Randi Hernandez was science editor at Pharmaceutical Technology from September 2014 to May 2017.

Randi Hernandez

	FDA granted a Breakthrough Therapy designation to AstraZeneca/MedImmune’s monoclonal antibody (mAb) durvalumab, a PD-L1 inhibitor meant to treat patients with PD-L1 positive inoperable or metastatic urothelial bladder cancer whose tumors have either progressed or did not respond to platinum-based chemotherapy. The agency 

 based on the results from a Phase I clinical trial.

	The status from FDA will help expedite the drug through the regulatory process. Bladder cancer is clearly an area of unmet need, as it is associated with a five-year overall survival rate of less than 15%.

	Durvalumab would block the cloaking mechanism of PD-L1 by blocking its interaction and binding with PD-1. The drug is also being investigated in clinical trials as a first-line monotherapy for bladder cancer and in combination with tremelimumab (a CTLA-4 mAb) as a first-line therapy for the condition. Both the monotherapy and the combination therapy have estimated filing dates of 2018 in the United States.

	If approved, durvalumab would likely compete with Roche's atezolizumab, which is also in development for the treatment of urothelial carcinoma. EvaluatePharma predicts atezolizumab could receive FDA approval in 2016. Roche's candidate will be submitted for consideration for a Breakthrough Therapy designation for patients whose metastatic bladder cancer expresses PD-L1, according to a Roche 

Articles

FDA fast-tracked the monoclonal antibody based on early clinical data from a Phase I trial.

Durvalumab Receives Breakthrough Therapy Status

	In an interesting move, FDA sent out eight warning letters on Feb. 4, 2016 to various makers of a dietary supplement called cannabidiol, which is derived from the 

 plant. Cannabidiol, which is also known as CBD oil, is described as a nonpsychoactive (no THC) dietary supplement that is purported to have numerous benefits, including anti-inflammatory and antiemetic properties. The oils are also advertised as being able to reduce depression, combat cancer, shrink tumors, facilitate wound healing, and treat other serious, chronic conditions, such as rheumatoid arthritis, schizophrenia, diabetes, lupus, and Crohn's disease, among others.

	The companies that received warning letters about the claims associated with cannabidiol include Sana Te, PainBomb, Morguetorium, LLC, Michigan Herbal Remedies, HealthyHempOil.com, Dose of Nature, Green Garden Gold, and ABC Productions. FDA reviewed the websites, Etsy stores, and Facebook pages of the companies, and concluded the companies were selling products marketed as new drugs. FDA said the CBD oil products are being marketed as medications and have not been adequately tested to prove they are safe and effective. The agency wrote, “drugs may not be legally introduced or delivered for introduction into interstate commerce without prior approval from the FDA.”

	To FDA, CBD products are excluded from the dietary supplement definition, as CBD oil is already being investigated for its medicinal benefits in clinical trials. The agency pointed out that CBD oil is currently undergoing clinical investigation, citing GW Pharmaceuticals’ studies in the United States of the products Sativex and Epidiolex for the treatment of cancer pain and a form of epilepsy called Dravet Syndrome, respectively. The agency says that unless a clinical investigation meets the limited criteria in that particular regulation, an investigational new drug (IND) application is required for all other clinical investigations of products. Thus, any manufacturers of CBD oil making claims about clinical efficacy for the treatment of disease must file an IND with the agency and have scientific data to back up their claims.

	It should be noted that in Canada, GW Pharmaceuticals’ Sativex was approved by authorities in 2005 to alleviate pain associated with spasticity in patients with multiple sclerosis. In 2007, the company got 

 for the medication to treat patients who suffer from pain as a result of advanced cancer. The product is distributed in Canada by Bayer. Unlike the products marketed strictly as CBD oil, Sativex also contains the active ingredient THC.

