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Occupational therapy program helps thumb OA
TORONTO – A multimodal occupational therapy intervention in patients with thumb base osteoarthritis brought clinically meaningful improvements in pain, grip strength, and function, at least short term, in a Norwegian multicenter randomized clinical trial, Anne Therese Tveter reported at the OARSI 2019 World Congress.
OA of the thumb base – that is, the carpometacarpal joint – causes more pain and dysfunction than disease involvement at many other sites because of the evolutionary importance of the opposable thumb. Current guidelines recommend conservative therapies as first line for hand OA; however, there is a dearth of high-quality evidence for multimodal occupational therapy in the special setting of thumb-base OA. This was the impetus for a randomized trial of 170 consecutive patients with thumb OA who presented to three Norwegian rheumatology departments for surgical consultation, explained Ms. Tveter, a physiotherapist at the Norwegian National Advisory Unit on Rehabilitation in Rheumatology at Diakonhjemmet Hospital in Oslo.
Participants were randomized to a 3-month, multimodal self-management intervention. It included education about OA; ergonomic principles; the importance of using separate orthoses as much as possible both day and night to stabilize the joint, improve performance, and relieve pain; and – at the heart of the program – instruction in hand exercises to enhance joint mobility, strength, and stability, as well as hand-stretching exercises. The exercises were to be done at home three times per week. Also, the active intervention group received five common assistive devices to help them in household tasks, such as opening jars. The control group received usual care, which was basically information about hand OA, she said at the meeting sponsored by the Osteoarthritis Research Society International.
Ms. Tveter presented an interim analysis focused on the 3-month outcomes. At 4 months, participants underwent surgical consultation. The study will continue for 2 years, with endpoints including the impact of the occupational therapy intervention on need for joint surgery, as well as long-term pain and function measures.
At baseline, most patients reported mild pain, with a median score of 3 on a 10-point numeric rating scale, and moderate disability. Baseline grip and pinch strength was 60%-65% of normal. The 3-month outcomes included pain at rest and during pinch- and grip-strength testing, range of motion through palmar abduction and abduction in the carpometacarpal joint, and self-reported function as measured using the validated MAP-Hand and QuickDASH physiotherapy measures. Adherence to the program was assessed by review of patient diaries.
At 3 months of follow-up, the active-intervention group showed significant improvements in all measures of pain and function except for the flexion deficit, which was minimal to begin with. In contrast, the control group showed no improvements and a trend towards deterioration in pain and function.
Specifically, the intervention group averaged a 1.4-point reduction in pain at rest on a self-reported 10-point scale, a 1.1-point improvement in pain following a grip strength test, and a 0.8-point improvement in pain following a pinch test. On the MAP-Hand self-reported test of function, the intervention group showed a 0.18-point improvement from a baseline of 2 on the 1-4 scale, coupled with an 8.1-point improvement on the QuickDASH, which is scored 0-100.
Adherence to the program was deemed acceptable: 82% of patients reported doing their hand exercises at least twice per week for at least 8 of the 12 weeks, 61% used their day orthotic devices at least 4 days per week for 8 weeks, 54% used the night orthoses at least 5 nights per week for 8 weeks, and 69% utilized at least three of the five home-assist devices. In total, 64% of patients adhered to at least three of the four program components.
Asked for the rationale in requesting that patients do their home exercises three times per week instead of daily, Ms. Tveter replied that three times per week is more realistic and is consistent with major guidelines.
“It would be nice to exercise every day. I don’t think it would be possible to get adherence to that,” she said.
She reported having no financial conflicts regarding the study, funded by scientific research grants from the Norwegian government.
TORONTO – A multimodal occupational therapy intervention in patients with thumb base osteoarthritis brought clinically meaningful improvements in pain, grip strength, and function, at least short term, in a Norwegian multicenter randomized clinical trial, Anne Therese Tveter reported at the OARSI 2019 World Congress.
OA of the thumb base – that is, the carpometacarpal joint – causes more pain and dysfunction than disease involvement at many other sites because of the evolutionary importance of the opposable thumb. Current guidelines recommend conservative therapies as first line for hand OA; however, there is a dearth of high-quality evidence for multimodal occupational therapy in the special setting of thumb-base OA. This was the impetus for a randomized trial of 170 consecutive patients with thumb OA who presented to three Norwegian rheumatology departments for surgical consultation, explained Ms. Tveter, a physiotherapist at the Norwegian National Advisory Unit on Rehabilitation in Rheumatology at Diakonhjemmet Hospital in Oslo.
Participants were randomized to a 3-month, multimodal self-management intervention. It included education about OA; ergonomic principles; the importance of using separate orthoses as much as possible both day and night to stabilize the joint, improve performance, and relieve pain; and – at the heart of the program – instruction in hand exercises to enhance joint mobility, strength, and stability, as well as hand-stretching exercises. The exercises were to be done at home three times per week. Also, the active intervention group received five common assistive devices to help them in household tasks, such as opening jars. The control group received usual care, which was basically information about hand OA, she said at the meeting sponsored by the Osteoarthritis Research Society International.
Ms. Tveter presented an interim analysis focused on the 3-month outcomes. At 4 months, participants underwent surgical consultation. The study will continue for 2 years, with endpoints including the impact of the occupational therapy intervention on need for joint surgery, as well as long-term pain and function measures.
At baseline, most patients reported mild pain, with a median score of 3 on a 10-point numeric rating scale, and moderate disability. Baseline grip and pinch strength was 60%-65% of normal. The 3-month outcomes included pain at rest and during pinch- and grip-strength testing, range of motion through palmar abduction and abduction in the carpometacarpal joint, and self-reported function as measured using the validated MAP-Hand and QuickDASH physiotherapy measures. Adherence to the program was assessed by review of patient diaries.
At 3 months of follow-up, the active-intervention group showed significant improvements in all measures of pain and function except for the flexion deficit, which was minimal to begin with. In contrast, the control group showed no improvements and a trend towards deterioration in pain and function.
Specifically, the intervention group averaged a 1.4-point reduction in pain at rest on a self-reported 10-point scale, a 1.1-point improvement in pain following a grip strength test, and a 0.8-point improvement in pain following a pinch test. On the MAP-Hand self-reported test of function, the intervention group showed a 0.18-point improvement from a baseline of 2 on the 1-4 scale, coupled with an 8.1-point improvement on the QuickDASH, which is scored 0-100.
Adherence to the program was deemed acceptable: 82% of patients reported doing their hand exercises at least twice per week for at least 8 of the 12 weeks, 61% used their day orthotic devices at least 4 days per week for 8 weeks, 54% used the night orthoses at least 5 nights per week for 8 weeks, and 69% utilized at least three of the five home-assist devices. In total, 64% of patients adhered to at least three of the four program components.
Asked for the rationale in requesting that patients do their home exercises three times per week instead of daily, Ms. Tveter replied that three times per week is more realistic and is consistent with major guidelines.
“It would be nice to exercise every day. I don’t think it would be possible to get adherence to that,” she said.
She reported having no financial conflicts regarding the study, funded by scientific research grants from the Norwegian government.
TORONTO – A multimodal occupational therapy intervention in patients with thumb base osteoarthritis brought clinically meaningful improvements in pain, grip strength, and function, at least short term, in a Norwegian multicenter randomized clinical trial, Anne Therese Tveter reported at the OARSI 2019 World Congress.
OA of the thumb base – that is, the carpometacarpal joint – causes more pain and dysfunction than disease involvement at many other sites because of the evolutionary importance of the opposable thumb. Current guidelines recommend conservative therapies as first line for hand OA; however, there is a dearth of high-quality evidence for multimodal occupational therapy in the special setting of thumb-base OA. This was the impetus for a randomized trial of 170 consecutive patients with thumb OA who presented to three Norwegian rheumatology departments for surgical consultation, explained Ms. Tveter, a physiotherapist at the Norwegian National Advisory Unit on Rehabilitation in Rheumatology at Diakonhjemmet Hospital in Oslo.
Participants were randomized to a 3-month, multimodal self-management intervention. It included education about OA; ergonomic principles; the importance of using separate orthoses as much as possible both day and night to stabilize the joint, improve performance, and relieve pain; and – at the heart of the program – instruction in hand exercises to enhance joint mobility, strength, and stability, as well as hand-stretching exercises. The exercises were to be done at home three times per week. Also, the active intervention group received five common assistive devices to help them in household tasks, such as opening jars. The control group received usual care, which was basically information about hand OA, she said at the meeting sponsored by the Osteoarthritis Research Society International.
Ms. Tveter presented an interim analysis focused on the 3-month outcomes. At 4 months, participants underwent surgical consultation. The study will continue for 2 years, with endpoints including the impact of the occupational therapy intervention on need for joint surgery, as well as long-term pain and function measures.
At baseline, most patients reported mild pain, with a median score of 3 on a 10-point numeric rating scale, and moderate disability. Baseline grip and pinch strength was 60%-65% of normal. The 3-month outcomes included pain at rest and during pinch- and grip-strength testing, range of motion through palmar abduction and abduction in the carpometacarpal joint, and self-reported function as measured using the validated MAP-Hand and QuickDASH physiotherapy measures. Adherence to the program was assessed by review of patient diaries.
At 3 months of follow-up, the active-intervention group showed significant improvements in all measures of pain and function except for the flexion deficit, which was minimal to begin with. In contrast, the control group showed no improvements and a trend towards deterioration in pain and function.
Specifically, the intervention group averaged a 1.4-point reduction in pain at rest on a self-reported 10-point scale, a 1.1-point improvement in pain following a grip strength test, and a 0.8-point improvement in pain following a pinch test. On the MAP-Hand self-reported test of function, the intervention group showed a 0.18-point improvement from a baseline of 2 on the 1-4 scale, coupled with an 8.1-point improvement on the QuickDASH, which is scored 0-100.
Adherence to the program was deemed acceptable: 82% of patients reported doing their hand exercises at least twice per week for at least 8 of the 12 weeks, 61% used their day orthotic devices at least 4 days per week for 8 weeks, 54% used the night orthoses at least 5 nights per week for 8 weeks, and 69% utilized at least three of the five home-assist devices. In total, 64% of patients adhered to at least three of the four program components.
Asked for the rationale in requesting that patients do their home exercises three times per week instead of daily, Ms. Tveter replied that three times per week is more realistic and is consistent with major guidelines.
“It would be nice to exercise every day. I don’t think it would be possible to get adherence to that,” she said.
She reported having no financial conflicts regarding the study, funded by scientific research grants from the Norwegian government.
REPORTING FROM OARSI 2019
Key clinical point: A multimodal occupational therapy intervention brought significant improvements in pain and function in patients with thumb-base OA.
Major finding: The intervention resulted in a mean 1.4-point decrease in self-reported pain at rest from a baseline of 3 on a 10-point scale, while most usual care controls showed a modest trend for worsening.
Study details: This was an interim 3-month report from a 2-year, randomized, multicenter trial including 170 consecutive patients who presented for surgical consultation regarding their thumb base OA.
Disclosures: The presenter reported having no financial conflicts regarding the study, funded by Norwegian governmental scientific research grants.
Liposomal steroid brings durable pain relief in knee OA
TORONTO – A single intra-articular injection of a novel, sustained-release liposomal formulation of dexamethasone in patients with symptomatic knee osteoarthritis brought at least 6 months of pain control in a multicenter, phase 2a trial, David Hunter, MD, reported at the OARSI 2019 World Congress.
This is a product that could fill a significant unmet medical need. Current therapies for knee OA have modest efficacy, and the injectable ones provide only 2-4 weeks of benefit. The ability to obtain significant pain relief with just a couple of intra-articular injections per year would be an important therapeutic advance, observed Dr. Hunter, professor of medicine at the University of Sydney.
He presented a 24-week study of 75 patients with symptomatic knee OA randomized at 13 sites in Australia and Taiwan to a single intra-articular injection of either 12 or 18 mg of the liposomal dexamethasone or to normal saline. One knee per patient was treated.
The primary outcome was the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score from baseline to week 12. The 12-mg formulation of steroid significantly outperformed placebo at that time point as well as at all others. From a mean baseline WOMAC pain score of 1.49 on the 0-4 scale, patients in the 12-mg group averaged reductions of 0.83 points at 12 weeks, 0.85 at both weeks 16 and 20, and 0.87 at week 24. A statistically significant between-group difference was seen as early as day 3 after injection.
More than half (52%) of recipients of the 12-mg dose of liposomal dexamethasone, a product known for now simply as TLC599, maintained at least 30% pain relief at all visits through the study close at 24 weeks, as did 22% of controls, the rheumatologist reported at the meeting sponsored by the Osteoarthritis Research Society International.
