Suzana Nahum Zilberberg, CEO of BioLight Life Sciences

DiagnosTear, the dry eye diagnostic subsidiary of BioLight Life Sciences (TASE:BOLT), hopes to file by the end of 2017 for CE Mark approval in Europe and begin a pivotal trial in the U.S. in mid-2018 with its TeaRx device to aid in the diagnosis and monitoring of dry eye syndrome (DES).

“Currently, we are developing two product lines for TeaRx: a point-of-care diagnostic of tear film for the physician’s office and a companion diagnostic for pharmaceutical companies to identify responders to a specific therapy and the therapy’s mode of action,” Suzana Nahum Zilberberg, chairperson of DiagnosTear, says in an interview with BioTuesdays.

Ms. Zilberberg also is CEO of BioLight, which owns more than 80% of DiagnosTear.

DES is a common disorder of the ocular surface in which the eye produces insufficient tears or tears with abnormal composition. In its mild-to-moderate forms, DES causes pain and discomfort, can impact vision quality and the ability to go about daily activities.

According to Ms. Zilberberg, more than 350 million people worldwide are affected by DES, one of the leading causes of patients’ visits to eye care practitioners in the U.S. “So, there is strong demand for better patient diagnosis, and companion diagnostic solutions to determine which patients will respond to the potential of personalized treatment,” she adds.

Current diagnostic devices measure only one biomarker. “We took a different approach and developed a device to measure different biomarkers related to different elements of dry eye to identify not only if a patient has dry eye but also the underlying cause of the disease,” Ms. Zilberberg points out. “This is intended to improve patient outcomes.”

Current diagnostic devices measure only a single parameter

She contends that dry eye is a complex, multi-factorial disease and a technology like TeaRx has the potential to improve the diagnosis and differentiation between its various underlying causes. “A multi-assay approach should facilitate tailored treatment modalities as additional and more targeted therapies become available.” 

The FDA to date has approved only two drugs for DES. “When we look at the dry eye landscape over the next two-to-three years, we see many compounds in development, which we believe will make TeaRx very relevant to pharmaceutical companies trying to get to the market and also to physicians looking for optimizing patients’ treatment,” she adds.

Ms. Zilberberg indicates that in an original clinical trial with 200 DES patients in the U.S., TeaRx demonstrated a strong correlation with widely used benchmark tests now being used. A follow-up study with 74 patients showed a 86% sensitivity and 87% specificity, which is “very high compared with what is in the market place now,” she says, in distinguishing between DES patients and healthy subjects.

At the end of August, DiagnosTear began an additional clinical trial at two medical centers in the U.S. with 41 healthy and 41 DES subjects to ensure the repeatability of positive findings from two earlier studies. Final statistical results are expected before the end of 2017. The study will expand the clinical database prior to submitting TeaRx for marketing approval as a hand held point-of-care device in Europe.

Ms. Zilberberg says the company also has submitted a pre-investigational device exemption with the FDA for a pivotal trial to begin in mid-2018. “The trial will take only several months to complete and, if successful, would allow us to file for regulatory approval by the end of 2018,” she adds.

The TeaRx collects 1 microliter of tear and dilute it by 200

Regarding development of TeaRx as a companion diagnostic, Ms. Zilberberg contends that DiagnosTear has developed a set of objective biomarkers, which represent different aspects of dry eye and can differentiate between responders and non-responders to a specific treatment. “This can offer drug developers the potential of successful clinical trials and a commercial differentiation.”

These companies are facing major challenges: the first is patient selection to their trials and the second is setting the right endpoints for the trail, Ms. Zilberberg points out. 

TeaRx also can support identifying the sub-populations of responders and non responders to a specific therapy, and understanding the mode of action by comparing findings from patients’ tear film compositions at the end of the trial against visit one, she adds. “This has the potential of a commercial collaboration following approval of a new therapeutic.”

DiagnosTear previously has added TeaRx as a companion diagnostic in a drug company’s Phase 3 clinical trial for a DES drug and is at different stages of  collaborating with pharmaceutical and medical device companies that treat DES.

“As we saw at the recent meeting of the American Academy of Ophthalmology, the DES sector is very active and the medical need is understandable,” she adds.

