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Arthritis Pain Treatment

Tanezumab (Pfizer ) Review: Chronic Pain Relief

Monoclonal antibody for Osteoarthritis pain relief

arthritis-pain: Arthritis Pain Treatment Tanezumab (Pfizer) targets nerve growth factor IgG; the humanized mAbs is in Phase III trials for osteoarthritis pain relief and lower back pain. Large number of active Phase III trials show Pfizer management strong belief and backing for the product. Phase II data shows 50% pain reduction in over 57% of treated patients compared to only 20% for the naproxen group. The active drug is tried in different dose schedules (2.5, 5, 10 and 20 mg iv) every 8 weeks in osteoarthritis of the knee, hip, low back pain and other painful conditions. Preliminary Phase III data in 690 OA patients presented at EULAR 2010 showed significant reduction in pain scores and improvement in physical function tests at the 3 doses levels tested 2.5, 5 and 10 mg in comparison to the placebo group. Pfizer has suspended dosing and recruitment of patients in all ongoing studies in osteoarthritis, low back pain and neuropathic diabetes pain with Tanezumab. FDA put the clinical hold after reports of worsening of OA in some patients resulting in surgery and joint replacement. Trials in other indications for pain relief continue and are not affected. In a NEJM paper, authors reported that Tanezumab was effective in reducing joint pain in severe OA patients. It is time for both the FDA and EMA to reconsider the clinical hold and allow resumption of trials in OA patients. The FDA placed a clinical hold on OA trials with all NGF acting mabs in December 2010. This stops all new patient recruitment and dosing in Phase II trials with REGN 475 (Regeneron, Sanofi Aventis) and Phase I trials with Fulranumab (J&J) and MEDI 578 (Astra Zeneca).

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Patient's Testimony GM
As co-author and an osteoarthritis patient since childhood I would like to share my views with readers. I recently had total knee arthroplasty surgery to correct my knee necrosis and advanced OA. Before surgery I had unbearable pain (scale 9/10 on Visual Analogue Scale) that prevented me from walking and even forced me to visit an emergency clinic. During the visit to the clinic I was hospitalized for nine days for all tests (radiographs, MRI and scintigraphy). The pain was so intense that I was given injections of morphine (about thirty in number).
I would have preferred to have a drug like Tanezumab even without knowing its contra-indications and adverse events. Sooner or later a patient suffering from a knee at a certain age should have the operation anyway. Better to have no pain (they are unbearable) and risk of having an operation earlier. This risk must be assessed for each OA patient and taking into account the age and OA status. In my case, I am 55 now (2010), the operation was inevitable anyway, and I wish this drug was available.

My full testimony can be seen here in French:

Breaking News

Tanezumab single injection provides effective pain relief in Phase II trial in interstiticial cystitis painProof of Concept Trial of Tanezumab for Treatment of Symptoms Associated With Interstitial Cystitis J. Urology.
FDA Extends clinical hold on all NGF targeting monoclonal antibodies and thinks that there may be a class toxicity issue to resolve. The FDA clinical hold stops all new patient recruitment and dosing with all the monoclonal antibodies acting on the nerve growth factor NGF. FDA considers all reported cases of drug related adverse reactions as a class toxicity issue unless proven otherwise by robust data. The reported adverse reactions were rapidly progressive osteoarthritis or osteonecrosis which may lead to surgery and joint replacement (16 cases out of 6800 patients treated with Tanezumab) and a case of avascular necrosis of a joint in a trial with a non disclosed drug. This clinical hold is valid for the Phase III trials with Tanezumab (Pfizer), Phase II trials with REGN 475 (Regeneron, Sanofi Aventis) and Phase I trials with Fulranumab (J&J) and MEDI 578 (Astra Zeneca). The market potential of anti NGF monoclonal antibodies for non addictive pain relief for months with a single injection was projected at 11 billion dollars.

Call for lifting the clinical hold
In the light of the NEJM data and in the best interest of OA patients with intense chronic pain, both the FDA and EMA should lift the clinical hold and allow resumption of trials in OA patients even the ones with advanced disease. It is in the best interest of patients to live pain free and have the inevitable knee/hip replacement surgery done earlier. It seems that tanezumab is not causing the accelerated joint destruction but the pain free patients putting more stress on joints.