The 12-mg injection also proved superior to placebo for the secondary endpoint of change in WOMAC function score. From a mean baseline score of 1.53, recipients of the 12-mg dose had improvements ranging from 0.82 points at week 12 to 0.85 points at week 24.
Of note, total acetaminophen intake over the course of the trial in the 12-mg steroid group was less than one-third of that in controls.
The 18-mg dose didn’t result in significantly greater reduction in pain scores than placebo. This is because dexamethasone release in the higher-dose formulation as presently constituted turned out to be less efficient, Dr. Hunter explained.
The safety profile was closely similar in all three study arms.
In phase 3 clinical trials, TLC599 will be compared with standard intra-articular triamcinolone, according to the rheumatologist.
He reported serving as a consultant to the Taiwan Liposome Company, which sponsored the phase 2a study, as well as to a handful of other pharmaceutical companies.
TORONTO – A single intra-articular injection of a novel, sustained-release liposomal formulation of dexamethasone in patients with symptomatic knee osteoarthritis brought at least 6 months of pain control in a multicenter, phase 2a trial, David Hunter, MD, reported at the OARSI 2019 World Congress.
This is a product that could fill a significant unmet medical need. Current therapies for knee OA have modest efficacy, and the injectable ones provide only 2-4 weeks of benefit. The ability to obtain significant pain relief with just a couple of intra-articular injections per year would be an important therapeutic advance, observed Dr. Hunter, professor of medicine at the University of Sydney.
He presented a 24-week study of 75 patients with symptomatic knee OA randomized at 13 sites in Australia and Taiwan to a single intra-articular injection of either 12 or 18 mg of the liposomal dexamethasone or to normal saline. One knee per patient was treated.
The primary outcome was the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score from baseline to week 12. The 12-mg formulation of steroid significantly outperformed placebo at that time point as well as at all others. From a mean baseline WOMAC pain score of 1.49 on the 0-4 scale, patients in the 12-mg group averaged reductions of 0.83 points at 12 weeks, 0.85 at both weeks 16 and 20, and 0.87 at week 24. A statistically significant between-group difference was seen as early as day 3 after injection.
More than half (52%) of recipients of the 12-mg dose of liposomal dexamethasone, a product known for now simply as TLC599, maintained at least 30% pain relief at all visits through the study close at 24 weeks, as did 22% of controls, the rheumatologist reported at the meeting sponsored by the Osteoarthritis Research Society International.
The 12-mg injection also proved superior to placebo for the secondary endpoint of change in WOMAC function score. From a mean baseline score of 1.53, recipients of the 12-mg dose had improvements ranging from 0.82 points at week 12 to 0.85 points at week 24.
Of note, total acetaminophen intake over the course of the trial in the 12-mg steroid group was less than one-third of that in controls.
The 18-mg dose didn’t result in significantly greater reduction in pain scores than placebo. This is because dexamethasone release in the higher-dose formulation as presently constituted turned out to be less efficient, Dr. Hunter explained.
The safety profile was closely similar in all three study arms.
In phase 3 clinical trials, TLC599 will be compared with standard intra-articular triamcinolone, according to the rheumatologist.
He reported serving as a consultant to the Taiwan Liposome Company, which sponsored the phase 2a study, as well as to a handful of other pharmaceutical companies.
TORONTO – A single intra-articular injection of a novel, sustained-release liposomal formulation of dexamethasone in patients with symptomatic knee osteoarthritis brought at least 6 months of pain control in a multicenter, phase 2a trial, David Hunter, MD, reported at the OARSI 2019 World Congress.
This is a product that could fill a significant unmet medical need. Current therapies for knee OA have modest efficacy, and the injectable ones provide only 2-4 weeks of benefit. The ability to obtain significant pain relief with just a couple of intra-articular injections per year would be an important therapeutic advance, observed Dr. Hunter, professor of medicine at the University of Sydney.
He presented a 24-week study of 75 patients with symptomatic knee OA randomized at 13 sites in Australia and Taiwan to a single intra-articular injection of either 12 or 18 mg of the liposomal dexamethasone or to normal saline. One knee per patient was treated.
The primary outcome was the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score from baseline to week 12. The 12-mg formulation of steroid significantly outperformed placebo at that time point as well as at all others. From a mean baseline WOMAC pain score of 1.49 on the 0-4 scale, patients in the 12-mg group averaged reductions of 0.83 points at 12 weeks, 0.85 at both weeks 16 and 20, and 0.87 at week 24. A statistically significant between-group difference was seen as early as day 3 after injection.
More than half (52%) of recipients of the 12-mg dose of liposomal dexamethasone, a product known for now simply as TLC599, maintained at least 30% pain relief at all visits through the study close at 24 weeks, as did 22% of controls, the rheumatologist reported at the meeting sponsored by the Osteoarthritis Research Society International.
The 12-mg injection also proved superior to placebo for the secondary endpoint of change in WOMAC function score. From a mean baseline score of 1.53, recipients of the 12-mg dose had improvements ranging from 0.82 points at week 12 to 0.85 points at week 24.
Of note, total acetaminophen intake over the course of the trial in the 12-mg steroid group was less than one-third of that in controls.
The 18-mg dose didn’t result in significantly greater reduction in pain scores than placebo. This is because dexamethasone release in the higher-dose formulation as presently constituted turned out to be less efficient, Dr. Hunter explained.
The safety profile was closely similar in all three study arms.
In phase 3 clinical trials, TLC599 will be compared with standard intra-articular triamcinolone, according to the rheumatologist.
He reported serving as a consultant to the Taiwan Liposome Company, which sponsored the phase 2a study, as well as to a handful of other pharmaceutical companies.
REPORTING FROM OARSI 2019
What’s up in the osteoarthritis drug pipeline
TORONTO – Philip G. Conaghan, MBBS, PhD, observed at the OARSI 2019 World Congress.
“Not only have things not improved during my time in osteoarthritis-land, they’ve gotten worse. We’ve lost therapies,” said Dr. Conaghan, professor of musculoskeletal medicine at the University of Leeds (England) and director of the Leeds Institute of Rheumatic and Musculoskeletal Medicine.
Specifically, opioids are now shunned because of the ongoing epidemic of addiction and a belated recognition that opioids are not a good option for pain relief in OA patients who want to have active lives. And acetaminophen has fallen by the wayside in light of recent evidence of lack of effectiveness: “It’s what our patients have been telling us for a long period of time,” he noted at the meeting sponsored by the Osteoarthritis Research Society International.
But change is in the air.
“I think we’ve got some things coming that look promising. What do I think will be the fastest to get to market? The peripheral nerve modulators look to me like the ones closest to going forward,” according to the rheumatologist, who provided an overview of the OA drug development pipeline, organized by treatment target.
Nerves
“Nerves as a treatment target in OA is a hot area. We’ve seen quite a slew of products recently looking at this. I think it’s a really fascinating area to play in: looking at how we modulate peripheral nociceptive pain,” Dr. Conaghan continued.
Tanezumab, an inhibitor of nerve growth factor, demonstrated very good pain relief and improvement in physical function in a phase 3 trial, although the occurrence of rapidly progressive OA in a subset of patients has bedeviled the drug development program. The hope is that a new subcutaneous drug delivery system coupled with careful patient pretreatment screening will mitigate the problem.
Tanezumab’s efficacy has contributed to a new understanding of the nature of pain in OA.
“I know I’m going to upset some people, but if you think central sensitization is the biggest driver of pain, I’d have to argue that the tanezumab program is the biggest single argument against that, since tanezumab is a large monoclonal antibody that doesn’t cross the blood-brain barrier and yet it has some of the best pain responses that we’ve seen,” Dr. Conaghan said.
Another peripheral nerve modulator, known for now as CNTX-4975, exhibited dose-dependent improvement in knee OA pain in the 175-patient, phase 2b TRIUMPH trial (Arthritis Rheumatol. 2019 Mar 19. doi: 10.1002/art.40894). CNTX-4975, which is delivered by intra-articular injection, is a synthetic form of capsaicin specific to pain nociceptors within the joint. Other sensory fibers remain unaffected.
Cartilage
Sprifermin, a recombinant human fibroblast growth factor 18 given by intra-articular injection, stimulates chondrocyte growth and decreases type 1 collagen expression. At year 2 in the ongoing 549-patient, 5-year, phase 2 FORWARD study, a dose-dependent increase in cartilage thickness at the tibiofemoral joint became apparent in sprifermin-treated patients, compared with those on placebo. This cartilage rebuilding effect was maintained at year 3, Dr. Conaghan said.
Bone
At the OARSI meeting, Dr. Conaghan and coinvestigators presented the results of a 6-month, open-label extension of their previously reported 6-month, placebo-controlled, phase 2 study of MIV-711, a potent selective reversible inhibitor of cathepsin K. The disease-modifying effects of MIV-711 seen in the first 6 months of the study, based on MRI-based measurements of changes in three-dimensional bone shape and cartilage thickness, were maintained in the second 6 months. Notably, MIV-711 slowed the rate of increase in bone area in the medial femur region and reduced loss of cartilage thickness relative to placebo. MIV-711 has also been shown to achieve a rapid and sustained reduction in the bone turnover biomarkers CTX-1 and -2, providing a rational mechanism to explain the drug’s observed structural benefits.
“So we’ve now got two agents – sprifermin for cartilage and MIV-711 for bone – showing that it’s possible to get some structural change, but no symptomatic benefit within the period of those trials,” the rheumatologist noted.
Wnt pathway inhibition
Samumed has launched a phase 3 clinical trials program, known as STRIDES, for lorecivivint, the company’s investigational small molecule inhibitor of the Wnt pathway. In phase 2 studies, including one led by Dr. Conaghan, intra-articular injection of lorecivivint, previously known as SMO4690, improved pain and physical function as well as medial joint space width. The drug’s potential effects on multiple tissues offers the promise of providing both symptomatic improvement and modification of the course of structural disease progression.
Inflammation
Lutikizumab, an anti–interleukin-1 alpha/beta immunoglobulin, proved to be a disappointment in a recent phase 2, placebo-controlled trial carried out in 350 patients with knee OA and synovitis. The IL-1 inhibitor had no benefit on synovitis, joint space narrowing, or cartilage thickness. Nor was it significantly better than placebo for pain reduction (Arthritis Rheumatol. 2019 Jul;71[7]:1056-69).
Anti–tumor necrosis factor agents haven’t exactly set the OA world on fire, either.
“In rheumatoid arthritis we know they’re stupendously effective, but the data from a number of trials in OA show they’re not so effective on symptoms and signs,” Dr. Conaghan said.
Colchicine and hydroxychloroquine are other anti-inflammatory agents which, while in theory might be helpful, have in actuality shown no benefit for OA symptoms in controlled clinical trials and are now considered dead ends.
On the other hand, the sustained delivery of intra-articular corticosteroids through the use of microsphere technology is advancing smartly through the developmental pipeline. Dr. Conaghan was first author of a multicenter, double-blind, phase 3 trial of FX006, a sustained-release formulation of triamcinolone acetonide, which showed that a single intra-articular injection provided at least 3 months of pain relief in knee OA patients, along with reduced systemic drug exposure, compared with standard intra-articular corticosteroids (J Bone Joint Surg Am. 2018 Apr 18;100[8]:666-77).
FX006 also performed well in another phase 3 trial, this one featuring repeated dosing on a flexible schedule based upon patient response (Rheumatol Ther. 2019 Mar;6[1]:109-24).
Reassuringly, this slow-release corticosteroid doesn’t appear to worsen glycemic control in knee OA patients with type 2 diabetes (Rheumatology [Oxford]. 2018 Dec 1;57[12]:2235-41).
“This is the start of a revolution in nanotechnology and the ability to slowly deliver a variety of drugs within the joint,” Dr. Conaghan predicted.
Although he was tasked at OARSI 2019 with providing an overview of the OA pharmacologic pipeline, he stressed that in his clinical practice, as opposed to his work as a clinical trialist, he functions more like a physical therapist.
“I actually spend my whole time in the OA clinic being a physical therapist and trying to get people strong, because that does work and it has no side effects. It’s just that nobody does it. We have a real adherence problem,” he said. “My favorite thought is this: keep people strong. If a patient can’t get out of a chair easily or can’t undo a jar, then they’ve got a problem.”
Dr. Conaghan reported receiving research funding from and serving as a consultant to many of the companies developing novel drug treatments for OA.
TORONTO – Philip G. Conaghan, MBBS, PhD, observed at the OARSI 2019 World Congress.
“Not only have things not improved during my time in osteoarthritis-land, they’ve gotten worse. We’ve lost therapies,” said Dr. Conaghan, professor of musculoskeletal medicine at the University of Leeds (England) and director of the Leeds Institute of Rheumatic and Musculoskeletal Medicine.
