The Food and Drug Administration has approved the aspirin/omeprazole combination drug Yosprala for patients who seek to prevent secondary cardiovascular events but who avoid aspirin because of their risk for gastric ulcers. The approval was announced in a press release Sept. 15 from Aralez Pharmaceuticals.

The medication contains 40 mg of immediate-release omeprazole and either 81 mg or 325 mg of aspirin in an enteric-coated core for delayed release. The immediate-release omeprazole “is designed to elevate the gastric pH into a gastroprotective zone,” according to the company. “The enteric-coated aspirin dissolves after the pH has been elevated to at least 5.5 within the gastroprotective zone, thereby reducing stomach ulcer risk.”

The approval is based on data from a pair of randomized, double-blind, controlled trials. In these studies, patients at risk for gastric ulcers were significantly less likely to report ulcers and significantly less likely to discontinue the medication than were controls who received aspirin alone. Side effects were not significantly different between the groups; the most common side effects were indigestion, stomach pain, nausea, diarrhea, gastric polyps, and chest pain.

The studies did not examine whether the medication had an impact on the risk of GI bleeding. The drug is not approved for use in children.

The Food and Drug Administration has approved the aspirin/omeprazole combination drug Yosprala for patients who seek to prevent secondary cardiovascular events but who avoid aspirin because of their risk for gastric ulcers. The approval was announced in a press release Sept. 15 from Aralez Pharmaceuticals.

The medication contains 40 mg of immediate-release omeprazole and either 81 mg or 325 mg of aspirin in an enteric-coated core for delayed release. The immediate-release omeprazole “is designed to elevate the gastric pH into a gastroprotective zone,” according to the company. “The enteric-coated aspirin dissolves after the pH has been elevated to at least 5.5 within the gastroprotective zone, thereby reducing stomach ulcer risk.”

The approval is based on data from a pair of randomized, double-blind, controlled trials. In these studies, patients at risk for gastric ulcers were significantly less likely to report ulcers and significantly less likely to discontinue the medication than were controls who received aspirin alone. Side effects were not significantly different between the groups; the most common side effects were indigestion, stomach pain, nausea, diarrhea, gastric polyps, and chest pain.

The studies did not examine whether the medication had an impact on the risk of GI bleeding. The drug is not approved for use in children.

The Food and Drug Administration has approved the aspirin/omeprazole combination drug Yosprala for patients who seek to prevent secondary cardiovascular events but who avoid aspirin because of their risk for gastric ulcers. The approval was announced in a press release Sept. 15 from Aralez Pharmaceuticals.

The medication contains 40 mg of immediate-release omeprazole and either 81 mg or 325 mg of aspirin in an enteric-coated core for delayed release. The immediate-release omeprazole “is designed to elevate the gastric pH into a gastroprotective zone,” according to the company. “The enteric-coated aspirin dissolves after the pH has been elevated to at least 5.5 within the gastroprotective zone, thereby reducing stomach ulcer risk.”

The approval is based on data from a pair of randomized, double-blind, controlled trials. In these studies, patients at risk for gastric ulcers were significantly less likely to report ulcers and significantly less likely to discontinue the medication than were controls who received aspirin alone. Side effects were not significantly different between the groups; the most common side effects were indigestion, stomach pain, nausea, diarrhea, gastric polyps, and chest pain.

The studies did not examine whether the medication had an impact on the risk of GI bleeding. The drug is not approved for use in children.

MUNICH – Enough studies exist now to support the notion of dual therapy in type 2 diabetes. But, with 13 classes of antihyperglycemic drugs approved in the United States – 7 of which are considered major – how does anyone make sense of the myriad of possible combinations?

It’s not a bad problem to have, Ele Ferrannini, MD, said shortly before the DURATION-8 data were presented at the annual meeting of the European Association for the Study of Diabetes.

“We have seen an explosion of pharmacological treatment options for type 2 diabetes in the last 20 years, which is really unprecedented, especially if we compare that to what has happened in hypertension or cardiology,” said Dr. Ferrannini of the University of Pisa (Italy). “This has given us the blessing of multiple options for treatment. But we are also now at a slight disadvantage. We all agree that we should advocate for combination treatment as early and aggressively as possible for our type 2 diabetes patients, but the question is, What combination?”

The question cannot be answered fully, he said. “If we had to test each possible combination in dual therapy, and counted all 13 classes, that would be 78 combinations. And if we started talking about triple therapy – which may eventually arrive – we could be talking about 286 possible combinations. So it’s just not possible to formally test the efficacy and the risk/benefit profile of every one. That means we have to start thinking about rational combinations based on mechanism of action.”

The combination of dapagliflozin and exenatide, tested in DURATION-8 is a good example, he said. “It’s rational,” because exenatide and dapagliflozin work completely independently of each other, each adding a unique method of action without overtargeting the same system and increasing the risk of adverse events.

Dapagliflozin is an inhibitor of the renal sodium-glucose cotransporter–2 (SGLT-2). This class of drugs works in the proximal renal tubule, where these glucose transporters absorb “huge amounts” of glucose, he said. “Whatever escapes there is then mopped up by the SGLT-1 cotransporters further along the nephron,” Dr. Ferrannini said. “SGLT inhibitors cause an upward and leftward shift of the relationship between plasma glucose and glycosuria for the same glomerular filtration rate.”

In the presence of an SGLT-2 inhibitor, glycosuria is increased, no matter what the plasma glucose level is. “This even takes place well within the euglycemic range, which is why these drugs cause glycosuria even in nondiabetic individuals,” Dr. Ferrannini said.

Numerous studies have shown that this class of drugs works well independently, and also pairs well with metformin, sulfonylureas, dipeptidyl peptidase–4 inhibitors, and insulin. Several studies of dapagliflozin have found that adding 10 mg to monotherapy reduced HbA_1c on the order of almost 1%, regardless of the concomitant medication.

Dapagliflozin works especially well in patients with very high HbA_{1c levels}, Dr. Ferrannini said, as shown in a 2010 dose-ranging study he led. “If the initial HbA_1c was above 10%, the drop associated with adding dapagliflozin was surprisingly large, on the order of 3%-4%,” he said Diabetes Care 2010 Oct;33(10):2217-24.

The primary response on HbA_1c is also quite durable, unlike the response seen in sulfonylureas, for example, which eventually wanes. “Every time you give this pill, you get glycosuria. It just doesn’t change,” he said.

Dapagliflozin also exerts a sustained benefit on systolic blood pressure, and causes a very consistent 2- to 3-kg decrease in body weight, no matter whether it’s given alone or with metformin, insulin, or a sulphonylurea.

But when it comes to shedding calories through urine, the body can’t be tricked forever, it seems. “You could assume very easily that body weight would continue to decline with an SGLT-2 inhibitor, but in fact it levels off after 2-3 kg. There can only be one explanation for this, and that is an increase in calorie intake. The body feels this loss of calories, particularly this massive loss of carbohydrate calories through the urine, and responds by implementing adaptive behaviors that increase calorie intake,” Dr. Ferrannini said.

In other words, hunger strikes. And strikes hard. That’s where the incretins come into play, he said.

“If we could interfere with this response that limits weight loss, we could probably continue to lose weight, and also see general improvements in HbA_1c. And a very important element of incretin action is that they restore insulin release in patients with diabetes” and moderate appetite, he said.

Incretins like exenatide, a glucagonlike peptide–1 receptor agonist, impose their weight loss effect through an entirely different system. “By delaying gastric emptying and also – more importantly – through neural signaling, they potentiate satiety, thus limiting calorie intake, reducing energy balance, and leading to a reduction in body weight,” Dr. Ferrannini said.

Therefore, using a combination like dapagliflozin and exenatide makes complete physiologic sense, he said. Both drugs improve HbA_1c, and decrease body weight and systolic blood pressure. Dapagliflozin accomplishes these tasks by increasing urinary glucose excretion, which leads to decreased vascular stiffness and better blood pressure. Exenatide works in a completely different pathway - insulin signaling - and has the additional benefit of decreasing inflammation.

The positive results of DURATION-8 support this clinical assumption, he concluded. “I would submit that combination therapy with exenatide and dapagliflozin is a rational approach, and takes advantage of the unique properties of both of these drugs,” he said.

Dr. Ferrannini has received research finding from AstraZeneca, which manufactures dapagliflozin and exenatide, as well as other companies that market diabetes drugs.

[email protected]

On Twitter @Alz_Gal

MUNICH – Enough studies exist now to support the notion of dual therapy in type 2 diabetes. But, with 13 classes of antihyperglycemic drugs approved in the United States – 7 of which are considered major – how does anyone make sense of the myriad of possible combinations?

It’s not a bad problem to have, Ele Ferrannini, MD, said shortly before the DURATION-8 data were presented at the annual meeting of the European Association for the Study of Diabetes.

“We have seen an explosion of pharmacological treatment options for type 2 diabetes in the last 20 years, which is really unprecedented, especially if we compare that to what has happened in hypertension or cardiology,” said Dr. Ferrannini of the University of Pisa (Italy). “This has given us the blessing of multiple options for treatment. But we are also now at a slight disadvantage. We all agree that we should advocate for combination treatment as early and aggressively as possible for our type 2 diabetes patients, but the question is, What combination?”

The question cannot be answered fully, he said. “If we had to test each possible combination in dual therapy, and counted all 13 classes, that would be 78 combinations. And if we started talking about triple therapy – which may eventually arrive – we could be talking about 286 possible combinations. So it’s just not possible to formally test the efficacy and the risk/benefit profile of every one. That means we have to start thinking about rational combinations based on mechanism of action.”

The combination of dapagliflozin and exenatide, tested in DURATION-8 is a good example, he said. “It’s rational,” because exenatide and dapagliflozin work completely independently of each other, each adding a unique method of action without overtargeting the same system and increasing the risk of adverse events.

Dapagliflozin is an inhibitor of the renal sodium-glucose cotransporter–2 (SGLT-2). This class of drugs works in the proximal renal tubule, where these glucose transporters absorb “huge amounts” of glucose, he said. “Whatever escapes there is then mopped up by the SGLT-1 cotransporters further along the nephron,” Dr. Ferrannini said. “SGLT inhibitors cause an upward and leftward shift of the relationship between plasma glucose and glycosuria for the same glomerular filtration rate.”

In the presence of an SGLT-2 inhibitor, glycosuria is increased, no matter what the plasma glucose level is. “This even takes place well within the euglycemic range, which is why these drugs cause glycosuria even in nondiabetic individuals,” Dr. Ferrannini said.

Numerous studies have shown that this class of drugs works well independently, and also pairs well with metformin, sulfonylureas, dipeptidyl peptidase–4 inhibitors, and insulin. Several studies of dapagliflozin have found that adding 10 mg to monotherapy reduced HbA_1c on the order of almost 1%, regardless of the concomitant medication.

Dapagliflozin works especially well in patients with very high HbA_{1c levels}, Dr. Ferrannini said, as shown in a 2010 dose-ranging study he led. “If the initial HbA_1c was above 10%, the drop associated with adding dapagliflozin was surprisingly large, on the order of 3%-4%,” he said Diabetes Care 2010 Oct;33(10):2217-24.

The primary response on HbA_1c is also quite durable, unlike the response seen in sulfonylureas, for example, which eventually wanes. “Every time you give this pill, you get glycosuria. It just doesn’t change,” he said.

Dapagliflozin also exerts a sustained benefit on systolic blood pressure, and causes a very consistent 2- to 3-kg decrease in body weight, no matter whether it’s given alone or with metformin, insulin, or a sulphonylurea.