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Jesús Martin-Garcia, CEO and co-founder

Swiss-based GeNeuro (Euronext Paris: CH0308403085 – GNRO) is leveraging the biology of human endogenous retroviruses (HERVs) to stop the causes of neurodegenerative and autoimmune diseases, such as multiple sclerosis (MS) and Type 1 diabetes, both of which are in Phase 2 trials, with data expected in 2018.

“The HERV field is a new frontier pioneered by GeNeuro since 2006, based on 15 years of R&D at Institut Mérieux and INSERM,” CEO and co-founder of GeNeuro, Jesús Martin-Garcia, says in an interview with BioTuesdays.

Mr. Martin-Garcia explains that HERVs represent about 8% of the human genome, are normally latent, but may become de-repressed and produce viral proteins. “HERVs may represent the missing link between viral infection and poorly understood diseases,” he adds.

While viruses do not appear to play a direct role in the development of autoimmune diseases, he suggests they may trigger the expression of HERV proteins in the cells they infect, allowing them to replicate. “This expression may include pathogenic HERV proteins, which play a key role in autoimmune and neurodegenerative disorders.”

Viruses triggering HERV Proteins and link to disease

In MS, GeNeuro is testing a therapeutic antibody, GNbAC1, against the envelope protein, pHERV-W Env, which may feed the inflammation and neurodegeneration characteristics of MS. 

“The upstream neutralization of this protein is the first approach against a causative factor of the disease,” Mr. Martin-Garcia points out.

Currently approved MS drugs, which accounted for some $20-billion in 2016 sales, focus on reducing relapse of MS, with an associated impact on the immune system and potential side effects. But eight-of-10 people who are diagnosed with relapsing-remitting MS (RRMS) develop secondary progressive MS (SPMS) and there are no drugs preventing the progression of the disease, he adds. 

According to Mr. Martin-Garcia, pathogenic pHERV-W Env is found in 100% of brain lesions and 75% of MS patients’ blood. The mode of action of pHERV-W Env in MS is to fuel inflammation and neurodegeneration, he contends.

“Our objective is to develop a new treatment able to stop disease progression in all MS forms by enabling the repair mechanism of myelin, which is the key unmet medical need in MS, and reducing the number of relapses in RRMS by neutralizing pro-inflammatory proteins present in the brain, all with an excellent safety profile.”

At the end of 2014, GeNeuro inked a partnership in MS with Servier, a closely- held French company, which is funding the ongoing Phase 2b CHANGE-MS trial. Servier also has an option to acquire a license for GNbAC1 in MS for all territories, excluding the U.S. and Japan, and fund a global Phase 3 trial, including in the U.S. 

GeNeuro, would be in line to receive up to €350 million under a licensing agreement with Servier plus tiered royalties up to the mid-teens on future sales. GeNeuro also would retain rights for GNbAC1 in the U.S. and Japan, which covers 67% of the worldwide MS population, and other GNbAC1 indications.

GeNeuro is scheduled to release 48-week Phase 2b results for GNbAC1 in RRMS patients in the first quarter of 2018 and Mr. Martin-Garcia believes that if the data are positive, a Phase 3 trial could be launched later in the year.

Results of an earlier Phase 2a study on progressive patients were published in the MS Journal in 2014, demonstrating a good safety profile over one year after repeated administrations of GNbAC1, and early signs of clinical benefit.

Specifically, GNbAC1 patients were radiologically stable after one year, with no new lesions or increase in existing lesions. Patients also had stable expanded disability status scale scores, representing levels of disability, over one year.

The CHANGE-MS Phase 2b study is a 48-week placebo-controlled study of 270 RRMS patients in 50 clinical centers in 12 European countries. At the end of 24-weeks, placebo patients were randomized into one of the three treatment arms.

The primary endpoint is an assessment of the efficacy of GNbAC1 based on the cumulative number of inflammatory lesions on brain MRI. Secondary endpoints at 48 weeks will include MRI measures of inflammation and neurodegeneration, clinical parameters, and biomarkers, including the pathogenic protein, pHERV-W Env. 

In October, GeNeuro and Servier presented promising “post hoc” analyses of 24-week data from the Phase 2b study. The results showed an anti-inflammatory effect in active patients at the highest of three doses tested at week 24. In addition, at the same dose, a promising effect on remyelination was observed at 24 weeks.