NEJM Paper : Lane, NE. Schnitzer, TJ. Birbara, CA., Mokhtarani, M. Shelton, DL. Smith, MD. Brown, MT. Tanezumab for the Treatment of Pain from Osteoarthritis of the Knee.September 29, 2010 (10.1056/NEJMoa0901510)
Wood, JN. Nerve Growth Factor and Pain.September 29, 2010 (10.1056/NEJMe1004416)
Treatment with tanezumab was associated with significant reduction of joint pain and improvements in functions. The most common drug related ADRs were headache, upper respiratory infections and paresthesia. Tanezumab seems to be free from traditional analgesic side effects like ulcers, GI toxicity, hepatotoxicity, increased cardiovascular risk and provides sustained pain relief for upto 2 months with a single injection. Significant pain reduction may have contributed to the overuse of joints in some patients leading to accelerated knee replacement. Thus Chronic pain may have a protective role in joint protection? As most of the advanced OA patients are likely to progress to joint replacement surgery, the paradox of a drug providing pain relief and accelerated OA and knee replacement surgery requires open debate to define a way forward in the best interests of patients. Out of 6800 patients treated with Tanezumab, 16 progressed to joint surgery.
Novel Drug Eases Osteoarthritis Knee Pain
BusinessWeek - Steven Reinberg - Sep 29, 2010WEDNESDAY, Sept. 29 (HealthDay News) -- A new painkilling drug called tanezumab appears effective in relieving knee pain from osteoarthritis, researchers are reporting.Pfizer Arthritis Drug Quenched Pain Too Well, Leading to Damage BloombergTanezumab Reduces Joint Pain, Improves Function in Knee Osteoarthritis Medscape FDA has put a clinical hold on Tanezumab OA trials including dosing and recuitment of OA patients in other indications of chronic pain relief. PFE has stopped recruitment and dosing of patients in all osteoarthritis trials with its new monoclonal antibody Tanezumab. The osteoarthritis of some patients in trials after dosing worsened leading to surgery and joint replacement. Trials for chronic pain relief in other indications continue under close regulatory watch. FDA has extended clinical hold to recruitment of new patients and treatment with the new drug in chronic low back pain and painful nerve damage in diabetic patients and Pfizer has stopped treatment in these trials.
It seems that Pfizer analysis shows that OA disease progression occurred when Tanezumab treatment was withdrawn. Key points to resolve: ADRs reported in the placebo and active drug groups? Was it natural progressive disease in patients with advanced OA ? Background rates of ADRs pooled from placebo control groups in recent published OA trials. In the latest Phase III data in patients with advanced OA knee treated with ChondroCelect, there were lots of reported muscoskeltal and connective tissue disorders . ADR profile of control group in Chondro Celect OA knee trial. http://www.ema.europa.eu/humandocs/PDFs/EPAR/chondrocelect/emea-combined-h878en.pdf
PFE to collect, review and assess all ADR reports in Tanazumab trials and present data to the FDA next week. In the absence of detailed ADR reports and analysis in the public domain, it is too early to jump to conclusions about the future of Tanezumab. The clinical trials are double blind placebo controlled studies.
July 20 Pfizer halts two more studies of experimental pain drugTheDay.com - Lee Howard - 57 minutes ago Pfizer Inc. has halted clinical studies of its once-heralded experimental drug tanezumab for use in treating back and diabetes-related pain. Pfizer Axes Two More Pain Trials with Tanezumab Genetic Engineering News Pfizer Halts Tanezumab Studies For Back Pain, Diabetes Wall Street Journal
June 23, 2010 - Pfizer Suspends Tanezumab Osteoarthritis Clinical Trial Program

Pfizer Suspends Tanezumab Osteoarthritis Clinical Trial Program
Tanezumab Trials in Other Disease Areas Under Review by FDA

Jun 23, 2010
5:20pm

NEW YORK, June 23 /PRNewswire-FirstCall/ -- Pfizer Inc. (NYSE: PFE) announced today the suspension of the osteoarthritis clinical program for the investigational compound tanezumab following a request by the U.S. Food and Drug Administration (FDA). The worldwide suspension - which is effective immediately - follows a small number of reports of tanezumab patients experiencing the worsening of osteoarthritis leading to joint replacement. To date, this adverse event has not been observed in non-osteoarthritis patient populations taking tanezumab.

