Research presented at the 2017 Annual Meeting of the American Society of Clinical Oncology (ASCO) 

 biosimilar, is safe and effective as a neoadjuvant treatment in human epidermal growth factor receptor 2—positive (HER2–positive) early breast cancer (EBC). 

CT-P6, a recombinant humanized monoclonal antibody that targets HER2 approved by the Ministry of Food and Drug Safety, a government body in Korea, has an identical amino acid sequence and highly similar physicochemical and in vitro functional properties to trastuzumab. A phase 1 trial demonstrated similar pharmacokinetics (PK), safety, and immunogenicity between the 2 products. 

This double-blind, randomized, phase 3 study sought to demonstrate the therapeutic response equivalence of CT-P6 and its reference product as determined by the pathological complete response (pCR), defined as the absence of invasive cancer in the breast and axillary nodes, irrespective of ductal carcinoma in situ. Secondary objectives for the study included obtaining additional PK, pharmacodynamic, and safety data. The researchers also sought to evaluate additional efficacy parameters, including breast pCR (bpCR), defined as the absence of invasive cancer in the breast irrespective of ductal carcinoma in situ or nodal involvement; pCR without ductal carcinoma in situ (DCIS), defined as absence of invasive cancer and in situ cancer in the breast and axillary nodes; overall response rate (ORR); and breast conservation rate. 

The researchers considered 549 female patients 18 years or older who had been diagnosed with HER2—positive EBC of clinical stage I to IIIa. The patients had generally balanced demographics and disease characteristics, and were randomized at 112 centers in 22 countries. The 2 groups were treated with CT-P6 (n = 271) or the reference trastuzumab (n = 278). Patients were treated with the biosimilar or the reference product, in combination with chemotherapy, as neoadjuvant treatment for 8 cycles, and for up to 1 year (or 10 cycles) of monotherapy as adjuvant treatment. Following neoadjuvant treatment, patients underwent surgery, when pathological response, PK, and immunogenicity were assessed. 

The pre-defined therapeutic equivalence margin for the risk ratio was 0.74 to 1.35, and the margin for the risk difference was -15% to 15%. The researchers found, with a 95% confidence interval, that the treatment risk ratio for the per-protocol set (PPS) was 0.93 (range, 0.78 to 1.11), and the treatment difference estimate for the PPS was -3.62% (range, -12.38 to 5.16), both within the pre-defined equivalence margin. The proportion of pCR without DCIS and the bpCR were similar between the 2 treatment groups, as was ORR.

The study further found that serum concentrations of the treatment products, HER2-shed antigen levels, the proportion of patients who underwent breast conservation surgery, and rates of treatment emergent adverse events (with neutropenia, anemia, and leukopenia being the most commonly reported adverse events) were similar for the 2 groups during the neoadjuvant period. None of the patients developed anti-drug antibodies during the study. 

While adjuvant period data will be generated in the future, the researchers concluded that:

CT-P6 and trastuzumab are therapeutically equivalent in terms of pCR for both the PPS and the intent-to-treat set.

CT-P6 and the reference product had similar safety profiles in the neoadjuvant period. 

Secondary efficacy endpoints, as well as the results of 

 analysis, further supported the similarity of the 2 products. 

Articles

ASCO

Research presented at the 2017 Annual Meeting of the American Society of Clinical Oncology (ASCO) shows that CT-P6, a proposed trastuzumab biosimilar, is safe and effective as a neoadjuvant treatment in HER2–positive early breast cancer. 

CT-P6, a Trastuzumab Biosimilar, Shares the Safety and Efficacy Profile of Its Reference

A study presented at the 2017 Annual Meeting of the American Society of Clinical Oncology (ASCO) demonstrates that SB3, a proposed biosimilar to 

 (TRZ), has comparable efficacy, safety, immunogenicity, and pharmacokinetics (PK) to the reference product based on the breast pathological complete response (bpCR), which was the primary endpoint. 

The phase 3, double-blind, randomized, parallel-group, multicenter 

, sponsored by Samsung Bioepis, sought to demonstrate the comparable efficacy of SB3 (which has an identical primary amino acid sequence to TRZ) and TRZ in terms of bpCR when the products are used in neoadjuvant settings in women who have either epidermal growth factor receptor 2—positive early breast cancer or locally advanced breast cancer.

