Pharmacology

For patients with heavily-pretreated multiple myeloma, the early and deep responses seen with the novel chimeric antigen receptor T-cell (CAR T-cell) construct ciltacabtagene autoleucel (cilta-cel) have also been durable, according to investigators in the CARTITUDE-1 trial.

Among 97 patients with multiple myeloma that had progressed on three or more prior lines of therapy or following treatment with at least two lines of therapy with a proteasome inhibitor and immunomodulating agent, the overall response rate (ORR) was 96.9%, with a median duration of response not reached after a median of 12.4 months of follow-up, reported Deepu Madduri, MD of Mount Sinai Medical Center in New York, and colleagues.

“We saw how heavily pretreated these patients were, and to see a one-time treatment get these kind of response rates is quite exceptional. What’s even more impressive is that 72% of these patients were still maintaining their response at the time of data cutoff,“ she said in an oral abstract presented during the virtual American Society of Hematology annual meeting.

Cilta-cel is a second-generation CAR T containing two single-domain antibodies targeted against B-cell maturation protein (BCMA). BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells.

As previously reported, the same CAR T-cell construct showed a high overall response with manageable toxicities in 74 patients with relapsed/refractory multiple myeloma.

Ciltacabtagene autoleucel was granted a breakthrough therapy designation for relapsed/refractory multiple myeloma by the Food and Drug Administration in December 2019, a priority medicines (PRIME) designation by the European Medicines Agency in April 2019, and breakthrough designation in China in September 2020.

At the 2019 ASH annual meeting, Dr. Madduri reported phase 1b results from the trial, which showed that for 29 patients with heavily pretreated, relapsed/refractory multiple myeloma, the ORR at 6 months median follow-up was 100%, including 69% complete responses, with 27 patients remaining free of disease progression.
 

Combined data

For the 2020 ASH annual meeting, Dr. Madduri reported combined results from phases 1b and 2 of the CARTITUDE-1 study.

The investigators enrolled patients with multiple myeloma with measurable diseases as assessed by M-protein or serum free light chain levels who had experienced disease progression on at least three prior lines of therapy, or whose disease was refractory to at least two lines of therapy with a proteasome inhibitor, immunomodulatory drug, and an anti-CD38 antibody.

Patients underwent apheresis for T-cell collection, with bridging therapy allowed until the expanded T cells could be delivered.

Following T-cell depletion with cyclophosphamide 300 mg/m² and fludarabine 30 mg/m² over 3 days, patients received a single weight-based infusion (compared with fixed-dose infusions used with other CAR T-cell constructs).

The dose was targeted at 0.75x106 CAR-positive cells/kg, with a target range of 0.5–1.0x106, administered 5-7 days after the start of the conditioning regimen.

Of the 101 patients who underwent lymphodepletion, 97 (29 in phase 1b and 68 in phase 2) were treated with cilta-cel. Five of the patients in phase 1b and nine in phase 2 died on study, five of whom succumbed to progressive disease, and three due to adverse events unrelated to treatment. The remaining six patients died from treatment-related causes, including two patients from sepsis or septic shock, and one each from the cytokine release syndrome (CRS)/hemophagocytic lymphohistiocytosis (HLH), lung abscess, respiratory failure, and neurotoxicity.

At the time of data cutoff, 83 patients remained on study.
 

High ORR

The ORR was 96.9% (94 of 97 patients), comprising 67% stringent complete responses (sCR), 25.8% very good partial responses (VGPR), and 4.1% partial responses (PR).

Among 57 patients evaluable for minimal residual disease (MRD), 53 (93%) were MRD negative. Of this group, 49 had a VGPR or better.

The median time to first response was 1 month (range 0.9 to 8.5 months). At the time of data cutoff 70 patients had an ongoing response.

Among patients followed for a minimum of 6 months, most had cilta-cel CAR T-cells below the level of quantification (2 cells per microliter) in peripheral blood.

At a median follow-up of 12.4 months, 12-month overall progression-free survival rate was 76%, with the median PFS not reached. The 12-month overall survival rate was 88.5%, with the median OS not reached.
 

Safety data

All patients had at least one hematologic adverse event, 96 of which were grade 3 or 4 in severity. The events include neutropenia, anemia, thrombocytopenia, leukopenia, and lymphopenia. The median time to recovery was 2 weeks for grade 3 or 4 neutropenia and 4 weeks for thrombocytopenia.

Infections of any grade occurred in 57.7% of patients, including grade 3/4 pneumonia in 8.2% and grade 3/4 sepsis in 4.1%.

Grade 3 or 4 nonhematologic toxicities were uncommon, Dr. Madduri noted.

CRS of any grade occurred in 92 patients, but only 4 had grade 3 or 4 CRS.

Neurotoxicities occurred in 20 patients, of whom 10 had grade 3 or 4 neurotoxicity.

Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 16 patients, with 2 having grade 3 or greater ICANS. Other neurotoxicities of any grade, many which overlapped with ICANS, occurred in 12 patients, with 9 having grade 3 or 4 neurotoxicity.

The median time to ICANS onset was 8 days, with a median time to recovery of 4 days. Other neurotoxicities took longer to manifest and disappear, however, with a median time to onset of 27 days, and median time to recovery of 75 days.
 

Neurotoxicity mechanism questioned

In the question-and-answer session following her presentation, an audience member asked whether the investigators had any insights into the mechanism underlying the non-ICANS neurotoxicities they saw.

“We saw no clear etiology in the other neurotoxicities, but we saw that maybe there could be some mild associations with high tumor burden, prior CRS, ICANS, or even the higher expansion and persistence of these cells,” Dr. Madduri replied.

She noted that subsequent to these findings, the investigators have implemented mitigation strategies including allowing patients to have more bridging chemotherapy, more aggressive steroid use for early ICANS, and extensive monitoring.

Eric Smith, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, said that the non-ICANS neurotoxicity profile of cilta-cel was different from that seen in other CAR T-cell trials, and asked how it compared to that of bi-specific BCMA/CD3 CAR T constructs.

“We did see some nerve palsies and peripheral motor neuropathy, but it wasn’t that many patients, and it’s really hard to compare what happened here with the bi-specifics, as every product is very different,” she said.

The study was sponsored by Janssen Research & Development and Legend Biotech. Dr. Madduri disclosed honoraria, consultancy, and speakers bureau activities for those companies and others.
 

SOURCE: Madduri D et al. ASH 2020. Abstract 177.

For patients with heavily-pretreated multiple myeloma, the early and deep responses seen with the novel chimeric antigen receptor T-cell (CAR T-cell) construct ciltacabtagene autoleucel (cilta-cel) have also been durable, according to investigators in the CARTITUDE-1 trial.

Among 97 patients with multiple myeloma that had progressed on three or more prior lines of therapy or following treatment with at least two lines of therapy with a proteasome inhibitor and immunomodulating agent, the overall response rate (ORR) was 96.9%, with a median duration of response not reached after a median of 12.4 months of follow-up, reported Deepu Madduri, MD of Mount Sinai Medical Center in New York, and colleagues.

“We saw how heavily pretreated these patients were, and to see a one-time treatment get these kind of response rates is quite exceptional. What’s even more impressive is that 72% of these patients were still maintaining their response at the time of data cutoff,“ she said in an oral abstract presented during the virtual American Society of Hematology annual meeting.

Cilta-cel is a second-generation CAR T containing two single-domain antibodies targeted against B-cell maturation protein (BCMA). BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells.

As previously reported, the same CAR T-cell construct showed a high overall response with manageable toxicities in 74 patients with relapsed/refractory multiple myeloma.

Ciltacabtagene autoleucel was granted a breakthrough therapy designation for relapsed/refractory multiple myeloma by the Food and Drug Administration in December 2019, a priority medicines (PRIME) designation by the European Medicines Agency in April 2019, and breakthrough designation in China in September 2020.

At the 2019 ASH annual meeting, Dr. Madduri reported phase 1b results from the trial, which showed that for 29 patients with heavily pretreated, relapsed/refractory multiple myeloma, the ORR at 6 months median follow-up was 100%, including 69% complete responses, with 27 patients remaining free of disease progression.
 

Combined data

For the 2020 ASH annual meeting, Dr. Madduri reported combined results from phases 1b and 2 of the CARTITUDE-1 study.

The investigators enrolled patients with multiple myeloma with measurable diseases as assessed by M-protein or serum free light chain levels who had experienced disease progression on at least three prior lines of therapy, or whose disease was refractory to at least two lines of therapy with a proteasome inhibitor, immunomodulatory drug, and an anti-CD38 antibody.

Patients underwent apheresis for T-cell collection, with bridging therapy allowed until the expanded T cells could be delivered.

Following T-cell depletion with cyclophosphamide 300 mg/m² and fludarabine 30 mg/m² over 3 days, patients received a single weight-based infusion (compared with fixed-dose infusions used with other CAR T-cell constructs).

The dose was targeted at 0.75x106 CAR-positive cells/kg, with a target range of 0.5–1.0x106, administered 5-7 days after the start of the conditioning regimen.

Of the 101 patients who underwent lymphodepletion, 97 (29 in phase 1b and 68 in phase 2) were treated with cilta-cel. Five of the patients in phase 1b and nine in phase 2 died on study, five of whom succumbed to progressive disease, and three due to adverse events unrelated to treatment. The remaining six patients died from treatment-related causes, including two patients from sepsis or septic shock, and one each from the cytokine release syndrome (CRS)/hemophagocytic lymphohistiocytosis (HLH), lung abscess, respiratory failure, and neurotoxicity.

At the time of data cutoff, 83 patients remained on study.
 

High ORR

The ORR was 96.9% (94 of 97 patients), comprising 67% stringent complete responses (sCR), 25.8% very good partial responses (VGPR), and 4.1% partial responses (PR).

Among 57 patients evaluable for minimal residual disease (MRD), 53 (93%) were MRD negative. Of this group, 49 had a VGPR or better.

The median time to first response was 1 month (range 0.9 to 8.5 months). At the time of data cutoff 70 patients had an ongoing response.

Among patients followed for a minimum of 6 months, most had cilta-cel CAR T-cells below the level of quantification (2 cells per microliter) in peripheral blood.

At a median follow-up of 12.4 months, 12-month overall progression-free survival rate was 76%, with the median PFS not reached. The 12-month overall survival rate was 88.5%, with the median OS not reached.
 

Safety data

All patients had at least one hematologic adverse event, 96 of which were grade 3 or 4 in severity. The events include neutropenia, anemia, thrombocytopenia, leukopenia, and lymphopenia. The median time to recovery was 2 weeks for grade 3 or 4 neutropenia and 4 weeks for thrombocytopenia.

Infections of any grade occurred in 57.7% of patients, including grade 3/4 pneumonia in 8.2% and grade 3/4 sepsis in 4.1%.

Grade 3 or 4 nonhematologic toxicities were uncommon, Dr. Madduri noted.

CRS of any grade occurred in 92 patients, but only 4 had grade 3 or 4 CRS.

Neurotoxicities occurred in 20 patients, of whom 10 had grade 3 or 4 neurotoxicity.

Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 16 patients, with 2 having grade 3 or greater ICANS. Other neurotoxicities of any grade, many which overlapped with ICANS, occurred in 12 patients, with 9 having grade 3 or 4 neurotoxicity.

The median time to ICANS onset was 8 days, with a median time to recovery of 4 days. Other neurotoxicities took longer to manifest and disappear, however, with a median time to onset of 27 days, and median time to recovery of 75 days.
 

Neurotoxicity mechanism questioned

In the question-and-answer session following her presentation, an audience member asked whether the investigators had any insights into the mechanism underlying the non-ICANS neurotoxicities they saw.

“We saw no clear etiology in the other neurotoxicities, but we saw that maybe there could be some mild associations with high tumor burden, prior CRS, ICANS, or even the higher expansion and persistence of these cells,” Dr. Madduri replied.

She noted that subsequent to these findings, the investigators have implemented mitigation strategies including allowing patients to have more bridging chemotherapy, more aggressive steroid use for early ICANS, and extensive monitoring.

Eric Smith, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, said that the non-ICANS neurotoxicity profile of cilta-cel was different from that seen in other CAR T-cell trials, and asked how it compared to that of bi-specific BCMA/CD3 CAR T constructs.

“We did see some nerve palsies and peripheral motor neuropathy, but it wasn’t that many patients, and it’s really hard to compare what happened here with the bi-specifics, as every product is very different,” she said.

The study was sponsored by Janssen Research & Development and Legend Biotech. Dr. Madduri disclosed honoraria, consultancy, and speakers bureau activities for those companies and others.
 

SOURCE: Madduri D et al. ASH 2020. Abstract 177.

For patients with heavily-pretreated multiple myeloma, the early and deep responses seen with the novel chimeric antigen receptor T-cell (CAR T-cell) construct ciltacabtagene autoleucel (cilta-cel) have also been durable, according to investigators in the CARTITUDE-1 trial.

Among 97 patients with multiple myeloma that had progressed on three or more prior lines of therapy or following treatment with at least two lines of therapy with a proteasome inhibitor and immunomodulating agent, the overall response rate (ORR) was 96.9%, with a median duration of response not reached after a median of 12.4 months of follow-up, reported Deepu Madduri, MD of Mount Sinai Medical Center in New York, and colleagues.

“We saw how heavily pretreated these patients were, and to see a one-time treatment get these kind of response rates is quite exceptional. What’s even more impressive is that 72% of these patients were still maintaining their response at the time of data cutoff,“ she said in an oral abstract presented during the virtual American Society of Hematology annual meeting.

Cilta-cel is a second-generation CAR T containing two single-domain antibodies targeted against B-cell maturation protein (BCMA). BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells.

As previously reported, the same CAR T-cell construct showed a high overall response with manageable toxicities in 74 patients with relapsed/refractory multiple myeloma.

Ciltacabtagene autoleucel was granted a breakthrough therapy designation for relapsed/refractory multiple myeloma by the Food and Drug Administration in December 2019, a priority medicines (PRIME) designation by the European Medicines Agency in April 2019, and breakthrough designation in China in September 2020.

At the 2019 ASH annual meeting, Dr. Madduri reported phase 1b results from the trial, which showed that for 29 patients with heavily pretreated, relapsed/refractory multiple myeloma, the ORR at 6 months median follow-up was 100%, including 69% complete responses, with 27 patients remaining free of disease progression.
 

Combined data

For the 2020 ASH annual meeting, Dr. Madduri reported combined results from phases 1b and 2 of the CARTITUDE-1 study.

The investigators enrolled patients with multiple myeloma with measurable diseases as assessed by M-protein or serum free light chain levels who had experienced disease progression on at least three prior lines of therapy, or whose disease was refractory to at least two lines of therapy with a proteasome inhibitor, immunomodulatory drug, and an anti-CD38 antibody.

Patients underwent apheresis for T-cell collection, with bridging therapy allowed until the expanded T cells could be delivered.

Following T-cell depletion with cyclophosphamide 300 mg/m² and fludarabine 30 mg/m² over 3 days, patients received a single weight-based infusion (compared with fixed-dose infusions used with other CAR T-cell constructs).

The dose was targeted at 0.75x106 CAR-positive cells/kg, with a target range of 0.5–1.0x106, administered 5-7 days after the start of the conditioning regimen.

Of the 101 patients who underwent lymphodepletion, 97 (29 in phase 1b and 68 in phase 2) were treated with cilta-cel. Five of the patients in phase 1b and nine in phase 2 died on study, five of whom succumbed to progressive disease, and three due to adverse events unrelated to treatment. The remaining six patients died from treatment-related causes, including two patients from sepsis or septic shock, and one each from the cytokine release syndrome (CRS)/hemophagocytic lymphohistiocytosis (HLH), lung abscess, respiratory failure, and neurotoxicity.

At the time of data cutoff, 83 patients remained on study.
 

High ORR

The ORR was 96.9% (94 of 97 patients), comprising 67% stringent complete responses (sCR), 25.8% very good partial responses (VGPR), and 4.1% partial responses (PR).

Among 57 patients evaluable for minimal residual disease (MRD), 53 (93%) were MRD negative. Of this group, 49 had a VGPR or better.

The median time to first response was 1 month (range 0.9 to 8.5 months). At the time of data cutoff 70 patients had an ongoing response.

Among patients followed for a minimum of 6 months, most had cilta-cel CAR T-cells below the level of quantification (2 cells per microliter) in peripheral blood.

At a median follow-up of 12.4 months, 12-month overall progression-free survival rate was 76%, with the median PFS not reached. The 12-month overall survival rate was 88.5%, with the median OS not reached.
 

Safety data

All patients had at least one hematologic adverse event, 96 of which were grade 3 or 4 in severity. The events include neutropenia, anemia, thrombocytopenia, leukopenia, and lymphopenia. The median time to recovery was 2 weeks for grade 3 or 4 neutropenia and 4 weeks for thrombocytopenia.

Infections of any grade occurred in 57.7% of patients, including grade 3/4 pneumonia in 8.2% and grade 3/4 sepsis in 4.1%.

