The Center for Biosimilars Staff

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.

Articles

Case Study Indicates IVIG May Counteract Adalimumab

Dexpramipexole may be the most effective biologic drug available at this point when it comes to lowering eosinophil levels in both the blood and tissues of asthmatic patients. “Based on its safety profile and convenience,” it could be a good solution for many asthma patients who have both moderate and severe eosinophilic asthma, noted researchers at the 2017 Annual Meeting of the American Academy of Allergy, Asthma, and Immunology (AAAAI) in Atlanta, Georgia on March 4, 2017.

Asthmologists and immunologists have long been interested in biologic and biosimilar medications because their patients have sensitivities and allergies that prevent them from benefitting from “traditional” medications that might help them control their allergic and asthma-related symptoms. As early as 2015, AAAAI 

 the importance of research based around determining whether or not it would even be “possible to predict the response of particular treatments based on an asthma patient’s individual characteristics of disease” because so many asthma patients have unique combinations of sensitivities in varying degrees of severity. The research presented at AAAAI in early March bodes well, both for biologics’ efficacy in treating patients with eosinophilic disorders and for physicians’ ability to use them with some degree of predictability on outcomes.

Research like this study, which delved into the efficacy of dexpramipexole, an oral biologic, also supports the broader concept that biologics and their “follow-ons,” biosimilars, may be particularly effective in treating patients with unique health conditions. In this study, the researchers focused on eosinophil-lowering effects of dexpramipexole in patients with an eosinophil-associated disease that is common among asthmatics: chronic rhinosinusitis with nasal polyps (CRWsNP). Eosinophils tend to inflame CRWsNP and are often present at extremely high levels in the polyp tissues as well as patients’ blood, making a viable eosinophil-limiting drug attractive for treating these patients, who often are already taking multiple medications and may not tolerate more conventional drugs. These patients often also experience loss of lung function due to elevated eosinophil levels and may not respond well, if at all, to inhaled corticosteroids.

“We found that dexpramipexole’s eosinophil-lowering activity was as great or greater than seen with current biologics,” reported lead researcher Calman Prussin, MD, head of clinical and translational medicine in immunology at Knopp Biosciences LLC. Knopp is developing dexpramipexole, which is currently in phase 2/3 clinical studies for its effects on hypereosinophilic syndromes and phase 2 clinical studies for its effects on eosinophilic asthma.

The study involved a total of 20 patients with a mean age of 43.9 years. Sixteen of those subjects completed the trial, which involved taking 300 mg/day of dexpramipexole over 6 months. The team evaluated baseline changes in peripheral blood eosinophil counts and in total polyp score (TPS), which involved calculating eosinophil levels in the tissues of the patients’ nasal polyps. Patients had symptoms of CRWsNP for at least 10 years, and 43.75% of the study group that followed the study through to completion had a history of aspirin sensitivity. This sensitivity and the results of the study, indicating that these patients tolerate dexpramipexole with relatively minor side effects, are significant since aspirin-sensitive patients often have more extensive eosinophil-related inflammation than those who do not have this sensitivity. Furthermore, according to the World Allergy Organization (WAO), the 

 of aspirin sensitivity “are not immunological but…related to pharmacological properties of ASA and other NSAIDS,” making biologic treatment options that much more attractive for this subgroup of patients.

At the end of the study, all patients displayed eosinophil lowering in both blood and polyp tissue, but the overall polyp score, which involves the prevalence of polyps and the type of nasal obstructions they create, remained unchanged, implying that a primary benefit of the drug may not necessarily be in treating CRWsNP specifically, but rather in offering great “utility in eosinophilic asthma and other eosinophil diseases,” Prussin explained. Also notably, dexpramipexole treatments did not seem to elicit serious side effects. Although a number of patients did experience adverse events in the form of infections (10), respiratory issues (7), gastrointestinal disorders (4), metabolism and nutrition disorders (3), and musculoskeletal issues (3), none were rated “serious,” in and of itself notable in a population known for sensitivities and negative reactions to many medications. Seven of the 11 patients who had their polyps biopsied also demonstrated a 94% reduction in eosinophil levels in those tissues, indicating, said the research team, “the possibility that dexpramipexole may have direct activity on tissue eosinophil formation.”

Dexpramipexole Lowers Blood and Tissue Eosinophils Without Severe Adverse Reactions

A study in Israel, comparing use of ustekinumab (Stelara) and 3 other biologics used to treat inflammatory conditions has found that patients stayed on the drug longer compared with its comparators.

The authors of the study conducted a “drug survival” analysis among 907 patients with severe psoriasis who received adalimumab (Humira), infliximab (Remicade), etanercept (Enbrel), and ustekinumab for the treatment of psoriasis, using data drawn from a large health maintenance organization in Israel.