Patients, 18 to 65 years of age and newly diagnosed with stage II to III primary breast cancer, received either SB3 or the reference product for 8 treatment cycles, which were given concurrently with chemotherapy. The patients then underwent surgery and a subsequent 10 cycles of either SB3 or TRZ. 

The researchers defined bpCR rate as the primary endpoint of the study, which comprised 403 patients per arm. The study analyzed efficacy in a per-protocol set (PPS), comprising those who had completed neoadjuvant therapy and surgery without any pre-specified major deviations from protocol, and further considered a full-analysis set to provide supportive data. 

Drawing upon several published TRZ studies as a guideline, the researchers set equivalence margins in the PPS at a 90% confidence interval (CI) of the ratio of bpCR rates for SB3 and TRZ, or a 95% CI of the difference of bpCR rates for the 2 products. Secondary endpoints for the study included total pathologic complete response (tpCR), overall response rate (ORR), event-free survival, PK equivalence, immunogenicity, and safety. 

The researchers found that, after adjusting results by hormone receptor status, disease stage, and region, the adjusted bpCR ratio for the PPS was 1.259 (90% CI, 1.112-1.426), a value which falls within the pre-defined margin of 0.785 to 1.546. The adjusted difference was 10.7% (95% CI, 4.13%-17.26%), with the lower margin contained within and the upper margin falling outside the pre-defined margin (-13%-13%). The tpCR results were reflective of the bpCR findings, with an adjusted PPS ratio of 1.315 (90% CI, 1.137-1.520). Results for ORR also bore out bpCR results, with an adjusted ratio for the PPS at 1.055 (90% CI, 1.023-1.088).

Additionally, the study data demonstrate comparable safety between SB3 and TRZ, with neutropenia, alopecia, and nausea representing the most commonly reported adverse effects in both study arms. PK data demonstrated equivalent steady-state trough levels. Finally, immunogenicity was comparable between the 2 groups up to cycle 9 of treatment, with positive anti-drug antibody results reported for 3 patients in the group receiving SB3 and none in the group receiving TZB. 

While the report notes that complete safety and survival data will follow, the researchers concluded that SB3 and TZB had equivalent efficacy based on the ratio of bpCR rates, and that SB3 was both well tolerated and comparable to TZB in safety, immunogenicity, and PK.

A study at ASCO 2017 demonstrates that SB3, a proposed biosimilar to trastuzumab (Herceptin) has comparable efficacy and safety to the reference product based on the breast pathological complete response.

Research Demonstrates Efficacy and Safety of Trastuzumab Biosimilar SB3

 presented at the 22nd Annual International Meeting of The International Society for Pharmacoeconomics and Outcomes Research demonstrates gaps in physicians’ education on biosimilar agents.

Researchers from Cardinal Health Specialty Solutions sought to assess community oncologists’ understanding of biosimilars by surveying a group of 61 community-based US oncologists and hematologists during a live meeting. The clinicians—who came from practices of all sizes and from across the United States&mdash;were asked to respond to specific multiple-choice questions about their perceptions of biosimilar agents. 

The results of the survey showed that, when asked to describe their familiarity with biosimilars, many physicians reported a lack of clarity about the products: 

25% of respondents said that they lacked familiarity with biosimilars

45% stated that their practice partners lacked knowledge of biosimilars 

23% said that they had no knowledge of the regulatory process for biosimilars

19% believed the regulatory pathway for biosimilars to be the same as the pathway for other drugs or biologics 

The survey also revealed that, with respect to safety and efficacy considerations, many clinicians appear receptive to biosimilars, though some seek more information before they will consider prescribing them:

78% of respondents believed that biosimilars’ efficacy would prove comparable to that of reference products

90% did not associate the reduced costs presented by biosimilars with reduced safety 

36% said that they would treat biosimilars like generics with automatic substitution 

46% required additional evidence concerning biosimilars before they would consider prescribing a biosimilar for cancer treatment 

45% reported that familiarity with a product’s manufacturer would be critical in making the decision to prescribe a biosimilar 