Mr. Martin-Garcia suggests the results support the hypothesis of a late onset of action of GNbAC1 seen at six months, which could be due to its mode of action through neutralizing pHERV-W Env, without directly modulating or suppressing the immune system of patients, as well as to the time taken to reach a therapeutic concentration of the antibody in the brain.

“We have a number of hypotheses for the late onset of action of GNbAC1,” he says, noting that GNbAC1 has a half-life of one month, and reaches steady state concentration in serum after five-to-six months.

Since GNbAC1 does not modulate or suppress immune cells, he suggests that the effect of neutralizing a protein interacting with innate immunity may take time to show up on inflammatory measures.

GeNeuro also is offering patients completing the CHANGE-MS trial an option to continue treatment with GNbAC1 for 96 weeks in an open label extension study. Close to 95% of CHANGE-MS patients have moved into the extension study, which would give the company additional safety, efficacy and quality-of-life data.

In its Type 1 diabetes program, Mr. Martin-Garcia says data support the hypothesis of a causal role of the pHERV-W Env protein in the disease. Among other things, he notes that the protein was found in the pancreas of more than 60% of patients post-mortem.

GeNeuro currently is enrolling 60 recently diagnosed Type 1 diabetic adults in a Phase 2a placebo-controlled RAINBOW study of GNbAC1 in Australia. The trial should be fully enrolled by the end of 2017, with data released in the third quarter of 2018, he adds.

The primary endpoint of the RAINBOW study is safety. Secondary endpoints include the link between response and pHERV-W biomarkers; efficacy measures to demonstrate maintenance of insulin production; and other Type 1 diabetes-related biomarkers, such as insulin consumption, glycaemia and anti-beta cells antibodies.

“We are very excited about this program because it has the potential to be the first disease modifying therapy for Type 1 diabetes,” Mr. Martin-Garcia suggests.

The company also is preparing a Phase 2a proof-of-concept study with GNbAC1 in patients with chronic inflammatory demyelinating polyneuropathy, an orphan disease, also known as peripheral MS, following the receipt of scientific advice from the European Medicines Agency.

In addition, GeNeuro has a partnership with the NIH to achieve proof-of-concept that its HERV approach can address the pathogenesis of ALS. The company also has ongoing collaborations with research centers in France to develop a HERV approach against inflammatory psychosis.

“There are 26 families of HERVs identified to date and the scientific literature suggests that HERV families are involved in numerous pathologies,” Mr. Martin-Garcia says. “We are leveraging our first mover advantage to create a HERV platform and develop disruptive treatments for numerous additional diseases.”

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Pam Marrone, CEO and founder

Marrone Bio Innovations (NASDAQ:MBII), which recently received EPA approval for its newest biological fungicide, Stargus, is focused on commercializing its two near-term products: a new herbicide for improved weed control and new biofumigant to replace toxic chemicals.

“Our strategy is to provide a full suite of biological solutions across all farmers’ needs,” CEO and founder, Pam Marrone, says in an interview with BioTuesdays. “Both organic farmers and conventional farmers use our products as a key component of their integrated pest management programs."

Stargus is the seventh product commercialized by Marrone Bio in 11 years. “We are the only pure-play public biopesticide company in this disruptive, technology-driven market,” she adds.

In its near-term pipeline, Dr. Marrone says the company has completed R&D and is finalizing toxicology studies for its new herbicide, MBI 014, as part of an ongoing submission to the EPA.

MBI 014 is designed to control hard-to-kill weeds that are resistant to chemicals and for organic farmers who have few tools.

“Our product represents the first new mode-of-action in chemical herbicides in more than 30 years”

The company’s new biofumigant, MBI 601, represents a new genus of fungus discovered in the Honduran rain forest from inside the bark of a cinnamon tree, she adds. “You put it in the soil and it produces gases that fumigate around itself.” The biofumigant, which has been approved by the EPA, is named Ennoble.

In addition, Marrone Bio has at least seven additional products in its pipeline and is seeking partners to continue R&D and potential commercialization, she adds. The company currently has strategic collaborations with Koch Agronomic Services, Albaugh, Groundwork, Nufarm, Syngenta, FMC, Evogene and Isagro USA.

