Archive for the ‘Monoclonal antibody therapy’ Category

Despite heated discussion over whether it works, the FDA has approved Aduhelm, bringing a new ray of hope to the Alzheimer’s patients.

Curator and Reporter: Dr. Premalata Pati, Ph.D., Postdoc

On Monday, 7th June 2021, a controversial new Alzheimer’s Disease treatment was licensed in the United States for the first time in nearly 20 years, sparking calls for it to be made available worldwide despite conflicting evidence about its usefulness. The drug was designed for people with mild cognitive impairment, not severe dementia, and it was designed to delay the progression of Alzheimer’s disease rather than only alleviate symptoms.


The Controversies

The route to FDA clearance for Aducanumab has been bumpy – and contentious.

Though doctors, patients, and the organizations that assist them are in desperate need of therapies that can delay mental decline, scientists question the efficacy of the new medicine, Aducanumab or Aduhelm. In March 2019, two trials were halted because the medications looked to be ineffective. “The futility analysis revealed that the studies were most likely to fail,” said Isaacson of Weill Cornell Medicine and NewYork-Presbyterian. Biogen, the drug’s manufacturer revealed several months later that a fresh analysis with more participants found that individuals who got high doses of Aducanumab exhibited a reduction in clinical decline in one experiment. Patients treated with high-dose Aducanumab had 22% reduced clinical impairment in their cognitive health at 18 months, indicating that the advancement of their early Alzheimer’s disease was halted, according to FDA briefing documents from last year.

When the FDA’s members were split on the merits of the application in November, it was rejected. Three of its advisers went public, claiming that there was insufficient evidence that it worked in a scientific journal. They were concerned that if the medicine was approved, it might reduce the threshold for future approvals, owing to the scarcity of Alzheimer’s treatments.

Dr. Caleb Alexander, a drug safety and effectiveness expert at the Johns Hopkins Bloomberg School of Public Health, was one of the FDA advisers who was concerned that the data presented to the agency was a reanalysis after the experiment was stopped. It was “like the Texas sharpshooter fallacy,” he told the New York Times, “where the sharpshooter blows up a barn and then goes and paints a bullseye around the cluster of holes he loves.”

Some organizations, such as the non-profit Public Citizen’s Health Research Group, claimed that the FDA should not approve Aducanumab for the treatment of Alzheimer’s disease because there is insufficient proof of its efficacy.

The drug is a monoclonal antibody that inhibits the formation of amyloid protein plaques in the brain, which are thought to be the cause of Alzheimer’s disease. The majority of Alzheimer’s medications have attempted to erase these plaques.

Aducanumab appears to do this in some patients, but only when the disease is in its early stages. This means that people must be checked to see if they have the disease. Many persons with memory loss are hesitant to undergo testing because there is now no treatment available.

The few Alzheimer’s medications available appear to have limited effectiveness. When Aricept, also known as Donepezil, was approved more than 20 years ago, there was a major battle to get it. It was heralded as a breakthrough at the time – partly due to the lack of anything else. It has become obvious that it slows mental decline for a few months but makes little effect in the long run.

The findings of another trial for some patients backed up those conclusions.

Biogen submitted a Biologics License Application to the FDA in July 2020, requesting approval of the medicine.

The FDA’s decision has been awaited by Alzheimer’s disease researchers, clinicians, and patients since then.

Support for approval of the drug

Other groups, such as the Alzheimer’s Association, have supported the drug’s approval.

The Alzheimer’s Association‘s website stated on Friday, “This is a critical time, regardless of the FDA’s final judgment. We’ve never been this close to approving an Alzheimer’s drug that could affect the disease’s development rather than just the symptoms. We can keep working together to achieve our goal of a world free of Alzheimer’s disease and other dementias.”

The drug has gotten so much attention that the Knight Alzheimer Disease Research Center at Washington University in St. Louis issued a statement on Friday stating that even if it is approved, “it will still likely take several months for the medication to pass other regulatory steps and become available to patients.”

Biogen officials told KGO-TV on Monday that the medicine will be ready to ship in about two weeks and that they have identified more than 900 facilities across the United States that they feel will be medically and commercially suitable.

Officials stated the corporation will also provide financial support to qualifying patients so that their out-of-pocket payments are as low as possible. Biogen has also pledged not to raise the price for at least the next four years.

Most Medicare customers with supplemental plans, according to the firm, will have a limited or capped co-pay.

Case studies connected to the Drug Approval

Case 1

Ann Lange, one of several Chicago-area clinical trial volunteers who received the breakthrough Alzheimer’s treatment, said,

It really offers us so much hope for a long, healthy life.

Lange, 60, has Alzheimer’s disease, which she was diagnosed with five years ago. Her memory has improved as a result of the monthly infusions, she claims.

She said,

I’d forget what I’d done in the shower, so I’d scribble ‘shampoo, conditioner, face, body’ on the door. Otherwise, I’d lose track of what I’m doing “Lange remarked. “I’m not required to do that any longer.

Case 2

Jenny Knap, 69, has been receiving infusions of the Aducanumab medication for about a year as part of two six-month research trials. She told CNN that she had been receiving treatment for roughly six months before the trial was halted in 2019, and that she had recently resumed treatment.

Knap said,

I can’t say I noticed it on a daily basis, but I do think I’m doing a lot better in terms of checking for where my glasses are and stuff like that.

When Knap was diagnosed with mild cognitive impairment, a clinical precursor to Alzheimer’s disease, in 2015, the symptoms were slight but there.

Her glasses were frequently misplaced, and she would repeat herself, forgetting previous talks, according to her husband, Joe Knap.

Joe added,

We were aware that things were starting to fall between the cracks as these instances got more often

Jenny went to the Lou Ruvo Center for Brain Health at the Cleveland Clinic in Ohio for testing and obtained her diagnosis. Jenny found she was qualified to join in clinical trials for the Biogen medicine Aducanumab at the Cleveland Clinic a few years later, in early 2017. She volunteered and has been a part of the trial ever since.

It turns out that Jenny was in the placebo category for the first year and a half, Joe explained, meaning she didn’t get the treatment.

They didn’t realize she was in the placebo group until lately because the trial was blind. Joe stated she was given the medicine around August 2018 and continued until February 2019 as the trial progressed. The trial was halted by Biogen in March 2019, but it was restarted last October, when Jenny resumed getting infusions.

Jenny now receives Aducanumab infusions every four weeks at the Cleveland Clinic, which is roughly a half-hour drive from their house, with Joe by her side. Jenny added that, despite the fact that she has only recently begun therapy, she believes it is benefiting her, combined with a balanced diet and regular exercise (she runs four miles).

The hope of Aducanumab is to halt the progression of the disease rather than to improve cognition. We didn’t appreciate any significant reduction in her condition, Jenny’s doctor, Dr. Babak Tousi, who headed Aducanumab clinical studies at the Cleveland Clinic, wrote to CNN in an email.

