Eileen Oldfield, Associate Editor, Pharmacy Times

Chronic myeloid leukemia patients likely have comorbid conditions at the time of their diagnosis; however, most tyrosine-kinase inhibitor studies exclude patients with these conditions. 

Despite a lack of patients with chronic myeloid leukemia (CML) and comorbid conditions in clinical trials of tyrosine-kinase inhibitors (TKIs), the results of a study appearing in the October 2013 edition of 

 suggest that imatinib, dasatinib, and nilotinib tend to be well-tolerated by patients.

Despite the general safety of TKIs and the lack of a significant contraindication for the therapies, information on dasatinib and nilotinib remains limited, the authors noted.

“A comprehensive comorbidity evaluation may be useful to improve TKI selection and safety in CML patients, especially in those considered elderly simply on registry age,” the authors wrote.

The median age of CML diagnosis is between 60 and 65, which increases the chances of concurrent conditions such as diabetes mellitus, non-diabetes metabolic syndromes, hyper- or dyslipidemia, and cardiovascular conditions. Many older patients meet the trials’ exclusion criteria, so clinical trials tend to include patients with a median age of 50 years. As a result, the trials are conducted with low comorbidity prevalence, the authors noted.

“Considering the increasing prevalence and public health impact of comorbid patients, clinical trials should not only focus on the index condition but also give higher relevance to patients with comorbidities, limiting the exclusion criteria only to well-established risk conditions, and performing a careful evaluation of comorbidity effect on the treatment outcome,” they wrote.

It can be difficult to assess the impact of comorbid conditions on adverse effects in patients using TKIs because the comorbid conditions are often identified in retrospective studies exclusively, they noted. Their research revealed 4 CML studies using comorbidity indexes: 3 studies evaluated the efficacy and tolerability of imatinib exclusively, whereas a single study evaluated the use of dasatinib in patients who were resistant or intolerant to imatinib. In general, the researchers determined that the treatments were safe in patients with comorbid conditions, and indicated comorbidity scales that may assist in clinical decision-making.

Meanwhile, the researchers also assessed CML, comorbidities, treatment efficacy, and adverse reactions in the DASISION trial, a Phase III trial comparing dasatinib to imatinib in newly diagnosed Philadelphia Chromosome—positive CML patients. Although the trial does not use a comorbidity index, the authors noted frequency each disorder occurred as well as frequency of adverse effects. The most frequently occurring disorders included gastrointestinal disorders, followed by muscle-skeletal disorders, and non-diabetes endocrine-metabolic disorders, they noted. Although drug exposure, dose modification, and treatment discontinuation were similar between patients with preexisting comorbidities and patients without comorbidities, certain adverse effects occurred more frequently in patients with comorbidities.

In particular, nausea and vomiting, and rash tended to appear more frequently in patients with comorbid conditions receiving dasatinib than in patients without comorbidities receiving dasatinib. In addition, diarrhea and superficial edema tended to occur more frequently in patients with comorbid conditions who received imatinib than in patients without comorbidities who received the same therapy.

In addition, certain treatment side effects appeared to have little effect on comorbid conditions, the authors noted. Fluid retention, a toxic side effect of imatinib, was not found to relate to chronic heart failure, despite the conditions’ clinical resemblance. Meanwhile, pleural effusion, a side effect of dasatinib, was found to increase only slightly in patients with comorbid conditions; however, the increase was not statistically significant.

Bleeding complications, another side effect of dasatinib, were more prevalent in patients with known history of bleeding problems, and in those taking antiplatelet or anticoagulant drugs.

In patients with hyperglycemia being treated with nilotinib, therapy had no impact on hyperglycemia rates, the researchers determined. In addition, nilotinib’s safety and efficacy in patients with type 2 diabetes was similar to that of patients without the condition.

“According to available data, we may say that no absolute significant contraindication exist [sic] to treat a given CML patient with imatinib, dasatinib, or nilotinib. … these TKIs are characterized, in general, by a very good profile of safety and tolerability,” the authors wrote.

Articles

Chronic myeloid leukemia patients likely have comorbid conditions at the time of their diagnosis; however, most tyrosine-kinase inhibitor studies exclude patients with these conditions.

Tyrosine-Kinase Inhibitors Well Tolerated, Despite Lack of Tests in Chronic Myeloid Leukemia Patients With Comorbid Conditions 

HIV positive patients who become distressed more easily may be less likely to adhere to antiretroviral treatment (ART), suggest the results of a study appearing in the September 2013 edition of 

The ability to tolerate distress can further influence ART adherence when combined with negative emotions and negative medication side effects, the researchers from Brigham & Women’s Hospital, Stanford University, and the University of Maryland determined.

In addition, a patient’s belief in his or her ability to tolerate negative moods and ability to persevere through distressing tasks correlated to better adherence to ART and a lower viral load.