In their patient cohort, the authors documented 1575 biologic treatments and 865 discontinuation of treatments. Ustekinumab, which inhibits interleukin 12 and 23, had a significantly higher survival rate (40.8 months) than either one of the other 3 drugs, all tumor necrosis factor inhibitors. Adalimumab averaged at 26.4 months, etanercept at 26.35 months, and infliximab at 23.9 months. 

Important positive predictors of drug survival, the authors report, included treatment naivety and concomitant methotrexate intake. On the other hand, duration of the previous treatment as well as female gender were negative predictors of survival.

The authors concluded that biologics efficacy in real-life clinical practice decreases over time. They also noted that while ustekinumab survived longer among patients, most of its use was as a third-line in patients with severe psoriasis.

Shalom G, Cohen AD, Ziv M, et al. Biologic drug survival in Israeli psoriasis patients [published online December 28, 2016].  

. pii: S0190-9622(16)31008-8. doi: 10.1016/j.jaad.2016.10.033.

Does a Drug's Mechanism Regulate Retention by Patients With Psoriasis?

Hyderabad, India-based Aurobindo Pharma is the latest addition to the world of biosimilars. The company 

 that it has acquired 4 biosimilar products from TL Biopharmaceutical AG. Aurobindo plans to develop and commercialize the 4 molecules after it acquires the early stage data from TL.

An important molecule that the company will acquire with this agreement is the biosimilar for bevacizumab (Avastin), a monoclonal antibody developed by Genentech, which has been approved for treatment of a variety of tumor types: metastatic colorectal cancer, non—small cell lung cancer, platinum-resistant ovarian cancer, advanced cervical cancer, metastatic renal cell carcinoma, and recurrent glioblastoma. Bevacizumab is an angiogenesis inhibitor.

Aurobindo’s managing director, N. Govindarajan, said in a statement that the acquisition falls in line with the company’s strategy of establishing a biosimilar portfolio. Regulatory filings for the new acquisitions, 3 of which are in oncology molecules, are expected between 2020 and 2022.

New Player in the Biosimilars Game: Aurobindo Pharma

. Because the Court granted and consolidated Sandoz’s petition and Amgen’s conditional cross-petition, the Court has adopted a four-brief schedule, comparable to the procedure used in the courts of appeals.

According to the order, the briefing schedule will be as follows:

February 10, 2017: Sandoz’s opening brief due.

 Sandoz will submit its opening brief of up to 15,000 words on the question of whether the BPCIA notice of commercial marketing can be given before FDA approval.

February 17, 2017: Briefs of amicus curiae in support of Sandoz or in support of neither party due.

 Amgen will submit a consolidated brief of up to 19,000 words responding to Sandoz’s opening brief and opening on the question of whether the BPCIA patent dance is mandatory.

March 17, 2017: Briefs of amicus curiae in support of Amgen due.

March 31, 2017: Sandoz’s response and reply due.

 Sandoz will submit a consolidated brief of up to 10,000 words replying to Amgen’s response and responding to Amgen’s opening.

 Amgen will submit a reply to Sandoz’s response of up to 6,000 words.

Amici curiae may file only one brief; the due date is determined by which party the amicus supports, no matter which issue or issues the amicus addresses.

We expect oral argument to occur between April 24-26, the end of the Court’s final argument sitting, which would allow the Court to decide the case before the end of June.

The Supreme Court: Amgen v. Sandoz Briefing Schedule 

Biogen and Forward Pharma have reached a settlement in their Tecfidera (dimethyl fumarate) patent dispute over the active ingredient for the 

 used treat people with relapsing forms of the disease. 

Biogen will pay Forward $1.25 billion, as well as royalties in exchange for an irrevocable license to all intellectual property. The level of royalties will depend upon any interference proceeding the hearing decision., with the royalty rate ranging from 1% to 10% -- and could go as high as 20%, depending upon the resolution. Around 77% of Forward Pharma shareholders have already agreed to vote in favor of the deal, with a final vote scheduled for Feb. 1.

The intellectual property associated with the 480mg dose of oral dimethyl fumarate, the active compound in Tecfidera, has been the subject of the ongoing litigation through the Patent Trial and Appeal Board (PTAB), the US Court of Appeals for the Federal Circuit, the European Patent Office, the Technical Board of Appeal and the Enlarged Board of Appeal, with a decision expected March 17.

Analysts predicted Biogen's success with the case, even though they will pay more than a billion dollars upfront to Forward Pharma. Early sales figures had cemented it as one of the "blockbuster" drugs, but fell after safety issues were discovered--and marketing took a hit when the consumer advertising campaign was cut after it did not produce an uptick in fulfilled prescriptions.

Biogen's Tecfidera Settles Intellectual Patent Dispute 

Bristol-Myers Squibb announced a biomarker research collaboration to explore whether the application of GeneCentric’s Cancer Subtype Platform (CSP™) might be able to identify translational biomarkers for 

(nivolumab), which may help inform future clinical trials.