But when it comes to shedding calories through urine, the body can’t be tricked forever, it seems. “You could assume very easily that body weight would continue to decline with an SGLT-2 inhibitor, but in fact it levels off after 2-3 kg. There can only be one explanation for this, and that is an increase in calorie intake. The body feels this loss of calories, particularly this massive loss of carbohydrate calories through the urine, and responds by implementing adaptive behaviors that increase calorie intake,” Dr. Ferrannini said.

In other words, hunger strikes. And strikes hard. That’s where the incretins come into play, he said.

“If we could interfere with this response that limits weight loss, we could probably continue to lose weight, and also see general improvements in HbA_1c. And a very important element of incretin action is that they restore insulin release in patients with diabetes” and moderate appetite, he said.

Incretins like exenatide, a glucagonlike peptide–1 receptor agonist, impose their weight loss effect through an entirely different system. “By delaying gastric emptying and also – more importantly – through neural signaling, they potentiate satiety, thus limiting calorie intake, reducing energy balance, and leading to a reduction in body weight,” Dr. Ferrannini said.

Therefore, using a combination like dapagliflozin and exenatide makes complete physiologic sense, he said. Both drugs improve HbA_1c, and decrease body weight and systolic blood pressure. Dapagliflozin accomplishes these tasks by increasing urinary glucose excretion, which leads to decreased vascular stiffness and better blood pressure. Exenatide works in a completely different pathway - insulin signaling - and has the additional benefit of decreasing inflammation.

The positive results of DURATION-8 support this clinical assumption, he concluded. “I would submit that combination therapy with exenatide and dapagliflozin is a rational approach, and takes advantage of the unique properties of both of these drugs,” he said.

Dr. Ferrannini has received research finding from AstraZeneca, which manufactures dapagliflozin and exenatide, as well as other companies that market diabetes drugs.

[email protected]

On Twitter @Alz_Gal

MUNICH – Enough studies exist now to support the notion of dual therapy in type 2 diabetes. But, with 13 classes of antihyperglycemic drugs approved in the United States – 7 of which are considered major – how does anyone make sense of the myriad of possible combinations?

It’s not a bad problem to have, Ele Ferrannini, MD, said shortly before the DURATION-8 data were presented at the annual meeting of the European Association for the Study of Diabetes.

“We have seen an explosion of pharmacological treatment options for type 2 diabetes in the last 20 years, which is really unprecedented, especially if we compare that to what has happened in hypertension or cardiology,” said Dr. Ferrannini of the University of Pisa (Italy). “This has given us the blessing of multiple options for treatment. But we are also now at a slight disadvantage. We all agree that we should advocate for combination treatment as early and aggressively as possible for our type 2 diabetes patients, but the question is, What combination?”

The question cannot be answered fully, he said. “If we had to test each possible combination in dual therapy, and counted all 13 classes, that would be 78 combinations. And if we started talking about triple therapy – which may eventually arrive – we could be talking about 286 possible combinations. So it’s just not possible to formally test the efficacy and the risk/benefit profile of every one. That means we have to start thinking about rational combinations based on mechanism of action.”

The combination of dapagliflozin and exenatide, tested in DURATION-8 is a good example, he said. “It’s rational,” because exenatide and dapagliflozin work completely independently of each other, each adding a unique method of action without overtargeting the same system and increasing the risk of adverse events.

Dapagliflozin is an inhibitor of the renal sodium-glucose cotransporter–2 (SGLT-2). This class of drugs works in the proximal renal tubule, where these glucose transporters absorb “huge amounts” of glucose, he said. “Whatever escapes there is then mopped up by the SGLT-1 cotransporters further along the nephron,” Dr. Ferrannini said. “SGLT inhibitors cause an upward and leftward shift of the relationship between plasma glucose and glycosuria for the same glomerular filtration rate.”

In the presence of an SGLT-2 inhibitor, glycosuria is increased, no matter what the plasma glucose level is. “This even takes place well within the euglycemic range, which is why these drugs cause glycosuria even in nondiabetic individuals,” Dr. Ferrannini said.

Numerous studies have shown that this class of drugs works well independently, and also pairs well with metformin, sulfonylureas, dipeptidyl peptidase–4 inhibitors, and insulin. Several studies of dapagliflozin have found that adding 10 mg to monotherapy reduced HbA_1c on the order of almost 1%, regardless of the concomitant medication.

Dapagliflozin works especially well in patients with very high HbA_{1c levels}, Dr. Ferrannini said, as shown in a 2010 dose-ranging study he led. “If the initial HbA_1c was above 10%, the drop associated with adding dapagliflozin was surprisingly large, on the order of 3%-4%,” he said Diabetes Care 2010 Oct;33(10):2217-24.

The primary response on HbA_1c is also quite durable, unlike the response seen in sulfonylureas, for example, which eventually wanes. “Every time you give this pill, you get glycosuria. It just doesn’t change,” he said.

Dapagliflozin also exerts a sustained benefit on systolic blood pressure, and causes a very consistent 2- to 3-kg decrease in body weight, no matter whether it’s given alone or with metformin, insulin, or a sulphonylurea.

But when it comes to shedding calories through urine, the body can’t be tricked forever, it seems. “You could assume very easily that body weight would continue to decline with an SGLT-2 inhibitor, but in fact it levels off after 2-3 kg. There can only be one explanation for this, and that is an increase in calorie intake. The body feels this loss of calories, particularly this massive loss of carbohydrate calories through the urine, and responds by implementing adaptive behaviors that increase calorie intake,” Dr. Ferrannini said.

In other words, hunger strikes. And strikes hard. That’s where the incretins come into play, he said.

“If we could interfere with this response that limits weight loss, we could probably continue to lose weight, and also see general improvements in HbA_1c. And a very important element of incretin action is that they restore insulin release in patients with diabetes” and moderate appetite, he said.

Incretins like exenatide, a glucagonlike peptide–1 receptor agonist, impose their weight loss effect through an entirely different system. “By delaying gastric emptying and also – more importantly – through neural signaling, they potentiate satiety, thus limiting calorie intake, reducing energy balance, and leading to a reduction in body weight,” Dr. Ferrannini said.

Therefore, using a combination like dapagliflozin and exenatide makes complete physiologic sense, he said. Both drugs improve HbA_1c, and decrease body weight and systolic blood pressure. Dapagliflozin accomplishes these tasks by increasing urinary glucose excretion, which leads to decreased vascular stiffness and better blood pressure. Exenatide works in a completely different pathway - insulin signaling - and has the additional benefit of decreasing inflammation.

The positive results of DURATION-8 support this clinical assumption, he concluded. “I would submit that combination therapy with exenatide and dapagliflozin is a rational approach, and takes advantage of the unique properties of both of these drugs,” he said.

Dr. Ferrannini has received research finding from AstraZeneca, which manufactures dapagliflozin and exenatide, as well as other companies that market diabetes drugs.

[email protected]

On Twitter @Alz_Gal

Decisions in popliteal or below-knee atherectomy can be complicated by a wide array of devices and lesion types.

Limited data on the long-term durability of interventions, or direct comparisons of approaches, can also complicate the decision-making process, as do cost concerns.

In his Sunday, September 18 talk at VIVA, titled “Popliteal and Below-the-Knee Atherectomy – Which Tool in Which Circumstance and When Not to Bother,” James F. McKinsey, MD, aims to help clinicians navigate this quickly changing field, with updates on emerging technologies.

Directional atherectomy and laser devices continue to undergo innovation, with new devices introduced almost annually. The changing device picture can be confusing, acknowledged Dr. McKinsey of Mt. Sinai Health System in New York. “I am well versed with many of them because I have a high volume. But people with just a few cases a month may not be,” he said.

Lower volume practitioners “need to find at least one, if not two, devices that they are going to be comfortable with,” Dr. McKinsey said, noting that each is associated with a special technique and may require additional support or set-up costs, such as a laser box or a generator. “And it becomes a question of how many different things can you have on the shelf?”

Dr. McKinsey said his talk is aimed at helping practitioners decide which lesions to treat, and with which device – with close attention to the morphological characteristics of lesions. “It’s almost like an algorithm,” he said.

Increasingly, he noted, lower-limb atherectomy is being approached with more than one technique. There is a strong practice trend toward combining atherectomy with drug-coated balloon therapy, he said. “I think the idea of leaving nothing behind [in the vessel] before you do a drug-coated balloon has gotten much more support. People are coming in now and saying they want to prepare the artery by debulking it, then come back and do DCB.” A new rotational laser device, he says, has particular promise in combination with DCBs.

But combining approaches means cost increases at a time when “reimbursement is going down and the product costs and associated expenses are going up,” he said.

Also on the horizon is another, potentially game-changing technology: bioabsorbable stents. While these fall outside the scope of his talk, Dr. McKinsey said he’s assisted a number of lower-limb procedures in Europe this year using them. The technology is especially promising for “more complicated, more calcified lesions,” he said. “In Europe it is being used fairly extensively,” he noted, and likely to come online in the United States within a year or so.

As with the combined approaches, the introduction of drug-eluting bioabsorbable stents into the treatment of lower-limb lesions is also likely to incur high costs, Dr. McKinsey noted. What’s needed are longer-term studies that follow patients up to 5 years, to understand whether high upfront costs are offset by later benefits.

“We have to look at is not necessarily the cost of doing a case, but the cost of treating that patient. We may have a greater upfront cost, but if the intervention has greater durability, and the patient doesn’t have a repeat procedure, then society and healthcare providers do better,” he said.

Decisions in popliteal or below-knee atherectomy can be complicated by a wide array of devices and lesion types.

Limited data on the long-term durability of interventions, or direct comparisons of approaches, can also complicate the decision-making process, as do cost concerns.

In his Sunday, September 18 talk at VIVA, titled “Popliteal and Below-the-Knee Atherectomy – Which Tool in Which Circumstance and When Not to Bother,” James F. McKinsey, MD, aims to help clinicians navigate this quickly changing field, with updates on emerging technologies.

Directional atherectomy and laser devices continue to undergo innovation, with new devices introduced almost annually. The changing device picture can be confusing, acknowledged Dr. McKinsey of Mt. Sinai Health System in New York. “I am well versed with many of them because I have a high volume. But people with just a few cases a month may not be,” he said.

Lower volume practitioners “need to find at least one, if not two, devices that they are going to be comfortable with,” Dr. McKinsey said, noting that each is associated with a special technique and may require additional support or set-up costs, such as a laser box or a generator. “And it becomes a question of how many different things can you have on the shelf?”

Dr. McKinsey said his talk is aimed at helping practitioners decide which lesions to treat, and with which device – with close attention to the morphological characteristics of lesions. “It’s almost like an algorithm,” he said.

Increasingly, he noted, lower-limb atherectomy is being approached with more than one technique. There is a strong practice trend toward combining atherectomy with drug-coated balloon therapy, he said. “I think the idea of leaving nothing behind [in the vessel] before you do a drug-coated balloon has gotten much more support. People are coming in now and saying they want to prepare the artery by debulking it, then come back and do DCB.” A new rotational laser device, he says, has particular promise in combination with DCBs.

But combining approaches means cost increases at a time when “reimbursement is going down and the product costs and associated expenses are going up,” he said.

Also on the horizon is another, potentially game-changing technology: bioabsorbable stents. While these fall outside the scope of his talk, Dr. McKinsey said he’s assisted a number of lower-limb procedures in Europe this year using them. The technology is especially promising for “more complicated, more calcified lesions,” he said. “In Europe it is being used fairly extensively,” he noted, and likely to come online in the United States within a year or so.