“Our findings are largely consistent with past work in the areas of ART adherence and distress tolerance, and underscore the clinically relevant role of distress tolerance in models of adherence and disease status among HIV positive patients,” the researchers wrote. “ . . . future interventions for individuals with HIV may benefit from specifically targeting ability/willingness to tolerate distress through cognitive behavioral treatment approaches so that individuals may remain adherent in the face of treatment-related burdens.”

Researchers used measures of ART adherence, responses to ART, immunocompromise status, and measures of distress tolerance to gauge the relationship between distress tolerance and ART adherence. Noting evidence suggesting an association between poor distress tolerance, negative emotions, ART side effects, and nonadherence, researchers also investigated the association between distress and adherence when controlling for negative emotions and therapy side effects.

Researchers collected data from a cross-sectional study of 180 participants with HIV, finding 140 participants who met study inclusion criteria. Pill count tracking was used to measure patient adherence, and viral load and CD4 to determine therapy response.

Researchers used 4 scales to gauge HIV-related symptoms, distress, and positive and negative emotions, including a symptom checklist, measures of positive and negative emotions experienced during the week prior, a distress tolerance scale, and a computerized behavioral measure of distress tolerance.

Pill count data revealed an average adherence rate of 81.4%, which researchers noted was lower than the 95% recommended adherence rate for protease inhibitor ART, although it is still within the acceptable adherence range. Meanwhile, the average side-effect severity fell near the midpoint (31.5) of the 68-point side effect range. Participants reported negative emotions at a slightly higher rate than those seen in HIV-negative adults, whereas self-reported distress tolerance was slightly lower than the results established in a separate study. The behavioral measure of distress tolerance has not yet been used in another HIV-positive participant population; as a result, researchers compared their findings on that test to a sample of substance-abusing participants who also had affective disorders. Researchers noted that participants in their study tended to complete the task for about 67.2 seconds, whereas the sample of substance-abusing participants who also had affective disorders tended to complete the task for approximately 294 seconds.

“In addition to the severity of distress (ie, negative affect and bothersome medication side effects), the degree to which one is able and/or willing to tolerate such distress appears to be further influencing ART medication adherence and viral load status in our sample,” the researchers wrote. “Promoting tolerance of affective distress and distressing tasks associated with the high-adherence demands of ART for HIV management are worthwhile to consider in future research.”

HIV positive patients who become distressed more easily may be less likely to adhere to antiretroviral treatment (ART), suggest the results of a study appearing in the September 2013 edition of Behavior Therapy.

Distress Tolerance in Relation to Antiretroviral Treatment Adherence and Response Among Individuals Infected with HIV 

A recent study compared the annual cost per treated patient for a health plan for patients taking etanercept, adalimumab, or infliximab.

Among tumor necrosis factor (TNF) blockers, etanercept has a lower cost per treated patient than adalimumab or infliximab therapies for patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, psoriasis and any other condition, or a combination of the conditions, the results of a study appearing in the October 2013 edition of 

In patients with psoriasis alone, however, adalimumab proved to have a slightly lower cost per treated patient than etanercept or infliximab, the authors noted.

The findings may support formulary management decisions and highlight nonindex costs for managed care pharmacists.

“Examining these data separately allows managed care pharmacists to fully appreciate the important contribution of nonindex costs to total costs, as well as any differences between agents in these contributions,” the authors wrote.

“.  .  . These findings, when combined with the available evidence of the comparative efficacy and safety of TNF blockers in the treatment of rheumatoid arthritis, psoriasis, psoriatic arthritis, and ankylosing spondylitis, may be used by decision makers to support formulary decisions,” they added.

Researchers used data from the IMS LifeLink Health Plan Claims Database and included adults aged 18 to 64 with at least 1 insurance claim for etanercept, adalimumab, or infliximab between February 1, 2008, and July 5, 2010, in the study. Participants also needed diagnosis of rheumatoid arthritis, psoriasis, psoriatic arthritis, or ankylosing spondylitis, and were categorized as a new patient if there were no claims for the drugs prior to the study’s index date, or as a continuing patient if they had a claim prior to the study index date.

Patients with a diagnosis of juvenile idiopathic arthritis, Crohn’s disease, or ulcerative colitis were excluded from the study because the medications analyzed do not have those indications in common. In addition, researchers did not evaluate treatment effects or comparative statistical tests, as they were not pertinent to their analysis.

Researchers used April 2012 unit wholesale acquisition costs, as well as April 2012 update to the Medicare Physician Fee Schedule, to estimate budget impact. In addition, most participants were insured through commercial insurance plans or were self-insured, usually through either a preferred provider or an HMO plan.

The results showed etanercept was the most commonly used drug, followed by adalimumab, and infliximab.