This treatment is unlike anything we’ve ever received before. There has never been a drug that has slowed the growth of Alzheimer’s disease, he stated, Right now, existing medications like donepezil and memantine aid with symptoms but do not slow the disease’s progression.

Jenny claims that the medicine has had no significant negative effects on her.

There was signs of some very minor bleeding in the brain at one point, which was quite some time ago. It was at very low levels, in fact, Joe expressed concern about Jenny, but added that the physicians were unconcerned.

According to Tousi, with repeated therapy, “blood vessels may become leaky, allowing fluid and red blood cells to flow out to the surrounding area,” and “micro hemorrhages have been documented in 19.1% of trial participants who got” the maximal dose of therapy”.

Jenny and Joe’s attitude on the future has improved as a result of the infusions and keeping a healthy lifestyle, according to Joe. They were also delighted to take part in the trial, which they saw as an opportunity to make a positive influence in other people’s lives.

There was this apprehension of what was ahead before we went into the clinical trial, Joe recalled. “The medical aspect of the infusion gives us reason to be optimistic. However, doing the activity on a daily basis provides us with immediate benefits.”

The drug’s final commercialization announcement

Aducanumab, which will be marketed as Aduhelm, is a monthly intravenous infusion that is designed to halt cognitive decline in patients with mild memory and thinking issues. It is the first FDA-approved medication for Alzheimer’s disease that targets the disease process rather than just the symptoms.

The manufacturer, Biogen, stated Monday afternoon that the annual list price will be $56,000. In addition, diagnostic tests and brain imaging will very certainly cost tens of thousands of dollars.

The FDA approved approval for the medicine to be used but ordered Biogen to conduct a new clinical trial, recognizing that prior trials of the medicine had offered insufficient evidence to indicate effectiveness.

Biogen Inc said on Tuesday that it expects to start shipping Aduhelm, a newly licensed Alzheimer’s medicine, in approximately two weeks and that it has prepared over 900 healthcare facilities for the intravenous infusion treatment.

Other Relevant Articles

Gene Therapy could be a Boon to Alzheimer’s disease (AD): A first-in-human clinical trial proposed

Reporter: Dr. Premalata Pati, Ph.D., Postdoc


Alzheimer’s Disease – tau art thou, or amyloid

Curator: Larry H. Bernstein, MD, FCAP


Connecting the Immune Response to Amyloid-β Aggregation in Alzheimer’s Disease via IFITM3

Reporter : Irina Robu, PhD


Ustekinumab New Drug Therapy for Cognitive Decline resulting from Neuroinflammatory Cytokine Signaling and Alzheimer’s Disease

Curator: Aviva Lev-Ari, PhD, RN


Alnylam Announces First-Ever FDA Approval of an RNAi Therapeutic, ONPATTRO™ (patisiran) for the Treatment of the Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis in Adults

Reporter: Aviva Lev-Ari, PhD, RN


Recent progress in neurodegenerative diseases and gliomas

Curator: Larry H. Bernstein, MD, FCAP


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Reporter and Curator: Dr. Sudipta Saha, Ph.D.


Effective humoral immune responses to infection and immunization are defined by high-affinity antibodies generated as a result of B cell differentiation and selection that occurs within germinal centers (GC). Within the GC, B cells undergo affinity maturation, an iterative and competitive process wherein B cells mutate their immunoglobulin genes (somatic hypermutation) and undergo clonal selection by competing for T cell help. Balancing the decision to remain within the GC and continue participating in affinity maturation or to exit the GC as a plasma cell (PC) or memory B cell (MBC) is critical for achieving optimal antibody avidity, antibody quantity, and establishing immunological memory in response to immunization or infection. Humoral immune responses during chronic infections are often dysregulated and characterized by hypergammaglobulinemia, decreased affinity maturation, and delayed development of neutralizing antibodies. Previous studies have suggested that poor antibody quality is in part due to deletion of B cells prior to establishment of the GC response.


In fact the impact of chronic infections on B cell fate decisions in the GC remains poorly understood. To address this question, researchers used single-cell transcriptional profiling of virus-specific GC B cells to test the hypothesis that chronic viral infection disrupted GC B cell fate decisions leading to suboptimal humoral immunity. These studies revealed a critical GC differentiation checkpoint that is disrupted by chronic infection, specifically at the point of dark zone re-entry. During chronic viral infection, virus-specific GC B cells were shunted towards terminal plasma cell (PC) or memory B cell (MBC) fates at the expense of continued participation in the GC. Early GC exit was associated with decreased B cell mutational burden and antibody quality. Persisting antigen and inflammation independently drove facets of dysregulation, with a key role for inflammation in directing premature terminal GC B cell differentiation and GC exit. Thus, the present research defines GC defects during chronic viral infection and identify a critical GC checkpoint that is short-circuited, preventing optimal maturation of humoral immunity.


Together, these studies identify a key GC B cell differentiation checkpoint that is dysregulated during chronic infection. Further, it was found that the chronic inflammatory environment, rather than persistent antigen, is sufficient to drive altered GC B cell differentiation during chronic infection even against unrelated antigens. However, the data also indicate that inflammatory circuits are likely linked to perception of antigen stimulation. Nevertheless, this study reveals a B cell-intrinsic program of transcriptional skewing in chronic viral infection that results in shunting out of the cyclic GC B cell process and early GC exit with consequences for antibody quality and hypergammaglobulinemia. These findings have implications for vaccination in individuals with pre-existing chronic infections where antibody responses are often ineffective and suggest that modulation of inflammatory pathways may be therapeutically useful to overcome impaired humoral immunity and foster affinity maturation during chronic viral infections.
















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The late Cambridge Mayor Alfred Vellucci welcomed Life Sciences Labs to Cambridge, MA – June 1976

Reporter: Aviva Lev-Ari, PhD, RN

How Cambridge became the Life Sciences Capital

Worth watching is the video below, which captures the initial Cambridge City Council hearing on recombinant DNA research from June 1976. The first speaker is the late Cambridge mayor Alfred Vellucci.

Vellucci hoped to pass a two-year moratorium on gene splicing in Cambridge. Instead, the council passed a three-month moratorium, and created a board of nine Cambridge citizens — including a nun and a nurse — to explore whether the work should be allowed, and if so, what safeguards would be necessary. A few days after the board was created, the pro and con tables showed up at the Kendall Square marketplace.

At the time, says Phillip Sharp, an MIT professor, Cambridge felt like a manufacturing town that had seen better days. He recalls being surrounded by candy, textile, and leather factories. Sharp hosted the citizens review committee at MIT, explaining what the research scientists there planned to do. “I think we built a relationship,” he says.

By early 1977, the citizens committee had proposed a framework to ensure that any DNA-related experiments were done under fairly stringent safety controls, and Cambridge became the first city in the world to regulate research using genetic material.



How Cambridge became the life sciences capital

Scott Kirsner can be reached at kirsner@pobox.com. Follow him on Twitter@ScottKirsner and on betaboston.com.