	FDA can legally issue warnings to these retailers as a result of a technicality. Interestingly, if the products by these retailers had been sold as dietary supplements prior to the issuance of GW Pharmaceuticals’ IND, there would be no problem. FDA writes in the letters, "There is an exception if the substance [CBD oil] was 'marketed as' a dietary supplement or as a conventional food before the new drug investigations were authorized; however, based on available evidence, FDA has concluded that this is not the case for CBD."

	In an interesting news twist, a prominent seller of CBD oil is Wu-Tang Clan member Ghostface Killah, who is not related to the companies named in any of FDA’s warning letters. In a video response to Martin Shkreli, former CEO of Turing who became infamous for raising the price of Daraprim, Ghostface scolded the pharma bad boy. In the second half of the response video, the rapper used the platform and his current media notoriety to hawk Wu Goo Oil, his new CBD oil venture. Ghostface even invited his family members to give informal testimonials about the effectiveness of his new product-his sister claimed the oil helped her survive after a tumor was removed from her brain.

FDA cracks down on makers of products extracted from Cannabis and says the products cannot be considered dietary supplements.

FDA Issues Warnings to Various Cannabidiol Oil Sellers

	On Feb. 9, 2016, an FDA Arthritis Advisory Committee will meet to discuss a biologics license application (BLA) for CT-P13 (Remsima), a proposed biosimilar to Janssen Biotech's Remicade (infliximab), by South Korea’s Celltrion in partnership with Pfizer. The BLA was submitted via the abbreviated 351(k) pathway and seeks to cover all of the eight indications that are approved for Remicade. A biosimilar version of Remicade-under the names Inflectra and Remisima, depending on location-has already been approved in various regions, including parts of Europe, Canada, South Korea, Japan, and India.

	Although Remsima is already available in Canada, it is only approved for some of Remicade’s indications. Health Canada gave the drug the green light for rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA), and plaque psoriasis, but 

 for Crohn’s disease (CD) or ulcerative colitis (UC). Health Canada did not approve these indications based on the uncertainty surrounding the small differences in antibody-dependent cellular cytotoxicity (ADCC) for patients with inflammatory bowel disease (IBD). Although the European Medicines Agency (EMA) allowed for the extrapolation of all indications for CT-P13, the agency also asked Celltrion to conduct an 

 comparing CT-P13 to Remicade for the treatment of CD. Importantly, Celltrion is also seeking approval for the pediatric forms of UC and CD, which may be a point of concern at the meeting. An 

 released prior to the meeting indicates that FDA will allow for full extrapolation of all indications for Celltrion’s product, saying extrapolation is “scientifically justified.”

	Remicade is a monoclonal antibody (mAb) that binds to human tumor necrosis factor alpha (TNFα). Current anti-TNF therapies on the market that serve as competitors to infliximab include adalimumab, certolizumab pegol, and golimumab. This class of medication is typically administered in a hospital or a physician’s office.

	In briefing documents released in advance of the meeting, Celltrion wrote that from a structural and functional standpoint, CT-P13 was highly similar to the reference product and “residual uncertainties arising from physicochemical and structural studies had little or no impact on biological activities.” Celltrion says that no clinically meaningful differences were observed in pharmacokinetics, pharmacodynamics, efficacy, safety, or immunogenicity in AS and RA patients. More than 30 distinct orthogonal methods were used to evaluate the analytical similarity of CT-P13 to Remicade, including testing of quality attributes such as primary structure, protein content, higher-order structure, aggregates, charge, glycosylation profiles, mechanism of action exploration through multiple bioassays, and binding assays of TNF and the Fc receptors.

FcγRIII binding and glycosylation differences


	The “Chemistry, Manufacturing and Controls (CMC)” section of the briefing did note some differences in product glycosylation between Celltrion's candidate and Remicade. FDA wrote, "the binding affinity of CT-P13 to the NK [natural killer] expressed FcγRIIIa and b was shifted lower compared to US-licensed Remicade . . . this was associated with subtle shifts in glycosylation at Asn297 on the heavy chain of the two antibody products detected in the analysis using a HPAEC-PAD [high performance anion-exchange chromatography with pulsed amperometric detection] chromatography method (e.g., CT-P13 on average had <39% G0F, the predominant form, while US-licensed Remicade & EU-approved Remicade had 41–46% G0F).” Although the briefing articulates that glycosylation of antibodies is typically heterogeneous, and up to 20 different detectable N-linked glycan forms can exist in an antibody preparation, "the relative levels of minor species like G0 (no terminal galactoses, but no fucose), which were different between CT-P13 (0.7%) and US-licensed Remicade (1.4%), can have an impact on binding to FcγRIII and are important to measure and control in antibody-based biopharmaceuticals."

