Parimal Nathwani, President and CEO

Closely-held Vasomune Therapeutics found the right partner last month in AnGes (TYO:4563) to co-develop its Vasculotide drug candidate for the treatment of diseases associated with blood vessel leakage and pulmonary inflammation, with a lead program in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS).

“This is a nice fit because AnGes is committed to developing truly novel biotherapeutics medicines, which directly aligns with Vasomune’s objectives,” Parimal Nathwani, president and CEO of Vasomune, says in an interview with BioTuesdays.

“We will lead the execution and commercialization plan to develop Vasculotide through joint steering committees organized by the two companies,” he adds. “It is a true collaboration rather than a hand-over of the molecule.”

Under the accord, AnGes will provide Vasomune with multimillion-dollar co-development contributions, including upfront and clinical milestone fees. The initial objective of the partnership is to achieve human proof of concept in ARDS, for which there is no approved effective targeted therapeutic currently.

“We decided to go after lung injury as an initial indication because the current formulation of Vasculotide lends itself to intravenous administration in a critical care setting,” Mr. Nathwani suggests.

Vasomune, a spin out from Sunnybrook Hospital and MaRS Innovation in Toronto, has completed preclinical efficacy studies with Vasculotide and is now preparing to move into IND-enabling studies, with the goal of beginning human studies in 2020.

Fundamental Problem - Vascular Leakage and Destabilization

ARDS, for example, is characterized by widespread inflammation in the lungs, resulting in leakage of fluid from capillaries in the lungs into the alveoli where blood is oxygenated. The fluid keeps the lungs from filling with enough air, resulting in less oxygen reaching the bloodstream, which can lead to organ failure and death.

In addition, he points out that 10% of all intensive care unit admissions are for ARDS and the mortality rate for these patients from vascular leakage and pulmonary inflammation is 30% to 45%, “which is what we are targeting.” Survivors often suffer long-term mental and physical problems. 

The annual incidence of ARDS is nearly 300,000 in the U.S. and 170,000 in Europe, resulting in a market opportunity of greater than $2-billion based on competitive treatment costs. In addition, he notes that pathologies associated with lung injury are very high in Asia, relative to other parts of the world. 

“The transaction is structured in a way that allows either party to create a sales and marketing organization as part of this deal to commercialize the technology,” Mr. Nathwani says.

According to Mr. Nathwani, vascular leakage and destabilization is a runaway inflammatory response for many clinical indications with significant unmet medical needs, including ALI/ARDS, acute kidney injury, hemorrhagic shock, cutaneous burns, atopic dermatitis, diabetic wound healing, diabetic stroke and vascular dementia.

“We have preclinical data for all of these indications,” he says, adding that some of these indications would require different formulations of Vasculotide to support an optimal target product profile. The accord with AnGes provides options for continued development after proof of concept in ARDS and expansion to other indications. 

Vasculotide Mechanism of Action

Mr. Nathwani explains that Vasculotide is a Tie2 receptor agonist. The Tie2 receptor is expressed on the surface of endothelial cells, which line blood vessels. “This receptor can’t be directly targeted by traditional small molecules, so we think we have a unique advantage with our molecule.”

In addition to a high degree of specificity and wide therapeutic window, Vasculotide has shown efficacy at low doses, so “we don’t anticipate toxicity as a function of dose,” he adds.

Vasomune in January 2017 filed a new patent application based on a modification of its original Tie2 agonist, which is covered under a 2007 patent in North America and Europe. 

“This modification represents our clinical candidate going forward and should provide international protection on its clinical composition, methods and uses out to 2037,” he contends.

Mr. Nathwani explains that many pathogens can cause ARDS, such as influenza, SARS, MERS, bacterial pneumonia, malaria, tuberculosis and anthrax. “We don’t target the bug but rather target the pathology of the host vasculature, irrespective of the bug causing the lung injury. So we are not affected by resistance like bug-targeting agents.”

Vasomune has published data in three preclinical models of ALI, including influenza-induced ARDS, pneumococcal pneumonia and lipopolysaccharide-induced endotoxemia. “In all cases, we’ve seen enhanced survival and oxygenation, and decreased fluid in the lungs and capillary leakage,” he adds.

In preparation for clinical development, Mr. Nathwani says the company has dealt with most its pharmacology issues as well as chemistry, manufacturing and controls, including an agreement with a GMP company for the production of pilot toxicology batches.

“Our ongoing focus for 2018 and 2019 is pharmacokinetics and toxicology programs for IND-enabling studies in preparation for our Phase 1 study in 2020,” he adds. “We hope to have a pre-IND meeting with the FDA in the first half of 2019.”

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To connect with Vasomune, or any of the other companies featured on BioTuesdays, send us an email at editor@biotuesdays.com.