Grade 3 or 4 nonhematologic toxicities were uncommon, Dr. Madduri noted.

CRS of any grade occurred in 92 patients, but only 4 had grade 3 or 4 CRS.

Neurotoxicities occurred in 20 patients, of whom 10 had grade 3 or 4 neurotoxicity.

Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 16 patients, with 2 having grade 3 or greater ICANS. Other neurotoxicities of any grade, many which overlapped with ICANS, occurred in 12 patients, with 9 having grade 3 or 4 neurotoxicity.

The median time to ICANS onset was 8 days, with a median time to recovery of 4 days. Other neurotoxicities took longer to manifest and disappear, however, with a median time to onset of 27 days, and median time to recovery of 75 days.
 

Neurotoxicity mechanism questioned

In the question-and-answer session following her presentation, an audience member asked whether the investigators had any insights into the mechanism underlying the non-ICANS neurotoxicities they saw.

“We saw no clear etiology in the other neurotoxicities, but we saw that maybe there could be some mild associations with high tumor burden, prior CRS, ICANS, or even the higher expansion and persistence of these cells,” Dr. Madduri replied.

She noted that subsequent to these findings, the investigators have implemented mitigation strategies including allowing patients to have more bridging chemotherapy, more aggressive steroid use for early ICANS, and extensive monitoring.

Eric Smith, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, said that the non-ICANS neurotoxicity profile of cilta-cel was different from that seen in other CAR T-cell trials, and asked how it compared to that of bi-specific BCMA/CD3 CAR T constructs.

“We did see some nerve palsies and peripheral motor neuropathy, but it wasn’t that many patients, and it’s really hard to compare what happened here with the bi-specifics, as every product is very different,” she said.

The study was sponsored by Janssen Research & Development and Legend Biotech. Dr. Madduri disclosed honoraria, consultancy, and speakers bureau activities for those companies and others.
 

SOURCE: Madduri D et al. ASH 2020. Abstract 177.

Public spending on colchicine has grown exponentially over the past decade despite generics suggesting an uphill slog for patients seeking access to long-term therapy for gout or cardiac conditions.

Medicaid spending on single-ingredient colchicine jumped 2,833%, from $1.1 million in 2008 to $32.2 million in 2017, new findings show. Medicaid expansion likely played a role in the increase, but 58% was due to price hikes alone.

The centuries-old drug sold for pennies in the United States before increasing 50-fold to about $5 per pill in 2009 after the first FDA-approved colchicine product, Colcrys, was granted 3 years’ market exclusivity for the treatment of acute gout based on a 1-week trial.

If prices had remained at pre-Colcrys levels, Medicaid spending in 2017 would have totaled just $2.1 million rather than $32.2 million according to the analysis, published online Nov. 30 in JAMA Internal Medicine (doi: 10.1001/jamainternmed.2020.5017).

The study was motivated by difficulties gout patients have in accessing colchicine, but also last year’s COLCOT trial, which reported fewer ischemic cardiovascular events in patients receiving colchicine after MI, observed Natalie McCormick, PhD, of Massachusetts General Hospital and Harvard Medical School, both in Boston.

“They were suggesting it could be a cost-effective way for secondary prevention and it is fairly inexpensive in most countries, but not the U.S.,” she said in an interview. “So there’s really a potential to increase public spending if more and more patients are then taking colchicine for prevention of cardiovascular events and the prices don’t change.”

The current pandemic could potentially further increase demand. Results initially slated for September are expected this month from the COLCORONA trial, which is testing whether the anti-inflammatory agent can prevent hospitalizations, lung complications, and death when given early in the course of COVID-19.

University of Oxford (England) researchers also announced last week that colchicine is being added to the massive RECOVERY trial, which is studying treatments for hospitalized COVID-19 patients.

Notably, the Canadian-based COLCOT trial did not use Colcrys, but rather a colchicine product that costs just $0.26 a pill in Canada, roughly the price of most generics available worldwide.

Authorized generics typically drive down drug prices when competing with independent generics, but this competition is missing in the United States, where Colcrys holds patents until 2029, Dr. McCormick and colleagues noted. More than a half-dozen independent generics have FDA approval to date, but only authorized generics with price points set by the brand-name companies are available to treat acute gout, pericarditis, and potentially millions with MI.

“One of the key takeaways is this difference between the brand names and the authorized generics and the independents,” she said. “The authorized [generics] have really not saved money. The list prices were just slightly lower and patients can also have more difficulty in getting those covered.”

For this analysis, the investigators used Medicaid and Medicare data to examine prices for all available forms of colchicine from 2008 to 2017, including unregulated/unapproved colchicine (2008-2010), generic combination probenecid-colchicine (2008-2017), Colcrys (2009-2017), brand-name single-ingredient colchicine Mitigare (approved in late 2014 but not marketed until 2015), and their authorized generics (2015-2017). Medicare trends from 2012 to 2017 were analyzed separately because pre-Colcrys Medicare data were not available.

Based on the results, combined spending on Medicare and Medicaid claims for single-ingredient colchicine exceeded $340 million in 2017.

Inflation- and rebate-adjusted Medicaid unit prices rose from $0.24 a pill in 2008, when unapproved formulations were still available, to $4.20 a pill in 2011 (Colcrys only), and peaked at $4.66 a pill in 2015 (Colcrys plus authorized generics).

Prescribing of lower-priced probenecid-colchicine ($0.66/pill in 2017) remained stable throughout. Medicaid rebate-adjusted prices in 2017 were $3.99/pill for all single-ingredient colchicine products, $5.13/pill for Colcrys, $4.49/pill for Mitigare, and $3.88/pill for authorized generics.

Medicare rebate-adjusted 2017 per-pill prices were $5.81 for all single-ingredient colchicine products, $6.78 for Colcrys, $5.68 for Mitigare, $5.16 for authorized generics, and $0.70 for probenecid-colchicine.

“Authorized generics have still driven high spending,” Dr. McCormick said. “We really need to encourage more competition in order to improve access.”

In an accompanying commentary, B. Joseph Guglielmo, PharmD, University of California, San Francisco, pointed out that the estimated median research and development cost to bring a drug to market is between $985 million and $1,335 million, which inevitably translates into a high selling price for the drug. Such investment and its resultant cost, however, should be associated with potential worth to society.

“Only a fraction of an investment was required for Colcrys, a product that has provided no increased value and an unnecessary, long-term cost burden to the health care system,” he wrote. “The current study findings illustrate that we can never allow such an egregious case to take place again.”

Dr. McCormick reported grants from Canadian Institutes of Health Research during the conduct of the study. Dr. Guglielmo reported having no relevant conflicts of interest.

This article first appeared on Medscape.com.

Public spending on colchicine has grown exponentially over the past decade despite generics suggesting an uphill slog for patients seeking access to long-term therapy for gout or cardiac conditions.

Medicaid spending on single-ingredient colchicine jumped 2,833%, from $1.1 million in 2008 to $32.2 million in 2017, new findings show. Medicaid expansion likely played a role in the increase, but 58% was due to price hikes alone.

The centuries-old drug sold for pennies in the United States before increasing 50-fold to about $5 per pill in 2009 after the first FDA-approved colchicine product, Colcrys, was granted 3 years’ market exclusivity for the treatment of acute gout based on a 1-week trial.

If prices had remained at pre-Colcrys levels, Medicaid spending in 2017 would have totaled just $2.1 million rather than $32.2 million according to the analysis, published online Nov. 30 in JAMA Internal Medicine (doi: 10.1001/jamainternmed.2020.5017).

The study was motivated by difficulties gout patients have in accessing colchicine, but also last year’s COLCOT trial, which reported fewer ischemic cardiovascular events in patients receiving colchicine after MI, observed Natalie McCormick, PhD, of Massachusetts General Hospital and Harvard Medical School, both in Boston.

“They were suggesting it could be a cost-effective way for secondary prevention and it is fairly inexpensive in most countries, but not the U.S.,” she said in an interview. “So there’s really a potential to increase public spending if more and more patients are then taking colchicine for prevention of cardiovascular events and the prices don’t change.”

The current pandemic could potentially further increase demand. Results initially slated for September are expected this month from the COLCORONA trial, which is testing whether the anti-inflammatory agent can prevent hospitalizations, lung complications, and death when given early in the course of COVID-19.

University of Oxford (England) researchers also announced last week that colchicine is being added to the massive RECOVERY trial, which is studying treatments for hospitalized COVID-19 patients.

Notably, the Canadian-based COLCOT trial did not use Colcrys, but rather a colchicine product that costs just $0.26 a pill in Canada, roughly the price of most generics available worldwide.

Authorized generics typically drive down drug prices when competing with independent generics, but this competition is missing in the United States, where Colcrys holds patents until 2029, Dr. McCormick and colleagues noted. More than a half-dozen independent generics have FDA approval to date, but only authorized generics with price points set by the brand-name companies are available to treat acute gout, pericarditis, and potentially millions with MI.

“One of the key takeaways is this difference between the brand names and the authorized generics and the independents,” she said. “The authorized [generics] have really not saved money. The list prices were just slightly lower and patients can also have more difficulty in getting those covered.”

For this analysis, the investigators used Medicaid and Medicare data to examine prices for all available forms of colchicine from 2008 to 2017, including unregulated/unapproved colchicine (2008-2010), generic combination probenecid-colchicine (2008-2017), Colcrys (2009-2017), brand-name single-ingredient colchicine Mitigare (approved in late 2014 but not marketed until 2015), and their authorized generics (2015-2017). Medicare trends from 2012 to 2017 were analyzed separately because pre-Colcrys Medicare data were not available.

Based on the results, combined spending on Medicare and Medicaid claims for single-ingredient colchicine exceeded $340 million in 2017.

Inflation- and rebate-adjusted Medicaid unit prices rose from $0.24 a pill in 2008, when unapproved formulations were still available, to $4.20 a pill in 2011 (Colcrys only), and peaked at $4.66 a pill in 2015 (Colcrys plus authorized generics).

Prescribing of lower-priced probenecid-colchicine ($0.66/pill in 2017) remained stable throughout. Medicaid rebate-adjusted prices in 2017 were $3.99/pill for all single-ingredient colchicine products, $5.13/pill for Colcrys, $4.49/pill for Mitigare, and $3.88/pill for authorized generics.

Medicare rebate-adjusted 2017 per-pill prices were $5.81 for all single-ingredient colchicine products, $6.78 for Colcrys, $5.68 for Mitigare, $5.16 for authorized generics, and $0.70 for probenecid-colchicine.

“Authorized generics have still driven high spending,” Dr. McCormick said. “We really need to encourage more competition in order to improve access.”

In an accompanying commentary, B. Joseph Guglielmo, PharmD, University of California, San Francisco, pointed out that the estimated median research and development cost to bring a drug to market is between $985 million and $1,335 million, which inevitably translates into a high selling price for the drug. Such investment and its resultant cost, however, should be associated with potential worth to society.

“Only a fraction of an investment was required for Colcrys, a product that has provided no increased value and an unnecessary, long-term cost burden to the health care system,” he wrote. “The current study findings illustrate that we can never allow such an egregious case to take place again.”

Dr. McCormick reported grants from Canadian Institutes of Health Research during the conduct of the study. Dr. Guglielmo reported having no relevant conflicts of interest.

This article first appeared on Medscape.com.

Public spending on colchicine has grown exponentially over the past decade despite generics suggesting an uphill slog for patients seeking access to long-term therapy for gout or cardiac conditions.

Medicaid spending on single-ingredient colchicine jumped 2,833%, from $1.1 million in 2008 to $32.2 million in 2017, new findings show. Medicaid expansion likely played a role in the increase, but 58% was due to price hikes alone.

The centuries-old drug sold for pennies in the United States before increasing 50-fold to about $5 per pill in 2009 after the first FDA-approved colchicine product, Colcrys, was granted 3 years’ market exclusivity for the treatment of acute gout based on a 1-week trial.

If prices had remained at pre-Colcrys levels, Medicaid spending in 2017 would have totaled just $2.1 million rather than $32.2 million according to the analysis, published online Nov. 30 in JAMA Internal Medicine (doi: 10.1001/jamainternmed.2020.5017).

The study was motivated by difficulties gout patients have in accessing colchicine, but also last year’s COLCOT trial, which reported fewer ischemic cardiovascular events in patients receiving colchicine after MI, observed Natalie McCormick, PhD, of Massachusetts General Hospital and Harvard Medical School, both in Boston.

“They were suggesting it could be a cost-effective way for secondary prevention and it is fairly inexpensive in most countries, but not the U.S.,” she said in an interview. “So there’s really a potential to increase public spending if more and more patients are then taking colchicine for prevention of cardiovascular events and the prices don’t change.”

The current pandemic could potentially further increase demand. Results initially slated for September are expected this month from the COLCORONA trial, which is testing whether the anti-inflammatory agent can prevent hospitalizations, lung complications, and death when given early in the course of COVID-19.

University of Oxford (England) researchers also announced last week that colchicine is being added to the massive RECOVERY trial, which is studying treatments for hospitalized COVID-19 patients.

Notably, the Canadian-based COLCOT trial did not use Colcrys, but rather a colchicine product that costs just $0.26 a pill in Canada, roughly the price of most generics available worldwide.

Authorized generics typically drive down drug prices when competing with independent generics, but this competition is missing in the United States, where Colcrys holds patents until 2029, Dr. McCormick and colleagues noted. More than a half-dozen independent generics have FDA approval to date, but only authorized generics with price points set by the brand-name companies are available to treat acute gout, pericarditis, and potentially millions with MI.

“One of the key takeaways is this difference between the brand names and the authorized generics and the independents,” she said. “The authorized [generics] have really not saved money. The list prices were just slightly lower and patients can also have more difficulty in getting those covered.”

For this analysis, the investigators used Medicaid and Medicare data to examine prices for all available forms of colchicine from 2008 to 2017, including unregulated/unapproved colchicine (2008-2010), generic combination probenecid-colchicine (2008-2017), Colcrys (2009-2017), brand-name single-ingredient colchicine Mitigare (approved in late 2014 but not marketed until 2015), and their authorized generics (2015-2017). Medicare trends from 2012 to 2017 were analyzed separately because pre-Colcrys Medicare data were not available.

Based on the results, combined spending on Medicare and Medicaid claims for single-ingredient colchicine exceeded $340 million in 2017.

Inflation- and rebate-adjusted Medicaid unit prices rose from $0.24 a pill in 2008, when unapproved formulations were still available, to $4.20 a pill in 2011 (Colcrys only), and peaked at $4.66 a pill in 2015 (Colcrys plus authorized generics).

Prescribing of lower-priced probenecid-colchicine ($0.66/pill in 2017) remained stable throughout. Medicaid rebate-adjusted prices in 2017 were $3.99/pill for all single-ingredient colchicine products, $5.13/pill for Colcrys, $4.49/pill for Mitigare, and $3.88/pill for authorized generics.

Medicare rebate-adjusted 2017 per-pill prices were $5.81 for all single-ingredient colchicine products, $6.78 for Colcrys, $5.68 for Mitigare, $5.16 for authorized generics, and $0.70 for probenecid-colchicine.

“Authorized generics have still driven high spending,” Dr. McCormick said. “We really need to encourage more competition in order to improve access.”

In an accompanying commentary, B. Joseph Guglielmo, PharmD, University of California, San Francisco, pointed out that the estimated median research and development cost to bring a drug to market is between $985 million and $1,335 million, which inevitably translates into a high selling price for the drug. Such investment and its resultant cost, however, should be associated with potential worth to society.

“Only a fraction of an investment was required for Colcrys, a product that has provided no increased value and an unnecessary, long-term cost burden to the health care system,” he wrote. “The current study findings illustrate that we can never allow such an egregious case to take place again.”

Dr. McCormick reported grants from Canadian Institutes of Health Research during the conduct of the study. Dr. Guglielmo reported having no relevant conflicts of interest.

This article first appeared on Medscape.com.

LAS VEGAS – Current major guidelines for treatment of psoriatic arthritis (PsA) shortchange the value of the anti–interleukin-17 biologics for this disease, Kenneth B. Gordon, MD, said at MedscapeLive’s annual Las Vegas Dermatology Seminar, held virtually this year.

The 2018 joint American College of Rheumatology/National Psoriasis Association guidelines recommend the anti–tumor necrosis factor agents as first-line biologic therapy for PsA, with the anti–IL-17 biologics held in reserve as second-tier therapy for when the anti-TNFs don’t work. That’s largely because the guidance was developed before the compelling evidence for the anti–IL-17 agents as the biologics of choice was appreciated, according to Dr. Gordon, professor and chair of the department of dermatology at the Medical College of Wisconsin, Milwaukee.

“Many people go by these guidelines,” the dermatologist noted. “I think it’s really critical to look at the data and not just the guidelines because the guidelines don’t give full credit to the anti–IL-17 agents,” he added.

“Emerging psoriatic arthritis data may likely put this class of medications into the forefront of treatment for patients who have both psoriasis and psoriatic arthritis because you generally get higher responses for the skin disease than with anti-TNF therapy, and with similar responses in psoriatic arthritis.”

