Working to Bridge Gaps in Rare Disease Product Development

There are approximately 7,000 rare diseases affecting an estimated 30 million people in the United States. Many
of these diseases are serious or life-threatening and it is estimated that half affect children. Unfortunately, most rare diseases still do not have approved therapies.  In 2018 we saw a record number of novel drugs and biologics approved for rare diseases. In particular, there were 35 novel drugs and biologics approved in 2018 with orphan drug designation. This is the highest number since the passage of the Orphan Drug Act in 1983.

These approvals included drugs and biologics utilizing programs to facilitate and expedite development and review of medical products to address unmet medical need. Among the many new orphan therapies in 2018, the FDA approved the first drug to treat patients with a rare, inherited form of rickets, and the first orally-administered drug to treat Fabry disease. The FDA also approved a new biologic for patients when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.

The FDA will host a public meeting on April 29, 2019: ”Patient Perspectives of the Impact of Rare Diseases: Bridging the Commonalities.” This provides the opportunity to hear patients’ and caregivers’ perspectives on how rare diseases impact their daily lives and to assess commonalities that may help the Agency and medical product developers further understand and advance the development of treatments for rare diseases. While the differences between rare diseases are critically important, it is also important to assess commonalities to synergize product development in rare diseases.

Additionally the grant review process will be enhanced by providing grant reviewers with patient perspectives gleaned from listening sessions with patients about rare diseases. These enhancements will build on new priorities in grant review. Specifically, to address the unmet needs for rare diseases, the Office of Orphan Products has made meaningful changes to both funding focus and review process for the Clinical Trial and Natural History grants programs. They are focusing on studies of rare diseases with unmet needs that use efficient and innovative trial designs, such as adaptive and seamless trial designs, use of modeling and simulations, incorporation of real world data, and basket and umbrella trials studying multiple rare diseases/products. Applicants are asked to incorporate patient input into their research proposals.

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Clinical Trial of B244 for the Treatment of Pediatric Atopic Dermatitis

AOBiome Therapeutics, Inc. a clinical-stage microbiome company focusing on the research and development of therapeutics for dermatological conditions, announced the administering of its lead product candidate, B244, to the first patient in the Company’s Phase 1b clinical trial to treat pediatric patients with atopic dermatitis (eczema). Data from the First Pediatric Study are Anticipated in the Second Half of 2019.

“There is a significant medical need for new therapies to treat children with atopic dermatitis due to the high and increasing incidence of the disease and the limited number of safe and efficacious options to treat this sensitive population,” said President & CEO, Todd Krueger.  In the United States, 13% of children (or 9.6 million) under the age of 18 years suffer from eczema. Of these, approximately one third have moderate to severe eczema. Additionally, many children who suffer from atopic dermatitis in their youth also go on to disproportionally suffer from certain diseases later in life, including 43% of children with severe atopic dermatitis before the age of 8 developing asthma and 45% developing allergic rhinitis according to one recent study.

The clinical trial is an open-label, multicenter, Phase 1b study of B244, a first-in-class, topical formulation of beneficial ammonia oxidizing bacteria (“AOB”), delivered as a topical spray twice daily and is designed to assess safety and tolerability in 36 pediatric patients aged 2 to 17 years with mild to moderate atopic dermatitis over a 28-day period. The AOB platform is a patented, proprietary, topical and intranasal formulation incorporating a single strain of beneficial AOB, Nitrosomonas eutropha. The platform is designed to repopulate the skin or nasal microbiome with AOB. Once deployed, AOB produces nitric oxide, a signaling molecule known to regulate inflammation and vasodilation.

“Our goal is to alleviate both the symptoms that are associated with atopic dermatitis and to utilize AOB’s nitric oxide-mediated anti-inflammatory abilities coupled with its capability to reduce levels of pathogenic bacteria as a dual-modality approach to treatment,” said CMO, Dr. Judith Ng Cashin, M.D. “Current therapies for atopic dermatitis can cause side effects such as stinging, burning, and thinning of skin, especially in pediatric patients. B244’s innovative nature represents a novel therapeutic opportunity to address the significant market need and to impact the lives of patients.”

