Pfizer's (PFE) experimental medicine, tanezumab, relieved pain and improved physical functions in patients suffering from hip or knee osteoarthritis, as reported at the San Diego conference of the American College of Rheumatology in October.
The Phase 2 study conducted in 678 patients was originally halted in 2010 by an FDA order. The action came when Pfizer researchers reported that in a small group of patients the osteoarthritis worsened, causing osteonecrosis and requiring joint replacements. Osteonecrosis is the loss of blood and oxygen supply to the bones which may result in bone collapse.
But in 2012 an IAC (independent adjudication committee) determined that only two of the 87 cases of osteonecrosis were due to the treatment, although the drug did cause rapid worsening of osteoarthritis when taken in higher doses and in combination with nonsteroidal anti-inflammatory drugs (NSAIDs). The FDA then lifted the hold in part and allowed the continued development as long as safety precautions were observed.
Back in 2010 tanezumab was widely considered as a drug with high potential. Analysts projected at the time for the class of anti-nerve growth factor drugs a potential value of $11 billion. Then Pfizer's studies were shut down and along with it all other similar trials by major developers.
But this may change soon, as Pfizer is working on resurrecting the pain drug and if it succeeds, the former rivals certainly will take notice of that.
Stanley Cohen, MD of Rheumatology Associate in Dallas, Texas, stated:
In my 33 years of rheumatology practice, I've never seen anything like this drug in terms of its efficacy in alleviating pain and functional disability. We want to get it to market. We need to figure out how to prevent worsening osteoarthritis using lower doses of the drug and as monotherapy. We want to revive this program.
In order to continue development of the drug, Pfizer will have to submit a package of nonclinical data to the FDA. Pfizer is planning to submit the data in the first half of 2014.
In 2012 the IAC, the committee hired by the FDA to investigate what went wrong in the halted trials, quoted in the same Medscape article linked to above, concluded:
We found that despite initial reports from study investigators, tanezumab treatment was not associated with an increase in osteonecrosis, but was associated with an increase in rapid progression of osteoarthritis in 68 patients. These patients were administered higher doses of tanezumab, and were administered tanezumab in combination with NSAIDs (nonsteroidal anti-inflammatory drugs).
Based on that conclusion, Pfizer in future trials most likely will use smaller doses of the drug, like 2.5 or 5 milligrams and avoid combining it with NSAIDs. Also, X-rays and MRI images will be taken to track the strength of patients' bones throughout the trial.
There is a dire need for new concepts in pain medication.
Many patients do not respond to currently marketed medications, like Aleve and aspirin. Even when they work, they have severe shortcomings. Anti-inflammatory painkillers like Advil can cause stomach bleeding, while opiates carry a high risk of addiction and patients need ever increasing amounts to cope with the same pain.
Drugmakers consider anti-NGF drugs (nerve growth factor inhibitors) a potential breakthrough for treating osteoarthritis, back pain and other chronic pain conditions. The injectable nerve-silencing drugs offer a new approach by blocking proteins that control pain sensations throughout the body.
More studies are probably needed to determine why some patients taking the drugs saw their arthritis worsen, in some cases to the point of joint failure. But a simple explanation cannot be excluded, namely that tanezumab simply worked too well in patients. It reduced the pain that could have signaled to the patients that they were overusing fragile bones, and as a result people became more active and were not aware of the increased damage done to their most problematic joints.
In the discontinued trial, presented at the San Diego conference, tanezumab 2.5mg and 5mg were better tolerated than tanezumab 10mg, as reported by Leslie Tive, PhD, a director of Pfizer, and colleagues.
In the trial 678 patients with moderate to severe knee or hip osteoarthritis divided into groups to receive tanezumab 2.5mg (230 patients), 5mg (222 patients), or 10mg (226 patients) administered by injection every 8 weeks.
Patients received from 1 to 7 doses of tanezumab. The tanezumab 5mg and 10mg doses resulted in similar improvements from baseline at weeks 8 and 16 in pain and physical function and these improvements were greater than with the 2.5mg dose.
But adverse events were greatest with the 10 mg dose, followed by 5 mg and 2.5 mg. Osteonecrosis was reported in 4 patients treated with 10 mg, 4 patients in the 5 mg group, and 1 patient in the 2.5 mg group.
The conclusion can be drawn that overall, injected tanezumab provided improvements in pain, physical function, and assessment of osteoarthritis at all doses, but doses 5 and 2.5 mg were better tolerated than 10 mg.
The Pfizer-Lilly deal
Recently Pfizer chose Eli Lilly as a partner in the joint development of the drug.
Lilly will pay Pfizer $200 million upfront once the FDA lifts the hold from the program, and will pay another $350 million in regulatory milestones and also $1.23 billion in sales milestones.
That's all on top of Eli Lilly's commitment to share the cost of the Phase 3. The numbers leave no doubt that Lilly is highly optimistic about the potential rewards in the venture.
If Pfizer succeeds resolving the FDA's concerns about the drug and possibly about the whole class, this would reawaken some of the competing anti-NGF projects that were also frozen in 2010.
Projects like Sanofi (SNY) and Regeneron's (REGN) REGN475 or SAR164877, Johnson & Johnson's (JNJ) fulranumab in partnership with Amgen (AMGN) (JNJ42160443 or AMG-403), AstraZeneca's (AZN) Medi-578, a monoclonal single chain variable fragment against NGF, and Abbvie's ABT-110 for the treatment of multiple pain indications: all of these or many of them would gain a new lease on life.
Pfizer at the time was ahead of the pack, all of its Phase 3 trials either completed or underway, J&J and Regeneron were running Phase 2 trials and AstraZeneca and Abbvie Phase 1.
Pfizer in the third quarter reported total worldwide revenues of $12.6 billion, and adjusted diluted earnings per share of $0.58.
The company has repurchased $3.8 billion worth of its own shares in the third quarter and $13.1 billion worth of shares in the first 9 months.
The revenues decreased $310 million, or 2 percent, due to the continued drop in sales of branded Lipitor in the U.S., Europe and elsewhere. Revenues were also negatively impacted by the ongoing expiration of the Spiriva collaboration in certain countries, decreased government purchases of Prevnar and Enbrel in certain emerging markets. On the positive side there was an overall growth in sales of Lyrica, Enbrel, Inlyta and Xalkori, as well as Celebrex and Xeljanz in the U.S.
The company narrowed somewhat its revenue guidance for 2013 to $50.8 to $51.8 billion from $50.8 to $52.8 billion.
Given the weak launches of Eliquis and Xeljanz, Pfizer's hopes are now pinned on other top candidates like palbociclib, the breast cancer drug that is being tested in Phase 3, dacomitinib for lung cancer also in Phase 3 and a Staphylococcus aureus vaccine for MRSA.
Also hopeful are bococizumab (RN316), a PCSK9 monoclonal antibody to lower LDL cholesterol in Phase 3 and ertugliflozin, an SGLT2 inhibitor for the treatment of type 2 diabetes in collaboration with Merck (MRK).
Tanezumab's return to the fold would be a most welcome boost to Pfizer's pipeline.