	So, why does glycosylation matter in the context of the discussion of the approval of CT-P13? FDA writes in its briefing, "ADCC activity may vary with the strength of the FcγR:Fc bridging, which in turn may be dependent on the glycan composition on the antibody." Thus, glycan composition could play a part in ADCC activity, which could influence how effectively a drug works within the body. For emphasis, FDA pointed out that TNF inhibitor Enbrel (etanercept), which has low ADCC activity, is not approved for treatment of CD or UC. Despite these differences in glycosylation and binding, FDA concluded that when CT-P13 is compared with the reference product, “the biological functions that these subtle differences might impact (ADCC) are nevertheless within the quality range of the reference product.” FDA also admitted that it is difficult to pinpoint the exact mechanism of action of TNF inhibitors in IBD, and ADCC is only one of the many mechanisms of action (MoA) that could be at play: "It is noteworthy that products without any ADCC capability have been approved for the treatment of patients with Crohn’s Disease (i.e., certolizumab)." Celltrion further 

 this position: “Indeed, Cimzia (certolizumab pegol) lacks the Fc region required for ADCC and CDC activities yet is licensed in the US in RA, AS, PsA, and for reducing signs and symptoms of CD and maintaining clinical response in CD (Cimzia USPI, 2015), implying that CDC and ADCC activities do not play a critical role in the therapeutic MoA.”
	
	As Stacie Ropka, an IP attorney from Axinn Veltrop & Harkrider who holds a PhD in microbiology and immunology told 

, glycosylation differences can affect ADCC. "If ADCC is an important mechanism regarding efficacy of the antibody and changes to the glycosylation pattern either reduce or block ADCC, there is potential for reduced efficacy. If there are changes in the glycosylation pattern that interfere with the interaction between the Fc portion of the antibody and the receptors on the natural killer cells (cell B), you might not get ADCC or the ADCC might be less robust," Ropka said. "But I emphasize, this will depend on how important ADCC is to the overall efficacy in the first place and how much ADCC is diminished (if at all) by a different glycosylation pattern."

 that at a House committee on Feb. 4, 2016 FDA’s Center for Drug Evaluation and Research (CDER) Director Janet Woodcock hinted that the agency “may approve a biosimilar as interchangeable.” However, interchangeability is not proposed nor requested in Celltrion’s BLA. The company writes in a briefing prior to the meeting, "CELLTRION is not seeking an interchangeability designation between CT-P13 and US Remicade with this BLA at this time."

	Even though the company is clear that it does not seek this designation, it is still possible the company could request an interchangeability status if the product is approved by FDA. Evercore ISI’s Mark Shoenebaum told 

 that Celltrion will apply for this designation, but will likely be required to conduct further clinical trials, which may take a few years. In the meantime, Celltrion may already have some preliminary data to support switching-FDA wrote in its briefing, “the single transition from EU-approved Remicade to CT-P13 during the long-term extension studies in RA and AS did not result in worse safety or immunogenicity profile. This would support the safety of a clinical scenario where non-treatment naïve patients undergo a single transition to CT-P13.”

	Remicade generates $6.5 billion in annual sales for J&J-most of that revenue in the US-and analysts predict a biosimilar version would slash the price of Remicade by 25%. Overseas, Merck markets Remicade. Merck executives recently said on a fourth quarter earnings call that it expects biosimilars to continue to have a negative impact on earnings; sales of the drug 

 in the final quarter of 2015. Merck said, however, that is expects many new users to be attracted to biosimilars, and said that it has not yet seen significant switching in overseas markets.


