RMJH is seeking investment funds with which to conduct a Phase 3 clinical trial, the parameters of which have been agreed to by the U.S. Food and Drug Administration (FDA). RMJ Holdings LLC (RMJH) is a private Limited Liability Company domiciled in Virginia. Its mission is to develop promising repurposed drug candidates and to license them to well-funded alliance partners for commercialization, marketing and sales.
RMJH-111b is a post phase 2, phase 3 ready de-risked drug candidate. The novelty includes a patented inverted micellar technology to enhance uptake and target delivery of magnesium, an essential yet often deficient cell mineral. RMJH initial development focus is hypertension with a ‘first in class’ high value treatment. RMJH-111b is the first novel approach to manage hypertension in decades, combining technology with novel chemistry. Additional drug indications form a platform in cardiovascular medicine as well as offering an additional pipeline of drug indications described below. RMJH is utilizing the 505(b)(2) pathway for speed and economy.
The provisions of 505(b)(2) were created by the Hatch-Waxman Amendments of the Federal Food, Drug and Cosmetic Act, in part, to avoid unnecessary duplication of studies already performed on a previously approved (“reference” or “listed”) drug. The section gives FDA express permission to rely on data not developed by the NDA applicant regarding safety and efficacy. This results in a much less expensive and much faster route to approval, compared with a traditional development path while creating new, differentiated products with tremendous commercial value.
Practically every approved hypertension medication is known to impair magnesium uptake and/or increase its loss from the body. Two in three Americans are magnesium deficient. RMJH has exclusive worldwide pharmaceutical development rights to a fundamental, composition of matter patent (8,017,160) issued in Sept 2011 and expiring in 2027 that covers enhanced uptake and chaperoned delivery of oral magnesium to cells functionally impaired due to deficits in this required electrolyte.
A recently completed successful Phase 1 / 2 clinical trial under US IND 116966 for RMJH-111b included use of a novel softgel technology for which formula development is complete. The drug candidate has two plus years of stability confirmed under accelerated degradation conditions. This means an adequate shelf life for commercialization.
Results of the successful initial trial show that in just one week on RMJH-111b, blood pressure reduction (net 6 – 9 mm) exceeded what previous studies took 12 weeks to achieve. No intestinal or other adverse events were observed. This indicates encouraging safety and tolerability of 440 mg elemental magnesium taken twice daily to promptly replenish and maintain cell magnesium.
This is fundamental technology that ‘reinvents’ magnesium through novel uptake and cell delivery of ‘MAGique™ droplets’.
Company analysis suggests the improvement in blood pressure and blood vessel compliance seen in one week is a third of the potential total benefit. The projection is that benefits are likely to plateau in 6 – 8 weeks. This is based on changes in body exchangeable magnesium levels using a hypothetical model developed by RMJ Holdings scientists.
There has been a chorus of recent calls for safer, more effective blood pressure medications. The initial market is the 25 million Americans prescribed diuretics (thiazides). The shortest path to an initial new category of drug approval is as an adjunct to improve outcomes and reduce adverse effects of another approved, chronic use medication which is the foundation of our strategy.
Assuming a modest introductory price to increase market share and acceptance, the initial addressable annual revenue is calculated at $30 Billion globally with half from the United States. Based on a modest 15% market share in the United States revenue and a 10% royalty on gross net sales by the alliance licensing partner based on a drug price of $100 per month, United States royalty revenue of $225 Million annually is anticipated.
The potential market for all RMJH-111b drug indications is about ten times the initial market. The challenge is to execute a superior final, pivotal trial that addresses both agency and stakeholder needs. Results aim to affirm a superior, novel medication that can be used alone, in combination with other medications and as part of poly-pills. By cooperating through combinations with other medications and reducing their adverse effects, the peak sales are thus extended from 4 – 5 years to 8 – 10 years.
Supplemental NDAs are anticipated for four cardiovascular indications and special populations after the initial drug approval as agreed with FDA. The cardiovascular platform of indications includes atrial fibrillation, coronary insufficiency, resistant hypertension and heart failure.
The broader pipeline due to magnesium cell deficiencies co-exist with diabetes, metabolic syndrome, osteopenia and osteoporosis, eclampsia of pregnancy, migraine headaches, and sickle cell anemia (an orphan drug candidate), and as an adjunct to IV Mg in platinum-containing chemotherapy patients. Each indication can be licensed within its clinical indications through abbreviated and supplemental NDAs to promptly monetize the entire platform and pipeline of additional indications, each of which can be tracked separately, if necessary, with different alliance partners.
RMJH is negotiating with national clinical research organizations (CRO) on the budget and logistical details of the phase 3 trial. With validation of budget assumptions and agreement on interim funding milestones of the upcoming trial available, the pivotal Phase 3 trial is designed to start in 2019 and be complete within a year. The company is seeking $20 million to be disbursed based on milestones accomplished in exchange for 20 percent equity or an equivalent convertible instrument.
