New targets, small molecules, oral delivery
An orally active immunosuppressant, Pfizer's CP690550 could be the long-sought small-molecule treatment for rheumatoid arthritis, says Clare Davies, lead analyst for immunology
and inflammation at Datamonitor. An RA pill would help payers and patients alike, since monoclonal antibodies are all injectibles.
The new drug attacks lymphocytes by inhibiting the Janus-activated kinase 3 (JAK3) pathway. In addition to RA, the therapy
is being tested for Crohn's disease.
Another promising small molecule inhibits the related JAK2 enzyme. Incyte's INCB018424 not only promises efficacy against rheumatoid arthritis but is also in trials to treat multiple myeloma, prostate cancer,
and psoriasis. Once again, the fact that the drug is an orally available daily-dose treatment should encourage patient compliance.
ChemoCentryx and GlaxoSmithKline are partners in the discovery, development, and marketing of compounds targeting chemokine
and chemoattractant receptors for the treatment of inflammatory disorders. Two of these compounds aim to treat various forms
of inflammatory bowel disease, including Crohn's disease, celiac disease, and ulcerative colitis. Their mechanism: selective
binding to the CCR9 chemokine receptor, which according to the company is a "highly specific receptor expressed by T cells
that migrate selectively to the digestive tract."
Currently in a Phase II/III trial for Crohn's disease is the first of these compounds, Traficet-EN (CCX282-B). Behind it, in Phase I, is CCX025. GSK paid $63.5 million in upfront cash and equity investments for world marketing rights to Traficet-EN, CCX025, and two other
compounds. Milestones payments could reach $1.5 billion.
DIABETES: INHALED INSULIN
A breath of fresh air?
After Pfizer withdrew Exubera from the market in October 2007, the once-crowded field of inhaled insulin candidates thinned
to a single product: MannKind's Afresa. But instead of convenience, the product—still better known as Technosphere insulin—appears to be surviving on clinical benefit.
"I am still optimistic that MannKind's Afresa will be sufficiently beneficial because of its profile to be successful in the
market even though Exubera failed," says Jay Skyler.
MannKind's unique technology allows an acidic crystalline powder dusted with insulin to liquify at neutral pH deep inside
the lungs and seep into the bloodstream across tiny pulmonary membranes. The relatively quick delivery of insulin (slower
than the pancreas, but faster than subcutaneous injections) creates an insulin profile more like the body's own than any other
drug available, according to Skyler. In addition, the drug disappears faster from the bloodstream when its work is done.
In September, MannKind released top-line results of a Phase III clinical trial comparing Afresa to subcutaneous insulin aspart.
The inhaled product better prevented incidents of hypoglycemia and glucose spikes after meals. It had no pulmonary side effects,
and it had a welcome benefit for diabetes sufferers: an average weight loss of 4.4 pounds in 52 weeks for Afresa users with
type 1 diabetes, compared to a three-pound weight gain for patients on insulin aspart.
The drug may have to carry a class-wide warning for cancer, but company market research suggests that even with a tough label,
Afresa is a potential blockbuster.