In general, the annual TNF-blocker cost per treated patient was lowest for patients on etanercept, at $17,767 per treated participants for all participants in the study. Adalimumab therapy had an annual cost per treated patient of $19,272 of all treated participants, and infliximab had an annual cost per treated patient of $24,273.

In newly treated participants across all conditions, the annual cost per treated patient was $17,270 for etanercept, $17,959 for adalimumab, and $21,482 for infliximab. Meanwhile, participants on continuing treatment across all conditions saw annual costs per treated patient of $18,203 for etanercept, $20,453 for adalimumab, and $25,468 for infliximab.

The same trend of lower per patient per year costs for etanercept, adalimumab, and infliximab extended to the majority of conditions examined in the study, with the annual cost of therapy per treated patient being 3% to 31% greater for adalimumab than etanercept and 26% to 72% greater for infliximab than etanercept, the research noted.

Psoriasis without concomitant conditions was the only condition in which etanercept was not the least expensive therapy. In those patients, the cost of adalimumab was 6% lower than the cost of etanercept, although etanercept was still less expensive that infliximab. In this case, researchers noted a 3-month etanercept loading dose for patients with psoriasis that would likely increase overall costs in the first year of therapy.

The authors disclosed that Amgen Inc participated in study design, data analysis, and manuscript preparation. In addition, authors Crystal Watson, George J. Joseph, and David J. Harrison report being employed by Amgen at the time the study was conducted and the manuscript prepared.

In Most Managed Care Patients, Annual TNF Treatment Costs Lower with Etanercept

The Generic Pharmaceutical Association petition recommends that the FDA use the active ingredient in a reference biologic when naming a biosimilar product.

A Generic Pharmaceutical Association (GPhA) petition filed with the FDA last week requests that biosimilar products have the same name as compounds in the reference biologic.

The practice would not only follow naming conventions for pre- and postmanufacturing reference biologic products and traditional, small-molecule generic drugs, but would prevent confusion and duplicate therapy, the petition states.

The practice would also reflect European biosimilar naming conventions, which have been in place for years.

“It is simple: biosimilars have no clinically meaningful difference from the reference product, so they should have the same name,” Ralph G. Neas, GPhA president and CEO, said in a press release. “This approach works in Europe, it has worked in the United States for chemical drugs, and it should be the standard worldwide. To upset the naming system in place risks engendering confusion and would have a major negative impact throughout the global pharmaceutical supply chain, potentially jeopardizing patient access across the globe.”

GPhA submitted its petition on September 17, 2013. According to the FDA’s Code of Federal Regulations for the statute referenced by GPhA, the FDA Commissioner is expected to rule on petitions within 180 days of the filing. The commissioner may accept, reject, or provide a tentative response to the petition detailing why the FDA could not provide a final response by its deadline.

The commissioner is expected to consider the FDA’s available resources within the area the petition references; the priority assigned to the petition, which is based on the petition subject and the agency’s current projects within that area; and the time requirements established by the statute under which the petition is submitted.

Although the FDA has yet to release a final guidance on biosimilar approval, the 23-page petition requests that all biosimilar products have the same international nonproprietary name (INN) as the reference biologic. The INN, a naming convention administered by the World Health Organization (WHO), already figures into the selection of traditional generic product names within the United States, as the United States Adopted Name Council, the council responsible for product names, collaborates with the WHO. INNs, whether used for biologics or small-molecule drugs, typically reference the active ingredient in the therapy, GPhA’s petition notes.

“To keep with the intent of the INN, which is to allow immediate identification of a product’s active ingredient, all biosimilar products should share an INN with their RPP [reference protein product] because they must contain, as a fundamental requirement of their licensure, the same active ingredient,” the petition notes.

The petition also recommends that biosimilar product labels include a statement similar to that of generic drugs, which states the reference product’s brand name. Concerns regarding safety, traceability, and pharmacovigilance can be addressed using national drug codes, batch, and lot numbers, the petition notes. That practice is already in use with traditional generic and brand name drugs, as well as brand name biologics.

Petition Requests Consistency in Biosimilar and Reference Biologic Names

A study compared historical and contemporary multiple sclerosis cases to determine how first-generation disease-modifying drugs affected disease progression.

First-generation disease-modifying drugs (DMDs) tended to delay the onset of severe neurologic disabilities seen in later multiple sclerosis (MS) stages, suggest the results of a study published in the May edition of 

Study authors sought to determine differences in time to secondary disease progression, the MS stage marked by severe neurologic disabilities, by comparing an untreated historical cohort of participants to a contemporary participant cohort.

Although disease onset was relatively similar between the historic and contemporary cohorts, the research suggested more severe symptoms in the participants who did not have treatment available, and a greater therapeutic effect in those who began treatment early.

