electroCore focused on U.S. launch of gammaCore for acute treatment of episodic cluster headaches and migraines
Frank Amato, CEO
With FDA approval in hand for its gammaCore Sapphire therapy for the acute treatment of episodic cluster headaches and migraines, electroCore (NASDAQ:ECOR) is now focused on commercialization and reimbursement efforts in the U.S.
“We had two initial goals with our product registry in cluster headache: build advocacy among key opinion leaders to gain clinical experience with our therapy, and gain payer approval of electroCore as a pharmacy benefit,” Frank Amato, CEO, says in an interview with BioTuesdays, noting that the company launched gammaCore nationally on July 1.
“We then set out to leverage our success in cluster headache first to expand into migraine and ultimately use an expedited FDA pathway to expand our labeling claims with new clinical data to other areas of headache,” he adds.
electroCore, which went public in June, has made some early progress on attaining insurance coverage for gammaCore by engaging with more than 50 commercial payers targeting pharmacy benefit coverage.
“We have and are negotiating agreements with commercial payers that we believe, based on estimates, will provide pharmacy benefit reimbursement for at least 17 million lives and could grow to as many as 50 million lives under those agreements by Jan. 1, 2019,” Mr. Amato contends.
The company has established 32 sales territories in major population centers in the U.S. and hopes to scale up to 48 sales territories as it reaches additional insurance coverage agreements.
1st FDA-cleared non-invasive vagus nerve stimulator
gammaCore is the only FDA-cleared non-invasive vagus nerve stimulator for the acute treatment of cluster headache and migraine. In many countries outside the U.S., the therapy has been approved for the prevention and acute use in cluster headache and migraine. Clinical trials demonstrated mild, transient and inherently self-limiting side effects. The company plans to submit a 510(k) application with the FDA before the end of 2018 for the prevention of cluster headache.
Mr. Amato explains that the patient holds the therapy against the side of the neck, over the vagus nerve, for two minutes to stimulate the nerve, at which point the device turns itself off. Patients have the ability to administer as much therapy as they will likely need per day, as directed by their healthcare provider.
The vagus nerve is an important highway of communication between the brain and many parts of the body, and plays an important role in regulating pain. Non-invasive vagus nerve stimulation with gammaCore is believed to help block the pain signals that cause migraines and cluster headache attacks.
According to Mr. Amato, vagus nerve stimulation releases various neurotransmitters in the central nervous system, moderating neural hyperexcitability and pain perception.
electroCore holds more than 140 patents and patent applications, covering all non-invasive, transdermal neuro-stimulation of the neck. Key patents coverage extends through 2033, including high frequency burst signals capable of passing comfortably through the skin and low-pass signal filtration that reduces signal harmonics that cause pain.
Cluster headaches affect 350,000 people in the U.S., with patients incurring bouts of frequent attacks, known as cluster periods, often occurring every other day, and up to eight times a day. Individual attacks can last from 15 minutes to as long as three hours. Typically treated with a combination of high-flow oxygen and triptan injections, the disorder has a suicide rate 20 times greater than the U.S. average.
On the other hand, migraines affect 36 million people in the U.S., with multiple attacks monthly, lasting four-to-72 hours. Mr. Amato says 22 million patients are typically under the care of a physician and are being prescribed a migraine medication, with five million to six million patients referred to secondary care or a neurologist.
Cluster Headache & Migraine
Mr. Amato says migraine represents an estimated addressable market of $3.6-billion in the U.S., with cluster headache at $400-million.
In its PRESTO pivotal trial, where 285 patients were enrolled for acute migraine, 120 patients were treated with gammaCore and achieved statistical significance of pain freedom and pain relief, compared with placebo. Interim results from its PREMIUM pivotal study for migraine prevention demonstrated a reduction in monthly migraine days.
electroCore’s ACT 1 and ACT 2 pivotal trials for acute cluster headache also demonstrated that gammaCore achieved pain relief at 15 minutes for the first attack and pain-free attacks at 15 minutes. In addition, the studies found there were 42% of responders to treatment at 15 minutes in more than 50% of their attacks, compared with 15% in the control group.