Appendix: Stakeholder issues and analysis
Stakeholder issues that the company has anticipated and analyzed include:
1. Thought leaders:
RMJH has assembled a knowledge network that includes most of the current and rising clinical trial hypertension thought leaders, each of whom contributed specialized expertise to the pivotal trial final design. As a scientific team led by Drs. Harry Gavras1, Ron Elin2, George Bakrii3, Peter Feig4, and Bill Weglicki5, our professional network includes members of the advisory committee to the CardioRenal section of FDA as well as members of such as the American Heart Association and American College of Cardiology organizations that issue hypertension guidelines. Regulatory agencies, governmental agencies, journalists and private think tanks tend to follow and conform to such professional society guidelines. RMJH-111b is acknowledged by FDA to be a novel calcium channel blocker that uniquely affects the smallest blood vessels (microvasculature).
Most physicians want safer, more effective, high value medications. Clinician behavior is influenced by presentations at their medical society meetings, articles in their medical journals, and continuing education in the community. The pivotal Phase 3 trial includes information about effectiveness, safety, tolerability and adaptation as well as clinically useful assessments and participant case examples. The RMJH network of thought leaders will be a valuable resource in the strategic plan for communicating the news about safer, well documented, effective treatments, initially for blood pressure and as resources permit, each of the other indications and special populations that provide an increasingly robust support for healthier, and more resilient microvasculature.
Much chronic ill health is fundamentally a deficiency of magnesium inside cells with cascades of adverse consequences. Twenty-first century life is contributing to an epidemic of magnesium deficiency that impair quality of life, shorten life-span treatment resistance.
According to magnesium researcher Dr. Ronald Elin2, availability of magnesium in the human diet has fallen by about half in the last 50 years, while need for magnesium has more than doubled. Loss of magnesium is accelerated by stress hormones, processed foods, many common medications including stomach acid blockers, many oncology drugs, diuretics and other anti-hypertensive medications. RMJH-111b shows promise to be more effective by bringing together novel enhanced uptake, chaperoned delivery and softgels.
Most people with moderate hypertension want to lower their blood pressure without feeling worse in some other way. As with any new drug category, consumer education will need to be a focus of the strategic communication plan. The Phase 3 trial data can provide a compelling message for millions of consumers looking for safer more tolerable alternatives to their current medications. Consumers have been educated about the unique value of distilled fish oils as medications. They will similarly be educated on advanced delivery of magnesium as a safer alternative to the current standards of care.
4. Regulators and policy experts:
Generally, the guidelines from professional hypertension societies and comments from the advisory committee to FDA CardioRenal section are the basis of regulatory and policy decisions. The hypertension thought leaders engaged in RMJH-111b development will be poised to contribute to incorporating the new drug into clinical treatment guidelines issued by major cardiovascular societies.
The largest payers by far are Medicare (CMS) and Medicaid. At the moment, because there is nothing novel or proprietary, payment is based on the lowest bid that meets the quality standards. In other categories where there is a patented approved drug, the basis for payment is value. Value-based payments are based on a mix of how well tolerated, how effective and how robust are the data upon which approval is based. This phase 3 pivotal trial is well designed to meet and exceed such needs through tactically targeted assessments. In addition, payers usually follow the guidelines as issued by the appropriate medical societies’ consensus panels and standards of care.
Communicating a consistent message of safer, more effective results is always a beginning. Presentations by our knowledge network at high impact medical society meetings along with interviews on selected health and business channels can help add to demand for this breakthrough product family.
There are several strategic, tactical and logistical issues that demonstrate the extent to which this opportunity has been proactively de-risked:
1. Why is this inverted micellar nanodroplet so different from all other forms of the electrolyte?
The core technology reverses the polarity of the electrical charge, allowing this drug candidate the ability to be taken up more completely through neutral pores, and then have the needed mineral chaperoned to the cells in need. The usual ion channel used in other magnesium delivery systems (the calcium magnesium ATPase uptake path) is easily inhibited by toxic minerals, lack of magnesium in the diet and by certain hormone disrupting persisting pollutants, resulting in magnesium build-up in the intestines and consequent uncomfortable diarrhea.
2. How will different audiences be addressed during the proprietary window afforded to a ‘first in class’ approved medication?
Stakeholder perspectives are largely addressed in the above discussion of the stakeholder groups. Each stakeholder group has special interests and needs that have been incorporated into the design of the pivotal trial either as end points or as assessments.
Sufficient magnesium is essential for healthy, low risk living. Chronic latent magnesium deficiency (CLMD) has been defined as being in the lower half of the usual lab range for serum magnesium. The appropriate goal is to have sufficient magnesium that means being in the upper half of the usual lab range. It is also critical from a safety standpoint to not go above the usual lab range in people with moderate or better kidney function. (People with chronic kidney disease are a special population to be studied after the initial drug approval.) FDA agrees with RMJH that all special populations can be studied after RMJH-111b is approved initially as an adjunct to diuretics which is a chronically utilized medication. Such a use will expedite its approval and shorten the pathway to the market.. This is included in the minutes of the end of phase 2 (‘type B’) meeting with FDA in late October 2017.
It is important to have a generally available test to confirm need, benefit and safety in order to achieve new drug approval. In this case, re-interpreted serum magnesium serves all three important functions.
