dm+d

Unassigned

New Medicines

RaylumisOsteoarthritis

Information

Raylumis
New molecular entity
Pfizer
Pfizer

Development and Regulatory status

Phase III Clinical Trials
Not recommended for approval (Negative opinion)
Not recommended for approval (Negative opinion)
Sep 21EMA CHMP recommends the refusal of the marketing authorisation for Raylumis. Although it showed better pain relief and improved physical functioning vs. placebo, the difference was small. And there was no improvement in pain relief and physical functioning vs. NSAIDs. Patients on Raylumis were at an increased risk of side effects, such as rapid progressive osteoarthritis and joint replacement vs. placebo or NSAIDs. Therefore, the benefits were unclear and did not outweigh its risks [32].
Mar 21The Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 19-1 that a drug safety strategy proposed by the companies would not ensure the benefits of the drug, tanezumab, outweigh its risks. Pfizer have announced that they will continue to work with the FDA to determine next steps [31].
Mar 20Also pre-registration in the EU for treatment of moderate to severe chronic pain associated with OA in adult patients for whom treatment with NSAIDs and/or an opioid is ineffective, not tolerated or inappropriate. A CHMP positive opinion is expected in Jun 21 [29].
Mar 20Pfizer and Eli Lilly announce that the US FDA accepted for review a Biologics License Application (BLA) for tanezumab 2.5mg SC, which is being evaluated for chronic pain due to moderate-to-severe osteoarthritis who have experienced inadequate pain relief with other analgesics. The Prescription Drug User Fee Act (PDUFA) goal date for the FDA to make a decision is in December 2020. The US FDA is currently planning to hold an Advisory Committee meeting to discuss this application [28].
Jul 19Based on an assessment of the totality of subcutaneous (SC) tanezumab data and an initial discussion with the FDA during Q2 19, Pfizer and Eli Lilly have decided to pursue a US regulatory submission for tanezumab 2.5mg SC in patients with moderate-to-severe OA that is expected to be filed with the FDA in Q4 19 or early 2020, to be followed by potential regulatory filings in the EU and Japan. At this time, regulatory submissions are not planned for the tanezumab 5mg SC dose in OA or in patients with moderate-to-severe chronic low back pain [27].
Jan 18Pfizer has decided to stop internal neuroscience development. Ongoing trials may continue and disposition of tanezumab is underway [20].
Jun 17Granted Fast Track Status in US for treatment of chronic pain in patients with osteoarthritis (OA) and chronic low back pain (CLBP) [19].
Mar 16PIII trial programme restarted [18].
Mar 15Pfizer and Eli Lilly are getting ready to restart PIII clinical trials after the FDA lifted the partial clinical hold on the programme [16].
Feb 14Development still suspended pending safety concerns. [16]
Oct 13Lilly has agreed to share the cost of development of tanezumab with Pfizer. The FDA put a clinical hold on trials in 2010, but last year, an advisory panel noted that a more careful selection of patients most likely to benefit from anti-NGF therapies could be used to safely study the treatment for certain populations. The tanezumab programme currently is subject to a partial clinical hold pending submission of nonclinical data to the FDA, anticipated in 1H 2014 [15].
Aug 13PIII. Development of tanezumab is no longer on clinical hold [14].
Mar 12An FDA panel voted unanimously (21 to 0) to allow Pfizer (and other developers) to resume testing of anti-nerve growth factor drugs, concluding that benefits outweighed risks. The FDA will now determine whether Pfizer can start a new PIII trial adjusted to account for the threat to joints, or whether new safety studies will be required first [12].
Jun 10Worldwide suspension of the osteoarthritis clinical trial programme [9]
Dec 098 PIII trials of tanezumab in the treatment of musculoskeletal pain due to osteoarthritis are underway worldwide (3,4).

Category

Nerve growth factor inhibitor
Primary OA develops in previously healthy joints. Most cases develop in people over 50. By the age of 65, at least half of people have some OA in some joint(s). It is mild in many cases, but about 1 in 10 people over 65 have a major disability due to OA (mainly due to OA of one or both hips or knees) [17].
Osteoarthritis
Subcutaneous