As with the combined approaches, the introduction of drug-eluting bioabsorbable stents into the treatment of lower-limb lesions is also likely to incur high costs, Dr. McKinsey noted. What’s needed are longer-term studies that follow patients up to 5 years, to understand whether high upfront costs are offset by later benefits.

“We have to look at is not necessarily the cost of doing a case, but the cost of treating that patient. We may have a greater upfront cost, but if the intervention has greater durability, and the patient doesn’t have a repeat procedure, then society and healthcare providers do better,” he said.

Decisions in popliteal or below-knee atherectomy can be complicated by a wide array of devices and lesion types.

Limited data on the long-term durability of interventions, or direct comparisons of approaches, can also complicate the decision-making process, as do cost concerns.

In his Sunday, September 18 talk at VIVA, titled “Popliteal and Below-the-Knee Atherectomy – Which Tool in Which Circumstance and When Not to Bother,” James F. McKinsey, MD, aims to help clinicians navigate this quickly changing field, with updates on emerging technologies.

Directional atherectomy and laser devices continue to undergo innovation, with new devices introduced almost annually. The changing device picture can be confusing, acknowledged Dr. McKinsey of Mt. Sinai Health System in New York. “I am well versed with many of them because I have a high volume. But people with just a few cases a month may not be,” he said.

Lower volume practitioners “need to find at least one, if not two, devices that they are going to be comfortable with,” Dr. McKinsey said, noting that each is associated with a special technique and may require additional support or set-up costs, such as a laser box or a generator. “And it becomes a question of how many different things can you have on the shelf?”

Dr. McKinsey said his talk is aimed at helping practitioners decide which lesions to treat, and with which device – with close attention to the morphological characteristics of lesions. “It’s almost like an algorithm,” he said.

Increasingly, he noted, lower-limb atherectomy is being approached with more than one technique. There is a strong practice trend toward combining atherectomy with drug-coated balloon therapy, he said. “I think the idea of leaving nothing behind [in the vessel] before you do a drug-coated balloon has gotten much more support. People are coming in now and saying they want to prepare the artery by debulking it, then come back and do DCB.” A new rotational laser device, he says, has particular promise in combination with DCBs.

But combining approaches means cost increases at a time when “reimbursement is going down and the product costs and associated expenses are going up,” he said.

Also on the horizon is another, potentially game-changing technology: bioabsorbable stents. While these fall outside the scope of his talk, Dr. McKinsey said he’s assisted a number of lower-limb procedures in Europe this year using them. The technology is especially promising for “more complicated, more calcified lesions,” he said. “In Europe it is being used fairly extensively,” he noted, and likely to come online in the United States within a year or so.

As with the combined approaches, the introduction of drug-eluting bioabsorbable stents into the treatment of lower-limb lesions is also likely to incur high costs, Dr. McKinsey noted. What’s needed are longer-term studies that follow patients up to 5 years, to understand whether high upfront costs are offset by later benefits.

“We have to look at is not necessarily the cost of doing a case, but the cost of treating that patient. We may have a greater upfront cost, but if the intervention has greater durability, and the patient doesn’t have a repeat procedure, then society and healthcare providers do better,” he said.

There was no significant difference in serious infection and mortality rates between mycophenolate mofetil (MMF), azathioprine (AZA), and cyclophosphamide (CYC) for high-risk systemic lupus erythematosus patients who were newly initiating immunotherapy, according to Candace H. Feldman, MD, and her associates.

In a 6-month analysis of 1,350 systemic lupus erythematosus patients initiating MMF and 1,350 patients initiating AZA, the incidence rate of first hospitalized infection per 100 person-years for MMF users was 14.6, and the incidence rate for AZA was 15.2. In a separate 6-month analysis of 674 patients initiating MMF and 674 patients receiving CYC, the incidence rate of first hospitalized infection per 100 person-years was 24.1 for MMF and 24.6 for CYC. The hazard ratio for AZA was 0.99, and for CYC it was 0.95.

Mortality was also similar in both cohorts. In the MMF vs. AZA cohort, 13 deaths were reported in the MMF group, and 14 were reported in the AZA group. In the MMF vs. CYC cohort, 15 deaths were reported in each group. The hazard ratio for mortality in the AZA group was 0.90, and the HR for mortality in the CYC group was 0.95.

“Based on these findings, concerns about differential infection risks may not need to influence physician and patient choice between MMF vs. AZA and MMF vs. CYC, even in a population highly susceptible to adverse outcomes,” the investigators concluded.

Find the full study in Arthritis & Rheumatology (doi: 10.1002/art.39849).

[email protected]

There was no significant difference in serious infection and mortality rates between mycophenolate mofetil (MMF), azathioprine (AZA), and cyclophosphamide (CYC) for high-risk systemic lupus erythematosus patients who were newly initiating immunotherapy, according to Candace H. Feldman, MD, and her associates.

In a 6-month analysis of 1,350 systemic lupus erythematosus patients initiating MMF and 1,350 patients initiating AZA, the incidence rate of first hospitalized infection per 100 person-years for MMF users was 14.6, and the incidence rate for AZA was 15.2. In a separate 6-month analysis of 674 patients initiating MMF and 674 patients receiving CYC, the incidence rate of first hospitalized infection per 100 person-years was 24.1 for MMF and 24.6 for CYC. The hazard ratio for AZA was 0.99, and for CYC it was 0.95.

Mortality was also similar in both cohorts. In the MMF vs. AZA cohort, 13 deaths were reported in the MMF group, and 14 were reported in the AZA group. In the MMF vs. CYC cohort, 15 deaths were reported in each group. The hazard ratio for mortality in the AZA group was 0.90, and the HR for mortality in the CYC group was 0.95.

“Based on these findings, concerns about differential infection risks may not need to influence physician and patient choice between MMF vs. AZA and MMF vs. CYC, even in a population highly susceptible to adverse outcomes,” the investigators concluded.

Find the full study in Arthritis & Rheumatology (doi: 10.1002/art.39849).

[email protected]

There was no significant difference in serious infection and mortality rates between mycophenolate mofetil (MMF), azathioprine (AZA), and cyclophosphamide (CYC) for high-risk systemic lupus erythematosus patients who were newly initiating immunotherapy, according to Candace H. Feldman, MD, and her associates.

In a 6-month analysis of 1,350 systemic lupus erythematosus patients initiating MMF and 1,350 patients initiating AZA, the incidence rate of first hospitalized infection per 100 person-years for MMF users was 14.6, and the incidence rate for AZA was 15.2. In a separate 6-month analysis of 674 patients initiating MMF and 674 patients receiving CYC, the incidence rate of first hospitalized infection per 100 person-years was 24.1 for MMF and 24.6 for CYC. The hazard ratio for AZA was 0.99, and for CYC it was 0.95.

Mortality was also similar in both cohorts. In the MMF vs. AZA cohort, 13 deaths were reported in the MMF group, and 14 were reported in the AZA group. In the MMF vs. CYC cohort, 15 deaths were reported in each group. The hazard ratio for mortality in the AZA group was 0.90, and the HR for mortality in the CYC group was 0.95.

“Based on these findings, concerns about differential infection risks may not need to influence physician and patient choice between MMF vs. AZA and MMF vs. CYC, even in a population highly susceptible to adverse outcomes,” the investigators concluded.

Find the full study in Arthritis & Rheumatology (doi: 10.1002/art.39849).

[email protected]

LONDON – The investigational treatment benralizumab significantly reduced the number of exacerbations that patients with severe, uncontrolled asthma experienced during the course of a year in two phase III studies.

In the SIROCCO and CALIMA trials, which altogether involved more than 2,000 adult patients, the annual exacerbation rate (AER) was cut by 28%-51%, compared with placebo when benralizumab was added to standard combination therapy of an inhaled corticosteroid (ICS) and a long-acting beta-agonist (LABA).

Benralizumab treatment was also associated with significant improvements in lung function (up to 159 mL increase in FEV₁), and reduced daily asthma symptoms of wheeze, cough, and dyspnea versus placebo. There were also improvements seen in patient-reported measures of asthma control and quality of life.

The results of these two multicenter, randomized, double-blind, placebo-controlled, parallel group studies were published in full online in The Lancet to coincide with their presentation at the annual congress of the European Respiratory Society.

Benralizumab is a humanized, monoclonal antibody that has been shown to rapidly and almost completely deplete the number of eosinophils in the blood, airways, and bone marrow, Eugene R Bleecker, MD, who presented the results of the SIROCCO study, explained at the meeting.

Dr. Bleecker, who is the director of the Center for Genomics and Personalized Medicine Research at Wake Forest University in Winston-Salem, N.C., observed that benralizumab “works a little bit differently” to other interleukin (IL)-5–targeting monoclonal antibodies, such as mepolizumab and reslizumab. Rather than target the IL-5 ligand itself, benralizumab binds to IL-5 receptors present on the surface of eosinophils. This action activates natural killer cells, which then destroy the eosinophils via antibody-dependent cell-mediated cytotoxicity.

Phase IIb data have already shown a benefit for benralizumab versus placebo in patients with uncontrolled asthma with high (300 cells/mcL or greater) eosinophil counts in the blood. The aim of the SIROCCO and CALIMA phase III trials was thus to examine the efficacy and safety of the novel agent further in this patient population.

In SIROCCO, 1,205 patients were randomized, and 1,306 were randomized in CALIMA. Key inclusion criteria were physician-diagnosed asthma requiring ICS/LABA therapy and at least two exacerbations in the past 12 months. Patients also needed to be symptomatic during a 4-week run-in period before being randomized to one of three study groups. The groups included one that received benralizumab at a subcutaneous dose of 30 mg every 4 weeks; another that received benralizumab at a subcutaneous dose of 30 mg every 4 weeks for the first three doses then a 30 mg dose or placebo injection alternating every 4 weeks; and a third group that received placebo injections every 4 weeks.

The mean age of patients in both studies and across treatment arms was broadly similar, ranging from 47 to 50 years. Around two thirds of the study population was female, with similar baseline characteristics.

The primary endpoint was the AER in patients with a blood eosinophil count of 300 cells/mcL or higher. In SIROCCO this was measured at 48 weeks and in CALIMA at 56 weeks. The respective AERs for placebo and for the 4- and 8-week dosing regimens of benralizumab were 1.33, 0.73, and 0.65 in SIROCCO and 0.93, 0.6, and 0.66 in CALIMA. This represented a 45% reduction in the AER for the 4-week and a 51% reduction for the 8-week regimens of benralizumab versus placebo in SIROCCO, and a 36% and 28% reduction, respectively, in CALIMA.

There was a large placebo effect and the overall population recruited into CALIMA may have had less severe asthma than the patients who participated in SIROCCO, the principal investigator for CALIMA, Mark FitzGerald, MD, pointed out during a press briefing organized by AstraZeneca. “But when you look at the composite of both studies together, you can see that the results are quite robust,” said Dr. FitzGerald, the director of the Centre for Lung and Heart Health at Vancouver Coastal Health Research Institute.

There was also some evidence that patients who had three or more prior exacerbations fared better, he said, highlighting the importance of defining the patient population who may benefit the most from this treatment.

Something that needs to be investigated further is why patients given the 8-week benralizumab regimen seemed to do better, at least numerically, than those given the 4-week regimen. Dr. FitzGerald suggested that “because eosinophil cells are such a powerful driver of disease, perhaps you may not actually need to be treated as frequently as historically we might have done.”

