A Big R&D Challenge
May 9, 2019 | Disease
Lupus is a very challenging disease to treat effectively. This chronic, auto-immune disorder can affect multiple organs and systems, including joints, skin, the kidneys, brain, heart or lungs. It manifests very differently across the estimated 150 –per- 100,000 people worldwide with the condition – most of whom are women.
Only one drug, GlaxoSmithKline’s belimumab (Benlysta), is approved specifically for systemic lupus erythematosus (SLE), the most common form of the condition. The drug is a monoclonal antibody that dampens the activity of B cells within the immune system. But Benlysta does not work for everyone. And it’s indicated as an add-on therapy for those whose disease has not responded to standard, more generic treatments currently used to alleviate symptoms. These include glucocorticosteroids, non-steroidal anti-inflammatory drugs and other immune-suppressive treatments.
The good news is that Benlysta was approved in April 2019 for use in children suffering from lupus. The condition is often more aggressive in children, and damage can accrue very fast. Despite this, lupus remains a high unmet need. All current treatments come with significant side-effects, and cannot be tolerated by all patients. None provides anything near a cure. The upshot: poor quality of life for many, and high co-morbidity rates.
The disease’s heterogeneity makes it very tricky to define and accurately measure appropriate end-points during clinical trials. Multiple, sometimes organ-specific instruments may be required; each must be reliable and responsive to changes in symptoms. Many clinical trials have failed primary and secondary endpoints, in part due to this measurement challenge.
Bristol Myers-Squibb’s Orencia (abatacept) inhibits the activation of T-cells, another kind of immune system cell. It joined the ranks of disappointing Phase III results in lupus during 2018, after failing to meet a primary endpoint of complete renal response at one year. BMS promised more analysis, after noticing some positive signs among sub-groups.
AstraZeneca’s anifrolumab also flunked a Phase III trial in 2018. Anifrolumab is an antibody that neutralizes the receptors of interferon type 1, one of the proteins that regulate the immune system. It failed to reduce disease activity at 12 months, as measured by an index of 12 symptoms.
Anifrolumab and abatacept remain in their respective sponsors’ pipeline charts. So does Merck Serono’s Phase II fusion protein, atacicept, and ImmuPharma’s Lupuzor, a T-cell modulator. Lupuzor’s Phase III results did not quite make the mark, either – as measured by the SLE Responder Index, a composite outcome designed specifically for SLE. But ImmuPharma has announced an extension to the trial, and still hopes that its candidate may make it to market, potentially as a disease –modifying agent, rather than just a symptom-treater. (A partner has proven hard to come by, however.)
Although lupus remains un-tamed, hope remains for patients. Growth in disease prevalence should encourage drug developers to persist in seeking the most appropriate, sensitive and meaningful measures of the condition, and in designing their trials accordingly. Most of the mechanisms and molecules in development are more targeted than existing immuno-suppressants, so may one day provide relief, with fewer side-effects, even for just a sub-set of patients.
- March, 20 2020