In particular, participants who received treatment with first-generation DMDs, typically interferon beta or glatiramer acetate, tended to reach secondary progression later than those who did not.

The research cohorts included 186 participants diagnosed between 1950 and 1964 in the historical group, which researchers found via the Gothenburg Incidence Cohort. The contemporary group included 730 participants diagnosed between 1995 and 2004, found via the Swedish National MS Registry. The contemporary cohort’s results were followed until 2008.

The authors noted that 76 patients in the contemporary group changed their treatment to natalizumab; however, the change occurred in the last 3 years of the study period. Participants whose disease began after 2000 tended to be treated earlier than those whose disease began during the mid 1990s, the authors noted. In addition, the amount of participants receiving DMD therapy increased during the study period.

After combining scores from several clinical areas and performing Kaplan-Meier estimate analysis, researchers determined no conspicuous difference in onset composition between the 2 groups, although they did note a higher proportion of patients in complete remission in the contemporary group, and a higher proportion of patients presenting with central nervous system symptoms in the historical cohort.

In both cohorts, an older age at symptom onset tended to mean a shorter time to reach secondary progression. In addition, those with more intense severity scores tended to reach secondary progression faster. When analyzing the data by gender, the authors also noted a longer time to reach secondary progression in women than in men.

In general, those in the untreated historical cohort tended to reach secondary progression faster than those in the cohort receiving treatment, even when data were stratified by gender or severity index score.

A Cox-regression analysis of the gender-divided data confirmed the findings of the first analysis, showing complete remission and monofocal onset to diminish hazard ratio. Older age at symptom onset resulted in a higher hazard ratio.

Although the analysis did not indicate a significant effect from treatment initiation time, both estimates showed a larger hazard ratio if treatment was delayed.

“We found there was a convincing ‘period effect,’ with a longer time to the onset of secondary progression in the contemporarily-treated than in the historical patient data,” the authors wrote. “. . . With a baseline of disease onset, we found no convincing evidence for a large imbalance between groups of à priori mild cases; therefore, part of the observed delay to the transition to secondary progression was probably due to the sustained effects of long-term treatment with first generation DMDs.”

Early Disease-Modifying Drug Therapy Delays Multiple Sclerosis Progression

The Patients’ Access to Treatments Act of 2013 proposes limits on patients’ costs for specialty drugs.

A House of Representatives bill aimed at limiting cost-sharing requirements for specialty drugs would have minimal impact on overall health plan costs, according to an Avalere Health report commissioned by the Coalition for Accessible Treatments.

The bill, HR 460, amends title XXVII of the Public Health Service Act by limiting copayment, coinsurance, or cost-sharing requirements for specialty drugs, making the requirements for specialty drugs similar to those for prescription drugs in a nonpreferred brand drug tier. The bill would also limit the difference in total drug dollar costs between drug tiers at a 10% increase between tiers.

According to Avalere Health’s report, annual premiums would increase an average of $3 for plans with specialty drug tiers if the bill is enacted, assuming there are no additional changes to the plan’s benefit design. Plans with copays for specialty drugs would see an average annual increase of 37 cents, whereas plans using coinsurance for specialty tiers would see an average annual increase of $7.78.

The report estimated the increase in each type of prescription drug plan, so actual increases could differ from those cited. For plans with specialty drug tiers, the impact could be greater than the $3 estimate if the plan uses coinsurance rather than copays, the report stated. Plans with pre-existing copays would likely see a small change because the amount of cost sharing is fixed, although the potential for variation from the 37-cent estimate still exists. Although most plans with a specialty drug tier did not use coinsurance in 2012, the increase for those plans would likely be higher than for other plans, the report noted.

Noting the need to offset the legislation’s lower specialty drug costs, Avalere Health estimated the increase in premiums or cost sharing within other drug tiers as well. To offset the $3 average increase in annual premiums, Avalere Health’s research estimated a $6 increase in nonpreferred drug copays, a 75-cent increase in preferred tier copays, and a 50-cent increase in generic tier copays.

The bill was introduced on February 4, 2013, and referred to the House of Representatives House Energy and Commerce Committee’s subcommittee on Health. It has remained there since its introduction; the subcommittee will consider sending it to the full House.

According to govtrack.us, a government transparency website tracking bill progression through the legislative system, the bill has an 11% chance of getting past committee, and a 3% chance of being enacted—a prediction par for most bills introduced between 2011 and 2013.

The Coalition for Accessible Treatments, an interest group that includes professional medical associations and patient organizations as members, commissioned the study. Coalition members include the American Academy of Dermatology Association, American Academy of Neurology, American Autoimmune Related Diseases Association, American College of Rheumatology, The National Organization for Rare Disorders, and other organizations.

The Patients' Access to Treatments Act of 2013 proposes limits on patients' costs for specialty drugs.