Other similar biologic agents need dosing every 2 to 4 weeks, but perhaps every 8 weeks is a possibility in the future for benralizumab. A lot can be learned from how biologics are used in rheumatology, he suggested, where treatments have started being given less frequently, because the biology of the various rheumatic diseases is now better understood.

Any adverse event was reported by a similar percentage of actively-treated (71%-75%) and placebo-treated (73%-78%) patients. The frequency and nature of other adverse events were similar to placebo.

The SIROCCO and CALIMA trial data will form part of AstraZeneca’s U.S. and EU regulatory submissions later this year for benralizumab as a treatment for severe, uncontrolled, eosinophilic asthma.

“Potentially, when it becomes available, benralizumab will provide a new therapeutic option for this class of patient.” Dr. FitzGerald said.

Benralizumab is also being investigated as a possible treatment for patients with less severe eosinophilic asthma in the BISE phase III study and as an option for those with severe chronic obstructive pulmonary disease who have high levels of eosinophils in the phase III VOYAGER program.

AstraZeneca and Kyowa Hakko Kirin funded the studies. Dr. Bleecker is the principal investigator for the SIROCCO trial and disclosed receiving research funding or consulting for AstraZeneca-MedImmune, Boehringer Ingelheim, Genentech/Roche, GlaxoSmithKline, Johnson & Johnson (Janssen), Merck, Novartis, Sanofi, Cephalon/Teva, and Regeneron-Sanofi. Dr. FitzGerald disclosed acting as an advisory board participant, receiving funding or fees, or both from AstraZeneca, ALK Abello, Boehringer Ingelheim, Hoffman-La Roche, Genentech, GlaxoSmithKline, MedImmune, Merck, Novartis, and Teva.

LONDON – The investigational treatment benralizumab significantly reduced the number of exacerbations that patients with severe, uncontrolled asthma experienced during the course of a year in two phase III studies.

In the SIROCCO and CALIMA trials, which altogether involved more than 2,000 adult patients, the annual exacerbation rate (AER) was cut by 28%-51%, compared with placebo when benralizumab was added to standard combination therapy of an inhaled corticosteroid (ICS) and a long-acting beta-agonist (LABA).

Benralizumab treatment was also associated with significant improvements in lung function (up to 159 mL increase in FEV₁), and reduced daily asthma symptoms of wheeze, cough, and dyspnea versus placebo. There were also improvements seen in patient-reported measures of asthma control and quality of life.

The results of these two multicenter, randomized, double-blind, placebo-controlled, parallel group studies were published in full online in The Lancet to coincide with their presentation at the annual congress of the European Respiratory Society.

Benralizumab is a humanized, monoclonal antibody that has been shown to rapidly and almost completely deplete the number of eosinophils in the blood, airways, and bone marrow, Eugene R Bleecker, MD, who presented the results of the SIROCCO study, explained at the meeting.

Dr. Bleecker, who is the director of the Center for Genomics and Personalized Medicine Research at Wake Forest University in Winston-Salem, N.C., observed that benralizumab “works a little bit differently” to other interleukin (IL)-5–targeting monoclonal antibodies, such as mepolizumab and reslizumab. Rather than target the IL-5 ligand itself, benralizumab binds to IL-5 receptors present on the surface of eosinophils. This action activates natural killer cells, which then destroy the eosinophils via antibody-dependent cell-mediated cytotoxicity.

Phase IIb data have already shown a benefit for benralizumab versus placebo in patients with uncontrolled asthma with high (300 cells/mcL or greater) eosinophil counts in the blood. The aim of the SIROCCO and CALIMA phase III trials was thus to examine the efficacy and safety of the novel agent further in this patient population.

In SIROCCO, 1,205 patients were randomized, and 1,306 were randomized in CALIMA. Key inclusion criteria were physician-diagnosed asthma requiring ICS/LABA therapy and at least two exacerbations in the past 12 months. Patients also needed to be symptomatic during a 4-week run-in period before being randomized to one of three study groups. The groups included one that received benralizumab at a subcutaneous dose of 30 mg every 4 weeks; another that received benralizumab at a subcutaneous dose of 30 mg every 4 weeks for the first three doses then a 30 mg dose or placebo injection alternating every 4 weeks; and a third group that received placebo injections every 4 weeks.

The mean age of patients in both studies and across treatment arms was broadly similar, ranging from 47 to 50 years. Around two thirds of the study population was female, with similar baseline characteristics.

The primary endpoint was the AER in patients with a blood eosinophil count of 300 cells/mcL or higher. In SIROCCO this was measured at 48 weeks and in CALIMA at 56 weeks. The respective AERs for placebo and for the 4- and 8-week dosing regimens of benralizumab were 1.33, 0.73, and 0.65 in SIROCCO and 0.93, 0.6, and 0.66 in CALIMA. This represented a 45% reduction in the AER for the 4-week and a 51% reduction for the 8-week regimens of benralizumab versus placebo in SIROCCO, and a 36% and 28% reduction, respectively, in CALIMA.

There was a large placebo effect and the overall population recruited into CALIMA may have had less severe asthma than the patients who participated in SIROCCO, the principal investigator for CALIMA, Mark FitzGerald, MD, pointed out during a press briefing organized by AstraZeneca. “But when you look at the composite of both studies together, you can see that the results are quite robust,” said Dr. FitzGerald, the director of the Centre for Lung and Heart Health at Vancouver Coastal Health Research Institute.

There was also some evidence that patients who had three or more prior exacerbations fared better, he said, highlighting the importance of defining the patient population who may benefit the most from this treatment.

Something that needs to be investigated further is why patients given the 8-week benralizumab regimen seemed to do better, at least numerically, than those given the 4-week regimen. Dr. FitzGerald suggested that “because eosinophil cells are such a powerful driver of disease, perhaps you may not actually need to be treated as frequently as historically we might have done.”

Other similar biologic agents need dosing every 2 to 4 weeks, but perhaps every 8 weeks is a possibility in the future for benralizumab. A lot can be learned from how biologics are used in rheumatology, he suggested, where treatments have started being given less frequently, because the biology of the various rheumatic diseases is now better understood.

Any adverse event was reported by a similar percentage of actively-treated (71%-75%) and placebo-treated (73%-78%) patients. The frequency and nature of other adverse events were similar to placebo.

The SIROCCO and CALIMA trial data will form part of AstraZeneca’s U.S. and EU regulatory submissions later this year for benralizumab as a treatment for severe, uncontrolled, eosinophilic asthma.

“Potentially, when it becomes available, benralizumab will provide a new therapeutic option for this class of patient.” Dr. FitzGerald said.

Benralizumab is also being investigated as a possible treatment for patients with less severe eosinophilic asthma in the BISE phase III study and as an option for those with severe chronic obstructive pulmonary disease who have high levels of eosinophils in the phase III VOYAGER program.

AstraZeneca and Kyowa Hakko Kirin funded the studies. Dr. Bleecker is the principal investigator for the SIROCCO trial and disclosed receiving research funding or consulting for AstraZeneca-MedImmune, Boehringer Ingelheim, Genentech/Roche, GlaxoSmithKline, Johnson & Johnson (Janssen), Merck, Novartis, Sanofi, Cephalon/Teva, and Regeneron-Sanofi. Dr. FitzGerald disclosed acting as an advisory board participant, receiving funding or fees, or both from AstraZeneca, ALK Abello, Boehringer Ingelheim, Hoffman-La Roche, Genentech, GlaxoSmithKline, MedImmune, Merck, Novartis, and Teva.

LONDON – The investigational treatment benralizumab significantly reduced the number of exacerbations that patients with severe, uncontrolled asthma experienced during the course of a year in two phase III studies.

In the SIROCCO and CALIMA trials, which altogether involved more than 2,000 adult patients, the annual exacerbation rate (AER) was cut by 28%-51%, compared with placebo when benralizumab was added to standard combination therapy of an inhaled corticosteroid (ICS) and a long-acting beta-agonist (LABA).

Benralizumab treatment was also associated with significant improvements in lung function (up to 159 mL increase in FEV₁), and reduced daily asthma symptoms of wheeze, cough, and dyspnea versus placebo. There were also improvements seen in patient-reported measures of asthma control and quality of life.

The results of these two multicenter, randomized, double-blind, placebo-controlled, parallel group studies were published in full online in The Lancet to coincide with their presentation at the annual congress of the European Respiratory Society.

Benralizumab is a humanized, monoclonal antibody that has been shown to rapidly and almost completely deplete the number of eosinophils in the blood, airways, and bone marrow, Eugene R Bleecker, MD, who presented the results of the SIROCCO study, explained at the meeting.

Dr. Bleecker, who is the director of the Center for Genomics and Personalized Medicine Research at Wake Forest University in Winston-Salem, N.C., observed that benralizumab “works a little bit differently” to other interleukin (IL)-5–targeting monoclonal antibodies, such as mepolizumab and reslizumab. Rather than target the IL-5 ligand itself, benralizumab binds to IL-5 receptors present on the surface of eosinophils. This action activates natural killer cells, which then destroy the eosinophils via antibody-dependent cell-mediated cytotoxicity.

Phase IIb data have already shown a benefit for benralizumab versus placebo in patients with uncontrolled asthma with high (300 cells/mcL or greater) eosinophil counts in the blood. The aim of the SIROCCO and CALIMA phase III trials was thus to examine the efficacy and safety of the novel agent further in this patient population.

In SIROCCO, 1,205 patients were randomized, and 1,306 were randomized in CALIMA. Key inclusion criteria were physician-diagnosed asthma requiring ICS/LABA therapy and at least two exacerbations in the past 12 months. Patients also needed to be symptomatic during a 4-week run-in period before being randomized to one of three study groups. The groups included one that received benralizumab at a subcutaneous dose of 30 mg every 4 weeks; another that received benralizumab at a subcutaneous dose of 30 mg every 4 weeks for the first three doses then a 30 mg dose or placebo injection alternating every 4 weeks; and a third group that received placebo injections every 4 weeks.

The mean age of patients in both studies and across treatment arms was broadly similar, ranging from 47 to 50 years. Around two thirds of the study population was female, with similar baseline characteristics.

The primary endpoint was the AER in patients with a blood eosinophil count of 300 cells/mcL or higher. In SIROCCO this was measured at 48 weeks and in CALIMA at 56 weeks. The respective AERs for placebo and for the 4- and 8-week dosing regimens of benralizumab were 1.33, 0.73, and 0.65 in SIROCCO and 0.93, 0.6, and 0.66 in CALIMA. This represented a 45% reduction in the AER for the 4-week and a 51% reduction for the 8-week regimens of benralizumab versus placebo in SIROCCO, and a 36% and 28% reduction, respectively, in CALIMA.

There was a large placebo effect and the overall population recruited into CALIMA may have had less severe asthma than the patients who participated in SIROCCO, the principal investigator for CALIMA, Mark FitzGerald, MD, pointed out during a press briefing organized by AstraZeneca. “But when you look at the composite of both studies together, you can see that the results are quite robust,” said Dr. FitzGerald, the director of the Centre for Lung and Heart Health at Vancouver Coastal Health Research Institute.

There was also some evidence that patients who had three or more prior exacerbations fared better, he said, highlighting the importance of defining the patient population who may benefit the most from this treatment.

Something that needs to be investigated further is why patients given the 8-week benralizumab regimen seemed to do better, at least numerically, than those given the 4-week regimen. Dr. FitzGerald suggested that “because eosinophil cells are such a powerful driver of disease, perhaps you may not actually need to be treated as frequently as historically we might have done.”