Two IL-17 inhibitors are approved for both PsA and psoriasis: secukinumab (Cosentyx) and ixekizumab (Taltz). In addition, brodalumab (Siliq), approved for psoriasis, is expected to receive an expanded indication for PsA based upon its strong showing in the AMVISION-1 and -2 trials. Data from those trials, as well as the FUTURE 2 trial for secukinumab and SPIRIT-P1 for ixekizumab, consistently document at least 20% improvement in the ACR criteria for PsA severity – that is, an ACR 20 response – in 50%-60% of patients on one of the three IL-17 inhibitors, as well as ACR 50 response rates of around 30%. Those outcomes are quite consistent with the impact of the anti-TNF biologics on joint disease. But the TNF inhibitors can’t touch the anti–IL-17 biologics when it comes to improvement in Psoriasis Area and Severity Index (PASI) scores: The anti–IL-17 agents have week-52 PASI 75 response rates in the range of 80%, PASI 90 response rates of 70%-75%, and PASI 100 response rates of 40%-55%, with the highest-end results being seen with brodalumab, he continued.

A point worth remembering when prescribing secukinumab is that the approved dose for PsA is 150 mg every 4 weeks, which is just half of the typical dose in psoriasis.

“I spend a lot of time convincing my rheumatology colleagues that if you’re treating both psoriasis and psoriatic arthritis, use the psoriasis dose. There’s some evidence that the higher dose provides some benefit in terms of prevention of permanent joint damage by x-ray,” Dr. Gordon said.

Evidence that TNF inhibitors inhibit permanent joint damage in patients with PsA has been considered a major advantage, establishing this medication class as first-line biologic therapy. But anti–IL-17 therapies appear to have a similar beneficial effect. That was demonstrated in the SPIRIT-P1 trial, where Sharp scores – a radiographic measure of progression of joint damage – were similar at 24 weeks in PsA patients randomized to ixekizumab as compared to adalimumab, with both biologics being superior to placebo. An Assessment of SpondyloArthritis International Society 20% improvement (ASAS 20) response or an ACR 50 response doesn’t capture what’s going on with regard to axial disease. That’s assessed through ASAS 20 and ASAS 40 responses – that is, at least 20% or 40% improvement, compared with baseline, in Assessment in Ankylosing Spondylitis scores. And in the MEASURE 1 and 2 trials, secukinumab achieved robust improvement in axial disease as reflected in favorable ASAS 20 and ASAS 40 responses through 52 weeks in patients with active ankylosing spondylitis.

“The anti–IL-17 agents do actually work in ankylosing spondylitis, which might be a surrogate for the treatment effect in axial psoriatic arthritis,” Dr. Gordon commented.

The phase 3b MAXIMISE trial presented at the 2019 EULAR meeting looked specifically at the impact of secukinumab in patients with psoriatic arthritis with axial involvement. An ASAS 20 response at week 12 was seen in 67% and 65% of patients randomized to secukinumab at 150 or 300 mg, respectively, if they were on concomitant methotrexate, and 64% and 61% if they were not, compared with ASAS 20 rates of 34% and 31% in placebo-treated controls.

“This is the only study of an anti–IL-17 agent that’s been done for axial disease to date in psoriatic arthritis. It’s very, very encouraging,” the dermatologist commented.

 

Durability of response and safety

“In terms of safety, the anti–IL-17s have been a truly remarkable success story. There are very low rates of things to be concerned about,” Dr. Gordon said.

Oral candidiasis occurs in 2%-4% of treated patients, but he noted, “It’s almost always very mild disease” that’s easily treatable with nystatin or, in the worst case, with some fluconazole.

Inflammatory bowel disease (IBD) as a side effect of anti–IL-17 therapy has been a controversial issue. Dr. Gordon’s interpretation of the evidence is that there probably is a very slight increase in the risk of developing ulcerative colitis, but not Crohn’s disease.

“This rate is extraordinarily low, so while it’s something that I consider, and if a patient has a personal history of IBD I will sometimes hesitate to use an anti–IL-17 agent, in patients who don’t have a personal history I’ll go ahead,” he explained.

There is a signal of a slight increase in risk of depression in patients on brodalumab, which isn’t the case for secukinumab or ixekizumab.

Importantly, large long-term extension studies with years of follow-up show that the initially low adverse event rates associated with the IL-17 inhibitors don’t increase over time; rather, they remain steady over years of use.

Long-term maintenance of response with these biologics is impressive. “It’s not perfect, but it’s still a tremendous advantage for patients, especially if you can get them through that initial period,” Dr. Gordon said.

For example, in the long-term extension of the UNCOVER-1 trial, psoriasis patients who had clear or almost clear skin at week 12 on ixekizumab and continued to take the medication open label for 5 years had PASI 75, 90, and 100 response rates of 94%, 82%, and 47%, respectively, at week 264.
 

What about IL-12/23 and IL-23 inhibitors in PsA?

In a separate presentation at the MedscapeLive seminar, Bruce E. Strober, MD, PhD, said that, although ustekinumab (Stelara) is approved for both psoriasis and PsA, the IL-12/-23 inhibitor’s efficacy in PsA is inconsistent and lower than other approved biologics. In contrast, the IL-23 inhibitor guselkumab (Tremfya), which also has the dual indications, is a strong performer in both. In the DISCOVER-2 trial, conducted in treatment-naive patients with PsA, guselkumab at the approved dose of 100 mg every 8 weeks achieved ACR 20, 50, and 70 rates of 64%, 31%, and 19%, respectively. It was also significantly better than placebo for resolution of enthesitis.

An important caveat: While radiographic inhibition of progression of joint disease occurred with guselkumab dosed at 100 mg every 4 weeks in DISCOVER-2, that’s not the approved dose. At 100 mg every 8 weeks – the FDA-approved dosing for both psoriatic arthritis and psoriasis – radiographic inhibition wasn’t better than with placebo, noted Dr. Strober, a dermatologist at Yale University, New Haven, Conn.

Dr. Gordon and Dr. Strober are clinical trialists who reported receiving research support and/or honoraria from more than a dozen pharmaceutical companies, including virtually all of those with biologics for dermatology.

MedscapeLive and this news organization are owned by the same parent company.

[email protected]

LAS VEGAS – Current major guidelines for treatment of psoriatic arthritis (PsA) shortchange the value of the anti–interleukin-17 biologics for this disease, Kenneth B. Gordon, MD, said at MedscapeLive’s annual Las Vegas Dermatology Seminar, held virtually this year.

The 2018 joint American College of Rheumatology/National Psoriasis Association guidelines recommend the anti–tumor necrosis factor agents as first-line biologic therapy for PsA, with the anti–IL-17 biologics held in reserve as second-tier therapy for when the anti-TNFs don’t work. That’s largely because the guidance was developed before the compelling evidence for the anti–IL-17 agents as the biologics of choice was appreciated, according to Dr. Gordon, professor and chair of the department of dermatology at the Medical College of Wisconsin, Milwaukee.

“Many people go by these guidelines,” the dermatologist noted. “I think it’s really critical to look at the data and not just the guidelines because the guidelines don’t give full credit to the anti–IL-17 agents,” he added.

“Emerging psoriatic arthritis data may likely put this class of medications into the forefront of treatment for patients who have both psoriasis and psoriatic arthritis because you generally get higher responses for the skin disease than with anti-TNF therapy, and with similar responses in psoriatic arthritis.”

Two IL-17 inhibitors are approved for both PsA and psoriasis: secukinumab (Cosentyx) and ixekizumab (Taltz). In addition, brodalumab (Siliq), approved for psoriasis, is expected to receive an expanded indication for PsA based upon its strong showing in the AMVISION-1 and -2 trials. Data from those trials, as well as the FUTURE 2 trial for secukinumab and SPIRIT-P1 for ixekizumab, consistently document at least 20% improvement in the ACR criteria for PsA severity – that is, an ACR 20 response – in 50%-60% of patients on one of the three IL-17 inhibitors, as well as ACR 50 response rates of around 30%. Those outcomes are quite consistent with the impact of the anti-TNF biologics on joint disease. But the TNF inhibitors can’t touch the anti–IL-17 biologics when it comes to improvement in Psoriasis Area and Severity Index (PASI) scores: The anti–IL-17 agents have week-52 PASI 75 response rates in the range of 80%, PASI 90 response rates of 70%-75%, and PASI 100 response rates of 40%-55%, with the highest-end results being seen with brodalumab, he continued.

A point worth remembering when prescribing secukinumab is that the approved dose for PsA is 150 mg every 4 weeks, which is just half of the typical dose in psoriasis.

“I spend a lot of time convincing my rheumatology colleagues that if you’re treating both psoriasis and psoriatic arthritis, use the psoriasis dose. There’s some evidence that the higher dose provides some benefit in terms of prevention of permanent joint damage by x-ray,” Dr. Gordon said.

Evidence that TNF inhibitors inhibit permanent joint damage in patients with PsA has been considered a major advantage, establishing this medication class as first-line biologic therapy. But anti–IL-17 therapies appear to have a similar beneficial effect. That was demonstrated in the SPIRIT-P1 trial, where Sharp scores – a radiographic measure of progression of joint damage – were similar at 24 weeks in PsA patients randomized to ixekizumab as compared to adalimumab, with both biologics being superior to placebo. An Assessment of SpondyloArthritis International Society 20% improvement (ASAS 20) response or an ACR 50 response doesn’t capture what’s going on with regard to axial disease. That’s assessed through ASAS 20 and ASAS 40 responses – that is, at least 20% or 40% improvement, compared with baseline, in Assessment in Ankylosing Spondylitis scores. And in the MEASURE 1 and 2 trials, secukinumab achieved robust improvement in axial disease as reflected in favorable ASAS 20 and ASAS 40 responses through 52 weeks in patients with active ankylosing spondylitis.

“The anti–IL-17 agents do actually work in ankylosing spondylitis, which might be a surrogate for the treatment effect in axial psoriatic arthritis,” Dr. Gordon commented.

The phase 3b MAXIMISE trial presented at the 2019 EULAR meeting looked specifically at the impact of secukinumab in patients with psoriatic arthritis with axial involvement. An ASAS 20 response at week 12 was seen in 67% and 65% of patients randomized to secukinumab at 150 or 300 mg, respectively, if they were on concomitant methotrexate, and 64% and 61% if they were not, compared with ASAS 20 rates of 34% and 31% in placebo-treated controls.

“This is the only study of an anti–IL-17 agent that’s been done for axial disease to date in psoriatic arthritis. It’s very, very encouraging,” the dermatologist commented.

 

Durability of response and safety

“In terms of safety, the anti–IL-17s have been a truly remarkable success story. There are very low rates of things to be concerned about,” Dr. Gordon said.

Oral candidiasis occurs in 2%-4% of treated patients, but he noted, “It’s almost always very mild disease” that’s easily treatable with nystatin or, in the worst case, with some fluconazole.

Inflammatory bowel disease (IBD) as a side effect of anti–IL-17 therapy has been a controversial issue. Dr. Gordon’s interpretation of the evidence is that there probably is a very slight increase in the risk of developing ulcerative colitis, but not Crohn’s disease.

“This rate is extraordinarily low, so while it’s something that I consider, and if a patient has a personal history of IBD I will sometimes hesitate to use an anti–IL-17 agent, in patients who don’t have a personal history I’ll go ahead,” he explained.

There is a signal of a slight increase in risk of depression in patients on brodalumab, which isn’t the case for secukinumab or ixekizumab.

Importantly, large long-term extension studies with years of follow-up show that the initially low adverse event rates associated with the IL-17 inhibitors don’t increase over time; rather, they remain steady over years of use.

Long-term maintenance of response with these biologics is impressive. “It’s not perfect, but it’s still a tremendous advantage for patients, especially if you can get them through that initial period,” Dr. Gordon said.

For example, in the long-term extension of the UNCOVER-1 trial, psoriasis patients who had clear or almost clear skin at week 12 on ixekizumab and continued to take the medication open label for 5 years had PASI 75, 90, and 100 response rates of 94%, 82%, and 47%, respectively, at week 264.
 

What about IL-12/23 and IL-23 inhibitors in PsA?

In a separate presentation at the MedscapeLive seminar, Bruce E. Strober, MD, PhD, said that, although ustekinumab (Stelara) is approved for both psoriasis and PsA, the IL-12/-23 inhibitor’s efficacy in PsA is inconsistent and lower than other approved biologics. In contrast, the IL-23 inhibitor guselkumab (Tremfya), which also has the dual indications, is a strong performer in both. In the DISCOVER-2 trial, conducted in treatment-naive patients with PsA, guselkumab at the approved dose of 100 mg every 8 weeks achieved ACR 20, 50, and 70 rates of 64%, 31%, and 19%, respectively. It was also significantly better than placebo for resolution of enthesitis.

An important caveat: While radiographic inhibition of progression of joint disease occurred with guselkumab dosed at 100 mg every 4 weeks in DISCOVER-2, that’s not the approved dose. At 100 mg every 8 weeks – the FDA-approved dosing for both psoriatic arthritis and psoriasis – radiographic inhibition wasn’t better than with placebo, noted Dr. Strober, a dermatologist at Yale University, New Haven, Conn.

Dr. Gordon and Dr. Strober are clinical trialists who reported receiving research support and/or honoraria from more than a dozen pharmaceutical companies, including virtually all of those with biologics for dermatology.

MedscapeLive and this news organization are owned by the same parent company.

[email protected]

LAS VEGAS – Current major guidelines for treatment of psoriatic arthritis (PsA) shortchange the value of the anti–interleukin-17 biologics for this disease, Kenneth B. Gordon, MD, said at MedscapeLive’s annual Las Vegas Dermatology Seminar, held virtually this year.

The 2018 joint American College of Rheumatology/National Psoriasis Association guidelines recommend the anti–tumor necrosis factor agents as first-line biologic therapy for PsA, with the anti–IL-17 biologics held in reserve as second-tier therapy for when the anti-TNFs don’t work. That’s largely because the guidance was developed before the compelling evidence for the anti–IL-17 agents as the biologics of choice was appreciated, according to Dr. Gordon, professor and chair of the department of dermatology at the Medical College of Wisconsin, Milwaukee.

“Many people go by these guidelines,” the dermatologist noted. “I think it’s really critical to look at the data and not just the guidelines because the guidelines don’t give full credit to the anti–IL-17 agents,” he added.

“Emerging psoriatic arthritis data may likely put this class of medications into the forefront of treatment for patients who have both psoriasis and psoriatic arthritis because you generally get higher responses for the skin disease than with anti-TNF therapy, and with similar responses in psoriatic arthritis.”

Two IL-17 inhibitors are approved for both PsA and psoriasis: secukinumab (Cosentyx) and ixekizumab (Taltz). In addition, brodalumab (Siliq), approved for psoriasis, is expected to receive an expanded indication for PsA based upon its strong showing in the AMVISION-1 and -2 trials. Data from those trials, as well as the FUTURE 2 trial for secukinumab and SPIRIT-P1 for ixekizumab, consistently document at least 20% improvement in the ACR criteria for PsA severity – that is, an ACR 20 response – in 50%-60% of patients on one of the three IL-17 inhibitors, as well as ACR 50 response rates of around 30%. Those outcomes are quite consistent with the impact of the anti-TNF biologics on joint disease. But the TNF inhibitors can’t touch the anti–IL-17 biologics when it comes to improvement in Psoriasis Area and Severity Index (PASI) scores: The anti–IL-17 agents have week-52 PASI 75 response rates in the range of 80%, PASI 90 response rates of 70%-75%, and PASI 100 response rates of 40%-55%, with the highest-end results being seen with brodalumab, he continued.

A point worth remembering when prescribing secukinumab is that the approved dose for PsA is 150 mg every 4 weeks, which is just half of the typical dose in psoriasis.

“I spend a lot of time convincing my rheumatology colleagues that if you’re treating both psoriasis and psoriatic arthritis, use the psoriasis dose. There’s some evidence that the higher dose provides some benefit in terms of prevention of permanent joint damage by x-ray,” Dr. Gordon said.

Evidence that TNF inhibitors inhibit permanent joint damage in patients with PsA has been considered a major advantage, establishing this medication class as first-line biologic therapy. But anti–IL-17 therapies appear to have a similar beneficial effect. That was demonstrated in the SPIRIT-P1 trial, where Sharp scores – a radiographic measure of progression of joint damage – were similar at 24 weeks in PsA patients randomized to ixekizumab as compared to adalimumab, with both biologics being superior to placebo. An Assessment of SpondyloArthritis International Society 20% improvement (ASAS 20) response or an ACR 50 response doesn’t capture what’s going on with regard to axial disease. That’s assessed through ASAS 20 and ASAS 40 responses – that is, at least 20% or 40% improvement, compared with baseline, in Assessment in Ankylosing Spondylitis scores. And in the MEASURE 1 and 2 trials, secukinumab achieved robust improvement in axial disease as reflected in favorable ASAS 20 and ASAS 40 responses through 52 weeks in patients with active ankylosing spondylitis.