Marrone Bio Innovations current R&D is primarily focused on supporting existing commercial products; however, we have a very robust pipeline of products in queue

Dr. Marrone, who started the company in 2006, explains that biologicals are microorganisms, plant extracts, pheromones, soaps, fatty acids and other natural substances that offer key benefits to manufactures, growers and consumers.

There are three categories of biologicals, including biopesticides, which are used for crop protection and are EPA-registered; biostimulants, which are used for crop health; and biofertilizers, which are used for crop nutrition. Biostimulants and biofertilizers are state controlled. 

Marrone Bio’s product portfolio includes six EPA-registered biopesticides and one biostimulant.
In addition to being environmentally friendly, and improving crop quality and yields, biologicals prevent pest resistance unlike traditional chemicals. Biologicals also do not produce residues, which facilitates their access to export markets.

According to Dr. Marrone, development of biologicals can reach market in some four years, compared with more than 11 years for chemicals. The EPA also grants expedited registration for biologicals. That significantly lowers development costs to less than $10-million for biologicals, compared with nearly $300-million for chemicals, she adds.

Industry surveys peg biopesticides as holding only 5% of the total crop protection market, representing significant room for growth, Dr. Marrone points out. The biopesticide market is growing at a compound annual growth rate of 17.4%, compared with about 2% in the chemical pesticide market. 

“Cannabis growers have been beating down our door,” she suggests, as state legislatures continue to approve recreational use of cannabis. In a study conducted by University of California at Davis, the market for biopesticides in the cannabis industry is estimated to grow from $91-million in 2016 to $1.4-billion in 2021 in California, Oregon, Washington and Colorado, alone.

Marrone Bio’s products are used across all production systems and integrated pest management programs for growers of organic and conventional crops, and those for export markets.

Citing higher returns of investment for growers, she says the company’s Regalia biofungicide has achieved a $1,400 per acre increase in terms of size and weight of strawberries; an increase of 1,000 pounds per acre for rice growers, also with Regalia; an increase in six bushels per acre for corn; and a 10-pound per acre increase for potatoes, including a better grade, with its Majestene bionematicide.

Marrone Bio’s product portfolio also includes Grandevo, the first broad spectrum microbial insecticide in 50 years; Venerate, a new species of insecticidal bacteria, with novel compounds as potent as the best chemicals; Haven, an extract of coconut oil, is designed to reduce sun and water stress on crops, increasing yields and quality; and Stargus, a new strain of Bacillus amyloliquefaciens discovered by MBI, which also controls pathogenic soil fungi. 

Marrone Bio’s Zequanox was discovered by the State of New York and is the industry’s only biological solution for invasive mussels in pipes and lakes. “This is highly effective and selective product but is not in our core market, so we are finalizing an agreement with a large water treatment company to distribute it for us,” Dr. Marrone says.

“Our competitive advantage is taking in-house and in-licensed discoveries quickly to the market and testing and screening the broadest range of targets,” Dr. Marrone contends. 

“Our products stand out because we are a natural product chemistry company (versus just living microbes), just like the pharmaceutical companies that develop drugs from microbes and plant extracts,” she adds. “We optimize that chemistry in manufacturing so every batch has a specific level of the marker compounds that we know are important for efficacy.”

The global biopesticides market is forecast to reach $8.8-billion by 2022, compared with $3.4-billion in 2016. Since Marrone Bio’s products are also used in conventional farming, the current market opportunity for its products exceeds $30-billion. 

In 2012, Marrone Bio purchased a manufacturing plant in Bangor, MI to reduce its reliance on contract manufacturers of its microbes. The company spent nearly $15-million to retrofit the plant.

According to Dr. Marrone, the plant is generating better margins, costs controls and return on investment. It also provides flexible and faster scale-up, and additional control of IP, which includes a portfolio of more than 400 issued and pending patents.

The Marrone Michigan Manufacturing plant currently produces Regalia, Grandevo and Zequanox, with plans to add production of Venerate and Majestene. Planned future additions at the plant include packaging and granulation (on-line in November), larger fermentation tanks and full-scale drying for granules.

