A Big R&D Challenge

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.

Cannabis-based Epidiolex helps some epilepsy sufferers

Epilepsy is characterized by recurrent, unprovoked seizures. These result from disturbances to the brain’s normal patterns of electrical impulses.  A seizure may last a few seconds or a few minutes, causing changes in movement, behavior, feeling or awareness.

Injury to the brain is one of the most common causes of epilepsy, but for many of the estimated 65 million epilepsy sufferers worldwide, the cause remains unknown. Most cases are adequately treated with one or more of the dozen or so drugs on the market, which include UCB’s Keppra (leveteracitam) and Vimpat (lacosamide) and GlaxoSmithKline’s Lamictal (lamotrigine). Generic carbamazepine and formulations of valproic acid are also widely used.

The challenge in treating epilepsy is two-fold. The first issue, common to many areas of medicine, is diagnosing the disease and finding the right treatment for the right patient. A diagnosis of epilepsy occurs when a person has experienced two or more unprovoked seizures over 24 hours apart. But often the condition is not picked up. Even when it is, our lack of understanding of the disease’s precise causes in each individual, and of how some of the available treatments actually work, means patients often have to try out multiple medications one after the other.

Key opinion leaders in the field report that only 70% of patients fully respond to therapy and are freed from seizures.

A second area of unmet need in epilepsy is among the rarer forms of the disease, many among children, that are highly resistant to existing drugs. These include Lennox-Gastaut Syndrome (LGS), a severe form of childhood-onset epilepsy characterized by multiple seizures, cognitive dysfunction and with a very poor prognosis, and Dravet Syndrome.

A new category of epilepsy treatment, derived from cannabis, was approved in the US in 2018 for both these rarer forms of the condition. GW Pharmaceuticals’ Epidiolex (cannabidiol) is the first prescription medication formulation of highly-purified, plant-derived cannabidiol – a molecule found in the cannabis plant (but not the one responsible for highs associated with recreational use of cannabis). The drug was found in Phase III trials to reduce the frequency of seizures among patients taking it alongside their standard medications, relative to those taking only standard treatments.

Epidiolex is currently under review in Europe, and is also in Phase III trials for seizures associated with tuberous sclerosis complex (TSC). TSC is a rare, multi-system genetic disease that causes benign tumors to grow in the brain and other vital organs, and is closely associated with epilepsy.

Cenobamate is another promising anti-epileptic drug candidate, whose approval submission has just been accepted by the US FDA.  Developed by Korean company SK Life Science, the molecule showed promising efficacy results in Phase III trials of adults with partial-onset seizures. As is the case for several approved epilepsy treatments, cenobamate’s mechanism of action is not completely understood, and trials also revealed some safety issues. These may well prove surmountable, though, given unmet need among the estimated third of epilepsy sufferers whose seizures remain uncontrolled.