(Logo: http://photos.prnewswire.com/prnh/20100416/PFIZERLOGO )

(Logo: http://www.newscom.com/cgi-bin/prnh/20100416/PFIZERLOGO )

The clinical hold includes both the suspension of recruitment of new patients and the dosing of existing patients in the osteoarthritis program, as well as patients with osteoarthritis in other studies. The FDA has asked that, later this week, the company present its assessment of the potential implications of the adverse events in the osteoarthritis program for the other tanezumab clinical programs involving non-osteoarthritis patients, which include patients with cancer pain, interstitial cystitis, chronic low back pain and painful diabetic peripheral neuropathy. The company is actively working with the FDA, to determine the appropriate course of action, which will serve the best interest of patients.

Introduction

Global estimate for osteoarthritis: Global data estimates the prevalence rate of 10.1% for osteoarthritis and about 76 million patients worldwide (mainly USA, Europe, Japan, OECD countries). Latest WHO estimates date back to 2003 and are not used (over 150 million persons suffer from arthritis pain)
In the USA, 35 million persons suffer from Osteoarthritis resulting in 11 million annual visits to doctors for consultations. The cost of joint replacements, hospitalizations, disability and joint devices annual cost to the society is estimated at 30 billion dollars. The average annual cost of an OA patient is $ 5700 including $ 2600 direct costs.
Europe (EMA): Using a rate of 10%, one gets a figure of 40 million European suffering from OA.
Agency for Healthcare Research, USA data

In the US, about 400, 000 patients have 1 or more joint replaced each year.

Cost of a new hip or knee joint $ 30, 000- 40, 000

Out of pocket patient contribution $ 3000-4000.

Total cost of hip replacement $ 19 billion

Total cost of knee replacement $ 26 billion

27% of hip replacements & 69% of knee replacements are due to obesity.
Chronic Pain

70 million persons in US suffer from Pain

40 million have chronic pain (22-33% of US population has chronic non cancer pain)

50 million persons have partial disability due to chronic pain

254 million US prescriptions for opioid analgesics in 2009 (IMS data), 13000 fatal overdose cases, 1.6 million addiction cases.

Available Translations

This knol is also translated into French by Dr. Lyonel BAUM:

Le Tanezumab (Pfizer ) soulage la douleur chronique

Knol livre-l'arthrose et ses consquences

Chronic pain The Wellcome Trust Pain website http://www.wellcome.ac.uk/en/pain/ The London Pain Consortium http://www.lpc.ac.uk/html/
Under Creative Commons Attribution 3.0 License Images from London Pain Consortium | Wellcome Trust Pain and sensory touch fibres Chronic Pain Art Europain http://www.fi.dk/internationalt/eus7rammeprogramforforskning/indholdifp7/jtier-felles-teknologiinitiativer/imi-innovative-legemidler/praesentationer-fra-informationsmoede-om-imi-den-18-maj-2010/IMI%20Europain.pdf http://shaunaslifeinpain.blogspot.com/
YouTube Video
YouTube Video Osteoarthritis OA
Osteoarthritis or OA is the most common of all the arthritis diseases and patients with OA probably outnumber patients of all the other related conditions. In spite of millions of OA patients in constant pain, the R&D to understand its mechanisms and pathogenesis has remained underfunded, understudied and under diagnosed. In a way OA is the modern neglected and orphan disease despite millions of patients as silent sufferers of chronic and debilitating pain. The regulatory spotlight on NSAIDs and Cox II inhibitors and adverse drug reactions, several drug withdrawals of these classes, public hearings and class action litigation, billion dollars of drug injury awards or settlements, resulted in industry bail out of new drug R&D for OA. No new drug has been approved for pain relief in OA for several years, there are no biomarkers, no objective criteria of evaluation and no new drug has been developed to stop, correct or reverse the degenerative connective tissue destruction. Oseoarthritis does not have a strong unified patient advocacy or lobby group, there is no World Osteoarthritis Day to press for increased R&D funding at NIH, fast track and priority regulatory review and pressure on the industry and research community to develop new innovative drugs to tackle the disease.[1][2][3][4][5]
FDA Critical Path Inititative, NIH Biomarker Consortium and Osteoarthritis Initiative have included osteoarthritis as one of the area of focus. This industry-government partnership to to speed up new drug discovery, understand the mechanisms involved in OA pathogenesis, new validated criteria for efficacy and surrogate validated biomarkers. FDA and EMA have issued new regulatory guidelines for approval of new drugs to treat osteoarthritis.[6][7][8][9][10][11]