In addition to the ongoing pediatric study, AOBiome is currently conducting a Phase 2 clinical trial investigating B244 for the treatment of adult atopic dermatitis with expected top-line data readout in 2019. See: www.clinicaltrials.gov.

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New Public Health Crisis? Study Urged on Marijuana Smoking & Lung Cancer

As marijuana becomes mainstream and usage rates skyrocket, some of the nation’s top cancer doctors are urging the Surgeon General to investigate the link between smoking marijuana and lung cancer.

Among the renowned doctors calling for more study is Dr. Joseph Friedberg, head of the Division of Thoracic Surgery at the University of Maryland School of Medicine. Publishing his concerns on SurvivorNet, the cancer site providing the latest information and treatment options from foremost cancer experts, Dr. Friedberg is calling for a federal study citing increased rates of lung cancer in their practices from patients whose only discernible risk factor is marijuana smoking. SurvivorNet released a documentary outlining the concerns surrounding the lack of research on the link between smoking marijuana and lung cancer in hopes of bringing widespread attention to the need for this study.

Dr. Friedberg states “Given the expanding legalization of marijuana, and the anticipated wave of increased use, there is clearly a need to study the cancer risks of marijuana with the same rigor that has been devoted to tobacco smoke. Both types of smoke contain some of the same carcinogens, so the widely held belief that tobacco smoke causes cancer and marijuana smoke does not is inherently flawed. “We have an opportunity to avoid a potential marijuana-related public health crisis similar to what we are still dealing with from cigarettes being introduced to the public without any health risk warnings.”

Previously, the only study on long term use of cannabis and lung cancer was a 2008 NIH study conducted in New Zealand which found that long term cannabis use increases the risk of lung cancer in young adults. The study cites other reputable scientific findings that state cannabis smoke is similar to tobacco smoke but with twice as many carcinogens and because people smoke joints without filters and hold the smoke in their lungs longer it can increase the risk of lung cancer. The major finding from this study was that for each joint-year of cannabis exposure, the risk of lung cancer increased by 8%, after adjustment for confounding variables including tobacco smoking.

A major differential risk between cannabis and cigarette smoking was observed, with 1 joint of cannabis similar to about 20 cigarettes for risk of lung cancer. This study was not extensive or long enough to be definitive but it raises concerns about the drug. This study would be the first of its kind to bring groundbreaking research and information to millions of Americans who smoke marijuana without understanding the potentially lethal side effects. Much like tobacco’s earliest days, if something is not done about this now, we risk another major health emergency.

SurvivorNet was founded to fill an urgent need for better information about cancer prevention and treatment. “By bringing attention to crucial findings from some of the country’s leading cancer doctors, we are hoping to save lives. We know marijuana is alleviating suffering for a great many cancer patients. We also think people who smoke and vape marijuana recreationally should have accurate information about whether there is an increased risk for cancer and then make their own choices. It’s clear a major national study is needed so we can really understand this issue.”

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Dr. John S. Macdonald Honored at 2018 Luminary Awards

John S. Macdonald, MD, is the Senior Medical Advisor for AGICC (Academic GI Cancer Consortium) and the consolidated Oncology Consortia of Criterium groups, including: AMyC (Academic Myeloma Consortium), ATOMIC (Academic Thoracic Oncology Medical Investigators Consortium) and ABRCC (Academic Breast Cancer Consortium). He is a leading supporter and advocate of the Translational Research methodology.

Dr. Macdonald was one of a few select honorees at The Ruesch Center for the Cure of Gastrointestinal Cancers Annual Luminary Awards on November 30th, 2018.