Other similar biologic agents need dosing every 2 to 4 weeks, but perhaps every 8 weeks is a possibility in the future for benralizumab. A lot can be learned from how biologics are used in rheumatology, he suggested, where treatments have started being given less frequently, because the biology of the various rheumatic diseases is now better understood.

Any adverse event was reported by a similar percentage of actively-treated (71%-75%) and placebo-treated (73%-78%) patients. The frequency and nature of other adverse events were similar to placebo.

The SIROCCO and CALIMA trial data will form part of AstraZeneca’s U.S. and EU regulatory submissions later this year for benralizumab as a treatment for severe, uncontrolled, eosinophilic asthma.

“Potentially, when it becomes available, benralizumab will provide a new therapeutic option for this class of patient.” Dr. FitzGerald said.

Benralizumab is also being investigated as a possible treatment for patients with less severe eosinophilic asthma in the BISE phase III study and as an option for those with severe chronic obstructive pulmonary disease who have high levels of eosinophils in the phase III VOYAGER program.

AstraZeneca and Kyowa Hakko Kirin funded the studies. Dr. Bleecker is the principal investigator for the SIROCCO trial and disclosed receiving research funding or consulting for AstraZeneca-MedImmune, Boehringer Ingelheim, Genentech/Roche, GlaxoSmithKline, Johnson & Johnson (Janssen), Merck, Novartis, Sanofi, Cephalon/Teva, and Regeneron-Sanofi. Dr. FitzGerald disclosed acting as an advisory board participant, receiving funding or fees, or both from AstraZeneca, ALK Abello, Boehringer Ingelheim, Hoffman-La Roche, Genentech, GlaxoSmithKline, MedImmune, Merck, Novartis, and Teva.

LONDON—Autoimmune adverse events over five years were generally mild or moderate in intensity in alemtuzumab-treated patients from the CARE-MS trials, according to data presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). “No patients withdrew from the extension studies due to autoimmune adverse events,” said Colin Dayan, MD, PhD, Clinical Professor, Cardiff University School of Medicine, Cardiff, United Kingdom, and his research colleagues. “Consistent with previous reports, most autoimmune adverse events were thyroid-related events.”

Alemtuzumab significantly improved clinical and MRI outcomes versus subcutaneous interferon beta-1a over two years in patients with relapsing-remitting multiple sclerosis (MS) who were treatment-naive in the CARE-MS I trial or had an inadequate response (ie, one or more relapses) to prior therapy at baseline in the CARE-MS II trial. Durable efficacy over five years was observed in an extension study in the absence of continuous treatment. The most frequent adverse events with alemtuzumab were infusion-associated reactions; other adverse events included autoimmune adverse events. According to researchers, patient education and the drug’s safety monitoring program enable timely detection and treatment of autoimmune adverse events in patients treated with alemtuzumab.

The goal of the present study was to evaluate the occurrence of autoimmune adverse events over five years in patients with relapsing-remitting MS treated with alemtuzumab.

Patients participating in the study received two courses of alemtuzumab 12 mg (Month 0: 5 days; Month 12: 3 days) in the CARE-MS core studies, with as-needed alemtuzumab for relapse or MRI activity in the extension. Patients were monitored for autoimmune adverse events. Safety measures included quarterly thyroid function testing, monthly complete blood counts with platelets and symptom monitoring for immune thrombocytopenia, and monthly serum creatinine and urinalysis.

Results were reported for pooled data from the CARE-MS I and II studies. A total of 811 patients received alemtuzumab 12 mg in the CARE-MS I and II core studies; 742 (91%) entered the extension, and 692 (93%) of those remained in the study at five years. Most autoimmune adverse events were mild or moderate in intensity. Serious autoimmune adverse events were uncommon (67 events; 1.8/100 patient-years over five years). None of the adverse events led to study withdrawal. The most common autoimmune adverse events were thyroid adverse events, the rate of which peaked in Year 3 (227 events; 31.3/100 patient-years) and subsequently declined in Years 4 (126 events; 17.6/100 patient-years) and 5 (95 events; 13.6/100 patient-years). Serious thyroid adverse event rates remained low. Over Years 0-5, 22 immune thrombocytopenia events were observed (cumulative rate: 0.59) with no fatalities. Two nephropathies were reported over Years 0-5 (cumulative rate: 0.05); serum creatinine remained normal in both cases.

This study was supported by Sanofi Genzyme and Bayer HealthCare Pharmaceuticals.

—Glenn S. Williams

LONDON—Autoimmune adverse events over five years were generally mild or moderate in intensity in alemtuzumab-treated patients from the CARE-MS trials, according to data presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). “No patients withdrew from the extension studies due to autoimmune adverse events,” said Colin Dayan, MD, PhD, Clinical Professor, Cardiff University School of Medicine, Cardiff, United Kingdom, and his research colleagues. “Consistent with previous reports, most autoimmune adverse events were thyroid-related events.”

Alemtuzumab significantly improved clinical and MRI outcomes versus subcutaneous interferon beta-1a over two years in patients with relapsing-remitting multiple sclerosis (MS) who were treatment-naive in the CARE-MS I trial or had an inadequate response (ie, one or more relapses) to prior therapy at baseline in the CARE-MS II trial. Durable efficacy over five years was observed in an extension study in the absence of continuous treatment. The most frequent adverse events with alemtuzumab were infusion-associated reactions; other adverse events included autoimmune adverse events. According to researchers, patient education and the drug’s safety monitoring program enable timely detection and treatment of autoimmune adverse events in patients treated with alemtuzumab.

The goal of the present study was to evaluate the occurrence of autoimmune adverse events over five years in patients with relapsing-remitting MS treated with alemtuzumab.

Patients participating in the study received two courses of alemtuzumab 12 mg (Month 0: 5 days; Month 12: 3 days) in the CARE-MS core studies, with as-needed alemtuzumab for relapse or MRI activity in the extension. Patients were monitored for autoimmune adverse events. Safety measures included quarterly thyroid function testing, monthly complete blood counts with platelets and symptom monitoring for immune thrombocytopenia, and monthly serum creatinine and urinalysis.

Results were reported for pooled data from the CARE-MS I and II studies. A total of 811 patients received alemtuzumab 12 mg in the CARE-MS I and II core studies; 742 (91%) entered the extension, and 692 (93%) of those remained in the study at five years. Most autoimmune adverse events were mild or moderate in intensity. Serious autoimmune adverse events were uncommon (67 events; 1.8/100 patient-years over five years). None of the adverse events led to study withdrawal. The most common autoimmune adverse events were thyroid adverse events, the rate of which peaked in Year 3 (227 events; 31.3/100 patient-years) and subsequently declined in Years 4 (126 events; 17.6/100 patient-years) and 5 (95 events; 13.6/100 patient-years). Serious thyroid adverse event rates remained low. Over Years 0-5, 22 immune thrombocytopenia events were observed (cumulative rate: 0.59) with no fatalities. Two nephropathies were reported over Years 0-5 (cumulative rate: 0.05); serum creatinine remained normal in both cases.

This study was supported by Sanofi Genzyme and Bayer HealthCare Pharmaceuticals.

—Glenn S. Williams

LONDON—Autoimmune adverse events over five years were generally mild or moderate in intensity in alemtuzumab-treated patients from the CARE-MS trials, according to data presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). “No patients withdrew from the extension studies due to autoimmune adverse events,” said Colin Dayan, MD, PhD, Clinical Professor, Cardiff University School of Medicine, Cardiff, United Kingdom, and his research colleagues. “Consistent with previous reports, most autoimmune adverse events were thyroid-related events.”

Alemtuzumab significantly improved clinical and MRI outcomes versus subcutaneous interferon beta-1a over two years in patients with relapsing-remitting multiple sclerosis (MS) who were treatment-naive in the CARE-MS I trial or had an inadequate response (ie, one or more relapses) to prior therapy at baseline in the CARE-MS II trial. Durable efficacy over five years was observed in an extension study in the absence of continuous treatment. The most frequent adverse events with alemtuzumab were infusion-associated reactions; other adverse events included autoimmune adverse events. According to researchers, patient education and the drug’s safety monitoring program enable timely detection and treatment of autoimmune adverse events in patients treated with alemtuzumab.

The goal of the present study was to evaluate the occurrence of autoimmune adverse events over five years in patients with relapsing-remitting MS treated with alemtuzumab.

Patients participating in the study received two courses of alemtuzumab 12 mg (Month 0: 5 days; Month 12: 3 days) in the CARE-MS core studies, with as-needed alemtuzumab for relapse or MRI activity in the extension. Patients were monitored for autoimmune adverse events. Safety measures included quarterly thyroid function testing, monthly complete blood counts with platelets and symptom monitoring for immune thrombocytopenia, and monthly serum creatinine and urinalysis.

Results were reported for pooled data from the CARE-MS I and II studies. A total of 811 patients received alemtuzumab 12 mg in the CARE-MS I and II core studies; 742 (91%) entered the extension, and 692 (93%) of those remained in the study at five years. Most autoimmune adverse events were mild or moderate in intensity. Serious autoimmune adverse events were uncommon (67 events; 1.8/100 patient-years over five years). None of the adverse events led to study withdrawal. The most common autoimmune adverse events were thyroid adverse events, the rate of which peaked in Year 3 (227 events; 31.3/100 patient-years) and subsequently declined in Years 4 (126 events; 17.6/100 patient-years) and 5 (95 events; 13.6/100 patient-years). Serious thyroid adverse event rates remained low. Over Years 0-5, 22 immune thrombocytopenia events were observed (cumulative rate: 0.59) with no fatalities. Two nephropathies were reported over Years 0-5 (cumulative rate: 0.05); serum creatinine remained normal in both cases.

This study was supported by Sanofi Genzyme and Bayer HealthCare Pharmaceuticals.

—Glenn S. Williams

MUNICH – Liraglutide posted positive secondary endpoints in a large randomized trial, reducing the risk of microvascular events by 16% and protecting renal function in people with type 2 diabetes.

A 22% decreased risk of renal complications was the major driver of microvascular protection in the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome) trial, Johannes Mann, MD, said at the annual meeting of the European Association for the Study of Diabetes. Somewhat disappointingly, the glucagonlike peptide–1 (GLP-1) receptor inhibitor didn’t decrease the chance of an eye-related microvascular event, said Dr. Mann of Friedrich Alexander University in Erlangen, Germany.

LEADER randomized 9,340 patients with type 2 diabetes to 1.8 mg or the maximum tolerated dose of subcutaneous liraglutide once daily or to placebo, in addition to standard care (N Engl J Med. 2016 June 13. doi: 10.1056/NEJMoa1603827)

The primary endpoint, reported in June, was a 13% reduction in the risk of a composite cardiovascular outcome (cardiovascular death, nonfatal heart attack, or nonfatal stroke) over 3.8 years of follow-up. This was driven by a 22% reduction in the risk of cardiovascular death; the drug did not significantly impact the other endpoints.

Microvascular and safety endpoints were key secondary outcomes. The study population was already at high risk for renal complications, Dr. Mann said: 20% had a moderate renal impairment at baseline, 20% had microalbuminuria, and 5% had macroalbuminuria.

The renal microvascular endpoint was a composite of several measures: new-onset persistent macroalbuminuria, persistent doubling of serum creatinine, end-stage renal disease, or death from renal failure. It occurred in 7.6% of the liraglutide group and 8.9% of the placebo group. The difference represented a 22% reduction in the time to a first renal event (hazard ratio, 0.78). This was entirely driven by a significant 23% decrease in the chance of new-onset macroalbuminuria (hazard ratio, 0.74), which occurred in 3.4% of the liraglutide group and 4.6% of the placebo group.