Osteoarthritis related pain, inflammation and reduced mobility of joints (mainly hand, knee, hips and supine) is a heterogeneous and multi factorial disease of the connective tissue and results from metabolic, trauma, accident, immunological and inflammatory alterations. some forms of OA have a genetic or inherited component in the form of alteration in the gene for cartilage. OA is unbalanced degeneration and regeneration of articular cartilage and bone with insufficient repairs of synovial joints. The incidence increases with age and obesity and metabolic syndrome. A variety of diverse heterogeneous diseases are grouped under osteoarthritis like OA of the hip, OA knee, OA hand, OA supine etc. Findings from one joint in the same patients may not work in other joints, hand OA is much different from Knee OA. Thus new drugs must be evaluated for different joints.[5][7][9][12][13][14][15].

Image Source

Our joints are fragile, when accident, shock, extra weight, intense physical activity, wear and tear make cartilage wears away, it fails to regenerate or grow back. Thinning or broken cartilage contributes to osteoarthritis or degenerative arthritis. OA is showing up in younger patients in the early 30-40 years of age down from the usual 50-60 years age bracket. Women are at higher risk as are elite sport athletes, obesity is a major contributory factor.

For evaluation of new drugs Western Ontario and McMaster Oseoarthritis WOMAC Index and its subscales for Pain, Physical Functions, Stiffness are used. Outcome measures in Osteoarthritis Research International (OARSI) responder index is used. For new drugs affecting the disease, imaging techniques like X rays, MRI, CT scan, Scintigraphy ( PET/SPECT using radiopharmaceuticals), Ultrasonography are utilized to measure joint space narrowing etc but are considered experimental by regulators.[12][16][17][18][19]

YouTube Video

Images and Official recommendations

Under Creative Commons Attribution 3.0 License Images and Official recommendations from [1]
NIAMS Banner

Cartilage: The Key to Healthy Joints [1]

Joint cartilage serves the dual role of low friction movement under varying load and as a shock absorber. Cartilage is 65 to 80 percent water. The remaining three components - collagen, proteoglycans, and chondrocytes - are described below.

collagen: A family of fibrous proteins, collagens are the building blocks of skin, tendon, bone, and other connective tissues.
proteoglycans: Made up of proteins and sugars, strands of proteoglycans interweave with collagens and form a mesh-like tissue. This allows cartilage to flex and absorb physical shock.
chondrocytes: are cells that produce cartilage and help it stay healthy as it grows. Sometimes, they release proteolytic enzymes that destroy collagen and other proteins.

The Warning Signs of Osteoarthritis

The Warning Signs of Osteoarthritis [1]

stiffness
swelling
a crunching feeling or the sound of bone rubbing on bone

About a third of people whose x rays show evidence of osteoarthritis report pain or other symptoms. For those who experience steady or intermittent pain, it is typically aggravated by activity and relieved by rest.

X rays

X rays can reveal the extent of joint damage, cartilage loss, bone damage, space narrowing and bone spurs but may not show in early onset OA.

The following imaging techniques require validation in clinical trials for acceptance by the FDA and EMA for new drug approvals. A general introduction to radiology is provided. [20]. Contrast agents are used to enhance the images in X rays, MRI and Ultrasound.

Magnetic resonance imaging (MRI [EN], IRM [FR])

MRI provides high-resolution computerized images of internal body tissues. MRI is used if x-ray findings are minimal; and if the findings suggest damage to other joint tissues such as a ligament, or the pad of connective tissue in the knee known as the meniscus.

[20]

Have a look here for MRI images of a knee.

Ultrasonography

Ultrasound scan use high frequency sound waves generated by a probe. The echo that bounce back from the body structures are projected on a screen. US giving colored images is called Color Doppler. [20]

Computed Tomograpghy CT

Computerized tomography uses multiple X rays to give a slice by slice image of the body. [20]

Scintigraphy

PET/SPECT Bone/Joint Scan with Radiopharmaceuticals

A bone scan involves injecting a radioactive substance which collects in the bone. A camera which detects radioactivity is used to scan the whole body, specific organ like heart, brain or area of interest.[21][22]

Nuclear medicine imaging techniques use both PET and SPECT imaging.