David Gonyer, President and CEO

Evoke Pharma’s (NASDAQ:EVOK) discovery that its metoclopramide nasal spray, known as Gimoti, to treat symptoms of gastroparesis, a delayed emptying of stomach contents, reduced symptoms in women, but not in men, and that metoclopramide has significantly different exposure in men, compared with women, led the company to file a female-only NDA with the FDA in June.

Last week, the FDA accepted the NDA for review and set a PDUFA date of April 1, 2019 for a decision on the application.

“Unlike Reglan, the approved oral medication for gastroparesis, nasal delivery of Gimoti has been shown to bypass the gastrointestinal tract and directly enters the bloodstream,” David Gonyer, president and CEO, says in an interview with BioTuesdays.

Mr. Gonyer explains that Gimoti is similar to the approved oral formulation of metoclopramide but with a new mode of delivery. “Nasal delivery of metoclopramide has the potential for predictable absorption regardless of gastric emptying delays and symptom relief even during flares,” he adds, noting that absorption via a nasal spray would not be affected by patient nausea and vomiting.

In December 2016, the FDA agreed that a pharmacokinetic (PK) trial of Gimoti could serve as the basis for a 505(b)(2) NDA submission, along with efficacy and safety data from earlier clinical trials. Gimoti met comparative bioavailability criteria in a PK study, compared with Reglan, the reference listed drug.

“As we analyzed the PK data, we found significantly lower levels of the drug in men, compared with women, that could not be explained by body mass or weight, regardless of the route of administration of the drug,” he recalls. The company has filed new patent applications related to the discovery.

Mr. Gonyer points out that differences in metoclopramide PK measurements between women and men, regardless of the route of administration, were also found in a retrospective analysis of data from an earlier PK study conducted by the company.

Evoke’s female-only NDA for the treatment of gastroparesis is based on a dose in women equivalent to Reglan tablets. The filing also included supporting efficacy and safety data from earlier Phase 2b and Phase 3 trials, specifically for women, as well as plans for a post-approval safety study. Evoke is hoping for FDA approval of Gimoti during the first half of 2019.

FDA Meetings: Pathway to an NDA

There are some 12 million to 16 million patients with symptoms of gastroparesis in the U.S., of which 80% are women, with only one FDA-approved drug. However, delayed emptying of the contents in the stomach into the small intestine, in the absence of an obstruction, interferers with the oral drug’s absorption. 

“This is clearly an unmet clinical need,” Mr. Gonyer contends, noting that the prevalence of the disorder is rising because of the growing number of patients with diabetes, a leading cause of gastroparesis.

He suggests that only an estimated two million to three million patients are now receiving treatment for gastroparesis, resulting in some four million prescriptions of oral metoclopramide written annually. “This is the market we would go after initially,” he suggests, adding that the estimated prescription market for gastroparesis could reach $4-billion.

Symptoms of the disorder include nausea, abdominal pain, early satiety, bloating, prolonged fullness and vomiting, which can further complicate with the effectiveness of Reglan tablets.

The impact on patients includes diminished quality of life, malnourishment, poor diabetes control and hospitalizations that can average six days at costs of $3.5-million in 2004, the latest year for which figures are available, Mr. Gonyer points out.

Evoke has patent protection for a nasal administration of metoclopramide to treat symptoms associated with gastroparesis and nasal formulations of metoclopramide, and has filed patents to cover gender differences of gastroparesis that would expire in 2032.

Mr. Gonyer points out that Evoke currently is putting the initial steps in place to commercialize Gimoti. “We have developed considerable chemistry, manufacturing and controls data, three years of product stability and a commercial agreement with a contract manufacturer.”

In addition, he says the company has an ongoing relationship with Syneos Health to arrange a commercial infrastructure for sales and marketing. 

There are about 7,200 metoclopramide prescribing gastroenterologists in the U.S., which would require a small sales force of 50-to-100 people, he suggests. “Market research shows that physicians understand that a nasal delivery may improve absorption and provide faster absorption of metoclopramide, compared with the oral product, and may allow patients with vomiting to absorb the medication.” 

According to Mr. Gonyer, Gimoti should be widely available to members of commercial insurance plans, with Tier 3 “unrestricted” or “restricted” coverage, which is typical for branded products. In addition, reimbursement would likely take into account a lack of competitive products, a large unmet medical need and a potential reduction in hospitalization costs, he adds.

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To connect with Evoke, or any of the other companies featured on BioTuesdays, send us an email at editor@biotuesdays.com.

Daniel Cohen, Co-founder and CEO

A new drug discovery paradigm, PLEOTHERAPY, developed by Pharnext SA (FR0011191287-ALPHA) is based on big genomic data, artificial intelligence, and rigorous experimental analysis that involves innovative combinations of repositioned drugs, called PLEODRUGs, to treat orphan and common neurodegenerative diseases with high unmet medical needs.