“The anti–IL-17 agents do actually work in ankylosing spondylitis, which might be a surrogate for the treatment effect in axial psoriatic arthritis,” Dr. Gordon commented.

The phase 3b MAXIMISE trial presented at the 2019 EULAR meeting looked specifically at the impact of secukinumab in patients with psoriatic arthritis with axial involvement. An ASAS 20 response at week 12 was seen in 67% and 65% of patients randomized to secukinumab at 150 or 300 mg, respectively, if they were on concomitant methotrexate, and 64% and 61% if they were not, compared with ASAS 20 rates of 34% and 31% in placebo-treated controls.

“This is the only study of an anti–IL-17 agent that’s been done for axial disease to date in psoriatic arthritis. It’s very, very encouraging,” the dermatologist commented.

 

Durability of response and safety

“In terms of safety, the anti–IL-17s have been a truly remarkable success story. There are very low rates of things to be concerned about,” Dr. Gordon said.

Oral candidiasis occurs in 2%-4% of treated patients, but he noted, “It’s almost always very mild disease” that’s easily treatable with nystatin or, in the worst case, with some fluconazole.

Inflammatory bowel disease (IBD) as a side effect of anti–IL-17 therapy has been a controversial issue. Dr. Gordon’s interpretation of the evidence is that there probably is a very slight increase in the risk of developing ulcerative colitis, but not Crohn’s disease.

“This rate is extraordinarily low, so while it’s something that I consider, and if a patient has a personal history of IBD I will sometimes hesitate to use an anti–IL-17 agent, in patients who don’t have a personal history I’ll go ahead,” he explained.

There is a signal of a slight increase in risk of depression in patients on brodalumab, which isn’t the case for secukinumab or ixekizumab.

Importantly, large long-term extension studies with years of follow-up show that the initially low adverse event rates associated with the IL-17 inhibitors don’t increase over time; rather, they remain steady over years of use.

Long-term maintenance of response with these biologics is impressive. “It’s not perfect, but it’s still a tremendous advantage for patients, especially if you can get them through that initial period,” Dr. Gordon said.

For example, in the long-term extension of the UNCOVER-1 trial, psoriasis patients who had clear or almost clear skin at week 12 on ixekizumab and continued to take the medication open label for 5 years had PASI 75, 90, and 100 response rates of 94%, 82%, and 47%, respectively, at week 264.
 

What about IL-12/23 and IL-23 inhibitors in PsA?

In a separate presentation at the MedscapeLive seminar, Bruce E. Strober, MD, PhD, said that, although ustekinumab (Stelara) is approved for both psoriasis and PsA, the IL-12/-23 inhibitor’s efficacy in PsA is inconsistent and lower than other approved biologics. In contrast, the IL-23 inhibitor guselkumab (Tremfya), which also has the dual indications, is a strong performer in both. In the DISCOVER-2 trial, conducted in treatment-naive patients with PsA, guselkumab at the approved dose of 100 mg every 8 weeks achieved ACR 20, 50, and 70 rates of 64%, 31%, and 19%, respectively. It was also significantly better than placebo for resolution of enthesitis.

An important caveat: While radiographic inhibition of progression of joint disease occurred with guselkumab dosed at 100 mg every 4 weeks in DISCOVER-2, that’s not the approved dose. At 100 mg every 8 weeks – the FDA-approved dosing for both psoriatic arthritis and psoriasis – radiographic inhibition wasn’t better than with placebo, noted Dr. Strober, a dermatologist at Yale University, New Haven, Conn.

Dr. Gordon and Dr. Strober are clinical trialists who reported receiving research support and/or honoraria from more than a dozen pharmaceutical companies, including virtually all of those with biologics for dermatology.

MedscapeLive and this news organization are owned by the same parent company.

[email protected]

Black patients with extensive-stage small cell lung cancer (ES-SCLC) are less likely to receive chemotherapy but have better survival, compared with White patients, according to a study published in JTO Clinical Research and Reports.

This study provides a large-scale analysis of real-world data identifying racial and socioeconomic factors impacting systemic therapy delivery and survival in ES-SCLC.

“The most important finding was the significant disparity in receipt of chemotherapy,” said study author Umit Tapan, MD, of Boston Medical Center.

“Black individuals with ES-SCLC were less likely to receive chemotherapy compared to Whites and other racial groups. Similarly, elderly, uninsured patients, patients with nonprivate health insurance, and those with lower education levels were less likely to be treated with chemotherapy,” Dr. Tapan said.

Using the National Cancer Data Base (NCDB), Dr. Tapan and colleagues identified 148,961 patients who were diagnosed with stage IV ES-SCLC during 2004-2016. In all, 82,592 patients were included in the study.
 

Results: Treatment and survival

Compared with White patients, Black patients (adjusted odds ratio, 0.85; P = .0004) and patients from other racial groups (aOR, 0.87; P = .126) had lower odds of receiving chemotherapy on multivariate analysis.

However, survival was superior in Black patients (adjusted hazard ratio, 0.92; P < .0001) and other non-White patients (aHR 0.86; P < .0001).

“We speculate that additional factors, such as performance status, which is not captured by NCDB, might have accounted for better survival for Black patients,” Dr. Tapan said, noting that the analysis was adjusted for known possible confounding factors, such as age, gender, and comorbidity status.

Black patients had higher odds of receiving chemotherapy between 2010 and 2016 compared with 2004 and 2009. “This suggests a positive impact of the Patient Protection and Affordable Care Act (ACA) in 2010,” Dr. Tapan said.

Another surprising finding pertained to patients with nonprivate insurance. These patients had even lower odds of getting chemotherapy after the implementation of ACA, Dr. Tapan said. Patients who had private insurance had higher survival compared with those who were uninsured.

Higher level of education, measured by percentage of residents with a high school degree, increased the odds of receiving chemotherapy.

Age also had a significant impact on receipt of chemotherapy. About 83% of patients over age 80 years received chemotherapy, compared with 94% of patients aged 40-64 years.
 

Real-world data

Minorities are underrepresented in cancer clinical trials in the United States, with only 2% of National Cancer Institute trials having sufficient minority participants, Dr. Tapan said. A study published in Academic Medicine in 2018 showed that only 13% of 782 National Institute of Health–sponsored clinical trials reported outcomes by race and ethnicity.

As a result, we are missing data on patient care in minority populations, Dr. Tapan said. “Collecting and analyzing real-world data becomes critical to study treatment patterns and outcomes,” he added.

The current real-world study had a somewhat diverse patient population, but 90.6% of patients were White, 7.8% were Black, and 1.7% were other races.

“We would have expected a higher percentage of Black patients considering the most recent U.S. Census Bureau estimates that 76.3% of the U.S. population is White and 13.4% is Black,” Dr. Tapan said. “There are conflicting results in the literature regarding racial disparities in SCLC and survival. Many of these studies were performed via state-based cancer registries instead of on a national level, making prior reports less generalizable.”
 

‘More work to do’

While the new study showed patients with nonprivate insurance or those with no insurance were less likely to receive chemotherapy, studies have shown that chemotherapy administration was not impacted by insurance status in limited-stage SCLC.

This is in contrast to radiotherapy delivery. Studies have revealed a lower likelihood of radiotherapy delivery in limited-stage SCLC for patients with government health insurance such as Medicare/Medicaid, Dr. Tapan said.

“Access to cancer care has been shown to be one of the most important barriers in racial disparity. Studies analyzing outcomes in the equal access health systems, such as the Veteran Administration, have revealed less racial disparities,” Dr. Tapan said.

Even when Black patients have equal access to care, they might receive suboptimal treatment, Dr. Tapan noted.

“Studies have shown that Black patients are not only more likely to refuse surgery, but also are more likely to be given a negative recommendation by a surgeon as compared to Whites, suggesting potential involvement of miscommunication or bias during patient-physician encounters,” Dr. Tapan said. “In the same vein, physicians would need to acknowledge their patients’ beliefs. Not doing so may lead to unsatisfactory physician-patient interactions and suboptimal decision-making.”

“Measures to reduce physician bias are an important step to reduce disparities,” Dr. Tapan continued. “Studies have shown that Black patients are perceived to be less intelligent and educated, less likely to have social support, and more likely to be at risk of noncompliance. For some patients and oncologists, extra effort is needed so that every patient can access the best possible treatments and outcomes. It is the oncologist’s responsibility to advocate for patients, but, ultimately, further legislative actions are needed to mitigate the disparities around cancer care.”

Dr. Tapan noted that, in 1966, Martin Luther King Jr., PhD, stated that “of all the forms of inequality, injustice in health care is the most shocking and inhumane.”

Dr. Tapan said: “We have overcome some barriers since 1966, but we have more work to do.” He and colleagues had no disclosures related to this study.

SOURCE: Tapan U et al. JTO Clin Res Rep. 2020. doi: 10.1016/j.jtocrr.2020.100109.

Black patients with extensive-stage small cell lung cancer (ES-SCLC) are less likely to receive chemotherapy but have better survival, compared with White patients, according to a study published in JTO Clinical Research and Reports.

This study provides a large-scale analysis of real-world data identifying racial and socioeconomic factors impacting systemic therapy delivery and survival in ES-SCLC.

“The most important finding was the significant disparity in receipt of chemotherapy,” said study author Umit Tapan, MD, of Boston Medical Center.

“Black individuals with ES-SCLC were less likely to receive chemotherapy compared to Whites and other racial groups. Similarly, elderly, uninsured patients, patients with nonprivate health insurance, and those with lower education levels were less likely to be treated with chemotherapy,” Dr. Tapan said.

Using the National Cancer Data Base (NCDB), Dr. Tapan and colleagues identified 148,961 patients who were diagnosed with stage IV ES-SCLC during 2004-2016. In all, 82,592 patients were included in the study.
 

Results: Treatment and survival

Compared with White patients, Black patients (adjusted odds ratio, 0.85; P = .0004) and patients from other racial groups (aOR, 0.87; P = .126) had lower odds of receiving chemotherapy on multivariate analysis.

However, survival was superior in Black patients (adjusted hazard ratio, 0.92; P < .0001) and other non-White patients (aHR 0.86; P < .0001).

“We speculate that additional factors, such as performance status, which is not captured by NCDB, might have accounted for better survival for Black patients,” Dr. Tapan said, noting that the analysis was adjusted for known possible confounding factors, such as age, gender, and comorbidity status.

Black patients had higher odds of receiving chemotherapy between 2010 and 2016 compared with 2004 and 2009. “This suggests a positive impact of the Patient Protection and Affordable Care Act (ACA) in 2010,” Dr. Tapan said.

Another surprising finding pertained to patients with nonprivate insurance. These patients had even lower odds of getting chemotherapy after the implementation of ACA, Dr. Tapan said. Patients who had private insurance had higher survival compared with those who were uninsured.

Higher level of education, measured by percentage of residents with a high school degree, increased the odds of receiving chemotherapy.

Age also had a significant impact on receipt of chemotherapy. About 83% of patients over age 80 years received chemotherapy, compared with 94% of patients aged 40-64 years.
 

Real-world data

Minorities are underrepresented in cancer clinical trials in the United States, with only 2% of National Cancer Institute trials having sufficient minority participants, Dr. Tapan said. A study published in Academic Medicine in 2018 showed that only 13% of 782 National Institute of Health–sponsored clinical trials reported outcomes by race and ethnicity.

As a result, we are missing data on patient care in minority populations, Dr. Tapan said. “Collecting and analyzing real-world data becomes critical to study treatment patterns and outcomes,” he added.

The current real-world study had a somewhat diverse patient population, but 90.6% of patients were White, 7.8% were Black, and 1.7% were other races.

“We would have expected a higher percentage of Black patients considering the most recent U.S. Census Bureau estimates that 76.3% of the U.S. population is White and 13.4% is Black,” Dr. Tapan said. “There are conflicting results in the literature regarding racial disparities in SCLC and survival. Many of these studies were performed via state-based cancer registries instead of on a national level, making prior reports less generalizable.”
 

‘More work to do’

While the new study showed patients with nonprivate insurance or those with no insurance were less likely to receive chemotherapy, studies have shown that chemotherapy administration was not impacted by insurance status in limited-stage SCLC.

This is in contrast to radiotherapy delivery. Studies have revealed a lower likelihood of radiotherapy delivery in limited-stage SCLC for patients with government health insurance such as Medicare/Medicaid, Dr. Tapan said.

“Access to cancer care has been shown to be one of the most important barriers in racial disparity. Studies analyzing outcomes in the equal access health systems, such as the Veteran Administration, have revealed less racial disparities,” Dr. Tapan said.

Even when Black patients have equal access to care, they might receive suboptimal treatment, Dr. Tapan noted.

“Studies have shown that Black patients are not only more likely to refuse surgery, but also are more likely to be given a negative recommendation by a surgeon as compared to Whites, suggesting potential involvement of miscommunication or bias during patient-physician encounters,” Dr. Tapan said. “In the same vein, physicians would need to acknowledge their patients’ beliefs. Not doing so may lead to unsatisfactory physician-patient interactions and suboptimal decision-making.”

“Measures to reduce physician bias are an important step to reduce disparities,” Dr. Tapan continued. “Studies have shown that Black patients are perceived to be less intelligent and educated, less likely to have social support, and more likely to be at risk of noncompliance. For some patients and oncologists, extra effort is needed so that every patient can access the best possible treatments and outcomes. It is the oncologist’s responsibility to advocate for patients, but, ultimately, further legislative actions are needed to mitigate the disparities around cancer care.”

Dr. Tapan noted that, in 1966, Martin Luther King Jr., PhD, stated that “of all the forms of inequality, injustice in health care is the most shocking and inhumane.”

Dr. Tapan said: “We have overcome some barriers since 1966, but we have more work to do.” He and colleagues had no disclosures related to this study.

SOURCE: Tapan U et al. JTO Clin Res Rep. 2020. doi: 10.1016/j.jtocrr.2020.100109.

Black patients with extensive-stage small cell lung cancer (ES-SCLC) are less likely to receive chemotherapy but have better survival, compared with White patients, according to a study published in JTO Clinical Research and Reports.

This study provides a large-scale analysis of real-world data identifying racial and socioeconomic factors impacting systemic therapy delivery and survival in ES-SCLC.

“The most important finding was the significant disparity in receipt of chemotherapy,” said study author Umit Tapan, MD, of Boston Medical Center.

“Black individuals with ES-SCLC were less likely to receive chemotherapy compared to Whites and other racial groups. Similarly, elderly, uninsured patients, patients with nonprivate health insurance, and those with lower education levels were less likely to be treated with chemotherapy,” Dr. Tapan said.

Using the National Cancer Data Base (NCDB), Dr. Tapan and colleagues identified 148,961 patients who were diagnosed with stage IV ES-SCLC during 2004-2016. In all, 82,592 patients were included in the study.
 

Results: Treatment and survival

Compared with White patients, Black patients (adjusted odds ratio, 0.85; P = .0004) and patients from other racial groups (aOR, 0.87; P = .126) had lower odds of receiving chemotherapy on multivariate analysis.

However, survival was superior in Black patients (adjusted hazard ratio, 0.92; P < .0001) and other non-White patients (aHR 0.86; P < .0001).

“We speculate that additional factors, such as performance status, which is not captured by NCDB, might have accounted for better survival for Black patients,” Dr. Tapan said, noting that the analysis was adjusted for known possible confounding factors, such as age, gender, and comorbidity status.

Black patients had higher odds of receiving chemotherapy between 2010 and 2016 compared with 2004 and 2009. “This suggests a positive impact of the Patient Protection and Affordable Care Act (ACA) in 2010,” Dr. Tapan said.

Another surprising finding pertained to patients with nonprivate insurance. These patients had even lower odds of getting chemotherapy after the implementation of ACA, Dr. Tapan said. Patients who had private insurance had higher survival compared with those who were uninsured.

Higher level of education, measured by percentage of residents with a high school degree, increased the odds of receiving chemotherapy.

Age also had a significant impact on receipt of chemotherapy. About 83% of patients over age 80 years received chemotherapy, compared with 94% of patients aged 40-64 years.
 

Real-world data

Minorities are underrepresented in cancer clinical trials in the United States, with only 2% of National Cancer Institute trials having sufficient minority participants, Dr. Tapan said. A study published in Academic Medicine in 2018 showed that only 13% of 782 National Institute of Health–sponsored clinical trials reported outcomes by race and ethnicity.

As a result, we are missing data on patient care in minority populations, Dr. Tapan said. “Collecting and analyzing real-world data becomes critical to study treatment patterns and outcomes,” he added.

The current real-world study had a somewhat diverse patient population, but 90.6% of patients were White, 7.8% were Black, and 1.7% were other races.

“We would have expected a higher percentage of Black patients considering the most recent U.S. Census Bureau estimates that 76.3% of the U.S. population is White and 13.4% is Black,” Dr. Tapan said. “There are conflicting results in the literature regarding racial disparities in SCLC and survival. Many of these studies were performed via state-based cancer registries instead of on a national level, making prior reports less generalizable.”
 