Specifically, opioids are now shunned because of the ongoing epidemic of addiction and a belated recognition that opioids are not a good option for pain relief in OA patients who want to have active lives. And acetaminophen has fallen by the wayside in light of recent evidence of lack of effectiveness: “It’s what our patients have been telling us for a long period of time,” he noted at the meeting sponsored by the Osteoarthritis Research Society International.
But change is in the air.
“I think we’ve got some things coming that look promising. What do I think will be the fastest to get to market? The peripheral nerve modulators look to me like the ones closest to going forward,” according to the rheumatologist, who provided an overview of the OA drug development pipeline, organized by treatment target.
Nerves
“Nerves as a treatment target in OA is a hot area. We’ve seen quite a slew of products recently looking at this. I think it’s a really fascinating area to play in: looking at how we modulate peripheral nociceptive pain,” Dr. Conaghan continued.
Tanezumab, an inhibitor of nerve growth factor, demonstrated very good pain relief and improvement in physical function in a phase 3 trial, although the occurrence of rapidly progressive OA in a subset of patients has bedeviled the drug development program. The hope is that a new subcutaneous drug delivery system coupled with careful patient pretreatment screening will mitigate the problem.
Tanezumab’s efficacy has contributed to a new understanding of the nature of pain in OA.
“I know I’m going to upset some people, but if you think central sensitization is the biggest driver of pain, I’d have to argue that the tanezumab program is the biggest single argument against that, since tanezumab is a large monoclonal antibody that doesn’t cross the blood-brain barrier and yet it has some of the best pain responses that we’ve seen,” Dr. Conaghan said.
Another peripheral nerve modulator, known for now as CNTX-4975, exhibited dose-dependent improvement in knee OA pain in the 175-patient, phase 2b TRIUMPH trial (Arthritis Rheumatol. 2019 Mar 19. doi: 10.1002/art.40894). CNTX-4975, which is delivered by intra-articular injection, is a synthetic form of capsaicin specific to pain nociceptors within the joint. Other sensory fibers remain unaffected.
Cartilage
Sprifermin, a recombinant human fibroblast growth factor 18 given by intra-articular injection, stimulates chondrocyte growth and decreases type 1 collagen expression. At year 2 in the ongoing 549-patient, 5-year, phase 2 FORWARD study, a dose-dependent increase in cartilage thickness at the tibiofemoral joint became apparent in sprifermin-treated patients, compared with those on placebo. This cartilage rebuilding effect was maintained at year 3, Dr. Conaghan said.
Bone
At the OARSI meeting, Dr. Conaghan and coinvestigators presented the results of a 6-month, open-label extension of their previously reported 6-month, placebo-controlled, phase 2 study of MIV-711, a potent selective reversible inhibitor of cathepsin K. The disease-modifying effects of MIV-711 seen in the first 6 months of the study, based on MRI-based measurements of changes in three-dimensional bone shape and cartilage thickness, were maintained in the second 6 months. Notably, MIV-711 slowed the rate of increase in bone area in the medial femur region and reduced loss of cartilage thickness relative to placebo. MIV-711 has also been shown to achieve a rapid and sustained reduction in the bone turnover biomarkers CTX-1 and -2, providing a rational mechanism to explain the drug’s observed structural benefits.
“So we’ve now got two agents – sprifermin for cartilage and MIV-711 for bone – showing that it’s possible to get some structural change, but no symptomatic benefit within the period of those trials,” the rheumatologist noted.
Wnt pathway inhibition
Samumed has launched a phase 3 clinical trials program, known as STRIDES, for lorecivivint, the company’s investigational small molecule inhibitor of the Wnt pathway. In phase 2 studies, including one led by Dr. Conaghan, intra-articular injection of lorecivivint, previously known as SMO4690, improved pain and physical function as well as medial joint space width. The drug’s potential effects on multiple tissues offers the promise of providing both symptomatic improvement and modification of the course of structural disease progression.
Inflammation
Lutikizumab, an anti–interleukin-1 alpha/beta immunoglobulin, proved to be a disappointment in a recent phase 2, placebo-controlled trial carried out in 350 patients with knee OA and synovitis. The IL-1 inhibitor had no benefit on synovitis, joint space narrowing, or cartilage thickness. Nor was it significantly better than placebo for pain reduction (Arthritis Rheumatol. 2019 Jul;71[7]:1056-69).
Anti–tumor necrosis factor agents haven’t exactly set the OA world on fire, either.
“In rheumatoid arthritis we know they’re stupendously effective, but the data from a number of trials in OA show they’re not so effective on symptoms and signs,” Dr. Conaghan said.
Colchicine and hydroxychloroquine are other anti-inflammatory agents which, while in theory might be helpful, have in actuality shown no benefit for OA symptoms in controlled clinical trials and are now considered dead ends.
On the other hand, the sustained delivery of intra-articular corticosteroids through the use of microsphere technology is advancing smartly through the developmental pipeline. Dr. Conaghan was first author of a multicenter, double-blind, phase 3 trial of FX006, a sustained-release formulation of triamcinolone acetonide, which showed that a single intra-articular injection provided at least 3 months of pain relief in knee OA patients, along with reduced systemic drug exposure, compared with standard intra-articular corticosteroids (J Bone Joint Surg Am. 2018 Apr 18;100[8]:666-77).
FX006 also performed well in another phase 3 trial, this one featuring repeated dosing on a flexible schedule based upon patient response (Rheumatol Ther. 2019 Mar;6[1]:109-24).
Reassuringly, this slow-release corticosteroid doesn’t appear to worsen glycemic control in knee OA patients with type 2 diabetes (Rheumatology [Oxford]. 2018 Dec 1;57[12]:2235-41).
“This is the start of a revolution in nanotechnology and the ability to slowly deliver a variety of drugs within the joint,” Dr. Conaghan predicted.
Although he was tasked at OARSI 2019 with providing an overview of the OA pharmacologic pipeline, he stressed that in his clinical practice, as opposed to his work as a clinical trialist, he functions more like a physical therapist.
“I actually spend my whole time in the OA clinic being a physical therapist and trying to get people strong, because that does work and it has no side effects. It’s just that nobody does it. We have a real adherence problem,” he said. “My favorite thought is this: keep people strong. If a patient can’t get out of a chair easily or can’t undo a jar, then they’ve got a problem.”
Dr. Conaghan reported receiving research funding from and serving as a consultant to many of the companies developing novel drug treatments for OA.
TORONTO – Philip G. Conaghan, MBBS, PhD, observed at the OARSI 2019 World Congress.
“Not only have things not improved during my time in osteoarthritis-land, they’ve gotten worse. We’ve lost therapies,” said Dr. Conaghan, professor of musculoskeletal medicine at the University of Leeds (England) and director of the Leeds Institute of Rheumatic and Musculoskeletal Medicine.
Specifically, opioids are now shunned because of the ongoing epidemic of addiction and a belated recognition that opioids are not a good option for pain relief in OA patients who want to have active lives. And acetaminophen has fallen by the wayside in light of recent evidence of lack of effectiveness: “It’s what our patients have been telling us for a long period of time,” he noted at the meeting sponsored by the Osteoarthritis Research Society International.
But change is in the air.
“I think we’ve got some things coming that look promising. What do I think will be the fastest to get to market? The peripheral nerve modulators look to me like the ones closest to going forward,” according to the rheumatologist, who provided an overview of the OA drug development pipeline, organized by treatment target.
Nerves
“Nerves as a treatment target in OA is a hot area. We’ve seen quite a slew of products recently looking at this. I think it’s a really fascinating area to play in: looking at how we modulate peripheral nociceptive pain,” Dr. Conaghan continued.
Tanezumab, an inhibitor of nerve growth factor, demonstrated very good pain relief and improvement in physical function in a phase 3 trial, although the occurrence of rapidly progressive OA in a subset of patients has bedeviled the drug development program. The hope is that a new subcutaneous drug delivery system coupled with careful patient pretreatment screening will mitigate the problem.
Tanezumab’s efficacy has contributed to a new understanding of the nature of pain in OA.
“I know I’m going to upset some people, but if you think central sensitization is the biggest driver of pain, I’d have to argue that the tanezumab program is the biggest single argument against that, since tanezumab is a large monoclonal antibody that doesn’t cross the blood-brain barrier and yet it has some of the best pain responses that we’ve seen,” Dr. Conaghan said.
Another peripheral nerve modulator, known for now as CNTX-4975, exhibited dose-dependent improvement in knee OA pain in the 175-patient, phase 2b TRIUMPH trial (Arthritis Rheumatol. 2019 Mar 19. doi: 10.1002/art.40894). CNTX-4975, which is delivered by intra-articular injection, is a synthetic form of capsaicin specific to pain nociceptors within the joint. Other sensory fibers remain unaffected.
Cartilage
Sprifermin, a recombinant human fibroblast growth factor 18 given by intra-articular injection, stimulates chondrocyte growth and decreases type 1 collagen expression. At year 2 in the ongoing 549-patient, 5-year, phase 2 FORWARD study, a dose-dependent increase in cartilage thickness at the tibiofemoral joint became apparent in sprifermin-treated patients, compared with those on placebo. This cartilage rebuilding effect was maintained at year 3, Dr. Conaghan said.
Bone
At the OARSI meeting, Dr. Conaghan and coinvestigators presented the results of a 6-month, open-label extension of their previously reported 6-month, placebo-controlled, phase 2 study of MIV-711, a potent selective reversible inhibitor of cathepsin K. The disease-modifying effects of MIV-711 seen in the first 6 months of the study, based on MRI-based measurements of changes in three-dimensional bone shape and cartilage thickness, were maintained in the second 6 months. Notably, MIV-711 slowed the rate of increase in bone area in the medial femur region and reduced loss of cartilage thickness relative to placebo. MIV-711 has also been shown to achieve a rapid and sustained reduction in the bone turnover biomarkers CTX-1 and -2, providing a rational mechanism to explain the drug’s observed structural benefits.
“So we’ve now got two agents – sprifermin for cartilage and MIV-711 for bone – showing that it’s possible to get some structural change, but no symptomatic benefit within the period of those trials,” the rheumatologist noted.
Wnt pathway inhibition
Samumed has launched a phase 3 clinical trials program, known as STRIDES, for lorecivivint, the company’s investigational small molecule inhibitor of the Wnt pathway. In phase 2 studies, including one led by Dr. Conaghan, intra-articular injection of lorecivivint, previously known as SMO4690, improved pain and physical function as well as medial joint space width. The drug’s potential effects on multiple tissues offers the promise of providing both symptomatic improvement and modification of the course of structural disease progression.
Inflammation
Lutikizumab, an anti–interleukin-1 alpha/beta immunoglobulin, proved to be a disappointment in a recent phase 2, placebo-controlled trial carried out in 350 patients with knee OA and synovitis. The IL-1 inhibitor had no benefit on synovitis, joint space narrowing, or cartilage thickness. Nor was it significantly better than placebo for pain reduction (Arthritis Rheumatol. 2019 Jul;71[7]:1056-69).
Anti–tumor necrosis factor agents haven’t exactly set the OA world on fire, either.
“In rheumatoid arthritis we know they’re stupendously effective, but the data from a number of trials in OA show they’re not so effective on symptoms and signs,” Dr. Conaghan said.
Colchicine and hydroxychloroquine are other anti-inflammatory agents which, while in theory might be helpful, have in actuality shown no benefit for OA symptoms in controlled clinical trials and are now considered dead ends.
On the other hand, the sustained delivery of intra-articular corticosteroids through the use of microsphere technology is advancing smartly through the developmental pipeline. Dr. Conaghan was first author of a multicenter, double-blind, phase 3 trial of FX006, a sustained-release formulation of triamcinolone acetonide, which showed that a single intra-articular injection provided at least 3 months of pain relief in knee OA patients, along with reduced systemic drug exposure, compared with standard intra-articular corticosteroids (J Bone Joint Surg Am. 2018 Apr 18;100[8]:666-77).
FX006 also performed well in another phase 3 trial, this one featuring repeated dosing on a flexible schedule based upon patient response (Rheumatol Ther. 2019 Mar;6[1]:109-24).
Reassuringly, this slow-release corticosteroid doesn’t appear to worsen glycemic control in knee OA patients with type 2 diabetes (Rheumatology [Oxford]. 2018 Dec 1;57[12]:2235-41).
“This is the start of a revolution in nanotechnology and the ability to slowly deliver a variety of drugs within the joint,” Dr. Conaghan predicted.
Although he was tasked at OARSI 2019 with providing an overview of the OA pharmacologic pipeline, he stressed that in his clinical practice, as opposed to his work as a clinical trialist, he functions more like a physical therapist.