Dr. Macdonald successfully developed and led the Comprehensive Cancer Center at St. Vincent’s in New York City between 1997 and 2007. He is widely recognized as an industry and academic expert in gastrointestinal oncology and has written and lectured on the advantages of translational research. In addition to his responsibilities at Saint Vincent’s, Dr. Macdonald served as Chief of Medical Oncology there, and as the Lynn Wood Neag Endowed Professor of Medicine at the New York Medical College. He is acknowledged as a leading educator in Medical Oncology. 

Macdonald pioneered the use of chemoradiation after surgical resection of gastric cancers. This treatment regimen, aptly named the “Macdonald Regimen,” has helped turn the idea of a cure into a reality for thousands of patients with gastric cancers. This has also paved the way for the development of new treatment options for gastric cancers.  “[Macdonald] is a groundbreaking researcher, dedicated educator, and outstanding clinician,” said Sunnie Kim, MD, of the Ruesch Center for the Cure of Gastrointestinal Cancers, prior to presenting Macdonald with his award. “He has changed the lives of countless patients with some of the deadliest cancers.”

Dr. Macdonald has authored over 400 articles, abstracts and book chapters and has been both published in, and editor of, many prestigious medical journals. Macdonald has received numerous awards and distinctions, including being named among Good Housekeeping’s Best 300 Doctors in America and, over a seven-year period, New York magazine’s Best Doctors in New York.

Visit the website to see Dr. Macdonald’s profile and all the Consortia groups.

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The Emerging Breast Imaging Standard

Many breast imaging centers have launched high risk screening clinics to augment their existing services. This has already become the new standard, as organizations look for justification to expand patient services, recommend breast MRI screening exams, and provide referrals for genetic counseling.  Offering a service dedicated to screening patients for high risk, without the proper tools, can put more stress on the breast imaging workflow.

The problem is that many systems are not set up to function on this plane. Subsequently, some sites resort to manual data entry on risk model websites to calculate each score individually. Calculated risk models, such as Tyrer-Cuzick and the Gail Model, are simply not built into the RIS mammography tracking module, mammography information system, or EMR module.

Some programs offer standalone, web-based risk platforms only, although this method adds to system fragmentation, redundancy, and increased room for error. This is especially true when the reader wants to add the risk score to their finding report, or if the site wants to include risk-related information in the patient notification letter.

Tyrer-Cuzick version 8 has 25 elements and family history factors alone, so the time required to enter this for every patient, every study, and every day adds up fast. In most cases, the facility is already required to enter this information into their existing mammography tracking solution and, in order to generate the risk score, that same information has to be re-entered into an online calculator.

MagView, however, has considered this workflow and incorporated several breast cancer risk models into their base program. They offer automated calculations for all available risk models, such as Tyrer-Cuzick, Gail, BRCAPro, and Claus. In their program, patients can enter breast cancer risk factors in advance of the appointment using a patient history portal, saving the facility staff countless hours a day. The patients can also use the patient history tablet module for electronic submission to the breast center and MagView system.

These factors are saved from year to year, so the patient only needs to modify any changes in the previous history on subsequent visits. The calculators are built into the program, so no external websites or third-party programs are needed. The data is then used in the automatic risk calculation, and the radiologists can see the score in real-time, affecting their decision on follow-up recommendation. Scores can automatically be included in the finding reports, saving the readers additional time, and patients can be notified with automated text inserted into the letter based on their score.

Evidence has shown that including risk information in both the finding reports and patient letters has increased awareness along all fronts, especially when qualifying patients for additional imaging, like breast MRIs. One site reported a 100% increase in breast MRI referrals from their previous workflow using their RIS mammography tracking module as a reporting tool.

The bottom line is, increased high risk screening has improved the detection of cancers by ensuring patients who are at a high risk receive the care and additional imaging they need. In a recent study of BRCA mutation carriers and women of 20% or higher lifetime risk for breast cancer, sensitivity for breast cancer detection was 90.0% using MRI versus 37.5% for mammography and 37.5% for ultrasound (Source: Journal of Clinical Oncology. 2015;33(10):1128-35).

