The conversation around the anti-nerve growth factor MAbs has often focused on their safety. But in trying to solve this issue with their candidate, tanezumab, it looks like Pfizer and Lilly have hit upon another potential problem: dwindling efficacy.
The first pivotal trial of tanezumab was technically a success, but full data revealed a drop-off in effectiveness versus older trials testing higher doses of the drug. This could leave the way clear for Teva and Regeneron to steal a march with their rival, fasinumab.
Pfizer and Lilly said in July that their phase III study, in patients with osteoarthritis of the hip or knee, had met all of its three co-primary endpoints, but did not give more details.
In the event the full results, presented at the American College of Rheumatology meeting yesterday, underwhelmed.
On the positive side the incidence of rapidly progressive osteoarthritis (RPOA), a side-effect linked with the anti-NGF class, did not raise alarm bells. Indeed, the Evercore ISI analyst Umer Raffat described tanezumab’s safety profile as “better than expected”.
But Pfizer and Lilly appear to have achieved this by using a lower dose of the drug than previously tested, leading to less impressive efficacy than formerly seen.
The latest study evaluated two regimens of tanezumab, each comprising two injections given eight weeks apart: one group received two doses of 2.5mg, while the other got 2.5mg followed by 5mg.
These resulted in a respective 0.6 and 0.8-point placebo-adjusted improvement in one of the co-primary endpoints, Womac pain score. The results were statistically significant – but look disappointing compared with the 1.2-point placebo-adjusted improvement with two 5mg doses of tanezumab in a previous trial.
Still, safety concerns in earlier development led to a partial clinical hold of tanezumab, which was only lifted in 2015.
|The battle of the anti-NGFs|
|Tanezumab 16-week phase III data (NCT02697773)|
|Endpoint||Placebo||Tanezumab 2.5 mg||Tanezumab 2.5/5 mg|
|Change in Womac pain score||-2.6||-3.2 (p≤0.05)||-3.4 (p≤0.01)|
|Change in Womac physical function score||-2.6||-3.2 (p≤0.01)||-3.5 (p≤0.001)|
|Change in PGA-OA||-0.65||-0.87 (p≤0.05)||-0.90 (p≤0.01)|
|Fasinumab 16-week phase III data (NCT03161093*)|
|Endpoint||Placebo||Fasinumab 1mg every 8 weeks||Fasinumab 1mg every 4 weeks|
|Change in Womac pain score||-1.56||-2.25 (p=0.0019)||-2.78 (p=0.0001)|
|Change in Womac physical function score||-1.37||-2.10 (p=0.0011)||-2.57 (p=0.0001)|
|*Higher doses discontinued for safety reasons. PGA-OA: Patient’s overall assessment of their osteoarthritis. Source: Company press releases.|
The class has seen a resurgence recently, particularly as regulators look for non-opioid painkillers, and Teva/Regeneron’s fasinumab is also vying for a place at the table. Placebo-adjusted phase III results with that that candidate looked slightly better, at least at the higher dose studied (Not so fast with fasinumab celebrations, August 16, 2018).
Those fasinumab data came from a sub-study of a one-year safety trial, the full results of which will be key. So far, the trial has shown a 2% placebo-adjusted increase in RPOA, but the companies did not say whether any fasinumab patients had experienced type 2 RPOA, the more severe form.
On this measure, tanezumab seems to have the edge: its overall placebo-adjusted increase in RPOA was 1.5%. The placebo-adjusted incidence of type 1 RPOA in the pivotal trial was 1.3% and 0.4% in the 2.5mg and 2.5/5mg arms respectively, while the figures for type 2 RPOA were 0.9% and 0% respectively, Pfizer and Lilly revealed yesterday.
More details on fasinumab’s safety, plus further phase III readouts with tanezumab, could give more clues about which agent has better walked the risk/benefit tightrope.
|Selected upcoming tanezumab phase III trials|
|Osteoarthritis of the hip/knee||2.5mg or 5mg||NCT02709486||Jun 2018|
|Osteoarthritis of the hip/knee||2.5mg or 5mg||NCT02528188||Oct 2018|
|Chronic low back pain (Japan)||5mg or 10mg||NCT02725411||Dec 2018|
|Cancer pain due to bone metastasis||20mg||NCT02609828||Mar 2020|
|Source: EvaluatePharma; Clinicaltrials.gov.|