	The Crohn's & Colitis Foundation of America 

 about its major concerns about the safety of biosimilars in a press release. The organization insisted that all biosimilars should undergo human testing to reduce immunogenicity risk, and reasonable proof must be provided before a patient switched from the reference product to the biosimilar version, writing, “We are opposed to indiscriminant switching of therapies by pharmacies or payers.” The consortium also stressed the importance of transparency in prescribing.

	Sources: FDA, RAPS, Celltrion, The Crohn's & Colitis Foundation of America

There are no clinically meaningful differences between Celltrion’s CT-P13 and Remicade, according to an FDA briefing released ahead of the formal panel meeting.

Celltrion’s Biosimilar to Remicade Likely to be Approved for All Indications

	To determine the higher-order structure of CT-P13, a biosimilar to Remicade (infliximab) that is under consideration by FDA, biologics manufacturer Celltrion used six different analytical techniques: far and near UV circular dichroism, Fourier transform infrared spectroscopy (FTIR), free thiols, antibody array, liquid chromatography coupled with mass spectrometry (LC–MS)(disulfide bond characterization), and differential scanning calorimetry. Methods like FTIR and Raman spectroscopy are low-resolution options, according to a new correspondence published in 

, and a new method called two-dimensional nuclear magnetic resonance spectroscopy (2D-NMR) is now available to characterize structural differences.

	In an experiment comparing the reference product Neupogen (filgrastim) with three unapproved, non-US-sourced biosimilars for filgrastim, investigators were able to conclude that 2D-NMR facilitated visual comparison of the spectral patterns of the products and allowed the researchers to directly assess sample similarity.

	Differences in temperature in separate spectrometers caused changes in spectral arrays, demonstrating the importance of proper instrument calibration. Once the spectrometers were adjusted, the discrepancies in spectral patterns disappeared. This observation caused investigators to stress the importance of “matched experimental conditions if the method is to be used as a structure comparability tool.” Other than the issue with temperature, investigators said the data they acquired with 2D-NMR showed “minimal measurement drift.”

	Although the researchers saw the value in this new analytical tool, they warned that only a small number of samples would be suitable for characterization by 2D-NMR. The technique should not be used to compare similarity for the monitoring of lot-to-lot consistency in large batches, they said, and they suggested that in studies across large numbers of samples, multivariate statistical analysis would still likely be the most suitable option.

	Importantly, the researchers reported that on all but one of the spectrometers, all of the drug products that were reviewed had highly similar higher-order structures. “The results clearly demonstrate both the precision and the robustness of 2D-NMR as a multifrequency-based higher-order structure assessment tool,” the authors wrote. “To our knowledge, this is the first reported interlaboratory study of a high-resolution 2D-NMR method to assess biotherapeutic higher-order structure.”

Researchers describe a new method to compare the higher-order structure of a reference biologic with its proposed biosimilar product candidates.

The Use of 2D-NMR for the Assessment of Biosimilarity

	During a Q4 call with Merck, executives admitted the company's market share for Remicade (infliximab) has begun to dwindle. Remicade's share of the market decreased 5% (from 90% to 85%) from the third quarter to the fourth quarter. 

	Merck’s Adam Schecter, executive vice-president and president, global human health said during the call that the percentage of new patients that will use biosimilars is "going to only grow over time," and noted that currently, approximately 10% to 20% of the biosimilar business per year is new patients. "We are seeing substitution of existing patients in some smaller markets, such as the Nordics. At this point in time, we’re not seeing it in the larger markets. But we continue to anticipate that the impact of biosimilars is going to accelerate as we go into 2016, as there are more and more new patients coming into the market and they become a larger percent of the sales."

	In fact, Merck reported lower-than-expected sales in the fourth quarter; Remicade sales fell 

. Of all of Merck's drugs, Remicade was associated with the largest loss in the quarter. The company's largest gain was in another biologic category: Sales of Gardasil and Gardasil 9 increased a whopping 40% over the fourth quarter.