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Hong Kong Dept of Health Approves Biktarvy® for HIV, following FDA and EC

In Phase 3 Clinical Trials, Biktarvy® Demonstrated High Efficacy and Zero Resistance Through 48 Weeks

The triple-combination, single-tablet therapy combines the potency of the novel integrase strand transfer inhibitor (INSTI) bictegravir, with the demonstrated safety and efficacy profile of a guideline recommended dual nucleoside reverse transcriptase inhibitor (NRTI) backbone – Descovy® (emtricitabine 200 mg/tenofovir alafenamide 25 mg; FTC/TAF). BIC/FTC/TAF provides a convenient once-daily dosing STR without regards to food. Furthermore, BIC/FTC/TAF’s use is not restricted by the patient’s baseline viral load, CD4 cell count or HLA-B 5701 status.

“Safety and resistance profiles are important considerations for HIV patients, as the disease requires long-term care. In addition, potent treatments with convenient dosing can potentially improve adherence and outcomes for patients,” said Dr Chan Kai Ming, Specialist in Infectious Disease, Consultant in Internal Medicine, Union Hospital, Hong Kong.

The Hong Kong Dept of Health has approved Biktarvy® (bictegravir 50mg/emtricitabine 200 mg/tenofovir alafenamide 25 mg; BIC/FTC/TAF), a once-daily single tablet regimen (STR) for the treatment of HIV-1 infection in adults*. Hong Kong is the first market in Asia to approve Biktarvy. BIC/FTC/TAF was approved by the U.S. Food and Drug Administration (FDA) on February 7, 2018 and the European Commission on June 21, 2018.

The approval was based upon data from four ongoing Phase 3 studies: Studies 1489 and 1490 in treatment-naive HIV-1 infected adults, and Studies 1844 and 1878 in virologically suppressed adults. The trials are comprised of a population of 2,414 participants, and BIC/FTC/TAF met its primary efficacy objective at 48 weeks in all four studies, with no participants in any of the four BIC/FTC/TAF studies developing treatment-emergent virologic resistance. There were no cases of renal discontinuation, proximal renal tubulopathy or Fanconi syndrome in the BIC/FTC/TAF arms at 48 weeks. Additional ongoing studies not included in the marketing authorization application involve dedicated studies in women, adolescents and children.

“We welcome the timely approval of BIC/FTC/TAF in Hong Kong, a novel treatment option for people living with HIV,” said Andrew Hexter, Vice President and GM for Gilead Sciences Asia. “We are committed to serving the needs of HIV patients and medical communities in Asia, and are working with public health authorities to make the treatment available in this region.”

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September is Blood Cancer Awareness Month

September was designated as National Blood Cancer Awareness Month in 2010 by the United States Congress. Approximately every 3 minutes one person in the United States is diagnosed with a blood cancer. That means that during September, Blood Cancer Awareness Month, more than 14,000 people will be informed that they have one of these terrible diseases.

Blood cancers are a group of diseases that affect the production and function of blood cells. The three main types are leukemia (found in blood and bone marrow), lymphoma (affects the body’s lymphatic system) and myeloma (impacts plasma cells). Nearly 172,000 people in the U.S. are living with a blood cancer, according to Kevin Radelet, executive director, Leukemia Research Foundation.

In recognition of Blood Cancer Awareness Month, the Leukemia Research Foundation is conducting a social media initiative called The Heroes Among Us to increase awareness about ALL blood cancers, including leukemia, lymphoma, multiple myeloma, and myelodysplastic syndromes.

The LRF Facebook?and Instagram pages will highlight Heroes through uplifting stories. You will have the opportunity to share, mention and comment on posts on Twitter, YouTube, and LinkedIn too.