Cost savings appear to be an important factor in clinicians’ willingness to prescribe biosimilar agents rather than reference products: 

57% of clinicians said that reducing costs by prescribing biosimilars is “very important”

79% reported that a price discount of 11% to 30% would be necessary in order for them to consider prescribing a biosimilar over a reference product 

8% sought a discount greater than 40% before they would consider prescribing a biosimilar 

The survey also asked clinicians to consider patient case examples for 5 conditions, and to report how likely they were to prescribe a biosimilar over a reference product to treat each condition. The reported likelihood of the respondents to prescribe biosimilars is as follows:

Trastuzumab for breast cancer in an adjuvant setting: 39%

The researchers concluded that, while clinicians appear receptive to the idea of prescribing biosimilar products in oncology, significant gaps in education pose a barrier to physicians’ acceptance of these products. It will be critical, the researchers suggest, to overcome this educational barrier in order to increase the uptake of biosimilars and to realize cost-savings in patient treatment. 

Virtual ISPOR

Research presented at the 22nd Annual International Meeting of The International Society for Pharmacoeconomics and Outcomes Research demonstrates gaps in physicians’ education on biosimilar agents. 

Study Underscores Need for Educating Community Oncologists on Biosimilars

To date, there has been little information available about the uptake of filgrastim-sndz in the United States compared to the use of other granulocyte colony-stimulating factor (G-CSF) agents. In a 

 funded by Envision Market Access Solutions (part of Envision Pharma Group) and presented at the 22nd Annual International Meeting of The International Society for Pharmacoeconomics and Outcomes Research, researchers sought to identify physicians’ documented G-CSF use, with a particular focus on the use of filgrastim-sndz since its entry into the marketplace.

The first biosimilar approved in the United States, 

 has been approved for 5 of 6 licensed indications for its reference product (including prophylaxis for and treatment of febrile neutropenia in patients undergoing myelosuppressive chemotherapy) and has been available in the US market since September 2015. 

The researchers identified mentions of G-CSF agents in physicians’ records of patient consultation as documented in RealHealthData (a transcription database) for the period of January 1, 2016, to March 31, 2017. The records comprise notes from both office visits and healthcare facility consultations, and included physicians’ intentions to treat with a G-CSF at the time of the consultation, a patient’s G-CSF treatment history, or both. 

In addition to tabulating occurrences of the names of 4 G-CSF agents, namely pegfilgrastim (Neulasta), filgrastim (Neupogen), tbo-filgrastim (Granix, Neutroval), and filgrastim-sndz (Zarxio, Zarzio), the researchers also evaluated their prophylactic or curative use against 

Per the analysis, physicians made 17,770 mentions of G-CSF agents in 2016: 

In the first quarter of 2017, mentions of filgrastim increased to 39.6% of the total number of G-CSF mentions, while mentions of tbo-filgrastim increased to 12.8%. Pegfilgrastim, however, retained the highest share of the total with 47% of mentions. 

The data show that, over the full study period, general practitioners were the most frequent providers to mention pegfilgrastim, filgrastim, and tbo-filgrastim (though hospitalists mentioned tbo-filgratim the most often). Data also demonstrate an influence of location: physicians in Pennsylvania mentioned pegfilgrastim the most often, physicians in Texas noted tbo-filgrastim the most often, and providers in Kansas mentioned filgrastim-sndz the most often. 

Explaining that their study provides only a proxy of G-CSF use for specific time periods rather than documented treatment patterns for such agents, the authors state that providers’ notes may have been repeated in cases of patient hospitalization over a period of days. Furthermore, the data do not represent all US states, so the study’s findings are not representative of national trends. 

Yet the researchers conclude that, among 21,222 records considered in this study, only 140 mentions (0.7% of total mentions) of filgrastim-sndz were noted in the first 18 months of the product’s entry into the US market, and there was no significant increase in the product’s mentions in the first quarter of 2017 when compared with the 2016 period. The researchers also suggest that differences among mentions of filgrastim-sndz and other G-CSF agents across provider types and geographies may indicate differences in formulary listings and clinical treatment patterns across regions. 

 of biosimilars among clinicians and payers, the authors conclude, may be required in order for filgrastim-sndz to see increased uptake. 