For the first half of 2017, product shipments grew 51% to $12.1-million, compared with $8.1-million in the first half a year ago.

In North America, Marrone Bio sells its products through established national and regional distributors, with its sales and technical services specialists conducting on-farm demonstrations of its products to facilitate demand.

Dr. Marrone says that in international markets, where Syngenta distributes the company’s Regalia under a legacy agreement, the company now is working with four regional companies – Nufarm, Jocanima, Disagro, Kenya Biologics and Elephant Vert - to distribute its new products.

“We are focusing our international efforts on countries where we can get fast registration to generate revenue, such has the Philippines, Korea, Mexico and Central America.”

In Europe, she says there is no current fast track for approval of biologicals, even through the EU has eliminated the use of many traditional chemicals in farming, making product registration a lengthy and costly process.

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Dr. Roger Crystal, CEO

As access and use of its NARCAN Nasal Spray for opioid overdose continue to grow, Opiant Pharmaceuticals’ (NASDAQ:OPNT) core focus remains on the development of nasal opioid antagonists for chronic addictions, such as alcohol use disorder (AUD) and bulimia nervosa (BN).

“Addiction is now recognized as a brain disease, yet only one-in-nine addicts is receiving appropriate treatment,” CEO, Dr. Roger Crystal, says in an interview with BioTuesdays. “Going forward, pharmacotherapy should represent a minimum standard-of-care for opioid use disorder (OUD).”

In addition to its own pipeline, Opiant is collaborating with Titan Pharmaceuticals (NASDAQ:TTNP) to explore development of a six-month implant to prevent opioid relapse and overdose in patients with OUD.

“Addiction is now recognized as a brain disease, yet only one-in-nine addicts is receiving appropriate treatment”

“We know that the longer OUD patients are on medical treatment, the far more likely they are to have better long-term outcomes in terms of recovery and reduction in relapse,” Dr. Crystal says. “An opioid antagonist implant of six months duration represents a significant advancement in treatment for this patient population.”

Opiant also has a heroin vaccine in preclinical development, but Dr. Crystal points out that while the product is compelling, “it’s not for tomorrow” and a six-month implant has the potential for a much faster development program.

Dr. Crystal explains that addiction is driven by the brain’s reward center releasing dopamine. Opioids flood the brain with dopamine, leading to misuse and abuse. Opioid antagonists, on the other hand, bind to opiate receptors that modulate and normalize dopamine release. As a result, the feelings of pleasure produced by these substances are blocked.

NARCAN® Nasal Spray is the easiest to use, needle-free and among the least expensive available alternatives

“The advantage of a nasal spray is that it opens the patient population to millions of individuals seeking a better medical treatment than what’s currently offered, so the markets are massive,” he adds.

For example, he points out that the use of injectable naloxone (the medication delivered in NARCAN Nasal Spray, the only FDA-approved nasal naloxone formulation) for opioid overdose is limited to trained personnel, while naloxone delivered as a nasal spray can be used by anyone and can even be co-prescribed alongside opioid painkiller prescriptions – an approach taken by states like Virginia and Vermont, which are now mandating prescribing of naloxone for patients considered at high-risk for opioid overdose.

Leading medical authorities, including the American Medical Association and Centers for Disease Control and Prevention, also recommend co-prescribing.

“If you’re a parent of a teen, who you find in your home unresponsive, using a nasal spray is more intuitive for a non-medically trained person, and therefore a far more attractive route of administration, especially when every second counts,” Dr. Crystal contends.

“Co-prescribing naloxone alongside opioids not only helps reduce the risk of overdose with that prescription, but also places a layperson-friendly naloxone in cabinets and homes across America, providing an on-site, in-home emergency response for overdose caused by any opioid, including heroin and fentanyl,” he adds.

“Not only is NARCAN Nasal Spray an easy-to-use use form of naloxone for opioid overdose, it is also needle-free and among the least expensive of available alternatives, such as injectable naloxone, auto injectors and improvised nasal kits,” according to Dr. Crystal.

NARCAN® Nasal Spray is the easiest to use, needle-free and among the least expensive available alternatives

“NARCAN appears to be the mainstream opioid overdose rescue product across the U.S.,” he adds, especially among first responder organizations such as the police, who are often the first at the scene of an opioid overdose.