“Patients who get relief from our therapy can expect to have a consistent response in pain relief and pain freedom at 15 minutes,” Mr. Amato points out.
In its PREVA pivotal trial for the prevention of cluster headache in 97 patients at 10 sites across Europe. The patients were randomized into two arms: one, using gammaCore plus the standard of care, and the other, the standard of care alone. The study showed 40% of patients using gammaCore, in addition to the standard of care, had a greater than 50% reduction in the number of weekly cluster headache attacks, compared with 8% in patients treated with the standard of care alone.
electroCore also is planning to begin additional pivotal trials in the second half of 2018: migraine in adolescents and migraine prevention.
“What we’ve learned in the short time our therapy has been in the U.S. market is that there are more physicians and patients looking for options beyond the current standard of care,” Mr. Amato says.
“There are 800 physicians now prescribing our product, instead of the 250-to-300 neurologists we were hoping for originally, and some 4,500 patient claims that have been submitted to commercial payers for reimbursement, instead of the 1,000 claims we originally set out to achieve,” he adds.
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Ronen Gadot, CEO
Closely-held elminda’s Brain Networks Analytics (BNA) technology is going beyond genetics, imaging and behavioral tests to unlock brain functioning and how the brain changes over time, combining Big Data and AI-driven analytics in a single technology platform.
“BNA is a validated, reproducible and efficient way to measure brain function. As it grows, it will become the go-to analysis tool to diagnose and predict brain function and a way to measure the impact of therapeutic intervention on the brain,” CEO, Ronen Gadot, says in an interview with BioTuesdays.
“We believe that if you wish to effectively treat something, you first must be able to measure it,” he adds.
However, there are currently no good ways to accurately measure brain functions, such as sensory processing, attention, memory and response precision, he points out. “That was the problem we set out to solve in order to provide early detection of brain disorders and eliminate trial and error from therapeutic interventions of those disorders.”
In addition, he suggests that BNA can help pharmaceutical companies develop new therapies for the brain.
Mr. Gadot, who was selected by the World Economic Forum to serve on a council about the future of neurotechnologies and brain sciences, explains that the input to BNA is a 12-to-50 minute non-invasive standard EEG recording of specific brain functions.
Data are uploaded to the cloud and automatically validated, cleaned and analyzed. The technology interprets brain functions, disorders and the effect of therapeutics, creating customized actionable reports for a physician.
BNA™ - a cloud based software service
“We have collected a very large amount of demographic and clinical data coupled with electrical brain recordings over the past decade in order to determine what is normal brain functioning and abnormal brain functioning,” he adds.
According to Mr. Gadot, elminda’s big database, which is already the world’s largest and continues to grow rapidly, provides “core knowledge-based interpretation of brain activity patterns.” In addition, the company’s AI-driven analytics platform removes “noise” from the EEG signal, extracts clinically relevant information from Big Data through secondary analysis and simplifies an individual’s complex brain activities into actionable clinical insights.
elminda currently has datasets of healthy and unhealthy brain functions from more than 400,000 specific brain recordings, which Mr. Gadot predicts will grow to more than one million by mid-2020.
“As this database grows, we can extract more insights for early detection of brain problems, better diagnosis, and ultimately better treatment and management of brain disorders,” he contends.
BNA has CE Mark approval in Europe, including Israel, with wide coverage for clinical use. In the U.S., BNA has FDA clearance to be used for six brain functions in individuals aged 14-to-25. There are more than 25 clinical sites around the world using BNA.
That early international success hasn’t gone unnoticed. Last year, well-known North American medical technology industry veteran, Arun Menawat, was appointed elminda’s chairman. Dr. Menawat is currently CEO of Profound Medical (TSX:PRN; OTCQX:PRFMF) and, before joining Profound, he led fluorescence imaging pioneer and leader, Novadaq Technologies (acquired by Stryker).
