Tracking COVID-19 Vaccine Development Efforts Across the Globe

The past year has seen the rapid global spread of SARS-CoV-2—the virus responsible for the ongoing COVID-19 pandemic. While non-pharmaceutical interventions have been the mainstay of epidemic control to date, vaccination is likely to constitute the definitive, long-term defence strategy against SARS-CoV-2 morbidity, mortality, and transmission, offering the best hope of a return to normal life.

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Positive Trial Data with 100% Safe Delivery

Moleculin Announces Positive Trial Data with 100% Safe Delivery of p-STAT3 Inhibitor and Efficacy in Majority of Patients

Preliminary results from phase 1 clinical trial of WP1220 for treatment of cutaneous T-cell lymphoma (“CTCL”); supports phase 2 study.

“For years, p-STAT3 (the activated form of STAT3) has been considered an ‘undruggable’ target because of the difficulty of reaching and affecting this cell-signaling protein,” commented Walter Klemp, Moleculin’s Chairman and CEO. “Some consider it to be a master regulator of cancer-related gene transcription, so we believe the ability to show a therapeutic effect from a p-STAT3 inhibitor could be considered a significant breakthrough in cancer research.”

Results: There were 6 patients screened, and 5 patients enrolled between March and July 2019. Three are evaluable for both safety and efficacy after completing 3 months of treatment, with 2 ongoing and evaluable for safety. The only AE reported potentially related to study drug in one of the five patients was a mild contact dermatitis not requiring treatment. CAILS scores on index lesions were significantly decreased in the first 3 patients, who were stages IA, IB, and IIB, respectively, at entry. A composite score was obtained for all treated lesions for each patient, and percent changes were calculated from baseline to Day 84. There was a median reduction of 70.8% (range 62.1%-76.2%) for the 3 patients. Improvement was noted as early as 7 days after initiation of treatment, and maintenance of improvement was also shown at follow up (1 month after discontinuation, as per protocol). The fourth patient has also shown an initial reduction in the composite CAILS score after 56 days (26.7%), and is continuing on treatment. Evaluations of the biopsy samples for histopathology and status of p-STAT3 in treated lesions are in progress.

Conclusions: WP1220, an inhibitor of p-STAT3, has shown demonstrable safety and significant efficacy after at least 3 months of topical treatment in 3 patients with progressive MF, with a continuing trend towards improvement in additional patients currently in treatment. This is the first demonstration that inhibition of the STAT3 activation pathway with topical therapy has impacted the course of this disease. The trial is continuing, and updated and more comprehensive data from this study as well as assessment of STAT3 phosphorylation in treated lesions will be reported.

“This is the first topical delivery of a p-STAT3 inhibitor that we know of for CTCL, where there is a significant unmet need for improved treatment of the lesions associated with this potentially deadly skin cancer. But, we believe the significance of this data goes well beyond CTCL, as it speaks to the targeting of p-STAT3 as a general strategy. We are excited to share these preliminary results in association with ASH, especially because we believe showing activity here could have exciting implications for the future of STAT3 inhibitors in general. Although this is a relatively small pilot study, we believe the results justify an expansion to a larger patient population in a Phase 2 clinical trial,” added Dr. Sandra Silberman, CMO at Moleculin.

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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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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.

Orphan Drug Designation for Treatment of ALS – Amyotrophic Lateral Sclerosis

On March 29, 2018 the U.S. Food and Drug Administration (FDA) Office of Orphan Products Development granted Orphan Drug Designation (ODD) to experimental therapeutic EH301 for the treatment of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s Disease.

The Orphan Drug Designation submission included data from a 2017 double-blind placebo-controlled European pilot study in humans. To expand on the results of the pilot study, Elysium Health expects to initiate a placebo-controlled study in collaboration with Mayo Clinic to evaluate EH301 in up to 150 adults with ALS by the fourth quarter of 2018. The granting of ODD to EH301 does not alter the standard regulatory requirement through adequate and well-controlled studies to support FDA approval, and there is no guarantee EH301 will be approved for the treatment of ALS by FDA.

Elysium Health Chief Scientist Dr. Leonard Guarente remarked that “There is a great deal of work to be done to address the need for continued research to better understand and to treat all neurodegenerative diseases. We believe that the FDA’s granting of Orphan Drug Designation for EH301 for ALS underscores the need for novel treatments for this rare condition.”

ALS is a rare neurodegenerative disease that affects nerve cells that control voluntary muscles throughout the body to produce movements including talking, eating, walking, and breathing. ALS is progressive, meaning it gets worse over time. As the nerves lose the ability to control muscles, the muscles become weak and eventually lead to paralysis. Most people with ALS succumb to respiratory failure, usually within three to five years from when symptoms first appear. Please visit the ALS website for more information.

The FDA’s ODD program provides orphan status to drugs intended for the safe and effective treatment, diagnosis, or prevention of rare diseases or disorders that affect fewer than 200,000 people in the United States. It is estimated that there are approximately 15,000-20,000 Americans with ALS. Please see the NIH ALS Fact Sheet for details.

Additional information can be found on the Christopher & Dana Reeve Foundation website regarding current therapies and disease trends.

Disclosure: Mayo Clinic has a financial interest in Elysium Health. All revenue Mayo Clinic receives will be used to fund its not-for-profit mission in medical research and education.

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