PET is positron emission tomography and use contrast and ionizing radiation to produce images

SPECT (Single photon emission computed tomography) uses gamma rays to generate images

Treatment of OA

Goals of Osteoarthritis Treatment [1]

Pain management and control
to improve joint function
to maintain normal body weight
to achieve a healthy lifestyle

http://www.med.nyu.edu/medicine/labs/abramsonlab/images/Fig-1-pathogenesis_osteoarthritis-orig.jpg

Treatment Approaches to Osteoarthritis [1]

exercise
weight control
rest and relief from stress on joints
nondrug pain relief techniques
medications to control pain
surgery
complementary and alternative therapies [21]

The following types of medicines are commonly used in treating osteoarthritis:[1]

Acetaminophen: An OTC drug for pain relief brands like Tylenol.

NSAIDs (nonsteroidal anti-inflammatory drugs): A large class of medications useful against both pain and inflammation, (NSAIDs). Aspirin, ibuprofen, diclofenac and naproxen are examples of NSAIDs. [16][22]

Some NSAIDS are available over the counter, while more than a dozen others, including a subclass called COX-2 inhibitors, are available only with a prescription. About 30% of patients switch to another NSAID within a year due to lack of efficacy or side effects. Patient compliance with NSAID is low as over 50% of patients may suffer from GI toxicity and require gastric protective treatment.

FDA has approved naproxen/esomeprazole delayed release combination for pain relief in arthritis

patients.(4/2010) Astra Zeneca and Pozen market it under the brand name Vimovo. Another formulation using naproxen is Naproxinod by NicOx for relief from OA symptoms and signs is under review by the FDA and EMA. The FDA advisory (4/2010) panel voted for its rejection and asked for additional clinical trials and data to prove its cardiovascular benefits, GI sparing action and improved efficacy vs naproxen in elderly patients.

An FDA advisory committee voted by 8 vs 6 votes to recommend approval of the Lilly blockbuster drug Cymbalta (duloxetine) for chronic low back pain. The advisory committee voted by 4 vs 9 votes against approval for use in chronic osteoarthritis pain. (August 2010). The drug had 2009 sales of over $ 3 billion and is approved for depression, diabetic nerve pain (2004), anxiety disorder (2007) and fibromyalgia (2008). The drug was used by 2.8 million patients with 14.6 million prescriptions last year, according to an F.D.A. report, about 400, 000 of them off-label for musculoskeletal pain, headaches or nerve pain. If approved it may add 500 million dollars in annual sales.

All NSAIDS can have significant side effects, and for unknown reasons, some people seem to respond better to one NSAID than another. Any person taking NSAIDS regularly should be monitored by a doctor for signs of ulcers, GI, hepatic and nephrotoxicity.

Topical pain-relieving creams, rubs, and sprays: These products, which are applied directly to the skin over painful joints like Zostrix, Icy Hot, Therapeutic Mineral Ice, Aspercreme, and Ben Gay.

Tramadol (Ultram): A prescription pain reliever that is sometimes prescribed when over-the-counter medications don't provide sufficient relief. It carries risks that don't exist with acetaminophen and NSAIDs, including the potential for addiction.

Mild narcotic painkillers: Medications containing narcotic analgesics such as codeine or hydrocodone are often effective against osteoarthritis pain. But because of concerns about the potential for physical and psychological dependence on these drugs, reserved for short-term use.[23]

Corticosteroids: Corticosteroids are powerful antiinflammatory hormones made naturally in the body or man-made for use as medicine. They may be injected into the affected joints to temporarily relieve pain. This is a short-term measure, generally not recommended for more than two to four treatments per year. Oral corticosteroids are not routinely used to treat osteoarthritis. They are occasionally used for inflammatory flares.

Drugs in R&D : novel synthetic or biological targeted compounds can be tracked by a systematic review of the website www.clinicaltrials.gov. Other products in testing: iGluR5 antagonists, Cannabinoid receptor-2, TRPV1 agonists or bradykinin B2 receptor antagonists are examples of targets studied in humans. Current symptomatic drugs (NSAIDs) with a claim for a better benefit/risk ratio (NO-NSAIDs or CINODs) are in clinical development, too.

YouTube Video

Hyaluronic acid substitutes: Sometimes called viscosupplements, these products are designed to replace a normal component of the joint involved in joint lubrication and nutrition. Depending on the particular product your doctor prescribes, it will be given in a series of three to five injections. These products are approved only for osteoarthritis of the knee.[17][18]

Results of clinical trials in OA with glucosamine and chondroitin sulfate are inconclusive.