There were no significant between-group differences in any of the other renal endpoints, Dr. Mann said.

The eye microvascular endpoint was a composite of vitreous hemorrhage or treatment with photocoagulation or an intravitreal agent. The composite endpoint occurred in 2.3% of the liraglutide group and 2% of the placebo group, which was not a significant difference (HR, 1.15).

The drug was not associated with an increased risk of pancreatitis, with 18 suspected events in the treated group vs. 33 in the placebo group, not a significant difference. None of the cases was time bound; they occurred randomly throughout the trial in both treatment arms, said Michael A. Nauck, MD, of St. Josef Hospital, Bochum, Germany,

But any cases were a cause of concern, Dr. Nauck said, especially since liraglutide, like any GLP-1 agonist, causes increases in the pancreatic enzymes lipase and amylase. Therefore, each suspected case of acute pancreatitis that occurred in either group was fully adjudicated according to three diagnostic criteria: characteristic upper abdominal pain, increased pancreatic enzymes, and imaging findings.

Most of the cases (79% on liraglutide and 58% on placebo) had two of these criteria; the rest fulfilled all three. Any one was enough to prompt a pancreatitis work-up. Pain was the presenting symptom in 40% of liraglutide patients and 74% of placebo patients. Elevated enzymes prompted the work-up in another 40% of liraglutide patients and in 26% of placebo patients. The combination of pain and elevated enzymes was present in 6% of liraglutide patients, and in none of the placebo patients.

But pancreatic imaging was negative in 77% of liraglutide patients and 61% of placebo patients, suggesting that most of the reports did not represent a true acute inflammatory pancreatitis, Dr. Nauck said.

There was no significant liraglutide-associated increase in the risk of any neoplasm, whether malignant (HR, 1.06) or benign (HR, 1.16).

Pancreatic cancer occurred in 13 patients taking liraglutide and 9 taking placebo – not a significant difference. There were numerically fewer cases of prostate cancer and leukemia among those taking the drug, but again, the difference was not statistically significant, and the analysis didn’t control for any confounding factors.

“We are not going to say that liraglutide is in any way protective against these cancers,” Dr. Nauck said.

LEADER was sponsored by Novo Nordisk and the National Institutes of Health. Dr. Nauck is on Novo Nordisk’s advisory panel and speakers board, and receives research funding from the company. Dr Mann is an investigator and consultant for the company.

[email protected]

MUNICH – Liraglutide posted positive secondary endpoints in a large randomized trial, reducing the risk of microvascular events by 16% and protecting renal function in people with type 2 diabetes.

A 22% decreased risk of renal complications was the major driver of microvascular protection in the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome) trial, Johannes Mann, MD, said at the annual meeting of the European Association for the Study of Diabetes. Somewhat disappointingly, the glucagonlike peptide–1 (GLP-1) receptor inhibitor didn’t decrease the chance of an eye-related microvascular event, said Dr. Mann of Friedrich Alexander University in Erlangen, Germany.

LEADER randomized 9,340 patients with type 2 diabetes to 1.8 mg or the maximum tolerated dose of subcutaneous liraglutide once daily or to placebo, in addition to standard care (N Engl J Med. 2016 June 13. doi: 10.1056/NEJMoa1603827)

The primary endpoint, reported in June, was a 13% reduction in the risk of a composite cardiovascular outcome (cardiovascular death, nonfatal heart attack, or nonfatal stroke) over 3.8 years of follow-up. This was driven by a 22% reduction in the risk of cardiovascular death; the drug did not significantly impact the other endpoints.

Microvascular and safety endpoints were key secondary outcomes. The study population was already at high risk for renal complications, Dr. Mann said: 20% had a moderate renal impairment at baseline, 20% had microalbuminuria, and 5% had macroalbuminuria.

The renal microvascular endpoint was a composite of several measures: new-onset persistent macroalbuminuria, persistent doubling of serum creatinine, end-stage renal disease, or death from renal failure. It occurred in 7.6% of the liraglutide group and 8.9% of the placebo group. The difference represented a 22% reduction in the time to a first renal event (hazard ratio, 0.78). This was entirely driven by a significant 23% decrease in the chance of new-onset macroalbuminuria (hazard ratio, 0.74), which occurred in 3.4% of the liraglutide group and 4.6% of the placebo group.

There were no significant between-group differences in any of the other renal endpoints, Dr. Mann said.

The eye microvascular endpoint was a composite of vitreous hemorrhage or treatment with photocoagulation or an intravitreal agent. The composite endpoint occurred in 2.3% of the liraglutide group and 2% of the placebo group, which was not a significant difference (HR, 1.15).

The drug was not associated with an increased risk of pancreatitis, with 18 suspected events in the treated group vs. 33 in the placebo group, not a significant difference. None of the cases was time bound; they occurred randomly throughout the trial in both treatment arms, said Michael A. Nauck, MD, of St. Josef Hospital, Bochum, Germany,

But any cases were a cause of concern, Dr. Nauck said, especially since liraglutide, like any GLP-1 agonist, causes increases in the pancreatic enzymes lipase and amylase. Therefore, each suspected case of acute pancreatitis that occurred in either group was fully adjudicated according to three diagnostic criteria: characteristic upper abdominal pain, increased pancreatic enzymes, and imaging findings.

Most of the cases (79% on liraglutide and 58% on placebo) had two of these criteria; the rest fulfilled all three. Any one was enough to prompt a pancreatitis work-up. Pain was the presenting symptom in 40% of liraglutide patients and 74% of placebo patients. Elevated enzymes prompted the work-up in another 40% of liraglutide patients and in 26% of placebo patients. The combination of pain and elevated enzymes was present in 6% of liraglutide patients, and in none of the placebo patients.

But pancreatic imaging was negative in 77% of liraglutide patients and 61% of placebo patients, suggesting that most of the reports did not represent a true acute inflammatory pancreatitis, Dr. Nauck said.

There was no significant liraglutide-associated increase in the risk of any neoplasm, whether malignant (HR, 1.06) or benign (HR, 1.16).

Pancreatic cancer occurred in 13 patients taking liraglutide and 9 taking placebo – not a significant difference. There were numerically fewer cases of prostate cancer and leukemia among those taking the drug, but again, the difference was not statistically significant, and the analysis didn’t control for any confounding factors.

“We are not going to say that liraglutide is in any way protective against these cancers,” Dr. Nauck said.

LEADER was sponsored by Novo Nordisk and the National Institutes of Health. Dr. Nauck is on Novo Nordisk’s advisory panel and speakers board, and receives research funding from the company. Dr Mann is an investigator and consultant for the company.

[email protected]

MUNICH – Liraglutide posted positive secondary endpoints in a large randomized trial, reducing the risk of microvascular events by 16% and protecting renal function in people with type 2 diabetes.

A 22% decreased risk of renal complications was the major driver of microvascular protection in the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome) trial, Johannes Mann, MD, said at the annual meeting of the European Association for the Study of Diabetes. Somewhat disappointingly, the glucagonlike peptide–1 (GLP-1) receptor inhibitor didn’t decrease the chance of an eye-related microvascular event, said Dr. Mann of Friedrich Alexander University in Erlangen, Germany.

LEADER randomized 9,340 patients with type 2 diabetes to 1.8 mg or the maximum tolerated dose of subcutaneous liraglutide once daily or to placebo, in addition to standard care (N Engl J Med. 2016 June 13. doi: 10.1056/NEJMoa1603827)

The primary endpoint, reported in June, was a 13% reduction in the risk of a composite cardiovascular outcome (cardiovascular death, nonfatal heart attack, or nonfatal stroke) over 3.8 years of follow-up. This was driven by a 22% reduction in the risk of cardiovascular death; the drug did not significantly impact the other endpoints.

Microvascular and safety endpoints were key secondary outcomes. The study population was already at high risk for renal complications, Dr. Mann said: 20% had a moderate renal impairment at baseline, 20% had microalbuminuria, and 5% had macroalbuminuria.

The renal microvascular endpoint was a composite of several measures: new-onset persistent macroalbuminuria, persistent doubling of serum creatinine, end-stage renal disease, or death from renal failure. It occurred in 7.6% of the liraglutide group and 8.9% of the placebo group. The difference represented a 22% reduction in the time to a first renal event (hazard ratio, 0.78). This was entirely driven by a significant 23% decrease in the chance of new-onset macroalbuminuria (hazard ratio, 0.74), which occurred in 3.4% of the liraglutide group and 4.6% of the placebo group.

There were no significant between-group differences in any of the other renal endpoints, Dr. Mann said.

The eye microvascular endpoint was a composite of vitreous hemorrhage or treatment with photocoagulation or an intravitreal agent. The composite endpoint occurred in 2.3% of the liraglutide group and 2% of the placebo group, which was not a significant difference (HR, 1.15).

The drug was not associated with an increased risk of pancreatitis, with 18 suspected events in the treated group vs. 33 in the placebo group, not a significant difference. None of the cases was time bound; they occurred randomly throughout the trial in both treatment arms, said Michael A. Nauck, MD, of St. Josef Hospital, Bochum, Germany,

But any cases were a cause of concern, Dr. Nauck said, especially since liraglutide, like any GLP-1 agonist, causes increases in the pancreatic enzymes lipase and amylase. Therefore, each suspected case of acute pancreatitis that occurred in either group was fully adjudicated according to three diagnostic criteria: characteristic upper abdominal pain, increased pancreatic enzymes, and imaging findings.

Most of the cases (79% on liraglutide and 58% on placebo) had two of these criteria; the rest fulfilled all three. Any one was enough to prompt a pancreatitis work-up. Pain was the presenting symptom in 40% of liraglutide patients and 74% of placebo patients. Elevated enzymes prompted the work-up in another 40% of liraglutide patients and in 26% of placebo patients. The combination of pain and elevated enzymes was present in 6% of liraglutide patients, and in none of the placebo patients.

But pancreatic imaging was negative in 77% of liraglutide patients and 61% of placebo patients, suggesting that most of the reports did not represent a true acute inflammatory pancreatitis, Dr. Nauck said.

There was no significant liraglutide-associated increase in the risk of any neoplasm, whether malignant (HR, 1.06) or benign (HR, 1.16).

Pancreatic cancer occurred in 13 patients taking liraglutide and 9 taking placebo – not a significant difference. There were numerically fewer cases of prostate cancer and leukemia among those taking the drug, but again, the difference was not statistically significant, and the analysis didn’t control for any confounding factors.

“We are not going to say that liraglutide is in any way protective against these cancers,” Dr. Nauck said.

LEADER was sponsored by Novo Nordisk and the National Institutes of Health. Dr. Nauck is on Novo Nordisk’s advisory panel and speakers board, and receives research funding from the company. Dr Mann is an investigator and consultant for the company.

[email protected]

LONDON – Improved lung function was seen in patients with chronic obstructive pulmonary disease (COPD) when an inhaled dual phosphodiesterase (PDE) inhibitor, RPL-554, was used on top of standard short-acting treatment in a single-center, crossover study.

There was a 51% increase in the peak forced expiratory volume in 1 second (FEV₁) from baseline to the time of measurement up to 12 hours later in patients given RPL-554 in addition to the short-acting beta2-agonist (SABA) salbutamol versus the SABA alone. A benefit also resulted from adding RPL-554 to the short-acting muscarinic antagonist (SAMA) ipratropium. Taking this second combination of drugs resulted in a 66% higher FEV₁, when compared with taking the SAMA alone (P less than .001 comparing the combinations with the SABA or SAMA alone).