‘More work to do’

While the new study showed patients with nonprivate insurance or those with no insurance were less likely to receive chemotherapy, studies have shown that chemotherapy administration was not impacted by insurance status in limited-stage SCLC.

This is in contrast to radiotherapy delivery. Studies have revealed a lower likelihood of radiotherapy delivery in limited-stage SCLC for patients with government health insurance such as Medicare/Medicaid, Dr. Tapan said.

“Access to cancer care has been shown to be one of the most important barriers in racial disparity. Studies analyzing outcomes in the equal access health systems, such as the Veteran Administration, have revealed less racial disparities,” Dr. Tapan said.

Even when Black patients have equal access to care, they might receive suboptimal treatment, Dr. Tapan noted.

“Studies have shown that Black patients are not only more likely to refuse surgery, but also are more likely to be given a negative recommendation by a surgeon as compared to Whites, suggesting potential involvement of miscommunication or bias during patient-physician encounters,” Dr. Tapan said. “In the same vein, physicians would need to acknowledge their patients’ beliefs. Not doing so may lead to unsatisfactory physician-patient interactions and suboptimal decision-making.”

“Measures to reduce physician bias are an important step to reduce disparities,” Dr. Tapan continued. “Studies have shown that Black patients are perceived to be less intelligent and educated, less likely to have social support, and more likely to be at risk of noncompliance. For some patients and oncologists, extra effort is needed so that every patient can access the best possible treatments and outcomes. It is the oncologist’s responsibility to advocate for patients, but, ultimately, further legislative actions are needed to mitigate the disparities around cancer care.”

Dr. Tapan noted that, in 1966, Martin Luther King Jr., PhD, stated that “of all the forms of inequality, injustice in health care is the most shocking and inhumane.”

Dr. Tapan said: “We have overcome some barriers since 1966, but we have more work to do.” He and colleagues had no disclosures related to this study.

SOURCE: Tapan U et al. JTO Clin Res Rep. 2020. doi: 10.1016/j.jtocrr.2020.100109.

Immune checkpoint inhibitor (ICI) therapy does not increase the risk of developing or dying from COVID-19, according to a pair of studies presented at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.

Cytokine storm plays a major role in the pathogenesis of COVID-19, according to research published in The Lancet Respiratory Medicine. This has generated concern about using ICIs during the pandemic, given their immunostimulatory activity and the risk of immune-related adverse effects.

However, two retrospective studies suggest ICIs do not increase the risk of developing COVID-19 or dying from the disease.

In a study of 1,545 cancer patients prescribed ICIs and 20,418 matched controls, the incidence of COVID-19 was 1.4% with ICI therapy and 1.0% without it (odds ratio, 1.38; P = .15).

In a case-control study of 50 patients with cancer and COVID-19, 28% of patients who had received ICIs died from COVID-19, compared with 36% of patients who had not received ICIs (OR, 0.36; P = .23).

Vartan Pahalyants and Kevin Tyan, both students in Harvard University’s joint MD/MBA program in Boston, presented these studies at the meeting.
 

COVID-19 incidence with ICIs

Mr. Pahalyants and colleagues analyzed data from cancer patients treated in the Mass General Brigham health care system. The researchers compared 1,545 patients with at least one ICI prescription between July 1, 2019, and Feb. 29, 2020, with 20,418 matched cancer patients not prescribed ICIs. The team assessed COVID-19 incidence based on positive test results through June 19, 2020, from public health data.

The incidence of COVID-19 was low in both groups – 1.4% in the ICI group and 1.0% in the matched control group (P = .16). Among COVID-19–positive patients, the all-cause death rate was 40.9% in the ICI group and 28.6% in the control group (P = .23).

In multivariate analysis, patients prescribed ICIs did not have a significantly elevated risk for COVID-19 relative to peers not prescribed ICIs (OR, 1.38; P = .15). However, risk was significantly increased for female patients (OR, 1.74; P < .001), those living in a town or county with higher COVID-19 positivity rate (OR, 1.59; P < .001), and those with severe comorbidity (vs. mild or moderate; OR, 9.77; P = .02).

Among COVID-19–positive patients, those prescribed ICIs did not have a significantly elevated risk for all-cause mortality (OR, 1.60; P = .71), but male sex and lower income were associated with an increased risk of death.

“We did not identify an increased risk of [COVID-19] diagnosis among patients prescribed ICIs compared to the controls,” Mr. Pahalyants said. “This information may assist patients and their providers in decision-making around continuation of therapy during this protracted pandemic. However, more research needs to be conducted to determine potential behavioral and testing factors that may have affected COVID-19 diagnosis susceptibility among patients included in the study.”

COVID-19 mortality with ICIs

For their study, Mr. Tyan and colleagues identified 25 cancer patients who had received ICIs in the year before a COVID-19 diagnosis between March 20, 2020, and June 3, 2020, at the Dana-Farber Cancer Institute and Mass General Brigham network. The researchers then matched each patient with a cancer patient having a COVID-19 diagnosis who had not received ICIs during the preceding year.

Overall, 28% of patients who had received ICIs before their COVID-19 diagnosis died from COVID-19, compared with 36% of those who had not received ICIs.

In multivariate analysis, ICI therapy did not predict COVID-19 mortality (OR, 0.36; P = .23). However, the risk of death from COVID-19 increased with age (OR, 1.14; P = .01) and for patients with chronic obstructive pulmonary disease (OR, 12.26; P = .01), and risk was lower for statin users (OR, 0.08; P = .02). Findings were similar in an analysis restricted to hospitalized patients in the ICI group and their matched controls.

Two ICI-treated patients with COVID-19 had persistent immune-related adverse events (hypophysitis in both cases), and one ICI-treated patient developed a new immune-related adverse event (hypothyroidism).

At COVID-19 presentation, relative to counterparts who had not received ICIs, patients who had received ICIs had higher platelet counts (P = .017) and higher D-dimer levels (P = .037). In the context of similar levels of other biomarkers, this finding is “of unclear significance, as all deaths in the cohort were due to respiratory failure as opposed to hypercoagulability,” Mr. Tyan said.

The patients treated with ICIs were more likely to die from COVID-19 if they had elevated troponin levels (P = .01), whereas no such association was seen for those not treated with ICIs.

“We found that ICI therapy is not associated with greater risk for COVID-19 mortality. Our period of follow-up was relatively short, but we did not observe a high incidence of new or persistent immune-related adverse events among our patients taking ICIs,” Mr. Tyan said.

“While larger prospective trials are needed to evaluate long-term safety in the context of COVID-19 infection, our findings support the continuation of ICI therapy during the pandemic as it does not appear to worsen outcomes for cancer patients,” he concluded.
 

ICI therapy can continue, with precautions

“The question of susceptibility to COVID-19 has been unclear as ICIs do not necessarily cause immunosuppression but certainly result in modulation of a patient’s immune system,” said Deborah Doroshow, MD, PhD, assistant professor at the Tisch Cancer Institute Icahn School of Medicine at Mount Sinai, New York. She was not involved in these studies.

“The findings of the study by Pahalyants and colleagues, which used a very large sample size, appear to convincingly demonstrate that ICI receipt is not associated with an increased susceptibility to COVID-19,” Dr. Doroshow said in an interview.

SOURCE: Pahalyants V et al. SITC 2020, Abstract 826. Tyan K et al. SITC 2020, Abstract 481.

Immune checkpoint inhibitor (ICI) therapy does not increase the risk of developing or dying from COVID-19, according to a pair of studies presented at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.

Cytokine storm plays a major role in the pathogenesis of COVID-19, according to research published in The Lancet Respiratory Medicine. This has generated concern about using ICIs during the pandemic, given their immunostimulatory activity and the risk of immune-related adverse effects.

However, two retrospective studies suggest ICIs do not increase the risk of developing COVID-19 or dying from the disease.

In a study of 1,545 cancer patients prescribed ICIs and 20,418 matched controls, the incidence of COVID-19 was 1.4% with ICI therapy and 1.0% without it (odds ratio, 1.38; P = .15).

In a case-control study of 50 patients with cancer and COVID-19, 28% of patients who had received ICIs died from COVID-19, compared with 36% of patients who had not received ICIs (OR, 0.36; P = .23).

Vartan Pahalyants and Kevin Tyan, both students in Harvard University’s joint MD/MBA program in Boston, presented these studies at the meeting.
 

COVID-19 incidence with ICIs

Mr. Pahalyants and colleagues analyzed data from cancer patients treated in the Mass General Brigham health care system. The researchers compared 1,545 patients with at least one ICI prescription between July 1, 2019, and Feb. 29, 2020, with 20,418 matched cancer patients not prescribed ICIs. The team assessed COVID-19 incidence based on positive test results through June 19, 2020, from public health data.

The incidence of COVID-19 was low in both groups – 1.4% in the ICI group and 1.0% in the matched control group (P = .16). Among COVID-19–positive patients, the all-cause death rate was 40.9% in the ICI group and 28.6% in the control group (P = .23).

In multivariate analysis, patients prescribed ICIs did not have a significantly elevated risk for COVID-19 relative to peers not prescribed ICIs (OR, 1.38; P = .15). However, risk was significantly increased for female patients (OR, 1.74; P < .001), those living in a town or county with higher COVID-19 positivity rate (OR, 1.59; P < .001), and those with severe comorbidity (vs. mild or moderate; OR, 9.77; P = .02).

Among COVID-19–positive patients, those prescribed ICIs did not have a significantly elevated risk for all-cause mortality (OR, 1.60; P = .71), but male sex and lower income were associated with an increased risk of death.

“We did not identify an increased risk of [COVID-19] diagnosis among patients prescribed ICIs compared to the controls,” Mr. Pahalyants said. “This information may assist patients and their providers in decision-making around continuation of therapy during this protracted pandemic. However, more research needs to be conducted to determine potential behavioral and testing factors that may have affected COVID-19 diagnosis susceptibility among patients included in the study.”

COVID-19 mortality with ICIs

For their study, Mr. Tyan and colleagues identified 25 cancer patients who had received ICIs in the year before a COVID-19 diagnosis between March 20, 2020, and June 3, 2020, at the Dana-Farber Cancer Institute and Mass General Brigham network. The researchers then matched each patient with a cancer patient having a COVID-19 diagnosis who had not received ICIs during the preceding year.

Overall, 28% of patients who had received ICIs before their COVID-19 diagnosis died from COVID-19, compared with 36% of those who had not received ICIs.

In multivariate analysis, ICI therapy did not predict COVID-19 mortality (OR, 0.36; P = .23). However, the risk of death from COVID-19 increased with age (OR, 1.14; P = .01) and for patients with chronic obstructive pulmonary disease (OR, 12.26; P = .01), and risk was lower for statin users (OR, 0.08; P = .02). Findings were similar in an analysis restricted to hospitalized patients in the ICI group and their matched controls.

Two ICI-treated patients with COVID-19 had persistent immune-related adverse events (hypophysitis in both cases), and one ICI-treated patient developed a new immune-related adverse event (hypothyroidism).

At COVID-19 presentation, relative to counterparts who had not received ICIs, patients who had received ICIs had higher platelet counts (P = .017) and higher D-dimer levels (P = .037). In the context of similar levels of other biomarkers, this finding is “of unclear significance, as all deaths in the cohort were due to respiratory failure as opposed to hypercoagulability,” Mr. Tyan said.

The patients treated with ICIs were more likely to die from COVID-19 if they had elevated troponin levels (P = .01), whereas no such association was seen for those not treated with ICIs.

“We found that ICI therapy is not associated with greater risk for COVID-19 mortality. Our period of follow-up was relatively short, but we did not observe a high incidence of new or persistent immune-related adverse events among our patients taking ICIs,” Mr. Tyan said.

“While larger prospective trials are needed to evaluate long-term safety in the context of COVID-19 infection, our findings support the continuation of ICI therapy during the pandemic as it does not appear to worsen outcomes for cancer patients,” he concluded.
 

ICI therapy can continue, with precautions

“The question of susceptibility to COVID-19 has been unclear as ICIs do not necessarily cause immunosuppression but certainly result in modulation of a patient’s immune system,” said Deborah Doroshow, MD, PhD, assistant professor at the Tisch Cancer Institute Icahn School of Medicine at Mount Sinai, New York. She was not involved in these studies.

“The findings of the study by Pahalyants and colleagues, which used a very large sample size, appear to convincingly demonstrate that ICI receipt is not associated with an increased susceptibility to COVID-19,” Dr. Doroshow said in an interview.

SOURCE: Pahalyants V et al. SITC 2020, Abstract 826. Tyan K et al. SITC 2020, Abstract 481.

Immune checkpoint inhibitor (ICI) therapy does not increase the risk of developing or dying from COVID-19, according to a pair of studies presented at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.

Cytokine storm plays a major role in the pathogenesis of COVID-19, according to research published in The Lancet Respiratory Medicine. This has generated concern about using ICIs during the pandemic, given their immunostimulatory activity and the risk of immune-related adverse effects.

However, two retrospective studies suggest ICIs do not increase the risk of developing COVID-19 or dying from the disease.

In a study of 1,545 cancer patients prescribed ICIs and 20,418 matched controls, the incidence of COVID-19 was 1.4% with ICI therapy and 1.0% without it (odds ratio, 1.38; P = .15).

In a case-control study of 50 patients with cancer and COVID-19, 28% of patients who had received ICIs died from COVID-19, compared with 36% of patients who had not received ICIs (OR, 0.36; P = .23).

Vartan Pahalyants and Kevin Tyan, both students in Harvard University’s joint MD/MBA program in Boston, presented these studies at the meeting.
 

COVID-19 incidence with ICIs

Mr. Pahalyants and colleagues analyzed data from cancer patients treated in the Mass General Brigham health care system. The researchers compared 1,545 patients with at least one ICI prescription between July 1, 2019, and Feb. 29, 2020, with 20,418 matched cancer patients not prescribed ICIs. The team assessed COVID-19 incidence based on positive test results through June 19, 2020, from public health data.

The incidence of COVID-19 was low in both groups – 1.4% in the ICI group and 1.0% in the matched control group (P = .16). Among COVID-19–positive patients, the all-cause death rate was 40.9% in the ICI group and 28.6% in the control group (P = .23).

In multivariate analysis, patients prescribed ICIs did not have a significantly elevated risk for COVID-19 relative to peers not prescribed ICIs (OR, 1.38; P = .15). However, risk was significantly increased for female patients (OR, 1.74; P < .001), those living in a town or county with higher COVID-19 positivity rate (OR, 1.59; P < .001), and those with severe comorbidity (vs. mild or moderate; OR, 9.77; P = .02).

Among COVID-19–positive patients, those prescribed ICIs did not have a significantly elevated risk for all-cause mortality (OR, 1.60; P = .71), but male sex and lower income were associated with an increased risk of death.

“We did not identify an increased risk of [COVID-19] diagnosis among patients prescribed ICIs compared to the controls,” Mr. Pahalyants said. “This information may assist patients and their providers in decision-making around continuation of therapy during this protracted pandemic. However, more research needs to be conducted to determine potential behavioral and testing factors that may have affected COVID-19 diagnosis susceptibility among patients included in the study.”

COVID-19 mortality with ICIs

For their study, Mr. Tyan and colleagues identified 25 cancer patients who had received ICIs in the year before a COVID-19 diagnosis between March 20, 2020, and June 3, 2020, at the Dana-Farber Cancer Institute and Mass General Brigham network. The researchers then matched each patient with a cancer patient having a COVID-19 diagnosis who had not received ICIs during the preceding year.

Overall, 28% of patients who had received ICIs before their COVID-19 diagnosis died from COVID-19, compared with 36% of those who had not received ICIs.

In multivariate analysis, ICI therapy did not predict COVID-19 mortality (OR, 0.36; P = .23). However, the risk of death from COVID-19 increased with age (OR, 1.14; P = .01) and for patients with chronic obstructive pulmonary disease (OR, 12.26; P = .01), and risk was lower for statin users (OR, 0.08; P = .02). Findings were similar in an analysis restricted to hospitalized patients in the ICI group and their matched controls.

Two ICI-treated patients with COVID-19 had persistent immune-related adverse events (hypophysitis in both cases), and one ICI-treated patient developed a new immune-related adverse event (hypothyroidism).

At COVID-19 presentation, relative to counterparts who had not received ICIs, patients who had received ICIs had higher platelet counts (P = .017) and higher D-dimer levels (P = .037). In the context of similar levels of other biomarkers, this finding is “of unclear significance, as all deaths in the cohort were due to respiratory failure as opposed to hypercoagulability,” Mr. Tyan said.

The patients treated with ICIs were more likely to die from COVID-19 if they had elevated troponin levels (P = .01), whereas no such association was seen for those not treated with ICIs.

“We found that ICI therapy is not associated with greater risk for COVID-19 mortality. Our period of follow-up was relatively short, but we did not observe a high incidence of new or persistent immune-related adverse events among our patients taking ICIs,” Mr. Tyan said.

“While larger prospective trials are needed to evaluate long-term safety in the context of COVID-19 infection, our findings support the continuation of ICI therapy during the pandemic as it does not appear to worsen outcomes for cancer patients,” he concluded.
 