In a study presented at the 22nd Annual International Meeting of The International Society for Pharmacoeconomics and Outcomes Research, researchers sought to identify physicians’ documented granulocyte colony-stimulating factor (G-CSF) use, with a particular focus on filgrastim-sndz since its entry into the marketplace, and identified a slow US uptake for the biosimilar. 

Analysis of Physicians' Notes Shows Slow Uptake for Filgrastim-sndz

 on May 22, 2017, at the 22nd Annual International Meeting of The International Society for Pharmacoeconomics and Outcomes Research, researchers from Brazil found that switching from reference products to biosimilars can create substantial cost savings for payers in private healthcare systems. 

The researchers developed a 5-year cost minimization analysis model to measure the impact of switching infliximab (

 in patients undergoing treatment for rheumatoid arthritis (RA) in the Brazilian private healthcare system. The analysis considered direct medicine costs (which are regulated by the Brazilian Ministry of Health) for the treatment of a cohort of 2 million patients, and drew upon data from the 10 largest private healthcare plans in Brazil. 

The model employed a switch rate of 30% in year 1, which increased by 5% annually, to arrive at 50% in year 5. Using this schedule, and employing a population growth-rate adjustment of 0.09% after year 1, the researchers found that switching RA patients to the infliximab biosimilar generated a cost savings of 15.6 million to 26.2 million Brazilian reais (an amount equivalent to 4.81 million to 8.08 million US dollars). That savings represents up to a 20.8% reduction of overall acquisition costs. When considering a reduced 5-year switch rate of only 40%, savings on acquisition costs were still strong at up to 13.78%. 

The researchers concluded that switching from reference products like infliximab to biosimilar products can provide payers with substantial cost-savings opportunities. Such savings, the researchers suggest, are not only positive news for payers seeking to reduce their expenditures, but also for patients; lower prices have the potential to spur greater patient access to biological agents, and may improve overall treatment availability. 

Research From Brazil Highlights the Role of Biosimilars in Reducing Private Healthcare Costs

The International Society for Pharmacoeconomics and Outcomes Research’s 22nd Annual International Meeting

 in Boston, researchers presented new findings concerning switching between Amgen’s biological agent etanercept (Enbrel) and its first biosimilar product in the German marketplace.

“Preliminary Real World Data on Switching Dynamics Between Etanercept and its Recently Marketed Biosimilar Counterpart,”

 a study sponsored by Pfizer and conducted by researchers from University Medicine Berlin, Pfizer, and QuintilesIMS, was designed to provide initial data concerning market penetration of the first etanercept biosimilar (EtnBS). The study sought to evaluate the switching dynamics between etanercept and EtnBS in real-world clinical settings. Following its launch in Germany in February 2016, EtnBS has been used by rheumatologists as an alternative to etanercept, a tumor necrosis factor inhibitor used in the treatment of certain 

The study considered 5349 patients, identified retroactively through the German Longitudinal Prescriptions database (which represents approximately 60% of the statutory health insurance market), who were initiating EtnBS therapy. Immediately prior to treatment with EtnBS, 48% of the study’s patients had not been treated with a biological agent, 36% had been treated with etanercept, and 16% had been treated with another biological agent. Of the patients who had been treated with etanercept previously, the majority had approximately 3 years of treatment prior to switching to the biosimilar. Among the patients previously treated with etanercept, 53% administered the product using injection pens, and 47% used pre-filled syringes. 

The researchers found that the use of EtnBS has been steadily increasing since the product’s 2016 launch in the German marketplace, and that EtnBS reached a market share of 10% in March 2017 (compared with a 31% market share for the originator product).

However, the researchers found that, among patients who changed their treatment from etanercept to EtnBS, 10% switched back to the original product within a 3-month period. Of those patients who returned to etanercept treatment, a large proportion (72%) returned to using the same administration method that they had employed previously. The study’s authors suggest that the type of device used may have influenced the patients’ decisions to switch back to etanercept. 

