Update note: Following the postponement of the September arthritis advisory committee meeting, a new meeting is tentatively set for March 12, 2012 according to the FDA website, however, the FDA is yet to confirm this date.
The future of the anti-nerve growth factor monoclonal antibody class of drugs for treating arthritis will be a little clearer after an FDA expert panel’s assessment of incidents involving destruction of bone tissue. Investigators have ceased most of the work in the class – with cancer-related pain relief an exception – as regulators and companies try to determine what indications, if any, are appropriate for continued testing of the pain-relieving biologicals.
Whilst the most advanced candidates in the class, Pfizer’s tanezumab and Johnson & Johnson’s fulranumab, have shown promise in relieving pain, the clear safety signal has prompted the US regulator to put clinical holds on both; AstraZeneca has voluntarily suspended work on MEDI-578. It has been a disappointing series of events particularly for Pfizer, whose antibody was once its second most valuable pipeline product.
Nerve growth factor is a protein that, as its name suggests, plays a role in growth and maintenance of certain neurons. Increased production in injured tissue has been implicated in increased pain; thus agents to block it are of interest to investigators in all pain indications.
Tanezumab, also known as PF-4383119, was the most advanced product in the class and was being tested in numerous indications including chronic pain and osteoarthritis (see table). Given the unmet medical need and growing numbers of elderly likely to suffer from arthritis, it was tipped as a potential blockbuster.
|Status||Product||Generic Name||Company||Originator||Indication Summary|
|Phase II||JNJ-42160443||fulranumab||Johnson & Johnson||Amgen||Pain, cancer-induced [Phase II]; Pain, chronic [Suspended - Phase II]; Pain, moderate to severe [Suspended - Phase II]; Pain, neuropathic [Suspended - Phase II]|
|PF-4,383,119||tanezumab||Pfizer||Genentech/Xoma||Pain, cancer-induced [Phase II]; Osteoarthritis [Suspended - Phase III]; Pain, moderate to severe [Suspended - Phase II]; Pain, chronic [Suspended - Phase II]; Diabetic neuropathy [Suspended - Phase II]; Post-herpetic neuralgia [Abandoned - Phase II]|
|Phase I||PG110||-||Abbott Laboratories||Lay Line Genomics/PanGenetics||Pain [Phase I]|
|AMG 403||fulranumab||Takeda||Amgen||Pain [Phase I]|
|MEDI-578||-||AstraZeneca||AstraZeneca||Osteoarthritis [Phase I]|
|Suspended - Phase II||SAR164877||-||Sanofi||Regeneron Pharmaceuticals||Pain [Suspended - Phase II]; Osteoarthritis [Suspended - Phase II]|
It was the osteoarthritis studies that tripped up the antibody; 16 patients in one of the 13 phase III trials showed worsening disease with radiographic evidence of bone necrosis in their hip, knee or shoulder, requiring total joint replacement. Continued concern led to a clinical hold in diabetic neuropathy and lower back pain (Safety concerns narrow tanezumab’s potential further, July 21, 2010).
Tanezumab remains active in a single phase II trial, as an add-on to opioids in 58 patients experiencing pain from bone metastases.
At the end of 2010, the FDA also ordered a hold on fulranumab, along with Regeneron Pharmaceuticals and Sanofi’s REGN475/SAR164877 (Clinical and regulatory events over the Christmas period, January 4, 2011).
As Astra has withdrawn its candidate, only Abbott Laboratories’ PG110 remains in active development in osteoarthritis, however, its one listed study at clinicaltrials.gov, a phase I trial in knee osteoarthritis, is listed as complete.
Abbott bought the product from PanGenetics at the end of 2009 in an unusual deal, paying $170m to own the compound outright (PanGenetics cashes in on Abbott's early stage bet, November 13, 2009). Safety concerns emerged a few months later with tanuzumab; the company's decision to buy rather license could turn out to be a costly one.
Uncommon class hearing
A US advisory committee’s pre-market assessment of the safety of an entire drug class is a rare, but not completely unprecedented occurrence. FDA watchers say no similar prospective look has been taken since 2003, following the deaths of two patients in gene therapy trials.
Given the shadow cast over the class with ongoing clinical holds, the hearing on September 13 will consider if anti-NGFs can proceed with clinical development, and if so, under what circumstances and in which indications.
The cancer-related pain would appear to be the most likely candidate for continued investigation, given the unmet medical need, ongoing trials and the shorter-term duration of treatment.
However, as osteoarthritis and chronic pain affect patients sometimes for decades, and there are effective alternative available, more persuasive data will be necessary for a lifting of clinical holds in these indications. If clinical holds are lifted in the pain-related indications, they will likely be under restricted circumstances to determine how significant the bone-destruction signal is.
As such, it may be awhile before confidence in this class returns, if it ever does. Only stellar safety performance could persuade observers that blockbuster forecasts are merited.