ICI therapy can continue, with precautions

“The question of susceptibility to COVID-19 has been unclear as ICIs do not necessarily cause immunosuppression but certainly result in modulation of a patient’s immune system,” said Deborah Doroshow, MD, PhD, assistant professor at the Tisch Cancer Institute Icahn School of Medicine at Mount Sinai, New York. She was not involved in these studies.

“The findings of the study by Pahalyants and colleagues, which used a very large sample size, appear to convincingly demonstrate that ICI receipt is not associated with an increased susceptibility to COVID-19,” Dr. Doroshow said in an interview.

SOURCE: Pahalyants V et al. SITC 2020, Abstract 826. Tyan K et al. SITC 2020, Abstract 481.

The US Food and Drug Administration (FDA) has expanded the indication for the antiviral baloxavir marboxil (Xofluza) to include postexposure prophylaxis of uncomplicated influenza in people aged 12 years and older.

“This expanded indication for Xofluza will provide an important option to help prevent influenza just in time for a flu season that is anticipated to be unlike any other because it will coincide with the coronavirus pandemic,” Debra Birnkrant, MD, director, Division of Antiviral Products, FDA Center for Drug Evaluation and Research, said in a press release.

In addition, Xofluza, which was previously available only in tablet form, is also now available as granules for mixing in water, the FDA said.

The agency first approved baloxavir marboxil in 2018 for the treatment of acute uncomplicated influenza in people aged 12 years or older who have been symptomatic for no more than 48 hours.

A year later, the FDA expanded the indication to include people at high risk of developing influenza-related complications, such as those with asthma, chronic lung disease, diabetes, heart disease, or morbid obesity, as well as adults aged 65 years or older.

The safety and efficacy of Xofluza for influenza postexposure prophylaxis is supported by a randomized, double-blind, controlled trial involving 607 people aged 12 years and older. After exposure to a person with influenza in their household, they received a single dose of Xofluza or placebo.

The primary endpoint was the proportion of individuals who became infected with influenza and presented with fever and at least one respiratory symptom from day 1 to day 10.

Of the 303 people who received Xofluza, 1% of individuals met these criteria, compared with 13% of those who received placebo.

The most common adverse effects of Xofluza include diarrhea, bronchitis, nausea, sinusitis, and headache.

Hypersensitivity, including anaphylaxis, can occur in patients taking Xofluza. The antiviral is contraindicated in people with a known hypersensitivity reaction to Xofluza.

Xofluza should not be coadministered with dairy products, calcium-fortified beverages, laxatives, antacids, or oral supplements containing calcium, iron, magnesium, selenium, aluminium, or zinc.

Full prescribing information is available online.

This article first appeared on Medscape.com.

The US Food and Drug Administration (FDA) has expanded the indication for the antiviral baloxavir marboxil (Xofluza) to include postexposure prophylaxis of uncomplicated influenza in people aged 12 years and older.

“This expanded indication for Xofluza will provide an important option to help prevent influenza just in time for a flu season that is anticipated to be unlike any other because it will coincide with the coronavirus pandemic,” Debra Birnkrant, MD, director, Division of Antiviral Products, FDA Center for Drug Evaluation and Research, said in a press release.

In addition, Xofluza, which was previously available only in tablet form, is also now available as granules for mixing in water, the FDA said.

The agency first approved baloxavir marboxil in 2018 for the treatment of acute uncomplicated influenza in people aged 12 years or older who have been symptomatic for no more than 48 hours.

A year later, the FDA expanded the indication to include people at high risk of developing influenza-related complications, such as those with asthma, chronic lung disease, diabetes, heart disease, or morbid obesity, as well as adults aged 65 years or older.

The safety and efficacy of Xofluza for influenza postexposure prophylaxis is supported by a randomized, double-blind, controlled trial involving 607 people aged 12 years and older. After exposure to a person with influenza in their household, they received a single dose of Xofluza or placebo.

The primary endpoint was the proportion of individuals who became infected with influenza and presented with fever and at least one respiratory symptom from day 1 to day 10.

Of the 303 people who received Xofluza, 1% of individuals met these criteria, compared with 13% of those who received placebo.

The most common adverse effects of Xofluza include diarrhea, bronchitis, nausea, sinusitis, and headache.

Hypersensitivity, including anaphylaxis, can occur in patients taking Xofluza. The antiviral is contraindicated in people with a known hypersensitivity reaction to Xofluza.

Xofluza should not be coadministered with dairy products, calcium-fortified beverages, laxatives, antacids, or oral supplements containing calcium, iron, magnesium, selenium, aluminium, or zinc.

Full prescribing information is available online.

This article first appeared on Medscape.com.

The US Food and Drug Administration (FDA) has expanded the indication for the antiviral baloxavir marboxil (Xofluza) to include postexposure prophylaxis of uncomplicated influenza in people aged 12 years and older.

“This expanded indication for Xofluza will provide an important option to help prevent influenza just in time for a flu season that is anticipated to be unlike any other because it will coincide with the coronavirus pandemic,” Debra Birnkrant, MD, director, Division of Antiviral Products, FDA Center for Drug Evaluation and Research, said in a press release.

In addition, Xofluza, which was previously available only in tablet form, is also now available as granules for mixing in water, the FDA said.

The agency first approved baloxavir marboxil in 2018 for the treatment of acute uncomplicated influenza in people aged 12 years or older who have been symptomatic for no more than 48 hours.

A year later, the FDA expanded the indication to include people at high risk of developing influenza-related complications, such as those with asthma, chronic lung disease, diabetes, heart disease, or morbid obesity, as well as adults aged 65 years or older.

The safety and efficacy of Xofluza for influenza postexposure prophylaxis is supported by a randomized, double-blind, controlled trial involving 607 people aged 12 years and older. After exposure to a person with influenza in their household, they received a single dose of Xofluza or placebo.

The primary endpoint was the proportion of individuals who became infected with influenza and presented with fever and at least one respiratory symptom from day 1 to day 10.

Of the 303 people who received Xofluza, 1% of individuals met these criteria, compared with 13% of those who received placebo.

The most common adverse effects of Xofluza include diarrhea, bronchitis, nausea, sinusitis, and headache.

Hypersensitivity, including anaphylaxis, can occur in patients taking Xofluza. The antiviral is contraindicated in people with a known hypersensitivity reaction to Xofluza.

Xofluza should not be coadministered with dairy products, calcium-fortified beverages, laxatives, antacids, or oral supplements containing calcium, iron, magnesium, selenium, aluminium, or zinc.

Full prescribing information is available online.

This article first appeared on Medscape.com.

Women with type 2 diabetes who take metformin during pregnancy to control their blood glucose levels experience a range of benefits, including reduced weight gain, reduced insulin doses, and fewer large-for-gestational-age babies, suggest the results of a randomized controlled trial.

However, the drug was associated with an increased risk of small-for-gestational-age babies, which poses the question as to risk versus benefit of metformin on the health of offspring.

“Better understanding of the short- and long-term implications of these effects on infants will be important to properly advise patients with type 2 diabetes contemplating use of metformin during pregnancy,” said lead author Denice S. Feig, MD, Mount Sinai Hospital, Toronto.

The research was presented at the Diabetes UK Professional Conference: Online Series on Nov. 17 and recently published in The Lancet Diabetes & Endocrinology.

Summing up, Dr. Feig said that, on balance, she would be inclined to give metformin to most pregnant women with type 2 diabetes, perhaps with the exception of those who may have risk factors for small-for-gestational-age babies; for example, women who’ve had intrauterine growth restriction, who are smokers, and have significant renal disease, or have a lower body mass index.
 

Increased prevalence of type 2 diabetes in pregnancy

Dr. Feig said that across the developed world there have been huge increases in the prevalence of type 2 diabetes in pregnancy in recent years.

Insulin is the standard treatment for the management of type 2 diabetes in pregnancy, but these women have marked insulin resistance that worsens in pregnancy, which means their insulin requirements increase, leading to weight gain, painful injections, high cost, and noncompliance.

So despite treatment with insulin, these women continue to face increased rates of adverse maternal and fetal outcomes.

And although metformin is increasingly being used in women with type 2 diabetes during pregnancy, there is a scarcity of data on the benefits and harms of metformin use on pregnancy outcomes in these women.

The MiTy trial was therefore undertaken to determine whether metformin could improve outcomes.

The team recruited 502 women from 29 sites in Canada and Australia who had type 2 diabetes prior to pregnancy or were diagnosed during pregnancy, before 20 weeks’ gestation. The women were randomized to metformin 1 g twice daily or placebo, in addition to their usual insulin regimen, at between 6 and 28 weeks’ gestation.

Type 2 diabetes was diagnosed prior to pregnancy in 83% of women in the metformin group and in 90% of those assigned to placebo. The mean hemoglobin A1c level at randomization was 47 mmol/mol (6.5%) in both groups.

The average maternal age at baseline was approximately 35 years and mean gestational age at randomization was 16 weeks. Mean prepregnancy BMI was approximately 34 kg/m².

Of note, only 30% were of European ethnicity.
 

Less weight gain, lower A1c, less insulin needed with metformin

Dr. Feig reported that there was no significant difference between the treatment groups in terms of the proportion of women with the composite primary outcome of pregnancy loss, preterm birth, birth injury, respiratory distress, neonatal hypoglycemia, or admission to neonatal intensive care lasting more than 24 hours (P = 0.86).

However, women in the metformin group had significantly less overall weight gain during pregnancy than did those in the placebo group, at –1.8 kg (P < .0001).

They also had a significantly lower last A1c level in pregnancy, at 41 mmol/mol (5.9%) versus 43.2 mmol/mol (6.1%) in those given placebo (P = .015), and required fewer insulin doses, at 1.1 versus 1.5 units/kg/day (P < .0001), which translated to a reduction of almost 44 units/day.

Women given metformin were also less likely to require Cesarean section delivery, at 53.4% versus 62.7% in the placebo group (P = .03), although there was no difference between groups in terms of gestational hypertension or preeclampsia.

The most common adverse events were gastrointestinal complications, which occurred in 27.3% of women in the metformin group and 22.3% of those given placebo.

There were no significant differences between the metformin and placebo groups in rates of pregnancy loss (P = .81), preterm birth (P = .16), birth injury (P = .37), respiratory distress (P = .49), and congenital anomalies (P = .16).
 

Average birth weight lower with metformin

However, Dr. Feig showed that the average birth weight was lower for offspring of women given metformin than those assigned to placebo, at 3.2 kg (7.05 lb) versus 3.4 kg (7.4 lb) (P = .002).

Women given metformin were also less likely to have a baby with a birth weight of 4 kg (8.8 lb) or more, at 12.1% versus 19.2%, or a relative risk of 0.65 (P = .046), and a baby that was extremely large for gestational age, at 8.6% versus 14.8%, or a relative risk of 0.58 (P = .046).

But of concern, metformin was associated with an increased risk of small-for-gestational-age babies, at 12.9% versus 6.6% with placebo, or a relative risk of 1.96 (P = .03).

Dr. Feig suggested that this may be due to a direct effect of metformin “because as we know metformin inhibits the mTOR pathway,” which is a “primary nutrient sensor in the placenta” and could “attenuate nutrient flux and fetal growth.”

She said it is not clear whether the small-for-gestational-age babies were “healthy or unhealthy.”

To investigate further, the team has launched the MiTy Kids study, which will follow the offspring in the MiTy trial to determine whether metformin during pregnancy is associated with a reduction in adiposity and improvement in insulin resistance in the babies at 2 years of age.
 

Who should be given metformin?

During the discussion, Helen R. Murphy, MD, PhD, Norwich Medical School, University of East Anglia, England, asked whether Dr. Feig would recommend continuing metformin in pregnancy if it was started preconception for fertility issues rather than diabetes.

She replied: “If they don’t have diabetes and it’s simply for PCOS [polycystic ovary syndrome], then I have either stopped it as soon as they got pregnant or sometimes continued it through the first trimester, and then stopped.

“If the person has diabetes, however, I think given this work, for most people I would continue it,” she said.

The study was funded by the Canadian Institutes of Health Research, Lunenfeld-Tanenbaum Research Institute, and the University of Toronto. The authors have reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Women with type 2 diabetes who take metformin during pregnancy to control their blood glucose levels experience a range of benefits, including reduced weight gain, reduced insulin doses, and fewer large-for-gestational-age babies, suggest the results of a randomized controlled trial.

However, the drug was associated with an increased risk of small-for-gestational-age babies, which poses the question as to risk versus benefit of metformin on the health of offspring.

“Better understanding of the short- and long-term implications of these effects on infants will be important to properly advise patients with type 2 diabetes contemplating use of metformin during pregnancy,” said lead author Denice S. Feig, MD, Mount Sinai Hospital, Toronto.

The research was presented at the Diabetes UK Professional Conference: Online Series on Nov. 17 and recently published in The Lancet Diabetes & Endocrinology.

Summing up, Dr. Feig said that, on balance, she would be inclined to give metformin to most pregnant women with type 2 diabetes, perhaps with the exception of those who may have risk factors for small-for-gestational-age babies; for example, women who’ve had intrauterine growth restriction, who are smokers, and have significant renal disease, or have a lower body mass index.
 

Increased prevalence of type 2 diabetes in pregnancy

Dr. Feig said that across the developed world there have been huge increases in the prevalence of type 2 diabetes in pregnancy in recent years.

Insulin is the standard treatment for the management of type 2 diabetes in pregnancy, but these women have marked insulin resistance that worsens in pregnancy, which means their insulin requirements increase, leading to weight gain, painful injections, high cost, and noncompliance.

So despite treatment with insulin, these women continue to face increased rates of adverse maternal and fetal outcomes.

And although metformin is increasingly being used in women with type 2 diabetes during pregnancy, there is a scarcity of data on the benefits and harms of metformin use on pregnancy outcomes in these women.

The MiTy trial was therefore undertaken to determine whether metformin could improve outcomes.

The team recruited 502 women from 29 sites in Canada and Australia who had type 2 diabetes prior to pregnancy or were diagnosed during pregnancy, before 20 weeks’ gestation. The women were randomized to metformin 1 g twice daily or placebo, in addition to their usual insulin regimen, at between 6 and 28 weeks’ gestation.

Type 2 diabetes was diagnosed prior to pregnancy in 83% of women in the metformin group and in 90% of those assigned to placebo. The mean hemoglobin A1c level at randomization was 47 mmol/mol (6.5%) in both groups.

The average maternal age at baseline was approximately 35 years and mean gestational age at randomization was 16 weeks. Mean prepregnancy BMI was approximately 34 kg/m².

Of note, only 30% were of European ethnicity.
 

Less weight gain, lower A1c, less insulin needed with metformin

Dr. Feig reported that there was no significant difference between the treatment groups in terms of the proportion of women with the composite primary outcome of pregnancy loss, preterm birth, birth injury, respiratory distress, neonatal hypoglycemia, or admission to neonatal intensive care lasting more than 24 hours (P = 0.86).

However, women in the metformin group had significantly less overall weight gain during pregnancy than did those in the placebo group, at –1.8 kg (P < .0001).

They also had a significantly lower last A1c level in pregnancy, at 41 mmol/mol (5.9%) versus 43.2 mmol/mol (6.1%) in those given placebo (P = .015), and required fewer insulin doses, at 1.1 versus 1.5 units/kg/day (P < .0001), which translated to a reduction of almost 44 units/day.

Women given metformin were also less likely to require Cesarean section delivery, at 53.4% versus 62.7% in the placebo group (P = .03), although there was no difference between groups in terms of gestational hypertension or preeclampsia.

The most common adverse events were gastrointestinal complications, which occurred in 27.3% of women in the metformin group and 22.3% of those given placebo.

There were no significant differences between the metformin and placebo groups in rates of pregnancy loss (P = .81), preterm birth (P = .16), birth injury (P = .37), respiratory distress (P = .49), and congenital anomalies (P = .16).
 

Average birth weight lower with metformin

However, Dr. Feig showed that the average birth weight was lower for offspring of women given metformin than those assigned to placebo, at 3.2 kg (7.05 lb) versus 3.4 kg (7.4 lb) (P = .002).

Women given metformin were also less likely to have a baby with a birth weight of 4 kg (8.8 lb) or more, at 12.1% versus 19.2%, or a relative risk of 0.65 (P = .046), and a baby that was extremely large for gestational age, at 8.6% versus 14.8%, or a relative risk of 0.58 (P = .046).

But of concern, metformin was associated with an increased risk of small-for-gestational-age babies, at 12.9% versus 6.6% with placebo, or a relative risk of 1.96 (P = .03).

Dr. Feig suggested that this may be due to a direct effect of metformin “because as we know metformin inhibits the mTOR pathway,” which is a “primary nutrient sensor in the placenta” and could “attenuate nutrient flux and fetal growth.”

She said it is not clear whether the small-for-gestational-age babies were “healthy or unhealthy.”

To investigate further, the team has launched the MiTy Kids study, which will follow the offspring in the MiTy trial to determine whether metformin during pregnancy is associated with a reduction in adiposity and improvement in insulin resistance in the babies at 2 years of age.
 