When considering all biological agents available (including adalimumab, rituximab, and infliximabBA, among others), the researchers found that 8% to 16% of patients initiating treatment with EtnBS changed to another biological agent within a 3- to 4-month period. The percentage of patients who switched from EtnBS was higher among those patients who had been treated with biological agents prior to initiating EtnBS.  

The study’s authors caution that longer-term studies will be necessary to confirm these preliminary findings, and to better understand why some patients choose to return to treatment with reference products after treatment with biosimilar products. Understanding these reasons may hold the key to increasing uptake of biosimilars and controlling the 

 of treating diseases using biological agents. 

Research Shows Patients Switching From Biosimilars to Reference Products

Several studies on omalizumab (Xolair), currently manufactured by Novartis through a partnership agreement with Genentech, recently presented at the 2017 Annual American Academy of Allergy, Asthma, and Immunology (AAAAI) meeting in Atlanta, Georgia, demonstrated why biologic therapies are considered by many to be the “future” of care.

Omalizumab, an injectable medicine for patients 12 years and older for treating severe-to-persistent allergic asthma not controlled by inhaled corticosteroids (ICS), was approved by the 

 in 2003 only for asthma. The indication was modified several times over the next decade, and included a warning of “slightly higher risk of heart- and brain-adverse events,” which was added in September 2014. While the warnings may have changed, the uses for this flexible biologic drug have clearly only begun to be discovered.

“Despite the availability of omalizumab since 2003, utilization trends have not been previously described,” observed 1 research team, headed by Matthew Rank, MD, a physician at the Mayo Clinic in Scottsdale, Arizona. The team identified 8545 patients who used omalizumab between 2003 and 2015. They excluded certain conditions in order to prevent “censoring based on insurance coverage,” and noted that individuals starting on the biologic peaked in 2005 at 9.56 new users per 100,000 insured people and declined to 5.22/100,000 in 2012. In 2015, that number had climbed back up to 12.13/100,000, although 59% of those users stopped using the drug after less than a year.

The increased usage and relatively short duration of use could be due, in part, to aggressive marketing on the part of Genentech, which forecasters 

 at the end of Q1 2016 would own about 40% of 2016’s “top 10 new drugs in peak projected sales,” in large part due to its biologic and biosimilar research. Back in the 1990s, Genentech “officially committed to oncology” in the words of then-CEO Arthur D. Levinson, PhD, and that decision led the company toward biopharmaceutical research that, including breakthrough treatments for multiple sclerosis and, eventually, to omalizumab, which was a blockbuster drug in 2014. Genentech and Novartis ultimately endured a nasty scandal when whistleblowers accused them of marketing omalizumab directly to healthcare providers for wide-ranging uses instead of the narrow window of use prescribed by the FDA. The fact remains that omalizumab usage spiked and has remained high since.

Perhaps more exciting than the usage study was a study indicating that baseline blood eosinophil levels and asthma exacerbations could be reduced in children with moderate-to-severe allergic asthma through use of omalizumab. This is particularly intriguing since FDA restrictions on using the drug in children under 12 have been problematic for both drug manufacturers and physicians wishing to treat pediatric patients who are not responding to other therapies, including ICS, with omalizumab. The researchers, led by author Stanley Szefler, MD, a physician at the Children’s Hospital in Colorado and a professor at the University of Colorado School of Medicine in Aurora, Colorado, conducted a 24-week inhaled steroid dose-stable phase of a double-blind, randomized, controlled trial in children 6 to 12 years of age with “inadequately controlled, moderate-to-severe, allergic asthma.” They reported, “Clinically significant asthma exacerbation rates were reduced by 31% (

 = .007) with omalizumab versus placebo. The study not only demonstrated a pediatric usage that might be beneficial to a younger age group, but also provided a method for physicians to predict how younger patients might respond to the treatment, since children with elevated baseline eosinophil counts ≥300µ showed a “significantly greater response” to the drug compared with placebo, while children with lower baseline eosinophils had “nonsignificant reductions.”