How Cambridge became the life sciences capital


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Monoclonal antibody treatment of Multiple Myeloma

Larry H. Bernstein, MD, FCAP, Curator









A SLAMF7-directed immunostimulatory antibody used to treat multiple myeloma.






Elotuzumab (brand name Empliciti, previously known as HuLuc63) is ahumanized monoclonal antibody used in relapsed multiple myeloma.[1] The package insert denotes its mechanism as a SLAMF7-directed (also known as CD 319) immunostimulatory antibody.[2]

Approvals and indications

In May 2014, it was granted “Breakthrough Therapy” designation by the FDA.[3] On November 30, 2015, FDA approved elotuzumab as a treatment for patients with multiple myeloma who have received one to three prior medications.[1] Elotuzumab was labeled for use with lenalidomide anddexamethasone. Each intravenous injection of elotuzumab should be premedicated with dexamethasone, diphenhydramine, ranitidine andacetaminophen.[2]


Elotuzumab is APPROVED for safety and efficacy in combination with lenalidomide and dexamethasone.

Monoclonal antibody therapy for multiple myeloma, a malignancy of plasma cells, was not very clinically efficacious until the development of cell surface glycoprotein CS1 targeting humanized immunoglobulin G1 monoclonal antibody – Elotuzumab. Elotuzumab is currently APPROVED in relapsed multiple myeloma.

Elotuzumab (HuLuc63) binds to CS1 antigens, highly expressed by multiple myeloma cells but minimally present on normal cells. The binding of elotuzumab to CS1 triggers antibody dependent cellular cytotoxicity in tumor cells expressing CS1. CS1 is a cell surface glycoprotein that belongs to the CD2 subset of immunoglobulin superfamily (IgSF). Preclinical studies showed that elotuzumab initiates cell lysis at high rates. The action of elotuzumab was found to be enhanced when multiple myeloma cells were pretreated with sub-therapeutic doses of lenalidomide and bortezomib. The impressive preclinical findings prompted investigation and analysis of elotuzumab in phase I and phase II studies in combination with lenalidomide and bortezomib.

Elotuzumab As Part of Combination Therapy: Clinical Trial Results

Elotuzumab showed manageable side effect profile and was well tolerated in a population of relapsed/refractory multiple myeloma patients, when treated with intravenous elotuzumab as single agent therapy. Lets’ take a look at how elotuzumab fared in combination therapy trials,

In phase I trial of elotuzumab in combination with Velcade/bortezomib in patients with relapsed/refractory myeloma, the overall response rate was 48% and activity was observed in patients whose disease had stopped responding to Velcade previously. The trial results found that elotuzumab enhanced Velcade activity.
A phase I/II trial in combination with lenalidomide and dexamethasone in refractory/relapsed multiple myeloma patients showed that 82% of patients responded to treatment with a partial response or better and 12% of patients showed complete response. Patients who had received only one prior therapy showed 91% response rate with elotuzumab in combination with lenalidomide and dexamethasone.



Phase I/II trials of the antibody drug has been very impressive and the drug is currently into Phase III trials. Two phase III trials are investigating whether addition of elotuzumab with Revlimid and low dose dexamethasone would increase the time to disease progression. Another phase III trial (ELOQUENT 2) is investigating and comparing safety and efficacy of lenalidomide plus low dose dexamethasone with or without 10mg/kg of elotuzumab in patients with relapsed/refractory multiple myeloma.

Elotuzumab is being investigated in many other trials too. It is being evaluated in combination with Revlimid and low-dose dexamethasone in multiple myeloma patients with various levels of kidney functions, while another phase II study is investigating elotuzumab’s efficacy in patients with high-risk smoldering myeloma.

The main target of multiple myeloma drug development is to satisfy the unmet need for drugs that would improve survival rates. Elotuzumab is an example that mandates much interest in this area and should be followed with diligence.



1 “Press Announcement—FDA approves Empliciti, a new immune-stimulating therapy to treat multiple myeloma”. U.S. Food and Drug Administration. Retrieved 3 December 2015.

2“Empliciti (elotuzumab) for Injection, for Intravenous Use. Full Prescribing Information” (PDF). Empliciti (elotuzumab) for US Healthcare Professionals. Bristol-Myers Squibb Company, Princeton, NJ 08543 USA.

3 “Bristol-Myers Squibb and AbbVie Receive U.S. FDA Breakthrough Therapy Designation for Elotuzumab, an Investigational Humanized Monoclonal Antibody for Multiple Myeloma” (Press release). Princeton, NJ & North Chicago, IL: Bristol-Myers Squibb. 2014-05-19. Retrieved 2015-02-05.

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Pharmacy International Conference

Larry H. Bernstein, MD, FCAP, Curator




3rd Nirma Institute of Pharmacy International Conference
NIPiCON – 2016
January 21 – 23, 2016 ………….http://www.nipicon.org/.

Anthony Melvin Crasto   https://www.facebook.com/groups/worlddrugtracker/permalink/1170816792946389/

The pharmaceutical sciences is a dynamic and interdisciplinary field that combines a broad range of scientific disciplines that are critical to the discovery and development of new drugs and therapies. Over the years, pharmaceutical scientists have been instrumental in discovering and developing innovative drugs that save people’s lives and improve the quality of life.

NIPiCON was initiated in a year 2013 to offer a common platform for academicians, researchers, industrialists, clinical practitioners and young budding pharmacists to share their ideas and research work and finally emerge with new concepts, innovations and novel strategies for various challenges in the pharmaceutical field.

The 3 International Conference, NIPiCON 2016 aims to provide a knowledge sharing experience in the area of “Global Challenges in Drug Discovery, Development and Regulatory Affairs”.

Pharmaceutical innovation is a complex creative process that harnesses the application of knowledge and creativity for discovering, developing and bringing to clinical use, new medicinal products that extend or improve the lives of patients.A successful pharmaceutical R&D process is one that minimizes the time and cost needed to bring a compound from the scientific ‘idea’, through discovery and clinical development, to final regulatory approval and delivery to the patient. This conference will provide an open forum for the academicians, researchers, clinicians and professionals of pharmaceutical industry to enrich their knowledge in the area of drug discovery, development and its regulatory requirements.

The conference features plenary sessions which will be delivered by eminent national and international speakers from different disciplines of pharmaceutical field. In addition, there will be invited lectures and sessions delivered by distinguished and young researchers in their respective fields during parallel technical sessions. The conference willalso provide the opportunity to scientists and research scholars from various organizations to put forth their innovative ideas and research findings by means of deliberations, discussions and poster presentations.


NIPiCON was initiated in a year 2013 to offer a common platform for academicians, researchers, industrialists, clinical practitioners and young budding pharmacists to share their ideas and research work and finally emerge with new concepts, innovations and novel strategies for various challenges in the pharmaceutical field.