Who should be given metformin?

During the discussion, Helen R. Murphy, MD, PhD, Norwich Medical School, University of East Anglia, England, asked whether Dr. Feig would recommend continuing metformin in pregnancy if it was started preconception for fertility issues rather than diabetes.

She replied: “If they don’t have diabetes and it’s simply for PCOS [polycystic ovary syndrome], then I have either stopped it as soon as they got pregnant or sometimes continued it through the first trimester, and then stopped.

“If the person has diabetes, however, I think given this work, for most people I would continue it,” she said.

The study was funded by the Canadian Institutes of Health Research, Lunenfeld-Tanenbaum Research Institute, and the University of Toronto. The authors have reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Women with type 2 diabetes who take metformin during pregnancy to control their blood glucose levels experience a range of benefits, including reduced weight gain, reduced insulin doses, and fewer large-for-gestational-age babies, suggest the results of a randomized controlled trial.

However, the drug was associated with an increased risk of small-for-gestational-age babies, which poses the question as to risk versus benefit of metformin on the health of offspring.

“Better understanding of the short- and long-term implications of these effects on infants will be important to properly advise patients with type 2 diabetes contemplating use of metformin during pregnancy,” said lead author Denice S. Feig, MD, Mount Sinai Hospital, Toronto.

The research was presented at the Diabetes UK Professional Conference: Online Series on Nov. 17 and recently published in The Lancet Diabetes & Endocrinology.

Summing up, Dr. Feig said that, on balance, she would be inclined to give metformin to most pregnant women with type 2 diabetes, perhaps with the exception of those who may have risk factors for small-for-gestational-age babies; for example, women who’ve had intrauterine growth restriction, who are smokers, and have significant renal disease, or have a lower body mass index.
 

Increased prevalence of type 2 diabetes in pregnancy

Dr. Feig said that across the developed world there have been huge increases in the prevalence of type 2 diabetes in pregnancy in recent years.

Insulin is the standard treatment for the management of type 2 diabetes in pregnancy, but these women have marked insulin resistance that worsens in pregnancy, which means their insulin requirements increase, leading to weight gain, painful injections, high cost, and noncompliance.

So despite treatment with insulin, these women continue to face increased rates of adverse maternal and fetal outcomes.

And although metformin is increasingly being used in women with type 2 diabetes during pregnancy, there is a scarcity of data on the benefits and harms of metformin use on pregnancy outcomes in these women.

The MiTy trial was therefore undertaken to determine whether metformin could improve outcomes.

The team recruited 502 women from 29 sites in Canada and Australia who had type 2 diabetes prior to pregnancy or were diagnosed during pregnancy, before 20 weeks’ gestation. The women were randomized to metformin 1 g twice daily or placebo, in addition to their usual insulin regimen, at between 6 and 28 weeks’ gestation.

Type 2 diabetes was diagnosed prior to pregnancy in 83% of women in the metformin group and in 90% of those assigned to placebo. The mean hemoglobin A1c level at randomization was 47 mmol/mol (6.5%) in both groups.

The average maternal age at baseline was approximately 35 years and mean gestational age at randomization was 16 weeks. Mean prepregnancy BMI was approximately 34 kg/m².

Of note, only 30% were of European ethnicity.
 

Less weight gain, lower A1c, less insulin needed with metformin

Dr. Feig reported that there was no significant difference between the treatment groups in terms of the proportion of women with the composite primary outcome of pregnancy loss, preterm birth, birth injury, respiratory distress, neonatal hypoglycemia, or admission to neonatal intensive care lasting more than 24 hours (P = 0.86).

However, women in the metformin group had significantly less overall weight gain during pregnancy than did those in the placebo group, at –1.8 kg (P < .0001).

They also had a significantly lower last A1c level in pregnancy, at 41 mmol/mol (5.9%) versus 43.2 mmol/mol (6.1%) in those given placebo (P = .015), and required fewer insulin doses, at 1.1 versus 1.5 units/kg/day (P < .0001), which translated to a reduction of almost 44 units/day.

Women given metformin were also less likely to require Cesarean section delivery, at 53.4% versus 62.7% in the placebo group (P = .03), although there was no difference between groups in terms of gestational hypertension or preeclampsia.

The most common adverse events were gastrointestinal complications, which occurred in 27.3% of women in the metformin group and 22.3% of those given placebo.

There were no significant differences between the metformin and placebo groups in rates of pregnancy loss (P = .81), preterm birth (P = .16), birth injury (P = .37), respiratory distress (P = .49), and congenital anomalies (P = .16).
 

Average birth weight lower with metformin

However, Dr. Feig showed that the average birth weight was lower for offspring of women given metformin than those assigned to placebo, at 3.2 kg (7.05 lb) versus 3.4 kg (7.4 lb) (P = .002).

Women given metformin were also less likely to have a baby with a birth weight of 4 kg (8.8 lb) or more, at 12.1% versus 19.2%, or a relative risk of 0.65 (P = .046), and a baby that was extremely large for gestational age, at 8.6% versus 14.8%, or a relative risk of 0.58 (P = .046).

But of concern, metformin was associated with an increased risk of small-for-gestational-age babies, at 12.9% versus 6.6% with placebo, or a relative risk of 1.96 (P = .03).

Dr. Feig suggested that this may be due to a direct effect of metformin “because as we know metformin inhibits the mTOR pathway,” which is a “primary nutrient sensor in the placenta” and could “attenuate nutrient flux and fetal growth.”

She said it is not clear whether the small-for-gestational-age babies were “healthy or unhealthy.”

To investigate further, the team has launched the MiTy Kids study, which will follow the offspring in the MiTy trial to determine whether metformin during pregnancy is associated with a reduction in adiposity and improvement in insulin resistance in the babies at 2 years of age.
 

Who should be given metformin?

During the discussion, Helen R. Murphy, MD, PhD, Norwich Medical School, University of East Anglia, England, asked whether Dr. Feig would recommend continuing metformin in pregnancy if it was started preconception for fertility issues rather than diabetes.

She replied: “If they don’t have diabetes and it’s simply for PCOS [polycystic ovary syndrome], then I have either stopped it as soon as they got pregnant or sometimes continued it through the first trimester, and then stopped.

“If the person has diabetes, however, I think given this work, for most people I would continue it,” she said.

The study was funded by the Canadian Institutes of Health Research, Lunenfeld-Tanenbaum Research Institute, and the University of Toronto. The authors have reported no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

A neoadjuvant strategy combining two immunostimulatory agents with differing mechanisms of action is efficacious and safe in patients with high-risk, resectable melanoma, according to final results of the phase 2 Neo-C-Nivo trial.

The two agents are the PD-1 inhibitor nivolumab and CMP-001, an investigational Toll-like receptor 9 agonist that activates tumor-associated plasmacytoid dendritic cells.

CMP-001 and nivolumab produced a major pathologic response in 60% of patients, and these patients had a 1-year relapse-free survival rate of 89%. About 23% of patients had grade 3 treatment-related adverse events, and there were no grade 4-5 treatment-related events.

These data were reported at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.

“Stage III melanoma is a very, very high risk disease. Despite appropriate management, which involves surgical resection followed by adjuvant immunotherapy, a large number of patients still relapse,” noted study author Diwakar Davar, MD, of the University of Pittsburgh Hillman Cancer Center.

“Neoadjuvant immunotherapy in this setting enhances the systemic T-cell response to tumor antigens,” he explained. “As a result, there is greater detection and killing of micrometastatic disease. And, indeed, neoadjuvant immunotherapy with anti–[programmed death–1] monotherapy or with anti-PD1 and anti-CTLA4 combination therapy produces high response rates, although the combination therapy is associated with significant toxicity.”
 

Patients, treatment, and response

The Neo-C-Nivo trial enrolled 31 patients with resectable stage IIIB/C/D melanoma having clinically apparent lymph node disease.

The patients were treated with three cycles of nivolumab given every 2 weeks. They also received seven weekly injections of CMP-001 subcutaneously and then intratumorally. After surgical resection, the patients received more of the same immunotherapy.

At a median follow-up of 15 months, 60% of patients had a major pathologic response, 50% had a complete response, and 10% had a major response. Some 70% of patients (after additionally including partial responders) had any pathologic response.

“More than half of the patients that we treated had more than one injectable lesion,” Dr. Davar noted. “I want to emphasize that only one lesion was injected, so the results we got illustrate that the rest of the patients who had more than one injectable lesion had regression in their injected and uninjected lesions.”

Biomarker analyses showed that response was associated with evidence of immune activation, both in the tumor and in the blood. With immunotherapy, the density of CD8 tumor-infiltrating lymphocytes increased by a median of 10.3-fold in pathologic responders as compared with only 0.8-fold in nonresponders (P < .05). In addition, responders had evidence of activated CD8-positive T cells peripherally, as well as presence of plasmacytoid dendritic cells within the tumor microenvironment.
 

Survival and safety

Patients had better median relapse-free survival if they attained a major pathologic response (not reached in either group, P = .0106) or any pathologic response (not reached vs. 5 months, P = .0001).

The landmark 1-year relapse-free survival rate was 89% for major pathologic responders and 90% for all pathologic responders.

Overall, 22.6% of patients experienced grade 3 treatment-related adverse events, the majority of which did not require medical intervention and none of which delayed planned surgery. There were no grade 4-5 treatment-related adverse events.

Cytokine release syndrome was uncommon, seen in 16.1% of patients, possibly because the cohort received prophylaxis, Dr. Davar proposed.
 

Another treatment option?

“Intratumoral CMP-001 increases clinical efficacy of PD-1 blockade with minimal additional toxicity in patients with regionally advanced melanoma. Further study of this combination in high-risk resectable melanoma is planned,” Dr. Davar concluded.

“This combination achieved high response rates and certainly should be considered for a larger trial,” agreed session cochair Brian Gastman, MD, of the Cleveland (Ohio) Clinic.

However, long-term outcomes are pending, and it is not clear how efficacy of the studied combination will ultimately stack up against that of other treatment options, Dr. Gastman cautioned in an interview. “For example, it’s hard to tell if this will lead to better results versus, say, T-VEC [talimogene laherparepvec] with an anti-PD-1 agent,” he elaborated.

Nonetheless, “the implication of these findings is that there is another potential injectable option that can be combined with checkpoint inhibitors, and it may be useful for patients with refractory disease,” Dr. Gastman concluded.

The trial was funded by Checkmate Pharmaceuticals. Dr. Davar disclosed relationships with Checkmate Pharmaceuticals, Array Biopharma, Merck, Shionogi, Vedanta, Bristol-Myers Squibb, CellSight Technologies, GlaxoSmithKline/Tesaro, and Medpacto. Dr. Gastman disclosed no relevant conflicts of interest.

SOURCE: Davar D et al. SITC 2020, Abstract 303.

A neoadjuvant strategy combining two immunostimulatory agents with differing mechanisms of action is efficacious and safe in patients with high-risk, resectable melanoma, according to final results of the phase 2 Neo-C-Nivo trial.

The two agents are the PD-1 inhibitor nivolumab and CMP-001, an investigational Toll-like receptor 9 agonist that activates tumor-associated plasmacytoid dendritic cells.

CMP-001 and nivolumab produced a major pathologic response in 60% of patients, and these patients had a 1-year relapse-free survival rate of 89%. About 23% of patients had grade 3 treatment-related adverse events, and there were no grade 4-5 treatment-related events.

These data were reported at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.

“Stage III melanoma is a very, very high risk disease. Despite appropriate management, which involves surgical resection followed by adjuvant immunotherapy, a large number of patients still relapse,” noted study author Diwakar Davar, MD, of the University of Pittsburgh Hillman Cancer Center.

“Neoadjuvant immunotherapy in this setting enhances the systemic T-cell response to tumor antigens,” he explained. “As a result, there is greater detection and killing of micrometastatic disease. And, indeed, neoadjuvant immunotherapy with anti–[programmed death–1] monotherapy or with anti-PD1 and anti-CTLA4 combination therapy produces high response rates, although the combination therapy is associated with significant toxicity.”
 

Patients, treatment, and response

The Neo-C-Nivo trial enrolled 31 patients with resectable stage IIIB/C/D melanoma having clinically apparent lymph node disease.

The patients were treated with three cycles of nivolumab given every 2 weeks. They also received seven weekly injections of CMP-001 subcutaneously and then intratumorally. After surgical resection, the patients received more of the same immunotherapy.

At a median follow-up of 15 months, 60% of patients had a major pathologic response, 50% had a complete response, and 10% had a major response. Some 70% of patients (after additionally including partial responders) had any pathologic response.

“More than half of the patients that we treated had more than one injectable lesion,” Dr. Davar noted. “I want to emphasize that only one lesion was injected, so the results we got illustrate that the rest of the patients who had more than one injectable lesion had regression in their injected and uninjected lesions.”

Biomarker analyses showed that response was associated with evidence of immune activation, both in the tumor and in the blood. With immunotherapy, the density of CD8 tumor-infiltrating lymphocytes increased by a median of 10.3-fold in pathologic responders as compared with only 0.8-fold in nonresponders (P < .05). In addition, responders had evidence of activated CD8-positive T cells peripherally, as well as presence of plasmacytoid dendritic cells within the tumor microenvironment.
 

Survival and safety

Patients had better median relapse-free survival if they attained a major pathologic response (not reached in either group, P = .0106) or any pathologic response (not reached vs. 5 months, P = .0001).

The landmark 1-year relapse-free survival rate was 89% for major pathologic responders and 90% for all pathologic responders.

Overall, 22.6% of patients experienced grade 3 treatment-related adverse events, the majority of which did not require medical intervention and none of which delayed planned surgery. There were no grade 4-5 treatment-related adverse events.

Cytokine release syndrome was uncommon, seen in 16.1% of patients, possibly because the cohort received prophylaxis, Dr. Davar proposed.
 

Another treatment option?

“Intratumoral CMP-001 increases clinical efficacy of PD-1 blockade with minimal additional toxicity in patients with regionally advanced melanoma. Further study of this combination in high-risk resectable melanoma is planned,” Dr. Davar concluded.

“This combination achieved high response rates and certainly should be considered for a larger trial,” agreed session cochair Brian Gastman, MD, of the Cleveland (Ohio) Clinic.

However, long-term outcomes are pending, and it is not clear how efficacy of the studied combination will ultimately stack up against that of other treatment options, Dr. Gastman cautioned in an interview. “For example, it’s hard to tell if this will lead to better results versus, say, T-VEC [talimogene laherparepvec] with an anti-PD-1 agent,” he elaborated.

Nonetheless, “the implication of these findings is that there is another potential injectable option that can be combined with checkpoint inhibitors, and it may be useful for patients with refractory disease,” Dr. Gastman concluded.

The trial was funded by Checkmate Pharmaceuticals. Dr. Davar disclosed relationships with Checkmate Pharmaceuticals, Array Biopharma, Merck, Shionogi, Vedanta, Bristol-Myers Squibb, CellSight Technologies, GlaxoSmithKline/Tesaro, and Medpacto. Dr. Gastman disclosed no relevant conflicts of interest.

SOURCE: Davar D et al. SITC 2020, Abstract 303.

A neoadjuvant strategy combining two immunostimulatory agents with differing mechanisms of action is efficacious and safe in patients with high-risk, resectable melanoma, according to final results of the phase 2 Neo-C-Nivo trial.

The two agents are the PD-1 inhibitor nivolumab and CMP-001, an investigational Toll-like receptor 9 agonist that activates tumor-associated plasmacytoid dendritic cells.

CMP-001 and nivolumab produced a major pathologic response in 60% of patients, and these patients had a 1-year relapse-free survival rate of 89%. About 23% of patients had grade 3 treatment-related adverse events, and there were no grade 4-5 treatment-related events.

These data were reported at the Society for Immunotherapy of Cancer’s 35th Anniversary Annual Meeting.

“Stage III melanoma is a very, very high risk disease. Despite appropriate management, which involves surgical resection followed by adjuvant immunotherapy, a large number of patients still relapse,” noted study author Diwakar Davar, MD, of the University of Pittsburgh Hillman Cancer Center.

“Neoadjuvant immunotherapy in this setting enhances the systemic T-cell response to tumor antigens,” he explained. “As a result, there is greater detection and killing of micrometastatic disease. And, indeed, neoadjuvant immunotherapy with anti–[programmed death–1] monotherapy or with anti-PD1 and anti-CTLA4 combination therapy produces high response rates, although the combination therapy is associated with significant toxicity.”
 

Patients, treatment, and response

The Neo-C-Nivo trial enrolled 31 patients with resectable stage IIIB/C/D melanoma having clinically apparent lymph node disease.

The patients were treated with three cycles of nivolumab given every 2 weeks. They also received seven weekly injections of CMP-001 subcutaneously and then intratumorally. After surgical resection, the patients received more of the same immunotherapy.

At a median follow-up of 15 months, 60% of patients had a major pathologic response, 50% had a complete response, and 10% had a major response. Some 70% of patients (after additionally including partial responders) had any pathologic response.