©decade3d/Thinkstock

“We were primarily interested to know if giving this novel drug in addition to a beta-agonist or antimuscarinic could produce more bronchodilation, and that’s what we saw,” said David Singh, MD, of the University of Manchester (England), who presented the study findings at the annual congress of the European Respiratory Society.

In addition to inducing “significant and clinically relevant” additional bronchodilation, a single dose of RPL-554 was found to increase lung volumes when administered on top of standard-of-care bronchodilators. The peak forced vital capacity (FVC) increased by 79.5% when RPL-554 was added to salbutamol and by 43.2% when it was added to ipratropium. There were also improvements in the baseline residual lung volume and in airway conductance.

RPL-554 is a novel inhaled dual PDE-3/4 inhibitor under investigation in the treatment of both COPD and asthmatic patients. “This is a reformulation of RPL-554, delivered by nebulization,” Dr. Singh observed. It has been shown to have both anti-inflammatory and bronchodilatory properties in clinical studies, he added, with the latter action thought to be additive to beta-agonists and synergistic with antimuscarinic agents according to preclinical data.

The aim of the study was to look at the potential additive or synergistic bronchodilatory effects of RPL-554 in a clinical study for patients who had moderate to severe COPD. A total of 36 patients (19 men and 17 women) were recruited; 30 completed the study. The mean age of the recruited patients was 61 years; mean body mass index was 27.7 kg/m², mean baseline FEV₁ was 50.4% or 1.44 L, and the patients exhibited a mean increase in FEV₁ of 17.7%, 30 minutes after being given salbutamol or ipratropium at screening. The latter “gives you an idea of the reversibility of the population,” Dr. Singh said.

Six treatment options were compared: salbutamol 200 mcg, salbutamol 200 mcg plus RPL-554 6 mg, ipratropium 40 mcg, ipratropium 40 mcg plus RPL-554 6 mg, RPL-554 6 mg, and placebo. At each treatment visit patients were dosed, in a double-blind fashion, with salbutamol, ipratropium, or placebo via a metered-dose inhaler (MDI), and then randomized to receive either inhaled RPL-554 or a placebo via a nasal nebulizer. Spirometry was performed before and up to 12 hours after treatment, and plethysmography was performed before and at 1 and 4 hours after dosing.

The addition of RPL-554 to standard bronchodilator therapy was associated with a faster onset of bronchodilation when compared to either the SABA or SAMA as monotherapies – at 3.6 minutes when added to salbutamol versus 5.2 minutes for the SABA alone, and 4.2 minutes when added to ipratropium versus 18.4 minutes for the SAMA alone. Used alone, however, RPL-554 had an onset of effect of 14.3 minutes.

Overall, the single-doses of RPL-554 used were well tolerated when given alone or in combination with the other treatments. “Obviously with a PDE-3 inhibitor we want to be careful about cardiovascular changes and monitor that, but we did not see anything,” Dr. Singh reported.

Verona Pharma Plc sponsored the study. Dr. Singh reported receiving sponsorship, honoraria, or research funding from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Genentech, GlaxoSmithKline, Glenmark, Johnson and Johnson, Merck, NAPP, Novartis, Pfizer, Skyepharma, Takeda, Teva, Theravance, and Verona Pharma Plc.

[email protected]

LONDON – Improved lung function was seen in patients with chronic obstructive pulmonary disease (COPD) when an inhaled dual phosphodiesterase (PDE) inhibitor, RPL-554, was used on top of standard short-acting treatment in a single-center, crossover study.

There was a 51% increase in the peak forced expiratory volume in 1 second (FEV₁) from baseline to the time of measurement up to 12 hours later in patients given RPL-554 in addition to the short-acting beta2-agonist (SABA) salbutamol versus the SABA alone. A benefit also resulted from adding RPL-554 to the short-acting muscarinic antagonist (SAMA) ipratropium. Taking this second combination of drugs resulted in a 66% higher FEV₁, when compared with taking the SAMA alone (P less than .001 comparing the combinations with the SABA or SAMA alone).

©decade3d/Thinkstock

“We were primarily interested to know if giving this novel drug in addition to a beta-agonist or antimuscarinic could produce more bronchodilation, and that’s what we saw,” said David Singh, MD, of the University of Manchester (England), who presented the study findings at the annual congress of the European Respiratory Society.

In addition to inducing “significant and clinically relevant” additional bronchodilation, a single dose of RPL-554 was found to increase lung volumes when administered on top of standard-of-care bronchodilators. The peak forced vital capacity (FVC) increased by 79.5% when RPL-554 was added to salbutamol and by 43.2% when it was added to ipratropium. There were also improvements in the baseline residual lung volume and in airway conductance.

RPL-554 is a novel inhaled dual PDE-3/4 inhibitor under investigation in the treatment of both COPD and asthmatic patients. “This is a reformulation of RPL-554, delivered by nebulization,” Dr. Singh observed. It has been shown to have both anti-inflammatory and bronchodilatory properties in clinical studies, he added, with the latter action thought to be additive to beta-agonists and synergistic with antimuscarinic agents according to preclinical data.

The aim of the study was to look at the potential additive or synergistic bronchodilatory effects of RPL-554 in a clinical study for patients who had moderate to severe COPD. A total of 36 patients (19 men and 17 women) were recruited; 30 completed the study. The mean age of the recruited patients was 61 years; mean body mass index was 27.7 kg/m², mean baseline FEV₁ was 50.4% or 1.44 L, and the patients exhibited a mean increase in FEV₁ of 17.7%, 30 minutes after being given salbutamol or ipratropium at screening. The latter “gives you an idea of the reversibility of the population,” Dr. Singh said.

Six treatment options were compared: salbutamol 200 mcg, salbutamol 200 mcg plus RPL-554 6 mg, ipratropium 40 mcg, ipratropium 40 mcg plus RPL-554 6 mg, RPL-554 6 mg, and placebo. At each treatment visit patients were dosed, in a double-blind fashion, with salbutamol, ipratropium, or placebo via a metered-dose inhaler (MDI), and then randomized to receive either inhaled RPL-554 or a placebo via a nasal nebulizer. Spirometry was performed before and up to 12 hours after treatment, and plethysmography was performed before and at 1 and 4 hours after dosing.

The addition of RPL-554 to standard bronchodilator therapy was associated with a faster onset of bronchodilation when compared to either the SABA or SAMA as monotherapies – at 3.6 minutes when added to salbutamol versus 5.2 minutes for the SABA alone, and 4.2 minutes when added to ipratropium versus 18.4 minutes for the SAMA alone. Used alone, however, RPL-554 had an onset of effect of 14.3 minutes.

Overall, the single-doses of RPL-554 used were well tolerated when given alone or in combination with the other treatments. “Obviously with a PDE-3 inhibitor we want to be careful about cardiovascular changes and monitor that, but we did not see anything,” Dr. Singh reported.

Verona Pharma Plc sponsored the study. Dr. Singh reported receiving sponsorship, honoraria, or research funding from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Genentech, GlaxoSmithKline, Glenmark, Johnson and Johnson, Merck, NAPP, Novartis, Pfizer, Skyepharma, Takeda, Teva, Theravance, and Verona Pharma Plc.

[email protected]

LONDON – Improved lung function was seen in patients with chronic obstructive pulmonary disease (COPD) when an inhaled dual phosphodiesterase (PDE) inhibitor, RPL-554, was used on top of standard short-acting treatment in a single-center, crossover study.

There was a 51% increase in the peak forced expiratory volume in 1 second (FEV₁) from baseline to the time of measurement up to 12 hours later in patients given RPL-554 in addition to the short-acting beta2-agonist (SABA) salbutamol versus the SABA alone. A benefit also resulted from adding RPL-554 to the short-acting muscarinic antagonist (SAMA) ipratropium. Taking this second combination of drugs resulted in a 66% higher FEV₁, when compared with taking the SAMA alone (P less than .001 comparing the combinations with the SABA or SAMA alone).

©decade3d/Thinkstock

“We were primarily interested to know if giving this novel drug in addition to a beta-agonist or antimuscarinic could produce more bronchodilation, and that’s what we saw,” said David Singh, MD, of the University of Manchester (England), who presented the study findings at the annual congress of the European Respiratory Society.

In addition to inducing “significant and clinically relevant” additional bronchodilation, a single dose of RPL-554 was found to increase lung volumes when administered on top of standard-of-care bronchodilators. The peak forced vital capacity (FVC) increased by 79.5% when RPL-554 was added to salbutamol and by 43.2% when it was added to ipratropium. There were also improvements in the baseline residual lung volume and in airway conductance.

RPL-554 is a novel inhaled dual PDE-3/4 inhibitor under investigation in the treatment of both COPD and asthmatic patients. “This is a reformulation of RPL-554, delivered by nebulization,” Dr. Singh observed. It has been shown to have both anti-inflammatory and bronchodilatory properties in clinical studies, he added, with the latter action thought to be additive to beta-agonists and synergistic with antimuscarinic agents according to preclinical data.

The aim of the study was to look at the potential additive or synergistic bronchodilatory effects of RPL-554 in a clinical study for patients who had moderate to severe COPD. A total of 36 patients (19 men and 17 women) were recruited; 30 completed the study. The mean age of the recruited patients was 61 years; mean body mass index was 27.7 kg/m², mean baseline FEV₁ was 50.4% or 1.44 L, and the patients exhibited a mean increase in FEV₁ of 17.7%, 30 minutes after being given salbutamol or ipratropium at screening. The latter “gives you an idea of the reversibility of the population,” Dr. Singh said.

Six treatment options were compared: salbutamol 200 mcg, salbutamol 200 mcg plus RPL-554 6 mg, ipratropium 40 mcg, ipratropium 40 mcg plus RPL-554 6 mg, RPL-554 6 mg, and placebo. At each treatment visit patients were dosed, in a double-blind fashion, with salbutamol, ipratropium, or placebo via a metered-dose inhaler (MDI), and then randomized to receive either inhaled RPL-554 or a placebo via a nasal nebulizer. Spirometry was performed before and up to 12 hours after treatment, and plethysmography was performed before and at 1 and 4 hours after dosing.

The addition of RPL-554 to standard bronchodilator therapy was associated with a faster onset of bronchodilation when compared to either the SABA or SAMA as monotherapies – at 3.6 minutes when added to salbutamol versus 5.2 minutes for the SABA alone, and 4.2 minutes when added to ipratropium versus 18.4 minutes for the SAMA alone. Used alone, however, RPL-554 had an onset of effect of 14.3 minutes.

Overall, the single-doses of RPL-554 used were well tolerated when given alone or in combination with the other treatments. “Obviously with a PDE-3 inhibitor we want to be careful about cardiovascular changes and monitor that, but we did not see anything,” Dr. Singh reported.

Verona Pharma Plc sponsored the study. Dr. Singh reported receiving sponsorship, honoraria, or research funding from Almirall, AstraZeneca, Boehringer Ingelheim, Chiesi, Genentech, GlaxoSmithKline, Glenmark, Johnson and Johnson, Merck, NAPP, Novartis, Pfizer, Skyepharma, Takeda, Teva, Theravance, and Verona Pharma Plc.

[email protected]

LONDON—The Expanded Disability Status Scale (EDSS) is largely insensitive to cognitive ability in patients with multiple sclerosis (MS) and does not comprehensively capture accumulated cognitive disability, according to research presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). “The EDSS’s use as the gold standard in measuring accumulated disability in patients with MS should be reconsidered as cognitive impairment–related disability can occur independent of EDSS,” said Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, New York.