Opiant’s NARCAN Nasal Spray is the only FDA-approved naloxone nasal spray for the reversal of opioid overdose. Opiant licensed NARCAN to Adapt Pharma in 2014 and the FDA approved NARCAN in 2015. NARCAN, which has seven FDA Orange Book-listed patents, is also cleared for sale in Canada.

Dr. Crystal points out that based on the licensing agreement with Adapt Pharma, if net sales of NARCAN Nasal Spray hit $75-million for all of 2017, Opiant again should receive royalty and milestone payments from Adapt Pharma in 2018.

In December 2016, Opiant signed a partial royalty monetization deal for NARCAN with SWK Holdings for up to $17.5-million, including a payment of $3.75-million in the third quarter of 2017, which was triggered by NARCAN’s net sales topping $25-million in the first half.

Dr. Crystal says nasal naltrexone (a short-acting opiate and alcohol blocking agent) has the potential to help the 2.2 million patients with AUD who are seeking treatment. Currently, the majority of this population does not take medication because of barriers such as requiring prior detoxification, fear of severe withdrawal symptoms, medication side effects and limited efficacy, he adds.

In its AUD program, Opiant has obtained Phase 1 data for OPNT002, nasal naltrexone. The company has an ongoing development underway for the product, including formulation and aiming to undertake further clinical trials in 2018.

Opiant is pursuing a 505(b)(2) regulatory pathway for OPNT002, which should speed FDA approval, compared to the development costs and timelines associated with the FDA’s review of a new chemical entity.

According to Dr. Crystal, there are nearly 16 million individuals in the U.S. that meet the criteria of AUD, of which 2.2 million are seeking treatment, but only 400,000 receiving pharmacotherapy. “AUD is a massive population with unmet medical needs.”

Dr. Crystal explains that drinking alcohol causes the release of endorphins, which are the body’s endogenous opioids, in the reward center of the brain. Naltrexone, an opioid antagonist, blocks the effects of these endorphins, reducing the downstream release of dopamine so that “patients reduce heavy drinking by blocking the endorphin reward.”

He adds that most existing pharmacotherapies for AUD typically require abstinence prior to beginning medication, so many patients are unwilling to go down this route. For those who choose to take existing medication, he says the drugs are poorly tolerated with limited efficacy so adherence is low.

“The advantage of our OPNT002 nasal spray is that we do not expect prior abstinence and therefore withdrawal, allowing patients to take the nasal spray whenever they have the urge to drink, potentially providing greater control over drinking,” he contends.

With Opiant’s nasal formulation, naltrexone also has the potential to promote fast absorption into the body, compared with the oral medication, Dr. Crystal points out.

Rapid nasal absorption vs oral ensures that the maximum amount of drug is present when it is most needed

The FDA now accepts harm reduction or a reduction in heavy drinking, not abstinence, as an acceptable outcome measure for AUD medications. “With AUD on the rise, this presents an attractive commercial opportunity,” he adds.

Dr. Crystal also points out that there are 2.5 million patients with BN in the U.S., of which 45% are receiving treatment with fluoxetine, but experiencing poor response rates to the medication.

Like alcohol, calorie-dense foods such as those consumed during a typical binge episode, also release endorphins. OPNT001 blocks the effects of these endorphins, so that consuming large quantities of calorie dense foods are no longer rewarding.

In its program for eating disorders, Opiant’s nasal opioid antagonist spray, OPNT001, is being tested in a Phase 2 placebo-controlled study with 80 patients suffering from BN. The primary endpoint for this study, which is being conducted in the UK, is a reduction in binge eating days and a data readout is slated for the second/third quarter of 2018.

In binge eating disorder (BED), a related condition, an earlier proof-of-concept study conducted in Helsinki, OPNT001 demonstrated a significant reduction from baseline bingeing after six months, compared with placebo.

OPNT001 shows promise for Binge Eating Disorder

Although eating disorders affect millions of people, Dr. Crystal says there is only one drug approved for each indication: fluoxetine for BN and Shire’s Vyvanse for BED.

 “As with our other nasal spray programs, we have the potential of improved compliance with on-demand dosing for these conditions,” he adds.

pipeline

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