Several buildings in downtown Chicago — LRF is located in Northfield, IL — will “light up orange” in recognition of Blood Cancer Awareness Month. Click here for details.

Here’s how you can participate:
? Share on social media channels online using hashtags: #LRFHeroes?and/or #HeroesWearOrange
? Share the link to the heroes stories with friends, family members and colleagues
? Buy a bag of orange ribbons and share them!?Send an email?to request ribbons
? Please donate today?to help LRF continue to raise awareness and funding for research and patient programs.
? For other ways to get involved, sign up for events, or volunteer, please click here.

Headquartered in Northfield, IL., the Leukemia Research Foundation is dedicated to conquering all blood cancers by funding research into their causes and cures and enriching the quality of life of those touched by these diseases. For more information, visit www.allbloodcancers.org or call 847-424-0600.

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A Phase 2/3 Clinical Trial of Trigriluzole for Alzheimer’s Disease

The first patient has been enrolled in a Phase 2/3 clinical trial of trigriluzole (BHV-4157), a novel glutamate modulator for the treatment of mild-to-moderate Alzheimer’s disease (AD). The trial is a randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of trigriluzole in patients diagnosed with AD of mild-to-moderate severity (Mini-Mental State Examination scores of 14-24 at screening), and is being conducted in collaboration with the Alzheimer’s Disease Cooperative Study (ADCS) at sites throughout the USA.Howard Feldman, MD, FRCP, Director of the ADCS and Professor of Neurosciences at University of California San Diego School of Medicine added, “The preclinical evidence for the active metabolite of trigriluzole to modulate glutamate and confer neuroprotective effects in patients with AD is compelling, and the new formulation of trigriluzole should improve its pharmaceutical properties with potential for efficacy in AD.”

Alzheimer’s disease is a progressive, fatal neurodegenerative dementia that accounts for 60 ? 80 percent of dementia cases. Alzheimer’s disease currently has no cure. Although there are FDA-approved medications for symptomatic treatment of AD, their clinical benefits are generally limited. Novel therapeutic approaches aimed at normalizing synaptic and extra-synaptic glutamate levels, such as trigriluzole, may offer the potential for symptomatic benefit in AD by improving cognitive function, as well as the potential for disease modification by preventing the loss of synapses.

The Phase 2/3 clinical trial (clinicaltrials.gov identifier NCT03605667) is a randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of trigriluzole in patients diagnosed with AD of mild-to-moderate severity (Mini-Mental State Examination scores of 14-24 at screening). Patients who have been taking stable doses of FDA-approved AD medications (AchEI also known as acetylcholinesterase inhibitors and/or memantine) for a minimum of three months prior to screening and who are willing to remain on the same regimen for the duration of the trial may be eligible to participate. Approximately 292 patients will be randomized on a 1:1 basis to receive 280 mg of trigriluzole or placebo, taken orally at bedtime. Duration of treatment will be 48 weeks.

About Trigriluzole
Trigriluzole is a third-generation prodrug and new chemical entity that modulates glutamate, the most abundant excitatory neurotransmitter in the human body. Trigriluzole has a wide range of pharmacological actions, including interactions with several types of ion channels, cellular signaling mechanisms and facilitation of glutamate reuptake. Some potential targets related to trigriluzole’s mechanism of action include (1) reducing presynaptic glutamate release through actions at the voltage-gated ion channels, (2) facilitating glutamate uptake via EAATs located on glial cells, (3) enhancing transmission through synaptic AMPA receptors, (4) altering GABAergic neurotransmission, and (5) effecting neurotrophic agents such as BDNF. Several of these targets of trigriluzole balance abnormalities observed in human AD post-mortem tissue as well as in AD animal models. As such, trigriluzole potentially offers neuroprotective effects at the level of the synapse as well as improved synaptic functioning, mechanisms that could exert both symptomatic and disease-modifying effects in AD.