The 3 International Conference, NIPiCON 2016 aims to provide a knowledge sharing experience in the area of “Global Challenges in Drug Discovery, Development and Regulatory Affairs”.

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Diabetic Retinopathy

Larry H. Bernstein, MD, FCAP, Curator



Lucentis effective for proliferative diabetic retinopathy

NIH-funded clinical trial marks first major advance in therapy in 40 years.


Illustration of ruptured blood vessels


Abnormal blood vessels bleeding into the center of the eye due to proliferative diabetic retinopathy.


A clinical trial funded by the National Institutes of Health has found that the drug ranibizumab (Lucentis) is highly effective in treating proliferative diabetic retinopathy. The trial, conducted by the Diabetic Retinopathy Clinical Research Network (DRCR.net) compared Lucentis with a type of laser therapy called panretinal or scatter photocoagulation, which has remained the gold standard for proliferative diabetic retinopathy since the mid-1970s. The findings demonstrate the first major therapy advance in nearly 40 years.

“These latest results from the DRCR Network provide crucial evidence for a safe and effective alternative to laser therapy against proliferative diabetic retinopathy,” said Paul A. Sieving, M.D., Ph.D., director of NIH’s National Eye Institute (NEI), which funded the trial.  The results were published online today in the Journal of the American Medical Association.

Treating abnormal retinal blood vessels with laser therapy became the standard treatment for proliferative diabetic retinopathy after the NEI announced results of the Diabetic Retinopathy Study in 1976. Although laser therapy effectively preserves central vision, it can damage night and side vision; so, researchers have sought therapies that work as well or better than laser but without such side effects.

A complication of diabetes, diabetic retinopathy can damage blood vessels in the light-sensitive retina in the back of the eye. As the disease worsens, blood vessels may swell, become distorted and lose their ability to function properly. Diabetic retinopathy becomes proliferative when lack of blood flow in the retina increases production of a substance called vascular endothelial growth factor, which can stimulate the growth of new, abnormal blood vessels. These new vessels are prone to bleeding into the center of the eye, often requiring a surgical procedure called a vitrectomy to clear the blood. The abnormal blood vessels can also cause scarring and retinal detachment. Lucentis is among several drugs that block the effects of vascular endothelial growth factor.

About 7.7 million U.S. residents have diabetic retinopathy, a leading cause of blindness among working-age Americans. Among these, about 1.5 percent have PDR.

The DRCR.net enrolled 305 participants (394 eyes) with proliferative diabetic retinopathy in one or both eyes at 55 clinical sites across the country. Eyes were assigned randomly to treatment with Lucentis or laser. For participants who enrolled both eyes in the study, one eye was assigned to the laser group and the other was assigned to the Lucentis group. About half of the eyes assigned to the laser group required more than one round of laser treatment. In the other group, Lucentis (0.5 mg/0.05 ml) was given via injections into the eye once per month for three consecutive months, and then as needed until the disease resolved or stabilized.

Because Lucentis is commonly used to treat diabetic macular edema—the build-up of fluid in the central area of the retina—the study permitted the use of Lucentis for diabetic macular edema in the laser group, if necessary. Slightly more than half (53 percent) of eyes in the laser group received Lucentis injections to treat diabetic macular edema. About 6 percent of eyes in the Lucentis group received laser therapy, mostly to treat retinal detachment or bleeding.

At two years, vision in the Lucentis group improved by about half a line on an eye chart compared with virtually no change in the laser group. There was little change in side vision with injection (average worsening of 23 decibels) but a substantial loss of side vision with laser (average worsening of 422 decibels).   The vitrectomy rate was lower in the Lucentis group (8 of 191 eyes) than in the laser group (30 of 203 eyes).

Rates of serious systemic adverse events, including cardiac arrest and stroke, were similar between the two groups. One patient in the Lucentis group developed endophthalmitis, an infection in the eye. Other side effects were low, with little difference between treatment groups.

“Lucentis should be considered a viable treatment option for people with proliferative diabetic retinopathy, especially for individuals needing anti-vascular endothelial growth factor for diabetic macular edema,” said Jeffrey G. Gross, M.D., of the Carolina Retina Center in Columbia, South Carolina, who chaired the study. Dr. Gross presented results November 13, 2015, at the annual meeting of the American Academy of Ophthalmology in Las Vegas.

In addition to treating proliferative diabetic retinopathy, the report suggests Lucentis may even help prevent diabetic macular edema from occurring. Among people without diabetic macular edema at the start of the study, only 9 percent of Lucentis-treated eyes developed diabetic macular edema during the study, compared with 28 percent in the laser group. The DRCR.net will continue to follow patients in this study for a total of five years.

The DRCR.net is dedicated to facilitating multicenter clinical research of diabetic eye disease. The network formed in 2002 and comprises more than 350 physicians practicing at more than 140 clinical sites across the country. For more information, visit the DRCR.net website at http://drcrnet.jaeb.org/(link is external).

The study was funded by NEI grants EY14231, EY23207, EY18817.

Lucentis was provided by Genentech. Additional research funding for this study was provided by the National Institute of Diabetes and Digestive and Kidney Diseases, also a part of the NIH.

The study is registered as NCT01489189 at ClinicalTrials.gov(link is external).

The NEI provides information about diabetic eye disease at http://www.nei.nih.gov/health/diabetic/.

Information about diabetes is available through the National Diabetes Education Program, www.ndep.nih.gov/.

View an NEI video about the study at https://youtu.be/jPoCIa0_1po(link is external).

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Amyloid-Targeting Immunotherapy

Curator: Larry H. Bernstein, MD, FCAP

Possible Reasons Found for Failure of Alzheimer’s Treatment

By Staff Editor


(HealthNewsDigest.com) – Agglutinated proteins in the brain, known as amyloid-β plaques, are a key characteristic of Alzheimer’s. One treatment option uses special antibodies to break down these plaques. This approach yielded good results in the animal model, but for reasons that are not yet clear, it has so far been unsuccessful in patient studies. Scientists at the Technical University of Munich (TUM) have now discovered one possible cause: they noticed that, in mice that received one antibody treatment, nerve cell disorders did not improve and were even exacerbated.

Immunotherapies with antibodies that target amyloid-β were long considered promising for treating Alzheimer’s. Experiments with animals showed that they reduced plaques and reversed memory loss. In clinical studies on patients, however, it has not yet been possible to confirm these results. A team of researchers working with Dr. Dr. Marc Aurel Busche, a scientist at the TUM hospital Klinikum rechts der Isar Klinik und Poliklinik für Psychiatrie und Psychotherapie and at the TUM Institute of Neuroscience, and Prof. Arthur Konnerth from the Institute of Neuroscience has now clarified one possible reason for this. The findings were published in Nature Neuroscience.

Immunotherapy Increases Number of Hyperactive Nerve Cells

The researchers used Alzheimer’s mice models for their study. These animals carry a transgene for the amyloid-β precursor protein, which, as in humans, leads to the formation of amyloid-β plaques in the brain and causes memory disorders. The scientists treated the animals with immunotherapy antibodies and then analyzed nerve cell activity using high-resolution two-photon microscopy. They found that, while the plaques disappeared, the number of abnormally hyperactive neurons rose sharply.