3. Why is RMJH able to deliver effective results when others have failed?
Through the globally patented novel inverted nanodroplet technology and novel softgel. The uniqueness in the inverted tiny micelle is that the charges are inside and the outside is neutral. This means that the tiny droplets can be efficiently and easily taken up by neutral pores. This allows for full bioavailability, the verification of which is part of the phase 3 trial. This novel technology is designed to reverse the many consequences of cell magnesium deficits by providing high value, safer, evidence- based medications.
4. Why is the phase 3 pivotal study able to achieve ‘once and done’ new drug approval?
The design is well powered statistically to achieve success on an agreed 505(b)2 path to satisfy all new drug approval requirements as agreed upon by FDA. The phase 3 study is to be conducted by experienced investigators and well monitored CROs.
The study design starts with a two week ‘wash out / run in’ period to qualify people for enrollment in the study. It is anticipated that four people will be screened for each qualified study subject. An initial ten-week double blind period will have an anticipated three to one randomization. This means there will be 700 hundred people receiving the active compound and 300 receiving the placebo. This will be followed by ten weeks of open label study with all people receiving the active compound.
The initial 300 participants to complete the protocol will then be re-randomized to assess adaptation (technically tachyphylaxis) over an additional eight weeks. Participants will return two weeks after completing the study for safety and final assessments.
End points include changes in systolic and in diastolic blood pressure. Assessments include routine safety lab studies, digital cardiogram and individual measurements and specimens taken at the initiation of study, at 10 weeks, at 20 weeks, at 28 weeks (for those in the adaptation phase) and at two weeks after completion of the study.
A five percent subset will include 24-hour ambulatory blood pressure monitoring (ABPM) while most subjects will be assessed using properly administered seated blood pressure. A brief questionnaire for participants and clinical investigators is being included at the agency’s suggestion.
Primary study objectives are statistically designed to achieve significant statistical significance (p value of <0.00125), a requirement for 505(b)2 path new drug approval (NDA). This meets the FDA requirement for a successful smaller, shorter, well executed single clinical trial for FDA 505(b)2 NDA approval.
5. Why is the budget reasonable?
By keeping overhead low without any sacrifice of quality criteria nor of verified data completeness. RMJH is negotiating with several CROs to verify each important variable in the pivotal, phase 3 study design and execution at forty clinical sites. The RMJH knowledge network includes a number of thought leaders in cardiovascular medicine. They are likely to have regular reviews with the local clinical investigators. Separately, study monitors and data analysts will use advanced tools to rapidly validate and secure data as it is obtained.
A data safety monitor board (DSMB) of three experts is anticipated for the pivotal trial.
Study design includes archiving of blood (serum, plasma and whole blood), urine, and saliva for analysis after the primary study objectives have been confirmed.
6. How is the timeline from initiation of study to completion of study less than nine months?
By using rapid enrollment of quality cases at a rate of 100+ per week over ten weeks. RMJH-111b achieved the development milestones of being ‘first in and first out of clinic’ in the phase 1 / 2 study.
7. Why will the trial adequately demonstrate what FDA requires for new drug approval in this instance?
Because of agreement between FDA and company, an amendment to the pending drug application is being prepared. The amendment addresses specifics about the chemistry, clinical, non-clinical, toxicology and statistical requirements RMJH-111b will meet for full new drug approval.
Much is known about the mechanisms of action of magnesium when it gets inside cells. RMJH has multiple advantages in getting the active drug agent into the body and then into the cells that get recharged when magnesium is regularly replenished.
8. Who are the logical alliance partners and why?
Companies where this technology improves efficacy and reduces adverse effects of their existing drug portfolio. Companies interested in high margin naturally based products are prime candidates. Familiarity with chronic disease and cardiovascular populations are qualities RMJH seeks in its development partner.
9. What are the current challenges?
Study execution and adequate pre-revenue support to monetize this value platform and pipeline family of medication indications. The novelty of enhanced uptake and engaged cell delivery is an emerging opportunity to build a platform and pipeline of medications on a strong foundation.
10. What is the unique selling proposition (USP) for RMJH-111b?
Enhanced uptake and engaged cell delivery to tiny blood vessels previously resistant to other treatments means improved blood pressure and autonomic regulation, with fewer adverse effects. Relief from common medication side effects that are often due to low cell magnesium including intestinal cramps, leg cramps (‘restless legs’) and diarrhea will be assessed in the phase 3 pivotal trial as discussed elsewhere.
Russell Jaffe, MD, Ph.D., Chairman and CEO of RMJ Holdings, LLC,
For additional information contact: MHall@RMJHoldings.com, +571.526.2937
1. Professor Ronald Elin, MD, Ph.D., University of Louisville, Director Laboratory Medicine
2. Gavras, Haralambos (Harry) and his wife Irene, helped introduce beta blockers and ace inhibitors
3. Dr. Jaffe and Dr. Elin trained together at the National Institutes of Health (NIH) Clinical Center Clinical Pathology Department
4. Cardiorenal researcher and thought leader, U Chicago Medical School
5. Cardiovascular researcher and specialist in new drug development
6. National cardiovascular specialist with an interest in essential minerals and microvascular medicine