BioMimetic Therapeutics probably will not be taking much solace from a close FDA advisory panel committee vote in favour of its synthetic joint fusion product, Augment Bone Graft. For one, there was the FDA staff challenge of the Tennessee group’s statistical methods in the trial demonstrating that the recombinant platelet-derived growth factor (PDGF) was as good as autologous bone grafts in ankle and foot procedures.
But hanging more ominously over Augment is questions about its long-term safety, especially as regulators have raised concerns over a cancer signal from two other products using PDGF, albeit in one case at a much higher dosage. Given these questions, along with the efficacy of grafts using a patient’s own bone, a first-pass approval by the FDA looks increasingly doubtful.
BioMimetic’s management called the expert panel’s support a “major milestone” for the company. Investors, however, were far from cheered by the series of close-but-positive votes on safety, efficacy and the risk-benefit balance of Augment - shares were down 4% to $8.85 in early trade today and have lost a third of their value since the FDA's briefing documents were released on May 10.
The key vote – whether the benefits of Augment outweigh the risks – was a very close 10-8 in favour, while panellists also voted 10-8 that the product is effective and 12-6 that it is safe. Three votes in favour of Augment but far from a resounding recommendation for FDA approval.
Given its importance to BioMimetic – Augment has a net present value of $736m, nearly three times the company’s market capitalisation – it is no surprise to see the dramatic investor reaction. Following the vote, bullish analysts at Canaccord trimmed their price target to $16 from $18 (Event - Adcom vote awaits BioMimetic's bone graft product, May 5, 2011).
Augment is a two-part product – a solution of recombinant PDGF and granules of beta-tricalcium phosphate (TCP) – combined at the time of the operation into a mixture that resembles wet sand and applied to gaps and the perimeter of the joint being fused. The beta-TCP provides a scaffold to which cells attach themselves, while PDGF is a protein that stimulates the bone healing cascade.
Data submitted to support approval was based on a head-to-head, non-inferiority trial against autologous bone grafts, with the primary measure being complete fusion at 24 weeks as measured by a CT scan. BioMimetic’s topline data suggested it was a success, with 61.2% of Augment patients and 62% of bone graft patients achieving complete fusion.
While it did not show superior efficacy, BioMimetic argued that the using Augment would avert a second incision to source the bone for the fusion procedure, thus making it a superior product from a clinical perspective.
However, the FDA challenged this analysis in briefing documents released Tuesday, causing the initial share price decline on May 10, from which the stock has not recovered.
The agency’s chief challenge was the company’s use of a modified analysis – one in which intraoperative screening failures were excluded from the results – rather than the more robust testing that would have included all randomised patients as the company originally proposed.
Using that more robust analysis, Augment did not demonstrate non-inferiority to autologous bone grafts. Furthermore, the FDA noted that even using BioMimetic’s statistical analysis its product was statistically inferior at 36 weeks, although the company argued that weakness was the result of fewer Augment patients taking part in that follow-up examination.
Larger questions surround cancer worries on Regranex and Gem 21S, which like Augment are recombinant PDGF products. Regranex, a topical gel for neuropathic ulcers in diabetics, already has a black box warning for those patients using more than three 15g tubes; Gem 21S is a periodontal product similar to Augment that is under a safety review.
In Augment’s favour, the FDA briefing document notes that the maximum Regranex dosage contains 36 times the amount of PDGF exposure of the maximum Augment dosage. However, Neoplastic events were reported in numerically more patients in the Augment arm than in the autologous graft arm, five versus two, with three of those five being high-grade, high-morbidity metastatic cancer which was present or suspected prior to treatment with Augment. The FDA document said failure to pre-screen and eliminate such patients from treatment was “potentially concerning” given the history of PDGF products.
Furthermore, the product appears to have created an immunostimulatory response in some patients, raising further worries about its use in pregnant women and creating autoimmune conditions.
A positive vote from an advisory committee is never a sure sign of US approval, and given the split nature of this vote it is clear that a large share of the clinical community remains to be convinced. It would be no surprise to see FDA ask BioMimetic to conduct a new trial to get better clarity on the safety and efficacy of Augment.