“Hyperactive neurons can no longer perform their normal functions and, after some time, wear themselves out. They then fall silent and, later, possibly die off,” says Busche, explaining the significance of their discovery. “This could explain why patients who received the immunotherapy experienced no real improvement in their condition despite the decrease in plaques,” he adds.

Released Oligomers Potential Reason for Hyperactivity

Even in young Alzheimer’s mice, when no plaques were yet detectable in the brain, the antibody treatment led to increased development of hyperactive nerve cells. “Looking at these findings, even using the examined immunotherapies at an early stage, before the plaques appear, would offer little chance of success. As the scientist explains, the treatment already exhibits these side effects here, too.

“We suspect that the mechanism is as follows: The antibodies used in treatment release increasing numbers of soluble oligomers. These are precursors of the plaques and have been considered problematic for some time now. This could cause the increase in hyperactivity,” says Busche.

The work was funded by an Advanced ERC grant to Prof. Arthur Konnerth, the EU FP7 program (Project Corticonic) and the Deutsche Forschungsgemeinschaft (IRTG 1373 and SFB870). Marc Aurel Busche was supported by the Hans und Klementia Langmatz Stiftung.

Marc Aurel Busche, Christine Grienberger, Aylin D. Keskin, Beomjong Song, Ulf Neumann, Matthias Staufenbiel, Hans Förstl and Arthur Konnerth, Decreased amyloid-β and increased neuronal hyperactivity by immunotherapy in Alzheimer’s models, Nature Neuroscience, November 9, 2015.
DOI: 10.1038/nn.4163

Amyloid-Targeting Immunotherapy Disrupts Neuronal Function

Some antibodies designed to eliminate the plaques prominent in Alzheimer’s disease can aggravate neuronal hyperactivity in mice.

By Karen Zusi | November 9, 2015  http://www.the-scientist.com//?articles.view/articleNo/44435/title/Amyloid-Targeting-Immunotherapy-Disrupts-Neuronal-Function/


Removing built-up plaques of amyloid-β in the brain is a long-sought therapy for patients with Alzheimer’s disease, but for a variety of reasons, few treatments have succeeded in alleviating symptoms once they reach clinical trials. In a study published today (November 9) in Nature Neuroscience, an international team examined the effects of two amyloid-β antibodies on neuronal activity in a mouse model, finding that the antibodies in fact led to an increase in neuronal dysfunction.

Decreased amyloid-β and increased neuronal hyperactivity by immunotherapy in Alzheimer’s models

Marc Aurel BuscheChristine GrienbergerAylin D KeskinBeomjong SongUlf NeumannMatthias StaufenbielHans Förstl & Arthur Konnerth
Nature Neuroscience (2015)

Among the most promising approaches for treating Alzheimer´s disease is immunotherapy with amyloid-β (Aβ)-targeting antibodies. Using in vivo two-photon imaging in mouse models, we found that two different antibodies to Aβ used for treatment were ineffective at repairing neuronal dysfunction and caused an increase in cortical hyperactivity. This unexpected finding provides a possible cellular explanation for the lack of cognitive improvement by immunotherapy in human studies.

Marc Busche, a psychiatrist at Technical University of Munich in Germany, and others had previously found that neuronal hyperactivity is common in mouse models of Alzheimer’s disease. The chronically rapid-firing neurons can interfere with normal brain function in mice. “There’s evidence from human fMRI [functional magnetic resonance imaging] studies that humans will show hyperactivation early in the disease, followed by hypoactivation later on,” Busche told The Scientist. “It’s an early stage of neuronal dysfunction that can later turn into neural silencing.”

To investigate whether certain antibodies would alleviate this Alzheimer’s disease-associated phenotype, Busche and his colleagues first turned to bapineuzumab—a human monoclonal antibody that initially showed promise in treating mice modeling Alzheimer’s disease, but failed in human clinical trials. The dominant hypothesis for bapineuzumab’s failure is that it was administered too late in the disease progression, said Busche. “But it’s still a hypothesis,” he added. “There’s no real explanation for why these antibodies failed.”

The team’s latest experimenters used mice with a genetic mutation that caused them to overexpress the human amyloid-β protein; these engineered mice also displayed neuronal hyperactivity. The researchers injected 3D6, the mouse version of bapineuzumab, into the engineered mice, as well as into wild-type mice that had normal expression levels of the mouse amyloid-β protein. The team observed the effects using two-photon calcium imaging in a blinded study.

As expected, 3D6 decreased the amount of amyloid-β plaques in the engineered mice, while the control mice displayed no reaction to the injected antibodies. However, the mice engineered to overexpress human amyloid-β showed increased neuronal hyperactivity in response to the antibody, regardless of what stage of plaque development they were in. Even mice too young to have developed plaques showed aggravated hyperactive neurons. The team observed the same phenomenon when it tested a second antibody, β1, which went through early stages of drug development but was never used in human clinical trials.

As expected, 3D6 decreased the amount of amyloid-β plaques in the engineered mice, while the control mice displayed no reaction to the injected antibodies. However, the mice engineered to overexpress human amyloid-β showed increased neuronal hyperactivity in response to the antibody, regardless of what stage of plaque development they were in. Even mice too young to have developed plaques showed aggravated hyperactive neurons. The team observed the same phenomenon when it tested a second antibody, β1, which went through early stages of drug development but was never used in human clinical trials.

The results surprised Busche. “When it turned out that the antibody group was worse than the control group, it was unbelievable. But we checked many times and there was no mistake,” he said. “We don’t see this effect in wild-type mice so it must be dependent on the interaction between the antibody and amyloid-β.”

Busche was quick to point out that the mouse model is not the same as a human Alzheimer’s patient. However, he said, “it gives a sense that we don’t understand the antibody’s action, and this might go on in the human brain as well.”

“I fully believe in their results, but I have some hesitation in saying that this result explains the failed clinical trials for amyloid-β immunotherapy,” said Cynthia Lemere, a neurologist and Alzheimer’s disease researcher at the Brigham and Women’s Hospital in Boston. “I think the major reason for clinical trials failing for immunotherapy is that up until now, they’ve been done in people with moderate-to-severe Alzheimer’s disease, and then mild-to-moderate. Now the studies are going further to include people with very early stages of clinical symptoms—and to my knowledge, they haven’t been stopped because patients are getting worse.”

Thomas Wisniewski, a cognitive neurologist at New York University, voiced a similar perspective. “I don’t think this is an explanation for why immunotherapy isn’t working—I think there are other more plausible reasons for that,” he said, citing clinical trials that treated patients during later stages of Alzheimer’s disease progression, as well as those that haven’t addressed tau-related pathologies, or didn’t target the key types of amyloid-β. “[The neuronal hyperactivity] is an interesting phenomenon to be studied,” he added, “but I think it’s a separate issue.”