Further information

Yes

Trial or other data

Mar 21A FDA briefing document suggests there is no convincing evidence that tanezumab works better than NSAIDs, such as ibuprofen and there are risks of serious side-effects such as neuropathy and destructive joint disease [31].
Jul 19PIII NCT02697773 study (n=698) found subcutaneous tanezumab resulted in statistically significant improvements in scores assessing pain and physical function & in patient global assessment of osteoarthritis (OA) at week 16, in patients with moderate to severe OA [26].
Apr 19Top line results from PIII trial (NCT02528188) evaluating tanezumab 2.5mg and tanezumab 5mg compared to NSAIDs in patients with moderate to severe osteoarthritis of the hip or knee. Tanezumab 5mg met two of the three co-primary efficacy endpoints at 16 weeks (improvements to pain and to physical function), but showed no statistically significant difference in patients´ overall assessment of their OA. Patients receiving tanezumab 2.5mg showed no statistically significant improvement in any of these three co-primary efficacy endpoints. A composite efficacy endpoint was referred to as "joint safety events" (adjudicated outcomes of rapidly progressive osteoarthritis (RPOA) type 1 or type 2; subchondral insufficiency fracture; osteonecrosis; or pathological fracture); at 80 weeks tanezumab had a higher rate of events (7.1% and 3.8% respectively for 5mg and 2.5mg) compared to NSAIDs (1.5%). Nine deaths in the tanezumab arm were reported, compared to one death in the NSAID arm; no death was considered to be related to treatment. [24,25]
Jan 19Top-line results from a randomised, double-blind, placebo-controlled, multicenter, parallel-group PIII study (NCT02709486) of tanezumab (in 849 pts with moderate-to-severe OA pain of the knee or hip with inadequate current pain relief) announced. Pts had been randomided to receive 3 SC injections over the 24-wks every 8 wks; i.e. 3 doses of tanezumab 2.5 mg or 5 mg or placebo. Efficacy was measured by changes from baseline in the WOMAC Pain subscale, the WOMAC Physical Function subscale, and the patient’s Global Assessment of OA. The trial also included a 24-week safety follow-up period. Tanezumab s.c. 2.5mg met 2 of 3 co-primary endpoints and at 5mg, it met all three co-primary endpoints in a Phase III trial. However, the patients’ overall evaluation of their OA wasn not statistically different vs. placebo. Overall, rapidly progressive osteoarthritis (RPOA) was observed in 2.1% of tanezumab-treated pts vs. 0% with placebo. There was 1 event of osteonecrosis and one event of subchondral insufficiency fracture in tanezumab-treated pts vs. 0 with placebo. The rate of total joint replacement was similar across the tanezumab treatment groups and placebo.[23]
Oct 18Further results from 16 week PIII study (n=697) announced at 2018 ACR/ARHP Annual Meeting. Study found tanezumab improved WOMAC pain scores >50% in 54.5% of patients vs 37.9% for placebo at 16 weeks [22].
Jul 18Positive topline results from a 16 week PIII trial of SC tanezumab for the treatment of osteoarthritis pain announced. Patients who received tanezumab experienced a statistically significant improvement in pain, physical function and the patients’ overall assessment of their OA, compared to those receiving placebo [21].
Mar 16EU PIII trial programme resumes, following re-start of US trials in January 16. In the US, NCT02697773 aims to recruit about 690 patients with moderate to severe OA of hip or knee to treatment with tanezumab or placebo; primary outcomes are changes in pain, function and global assessment at week 16, and estimated primary completion date is October 2017. NCT02709486 will recruit about 810 patients with OA unresponsive to existing treatments in the EU and Japan; it has the same primary outcomes, measured at 24 weeks, and estimated primary completion is November 2017 [18].
Jul 1332-wk PIII study published in Arthritis & Rheumatism. 621 pts were randomized 1:1:1:1 to treatment with iv tanezumab 2.5 mg, 5 mg, or 10 mg or placebo. Each tanezumab group showed significant improvement for the 3 co-primary end points (from baseline to week 16 in WOMAC Pain and Physical Function subscales and patient´s global assessment) vs. placebo (p≤0.001 for all). AE incidence ranged from 55% to 58% across tanezumab groups versus 44% for placebo. Safety findings were similar to those previously reported. The tanezumab OA clinical program was temporarily placed on hold because of AEs leading to joint replacement. Total joint replacements were reported in 8 patients: 1 in the 10 mg, 2 in the 5 mg, 2 in the 2.5 mg, and 3 in the placebo group. A total of 9 joints were replaced (8 hips [7 index joints] and 1 shoulder) [13].
Sep 10It has been proposed that bone destruction, which developed in 16 of 6,800 patients on tanezumab, as part of Pfizer’s development programm, all of whom needed joint replacement surgery could have been due to patients putting excessive pressure on their joints because of the level of pain control exerted. [11]
Jul 10The FDA has requested that Pfizer suspend two PIII studies in patients with chronic low back pain and painful diabetic peripheral neuropathy following reports of further adverse events in patients enrolled in the suspended osteoarthritis study. Pfizer says it will continue to work with the FDA to determine how best to proceed with other tanezumab studies [10].