“I actually spend my whole time in the OA clinic being a physical therapist and trying to get people strong, because that does work and it has no side effects. It’s just that nobody does it. We have a real adherence problem,” he said. “My favorite thought is this: keep people strong. If a patient can’t get out of a chair easily or can’t undo a jar, then they’ve got a problem.”
Dr. Conaghan reported receiving research funding from and serving as a consultant to many of the companies developing novel drug treatments for OA.
EXPERT ANALYSIS FROM OARSI 2019
FDA finds increased blood clot, death risk associated with Xeljanz
The Food and Drug Administration has issued a safety alert approving new boxed warnings about increased blood clot and mortality risk associated with the 10-mg, twice-daily dose of tofacitinib (Xeljanz), as well as a new limitation for patients with ulcerative colitis receiving the medication.
Tofacitinib, a Janus kinase inhibitor, was first approved by the FDA in 2012 for the treatment of rheumatoid arthritis (RA). An indication for psoriatic arthritis was added in 2017, and one for ulcerative colitis was added in 2018.
After the 2012 approval, the FDA commissioned a postmarketing trial in patients with RA on background methotrexate to evaluate safety and the risk of cancer, heart-related events, and infection. The 5- and 10-mg tofacitinib twice daily doses are being analyzed in an ongoing study in comparison with a tumor necrosis factor (TNF) inhibitor.
An interim analysis of the trial’s data, as of January 2019, found an increased risk of blood clots and death in patients receiving 10-mg tofacitinib twice daily, compared with the TNF inhibitor and the twice-daily, 5-mg dose. Overall, there were 19 cases of blood clots in the lung out of 3,884 patient-years of follow-up in patients who received tofacitinib 10 mg twice daily, compared with 3 cases out of 3,982 patient-years in patients who received TNF inhibitors. There were also 45 cases of death from all causes during follow-up for tofacitinib 10 mg twice daily, compared with 25 cases in patients who received TNF inhibitors.
Patients with symptoms of thrombosis also receiving tofacitinib should immediately discontinue the medication. Tofacitinib should not be given to patients with ulcerative colitis unless they are not treated effectively with a TNF inhibitor or do not tolerate TNF inhibitors; ulcerative colitis patients should receive the lowest effective dosage, and if the higher dosage is necessary, it should be limited to the shortest amount of time possible, the FDA noted.
The Food and Drug Administration has issued a safety alert approving new boxed warnings about increased blood clot and mortality risk associated with the 10-mg, twice-daily dose of tofacitinib (Xeljanz), as well as a new limitation for patients with ulcerative colitis receiving the medication.
Tofacitinib, a Janus kinase inhibitor, was first approved by the FDA in 2012 for the treatment of rheumatoid arthritis (RA). An indication for psoriatic arthritis was added in 2017, and one for ulcerative colitis was added in 2018.
After the 2012 approval, the FDA commissioned a postmarketing trial in patients with RA on background methotrexate to evaluate safety and the risk of cancer, heart-related events, and infection. The 5- and 10-mg tofacitinib twice daily doses are being analyzed in an ongoing study in comparison with a tumor necrosis factor (TNF) inhibitor.
An interim analysis of the trial’s data, as of January 2019, found an increased risk of blood clots and death in patients receiving 10-mg tofacitinib twice daily, compared with the TNF inhibitor and the twice-daily, 5-mg dose. Overall, there were 19 cases of blood clots in the lung out of 3,884 patient-years of follow-up in patients who received tofacitinib 10 mg twice daily, compared with 3 cases out of 3,982 patient-years in patients who received TNF inhibitors. There were also 45 cases of death from all causes during follow-up for tofacitinib 10 mg twice daily, compared with 25 cases in patients who received TNF inhibitors.
Patients with symptoms of thrombosis also receiving tofacitinib should immediately discontinue the medication. Tofacitinib should not be given to patients with ulcerative colitis unless they are not treated effectively with a TNF inhibitor or do not tolerate TNF inhibitors; ulcerative colitis patients should receive the lowest effective dosage, and if the higher dosage is necessary, it should be limited to the shortest amount of time possible, the FDA noted.
The Food and Drug Administration has issued a safety alert approving new boxed warnings about increased blood clot and mortality risk associated with the 10-mg, twice-daily dose of tofacitinib (Xeljanz), as well as a new limitation for patients with ulcerative colitis receiving the medication.
Tofacitinib, a Janus kinase inhibitor, was first approved by the FDA in 2012 for the treatment of rheumatoid arthritis (RA). An indication for psoriatic arthritis was added in 2017, and one for ulcerative colitis was added in 2018.
After the 2012 approval, the FDA commissioned a postmarketing trial in patients with RA on background methotrexate to evaluate safety and the risk of cancer, heart-related events, and infection. The 5- and 10-mg tofacitinib twice daily doses are being analyzed in an ongoing study in comparison with a tumor necrosis factor (TNF) inhibitor.
An interim analysis of the trial’s data, as of January 2019, found an increased risk of blood clots and death in patients receiving 10-mg tofacitinib twice daily, compared with the TNF inhibitor and the twice-daily, 5-mg dose. Overall, there were 19 cases of blood clots in the lung out of 3,884 patient-years of follow-up in patients who received tofacitinib 10 mg twice daily, compared with 3 cases out of 3,982 patient-years in patients who received TNF inhibitors. There were also 45 cases of death from all causes during follow-up for tofacitinib 10 mg twice daily, compared with 25 cases in patients who received TNF inhibitors.
Patients with symptoms of thrombosis also receiving tofacitinib should immediately discontinue the medication. Tofacitinib should not be given to patients with ulcerative colitis unless they are not treated effectively with a TNF inhibitor or do not tolerate TNF inhibitors; ulcerative colitis patients should receive the lowest effective dosage, and if the higher dosage is necessary, it should be limited to the shortest amount of time possible, the FDA noted.
Lupus nephritis treatment: Five key components
LAKE BUENA VISTA, FLA. – When it comes to lupus nephritis, the guidelines – and prevailing wisdom – don’t always get it quite right, according to Michelle A. Petri, MD.
During an update at the annual meeting of the Florida Society of Rheumatology, she outlined five key components of lupus nephritis treatment, and the status of the evidence for each.
Antihypertensive therapy
Antihypertensive therapy isn’t just for hypertension in patients with lupus nephritis – it’s for reducing proteinuria and preventing renal fibrosis, said Dr. Petri, professor of medicine and director of the Hopkins Lupus Center at Johns Hopkins University, Baltimore.
“I get a lot of push-back on this,” she added, explaining that other physicians often will stop the treatment as she prescribed it, because they believe it’s unnecessary.
She described a case involving a 33-year-old African American man with blood pressure of 132/86 mm Hg and grade 3+ ankle edema. Laboratory tests were remarkable for hematocrit (33.4%), white blood cell count (3.1), erythrocyte sedimentation rate (67 mm/hr) and urinalysis (2+ protein by dipstick, 3 red cells/high-power field, no casts). Additionally, 24-hour urine protein showed 400 mg of microalbumin, and he had a positive antinuclear antibody test, positive anti–double stranded DNA, and low complement.
“I’m going to argue really strenuously that he has to be on an ACE inhibitor or an ARB [angiotensin receptor blocker],” she said, explaining that even before an immunosuppressant therapy is started, optimizing ACE inhibitor or ARB therapy can reduce proteinuria by 50%.
The “sweet spot” for blood pressure in these patients is between 110 and 129, she said.
“You don’t want it too low, because you might hurt renal perfusion, but you sure don’t want it above 130,” she said.
The problem is that many physicians think 110 or 112 is too low.
“Not for a lupus nephritis patient,” she said. “It’s really where we want to be.”
ACE inhibitors and ARBs are preferable for reaching this goal, she said, noting that calcium channel blockers have been linked with shorter time to renal failure.
Hydroxychloroquine
Everyone with lupus nephritis should be on hydroxychloroquine, Dr. Petri argued.
“It improves renal outcomes,” she said. “It more than triples the chance that a patient will have a complete renal response.”
Guidelines from the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) are in agreement on this, she said.
Even the renal guidelines for lupus nephritis now include hydroxychloroquine as mandatory, she added, noting that it is not necessary to check glucose-6-phosphate dehydrogenase (G6PD) before starting treatment.
In fact, a recent study showed that only 2 of 11 patients with G6PD deficiency had episodes of hemolysis, and those episodes did not occur during hydroxychloroquine therapy. The authors concluded that the routine measurement of G6PD levels and withholding therapy among African American patients with G6PD deficiency is not supported, she said (Arthritis Care Res. 2018;70[3]:481-5).
“Of course, if your patient has renal insufficiency you’re going to have to reduce the dose in half,” she noted.
Vitamin D
Modestly increasing 25-hydroxyvitamin D can “greatly, significantly reduce the urine protein – with no cost, with no toxicity,” Dr. Petri said.
In a 2013 study, she and her colleagues showed that a 20‐ng/mL increase in the 25(OH)vitamin D level was associated with a 21% decrease in the odds of having a high disease-activity score, and with a 15% decrease in the odds of having clinically important proteinuria (Arthritis Rheumatol. 2013;65[7]:1865-71).
“But you’ll be fascinated to hear that vitamin D may be an antifibrotic drug, as well,” she noted. “This has been proven in animal models of pulmonary fibrosis ... and although we don’t have proof in lupus nephritis, the animal models are so strong that I think absolutely everybody with lupus nephritis needs to be on vitamin D, both to reduce proteinuria and then, hopefully, as a very cheap antifibrotic drug.”
Mycophenolate mofetil
The case Dr. Petri presented involved a patient with International Society of Nephrology class IV disease.
Left untreated, he would be in end-stage renal disease within a year, she said.
“But even with my maximal treatment he has a 23% chance of being in end-stage renal disease in 20 years,” she noted.
This patient had a high National Institutes of Health activity index, but low chronicity, and there were no crescents.
“The reason I mention this is because crescents mean rapidly progressive [glomerular nephritis],” she said. “That’s very urgent; it’s one of the situations where even I will dump on the steroids, because you’ve got to do something fast.”
In this case, however, the best induction therapy is mycophenolate mofetil, she said.
“Boy, our guidelines are wishy-washy on this, and they shouldn’t be,” she said, explaining that “because he’s African American, there are very clear data that mycophenolate is better than cyclophosphamide – our guidelines need to make that very clear.”
In fact, mycophenolate should be the first choice of induction therapy in all cases, except those involving rapidly progressive glomerulonephritis (RPGN), for which cyclophosphamide should be given for at least 3 months before trying to transition to mycophenolate, she stressed.
After about 1 year of treatment, 50% of patients will be complete renal responders, she noted, adding that “in Caucasians, mycophenolate is as good as cyclophosphamide, and in African Americans, mycophenolate is much better.”
“So mycophenolate has won, and for good reason. But is it sufficient to have 50% of patients be complete renal responders at 1 year?” she asked, noting the risk for renal fibrosis in those who respond late in that year or not at all.
“So we really need something that’s much more successful.”
Steroids
How much prednisone should lupus nephritis patients get?
As little as possible, according to Dr. Petri.
“I want you to think back to all those times you were taught during you fellowship about dumping on as much prednisone as possible,” she said. “[They] probably aren’t correct.”
She also pulled no punches when it comes to the ACR and EULAR guidelines on prednisone use.
“Both ... are wrong,” she said, explaining that the ACR guidelines are “top-heavy” on prednisone in calling for 0.5-1 mg/kg/day.
“One mg/kg? Like everybody’s the same? I do not object to 1 mg/kg if it’s RPGN, but not for everybody else,” she said.
EULAR guidelines are “less generous,” calling for 0.5 mg/kg/day for 4 weeks, and they make it clear that “you better taper that stuff off.”
“I like that part,” she said. “But still, you’re starting out with a lot of steroid.”
Why the objection? Data show that prednisone is directly or indirectly responsible for 80% of organ damage over 15 years, she said (J Rheumatol. 2003;30[9]:1955-9).
“It’s bad enough to have lupus nephritis; why should you have to be poisoned with prednisone, as well?” she asked. “Now, if the people on prednisone did better, of course I’d have to back off, wouldn’t I?”
Recent data, however, suggest that lupus nephritis patients who are treated with prednisone end up doing worse, and studies being performed outside the United States are beginning to use lower doses of prednisone, she said.
“The rest of the world is lowering the prednisone; our guidelines need to catch up,” she said, adding that she sees no reason why this shouldn’t apply in lupus nephritis.
“Their prednisone should be less than 6 mg, and doses above that level increase organ damage by 50%,” she said, citing a 2009 study in which she and her colleagues found that the hazard ratio for organ damage with prednisone vs. no prednisone was 1.50 for cumulative average doses of 180-360 mg/month, compared with 1.16 for doses up to 180 mg/month (J Rheumatol. 2009;36[3]:560-4).