ChondroCelect: from TiGenix was approved by European Medicinal Agency EMA in June 2009 for prevention of OA of the knee. The Committee for Advanced Therapies recommended its approval. The treatment consists of viable autologus cartilage forming cells, grown and multiplied in cell cultures, expressing a specific marker protein for the treatment of a single system cartilage defect in the femoral chondyte of the knee. (International Cartilage Repair Society Grade III or IV). These cells are taken from a small biopsy of the healthy cartilage from the patient, cell cultured in a medium and then reimplanted in the joint with the aim of repairing cartilage defect. This in turn reduces the risk of developing OA of the knee. [24][25]

Chondromimetic is a poros resorbable implant to stimulate regeneration repair of damaged joint surfaces and bone defects.

http://www.tigenix.com/en/index.php?id=71

Study Shows Higher Risks of Opioid Pain Drugs

Wall Street Journal - Thomas M. Burton - 4 hours ago

Arthritis patients taking opioid pain drugs had a higher risk of bone fractures and death compared with people taking other painkillers, according to a study that looked at Medicare claims records.

Opioids Pose Hazards in the Elderly MedPage Today

Under Creative Commons Attribution 3.0 License

Sites Of OA [1]

Exercises for Osteoarthritis[1]

Joint with severe OA

Healthy Joint

[1]

Image from www.noc.nhs.uk/.../conditions/arthritis.aspx

MRI (IRM) images from a knee

MRI Images of OA Knee with Necrosis

Copyright (C) by Gust MEES

29.03.2010

Total Knee Replacement

OA Market

The global market for OA treatment and drugs was $ 5 million in 2009. The market is dominated by NSAIDs, Cox II inhibitors, corticosteroids and opioid and non opioid analgesics. In addition, OTC drugs and alternative and complimentary remedies are used extensively and difficult to arrive at any valid estimates of sales in OA. Lack of an effective disease modifying treatment, a clinically valid diagnostic test or bio-maker and effective non addictive long term analgesics provide good market opportunities.[26][27]
Tanezumab if approved after positive Phase III safety and efficacy criteria outcome and has no long term effect on nerves or sensory perceptions and is non addictive with low abuse potential, can easily achieve peak sales of $ 3 billion within 5 years after approval in major markets. Its potential to provide long term pain relief gives it a strong selling point.[28][29]. Identification of NGF as a key regulator and mediator of pain has opened new R&D opportunities. inhibition of NGF provided strong analgesic effect in animal models and clinical trials. There are 5 NGF inhibitors in clinical trials, Tanezumab is the most advanced with results of Phase III trials expected in 2011 and filing and regulatory approvals in 2012. Analgesic market is very large but costly new products introductions led to market failures in the past and given mixed results. With over a billion persons living with chronic pain, there is a huge unmet medical need for safer and effective analgesics. [30] The cost of a single injection of Tanezumab in line with other bilogics may be in the range of $ 1000-2500 or 25000 per year. Past market experience shows that such products are prescribed as drugs of last choice. Majority of such patients will continue with low priced OTC analgesics, NSAIDS and generics. Only 1-5% of the patients with chronic pain may be shifted to higher priced NGF inhibitors or cheaper opioid analgesics. Inspite of small %, since the numbers are huge, Tanezumab can achieve blockbuster status within second full year of marketing and approval in major markets.
Neuropathic Pain

The FDA has approved six drugs for the treatment of neuropathic pain. These drugs are Lyrica (pregabalin), Cymbalta, Neurontin (gabapentin), Tegretol (carbamazepine), Lidoderm and Qutenza (capsaicin). Lyrica, Cymbalta, Lidoderm and Qutenza together contribute to the growth of the market. The market leader Neurontin (blockbuster) has generic versions approved and launched.

The neuropathic pain R&D developmental pipeline has 155 molecules in various phases of clinical development (ADis R&D). There are 77 first-in-class molecules over all of the phases of clinical development. The late stage pipeline contains a cannabinoid receptor modulator, a TRPV1 agonist, opioid receptor agonists and NMDA receptor antagonists. The pipeline also contains me-too drugs that target ion channels.