“More than half of the patients that we treated had more than one injectable lesion,” Dr. Davar noted. “I want to emphasize that only one lesion was injected, so the results we got illustrate that the rest of the patients who had more than one injectable lesion had regression in their injected and uninjected lesions.”

Biomarker analyses showed that response was associated with evidence of immune activation, both in the tumor and in the blood. With immunotherapy, the density of CD8 tumor-infiltrating lymphocytes increased by a median of 10.3-fold in pathologic responders as compared with only 0.8-fold in nonresponders (P < .05). In addition, responders had evidence of activated CD8-positive T cells peripherally, as well as presence of plasmacytoid dendritic cells within the tumor microenvironment.
 

Survival and safety

Patients had better median relapse-free survival if they attained a major pathologic response (not reached in either group, P = .0106) or any pathologic response (not reached vs. 5 months, P = .0001).

The landmark 1-year relapse-free survival rate was 89% for major pathologic responders and 90% for all pathologic responders.

Overall, 22.6% of patients experienced grade 3 treatment-related adverse events, the majority of which did not require medical intervention and none of which delayed planned surgery. There were no grade 4-5 treatment-related adverse events.

Cytokine release syndrome was uncommon, seen in 16.1% of patients, possibly because the cohort received prophylaxis, Dr. Davar proposed.
 

Another treatment option?

“Intratumoral CMP-001 increases clinical efficacy of PD-1 blockade with minimal additional toxicity in patients with regionally advanced melanoma. Further study of this combination in high-risk resectable melanoma is planned,” Dr. Davar concluded.

“This combination achieved high response rates and certainly should be considered for a larger trial,” agreed session cochair Brian Gastman, MD, of the Cleveland (Ohio) Clinic.

However, long-term outcomes are pending, and it is not clear how efficacy of the studied combination will ultimately stack up against that of other treatment options, Dr. Gastman cautioned in an interview. “For example, it’s hard to tell if this will lead to better results versus, say, T-VEC [talimogene laherparepvec] with an anti-PD-1 agent,” he elaborated.

Nonetheless, “the implication of these findings is that there is another potential injectable option that can be combined with checkpoint inhibitors, and it may be useful for patients with refractory disease,” Dr. Gastman concluded.

The trial was funded by Checkmate Pharmaceuticals. Dr. Davar disclosed relationships with Checkmate Pharmaceuticals, Array Biopharma, Merck, Shionogi, Vedanta, Bristol-Myers Squibb, CellSight Technologies, GlaxoSmithKline/Tesaro, and Medpacto. Dr. Gastman disclosed no relevant conflicts of interest.

SOURCE: Davar D et al. SITC 2020, Abstract 303.

Finerenone, the first nonsteroidal mineralocorticoid receptor antagonist to complete a phase 3 trial, showed cardiovascular benefits in patients with type 2 diabetes and chronic kidney disease, regardless of whether they entered the study with a history of cardiovascular disease, in follow-up analyses of the FIDELIO-DKD trial, which included 5,674 patients.

“Finerenone demonstrated benefits for primary and secondary cardiovascular disease protection,” said Gerasimos Filippatos, MD, at the American Heart Association scientific sessions. Finerenone treatment cut the rate of cardiovascular death, nonfatal MI or stroke, or heart failure hospitalization, when compared with placebo, by a relative 15% among patients with a history of cardiovascular disease (CVD), and by a relative 14% in patients without this history, differences that met a statistical test for consistency. But the absolute, drug-associated increments in benefit over placebo differed between the two CVD subgroups because of a sharp underlying difference in event rates.

In contrast, the analyses reported by Dr. Filippatos and associates from the FIDELIO-DKD study showed significant heterogeneity based on the presence or absence of CVD for the study’s primary endpoint, a composite renal metric that tallied the combined rate of death from renal causes, renal failure, or a sustained drop in estimated glomerular filtration rate of at least 40%. Researchers enrolled patients into FIDELIO-DKD based on having type 2 diabetes (T2D) and chronic kidney disease (CKD). The prevalence of a history of CVD was 46%.

Among patients with a history of CVD, the composite adverse CVD outcome occurred at a rate of 8.5/100 patient-years in patients on placebo and in 7.18/100 patients years among those on finerenone during a median of 2.6 years of follow-up, a 1.32/100–patient-year absolute between-group difference. Among patients in a primary prevention setting, incident CVD event rates during follow-up were roughly half that in the secondary prevention patients. The upshot was that, in the placebo group, the rate was 3.92/100 patient- years, and in those on finerenone was 3.43/100 patient-years, a 0.49/100–patient-year absolute difference.
 

CVD history produced heterogeneity for the primary endpoint

In the analysis that focused on the study’s primary, renal endpoint, among patients identified as having CVD at study entry, the outcome occurred at a rate of 9.06/100 patient-years in the placebo subgroup and at a rate of 6.6/100 patient years in those who received finerenone, a significant 30% relative risk reduction and an absolute between-group difference of 2.46/100 patient-years.

In contrast, among patients without a CVD history, the composite renal endpoint occurred at a rate of 9.1/100 patient-years in the placebo patients and 8.42/100 patient-years in those on finerenone, a 6% relative risk reduction that was not significant, and a 0.68/100–patient-year absolute difference. This disparity in the primary event rate between the two treatment arms reached statistical significance (P = .016), the investigators reported in the published version of the report in Circulation that simultaneously appeared online.

“The totality of evidence suggests that finerenone could be used in patients with T2D with or without a history of CVD,” explained Dr. Filippatos in an interview. “The P-interaction for the composite kidney outcome is significant, but it is not corrected for multiple testing; therefore, it might be a false-chance finding and must be interpreted cautiously.

Furthermore, in another prespecified kidney composite outcome the results were consistent in patients with and without a history of CVD. In sum, all the FIDELIO-DKD analyses so far are “suggestive of a beneficial effect in patients without a history of CVD.”

Despite these patients receiving guideline directed therapies, “there remains a high unmet medical need in patients with T2D and CKD,” added Dr. Filippatos, professor of cardiology at the University of Athens. “We use multiple treatments for patients with heart failure, and we should use the same mindset for treating patients with T2D and CKD. The costs of dialysis and kidney transplant are very high, so it is important to consider options that slow progression of CKD in these patients.”

In FIDELIO-DKD, virtually all patients were on background therapy with a renin-angiotensin-system (RAS) inhibitor, so the trial’s results suggest that treatment should at least involve dual therapy with finerenone and a RAS inhibitor. Fewer than 5% were on background therapy with a sodium-glucose cotransporter 2 (SGLT2) inhibitor, a drug class recently established as another key agent for treating CKD in patients with T2D, setting up the prospect for triple therapy, although this approach has not yet undergone prospective testing.

Combining RAS inhibition, finerenone, and an SGLT2 inhibitor is “potentially a marriage made in diabetes heaven,” commented Deepak L. Bhatt, MD, a professor of medicine at Harvard Medical School, Boston, who has not participated in finerenone studies.

Finerenone looks better for safety

Regardless of subgroup analyses based on history of CVD, the findings from all patients enrolled in FIDELIO-DKD were positive for the both the primary renal outcome and key secondary outcome of composite CVD events. In the total randomized cohort, treatment with finerenone on top of optimized treatment with an ACE inhibitor or angiotensin receptor blocker (RAS inhibition) led to a significant 18% relative risk reduction, compared with placebo, for the primary renal endpoint, and a significant 14% relative drop in the key secondary CVD outcome. Those results were published in October in the New England Journal of Medicine.

[email protected]

Finerenone, the first nonsteroidal mineralocorticoid receptor antagonist to complete a phase 3 trial, showed cardiovascular benefits in patients with type 2 diabetes and chronic kidney disease, regardless of whether they entered the study with a history of cardiovascular disease, in follow-up analyses of the FIDELIO-DKD trial, which included 5,674 patients.

“Finerenone demonstrated benefits for primary and secondary cardiovascular disease protection,” said Gerasimos Filippatos, MD, at the American Heart Association scientific sessions. Finerenone treatment cut the rate of cardiovascular death, nonfatal MI or stroke, or heart failure hospitalization, when compared with placebo, by a relative 15% among patients with a history of cardiovascular disease (CVD), and by a relative 14% in patients without this history, differences that met a statistical test for consistency. But the absolute, drug-associated increments in benefit over placebo differed between the two CVD subgroups because of a sharp underlying difference in event rates.

In contrast, the analyses reported by Dr. Filippatos and associates from the FIDELIO-DKD study showed significant heterogeneity based on the presence or absence of CVD for the study’s primary endpoint, a composite renal metric that tallied the combined rate of death from renal causes, renal failure, or a sustained drop in estimated glomerular filtration rate of at least 40%. Researchers enrolled patients into FIDELIO-DKD based on having type 2 diabetes (T2D) and chronic kidney disease (CKD). The prevalence of a history of CVD was 46%.

Among patients with a history of CVD, the composite adverse CVD outcome occurred at a rate of 8.5/100 patient-years in patients on placebo and in 7.18/100 patients years among those on finerenone during a median of 2.6 years of follow-up, a 1.32/100–patient-year absolute between-group difference. Among patients in a primary prevention setting, incident CVD event rates during follow-up were roughly half that in the secondary prevention patients. The upshot was that, in the placebo group, the rate was 3.92/100 patient- years, and in those on finerenone was 3.43/100 patient-years, a 0.49/100–patient-year absolute difference.
 

CVD history produced heterogeneity for the primary endpoint

In the analysis that focused on the study’s primary, renal endpoint, among patients identified as having CVD at study entry, the outcome occurred at a rate of 9.06/100 patient-years in the placebo subgroup and at a rate of 6.6/100 patient years in those who received finerenone, a significant 30% relative risk reduction and an absolute between-group difference of 2.46/100 patient-years.

In contrast, among patients without a CVD history, the composite renal endpoint occurred at a rate of 9.1/100 patient-years in the placebo patients and 8.42/100 patient-years in those on finerenone, a 6% relative risk reduction that was not significant, and a 0.68/100–patient-year absolute difference. This disparity in the primary event rate between the two treatment arms reached statistical significance (P = .016), the investigators reported in the published version of the report in Circulation that simultaneously appeared online.

“The totality of evidence suggests that finerenone could be used in patients with T2D with or without a history of CVD,” explained Dr. Filippatos in an interview. “The P-interaction for the composite kidney outcome is significant, but it is not corrected for multiple testing; therefore, it might be a false-chance finding and must be interpreted cautiously.

Furthermore, in another prespecified kidney composite outcome the results were consistent in patients with and without a history of CVD. In sum, all the FIDELIO-DKD analyses so far are “suggestive of a beneficial effect in patients without a history of CVD.”

Despite these patients receiving guideline directed therapies, “there remains a high unmet medical need in patients with T2D and CKD,” added Dr. Filippatos, professor of cardiology at the University of Athens. “We use multiple treatments for patients with heart failure, and we should use the same mindset for treating patients with T2D and CKD. The costs of dialysis and kidney transplant are very high, so it is important to consider options that slow progression of CKD in these patients.”

In FIDELIO-DKD, virtually all patients were on background therapy with a renin-angiotensin-system (RAS) inhibitor, so the trial’s results suggest that treatment should at least involve dual therapy with finerenone and a RAS inhibitor. Fewer than 5% were on background therapy with a sodium-glucose cotransporter 2 (SGLT2) inhibitor, a drug class recently established as another key agent for treating CKD in patients with T2D, setting up the prospect for triple therapy, although this approach has not yet undergone prospective testing.

Combining RAS inhibition, finerenone, and an SGLT2 inhibitor is “potentially a marriage made in diabetes heaven,” commented Deepak L. Bhatt, MD, a professor of medicine at Harvard Medical School, Boston, who has not participated in finerenone studies.

Finerenone looks better for safety

Regardless of subgroup analyses based on history of CVD, the findings from all patients enrolled in FIDELIO-DKD were positive for the both the primary renal outcome and key secondary outcome of composite CVD events. In the total randomized cohort, treatment with finerenone on top of optimized treatment with an ACE inhibitor or angiotensin receptor blocker (RAS inhibition) led to a significant 18% relative risk reduction, compared with placebo, for the primary renal endpoint, and a significant 14% relative drop in the key secondary CVD outcome. Those results were published in October in the New England Journal of Medicine.

[email protected]

Finerenone, the first nonsteroidal mineralocorticoid receptor antagonist to complete a phase 3 trial, showed cardiovascular benefits in patients with type 2 diabetes and chronic kidney disease, regardless of whether they entered the study with a history of cardiovascular disease, in follow-up analyses of the FIDELIO-DKD trial, which included 5,674 patients.

“Finerenone demonstrated benefits for primary and secondary cardiovascular disease protection,” said Gerasimos Filippatos, MD, at the American Heart Association scientific sessions. Finerenone treatment cut the rate of cardiovascular death, nonfatal MI or stroke, or heart failure hospitalization, when compared with placebo, by a relative 15% among patients with a history of cardiovascular disease (CVD), and by a relative 14% in patients without this history, differences that met a statistical test for consistency. But the absolute, drug-associated increments in benefit over placebo differed between the two CVD subgroups because of a sharp underlying difference in event rates.

In contrast, the analyses reported by Dr. Filippatos and associates from the FIDELIO-DKD study showed significant heterogeneity based on the presence or absence of CVD for the study’s primary endpoint, a composite renal metric that tallied the combined rate of death from renal causes, renal failure, or a sustained drop in estimated glomerular filtration rate of at least 40%. Researchers enrolled patients into FIDELIO-DKD based on having type 2 diabetes (T2D) and chronic kidney disease (CKD). The prevalence of a history of CVD was 46%.

Among patients with a history of CVD, the composite adverse CVD outcome occurred at a rate of 8.5/100 patient-years in patients on placebo and in 7.18/100 patients years among those on finerenone during a median of 2.6 years of follow-up, a 1.32/100–patient-year absolute between-group difference. Among patients in a primary prevention setting, incident CVD event rates during follow-up were roughly half that in the secondary prevention patients. The upshot was that, in the placebo group, the rate was 3.92/100 patient- years, and in those on finerenone was 3.43/100 patient-years, a 0.49/100–patient-year absolute difference.
 

CVD history produced heterogeneity for the primary endpoint

In the analysis that focused on the study’s primary, renal endpoint, among patients identified as having CVD at study entry, the outcome occurred at a rate of 9.06/100 patient-years in the placebo subgroup and at a rate of 6.6/100 patient years in those who received finerenone, a significant 30% relative risk reduction and an absolute between-group difference of 2.46/100 patient-years.

In contrast, among patients without a CVD history, the composite renal endpoint occurred at a rate of 9.1/100 patient-years in the placebo patients and 8.42/100 patient-years in those on finerenone, a 6% relative risk reduction that was not significant, and a 0.68/100–patient-year absolute difference. This disparity in the primary event rate between the two treatment arms reached statistical significance (P = .016), the investigators reported in the published version of the report in Circulation that simultaneously appeared online.

“The totality of evidence suggests that finerenone could be used in patients with T2D with or without a history of CVD,” explained Dr. Filippatos in an interview. “The P-interaction for the composite kidney outcome is significant, but it is not corrected for multiple testing; therefore, it might be a false-chance finding and must be interpreted cautiously.

Furthermore, in another prespecified kidney composite outcome the results were consistent in patients with and without a history of CVD. In sum, all the FIDELIO-DKD analyses so far are “suggestive of a beneficial effect in patients without a history of CVD.”

Despite these patients receiving guideline directed therapies, “there remains a high unmet medical need in patients with T2D and CKD,” added Dr. Filippatos, professor of cardiology at the University of Athens. “We use multiple treatments for patients with heart failure, and we should use the same mindset for treating patients with T2D and CKD. The costs of dialysis and kidney transplant are very high, so it is important to consider options that slow progression of CKD in these patients.”

In FIDELIO-DKD, virtually all patients were on background therapy with a renin-angiotensin-system (RAS) inhibitor, so the trial’s results suggest that treatment should at least involve dual therapy with finerenone and a RAS inhibitor. Fewer than 5% were on background therapy with a sodium-glucose cotransporter 2 (SGLT2) inhibitor, a drug class recently established as another key agent for treating CKD in patients with T2D, setting up the prospect for triple therapy, although this approach has not yet undergone prospective testing.

Combining RAS inhibition, finerenone, and an SGLT2 inhibitor is “potentially a marriage made in diabetes heaven,” commented Deepak L. Bhatt, MD, a professor of medicine at Harvard Medical School, Boston, who has not participated in finerenone studies.

Finerenone looks better for safety

Regardless of subgroup analyses based on history of CVD, the findings from all patients enrolled in FIDELIO-DKD were positive for the both the primary renal outcome and key secondary outcome of composite CVD events. In the total randomized cohort, treatment with finerenone on top of optimized treatment with an ACE inhibitor or angiotensin receptor blocker (RAS inhibition) led to a significant 18% relative risk reduction, compared with placebo, for the primary renal endpoint, and a significant 14% relative drop in the key secondary CVD outcome. Those results were published in October in the New England Journal of Medicine.

[email protected]