Even a 20-mg dose has been linked with a fivefold increase the risk of a vascular incident, she added, citing another such study (Am J Epidemiol. 2012;176:708-19).
Dr. Petri is a consultant for GlaxoSmithKline, Merck EMD Serono, Lilly, Janssen, Amgen, Novartis, Exagen, Inova Diagnostics, AstraZeneca, Blackrock Pharma, Glenmark, and UCB.
LAKE BUENA VISTA, FLA. – When it comes to lupus nephritis, the guidelines – and prevailing wisdom – don’t always get it quite right, according to Michelle A. Petri, MD.
During an update at the annual meeting of the Florida Society of Rheumatology, she outlined five key components of lupus nephritis treatment, and the status of the evidence for each.
Antihypertensive therapy
Antihypertensive therapy isn’t just for hypertension in patients with lupus nephritis – it’s for reducing proteinuria and preventing renal fibrosis, said Dr. Petri, professor of medicine and director of the Hopkins Lupus Center at Johns Hopkins University, Baltimore.
“I get a lot of push-back on this,” she added, explaining that other physicians often will stop the treatment as she prescribed it, because they believe it’s unnecessary.
She described a case involving a 33-year-old African American man with blood pressure of 132/86 mm Hg and grade 3+ ankle edema. Laboratory tests were remarkable for hematocrit (33.4%), white blood cell count (3.1), erythrocyte sedimentation rate (67 mm/hr) and urinalysis (2+ protein by dipstick, 3 red cells/high-power field, no casts). Additionally, 24-hour urine protein showed 400 mg of microalbumin, and he had a positive antinuclear antibody test, positive anti–double stranded DNA, and low complement.
“I’m going to argue really strenuously that he has to be on an ACE inhibitor or an ARB [angiotensin receptor blocker],” she said, explaining that even before an immunosuppressant therapy is started, optimizing ACE inhibitor or ARB therapy can reduce proteinuria by 50%.
The “sweet spot” for blood pressure in these patients is between 110 and 129, she said.
“You don’t want it too low, because you might hurt renal perfusion, but you sure don’t want it above 130,” she said.
The problem is that many physicians think 110 or 112 is too low.
“Not for a lupus nephritis patient,” she said. “It’s really where we want to be.”
ACE inhibitors and ARBs are preferable for reaching this goal, she said, noting that calcium channel blockers have been linked with shorter time to renal failure.
Hydroxychloroquine
Everyone with lupus nephritis should be on hydroxychloroquine, Dr. Petri argued.
“It improves renal outcomes,” she said. “It more than triples the chance that a patient will have a complete renal response.”
Guidelines from the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) are in agreement on this, she said.
Even the renal guidelines for lupus nephritis now include hydroxychloroquine as mandatory, she added, noting that it is not necessary to check glucose-6-phosphate dehydrogenase (G6PD) before starting treatment.
In fact, a recent study showed that only 2 of 11 patients with G6PD deficiency had episodes of hemolysis, and those episodes did not occur during hydroxychloroquine therapy. The authors concluded that the routine measurement of G6PD levels and withholding therapy among African American patients with G6PD deficiency is not supported, she said (Arthritis Care Res. 2018;70[3]:481-5).
“Of course, if your patient has renal insufficiency you’re going to have to reduce the dose in half,” she noted.
Vitamin D
Modestly increasing 25-hydroxyvitamin D can “greatly, significantly reduce the urine protein – with no cost, with no toxicity,” Dr. Petri said.
In a 2013 study, she and her colleagues showed that a 20‐ng/mL increase in the 25(OH)vitamin D level was associated with a 21% decrease in the odds of having a high disease-activity score, and with a 15% decrease in the odds of having clinically important proteinuria (Arthritis Rheumatol. 2013;65[7]:1865-71).
“But you’ll be fascinated to hear that vitamin D may be an antifibrotic drug, as well,” she noted. “This has been proven in animal models of pulmonary fibrosis ... and although we don’t have proof in lupus nephritis, the animal models are so strong that I think absolutely everybody with lupus nephritis needs to be on vitamin D, both to reduce proteinuria and then, hopefully, as a very cheap antifibrotic drug.”
Mycophenolate mofetil
The case Dr. Petri presented involved a patient with International Society of Nephrology class IV disease.
Left untreated, he would be in end-stage renal disease within a year, she said.
“But even with my maximal treatment he has a 23% chance of being in end-stage renal disease in 20 years,” she noted.
This patient had a high National Institutes of Health activity index, but low chronicity, and there were no crescents.
“The reason I mention this is because crescents mean rapidly progressive [glomerular nephritis],” she said. “That’s very urgent; it’s one of the situations where even I will dump on the steroids, because you’ve got to do something fast.”
In this case, however, the best induction therapy is mycophenolate mofetil, she said.
“Boy, our guidelines are wishy-washy on this, and they shouldn’t be,” she said, explaining that “because he’s African American, there are very clear data that mycophenolate is better than cyclophosphamide – our guidelines need to make that very clear.”
In fact, mycophenolate should be the first choice of induction therapy in all cases, except those involving rapidly progressive glomerulonephritis (RPGN), for which cyclophosphamide should be given for at least 3 months before trying to transition to mycophenolate, she stressed.
After about 1 year of treatment, 50% of patients will be complete renal responders, she noted, adding that “in Caucasians, mycophenolate is as good as cyclophosphamide, and in African Americans, mycophenolate is much better.”
“So mycophenolate has won, and for good reason. But is it sufficient to have 50% of patients be complete renal responders at 1 year?” she asked, noting the risk for renal fibrosis in those who respond late in that year or not at all.
“So we really need something that’s much more successful.”
Steroids
How much prednisone should lupus nephritis patients get?
As little as possible, according to Dr. Petri.
“I want you to think back to all those times you were taught during you fellowship about dumping on as much prednisone as possible,” she said. “[They] probably aren’t correct.”
She also pulled no punches when it comes to the ACR and EULAR guidelines on prednisone use.
“Both ... are wrong,” she said, explaining that the ACR guidelines are “top-heavy” on prednisone in calling for 0.5-1 mg/kg/day.
“One mg/kg? Like everybody’s the same? I do not object to 1 mg/kg if it’s RPGN, but not for everybody else,” she said.
EULAR guidelines are “less generous,” calling for 0.5 mg/kg/day for 4 weeks, and they make it clear that “you better taper that stuff off.”
“I like that part,” she said. “But still, you’re starting out with a lot of steroid.”
Why the objection? Data show that prednisone is directly or indirectly responsible for 80% of organ damage over 15 years, she said (J Rheumatol. 2003;30[9]:1955-9).
“It’s bad enough to have lupus nephritis; why should you have to be poisoned with prednisone, as well?” she asked. “Now, if the people on prednisone did better, of course I’d have to back off, wouldn’t I?”
Recent data, however, suggest that lupus nephritis patients who are treated with prednisone end up doing worse, and studies being performed outside the United States are beginning to use lower doses of prednisone, she said.
“The rest of the world is lowering the prednisone; our guidelines need to catch up,” she said, adding that she sees no reason why this shouldn’t apply in lupus nephritis.
“Their prednisone should be less than 6 mg, and doses above that level increase organ damage by 50%,” she said, citing a 2009 study in which she and her colleagues found that the hazard ratio for organ damage with prednisone vs. no prednisone was 1.50 for cumulative average doses of 180-360 mg/month, compared with 1.16 for doses up to 180 mg/month (J Rheumatol. 2009;36[3]:560-4).
Even a 20-mg dose has been linked with a fivefold increase the risk of a vascular incident, she added, citing another such study (Am J Epidemiol. 2012;176:708-19).
Dr. Petri is a consultant for GlaxoSmithKline, Merck EMD Serono, Lilly, Janssen, Amgen, Novartis, Exagen, Inova Diagnostics, AstraZeneca, Blackrock Pharma, Glenmark, and UCB.
LAKE BUENA VISTA, FLA. – When it comes to lupus nephritis, the guidelines – and prevailing wisdom – don’t always get it quite right, according to Michelle A. Petri, MD.
During an update at the annual meeting of the Florida Society of Rheumatology, she outlined five key components of lupus nephritis treatment, and the status of the evidence for each.
Antihypertensive therapy
Antihypertensive therapy isn’t just for hypertension in patients with lupus nephritis – it’s for reducing proteinuria and preventing renal fibrosis, said Dr. Petri, professor of medicine and director of the Hopkins Lupus Center at Johns Hopkins University, Baltimore.
“I get a lot of push-back on this,” she added, explaining that other physicians often will stop the treatment as she prescribed it, because they believe it’s unnecessary.
She described a case involving a 33-year-old African American man with blood pressure of 132/86 mm Hg and grade 3+ ankle edema. Laboratory tests were remarkable for hematocrit (33.4%), white blood cell count (3.1), erythrocyte sedimentation rate (67 mm/hr) and urinalysis (2+ protein by dipstick, 3 red cells/high-power field, no casts). Additionally, 24-hour urine protein showed 400 mg of microalbumin, and he had a positive antinuclear antibody test, positive anti–double stranded DNA, and low complement.
“I’m going to argue really strenuously that he has to be on an ACE inhibitor or an ARB [angiotensin receptor blocker],” she said, explaining that even before an immunosuppressant therapy is started, optimizing ACE inhibitor or ARB therapy can reduce proteinuria by 50%.
The “sweet spot” for blood pressure in these patients is between 110 and 129, she said.
“You don’t want it too low, because you might hurt renal perfusion, but you sure don’t want it above 130,” she said.
The problem is that many physicians think 110 or 112 is too low.
“Not for a lupus nephritis patient,” she said. “It’s really where we want to be.”
ACE inhibitors and ARBs are preferable for reaching this goal, she said, noting that calcium channel blockers have been linked with shorter time to renal failure.
Hydroxychloroquine
Everyone with lupus nephritis should be on hydroxychloroquine, Dr. Petri argued.
“It improves renal outcomes,” she said. “It more than triples the chance that a patient will have a complete renal response.”
Guidelines from the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) are in agreement on this, she said.
Even the renal guidelines for lupus nephritis now include hydroxychloroquine as mandatory, she added, noting that it is not necessary to check glucose-6-phosphate dehydrogenase (G6PD) before starting treatment.
In fact, a recent study showed that only 2 of 11 patients with G6PD deficiency had episodes of hemolysis, and those episodes did not occur during hydroxychloroquine therapy. The authors concluded that the routine measurement of G6PD levels and withholding therapy among African American patients with G6PD deficiency is not supported, she said (Arthritis Care Res. 2018;70[3]:481-5).
“Of course, if your patient has renal insufficiency you’re going to have to reduce the dose in half,” she noted.
Vitamin D
Modestly increasing 25-hydroxyvitamin D can “greatly, significantly reduce the urine protein – with no cost, with no toxicity,” Dr. Petri said.
In a 2013 study, she and her colleagues showed that a 20‐ng/mL increase in the 25(OH)vitamin D level was associated with a 21% decrease in the odds of having a high disease-activity score, and with a 15% decrease in the odds of having clinically important proteinuria (Arthritis Rheumatol. 2013;65[7]:1865-71).
“But you’ll be fascinated to hear that vitamin D may be an antifibrotic drug, as well,” she noted. “This has been proven in animal models of pulmonary fibrosis ... and although we don’t have proof in lupus nephritis, the animal models are so strong that I think absolutely everybody with lupus nephritis needs to be on vitamin D, both to reduce proteinuria and then, hopefully, as a very cheap antifibrotic drug.”
Mycophenolate mofetil
The case Dr. Petri presented involved a patient with International Society of Nephrology class IV disease.
Left untreated, he would be in end-stage renal disease within a year, she said.
“But even with my maximal treatment he has a 23% chance of being in end-stage renal disease in 20 years,” she noted.
This patient had a high National Institutes of Health activity index, but low chronicity, and there were no crescents.
“The reason I mention this is because crescents mean rapidly progressive [glomerular nephritis],” she said. “That’s very urgent; it’s one of the situations where even I will dump on the steroids, because you’ve got to do something fast.”
In this case, however, the best induction therapy is mycophenolate mofetil, she said.
“Boy, our guidelines are wishy-washy on this, and they shouldn’t be,” she said, explaining that “because he’s African American, there are very clear data that mycophenolate is better than cyclophosphamide – our guidelines need to make that very clear.”
In fact, mycophenolate should be the first choice of induction therapy in all cases, except those involving rapidly progressive glomerulonephritis (RPGN), for which cyclophosphamide should be given for at least 3 months before trying to transition to mycophenolate, she stressed.
After about 1 year of treatment, 50% of patients will be complete renal responders, she noted, adding that “in Caucasians, mycophenolate is as good as cyclophosphamide, and in African Americans, mycophenolate is much better.”