Tanezumab

Nomenclature

Prefix	Sub stem A	Sub stem B	Suffix common
Ta	ne	zu	mab
Innovator choice	neuro	humanized	monoclonal antibody

Tanezumab is a humanized monoclonal antibody for neurology indications.
Tanezumab was discovered and developed by Rinat Neurosciences which was bought by Pfizer in 2006. It is humanized monoclonal antibody targeting nerve growth factors involved in pain. It is under evaluation in 10 Phase III trials in osteoarthritis of the knee, hip and low back pain against placebo, alone or in combinations with NSAIDs. When completed, Phase III studies will have safety and efficacy data on over 7000 OA patients. In additional 21 studies (many in Phase I and II) are listed in clinical trials registries and 2 were completed in late 2009. With its new mode of action, Pfizer hopes that tanezumab turns out to be the first and best in the class blockbuster new drug.[31][32][33][34]
In a randomized double blind Phase II study in OA knee patients, 79 patients were given 0.1 or 0.3 mg/kg tanezumab or placebo and followed for 6 months. The end point of pain intensity during days 2-14 did not show any differences from placebo. A post study analysis showed clear differences in walking pain from the placebo group. In another Phase II study in low back pain, tanezumab 0.2mg/kg on day 1 was compared with naproxen 500 mg per day 1-85 days and iv+ oral placebo. The average low back pain intensity was lower in the mAbs group. A single dose of the mAbs can provide sustained pain relief over longer periods.[35]. There are some unconfirmed reports of functional improvements in some patients. The adverse drug reactions reported in Phase II trials included headache, upper respiratory tract infections, abnormal and decreased sensation and joint aches. A positive finding in reproductive toxicology precludes its use in pregnant women and in women with child bearing potential.

Results of 2 Phase III studies presented at the American Pain Society annula meeting in 2011 indicate that tanezumab, was efficacious in treating osteoarthritis pain and may provide greater symptomatic improvement compared with placebo and naproxen, .

Two randomized, double-blind, double-dummy, placebo- and naproxen-controlled (naproxen 500mg twice daily) multicenter studies evaluated the efficacy and safety of tanezumab 5mg or 10mg IV in patients with moderate-to-severe knee or hip osteoarthritis (OA). Tanezumab was given at Weeks 0 and 8 and efficacy was assessed at Week 16 with three coprimary endpoints: Western Ontario & McMaster Universities OA Index [WOMAC] Pain, WOMAC Physical Function, and Patient Global Assessment [PGA] of OA.

Tanezumab 5mg and 10mg provided superior efficacy vs. placebo for all coprimary endpoints in both studies (P0.014). Overall, nine of 12 contrasts for tanezumab vs. naproxen were statistically significant, including tanezumab 5mg vs. naproxen across all coprimary endpoints in both studies. However, only comparisons in WOMAC Physical Function were declared superior to naproxen with tanezumab 5mg for both studies since tanezumab 10mg failed to show consistent superiority over naproxen in WOMAC Pain and PGA. In addition, secondary endpoints demonstrated that both tanezumab 5mg and 10mg provided greater improvements compared with placebo and naproxen for WOMAC Pain, Outcome Measures in Rheumatology-Osteoarthritis Research Society International Responder Index, and WOMAC Stiffness responses at Week 16. Outcomes of both studies suggest, that tanezumab 5mg is the optimal dose.

Adverse events (AE) and withdrawals due to AEs were more common with active treatments than with placebo. Rates of serious AEs were similar across treatment groups. The most frequent AEs (5% in any active group) were arthralgia, pain in extremity, paresthesia, and peripheral edema. Tanezumab 5mg was better tolerated than tanezumab 10mg in both studies. Six patients (4 placebo, 1 tanezumab 5mg, 1 naproxen) required total joint replacements (TJRs). The tanezumab OA clinical program is on clinical hold due to potential AEs leading to TJRs.

The Phase III dose of Tanezumab is 2.5, 5, 10 mg iv repeated every 8 weeks for 32 weeks was a double blind placebo controlled parallel study in 690 OA patients (61% women). Preliminary results from OA Phase III trials were presented at the EULAR 2010 meeting in Rome. Tanezumab treatment resulted in significant reduction of pain scores at all dose levels in comparison to placebo and improved physical functions (WOMAC Scales and PGA) . ADRs were reported by 55-60% of patients on Tanezumab vs 48% on placebo. The most common AEs (>5% in any group) were arthralgia (range for tanezumab groups: 2.9-7.5%; placebo: 4.1%), peripheral odema (1.7-6.3%; 0.6%), headache (3.5-5.2%; 7.6%), paraesthesia (2.9-5.2%; 1.7%), pain in extremity (0.6-5.2%; 2.9%), and upper respiratory tract infection (4.0-6.4%; 4.1%).
OP0157 TANEZUMAB REDUCES OSTEOARTHRITIC KNEE PAIN: RESULTS OF A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE 3 TRIAL

