Pfizer and Eli Lilly jointly announced recently that the Phase III trial of their anti-NGF antibody: tanezumab for the treatment of osteoarthritis (OA) pain met all the 3 endpoints. No case of osteonecrosis was observed in the trial, the proportion of rapidly progressive osteoarthritis (RPOA) in the treatment group was less than 1.5%, and the safety was significantly improved than 2010 and 2013 data. Tanezumab has finally seen the dawn of victory amid twists and turns. Next, we will learn about the ups and downs experienced in the anti-NGF antibody drug development through tanezumab.

Rise of anti-NGF antibodies

Tanezumab (Pfizer and Eli Lilly), Fasinumab (Regeneron and Teva)、ABT-110(Abbive)、MEDI-578（AstraZeneca）and Fulranumab (Janssen and Amgen).

OA marks a huge market. There are about 20 million patients long troubled by the pain brought by OA in the U.S. Originally developed by Rinat, tanezumab was acquired by Pfizer in 2006 after it advanced to the clinical trial. It is a humanized monoclonal antibody drug that targets NGF (nerve growth factor); it reduces the conduction of pain sensation to the central nervous system (CNS) by blocking the binding of NGF and receptor TrkA, to achieve the analgesic effect, instead of acting on the CNS. Opioids that are deeply troubled by drug abuse are still a common drug in the pain killing area. Opioids reduce bodies’ perception of pain by acting on the CNS (including brain). Therefore, anti-NGF antibodies are completely different from opioids in terms of mechanism of action, and they created a small upsurge in the pain treatment area. The total market value was estimated to be above USD 10 billion at that time, and many multinational pharmaceutical enterprises started to stare at this big cake, with relevant drugs including tanezumab (Pfizer and Eli Lilly), fasinumab (Regeneron and Teva), ABT-110 (AbbVie), MEDI-578 (AstraZeneca), and fulranumab (Janssen and Amgen).

The first setback: clinical trials of all anti-NGF antibodies were suspended

Pfizer announced results of Phase III clinical trial of tanezumab in 2010, showing the significant improvement of pain, however, the subsequent results were desperate: after clinical treatment with tanezumab, patients’ joint injury aggravated, and osteonecrosis happened to other joints not targeted; some patients who participated in the third-stage osteoarthritis trial suffered severe joint injury, wherein, 16 patients needed whole knee and hip replacement. As a result, FDA rapidly halted the clinical trials of all anti-NGF antibodies including tanezumab.

Into the night after brief dawn

The subsequent studies did not find the direct relationship between patients’ osteonecrosis and relevant drugs. FDA permitted the restart of some anti-NGF clinical trials in 2013. Pfizer, not reconciled to its failure, restarted the Phase III clinical trial of tanezumab in 2013, however, misfortunes came one after another. Tanezumab was suspended again at the end of 2013 because its preclinical model was discovered the side effect possible to injure sympathetic neurons. Eli Lilly, while Pfizer hung back, took the opportunity to obtain the right to co-develop tanezumab with Pfizer. A lucky thing was that these two serious clinical setbacks also hurt confidence of competitors hard, wherein, AbbVie and AstraZeneca gave up own anti-NGF drugs: ABT-110 and MEDI-578 that were at Phase I clinical studies. There were only tanezumab, fasinumab and fulranumab left on the track with clinical trials still in progress.

Setting sail for the third time as a way out appeared

Then, detailed toxicology research discovered that the effect of tanezumab on sympathetic neurons was reversible, and the relevant symptoms could rapidly recover after drug withdrawal. As a result, FDA permitted again the restart of clinical trials of anti-NGF antibodies in 2015, however, strict monitoring, dose limitation, and patient enrollment screening were required. Pfizer finalized the dose to 5mg and gave up 10mg group after a review of the clinical studies of tanezumab. People did not hold out many hopes for the anti-NGF antibody field after these two hits, however, those who persevere will always get their opportunities.

Another two years later, Scott Gottlieb started to run FDA in May 2017 and made preventing and combating the abuse of opioids the top priority of future work. Anti-NGF antibodies seemed to be possible to make up some gap of market of those analgesics. There came another dawn. However, only tanezumab and fasinumab were left by then, wherein, the partner for fasinumab was changed from Sanofi to the present Teva.

Dawn breaking

Tanezumab finally sees the dawn after two setbacks. The Phase III study reported this time enrolled a total of 698 patients. Those patients suffered severe knee and hip OA, and their disease progression could not be controlled by existing therapies or they were intolerant of existing therapies. Patients were divided into three groups: one group received 2.5mg tanezumab for twice; one group received 2.5mg and 5mg tanezumab separately for once; and one group received placebo for twice. Drug or placebo was injected once every 8 weeks, and injected for twice in total. At week 16, single clinical endpoints were assessed according to pain, physical function, and the patient’s Global Assessment of OA in WOMAC. According to the trial results, tanezumab met all the 3 trial endpoints, no case of osteonecrosis was observed, the proportion of RPOA in the treatment group was less than 1.5%, and the safety was significantly improved than 2010 and 2013 data.

In light of the good safety and effectiveness, Pfizer and Eli Lilly expect FDA to approve the BLA of tanezumab in the first half of 2019.

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