“So mycophenolate has won, and for good reason. But is it sufficient to have 50% of patients be complete renal responders at 1 year?” she asked, noting the risk for renal fibrosis in those who respond late in that year or not at all.
“So we really need something that’s much more successful.”
Steroids
How much prednisone should lupus nephritis patients get?
As little as possible, according to Dr. Petri.
“I want you to think back to all those times you were taught during you fellowship about dumping on as much prednisone as possible,” she said. “[They] probably aren’t correct.”
She also pulled no punches when it comes to the ACR and EULAR guidelines on prednisone use.
“Both ... are wrong,” she said, explaining that the ACR guidelines are “top-heavy” on prednisone in calling for 0.5-1 mg/kg/day.
“One mg/kg? Like everybody’s the same? I do not object to 1 mg/kg if it’s RPGN, but not for everybody else,” she said.
EULAR guidelines are “less generous,” calling for 0.5 mg/kg/day for 4 weeks, and they make it clear that “you better taper that stuff off.”
“I like that part,” she said. “But still, you’re starting out with a lot of steroid.”
Why the objection? Data show that prednisone is directly or indirectly responsible for 80% of organ damage over 15 years, she said (J Rheumatol. 2003;30[9]:1955-9).
“It’s bad enough to have lupus nephritis; why should you have to be poisoned with prednisone, as well?” she asked. “Now, if the people on prednisone did better, of course I’d have to back off, wouldn’t I?”
Recent data, however, suggest that lupus nephritis patients who are treated with prednisone end up doing worse, and studies being performed outside the United States are beginning to use lower doses of prednisone, she said.
“The rest of the world is lowering the prednisone; our guidelines need to catch up,” she said, adding that she sees no reason why this shouldn’t apply in lupus nephritis.
“Their prednisone should be less than 6 mg, and doses above that level increase organ damage by 50%,” she said, citing a 2009 study in which she and her colleagues found that the hazard ratio for organ damage with prednisone vs. no prednisone was 1.50 for cumulative average doses of 180-360 mg/month, compared with 1.16 for doses up to 180 mg/month (J Rheumatol. 2009;36[3]:560-4).
Even a 20-mg dose has been linked with a fivefold increase the risk of a vascular incident, she added, citing another such study (Am J Epidemiol. 2012;176:708-19).
Dr. Petri is a consultant for GlaxoSmithKline, Merck EMD Serono, Lilly, Janssen, Amgen, Novartis, Exagen, Inova Diagnostics, AstraZeneca, Blackrock Pharma, Glenmark, and UCB.
REPORTING FROM FSR 2019
FDA advisors recommend nintedanib for SSc interstitial lung disease
The Food and Drug Administration Arthritis Advisory Committee recommended approval of nintedanib for the treatment of interstitial lung disease in patients with systemic sclerosis by a 10-7 vote on July 25, 2019. If the FDA acts in accord with the panel’s recommendation, it would make nintedanib (Ofev) the first drug to receive marketing approval for this indication.
Nintedanib has had FDA approval for treating idiopathic pulmonary fibrosis since 2014, and the manufacturer, Boehringer Ingelheim, designed the current pivotal trial with 576 patients to broaden the indication to patients with a different but similar fibrotic lung disease, interstitial lung disease (ILD), that is a common and eventually lethal complication of systemic sclerosis. The results of the pivotal study, the SENSCIS (Safety and Efficacy of Nintedanib in Systemic Sclerosis) trial, recently appeared in print and showed that patients randomized to receive 150 mg of nintedanib orally twice daily had an average 41-mL cut in the rate of loss of forced vital capacity (FVC) during 52 weeks on treatment, compared with those randomized to placebo. This was a 44% relative reduction in rate of FVC loss that was statistically significant for the study’s primary endpoint (N Engl J Med. 2019 June 27;380[26]:2518-28).
Votes in favor of FDA approval for many on the panel seemed to stem from a combination of the fact that nintedanib met the pivotal trial’s primary endpoint; which had been developed in consultation with the FDA, as well as the absence of any new safety signals when compared with prior experience using the drug; the lack of any treatment specifically recognized as beneficial to systemic sclerosis patients who develop the terminal complication of ILD; and the challenge of running a second trial in an orphan disease with an estimated U.S. prevalence of no more than 100,000 patients. Several committee members who voted in favor of nintedanib’s approval also voiced concern that the case in favor of its benefit/risk balance was not open and shut.
“I have a fair amount of apprehension,” admitted the committee’s chair, Daniel H. Solomon, MD, a rheumatologist and professor of medicine at Harvard Medical School, Boston. “I support the needs of patients, but we don’t want to give them false hope. We need to be able to say who will benefit, and the single study [SENSCIS] results don’t tell us how to use the drug. I want to understand which patient subgroups benefit.” He suggested that the FDA mandate further data collection through postmarketing studies.
Comments from panel members who voted against recommending approval generally focused on what was generally agreed to be a very modest treatment effect with a 41-mL average difference in FVC decline that has marginal clinical meaningfulness. Although the SENSCIS results met the study’s primary endpoint it was neutral for all prespecified secondary endpoints, including a measure of quality of life, although many on the panel agreed that a good measure of quality of life in the target patient population is lacking. Some sensitivity analyses run by FDA staffers also failed to confirm the primary result. Fewer questions arose about safety, although some panelists expressed concern about gastrointestinal effects, especially diarrhea, that seemed to link with treatment, as well as a signal for an increased incidence of pneumonia among patients on nintedanib. The data also showed a possible signal of reduced efficacy among patients who also received treatment with the immunosuppressive agent mycophenolate mofetil, often used off label to treat systemic sclerosis patients with ILD. However, a statistician involved in the discussion warned against overinterpreting this or other subgroup analyses.
Dr. Solomon has received research support from AbbVie, Amgen, Bristol-Myers Squibb, Genentech, Janssen, and Pfizer.
The Food and Drug Administration Arthritis Advisory Committee recommended approval of nintedanib for the treatment of interstitial lung disease in patients with systemic sclerosis by a 10-7 vote on July 25, 2019. If the FDA acts in accord with the panel’s recommendation, it would make nintedanib (Ofev) the first drug to receive marketing approval for this indication.
Nintedanib has had FDA approval for treating idiopathic pulmonary fibrosis since 2014, and the manufacturer, Boehringer Ingelheim, designed the current pivotal trial with 576 patients to broaden the indication to patients with a different but similar fibrotic lung disease, interstitial lung disease (ILD), that is a common and eventually lethal complication of systemic sclerosis. The results of the pivotal study, the SENSCIS (Safety and Efficacy of Nintedanib in Systemic Sclerosis) trial, recently appeared in print and showed that patients randomized to receive 150 mg of nintedanib orally twice daily had an average 41-mL cut in the rate of loss of forced vital capacity (FVC) during 52 weeks on treatment, compared with those randomized to placebo. This was a 44% relative reduction in rate of FVC loss that was statistically significant for the study’s primary endpoint (N Engl J Med. 2019 June 27;380[26]:2518-28).
Votes in favor of FDA approval for many on the panel seemed to stem from a combination of the fact that nintedanib met the pivotal trial’s primary endpoint; which had been developed in consultation with the FDA, as well as the absence of any new safety signals when compared with prior experience using the drug; the lack of any treatment specifically recognized as beneficial to systemic sclerosis patients who develop the terminal complication of ILD; and the challenge of running a second trial in an orphan disease with an estimated U.S. prevalence of no more than 100,000 patients. Several committee members who voted in favor of nintedanib’s approval also voiced concern that the case in favor of its benefit/risk balance was not open and shut.
“I have a fair amount of apprehension,” admitted the committee’s chair, Daniel H. Solomon, MD, a rheumatologist and professor of medicine at Harvard Medical School, Boston. “I support the needs of patients, but we don’t want to give them false hope. We need to be able to say who will benefit, and the single study [SENSCIS] results don’t tell us how to use the drug. I want to understand which patient subgroups benefit.” He suggested that the FDA mandate further data collection through postmarketing studies.
Comments from panel members who voted against recommending approval generally focused on what was generally agreed to be a very modest treatment effect with a 41-mL average difference in FVC decline that has marginal clinical meaningfulness. Although the SENSCIS results met the study’s primary endpoint it was neutral for all prespecified secondary endpoints, including a measure of quality of life, although many on the panel agreed that a good measure of quality of life in the target patient population is lacking. Some sensitivity analyses run by FDA staffers also failed to confirm the primary result. Fewer questions arose about safety, although some panelists expressed concern about gastrointestinal effects, especially diarrhea, that seemed to link with treatment, as well as a signal for an increased incidence of pneumonia among patients on nintedanib. The data also showed a possible signal of reduced efficacy among patients who also received treatment with the immunosuppressive agent mycophenolate mofetil, often used off label to treat systemic sclerosis patients with ILD. However, a statistician involved in the discussion warned against overinterpreting this or other subgroup analyses.
Dr. Solomon has received research support from AbbVie, Amgen, Bristol-Myers Squibb, Genentech, Janssen, and Pfizer.
The Food and Drug Administration Arthritis Advisory Committee recommended approval of nintedanib for the treatment of interstitial lung disease in patients with systemic sclerosis by a 10-7 vote on July 25, 2019. If the FDA acts in accord with the panel’s recommendation, it would make nintedanib (Ofev) the first drug to receive marketing approval for this indication.
Nintedanib has had FDA approval for treating idiopathic pulmonary fibrosis since 2014, and the manufacturer, Boehringer Ingelheim, designed the current pivotal trial with 576 patients to broaden the indication to patients with a different but similar fibrotic lung disease, interstitial lung disease (ILD), that is a common and eventually lethal complication of systemic sclerosis. The results of the pivotal study, the SENSCIS (Safety and Efficacy of Nintedanib in Systemic Sclerosis) trial, recently appeared in print and showed that patients randomized to receive 150 mg of nintedanib orally twice daily had an average 41-mL cut in the rate of loss of forced vital capacity (FVC) during 52 weeks on treatment, compared with those randomized to placebo. This was a 44% relative reduction in rate of FVC loss that was statistically significant for the study’s primary endpoint (N Engl J Med. 2019 June 27;380[26]:2518-28).
Votes in favor of FDA approval for many on the panel seemed to stem from a combination of the fact that nintedanib met the pivotal trial’s primary endpoint; which had been developed in consultation with the FDA, as well as the absence of any new safety signals when compared with prior experience using the drug; the lack of any treatment specifically recognized as beneficial to systemic sclerosis patients who develop the terminal complication of ILD; and the challenge of running a second trial in an orphan disease with an estimated U.S. prevalence of no more than 100,000 patients. Several committee members who voted in favor of nintedanib’s approval also voiced concern that the case in favor of its benefit/risk balance was not open and shut.
“I have a fair amount of apprehension,” admitted the committee’s chair, Daniel H. Solomon, MD, a rheumatologist and professor of medicine at Harvard Medical School, Boston. “I support the needs of patients, but we don’t want to give them false hope. We need to be able to say who will benefit, and the single study [SENSCIS] results don’t tell us how to use the drug. I want to understand which patient subgroups benefit.” He suggested that the FDA mandate further data collection through postmarketing studies.
Comments from panel members who voted against recommending approval generally focused on what was generally agreed to be a very modest treatment effect with a 41-mL average difference in FVC decline that has marginal clinical meaningfulness. Although the SENSCIS results met the study’s primary endpoint it was neutral for all prespecified secondary endpoints, including a measure of quality of life, although many on the panel agreed that a good measure of quality of life in the target patient population is lacking. Some sensitivity analyses run by FDA staffers also failed to confirm the primary result. Fewer questions arose about safety, although some panelists expressed concern about gastrointestinal effects, especially diarrhea, that seemed to link with treatment, as well as a signal for an increased incidence of pneumonia among patients on nintedanib. The data also showed a possible signal of reduced efficacy among patients who also received treatment with the immunosuppressive agent mycophenolate mofetil, often used off label to treat systemic sclerosis patients with ILD. However, a statistician involved in the discussion warned against overinterpreting this or other subgroup analyses.
Dr. Solomon has received research support from AbbVie, Amgen, Bristol-Myers Squibb, Genentech, Janssen, and Pfizer.
How common is accelerated knee OA?
TORONTO – Accelerated knee osteoarthritis – a particularly noxious form of the joint disease – occurred in more than one in seven women who developed knee osteoarthritis in the prospective, long-term Chingford Cohort Study, Jeffrey B. Driban, PhD, reported at the OARSI 2019 World Congress.