Mr. Gadot says that in the first half of 2019, elminda plans to seek FDA approval to expand the use of BNA for patients up to the age of 85 along with a greater range of brain functions.
The company’s business model is based primarily on charging per test, he says, adding that elminda expects to generate $1-million of revenue in 2018, its first year commercializing BNA.
The BNA technology is covered by 60 issued and pending patents that allow the company to take any electrical physiological data and analyze it to extract diagnostic information.
After considering many applications to use BNA, Mr. Gadot says elminda decided to initially focus on brain wellness and brain disorders, two very large markets with high unmet medical need.
Brain wellness involves “red flagging” people with potential problems so that intervention can take place at an earlier stage. For example, he contends that a lot can be done to delay the onset of dementia. For example, a leading accelerator of dementia is hearing loss, which is easy to treat even though many people delay the use of hearing aids by 10 years, Mr. Gadot notes.
“Including BNA testing as part of an annual physical checkup also can monitor the progress of brain wellness and determine the impact of therapeutic interventions,” he adds. Some 95% of people having annual checkups are healthy, or “at least think they are healthy” and may only need annual follow-ups to monitor their brain functions, he points out.
Regarding brain disorders, the company is initially focused on depression because of its prevalence and the current, ineffective trial and error approach to treatment. Approximately 52% of first prescriptions for depression are ineffective. Mr. Gadot says elminda is developing biomarkers with a predictive value of up to 90% to help determine which drugs and other therapies will work and which will not, and then optimize a treatment by measuring a drug’s effect on the brain after a week or two, way before a clinical effect can be observed. This approach is now being actively utilized in several psychiatric practices.
“BNA also can capture a treatable and reversible cause for cognitive dysfunction consistent with mood disorder, modification and monitoring.” And when BNA red flags someone possibly at risk for significant brain disease, the company can recommend referral to a neurologist for further evaluation. “In all these cases, we are providing valuable information while adding to our database and generating revenue.”
Brain Wellness Testing
In addition to brain wellness solutions, and medical diagnostic and treatment solutions, elminda has partnered with Novartis to use BNA for the development of new brain therapeutics.
Early in its development, elminda partnered with The Villages Health in Florida, which is the world’s largest older-adult community with a population of more than 120,000 people. The partnership has allowed elminda to build a large database of normal and aging brains at five BNA testing locations, and develop a lifetime brain health management service.
“At The Villages community, there is a strong interest to have their insured population tested annually to detect disease early and prevent degeneration because it will lower costs,” Mr. Gadot points out.
elminda also has produced a research study from its modeling of memory functions at The Villages, which has been nominated as a finalist for the Positive Aging Award for Excellence in Research by the American Public Health Association.
Mr. Gadot says the company’s initial commercial target for its Brain Wellness solution is China, which has a mature market for annual check ups and an established payment model for private and corporate insurers. “The Asian market is largely geared to healthy people who would like early detection of problems.”
elminda recently completed a pilot-testing program with iKang Guobin Medical Center in Shanghai and is now discussing collection of the first large China database and a commercial launch that would add BNA testing to annual checkups. elminda also has another client in China and one in Hong Kong.
elminda is often selected to showcase its breakthrough innovation to world leaders
There are more than 400 million annual health checkups conducted in China, growing at more than 10% a year, he points out. Globally, some 2.5 billion people undergo annual health checks, with brain-related disorders affecting more than one billion people.
That success hasn’t gone unnoticed either. Mr. Gadot notes that elminda recently received a proposal for an investment from a strategic Chinese player. “We are also exploring financing options to potentially combine that with a Series D round in the U.S. before ultimately going public on a U.S exchange.”*
In the U.S., Mr. Gadot says elminda intends to market BNA to psychiatric clinics and hospitals, with a traditional health insurance reimbursement-based business model. “People diagnosed with depression would trigger a BNA test to develop a baseline score and determine optimum medications and closely follow-up treatment efficacy.”
According to Mr. Gadot, “the annual health check up market in the U.S. is not a mature market that we can tap into as we are in Asia, but we are exploring how we might establish this.”