	Celltrion's Remsima and Inflectra biosimilars launched in the European market in early 2015. Celltrion predicted that over time, biosimilars would produce the biggest savings in France, Germany, and the UK. Additionally, the approval of a biosimilar Remicade in the United States may be occurring soon. Celltrion said FDA is scheduled to hold a committee meeting Feb. 9, 2016 to review and discuss Remsima’s approval in the North American market.

	“Given that Remsima has already been approved in 67 countries including those in Europe, the biosimilar drug is expected to be approved in the US as well,” Lee Seung-ho, NH investment and securities analyst, told the 

Although switching has occurred in European markets for some biosimilars, most biosimilar manufacturers will focus on securing new users, according to Merck.

Merck: Biosimilar Makers Likely to Target New Patients

	Schizophrenia may be more similar to many autoimmune conditions than previously imagined, according to a new groundbreaking study published online on Jan. 27, 2016 in the journal 

	In the study of 64,785 people, both with and without schizophrenia, scientists found that a particular gene in chromosome 6-C4-is responsible for what is known as overactive synaptic pruning. Pruning is the elimination of synapses, a function which is triggered by the immune system. The immune system tags synaptic interactions that are recognized as incorrect with complement protein C3, thereby sending a signal to remove these interactions so that synapses continue to fire efficiently. The researchers were guided by prior research from Beth Stevens, PhD, assistant professor of neurology at Boston Children’s Hospital and Harvard, who studied the role of complement proteins in synaptic pruning in mouse models.

	Lead study author Steven McCarroll, PhD, of the Stanley Center for Psychiatric Research at the Broad Institute, and his colleagues discovered that gene structure could predict gene activity in individuals with schizophrenia. People who had long versions of the C4 genes, or those who produced more copies of the gene, were more likely to develop schizophrenia. Although presence of this version of C4 (C4A) was not always indicative of disease development-there are more than 100 chromosomal sites that are already linked to genetic risk for schizophrenia-the appearance of this particular isotope of C4 increased the risk of developing schizophrenia. As Dr. McCarroll explained to 

, “If you focus on the four common alleles, the relative risk is 1.27. So that’s a 27% increase in risk per allele. A person who inherited the higher-risk allele from each parent would have about a 54% increase in risk relative to someone who inherited the lower-risk allele from each parent.”

	The authors suggest the effects of overpruning occur as early as adolescence, when brain development is at an all-time high. “Normally, pruning gets rid of excess connections we no longer need, streamlining our brain for optimal performance, but too much pruning can impair mental function,” noted Thomas Lehner, PhD, director of the Office of Genomics Research Coordination of the NIH’s National Institute of Mental Health (NIMH), which co-funded the study along with the Stanley Center for Psychiatric Research at the Broad Institute and other NIH components, in an 

. “It could help explain schizophrenia’s delayed age-of-onset of symptoms in late adolescence/early adulthood and shrinkage of the brain’s working tissue. Interventions that put the brakes on this pruning process-gone-awry could prove transformative.”

	Typical theories about the disease origin of schizophrenia have historically focused on viruses, prior exposure to infectious agents, classical inflammation, or autoimmunity, but these theories could never really explain the late-adolescence age of disease onset, McCarroll said. “This model is different: C4 is a molecule from the immune system, but the nervous system has repurposed it for brain development.”

	People with schizophrenia typically have fewer synapses, so the knowledge of unrestrained synapse editing could provide drug developers with clues to treat the underlying cause of disease. Therapeutics engineered to tame runaway C4 could be a good starting point for future treatments, the researchers suggest. These treatments could likely come in the form of immunomodulators, now that the researchers have uncovered that the origin of schizophrenia is likely the result of a normal immune function gone amiss. Presently, all treatments for schizophrenia only address disease symptoms, such as hallucinations, psychosis, and cognitive impairment.

The body’s over-editing of synaptic interactions is recognized as a probable cause of schizophrenia in a landmark study.