Finally, another group led by Shaun Kilty, MD, a physician in the University of Ottawa Hospital’s Otolaryngology-Head and Neck Surgery, presented evidence that omalizumab treatment “provided significant improvement in every major clinical symptom of chronic rhinosinusitis (CRS),” although the group emphasized that “a well-designed clinical trial is needed to further assess the efficacy and safety” of the treatment. The group evaluated 25 patients diagnosed with CRS and 5 control patients who would have qualified for the study but could not get insurance coverage for the treatment. The patients were treated for a mean duration of 19 months, and 76% had CRS with polyps while 33% had aspirin exacerbated respiratory disease. “The omalizumab therapy provided a mean overall symptom improvement of 69.5%,” Kilty reported, noting that this meant patients who received the omalizumab treatment experienced less facial pain, fewer nasal obstructions, and improvements in rhinorrhea and olfaction, while the control group, which also improved overall, experienced far less improvement.

These 3 studies, in conjunction, clearly demonstrate why biologic and biosimilar drugs represent such promise for pharmaceutical companies and for the fields of asthma, allergy, and immunology. With biologics and monoclonal antibodies (mAbs) in particular making up nearly a fifth of the asthma pipeline alone, according to business intelligence firm 

, these drugs often represent new options to patients with the most sensitive immune systems who have high levels of intolerance for many of the more “traditional” pharmaceutical options. One GBI analyst observed of the firm’s data, “Drug developers are looking to follow the example of Xolair by developing highly-targeted biologics and mAbs aimed at specific patient subtypes with the hope of benefiting previously underserved patients and generating strong revenues.” Another benefit of this strategy is that biologics often target pathogenesis that is relevant to multiple conditions, thereby opening up new uses for drugs in the future, as is currently the case with omalizumab.

AAAAI Annual Meeting

Omalizumab Biologic is Changing the Face of Asthma Therapeutics

 as early as April 2017 for sale by Sanofi and Regeneron Pharmaceuticals, Inc, under the brand name Dupixent, made headlines with another positive study indicating that the investigational human monoclonal antibody (mAb) intended to treat moderate-to-severe atopic dermatitis (AD) shows “sustained efficacy in reducing signs and symptoms and improving skin lesions and pruritus among AD patients without any major safety issues.”

Lead author on the study, Mette Deleuran, PhD, professor in the Dermatology Department at Aarhus University Hospital in Aarhus, Denmark, and her team revealed their results in a late-breaking abstract session at the 2017 annual American Academy of Asthma, Allergy, and Immunology (AAAAI) meeting in Atlanta, Georgia, on March 6. Deleuran and her team 

 the first-step analysis from an ongoing phase 3 multi-center, open-label trial of subcutaneous dupilumab that Elias Zerhouni, former head of the National Institutes of Health and current Sanofi Pasteur head of Research & Development, described as “an illustration of something more profound [than a single-product success], which is really the emergence of a new science and portfolio at Sanofi.” He went on to call dupilumab the “prototype of future medicine” in an interview with 

 because it is designed to target 2 different disease pathways at the same time: cytokines IL-4 and IL-13, both of which are believed to signal the body’s immune system to respond, resulting in inflammation and symptoms typical of the disease.

Although Sanofi is waiting on specific approval for dupilumab for treating atopic dermatitis, effective inhibition of these cytokines and the immune responses that they trigger would indicate broader reach of the drug. From a profit standpoint, it could solidify the potential in the biosimilar sector, demonstrating that the success of a single drug for a single purpose opens up what Zerhouni calls “a pipeline in a single drug,” since many of these cytokines play a role in everything, from seasonal allergies to cancer.

According to the study, adults with moderate-to-severe AD who had participated in previous dupilumab trials were eligible to participate in phase 3 of the trial. Of the 1491 patients (60% male, with an average age of 39.7 years) who received treatment, 106 withdrew from the study during a 1-year perios. There were no deaths reported in the study. “The most common adverse events (AEs) were nasopharyngitis (20.5% of patients), upper respiratory tract infection (9.5%), exacerbation of the condition (8.2%), and conjunctivitis (all etiologies 10.7%)” the team reported. Patients who withdrew cited AEs, with the most common being nasopharyngitis, headaches, and upper respiratory tract infections. At the week-52 assessment in the study, 48.6% of patients had a score between 0 and 1 on the Investigator’s Global Assessment (IGA) 

 for their symptoms with a “1” score being “almost clear” and a “0” being “clear;” 75.4% achieved ≥75% in eczema area and severity, and their pruritus scores decreased by 62.24%. The patients came from multiple parent studies and efficacy did not differ across the board.

