A novel class of highly targeted inflammatory disease treatments are on the horizon, with potential to compete against broader immunosuppressants such as anti-TNFs, one of the biggest classes of drugs.
Partners GlaxoSmithKline and ChemoCentryx initiated pivotal trials this week of an oral chemokine antagonist for Crohn’s disease, GSK’786, which promises an alternative to patients who have to endure some major side effects associated with injected TNF-alpha inhibitors. Specifically a CCR9 antagonist, GSK’786 is the most advanced pipeline candidate from the CCR antagonist class – immunotherapies that demonstrate selective efficacy in inflammatory and autoimmune disorders, as well as diabetes. Several CCR subclasses are in mid-stage development so strong data for GSK’786 could stimulate major interest in this fledgling field, although Glaxo's tie-up with ChemoCentryx leaves few licensing opportunities (see table below).
A divided class
CC chemokine receptors (CCRs) are G-protein-coupled membrane receptors that initiate cellular signaling cascades when bound by their associated chemokine, and stimulate T-cell migration during an immune response.
The CCR antagonist class is divided, and each subclass is associated with different disease types. CCR1 and CCR2 are involved in macrophage signaling and migration. Glaxo and ChemoCentryx’s CCR1 antagonist CCX354 is currently in phase II for rheumatoid arthritis, while a CCR2 antagonist developed by ChemoCentryx – CCX140 – is undergoing phase II trials for type 2 diabetes.
Meanwhile CCR5 antagonism is a validated means of targeting HIV on the host cell surface, as the receptor seems involved in increasing a person’s susceptibility to the virus. Glaxo and Pfizer’s Selzentry is the only marketed CCR-based product, although commercial success since its 2007 launch has been uninspiring (Glaxo and Pfizer to join forces on HIV, April 16, 2009). Multiple phase I programmes are nevertheless ongoing, including another Glaxo/Pfizer venture – GSK706769.
CCR9 is found specifically on T-cells in the gastrointestinal system, allowing migration and interaction in the small intestine mucosa. Hence, inhibiting its action can block specific inflammatory responses in cases such as Crohn’s disease and other inflammatory bowel disorders.
Crohn’s disease is an inflammation of the bowel that can result in diarrhoea, ulcers and other painful intestinal problems. Its cause is not absolutely known, although some hereditary element seems to exist. A common theory, according to the National Institute of Diabetes and Digestive and Kidney Diseases, is a pseudo-autoimmunity, where the immune system mistakes gut bacteria or antigens in food as pathogenic, resulting in a chronic immune response.
Safety, delivery, price
Crohn’s disease patients are generally prescribed antibodies targeting TNF-alpha, the top sellers being Abbott Laboratories’ Humira - set to take over Lipitor's crown as the industry's biggest selling product and with 2016 global sales of $1.9bn in Crohn’s disease alone - and Johnson & Johnson and Merck & Co’s Remicade, expected to sell $1.3bn for Crohn’s.
These however are dogged with safety problems such as infections as suppressing the ubiquitous immune factor TNF-alpha tends to also suppress the rest of the immune system. TNF-alpha antibodies also require delivery by intravenous infusion, and, being antibodies, are not cheap to produce.
Glaxo and ChemoCentryx reckon they can address all these limitations with orally-delivered GSK’786 (GSK1605786; formerly Traficet-EN and CCX282-B). The drug specifically targets CCR9 in the gut, with no other immunosuppressive effect, and as a small molecule is cheaper and easier to manufacture.
The companies have somewhat of a stranglehold on CCR9 antagonists, with GSK’786 the only pivotal candidate in development, a second Crohn’s disease drug, CCX025, in phase I, and pre-clinical gastrointestinal disorder project CCX807.
Millennium Pharmaceuticals and Takeda, and also Tejin are conducting CCR9-based programmes, but these are in pre-clinical stages.
All this considered, final validation of the CCR9 approach would be a significant progression for the inflammatory bowel disease community, while the lack of competitors in the pipeline means substantial potential value for the two collaborators.
Clearly Glaxo recognised that value quite early on, signing a deal in August 2006 worth a sizeable $63.5m upfront, and milestone payments of up to $1.5bn – big money for essentially an early-stage discovery collaboration and option to license GSK’786 worldwide.
Glaxo exercised its option a year ago after positive phase II data was reported from the Protect-1 trial, paying ChemoCentryx $35m.
The 52-week trial demonstrated GSK’786 to be safe and well-tolerated, with 47% of patients with moderate-to-severe disease in remission, versus 31% in the placebo arm. By comparison pivotal data showed a 33% remission rate with Humira.
Furthermore an additional GSK’786 dose between weeks 12 and 16 caused subjects’ clinical responses, based on the Crohn's Disease Activity Index (CDAI), to significantly decrease, while an increase was observed in the placebo group.
The phase III portion will study similar outcome measures, with separate trials including a maintenance study also expected, and will enrol a total of 2,500 patients.
Financial analysts have not yet attributed any sales to GSK’786, although this could soon change now Glaxo has been handed the baton. Time will tell how the candidate fares in phase III, but the outlook is encouraging on the basis of phase II efficacy and safety data. An eventual approval could open the doors on a pipeline of novel, targeted therapies in big disease areas, and more immediately provide a much-needed, safe therapy for inflammatory bowel diseases.
|Pipeline CCR antagonists|
|Status||Product||Pharmacological Class||Indication Summary||Company|
|Phase III||GSK'786 (Traficet-EN)||CCR9 antagonist||Crohn's disease [Phase III]; Ulcerative colitis [Phase II]||GlaxoSmithKline / ChemoCentryx|
|Phase II||MLN1202||Anti-CCR2 MAb||Atherosclerosis [Phase II]||Takeda / Millennium Pharmaceuticals|
|CCX354||CCR1 antagonist||Arthritis, rheumatoid [Phase II]||GlaxoSmithKline / ChemoCentryx|
|BMS-741672||CCR2 antagonist||Diabetes, type II (maturity onset) [Phase II]||Bristol-Myers Squibb|
|JNJ-17166864||CCR2 antagonist||Rhinitis, seasonal allergic/Hay fever [Phase II]||Johnson & Johnson|
|PF-4136309||CCR2 antagonist||Osteoarthritis [Phase II]; Hepatitis C treatment [Phase II]; Liver disorders [Phase II]||Pfizer / Incyte|
|CCX140||CCR2 antagonist||Diabetes, type II (maturity onset) [Phase II]||ChemoCentryx|
|AZD2423||Chemokine antagonist||Pain, neuropathic [Phase II]||AstraZeneca|
|Phase I||CCX025||CCR9 antagonist||Crohn's disease [Phase I]||GlaxoSmithKline / ChemoCentryx|