The company is conducting pilot programs with several U.S. psychiatric clinics to establish proof of commercial viability of BNA. Within a year of beginning a pilot program at a large Mid-Western psychiatric clinic, the company added a second BNA lab, with a third lab ordered in the third quarter of 2018 in order to increase capacity to 600 tests a month, he adds.
There are two Current Procedural Terminology (CPT) codes set by the American Medical Association for reimbursement of brain activation during an EEG recording and a digital analysis of an EEG, with an average national coverage of $780.
elminda has four U.S. sites that have billed for more than 5,000 cases with a high acceptance rate, he adds. “We are operating within these two CPT codes and have not yet developed our own potential codes that would cover BNA testing. But, we are certainly working on it.”
Mr. Gadot says BNA provides information “unattainable by clinical assessment alone and objectively detects early brain function abnormalities. After all, what is more important than your brain.”
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*This article does not constitute an offer to sell or the solicitation of an offer to buy any securities of elminda, and shall not constitute an offer, solicitation or sale of any security in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.
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Actinium Pharmaceuticals (NYSE American:ATNM) is improving patient access to bone marrow transplants (BMT) and treating cancers with high unmet medical need by combining the precision of sophisticated proteins, with the cell killing ability of alpha-emitting isotopes, to ablate cancer cells and leave healthy tissue intact.
“We’re arming targeted agents, such as monoclonal antibodies, with isotope payloads and essentially creating heat seeking missiles against cancer,” Steve O’Loughlin, principal financial and accounting officer, says in an interview with BioTuesdays.
Actinium is focused on developing targeted therapies to treat diseases, such as acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and multiple myeloma (MM).
Mr. O’Loughlin explains that Actinium’s most advanced product candidate, Iomab-B, was licensed from the Fred Hutchinson Cancer Research Center, and is designed to be used, if approved, in preparing patients for a hematopoietic stem cell transplant, more commonly known as BMT, by conditioning the bone marrow without the need for intense chemotherapy.
Prior to the BMT procedure, physicians administer a conditioning regiment that ablates the bone marrow to destroy cancer cells, makes way for the new donor marrow, and decreases the body’s ability to reject the transplant.
“Often the only potential cure for patients with blood-borne cancers is a BMT,” Mr. O’Loughlin says.
Iomab-B has been granted orphan drug designation for relapsed or refractory AML in senior patients by the FDA and the European Medicines Agency (EMA).
“Currently, the only conditioning for BMT is salvage chemotherapy and/or total body irradiation, both of which really beat the patient up because they are so toxic, and kill healthy tissue,” he adds.
In an MD Anderson Cancer Center outcomes analysis of 100 elderly patients with relapsed or refractory AML, conditioned with salvage chemotherapy and followed by BMT, zero percent of the patients survived at the two-year mark.
On the other hand, Mr. O’Loughlin points out that data from a Phase 2 Fred Hutchinson trial where patients were conditioned with Iomab-B prior to BMT, demonstrated that nearly 20% lived to celebrate their second anniversary, and were told they would most likely die of causes unrelated to AML.
Actinium expects to complete enrollment in 2019 in a 150-patient, Phase 3 SIERRA study of Iomab-B in relapsed or refractory AML in the elderly.
“We are really looking forward to the SIERRA interim results that are expected as early as this fall,” Mr. O’Loughlin says. “Our plan is to file with the FDA in early 2020 and commercialize Iomab-B ourselves.”
In addition to Iomab-B, Mr. O’Loughlin contends that Actinium has created a potentially best-in-class CD33 program. “We’re the only company to have CD33 targeting agents going after multiple disease indications, including AML, MDS and MM.”
CD33 is an antigen found on hematopoietic cells in certain blood cancers. The Actinium CD33 program is currently being studied in five Phase 1 and Phase 2 clinical trials for elderly patients with AML, MDS, and MM.
