administered subcutaneously.

Not boding well

Analysts’ sales forecasts remain very conservative at this stage for the Lilly drug and hopes are low for tabalumab to succeed. Unfortunately, the failure of Anthera’s blisibimod last week would not have made encouraging reading for the Lilly camp. While blisibimod is a polypeptide to Lilly’s antibody, the Anthera agent also targets both soluble and membrane bound forms of BAFF.

The company said last week a 200 mg dose of the BAFF inhibitor failed to significantly improve symptoms in a pooled group of patients at 24 weeks, the primary endpoint of the phase II study. A greater response in the most severely sick patients has helped define a patient population for late-stage study, Anthera said in announcing the results and pledging to continue to phase III.

A two-thirds drop in the company’s share price, to 81 cents, reflects a belief that results were not compelling enough to persuade investors to fund that study. Whether a partner can be persuaded to come on board remains to be seen.

Also in development

Also in the phase III pipeline is Merck KGaA’s atacicept, another subcutaneously delivered agent that also inhibits both B lymphocyte stimulator (BLyS) and a proliferating inducing ligand called APRIL. These have co-stimulatory activity on B cells.

A phase II/III trial that recruited 510 patients is due to report at the end of the year, measuring the reduction in flare ups. Clinical data to date has not been particularly encouraging – a previous phase II/III trial in lupus nephritis was terminated due to safety issues, including an increased risk of serious infection. It seems likely further trials will be needed before atacicept is sent before regulators.

Finally UCB is enrolling patients into two phase III studies of epratuzumab, called Embody 1 and 2, which are expected to report in 2014. The anti-CD22 MAb antagonises the CD22 receptor found on B cells. Phase II results were encouraging and although the drug must be infused, suggesting it will be confined to a more severe patient population, a more rigorous clinical programme seems to have prompted higher sales forecasts from analysts.

If any of these agents manages to prove as effective as Benlysta, sales forecasts will of course grow. The first subcutaneous drug to reach the market is also likely to have a big impact. Benlysta looks like it will continue to grow slowly, whatever company wins the battle for control. But treatment of lupus is shifting, and even if only one of these late-stage agents succeeds, patients stand to reap further benefits.

Selected late stage SLE pipeline
Annual Sales WW - Sales
Status Product Company Pharmacological Class 2011 2018 Trial ID
Marketed Benlysta Human Genome Sciences/GlaxoSmithKline Anti-B lymphocyte stimulator (BLyS) MAb 76 1,691  -
Phase III Epratuzumab UCB/Immunomedics Anti-CD22 MAb - 311 NCT01261793
NCT01262365
NCT01408576
Tabalumab/LY2127399 Eli Lilly Anti-B-cell activating factor (BAFF) MAb - 197 NCT01205438
NCT01196091
NCT01488708
Atacicept Merck KGaA/Bristol-Myers Squibb BLyS & proliferation-inducing ligand (APRIL) inhibitor - 179 NCT00624338
Blisibimod Undisclosed Partner Sales/Amgen/Anthera Pharmaceuticals BAFF inhibitor - - NCT01395745
NCT01162681
Benlysta SC Human Genome Sciences/GlaxoSmithKline Anti-BLyS MAb - - NCT01484496

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