“We’re systemizing new uses of FDA approved drugs to develop PLEODRUGs quickly, inexpensively, and with robust intellectual property, including several composition of matter patents already granted,” Dr. Daniel Cohen, co-founder and CEO, says in an interview with BioTuesdays. 

Paris-based Pharnext’s concept in drug development is centered on network pharmacology, utilizing complex and extensive genomic data to identify the thousands of molecules possibly involved in a disease, and then develop a customized approach to treatment.

Dr. Cohen explains that most diseases have more than one target, “so to simultaneously aim at several disease pathways, we deduce synergistic combinations of drugs approved for unrelated indications from the disease molecular network, and then formulate PLEODRUGs at new optimal, lower doses of their individual components.”

A PLEODRUG is then tested on humans through a full clinical development plan.

Dr. Cohen, who has been at the forefront of genetic research for over 30 years, says that our bodies are complex networks of molecules that are interconnected, physically and functionally, with fragilized zones in certain diseases, in certain patients. 

Various diseases share certain fragilized zones, such as Alzheimer’s and diabetes, or Alzheimer’s and amyotrophic lateral sclerosis (ALS), he notes. “We mine genetic variants from big data to identify fragilized zones, and then look at which zones are targets of known drugs.” By repurposing known drugs, combined with their proprietary data analysis, Pharnext is trimming as much as seven years off of the typical 15-to-20-year approval process, Dr. Cohen says.

“We are working with drugs that have already been established as safe,” he adds.

World-renowned scientists, including Nobel Prize laureates, Jean-Marie Lehn and Eric Kandel, have validated PLEOTHERAPY. 

Two lead PLEODRUG products currently in clinical development, PXT3003 and PXT864, were recently issued composition of matter patents by U.S. and European patent offices, “confirming the recognition of PLEODRUGs as new products,” Dr. Cohen points out. 

Proof of concept of the PLEOTHERAPY approach was obtained with PXT3003 for Charcot-Marie-Tooth disease type 1A (CMT1A) through positive Phase 2 results in 2014. “We are very encouraged, as patients’ abilities were shown to improve over time,” he says.

CMT1A is a rare, debilitative neurogenerative disease with high unmet medical needs. 

Dr. Cohen describes PXT3003 as a novel oral, fixed, low-dose combination of baclofen, naltrexone, and sorbitol, with orphan drug designation in Europe and U.S.

“A PXT3003 Phase 3 clinical trial, initiated in 2015, is currently ongoing in 323 patients with CMT1A at 30 sites across Europe, U.S. and Canada,” he says. “We are very anxious to get the topline results, which we expect by October 2018.”

Last month, Pharnext received agreement from the European Medicines Agency (EMA) for its pediatric investigation plan (PIP) for PXT3003 in CMT1A. 

“Much of the progression of this disease occurs in the first two decades of a patient’s life, so by intervening in childhood, we can have a greater impact on the disease trajectory,” Dr. Cohen explains.

EMA agreement with the PIP is required before a company can file a marketing authorization application for any new medicinal product in Europe.

The clinical study investigating the safety and efficacy of PXT3003 for CMT1A in children will be initiated in Europe, Canada and U.S. in late in 2018. 

Pharnext’s second PLEODRUG, PXT864, also generated positive Phase 2 data in Alzheimer’s disease during a clinical trial conducted in seven French memory centers, from 2013 to 2015. 

“These findings are evidence of PXT864 safety and efficacy in patients suffering from mild stages of Alzheimer’s disease, and could be a turning point in the effort to provide treatment for patients afflicted with this terrible disease, as we saw improvement beyond stabilization with a decrease in [patient] decline,” he contends. 

PXT864 is a rational-design, synergic, fixed combination of baclofen and acamprosate given orally as a capsule twice a day. 

According to Dr. Cohen, further Phase 2 studies are planned for PXT864 in Alzheimer’s disease.

“There’s an overflow of data out there, but there is a lot of missing data too,” he says. “We educate the computer with data, infer output, train the computer to look for new targets and then repurpose the drugs for broad use.”

While the Pharnext pipeline potential includes multiple indications, the company’s near future plans are to develop the same PXT864 in other orphan and common neurodegenerative diseases, such as Parkinson’s disease and ALS. 

“PLEOTHERAPY could be the magic bullet,” Dr. Cohen says. “It is universally applicable to any disease or compound, regardless of development stage or lifecycle status.”

Expected Upcoming Milestones

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To connect with Pharnext, or any of the other companies featured on BioTuesdays, send us an email at editor@biotuesdays.com.

David Giljohann, CEO

Exicure (OTCQB:XCUR) expects to report data around the end of the third quarter of 2018 from two Phase 1 clinical trials, one in mild-to-moderate psoriasis and one in healthy volunteers with its lead spherical nucleic acid (SNA) drug candidates.