Mr. O’Loughlin notes that underpinning Actinium’s CD33 program, is its Warhead Enabling (AWE) technology platform, where the company uses differentiated attributes of the potent cytotoxic radioisotope, actimium-225 (AC-225), in conjunction with select targeting agents.
Actinium’s lead AWE product candidate, Actimab-A, is a second-generation therapy from the HuM195-Alpha program developed at Memorial Sloan Kettering Cancer Center, Mr. O’Loughlin says.
“It’s being developed to induce remissions in elderly patients with AML, who lack effective treatment options, and often cannot tolerate the toxicities of standard frontline therapies,” he adds.
Actimab-A has been granted orphan drug designation from both the FDA and the EMA for newly diagnosed AML in elderly patients.
Another CD33 product candidate, Actimab-M, is being studied in a Phase 1 clinical trial for patients with relapsed or refractory MM. The trial will determine a maximum tolerated dose, assess adverse events, measure response rates, progression-free survival, and overall survival.
Mr. O’Loughlin says Actinium has also expanded its CD33 program beyond therapeutic use, and into targeted conditioning, with Actimab-MDS, “to provide treatment for the most difficult-to-treat MDS patients by rapidly and safely bridging them to transplant.”
In a Fred Hutchinson Phase 2 study, high-risk MDS patients were able to go to BMT after only one infusion of Actimab-MDS to condition bone marrow, he adds. “This drug is so targeted, we see very few side effects other than myeloablation, which is the burning out of the patient’s bone marrow, and which is necessary to the procedure.”
Actinium is finalizing discussions with the FDA for Actimab-MDS in order to set a clear path to a pivotal trial, Mr. O’Loughlin says.
Actimab-MDS is currently involved in a Phase 2 trial being conducted in collaboration with the MDS Clinical Research Consortium, which consists of the Cleveland Clinic, Johns Hopkins, Dana-Farber Cancer Institute, MD Anderson Cancer Center and Moffitt Cancer Center.
According to Mr. O’Loughlin, Actinium is the only company worldwide with a multi-product, multi-disease pipeline focused on improved transplant access and outcomes, via significantly enhanced conditioning.
“These are exciting times for Actinium as we’re working toward creating a world-class supply chain, and, by the 2020-21 timeframe, we expect to have two distinct drugs on the market, both of which will be in targeted conditioning but for different indications in 50 of the leading U.S. transplant centers,” he says.
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Andrew Ritter, Co-Founder and CEO
Ritter Pharmaceuticals’ (NASDAQ:RTTR) lead product candidate, RP-G28, which recently entered Phase 3 clinical trials, has the potential to become the first prescription therapy for lactose intolerance, a condition that causes millions worldwide to avoid dairy products.
“While there is no FDA-approved drug for lactose intolerance, surveys have shown that 60% of patients, and there are 40 million of them in the U.S., are seeking a better solution,” Andrew Ritter, co-founder and CEO, says in an interview with BioTuesdays.
“Lactose supplements are only modestly effective and work for short periods of time,” he points out, adding that it is challenging to consistently avoid all dairy products because hidden lactose in foods can cause unexpected symptoms. “Even physicians agree that current over-the-counter options to manage lactose intolerance do not work well for many people.”
RP-G28 is a powder to be mixed with water and taken twice daily during a 30-day course of treatment. “Early results suggest that one course of treatment may provide long-lasting, durable relief. And assessment of re-treatment safety and efficacy is underway,” he suggests.
Mr. Ritter explains that lactose intolerance symptoms in the GI tract are the result of bacteria in the gut fermenting lactose and causing gas production. The excess gas production can lead to symptoms of abdominal pain, bloating, flatulence, cramping and water retention in the gut can lead to diarrhea.
RP-G28 modulates the gut microbiome and is designed to stimulate the growth of lactose-metabolizing bacteria in the colon, he contends. As a result, lactose is broken down, reducing gas production and water retention, which in turn, reduces the gastric symptoms associated with lactose intolerance.