M.A. Busche et al., “Decreased amyloid-β and increased neuronal hyperactivity by immunotherapy in Alzheimer’s models,” Nature Neuroscience, doi:10.1038/nn.4163, 2015.

Figure 2: Worsening of neuronal dysfunction by anti-Aβ antibodies can occur independently of the effects on Aβ pathology.

Worsening of neuronal dysfunction by anti-A[beta] antibodies can occur independently of the effects on A[beta] pathology.

(a) Top, representative in vivo activity maps in WT (left) as well as isotype-treated (middle) and β1-treated (right) Tg2576 mice. Bottom, Ca2+ transients of neurons indicated above. The further aggravation of neuronal hyperactivity (mi…


Anti-Aβ treatment aggravates abnormal brain activity in a mouse model of Alzheimer’s disease

Nature Neuroscience   Nov 10, 2015


Therapies that reduce deposits of amyloid-β (Aβ) in the brain are ineffective at repairing neuronal impairment in mice and actually increase it, finds a study published online in Nature Neuroscience. Aβ deposits aggregate into clumps in the brain which are a pathological hallmark of Alzheimer’s disease.

Expression of mutant human amyloid protein in animals results in deposits of Aβ plaques that induce abnormal increases in neuronal activity and impair the normal function of neuronal circuits.

Arthur Konnerth, Marc Busche and colleagues explored whether they could reverse these impairments by treating mice that overexpress the human mutant amyloid precursor protein with either of two different antibodies targeting Aβ (14 mice) or a control antibody (19 mice). They found that, although treatment with the Aβ targeting antibodies reduced the amount of plaques in the animals’ brains, it also increased the amount of hyperactive neurons.

This was true whether the treatment was given to older mice (14 treated, 19 control) or younger mice in which the accumulation of Aβ had yet to occur (10 treated, 13 control). The same therapies had no effect on neuronal activity in a group of normal mice (5 treated, 3 control), suggesting that the observed exacerbation in mutant mice is dependent on the presence of Aβ and cannot be explained by incidental effects of inflammation in response to the antibodies.

The authors note that, although other research has shown that anti-Aβ treatment can prevent the weakening of neuronal connections and memory impairments in animal models of Alzheimer’s disease, these benefits are not enough to repair neuronal dysfunction.

They suggest that their findings provide a cellular mechanism that may explain, in part, why treatments targeting Aβ in human clinical trials have failed to improve cognitive deficits. However, the authors point out that future studies are needed to determine whether the increase in abnormal neural activity seen in their animal models is related to the poor efficacy of Aβ therapy in patients.


ANAVEX™ 2-73

ANAVEX™ 2-73 is an orally available drug candidate developed to potentially modify Alzheimer’s disease rather than temporarily address its symptoms. It has a clean Phase 1 data profile and shows reversal of memory loss (anti-amnesic properties) and neuroprotection in several models of Alzheimer’s disease.

Successful Phase 1 Clinical Trial

A Phase 1 single ascending dose human clinical trial of ANAVEX 2-73 was successfully completed in healthy human volunteers. It was a randomized, placebo-controlled study. Healthy male volunteers aged 18 to 55 received single, ascending oral doses over the course of the trial. The trial objectives were to define the maximum tolerated dose, assess pharmacokinetics (PK), clinical and lab safety.


  • Dosing from 1-60 mg.
  • Maximum tolerated dose 55-60 mg; above the equivalent dose shown to have positive effects in mouse models of Alzheimer’s disease.
  • Well tolerated below the 55-60 mg dose with only mild adverse events in some volunteers.
  • Observed adverse events at doses above the maximum tolerated single dose included headache and dizziness, which were moderate in severity and reversible. These side effects are often seen with drugs that target central nervous system (CNS) conditions, including Alzheimer’s disease.
  • No significant changes in blood safety measurements.
  • No changes in ECG.
  • Favorable PK profile.
    • Rapid absorption into blood.
    • Dose proportional kinetics.

The trial was conducted in Germany by ABX-CRO in collaboration with the Technical University of Dresden. ABX-CRO and the Technical University of Dresden are well regarded for their experience with clinical trials and CNS compounds.


ANAVEX 2-73,

Clinical-stage biopharmaceutical company Anavex Life Sciences Corp. is working on an investigational oral treatment for Alzheimer’s disease called ANAVEX 2-73, with full PART A data and preliminary PART B data from its ongoing Phase 2a clinical trial to be presented during the Clinical Trials on Alzheimer’s Disease (CTAD) conference, November 5 and 7 in Barcelona, Spain.

The trial’s Principal Investigator, Stephen Macfarlane, who also serves as director and associate professor at Aged Psychiatry, Caulfield Hospital in Melbourne, Australia, will represent the company and host a late-breaking oral session entitled “New Exploratory Alzheimer’s Drug ANAVEX 2-73: Assessment of Safety and Cognitive Performance in a Phase 2a Study in mild-to-moderate Alzheimer’s Patients.” During the presentation, which will take place Saturday, November 7, at 9:45 a.m. CET, at the Gran Hotel Princesa Sofia, in Barcelona, Macfarlane will focus on the the multicenter Phase 2a clinical trial of ANAVEX 2-73. The study includes two separate phases and includes 32 mild-to-moderate Alzheimer’s patients. While PART A is a simple randomized, open-label, two-period, cross-over, adaptive trial of up to 36 days, PART B is an open-label extension trial for an additional 52 weeks.

The research intends to assess the maximum dose of treatment tolerated by patients, and to explore cognitive efficacy using mini-mental state examination score (MMSE), dose response, bioavailability, Cogstate and electroencephalographic (EEG) activity, including event-related potentials (EEG/ERP), as well as the preformance of ANAVEX 2-73 as an add-on therapy to donepezil (Aricept).

ANAVEX 2-73 is Anavex’s lead investigational treatment for Alzheimer’s disease, in line with the company’s goal of finding effective therapies for Alzheimer’s disease, other central nervous system (CNS) diseases, pain, and various types of cancer. The novel drug targets sigma-1 and muscarinic receptors, which are thought to decrease the amount of protein misfolding, beta amyloid tau and inflammation through upstream actions.

Last November, the biopharmaceutical company presented encouraging results from their phase 1 clinical trial for Anavex 2-73, during the CNS Summit 2014 in Boca Raton, Florida. The phase 1 study demonstrated that the treatment is safe and well tolerated, suggesting a favorable pharmacokinetics profile. During the randomized, double-blind, placebo-controlled study no severe adverse events were registered, while the adverse events reported included moderate and reversible headache and dizziness, which are common symptoms associated with drugs that target central nervous system (CNS) conditions, such as Alzheimer’s.