M. T. Brown 1, *, F. T. Murphy 2, 3, D. M. Radin 4, I. Davignon 1, M. D. Smith 1, C. R. West 1

Tanezumab Clinical trialsTanezumab Clinical trials

Long Term Safety Issues

Does Tanezumab has addictive potential and can it be abused for recreational purpose?
Its long term effect on nerves and neuroreceptors in the brain?
Long term effect on alterations in pain threshold or its perception may make patients less alert or sensible to dangers and taking unnecessary risks
All advanced OA patients need knee replacement surgery at some time, is it better to be pain free and get early surgery or live with chronic pain and delay surgery?
Effect on vital functions and other sensory perceptions?
Overeating, depression or any suicidal tendencies?

Ethical, Legal, Moral Issues Cost of treatment, single injection, choice of analgesic by cost Dose schedule- regular fixed once a month, on demand by patient or doctor, medical insurance restrictions etc.

Rival Nerve Growth Factor mAbs
FDA clinical hold is now extended to all the NGF targeting mabs and clouds the horizon for $11 billion market potential of NGF mabs. The FDA clinical hold stops all new patient recruitment and dosing with all the monoclonal antibodies acting on the nerve growth factor NGF. FDA considers all reported cases of drug related adverse reactions as a class toxicity issue unless proven otherwise by robust data. The reported adverse reactions were rapidly progressive osteoarthritis or osteonecrosis which may lead to surgery and joint replacement (16 cases out of 6800 patients treated with Tanezumab) and a case of avascular necrosis of a joint in a trial with a non disclosed drug. This clinical hold is valid for the Phase III trials with Tanezumab (Pfizer), Phase II trials with REGN 475 (Regeneron, Sanofi Aventis) and Phase I trials with Fulranumab (J&J) and MEDI 578 (Astra Zeneca). The market potential of anti NGF monoclonal antibodies for non addictive pain relief for months with a single injection was projected at 11 billion dollars.
If the adverse events are linked only to Tanezumab then it opens a window of opportunity for REGN 475 and other follow up NGF mAbs. If this is a class effect, then all the mAbs targeting NGF are in danger.
Contrary to the clinical hold on tanezumab in OA, low back pain and diabetes neuropathy, the clinical hold on REGN 475/SAR164877 was placed a few months later in December 2010 in OA trials due to a report of avascular necrosis of the joint in a patient. It is a highly selective and specific binder of neutrophins. There are no active trials with the drug treating or enrolling patients. Regeneron has completed Phase II trials with its REGN475 anti NGF human mAbs (licensed to Sanofi Aventis) in OA patients. Sanofi Aventis holds the global marketing rights.

In an interim efficacy analysis of a randomized, double-blind, four-arm, placebo-controlled Phase 2 trial, in 217 patients with osteoarthritis of the knee, REGN475 demonstrated significant improvements at the two highest doses tested as compared to placebo in average walking pain scores over 8 weeks following a single intravenous infusion (p

Treatment options for 15 yr old dog with muscle/joint problems?
We put our 15 yr old dog to sleep yesterday. He had just turned 15 a few days ago. I am torn up with hurt over losing this dog who was my best friend. I just want to know that we made the right choice, and that we didn't have any good options other than euthanasia. I'll keep it short. 1. He had arthritis and joint problems that had gotten much worse in the past 2 years, was very stiff when he walked, often fell down when doing simple tasks like getting up from sleeping or walking down a couple of steps 2. He was all but deaf, and had cataracts 3. He could no longer control his bowels. He would often defecate where he slept/ate. Which leads me to 4 4. He had to sleep outside. During winters he would have trouble staying warm, and we'd often find him visibly shaking/shivering from the cold (despite being a snow dog). He still ate food, vet said his heart sounded fine before he was euthanized, he still ate/enjoyed dog treats. However, still had severe stiffness/arthritis. It happened so fast that I'm still coping. I can't believe he's gone. I've lost part of myself with that dog. Even if we got arthritis/pain treatment, would it have mattered much? Would he have still been in pain? On top of that, he would have still had to stay outside. He was 15, when the life-expectancy for his breed is 10-12 yrs. Somebody, especially a vet, please objectively tell me what you would have done if it were your dog please. It is such a painful experience to take a creature's life, that is essentially part of your family and has been for 15 yrs. Now he's gone within a couple of minutes.

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