Sanofi spent about $5.47 billion on research and development last year, all of which could pay off once dupilumab is approved for marketing in the United States this year. According to Zerhouni, biologic drugs account for two-thirds of Sanofi’s pipeline of experimental medicines, and if dupilumab is approved, it is likely that Sanofi, which has been considered somewhat of a laggard in recent years in the research-and-development sector, could suddenly find itself setting the precedent for future spending allocations across the industry, despite the fact that biologics have been considered a bigger risk than traditional pharmaceuticals because they are more expensive to develop, manufacture, and get approved. The next step will be to “persuade healthcare providers to pay for dupilumab,” observed 

 reporter Ben Hirschler. However, such difficulties could be well worth it if the drug company finds itself not only leading the pack in eliminating AD symptoms, but also ahead of the game as a result of dupilumab in many other areas of treatment as well.

Dupilumab Improves Signs and Symptoms of Atopic Dermatitis Without Safety Issues

Patients treated with humanized monoclonal antibodies (mAbs) do not tend to have adverse events (AEs) to the treatments and, when they do, they are mild, reported researchers presenting their findings at the 2017 annual American Academy of Allergy, Asthma, and Immunology (AAAAI) meeting in Atlanta, Georgia, on March 5.

“We wanted to characterize the hypersensitivity and infusion reactions that cause a change in the treatment of patients receiving mAbs,” explained Dasha Roa-Medellin, MD, a physician in the Department of Allergy at the Hospital General Universitario Gregorio Maranon, Madrid, Spain. “The real incidence of [these reactions] is unknown,” she added.

Given that biosimilars for mAb treatments, themselves biologic in nature, are considered by many 

 in the field to represent a sustainable, financially-viable, treatment-crucial option for the future of “treating life-threatening conditions in all disease areas.” In their article published in the European Society for Medical Oncology (ESMO)’s 

 journal, the authors write that mAb treatments are relatively rare, seldom necessitate treatment modifications, and are relatively easy to respond to, all of which is highly promising for the biosimilar research space. mAb treatments are particularly common in oncological therapies, where many patients must deal with compromised immune systems on an ongoing basis. The lack of allergic reactions, overall, to the mAb treatments is promising for biosimilars such infliximab, which was included in the AAAAI study.

Roa-Medellin and her research group conducted a retrospective study that included 5833 patients treated with mAbs between January 2010 and December 2015 at a “third-level hospital” in Madrid, Spain, with a special focus on treatment modifications that were a direct result of AEs to mAbs. That focal study group had a population of 119 patients who either had an infusion reaction or a hypersensitivity reaction following treatment with their specific mAb.

There were 12 mAbs in the study group, 3 of which dominated the AE results: infliximab (61 AEs), rituximab (28 AEs), and adalimumab (12 AEs). The research team characterized the AEs by symptom, as cutaneous, respiratory, glottis edema, cardiovascular, neurological, gastrointestinal, lumbar pain, or fever. A majority of AEs were mild or moderate and responded to premedication with antihistamines, corticosteroids, or acetaminophen or a change in the mAb used for treatment, they noted. Six of the AEs required desensitization, “but all of the procedures were finally tolerated,” said Roa-Medellin.

Based on the results the authors concluded that mAbs cause a low incidence of AEs that require treatment modification. “The reactions represented only a tenth of the cases in which the treatment needed to be changed,” they explained, noting that anti-TNF α was the most-commonly involved MoAb in the reactions. “Premedication seems a good option for mild to moderate reactions,” Roa-Medellin said, and added that her team believes desensitization to be a good first option in the event of severe reactions “or when premedication is not successful.”

Note: Thirteen out of 48 desensitizations in the study had mild reactions of urticaria and/or pruritis. Only two had both, but both of those received infliximab. 

Fewer AEs With Humanized Antibody Treatments Favorable for Biosimilar Development 

Patients taking adalimumab along with intravenous immunoglobulin (IVIG) treatments to fortify their immune system may find that they experience declining efficacy from adalimumab in the wake of IVIG treatments.