New Exploratory Alzheimer’s Drug ANAVEX 2-73: Assessment of Safety and Cognitive Performance in a Phase 2a Study in mild-to-moderate Alzheimer’s Patients

Steve Macfarlane, MD1 , Paul Maruff, PhD2 , Marco Cecchi, PhD3 , Dennis Moore, PhD3 , Anastasios Zografidis, PhD4 , Christopher Missling, PhD4 (1)

Caulfield Hospital, Melbourne, Australia (2), Cogstate, Melbourne, Australia (3), Neuronetrix, KY, USA (4), Anavex Life Sciences, Corp., New York, NY, USA

Background: Despite major efforts aimed at finding a treatment for Alzheimer’s disease (AD), progress in developing compounds that can relieve cognitive deficits associated with the disease has been slow. ANAVEX 2-73 is a sigma-1 and muscarinic receptor agonist that in preclinical studies has shown memory-preserving and neuroprotective effects. In our ongoing phase 2a clinical study we are assessing ANAVEX 2-73 safety in subjects with mild-to-moderated AD, and measuring drug effects on MMSE, EEG and Event Related Potentials (ERP) cognitive measures, and Cogstate test batteries to optimize dosing.

Methods: Thirty-two subjects that meet NINCDS-ADRDA criteria for probable AD are being recruited at up to seven clinical sites in Melbourne, Australia. Subjects are between 55 and 85 years of age, and have an MMSE of 16 to 28. In PART A of the study, participants are administered ANAVEX 2-73 orally and IV in an open-label, 2-period, cross-over trial with adaptive study design lasting up to 36 days for each participant. In PART B of the study, all participants are administered ANAVEX 2-73 daily orally. MMSE, EEG/ERP (P300) and Cogstate tests are performed at baseline and subsequently at weeks 12, 26, 38 and 52 of the PART B open label extension.

Results: The primary outcome of the study is safety, and ANAVEX 2-73 was well tolerated. In the secondary outcome endpoints preliminary analysis of data from subjects shows an average improvement of the MMSE score at week 5. A majority of all patients tested so far improved their respective MMSE score. The average EEG/ERP (P300 amplitude) signal also improved and also the average Cogstate test improved across the test batteries.

Conclusions: Data collected so far indicate that ANAVEX 2-73 is safe and well tolerated. Interim results also show improved cognitive performance after drug administration in subjects with mild-to-moderate AD. The current results seem to justify a prospective comparison with current standard of care in a larger clinical trial study. A more complete set of results will be available at the time of the conference.

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palivizumab prophylaxis for children with bronchiolitis

Larry H. Bernstein, MD, FCAP, Curator




Eligibility for palivizumab prophylaxis in a cohort of children with severe bronchiolitis
Kohei Hasegawa,1 Jonathan M. Mansbach,2 Pedro A. Piedra,3 Michelle B. Dunn,4 Sunday Clark,5 Ashley F. Sullivan1 and Carlos A. Camargo Jr1

Pediatrics International (2015) 57, 1031–1034          http://dx.doi.org:/10.1111/ped.12760


In 2014, the American Academy of Pediatrics (AAP) updated their recommendations for palivizumab prophylaxis for children who are at high risk for severe respiratory syncytial virus (RSV) infection. To investigate the potential impact of the more restrictive 2014 criteria on the eligibility for palivizumab prophylaxis, we applied the 2012 and 2014 AAP recommendations for palivizumab prophylaxis to a multicenter cohort of 2207 US children hospitalized for bronchiolitis. According to the 2012 AAP recommendations, 215 children (9.7%) were eligible for palivizumab prophylaxis, while 140 children (6.3%) would have been eligible based on the 2014 updated recommendations (34.9% relative decrease; 95% CI: 28.5–41.7%).  The  decrease was largely driven by the restriction of eligibility to preterm infants with gestational age < 29weeks. Further development of and refinement of cost-effective approaches for the prevention of severe RSV infection are needed.


Bronchiolitis remains an important public health problem in the USA. It is the leading cause of hospitalization in infants, accounting for 18% of all infant hospitalizations, with a total direct cost of $545m in 2009.1 Although many viruses are known to cause bronchiolitis, respiratory syncytial virus (RSV) is the most common etiology among children requiring hospitalization.2 Palivizumab, a humanized monoclonal antibody against the RSV Fglycoprotein, is licensed for the prevention of serious lower respiratory infection caused by RSV in high-risk children. Since palivizumab was first licensed, professional organizations have sought more precise guidance for determining who is at high risk.3

In 2014, the American Academy of Pediatrics (AAP) updated and replaced their recommendations for palivizumab prophylaxis from 2012.4  The updated guidelines support a more restrictive use of palivizumab:3 for example, they recommend against the use in infants born ≥ 29 weeks’ gestation who have no additional risk factors for severe RSV disease. Despite these substantial changes to the guideline recommendations, there are no publications that assess the potential impact on the eligibility for palivizumab prophylaxis in US children.

To address the knowledge gap in the literature, we investigate the potential impact of the more restrictive 2014 criteria on the eligibility for palivizumab prophylaxis in a well-characterized national cohort of children hospitalized for bronchiolitis.


Over the 3year study period, we enrolled 2207 children hospitalized for bronchiolitis to one of the 16 sites. Demographic characteristics, medical history, and clinical course are summarized in Table 1. Overall, the median age was 4months (IQR, 2–9 months) and 1311 (59.4%) were male. Additionally, 285 children (12.9%) were born at gestational age <35 weeks; 460 (20.8%) had one or more major comorbid medical disorders.

Table 1 Bronchiolitis patient characteristics vs AAP palivizumab recommendations

Table 2 Eligibility for palivizumab prophylaxis vs 2012 and 2014 AAP recommendations

According to the 2012 AAP recommendations, 215 children (9.7%) were eligible for palivizumab prophylaxis (Table 2), while 140 children (6.3%) would have been eligible based on the 2014 updated recommendations. Applying the more restrictive 2014 criteria would have led to 75 fewer children (34.9% relative decrease; 95%CI: 28.5–41.7%) being eligible for palivizumab prophylaxis. The most frequent reason for the loss of eligibility was the 2014 criterion for prematurity that restricts eligibility to infantswithgestationalage<29weeks;thischangeledto45fewer children being eligible (40.9% relative decrease; 95%CI: 31.6–50.7%). The next most frequent reason was the 2014 criteria that limit eligibility to infants with chronic lung disease or congenital heart disease in the first year of life;this change led to 22 fewer children being eligible for palivizumab prophylaxis (22.9%relative decrease; 95%CI: 15.0–32.6%).

Among the 2207 children in the cohort, 207 children (9.4%) had received palivizumab prophylaxis prior to the index hospitalization. Among 215 children eligible for prophylaxis based on the 2012 recommendations, 117 (54.4%) had received palivizumab prophylaxis. Among 140 children eligible for prophylaxis based on the 2014 recommendations, 72 (51.4%) had received palivizumab prophylaxis (Table 1).