Additionally, GeneCentric announced it has secured equity funding from Bristol-Myers Squibb that will support the clinical development of GeneCentric’s CSP™ and build-out of GeneCentric’s new laboratory in Research Triangle Park.

CSP™, GeneCentric's proprietary core technology, identifies biologic subtypes of cancer through an integrated analysis of tumor genomics. Cancer subtypes can support rational clinical trial design, as biomarkers to identify patient cohorts optimally suited for certain therapeutic compounds, and as companion diagnostics.

"We are very excited to have Bristol-Myers Squibb as both a collaboration partner and an investor in GeneCentric,” said Myla Lai-Goldman, M.D., CEO of GeneCentric. “Bristol-Myers Squibb is an industry leader in oncology, and we look forward to engaging with them to advance research that may benefit patient prognosis.”

“GeneCentric’s innovative approach to cancer biomarkers offers an opportunity to accelerate translational and exploratory biomarker research, with the potential to optimize assays that can better inform decisions about patient care and treatments,” said Fouad Namouni, M.D., head of Development, Oncology, Bristol-Myers Squibb. “We are very pleased to support GeneCentric’s long-term goals as a company and to explore the application of its technology towards more targeted approaches to help patients.”

Bristol-Myers Squibb and GeneCentric Diagnostics Exploring Lung Cancer Biomarker Research 

In what many observers and market players hope will clarify the biosimilar approval route, the U.S. Supreme Court has 

 two related lawsuits over certain Obamacare provisions governing biosimilars.

 -0.5%) Sandoz unit's marketing application for its biosimilar to Amgen's (

 +0.5%) Neupogen (filgrastim), approved in the U.S. in September 2015. Sandoz is marketing the product under the brand name Zarxio.

Amgen sued Sandoz in an attempt to block Zarxio's approval but failed. The ruling by the U.S. Court of Appeals, which set the approval date, was a bit muddled. Amgen and Sandoz both filed suit against portions of the decision.

The Appeals Court said Sandoz was not required to give Amgen information about its biosimilar application, including a description of the manufacturing process. It added that Amgen could file a patent infringement suit instead (it did so, the trial is set to start in December).

Amgen's position is that the law says Sandoz "shall" give the information and the failure to do so warrants an injunction barring Zarxio sales. Sandoz sued over the requirement that it had to give Amgen 180 days' notice after FDA approval before it could start selling the product.

The specific date of the hearing has not been set.

Breaking: US Supreme Court to Hear Biosimilars Lawsuits 

1. The Republican-led Congress, under pressure from President-elect Donald Trump to act quickly, 

made the first move toward scrapping Obamacare

 on Thursday. The nonpartisan Committee for a Responsible Federal Budget said earlier this month that repealing President Barack Obama's signature health insurance law in its entirety would cost roughly $350 billion over the next decade. Republicans say a good Obamacare replacement strategy would reduce government spending, but they have not agreed on a consensus plan.

2. Mylan gets competition in the form of a 

 of Epipen from CVS. At one-sixth of the original price. Health insurance giant Cigna announced this week it's dropping coverage for name brand $600 EpiPens, just as drugstore chain CVS nearly halved the price of a rival epinephrine autoinjector, Adrenaclick, to $109.

3.  The Biologics Prescribers Collaborative (BPC) has 

 that they are concerned with "random" suffixes for biosimilars naming guidance. As physicians who routinely prescribe biologic medicines, they believe a memorable suffix is needed; although, it is still considered a win for patients and physicians because distinguishable naming is essential for pharmacovigilance, patient safety and transparency.

What's on our radar in the healthcare world.

News and Views in Healthcare: This Weekend's Top 3 Reads

The US FDA will decide whether to approve Biocon and Mylan’s version of the Roche breast cancer drug Herceptin by the beginning of September, as reported by BioPharm Reporter.

Indian drugmakers Biocon and Mylan, which are developing six biosimilar monoclonal antibodies for global markets, announced today their first US submission has been accepted for review by the US Food and Drug Administration (FDA).

The biologics license application (BLA) for the proposed biosimilar version of Roche/Genetech’s Herceptin (trastuzumab) was filed through the 351(k) pathway and the Agency has given the date of September 3, 2017 as its decision date as to whether or not it is to be approved.

, and if approved the two companies say it will be the first biosimilar to challenge Herceptin in the US.

We believe that our comprehensive package of analytical similarity, non-clinical and clinical data submitted with the BLA will demonstrate similarity of the proposed biosimilar trastuzumab to the reference product,” Mylan’s president Rajiv Malik said in a statement.

This development positions Biocon and Mylan among the first companies to be able to address the critical need of U.S. patients for a high-quality biosimilar to treat certain HER2-positive breast cancers, in the near future.”

under review by the European Medicines Agency (EMA).