This finding from a unique prospective study of 1,003 middle-aged U.K. women who were followed for the development of knee osteoarthritis (OA) for 15 years is important because the participants represented a typical community-based population sample. And yet the Chingford results are consistent with and confirmatory of those found earlier in the Osteoarthritis Initiative, a U.S. cohort study of nearly 4,800 individuals, even though the Osteoarthritis Initiative featured a population enriched with established risk factors for knee OA, Dr. Driban explained at the meeting, sponsored by the Osteoarthritis Research Society International.
In Chingford, accelerated knee OA accounted for 15% of all incident cases of knee OA during follow-up, and for 17% of all newly affected knees, whereas 20% of incident knee OA in the Osteoarthritis Initiative was accelerated knee OA, noted Dr. Driban of Tufts University, Boston.
Accelerated knee OA is defined by rapidly progressive structural damage. Affected individuals streak from no radiographic evidence of knee OA to advanced-stage disease marked by a Kellgren-Lawrence score of 3 or more within 4 years, whereas the typical form of knee OA follows a more gradual course. Also, accelerated knee OA features greater pain and disability.
In the Chingford study, the cumulative incidence of accelerated knee OA was 3.9%, while typical knee OA occurred in 21.7% of women. During years 6-15 of follow-up, 21% of women with accelerated knee OA underwent total knee replacement, compared with 2% of those with typical knee OA and 0.9% of women without knee OA.
Dr. Driban reported having no financial conflicts regarding his analysis of the Chingford Cohort Study and the Osteoarthritis Initiative, supported by Arthritis Research UK and the National Institutes of Health, respectively.
SOURCE: Driban JB et al. Osteoarthritis Cartilage. 2019 Apr;27[suppl 1]:S250-S251, Abstract 352.
TORONTO – Accelerated knee osteoarthritis – a particularly noxious form of the joint disease – occurred in more than one in seven women who developed knee osteoarthritis in the prospective, long-term Chingford Cohort Study, Jeffrey B. Driban, PhD, reported at the OARSI 2019 World Congress.
This finding from a unique prospective study of 1,003 middle-aged U.K. women who were followed for the development of knee osteoarthritis (OA) for 15 years is important because the participants represented a typical community-based population sample. And yet the Chingford results are consistent with and confirmatory of those found earlier in the Osteoarthritis Initiative, a U.S. cohort study of nearly 4,800 individuals, even though the Osteoarthritis Initiative featured a population enriched with established risk factors for knee OA, Dr. Driban explained at the meeting, sponsored by the Osteoarthritis Research Society International.
In Chingford, accelerated knee OA accounted for 15% of all incident cases of knee OA during follow-up, and for 17% of all newly affected knees, whereas 20% of incident knee OA in the Osteoarthritis Initiative was accelerated knee OA, noted Dr. Driban of Tufts University, Boston.
Accelerated knee OA is defined by rapidly progressive structural damage. Affected individuals streak from no radiographic evidence of knee OA to advanced-stage disease marked by a Kellgren-Lawrence score of 3 or more within 4 years, whereas the typical form of knee OA follows a more gradual course. Also, accelerated knee OA features greater pain and disability.
In the Chingford study, the cumulative incidence of accelerated knee OA was 3.9%, while typical knee OA occurred in 21.7% of women. During years 6-15 of follow-up, 21% of women with accelerated knee OA underwent total knee replacement, compared with 2% of those with typical knee OA and 0.9% of women without knee OA.
Dr. Driban reported having no financial conflicts regarding his analysis of the Chingford Cohort Study and the Osteoarthritis Initiative, supported by Arthritis Research UK and the National Institutes of Health, respectively.
SOURCE: Driban JB et al. Osteoarthritis Cartilage. 2019 Apr;27[suppl 1]:S250-S251, Abstract 352.
TORONTO – Accelerated knee osteoarthritis – a particularly noxious form of the joint disease – occurred in more than one in seven women who developed knee osteoarthritis in the prospective, long-term Chingford Cohort Study, Jeffrey B. Driban, PhD, reported at the OARSI 2019 World Congress.
This finding from a unique prospective study of 1,003 middle-aged U.K. women who were followed for the development of knee osteoarthritis (OA) for 15 years is important because the participants represented a typical community-based population sample. And yet the Chingford results are consistent with and confirmatory of those found earlier in the Osteoarthritis Initiative, a U.S. cohort study of nearly 4,800 individuals, even though the Osteoarthritis Initiative featured a population enriched with established risk factors for knee OA, Dr. Driban explained at the meeting, sponsored by the Osteoarthritis Research Society International.
In Chingford, accelerated knee OA accounted for 15% of all incident cases of knee OA during follow-up, and for 17% of all newly affected knees, whereas 20% of incident knee OA in the Osteoarthritis Initiative was accelerated knee OA, noted Dr. Driban of Tufts University, Boston.
Accelerated knee OA is defined by rapidly progressive structural damage. Affected individuals streak from no radiographic evidence of knee OA to advanced-stage disease marked by a Kellgren-Lawrence score of 3 or more within 4 years, whereas the typical form of knee OA follows a more gradual course. Also, accelerated knee OA features greater pain and disability.
In the Chingford study, the cumulative incidence of accelerated knee OA was 3.9%, while typical knee OA occurred in 21.7% of women. During years 6-15 of follow-up, 21% of women with accelerated knee OA underwent total knee replacement, compared with 2% of those with typical knee OA and 0.9% of women without knee OA.
Dr. Driban reported having no financial conflicts regarding his analysis of the Chingford Cohort Study and the Osteoarthritis Initiative, supported by Arthritis Research UK and the National Institutes of Health, respectively.
SOURCE: Driban JB et al. Osteoarthritis Cartilage. 2019 Apr;27[suppl 1]:S250-S251, Abstract 352.
REPORTING FROM OARSI 2019
Hadlima approved as fourth adalimumab biosimilar in U.S.
The Food and Drug Administration has approved the Humira biosimilar Hadlima (adalimumab-bwwd), making it the fourth adalimumab biosimilar approved in the United States, the agency announced.
Hadlima is approved for seven of the reference product’s indications, which include rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, and ulcerative colitis.
The product will launch in the United States on June 30, 2023. Other FDA-approved adalimumab biosimilars – Amjevita (adalimunab-atto), Cyltezo (adalimumab-adbm), Hyrimoz (adalimumab-adaz) – similarly will not reach the U.S. market until 2023.
Hadlima is developed by Samsung Bioepis and commercialized by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co.
*This article was updated on July 24, 2019.
The Food and Drug Administration has approved the Humira biosimilar Hadlima (adalimumab-bwwd), making it the fourth adalimumab biosimilar approved in the United States, the agency announced.
Hadlima is approved for seven of the reference product’s indications, which include rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, and ulcerative colitis.
The product will launch in the United States on June 30, 2023. Other FDA-approved adalimumab biosimilars – Amjevita (adalimunab-atto), Cyltezo (adalimumab-adbm), Hyrimoz (adalimumab-adaz) – similarly will not reach the U.S. market until 2023.
Hadlima is developed by Samsung Bioepis and commercialized by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co.
*This article was updated on July 24, 2019.
The Food and Drug Administration has approved the Humira biosimilar Hadlima (adalimumab-bwwd), making it the fourth adalimumab biosimilar approved in the United States, the agency announced.
Hadlima is approved for seven of the reference product’s indications, which include rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, adult Crohn’s disease, and ulcerative colitis.
The product will launch in the United States on June 30, 2023. Other FDA-approved adalimumab biosimilars – Amjevita (adalimunab-atto), Cyltezo (adalimumab-adbm), Hyrimoz (adalimumab-adaz) – similarly will not reach the U.S. market until 2023.
Hadlima is developed by Samsung Bioepis and commercialized by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co.
*This article was updated on July 24, 2019.
FDA approves Otezla for treatment of Behçet’s-associated oral ulcers
The Food and Drug Administration has expanded the indication for apremilast (Otezla) to include the treatment of oral ulcers associated with Behçet’s disease in adults, according to an announcement from the manufacturer, Celgene.
FDA approval was based on results of the randomized, placebo-controlled, double-blind, phase 3 RELIEF trial, in which 207 patients with Behçet’s disease with active ulcers underwent treatment for 12 weeks with 30 mg apremilast or placebo. When measured on a visual analog scale, the reduction in pain from oral ulcers after 12 weeks in patients receiving apremilast was 42.7 points, compared with 18.7 points in the placebo group. Just over 50% of apremilast patients achieved complete response by week 12, compared with 22.3% in the placebo group.
The most common adverse events associated with apremilast during RELIEF were diarrhea, nausea, headache, and upper respiratory infection. This was consistent with apremilast’s known safety profile.
Apremilast is also indicated for treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy, and for patients with active psoriatic arthritis.
“Oral ulcers are a recurring and debilitating manifestation that affects nearly everyone living with Behçet’s disease and have an important negative impact on the quality of life for these patients. In the clinical trial, Otezla demonstrated improvements in measures of oral ulcers at week 12. Otezla has the potential to be a needed treatment option for U.S. patients and their physicians, who previously had limited options available,” Yusuf Yazici, MD, clinical associate professor in the department of medicine at New York University, said in the announcement.
The Food and Drug Administration has expanded the indication for apremilast (Otezla) to include the treatment of oral ulcers associated with Behçet’s disease in adults, according to an announcement from the manufacturer, Celgene.
FDA approval was based on results of the randomized, placebo-controlled, double-blind, phase 3 RELIEF trial, in which 207 patients with Behçet’s disease with active ulcers underwent treatment for 12 weeks with 30 mg apremilast or placebo. When measured on a visual analog scale, the reduction in pain from oral ulcers after 12 weeks in patients receiving apremilast was 42.7 points, compared with 18.7 points in the placebo group. Just over 50% of apremilast patients achieved complete response by week 12, compared with 22.3% in the placebo group.
The most common adverse events associated with apremilast during RELIEF were diarrhea, nausea, headache, and upper respiratory infection. This was consistent with apremilast’s known safety profile.
Apremilast is also indicated for treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy, and for patients with active psoriatic arthritis.
“Oral ulcers are a recurring and debilitating manifestation that affects nearly everyone living with Behçet’s disease and have an important negative impact on the quality of life for these patients. In the clinical trial, Otezla demonstrated improvements in measures of oral ulcers at week 12. Otezla has the potential to be a needed treatment option for U.S. patients and their physicians, who previously had limited options available,” Yusuf Yazici, MD, clinical associate professor in the department of medicine at New York University, said in the announcement.
The Food and Drug Administration has expanded the indication for apremilast (Otezla) to include the treatment of oral ulcers associated with Behçet’s disease in adults, according to an announcement from the manufacturer, Celgene.
FDA approval was based on results of the randomized, placebo-controlled, double-blind, phase 3 RELIEF trial, in which 207 patients with Behçet’s disease with active ulcers underwent treatment for 12 weeks with 30 mg apremilast or placebo. When measured on a visual analog scale, the reduction in pain from oral ulcers after 12 weeks in patients receiving apremilast was 42.7 points, compared with 18.7 points in the placebo group. Just over 50% of apremilast patients achieved complete response by week 12, compared with 22.3% in the placebo group.
The most common adverse events associated with apremilast during RELIEF were diarrhea, nausea, headache, and upper respiratory infection. This was consistent with apremilast’s known safety profile.
Apremilast is also indicated for treatment of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy, and for patients with active psoriatic arthritis.
“Oral ulcers are a recurring and debilitating manifestation that affects nearly everyone living with Behçet’s disease and have an important negative impact on the quality of life for these patients. In the clinical trial, Otezla demonstrated improvements in measures of oral ulcers at week 12. Otezla has the potential to be a needed treatment option for U.S. patients and their physicians, who previously had limited options available,” Yusuf Yazici, MD, clinical associate professor in the department of medicine at New York University, said in the announcement.
Filgotinib fares well in RA trial of inadequate methotrexate responders
MADRID – (cDMARD) in a phase 3 study.
The primary outcome results of the FINCH 1 study, which were presented at the European Congress of Rheumatology, showed that significantly more patients treated with filgotinib than placebo were able to achieve 20% improvement in American College of Rheumatology response criteria (ACR20).
At week 12, an ACR20 response was achieved by 69.8% of 480 patients treated with filgotinib 100 mg/day, 76.6% of 475 treated with filgotinib 200 mg/day, and 49.9% of 475 given a matching daily placebo (P less than .0001 for both comparisons). Adalimumab (Humira; 40 mg every 2 weeks) was used as an active comparator in the trial, and 70.8% of 325 patients treated with this biologic drug achieved an ACR20.
Similar patterns were seen for the ACR50 and ACR70 responses: more than 50% of patients treated with filgotinib or adalimumab achieved an ACR50 versus 33.3% of patients treated with placebo. The ACR70 response rate was more than 30% in patients treated with either biologic, compared against 14.9% with placebo.