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Finding New Treatments for Breast Cancer with Brain Metastases

As if Breast Cancer or Brain Cancer alone were not enough to combat — patients with both now?have new hope in light of fledgling research that is showing progress.

Once breast cancer metastasizes into other areas of the body, particularly the brain, it becomes much more dangerous. And while the National Cancer Institute spends more than $500 million dollars per year on breast cancer research, only two to five percent of this funding goes to study how the disease spreads.

A clinical trial is open nationwide through the Academic Breast Cancer Consortium (ABRCC), giving access to an exciting novel drug therapy combination. The tucatinib, palbocilib and letrozole trial is coordinated by ABRCC and currently open for enrollment at the University of Colorado Cancer Center; University of Texas Health and Science Center in San Antonio, TX; Stony Brook University, NY; University of Arizona, Tucson, AZ; and University of New Mexico, Albuquerque, NM and will also be accruing patients at Northwestern University, Chicago, IL.

There are three well-established predictive markers of breast cancer. They are estrogen receptors (ER), progesterone receptors (PR), and the growth factor receptor HER2, these receptors may be blocked with targeted drugs to stop cancer growth. Breast cancers lacking these three markers are referred to as ?triple-negative? but clinicians and scientists are quickly learning more about cancers that have all three receptors, which are often called ?triple-positive.? There are treatments against each target individually, but when multiple drivers are present, as in ?triple-positive? breast cancer, blocking one often results in cancer nimbly switching to driving its growth with the other two.

The study combines tucatinib, which inhibits HER2, with letrozole targeting ER and PR hormone receptors, and the drug palbociclib, which targets CDK proteins that help cancer cells rush through the process of replication. The three had not been tried together until Elena Shagisultanova, MD, PhD, a breast cancer specialist at UCH, hypothesized there could be a way to target all three drivers at the same time with better results than targeting combinations of any two.

?When metastatic cancer spreads to the brain, it can be especially challenging,? says Dr Peter Kabos, the National Medical Director of the Academic Breast Cancer Consortium (ABRCC) and the Kabos Research Lab for Breast Cancer at UC Denver. ?Many medications aren?t effective in the brain, but exciting early clinical trial data for tucatinib shows that it may be one of the drugs that can penetrate the blood-brain barrier to combat brain metastases.

The trial is funded by the Pfizer ASPIRE Award in Breast Cancer Research. Cascadian Therapeutics and Pfizer are providing the study drugs tucatinib and palbociclib. For more information about trial eligibility and participation, contact brad.mackay@ucdenver.edu or emily.berens@ucdenver.edu

Article excerpted with permission from the University of Colorado Cancer Center blog — for the complete story, click here.

LANTERN-2 Clinical Trial Aims at Reducing Use of Opioids

Bonti announced it has initiated dosing in its LANTERN-2 clinical trial, a Phase II clinical trial under Bonti?s LANTERN (Long-Acting NeuroToxin-E Relief, Non-opioid) clinical program aimed at treating focal muscle pain and reducing use of rescue medications, including opioids.

LANTERN-2 is a randomized, placebo-controlled, ascending dose, double-blind clinical trial to evaluate the safety and efficacy of intramuscular (IM) injections of Bonti?s therapeutic product candidate, EB-001T, in subjects undergoing elective abdominoplasty (tummy tuck) surgery. The primary endpoint in this trial will be reduction of post-operative pain at rest as measured by the Numeric Pain Rating Scale (NPRS) over the first 96 hours. Secondary endpoints include NPRS during activity and patient use of rescue medications, including opioids, to address unrelieved pain.

LANTERN-2 trial was based on favorable safety results from the recently completed LANTERN-1 clinical trial, which was Bonti?s first trial in the LANTERN program. EB-001T showed favorable safety in a wide dose range and was well tolerated, and in which the maximum tolerated dose was not reached. Learn more about EB-001T?at Bonti’s website.

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