According to a troubling case study presented at the 2017 Annual Meeting of the American Academy of Allergy, Asthma, and Immunology (AAAAI) in Atlanta, Georgia, on March 5, 2017, adalimumab (the generic biologic for Humira) was diminished in effect following IVIG. The patient, a 62-year-old woman with common variable immune deficiency (CVID), Crohn’s disease, and rheumatoid arthritis, was receiving adalimumab to alleviate joint pain, stiffness, and Crohn’s-related chronic diarrhea. She brought the issue of diminished efficacy to her physicians’ attention during a visit to her immunology clinic. “She stated that on the one week of the month when her adalimumab overlapped with her IVIG infusion, she experienced diminished relief of severe joint pain, stiffness, and diarrhea [that] resolved following her next dose of adalimumab,” study author Trisha Sharma, MD, a physician at the UCSD School of Medicine in San Diego, reported. Prior to beginning adalimumab therapy, the patient had received IVIG therapy over the course of the previous year.

Adalimumab, a biologic, has been approved by the FDA for treatment of rheumatoid arthritis, chronic plaque psoriasis, Crohn’s disease, psoriatic arthritis, and several other inflammatory conditions. The FDA classifies biologic drugs as those “composed of sugars, proteins, nucleic acids, or combinations of these substances” or “living entities such as cells and tissues.” They are isolated from natural sources, produced by biotechnological methods, and often can be used to treat conditions for which few or no other treatments are available. Biologics, and their follow-on biosimilars, often tend to be less likely to provoke inflammation in patients with inflammatory disorders, and are particularly interesting to immunologists, allergists, and asthmologists, whose patients already spend a great deal of their lives experiencing increased inflammation in various parts of their bodies.

Adalimumab is a humanized monoclonal antibody (mAb), which is less likely to be targeted by a sensitive immune system than other types of antibody therapies. However, in the above patient’s case, the IVIG therapy may have essentially caused her immune system to “attack” the adalimumab monoclonal antibodies immediately following the IVIG dose.

 “When duration between administration of adalimumab and IVIG was increased, on follow-up the patient reported no improvement,” noted Dr Sharma, adding that the patient’s IgG trough levels prior to IVIG transfusions “remained at therapeutic levels” even with the change in administrative schedule. “We hypothesize that coadministration of adalimumab with IVIG may result in reduced therapeutic effect from the mAb [monoclonal antibody] therapy,” the researchers concluded, speculating that the problem could lie with “anti-idiotypic antibodies within the suprephysiologic IgG levels immediately following IV dosing.”

“Understanding the mechanism [of the interaction] will be increasingly important as mAb therapies are more widely administered,” the authors added. A similar phenomenon was noted in a separate 

 involving IVIG and Alzheimer’s patients, wherein the IVIG treatment may have diminished the neuroprotective effects of certain antibodies following dual treatment. In that study, the authors speculated that an Alzheimer’s disease-specific IVIG treatment “might be the last and best chance for IVIG treatment” to succeed in the context of treating Alzheimer’s disease. However, they warned that this option would have substantial financial, regulatory, and production-related obstacles.

This case study’s indication of the interaction between IVIG and adalimumab, a popular biologic treatment, serves to emphasize the need for additional biologic and biosimilar treatments for inflammatory conditions. In Europe, 2 biosimilars for adalimumab were recently 

 for approval to the European Medicines Agency (EMA)’s committee for medicinal products for human use. Those biosimilars, Amjevita and Solymbic, are the first of their kind recommended for approval in the European Union (EU), and both are stated to provided comparable treatment for the conditions treated by adalimumab. Amgen’s biosimilar, adalimumab-atto, was 

 in the United States in late 2016 but was not approved to be interchangeable with adalimumab or to treat patients as young as are approved for adalimumab treatment. Although adalimumab-atto is now FDA-approved in a limited capacity, it is not being marketed in the United States due to a 

 filed by Humira’s manufacturer, Abbvie. Case studies like this one, wherein the patient’s experience with the biologic may be compromised due to concomitant treatments, demonstrate the importance of alternative treatments that may be more effective while continuing to provide symptom management in a manner similar to that of preceding drugs and biologics.

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