The percentages of patients in the filgotinib 100-mg, filgotinib 200-mg, adalimumab, and placebo arms who achieved a 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) of 3.2 or less at 12 weeks were 38.8%, 49.9%, 43.4%, and 23.4%. At 24 weeks, the rates were 53.1%, 60.6%, 50.5%, and 33.7%.
At 12 weeks, analysis showed that filgotinib 200 mg was noninferior to adalimumab in achieving a DAS28-CRP of 3.2 or less.
These study data, together with the results of two other phase 3 studies – FINCH 2 and FINCH 3 – will be used to submit a new drug application to the Food and Drug Administration for the use of filgotinib in the treatment of RA later this year, the drug’s developer, Gilead Sciences, announced on July 1. Each of the trials has addressed a different population of RA patients; while FINCH 1 looked at inadequate responders to methotrexate, FINCH 2 looked at those with an inadequate response to biologic DMARDs, and FINCH 3 recruited RA patients who were naive to methotrexate therapy.
FINCH 1 was a 1-year study, said presenting study investigator Bernard Combe, MD, PhD, professor of rheumatology at Montpellier (France) University and head of the bone and joint diseases department at the university. A total of 1,759 patients were randomized and 1,755 received study treatment with filgotinib, adalimumab, or placebo in addition to methotrexate. Data for the first 24 weeks were presented.
Dr. Combe and coauthors used hierarchical statistical testing to first compare the 200-mg dose versus placebo for the primary endpoint, and then, if positive, the percentage of patients at 12 weeks achieving a DAS28-CRP score of 3.2 or less and the score at 12 weeks on the Health Assessment Questionnaire – Disability Index (HAQ-DI), and then the DAS28-CRP again at 24 weeks. This was repeated with the 100-mg dose until finally noninferiority of the 200-mg dose versus adalimumab in DAS28-CRP at 12 weeks was tested.
Other findings included a significant reduction in radiographic progression at week 24 with both doses of filgotinib versus placebo; improvements in HAQ-DI and Functional Assessment of Chronic Illness Therapy-Fatigue scores also were seen at 12 and 24 weeks.
“The selective JAK1 inhibitor filgotinib, at doses of 200 and 100 mg per day, led to significant improvement in symptoms of RA patients with inadequate response to methotrexate,” Dr. Combe concluded. It “prevented radiographic progression, and improved physical function compared to placebo.”
Importantly, the drug was “well tolerated” and “a low frequency of venous thrombotic events, serious infections, and other adverse events of interest was observed.”
Commenting on the study during the Q&A session that followed Dr. Combe’s presentation, Roy M. Fleischmann, MD, clinical professor of medicine at the University of Texas Southwestern Medical Center in Dallas, noted that the choice of DAS28-CRP was “very unusual” as an endpoint after the ACR20 as it’s “almost always an ACR50 or 70.” There was also a “very high placebo response.”
Dr. Combe responded that he “wasn’t so surprised by the high placebo response. You know that this has been shown previously in some other trials.” As to why, he noted that there was an ongoing analysis but also proposed two reasons: First, the geographic region – with more than 1,700 patients from all over the world included in the trial, there could be variation in the placebo responses. Second, methotrexate might still be having a minor effect when the trial started.
The study was sponsored by Gilead Sciences in collaboration with Galapagos NV. Dr. Combe has received honoraria from AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, UCB, Genzyme, Sanofi, Regeneron, Sun Pharma Advanced Research, Boehringer Ingelheim, and Flexion. Dr. Combe is a shareholder in Novartis.
SOURCE: Combe B et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):77-8. Abstract LB0001, doi: 10.1136/annrheumdis-2019-eular.8676
MADRID – (cDMARD) in a phase 3 study.
The primary outcome results of the FINCH 1 study, which were presented at the European Congress of Rheumatology, showed that significantly more patients treated with filgotinib than placebo were able to achieve 20% improvement in American College of Rheumatology response criteria (ACR20).
At week 12, an ACR20 response was achieved by 69.8% of 480 patients treated with filgotinib 100 mg/day, 76.6% of 475 treated with filgotinib 200 mg/day, and 49.9% of 475 given a matching daily placebo (P less than .0001 for both comparisons). Adalimumab (Humira; 40 mg every 2 weeks) was used as an active comparator in the trial, and 70.8% of 325 patients treated with this biologic drug achieved an ACR20.
Similar patterns were seen for the ACR50 and ACR70 responses: more than 50% of patients treated with filgotinib or adalimumab achieved an ACR50 versus 33.3% of patients treated with placebo. The ACR70 response rate was more than 30% in patients treated with either biologic, compared against 14.9% with placebo.
The percentages of patients in the filgotinib 100-mg, filgotinib 200-mg, adalimumab, and placebo arms who achieved a 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) of 3.2 or less at 12 weeks were 38.8%, 49.9%, 43.4%, and 23.4%. At 24 weeks, the rates were 53.1%, 60.6%, 50.5%, and 33.7%.
At 12 weeks, analysis showed that filgotinib 200 mg was noninferior to adalimumab in achieving a DAS28-CRP of 3.2 or less.
These study data, together with the results of two other phase 3 studies – FINCH 2 and FINCH 3 – will be used to submit a new drug application to the Food and Drug Administration for the use of filgotinib in the treatment of RA later this year, the drug’s developer, Gilead Sciences, announced on July 1. Each of the trials has addressed a different population of RA patients; while FINCH 1 looked at inadequate responders to methotrexate, FINCH 2 looked at those with an inadequate response to biologic DMARDs, and FINCH 3 recruited RA patients who were naive to methotrexate therapy.
FINCH 1 was a 1-year study, said presenting study investigator Bernard Combe, MD, PhD, professor of rheumatology at Montpellier (France) University and head of the bone and joint diseases department at the university. A total of 1,759 patients were randomized and 1,755 received study treatment with filgotinib, adalimumab, or placebo in addition to methotrexate. Data for the first 24 weeks were presented.
Dr. Combe and coauthors used hierarchical statistical testing to first compare the 200-mg dose versus placebo for the primary endpoint, and then, if positive, the percentage of patients at 12 weeks achieving a DAS28-CRP score of 3.2 or less and the score at 12 weeks on the Health Assessment Questionnaire – Disability Index (HAQ-DI), and then the DAS28-CRP again at 24 weeks. This was repeated with the 100-mg dose until finally noninferiority of the 200-mg dose versus adalimumab in DAS28-CRP at 12 weeks was tested.
Other findings included a significant reduction in radiographic progression at week 24 with both doses of filgotinib versus placebo; improvements in HAQ-DI and Functional Assessment of Chronic Illness Therapy-Fatigue scores also were seen at 12 and 24 weeks.
“The selective JAK1 inhibitor filgotinib, at doses of 200 and 100 mg per day, led to significant improvement in symptoms of RA patients with inadequate response to methotrexate,” Dr. Combe concluded. It “prevented radiographic progression, and improved physical function compared to placebo.”
Importantly, the drug was “well tolerated” and “a low frequency of venous thrombotic events, serious infections, and other adverse events of interest was observed.”
Commenting on the study during the Q&A session that followed Dr. Combe’s presentation, Roy M. Fleischmann, MD, clinical professor of medicine at the University of Texas Southwestern Medical Center in Dallas, noted that the choice of DAS28-CRP was “very unusual” as an endpoint after the ACR20 as it’s “almost always an ACR50 or 70.” There was also a “very high placebo response.”
Dr. Combe responded that he “wasn’t so surprised by the high placebo response. You know that this has been shown previously in some other trials.” As to why, he noted that there was an ongoing analysis but also proposed two reasons: First, the geographic region – with more than 1,700 patients from all over the world included in the trial, there could be variation in the placebo responses. Second, methotrexate might still be having a minor effect when the trial started.
The study was sponsored by Gilead Sciences in collaboration with Galapagos NV. Dr. Combe has received honoraria from AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, UCB, Genzyme, Sanofi, Regeneron, Sun Pharma Advanced Research, Boehringer Ingelheim, and Flexion. Dr. Combe is a shareholder in Novartis.
SOURCE: Combe B et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):77-8. Abstract LB0001, doi: 10.1136/annrheumdis-2019-eular.8676
MADRID – (cDMARD) in a phase 3 study.
The primary outcome results of the FINCH 1 study, which were presented at the European Congress of Rheumatology, showed that significantly more patients treated with filgotinib than placebo were able to achieve 20% improvement in American College of Rheumatology response criteria (ACR20).
At week 12, an ACR20 response was achieved by 69.8% of 480 patients treated with filgotinib 100 mg/day, 76.6% of 475 treated with filgotinib 200 mg/day, and 49.9% of 475 given a matching daily placebo (P less than .0001 for both comparisons). Adalimumab (Humira; 40 mg every 2 weeks) was used as an active comparator in the trial, and 70.8% of 325 patients treated with this biologic drug achieved an ACR20.
Similar patterns were seen for the ACR50 and ACR70 responses: more than 50% of patients treated with filgotinib or adalimumab achieved an ACR50 versus 33.3% of patients treated with placebo. The ACR70 response rate was more than 30% in patients treated with either biologic, compared against 14.9% with placebo.
The percentages of patients in the filgotinib 100-mg, filgotinib 200-mg, adalimumab, and placebo arms who achieved a 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP) of 3.2 or less at 12 weeks were 38.8%, 49.9%, 43.4%, and 23.4%. At 24 weeks, the rates were 53.1%, 60.6%, 50.5%, and 33.7%.
At 12 weeks, analysis showed that filgotinib 200 mg was noninferior to adalimumab in achieving a DAS28-CRP of 3.2 or less.
These study data, together with the results of two other phase 3 studies – FINCH 2 and FINCH 3 – will be used to submit a new drug application to the Food and Drug Administration for the use of filgotinib in the treatment of RA later this year, the drug’s developer, Gilead Sciences, announced on July 1. Each of the trials has addressed a different population of RA patients; while FINCH 1 looked at inadequate responders to methotrexate, FINCH 2 looked at those with an inadequate response to biologic DMARDs, and FINCH 3 recruited RA patients who were naive to methotrexate therapy.
FINCH 1 was a 1-year study, said presenting study investigator Bernard Combe, MD, PhD, professor of rheumatology at Montpellier (France) University and head of the bone and joint diseases department at the university. A total of 1,759 patients were randomized and 1,755 received study treatment with filgotinib, adalimumab, or placebo in addition to methotrexate. Data for the first 24 weeks were presented.
Dr. Combe and coauthors used hierarchical statistical testing to first compare the 200-mg dose versus placebo for the primary endpoint, and then, if positive, the percentage of patients at 12 weeks achieving a DAS28-CRP score of 3.2 or less and the score at 12 weeks on the Health Assessment Questionnaire – Disability Index (HAQ-DI), and then the DAS28-CRP again at 24 weeks. This was repeated with the 100-mg dose until finally noninferiority of the 200-mg dose versus adalimumab in DAS28-CRP at 12 weeks was tested.
Other findings included a significant reduction in radiographic progression at week 24 with both doses of filgotinib versus placebo; improvements in HAQ-DI and Functional Assessment of Chronic Illness Therapy-Fatigue scores also were seen at 12 and 24 weeks.
“The selective JAK1 inhibitor filgotinib, at doses of 200 and 100 mg per day, led to significant improvement in symptoms of RA patients with inadequate response to methotrexate,” Dr. Combe concluded. It “prevented radiographic progression, and improved physical function compared to placebo.”
Importantly, the drug was “well tolerated” and “a low frequency of venous thrombotic events, serious infections, and other adverse events of interest was observed.”
Commenting on the study during the Q&A session that followed Dr. Combe’s presentation, Roy M. Fleischmann, MD, clinical professor of medicine at the University of Texas Southwestern Medical Center in Dallas, noted that the choice of DAS28-CRP was “very unusual” as an endpoint after the ACR20 as it’s “almost always an ACR50 or 70.” There was also a “very high placebo response.”
Dr. Combe responded that he “wasn’t so surprised by the high placebo response. You know that this has been shown previously in some other trials.” As to why, he noted that there was an ongoing analysis but also proposed two reasons: First, the geographic region – with more than 1,700 patients from all over the world included in the trial, there could be variation in the placebo responses. Second, methotrexate might still be having a minor effect when the trial started.
The study was sponsored by Gilead Sciences in collaboration with Galapagos NV. Dr. Combe has received honoraria from AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, UCB, Genzyme, Sanofi, Regeneron, Sun Pharma Advanced Research, Boehringer Ingelheim, and Flexion. Dr. Combe is a shareholder in Novartis.
SOURCE: Combe B et al. Ann Rheum Dis. Jun 2019;78(Suppl 2):77-8. Abstract LB0001, doi: 10.1136/annrheumdis-2019-eular.8676
REPORTING FROM EULAR 2019 CONGRESS