Jun 10Pfizer has initiated an immediate worldwide suspension of its osteoarthritis clinical program following a request by the FDA, after a small number of reports of patients treated with tanezumab experiencing worsening of osteoarthritis leading to joint replacement. To date, this adverse event has not been observed in non-osteoarthritis patients. 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 the company present its assessment of the potential implications 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 [9].
Jun 10Results of a 16 week, PIII study in 690 patients with chronic knee pain from osteoarthritis unresponsive to, or intolerant of a NSAID or Cox-2 inhibitor were reported at EULAR 2010. Pain was rated on a scale of 0 to 10, with 10 being most extreme pain. Most of the patients began the trial with a pain rating of about 7. Pain was reduced by a mean of 3.15 points in those taking 2.5mg tanezumab, 3.26 in the 5mg group and 3.62 in the 10mg group vs 2.42 points in the placebo group. Physical function improvement (0-10 scale) was 2.8, 3.02 and 3.29 points for the three tanezumab doses vs 2.04 on placebo. Patients were asked for a general assessment of how they were feeling on a 5-point scale with zero being very good, three representing fair and five very poor. All groups started the trial at around 3.4. Reported mean reductions were between 0.83 and 1point for those taking tanezumab vs 0.51 in the placebo group. Tanezumab was generally well-tolerated but more patients taking it had peripheral oedema, vs placebo [8].
May 10NCT01127893 a PIII, multicenter, randomized, double blind study will evaluate the long term safety of tanezumab (2.5, 5 or 10mg) given by subcutaneous injection every 8 weeks for up to 64 weeks in 510 patients with osteoarthritis of the knee. Patients must have participated in specific PIII parent study. The study will start Jun 10 and complete Aug 11. Primary outcome: haematology, ECG and clinical chemistry resultsand AEs over 64 weeks [7].
Mar 10A PIII study (NCT01089725) evaluating the efficacy and safety study of 3 doses (2.5, 5 and 10mg) of tanezumab administered subcutaneously vs placebo in 850 patients with osteoarthritis of the knee. The study will also compare SC vs IV administration of 10mg of tanezumab. The study will last 16 weeks for those who wish to enter a 64-week extension study or 24 weeks for those who do not. The primary endpoints are the change from baseline to week 16 in the WOMAC Pain subscale and Physical Function subscale and the change in the Patient Global Assessment of Osteoarthritis. The study started in Mar 10 and is expected to complete Jan 11 [6].
Feb 10Company presented the results from three randomized, double-blind, placebo-controlled, PII studies of tanezumab in patients with osteoarthritis, chronic low back pain and interstitial cystitis at the American Academy of Pain Medicine´s 26th Annual Meeting. In each trial, patients treated with tanezumab reported significantly greater reductions in pain vs placebo and in patients with back pain, also vs naproxen (p=0.04). The most commonly reported AEs were abnormal peripheral sensation, muscle ache and pain in the extremities [5].
Mar 09Two PIII trials of tanezumab in the treatment of pain due to osteoarthritis started Nov 08; one in patients with osteoarthritis of the knee (NCT00733902), the other trial in patients with osteoarthritis of the hip (NCT00744471). Both trials will enrol approximately 600 patients each. Two other PIII trials are planned: an extension study of tanezumab in osteoarthritis (NCT00809783) and a study of tanezumab in combination NSAIDs (NCT00809354). These trials are expected to begin in the first half of 2009 (1).

Evidence based evaluations

RaylumisCancer pain due to bone metastasis in adults already taking background opioid therapy

Information

Raylumis
Licence extension / variation
Pfizer
Pfizer

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
None

Category

Nerve growth factor inhibitor
Surgery, chemotherapy, and radiotherapy are cancer treatments that can cause persistent pain in cancer patients, up to 50% of whom may experience persistent pain [3]. In 2013, 292,680 patients were newly diagnosed with cancer in England [4].
Cancer pain due to bone metastasis in adults already taking background opioid therapy
Subcutaneous injection

Evidence based evaluations

RaylumisChronic low back pain

Information

Raylumis
New molecular entity
Pfizer
Pfizer

Development and Regulatory status

None
Phase III Clinical Trials
Phase III Clinical Trials

Category

Nerve growth factor inhibitor.
Lifetime prevalence of non-specific (common) low back pain is estimated at 60% to 70% in industrialised countries (one-year prevalence 15% to 45%, adult incidence 5% per year). The prevalence rate for children and adolescents is lower than that seen in adults but is rising. Prevalence increases and peaks between the ages of 35 and 55. As the world population ages, low back pain will increase substantially due to deterioration of intervertebral discs in older people [3].
Chronic low back pain
Subcutaneous injection