MS is typically measured by MRI changes, relapse rates, and EDSS. Changes in EDSS score are primarily driven by motor and walking impairment. According to Dr. Gudesblatt and colleagues, cognitive impairment, independent of EDSS, in patients with MS impacts employment, driving, fall risk, and quality of life. “Although the EDSS is universally accepted to measure treatment efficacy, cognitive function does not impact EDSS. Cognitive function greatly varies independently of walking ability and is an important aspect of disease impact for patients with MS,” Dr. Gudesblatt said.

To investigate the sensitivity of the EDSS in measuring cognitive ability in patients with MS, Dr. Gudesblatt and colleagues asked a group of patients with MS to complete a computerized cognitive assessment battery (NeuroTrax) with analysis of cognitive domain scores (ie, memory, executive function, visual spatial, and verbal function, attention, information processing, and motor skills). The average of these domain scores was defined as the global cognitive score. The number of cognitive domains impaired greater than one standard deviation from age- and education-matched norms were also recorded for each assessment battery. A certified grader assigned EDSS scores to participants at the date of their cognitive testing. EDSS groups were defined as low (EDSS 0 to 2.5), moderate (EDSS 3 to 4.5), high (EDSS 5 to 6.5), and severe (EDSS > 7). Percent overlap of NeuroTrax cognitive scores were calculated across EDSS both adjacent (low and moderate, moderate and high, high and severe) and extreme (low and severe) groups.

A total of 258 patients with MS were enrolled in the study; 72.5% were women and the average age was 46.2. For the global cognitive score in patients with MS, there was an average 65% overlap across adjacent EDSS groups and a 42.5% overlap across extreme EDSS groups. The overlap of the cognitive domain scores were: memory (65.3% average adjacent, 65.3% extreme), executive function (65.1% average adjacent, 35.1% extreme), attention (60.3% average adjacent, 38.1% extreme), information processing speed (58.0% average adjacent, 42.5% extreme), visual spatial (65.6% average adjacent, 63.2% extreme), verbal function (70.1% average adjacent, 66.4% extreme), motor skills (55.2% average adjacent, 32.3% extreme). The overlap of number of cognitive domains impaired one standard deviation or more below the normative means was 72.2% across EDSS adjacent groups and 38.1% across extreme EDSS groups.

—Glenn S. Williams

LONDON—The Expanded Disability Status Scale (EDSS) is largely insensitive to cognitive ability in patients with multiple sclerosis (MS) and does not comprehensively capture accumulated cognitive disability, according to research presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). “The EDSS’s use as the gold standard in measuring accumulated disability in patients with MS should be reconsidered as cognitive impairment–related disability can occur independent of EDSS,” said Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, New York.

MS is typically measured by MRI changes, relapse rates, and EDSS. Changes in EDSS score are primarily driven by motor and walking impairment. According to Dr. Gudesblatt and colleagues, cognitive impairment, independent of EDSS, in patients with MS impacts employment, driving, fall risk, and quality of life. “Although the EDSS is universally accepted to measure treatment efficacy, cognitive function does not impact EDSS. Cognitive function greatly varies independently of walking ability and is an important aspect of disease impact for patients with MS,” Dr. Gudesblatt said.

To investigate the sensitivity of the EDSS in measuring cognitive ability in patients with MS, Dr. Gudesblatt and colleagues asked a group of patients with MS to complete a computerized cognitive assessment battery (NeuroTrax) with analysis of cognitive domain scores (ie, memory, executive function, visual spatial, and verbal function, attention, information processing, and motor skills). The average of these domain scores was defined as the global cognitive score. The number of cognitive domains impaired greater than one standard deviation from age- and education-matched norms were also recorded for each assessment battery. A certified grader assigned EDSS scores to participants at the date of their cognitive testing. EDSS groups were defined as low (EDSS 0 to 2.5), moderate (EDSS 3 to 4.5), high (EDSS 5 to 6.5), and severe (EDSS > 7). Percent overlap of NeuroTrax cognitive scores were calculated across EDSS both adjacent (low and moderate, moderate and high, high and severe) and extreme (low and severe) groups.

A total of 258 patients with MS were enrolled in the study; 72.5% were women and the average age was 46.2. For the global cognitive score in patients with MS, there was an average 65% overlap across adjacent EDSS groups and a 42.5% overlap across extreme EDSS groups. The overlap of the cognitive domain scores were: memory (65.3% average adjacent, 65.3% extreme), executive function (65.1% average adjacent, 35.1% extreme), attention (60.3% average adjacent, 38.1% extreme), information processing speed (58.0% average adjacent, 42.5% extreme), visual spatial (65.6% average adjacent, 63.2% extreme), verbal function (70.1% average adjacent, 66.4% extreme), motor skills (55.2% average adjacent, 32.3% extreme). The overlap of number of cognitive domains impaired one standard deviation or more below the normative means was 72.2% across EDSS adjacent groups and 38.1% across extreme EDSS groups.

—Glenn S. Williams

LONDON—The Expanded Disability Status Scale (EDSS) is largely insensitive to cognitive ability in patients with multiple sclerosis (MS) and does not comprehensively capture accumulated cognitive disability, according to research presented at the 32nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). “The EDSS’s use as the gold standard in measuring accumulated disability in patients with MS should be reconsidered as cognitive impairment–related disability can occur independent of EDSS,” said Mark Gudesblatt, MD, Medical Director of the Comprehensive MS Care Center at South Shore Neurologic Associates in Islip, New York.

MS is typically measured by MRI changes, relapse rates, and EDSS. Changes in EDSS score are primarily driven by motor and walking impairment. According to Dr. Gudesblatt and colleagues, cognitive impairment, independent of EDSS, in patients with MS impacts employment, driving, fall risk, and quality of life. “Although the EDSS is universally accepted to measure treatment efficacy, cognitive function does not impact EDSS. Cognitive function greatly varies independently of walking ability and is an important aspect of disease impact for patients with MS,” Dr. Gudesblatt said.

To investigate the sensitivity of the EDSS in measuring cognitive ability in patients with MS, Dr. Gudesblatt and colleagues asked a group of patients with MS to complete a computerized cognitive assessment battery (NeuroTrax) with analysis of cognitive domain scores (ie, memory, executive function, visual spatial, and verbal function, attention, information processing, and motor skills). The average of these domain scores was defined as the global cognitive score. The number of cognitive domains impaired greater than one standard deviation from age- and education-matched norms were also recorded for each assessment battery. A certified grader assigned EDSS scores to participants at the date of their cognitive testing. EDSS groups were defined as low (EDSS 0 to 2.5), moderate (EDSS 3 to 4.5), high (EDSS 5 to 6.5), and severe (EDSS > 7). Percent overlap of NeuroTrax cognitive scores were calculated across EDSS both adjacent (low and moderate, moderate and high, high and severe) and extreme (low and severe) groups.

A total of 258 patients with MS were enrolled in the study; 72.5% were women and the average age was 46.2. For the global cognitive score in patients with MS, there was an average 65% overlap across adjacent EDSS groups and a 42.5% overlap across extreme EDSS groups. The overlap of the cognitive domain scores were: memory (65.3% average adjacent, 65.3% extreme), executive function (65.1% average adjacent, 35.1% extreme), attention (60.3% average adjacent, 38.1% extreme), information processing speed (58.0% average adjacent, 42.5% extreme), visual spatial (65.6% average adjacent, 63.2% extreme), verbal function (70.1% average adjacent, 66.4% extreme), motor skills (55.2% average adjacent, 32.3% extreme). The overlap of number of cognitive domains impaired one standard deviation or more below the normative means was 72.2% across EDSS adjacent groups and 38.1% across extreme EDSS groups.

—Glenn S. Williams

NEW YORK – In this first of four interviews, the new director of the National Institute of Mental Health, Joshua A. Gordon, MD, PhD, shares his thoughts about the emerging nosology of depression and whether it might be possible to identify and turn off genetic pathways implicated in depression without impacting creativity, sexual drive, and appetite.

Dr. Gordon is a practicing psychiatrist and a neuroscientist whose primary area of research is in the emerging field of optogenetics, which uses light to trace the genetically predetermined neurocircuitry of various mental states through the brain.

He steps into his leadership role with NIMH at a time when some have voiced concern that the institute has placed too much emphasis on future therapies, instead of on what can be done in the here and now to treat mental disorders.

Also in this series, Dr. Gordon discusses how, under his leadership, NIMH will balance the priorities of clinicians in everyday practice with those of researchers. He also explains the finer points of optogenetics. Currently, the technique is being studied only in mouse models; but if it makes it to human trials, researchers will explore the ability to switch on and off certain mental states.

Dr. Gordon talks about the ethical implications of optogenetics, as well as his belief in the biological basis of all thought and emotion, and how that guides the search for targeted treatments.

Finally, he’ll discuss what he believes NIMH’s top priorities should be, and whether he will blog as did his predecessor, Thomas R. Insel, MD.

[email protected]

On Twitter @whitneymcknight

NEW YORK – In this first of four interviews, the new director of the National Institute of Mental Health, Joshua A. Gordon, MD, PhD, shares his thoughts about the emerging nosology of depression and whether it might be possible to identify and turn off genetic pathways implicated in depression without impacting creativity, sexual drive, and appetite.

Dr. Gordon is a practicing psychiatrist and a neuroscientist whose primary area of research is in the emerging field of optogenetics, which uses light to trace the genetically predetermined neurocircuitry of various mental states through the brain.

He steps into his leadership role with NIMH at a time when some have voiced concern that the institute has placed too much emphasis on future therapies, instead of on what can be done in the here and now to treat mental disorders.

Also in this series, Dr. Gordon discusses how, under his leadership, NIMH will balance the priorities of clinicians in everyday practice with those of researchers. He also explains the finer points of optogenetics. Currently, the technique is being studied only in mouse models; but if it makes it to human trials, researchers will explore the ability to switch on and off certain mental states.

Dr. Gordon talks about the ethical implications of optogenetics, as well as his belief in the biological basis of all thought and emotion, and how that guides the search for targeted treatments.

Finally, he’ll discuss what he believes NIMH’s top priorities should be, and whether he will blog as did his predecessor, Thomas R. Insel, MD.

[email protected]

On Twitter @whitneymcknight

NEW YORK – In this first of four interviews, the new director of the National Institute of Mental Health, Joshua A. Gordon, MD, PhD, shares his thoughts about the emerging nosology of depression and whether it might be possible to identify and turn off genetic pathways implicated in depression without impacting creativity, sexual drive, and appetite.

Dr. Gordon is a practicing psychiatrist and a neuroscientist whose primary area of research is in the emerging field of optogenetics, which uses light to trace the genetically predetermined neurocircuitry of various mental states through the brain.

He steps into his leadership role with NIMH at a time when some have voiced concern that the institute has placed too much emphasis on future therapies, instead of on what can be done in the here and now to treat mental disorders.

Also in this series, Dr. Gordon discusses how, under his leadership, NIMH will balance the priorities of clinicians in everyday practice with those of researchers. He also explains the finer points of optogenetics. Currently, the technique is being studied only in mouse models; but if it makes it to human trials, researchers will explore the ability to switch on and off certain mental states.

Dr. Gordon talks about the ethical implications of optogenetics, as well as his belief in the biological basis of all thought and emotion, and how that guides the search for targeted treatments.

Finally, he’ll discuss what he believes NIMH’s top priorities should be, and whether he will blog as did his predecessor, Thomas R. Insel, MD.

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