In this analysis of a large multicenter cohort of children hospitalized for bronchiolitis, we found that approximately 10% of children were eligible for palivizumab prophylaxis based on the 2012 AAP recommendations. When applying the more restrictive criteria of the 2014 updated recommendations, one-third of these children would have become ineligible for palivizumab prophylaxis. To thebestofourknowledge,thisisthe firststudytoreportthepotential impact of the change in the AAP recommendations on the eligibility for palivizumab prophylaxis in young children, a finding of public health and research importance.

In 1998, palivizumab was licensed by the US Food and Drug Administration (FDA) for prevention of severe RSV diseases in children at high risk, but the FDA did not issue more specific recommendations, nor define high risk.This absence of a specific definition has led several groups to attempt to identify children at high risk who would be eligible for palivizumab prophylaxis.3,6 The AAP published the first policy statement on the use of palivizumab in 1998.7 On the basis of the availability of additional data, the AAP has updated the guidelines in 2003, 2006, 2009, 2012,4 and 2014.3 Since the last update of the AAP recommendations, some studies have reported a high cost but limited benefit from palivizumab prophylaxis.8 In this context, the 2014 AAP guidelines recommended a more restrictive use.3 In particular, preterm infants with gestational age ≥29 weeks without additional risk factors became ineligible for palivizumab.

In parallel with this change in recommendations, within the present high risk population, the most frequent reason for the loss of eligibility was the use of the restrictive criterion for prematurity: that is, preterm infants born from 29t o35 weeks’ gestation with no additional risk factors became ineligible. This specific group of preterm infants accounts fo ra large number of births in the US:approximately 10% of US births in 2012.9 Thus, one may argue that the use of this restrictive criterion would result in an increase in the number of preventable severe RSV infections,10 even considering the potentially limited efficacy of palivizumab in this population. As described in the technical report of the 2014 AAP recommendations, however, it is challenging to define an optimal threshold of gestational age in preterm infants for which palivizumab prophylaxis may be indicated. The present observations should facilitate further investigations that seek high-quality and cost-effective preventive strategies for a large number of vulnerable children.

This study has several potential limitations. First, the analysis was not designed to examine the efficacy or effectiveness of palivizumabprophylaxis. Rather, we sought to examinethe potential impact of the updated recommendations on the eligibility for palivizumab in a well-characterized national cohort of children hospitalized for bronchiolitis. Second, the present study investigated only children hospitalized for bronchiolitis; thus, those with other types of severe respiratory infection (e.g. pneumonia) were not examined. Inclusion of these populations may yield different inferences. Nevertheless, the present findings are directly relevant to >120 000 US children hospitalized for bronchiolitis (and their families) each year.1 Finally, the study participants were those who were hospitalized in academic centers. Therefore, the present inferences may not be generalizable to the US population as a whole. Children hospitalized at academic centers, however, have disproportionately high morbidity; it is in precisely this population for which targeted preventive measures are needed.

In conclusion, we found that 10% of children hospitalized for bronchiolitis were eligible for palivizumab prophylaxis based on the 2012 AAP recommendations. When we applied the more restrictive 2014criteria,one-third of these children were ineligible. The decrease was largely driven by the restriction of eligibility to preterminfantswithgestationalage <29weeks.Forpolicymakers and researchers, because bronchiolitis continues to be a substantial societal burden in an already-stressed health-care system,1 the present findings support further development and refinement of cost effective approaches for the prevention of severe RSV infection.



1 Hasegawa K,Tsugawa Y,Brown DF,Mansbach JM,Camargo CA Jr. Trends in bronchiolitis hospitalizations in the United States, 2000–2009. Pediatrics 2013; 132: 28 –36.

2 Hasegawa K, Mansbach JM,Camargo CAJr.Infectious pathogens and bronchiolitis outcomes. Expert Rev. Anti Infect. Ther. 2014; 12: 817 –28.

3 American Academy of Pediatrics Committee on Infectious Diseases and Bronchiolitis Guidelines Committee. Policy statement. Updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection. Pediatrics 2014; 134: 415 –20.

4 American Academy of Pediatrics. Respiratory syncytial virus. In: Pickering LK, Baker CJ, Kimberlin DW, Long SS (eds). Red Book: 2012. Report of the Committee on Infectious Diseases. American Academy of Pediatrics, Elk Grove Village, IL, 2012; 609–18.

5 Hasegawa K, Jartti T, Mansbach JM etal.Respiratory syncytial virus genomic load and disease severity among children hospitalized with bronchiolitis: Multicenter cohort studies in the United States and Finland. J. Infect. Dis. 2015; 211: 1550 –9.

6 NHS Commissioning Board. Clinical Commissioning Policy: Palivizumab to reduce the risk of RSV in high risk infants. 2012. Accessed 13 May 2015. Available from URL: http://www.england.nhs.uk/.

7 American Academy of P

ediatrics Committee on Infectious Diseases and Committee of Fetus and Newborn. Prevention of respiratory syncytial virus infections: Indications for the use of palivizumab and update on the use of RSV-IGIV. Pediatrics 1998; 102: 1211 –6.

8 Andabaka T, Nickerson JW, Rojas-Reyes MX, Rueda JD,  Bacic Vrca V, Barsic B. Monoclonal antibody for reducing the risk of respiratory syncytial virus infection in children. Cochrane Database Syst. Rev. 2013; 4 CD 006602.

9 American Academy of Pediatrics Committee on Infectious Diseases and Bronchiolitis Guidelines Committee. Technical report. Updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection. Pediatrics 2014; 134 (2): e620–38.

Appendix I. Principal Investigators at the 16 participating sites in MARC-30
Besh Barcega, MD Loma Linda University Children’s Hospital, Loma Linda, CA, USA

John Cheng, MD Children’s Healthcare of Atlanta at Egleston, Atlanta, GA, USA

Carlos Delgado, MD Children’s Healthcare of Atlanta at Egleston, Atlanta, GA, USA

Haitham Haddad, MD Rainbow Babies and Children’s Hospital, Cleveland, OH, USA

Frank LoVecchio, MD Maricopa Medical Center, Phoenix, AZ, USA

Eugene Mowad, MD Akron Children’s Hospital, Akron, OH, USA

Brian Pate, MD Children’s Mercy Hospital and Clinics, Kansas City, MO, USA

Mark Riederer, MD Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, TN, USA

Paul Hain, MD Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, TN, USA M

Jason Sanders, MD Children’s Memorial Hermann Hospital, Houston, TX, USA

Nikhil Shah, MD New York Presbyterian Hospital, New York, NY, USA

Dorothy Damore, MD New York Presbyterian Hospital, New York, NY, USA

Michelle Stevenson, MD Kosair Children’s Hospital, Louisville, KY, USA

Erin Stucky Fisher, MD Rady Children’s Hospital, San Diego, CA, USA

Stephen Teach, MD, MPH Children’s National Medical Center, Washington, DC, USA

Lisa Zaoutis, MD Children’s Hospital of Philadelphia, Philadelphia, PA, USA




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