Mechanism of Action – Microbiome Modulation
“From a durability of treatment standpoint, we believe these metabolites and bacteria continue to thrive as patients consume dairy products, which, in turn, continues to feed the bacteria,” he points out. “As long as you maintain a normal diet without disrupting the gut flora, we expect patients to be able to maintain tolerance.”
The company estimates that 20% to 30% of patients may need a re-treatment with RP-G28 following some sort of gut-disrupting episode, such as taking antibiotics or not eating dairy for a long time. “But all things being equal, most patients should remain tolerant for a long time,” Mr. Ritter says.
Of the 40 million people in the U.S. with lactose intolerance, some nine million are moderate-to-severe patients, which Mr. Ritter says would be the company’s initial target market. The estimated incidence of lactose intolerance in Europe is 65 million people, with 90 million in Japan.
Mr. Ritter co-founded Ritter Pharmaceuticals in 2007 as a result of his own personal affliction with lactose intolerance. So he enlisted a team of clinical, manufacturing, and regulatory professionals to develop RP-G28. Since 2014, he has served as the company’s president, and was appointed CEO in June 2018.
The company has more than 30 global formulation, methods of use and manufacturing patents, with 15 patent applications pending. Most patents expire in 2030. However, additional pending claims may extend patent life much further. As a new chemical entity, RP-G28 may be entitled to periods of regulatory market exclusivity in the U.S. and Europe, if approved.
In an earlier Phase 2a study with 62 patients, the company established the mode of action for RP-G28, the concept of “colonic adaptation,” as well as no serious adverse events. The findings were published in the peer-reviewed journal, the Proceedings of the National Academy of Sciences in 2017.
A subsequent Phase 2b study with 377 patients established efficacy, an optimal dose and a safety profile for RP-G28. The primary endpoint was the proportion of patients that had a meaningful reduction in lactose intolerance.
On analysis of the clinical trial, the company found that after a for-cause-audit, one of its 15 study centers differed in not following good clinical practices, and as a result, the trial narrowly missed statistical significance. “When we pulled this center’s data out of the results assessment, we analyzed the remaining subset of 296 patients from 14 study sites, and this subset met the trial’s primary endpoint with a statistically significant result,” Mr. Ritter notes.
In addition, this subset demonstrated a 14-percentage point difference in efficacy between RP-G28 and placebo in the Phase 2b trial, which compared favorably to recently FDA-approved GI drugs that average an 11-percentage point difference from placebo, he adds.
Among secondary endpoints, the Phase 2b trial found that a significant percent of treated patients reported elimination of lactose intolerance symptoms, compared with placebo. In addition, treated patients nearly doubled their consumption of milk and had improved quality of life.
According to Mr. Ritter, the gut microbiome data from the Phase 2b study also demonstrated that RP-G28 had a dramatic increase in the species of bifidobacterium in the GI tract, compared with placebo. These results were consistent with the Phase 2a study results.
Phase 2b: Secondary Endpoints
“As we learn more about how our product is doing in the gut, we believe it has great potential in other GI diseases as well. Thus, we are starting to explore additional indications,” he adds.
At the end of June, Ritter began its first Phase 3 trial with design input from the FDA, which includes, among other things, real-time data monitoring to help ensure site and data quality.
The purpose of the initial pivotal study is to determine the efficacy, safety and tolerability of RP-G28 to treat lactose intolerance, compared with placebo, with an estimated enrollment of 525 patients across approximately 28 sites in the U.S.
The protocol design includes a two-week screening period, a randomized 30-day drug treatment period and a 90-day period to assess drug response and durability of effect after treatment, as patients consume their normal diets, including dairy products.
Phase 3: Clinical Trial Protocol Design
There will be a second re-randomized, 30-day drug treatment period to assess safety and efficacy of a repeat round of therapy. The primary endpoint will be the mean change in lactose intolerance symptom composite score post-treatment, compared with baseline. The company expects to report results from the large-scale clinical trial in the second half of 2019.
“Our focus is to partner RP-G28 with a commercial company that has a specialty in GI diseases,” Mr. Ritter says, adding that the company is in various stages of discussions with potential partners.
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