“Data from our immuno-oncology trial in the UK are pending, and we plan to begin a U.S. Phase 1b/2 trial of AST-008 in combination with a checkpoint inhibitor before the end of 2018,” CEO, David Giljohann, says in an interview with BioTuesdays.

Dr. Giljohann explains that Exicure’s SNA technology consists of approximately 40 strands of synthetic DNA or RNA densely packed on the outside of a nanoparticle in order to address existing challenges in developing and delivery of nucleic acid therapeutics. 

Exicure’s Proprietary Technology: Spherical Nucleic Acids (SNA)

“This SNA architecture is what drives delivery of the payload into cells and how we differentiate ourselves in the nucleic acid space,” he adds. “We believe this ‘inside out’ architecture has never been done before.”

Exicure has built a broad IP portfolio protecting its SNA technology and has developed a large pipeline of SNA drug candidates for indications in dermatology, immunology, oncology, neurology, ophthalmology, respiratory and gastrointestinal diseases.

Development Pipeline

Lead programs include XCUR17, a topical gel designed to reduce the expression of the IL17RA gene for the treatment of psoriasis, and AST-008, which is designed to activate TLR9 and utilize the beneficial properties of SNA to drive a potent anti-cancer immune response.

The company also has demonstrated in preclinical models, superior efficacy and less toxicity of its SNA platform, compared with Spinraza, for the treatment of spinal muscular atrophy (SMA) and neurological diseases. Spinraza is the first drug approved to treat SMA, a devastating genetic disease.

In December 2016, Exicure inked a strategic research collaboration, option and license agreement, valued at more than $760-million, with Purdue Pharma to develop a treatment for psoriasis and other diseases that lend themselves to a gene regulation approach with Exicure’s SNA technology.

The Purdue accord covers four programs including, worldwide development and commercial rights to Exicure’s AST-005, which has completed a Phase 1b dermatology trial as well as the associated intellectual property.

“We believe Exicure has the potential to become a powerful player in the rising nucleic acid therapy space,” analyst Wangzhi Li of Ladenburg Thalmann said in an initiation report in July.

“The company has discovered that its spherical 3-D structure leads to transformational new properties that can address current challenges in developing nucleic acid therapeutics,” Mr. Li added.

Exicure’s U.S. Phase 1b/2 trial of AST-008 in combination with checkpoint inhibitors will include patients with a basket of cancers including, melanoma, and head and neck, who are refractory to standard of care with checkpoint inhibitors. The therapy will include intratumoral and lymphatic injections and the first of the trial data should be available in late 2019 or early 2020.

Dr. Giljohann points out that a number of “linear TLR9 therapies” in combination with checkpoint inhibitors have shown significantly improved response in new and patients refractory to checkpoint inhibitors. “However, our 3-D architecture may have advantages over other TLR9 agonists by virtue of entering cancer cells faster, with more stability and higher potency.”

He says the company has demonstrated efficacy of AST-008 in preclinical models of breast, lung, melanoma, colorectal and lymphoma cancers, with “activity as a monotherapy and better efficacy in combination with checkpoint inhibitors.”

In its preclinical SMA program, Dr. Giljohann says mice treated with Exicure’s Spinraza-SNA had fourfold prolonged survival out to 115 days, compared with 28 days for Spinraza alone, and also mitigated the toxicity associated with Spinraza. The company hopes to begin human testing in 2019.

“Our higher potency version of Spinraza in the SNA has the potential for less frequent injections, compared with Spinraza alone, and a better uptake profile that could enable targeting of peripheral tissue,” he adds.

In addition, the Exicure technology could be used in other neuromuscular disorders, such as Duchenne muscular dystrophy, Huntington’s disease and other genetic rare diseases.

Exicure’s XCUR17 is a topically applied gel, targeting the IL-17 receptor alpha. IL-17 is a cytokine that has been linked to activating the skin inflammation of psoriasis.

In a Phase 1 trial in Germany, some 25 patients are receiving topical applications of XCUR17 gel over 26 days to study safety and tolerability, biomarkers and skin histology. Results are expected at the end of the third quarter of 2018.

There are 7.5 million people in the U.S. affected with psoriasis, of which some six million have mild-to-moderate disease, which is the target population of XCUR17. “These patients are generally not treated with systemic antibody therapy and there are significant side effects with current topical therapies” Dr. Giljohann suggests.

Dr. Giljohann says the company plans to leverage its SNA platform through partnering opportunities across other therapeutic area. “We have data sets showing that we can potentially deliver the SNA technology as eye drops, a nebulizer for lung indications and orally to knock down genes in GI tissue, including preclinical models of inflammatory bowel disease.”

Better Delivery Leads to Broader Applications

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To connect with Exicure, or any of the other companies featured on BioTuesdays, send us an email at editor@biotuesdays.com.