Partnerships
Reveragen’s business model for development of vamorolone uses venture philanthropy partners rather than venture capital investors. These philanthropy partners include government programs and stake holder foundations to carry out the complex process of developing vamorolone for DMD. From the governmental side, this has included partnership with the NIH NCATS TRND program, multiple NIH small business grants, and critical early funding from the Department of Defense CDMRP program (Congressionally Directed Medical Research Program). In Europe, the European Commission has provided funding for vamorolone clinical trials in Duchenne muscular dystrophy throughout the EU (http://cordis.europa.eu/project/rcn/199721_en.html).
Multiple international stake-holder foundations have partnered with ReveraGen through grants and venture philanthropy programs. The venture philanthropy contracts with many foundations share the risk of developing vamorolone, while also sharing the long-term ‘upside’ of future drug sales should the drug be brought to market for DMD (and other disorders). In total, approximately $24M has been provided by stake holders and governments to lead vamorolone through the drug development pipeline.
The venture philanthropy business model for vamorolone development has a number of key consequences that can be described under the following topics:
- De-risking
- Peer review
- Innovation
- Lowered cost
De-risking:
A frequently cited problem in many drug development programs is one of ‘late stage failure‘ – where a drug progresses to large, expensive clinical trials, only to fail in showing adequate safety (side effects) and/or efficacy (benefit). These expensive late-stage failures add to the overall cost of successful drugs – the cost of bringing drugs to market is viewed as the combined cost of successful drug and unsuccessful drugs.
A key concept is de-risking of a drug development program – defined as attempts to build more confidence that a drug will ultimately proof safe and effective in patients, but earlier in the drug development process (prior to expensive late-stage clinical trials).
The NIH TRND program was a government-led effort to de-risk orphan drug programs. In this case, the government independently validated key tests of vamorolone, and also brought extensive drug development experience to the vamorolone team. In this manner, confidence in vamorolone was built, and the vamorolone program ‘de-risked’.
Peer review:
Grant applications to support research sent to governments and foundations typically undergo peer review – experts in the same or similar area of the proposed research are asked by the governments and foundations to critically evaluate the proposed research. The peer reviewers judge each proposal on significance (Why is the proposed research important?), innovation (What is really ‘new’ in the proposed research?), and impact (If the research is successful, how will this effectively change health and/or knowledge in a positive way?).
In developing vamorolone through a venture philanthropy model, this means that each piece of funding received from governments and foundations has been through peer review. Thus, the dozens of experts in DMD and drug development have thoroughly evaluated the vamorolone program. This evaluation often includes feed-back to improve the vamorolone program – criticisms or weaknesses in the proposed vamorolone plan were thus addressed through ongoing modifications in the plan. Thus, the vamorolone program has received the scientific and medical input of many of the best minds in neuromuscular disease research. This is an important form of ‘de-risking’ the vamorolone program, and ensuring it is scientifically robust.
Innovation:
Innovation drives improvements – it is widely recognized that innovation in drug development is needed to bring new therapies to patients more quickly and at lower cost. However, many drug development programs are risk-averse; adding innovation to a drug program is felt to increase risk to that program, rather than decrease risk (e.g. de-risk). For example, the six minute walk test in a DMD child is increasingly felt to be an unreliable test for benefit of a drug. But the six minute walk test has regulatory precedent with FDA, so may be the least risky outcome to use. But without a precedent for an alternative outcome, there is risk that FDA may not accept the data showing improvements. Stock holders of a pharma company want the path of least resistance to drug approval and return on investment, and may discourage innovation such as alternatives to six minute walk, even if the alternatives make much more sense. The fiduciary duty of for-profit companies to stock holders is effectively risk-averse, and thus less supportive of innovation.
The venture philanthropy model helps break out of this cyclical risk aversion – it changes the fiduciary duty of stock holders to fiduciary duty to stake holders. Non-profit stake holder foundations embrace innovation as it drives improvements in care for their constituencies. Governments embrace innovation as a driver of successful enterprise and economic health. Peer reviewers of both foundation and government grants demand innovation as a key part of research.
The vamorolone program, through its fiduciary duty to stake holders rather than stock holders is making innovations in clinical trial design, clinical outcomes, biomarker outcomes, and regulatory pathways.
Lowered cost:
The cost of bringing a single drug to market is oft quoted as somewhere between $300M and $1B. Cost for an orphan drug may be towards the lower end of this range, where regulatory authorities may require less extensive late-stage clinical testing. Amortizing these costs in prescription to patients with rare disease can lead to very high costs, sometimes $300,000/yr or more per patient. As increasing numbers of drugs are developed for both orphan disorders and smaller sub-groups of common disorders (e.g. different types of breast cancer), the cost of drugs to our health care system increases quite dramatically. Indeed, it is widely recognized that drug costs are rising much more rapidly than clinical costs throughout health care systems.
Efforts to decrease the ultimate cost of prescriptions is focused in part on decreasing the cost of drug development. Decreasing drug development costs focus on de-risking (avoiding drug failures), and decreasing the development time required for development (often quoted as 15 years).
The vamorolone program, through extensive de-risking and innovations in both drug development and business models, is anticipated to take ~12 years and cost ~$80M – less time and far less cost than typically quoted.
In September 2020, ReveraGen licensed the commercialization of vamorolone to Santhera Pharmaceuticals.
Below we acknowledge the governments and foundations that have been critical partners in the vamorolone development program:
The Foundation to Eradicate Duchenne (FED)
The Foundation to Eradicate Duchenne (FED) was founded in 2002 by Joel and Dana Wood to help both directly fund DMD research through their fundraising efforts in the Washington DC area, as well as facilitate government funding through NIH, CDC, and Department of Defense. FED played an instrumental role in initiating the vamorolone program through facilitation of Department of Defense CDMRP funding of initial basic science studies, and lead compound selection. FED has also provided seed funding for ReveraGen, including a $250,000 grant in 2014 to aid in completion of chronic toxicology studies in support of Phase 2a clinical trials of vamorolone in DMD boys. FED is a co-founder of ReveraGen, and retains founder shares.
Therapeutics for Rare and Neglected Diseases (TRND)
The National Institutes of Health (NIH) initiated the Therapeutics for Rare and Neglected Diseases (TRND) program in 2011 within the National Center for Advancing Translational Sciences (NCATS) Division of Pre-Clinical Innovation. Through a competitive process, TRND partners with sponsors of a lead drug for a rare or neglected disease, and works to help ‘de-risk’ the program, and encourage and speed the development of new drugs. Once accepted into the TRND program, an expert NIH program officer team well versed in drug development provides consultation and support for advancement of the drug program. This often involves independent validation of key in vitro and in vivo assays previously carried out by the drug sponsors (pharmaceutical, biotech, academic, or non-profit partner).
Vamorolone was one of the three initial drugs accepted into the TRND program in 2011. ReveraGen staff has worked closely with NIH TRND program officers and drug development experts to develop vamorolone for Duchenne muscular dystrophy. This included independent validation of key properties of vamorolone, and extensive collaborative work on the chemistry, manufacturing, controls, and formulation of the drug. The drug development partnership between TRND and ReveraGen ended in mid-2014.
MDA Venture Philanthropy (MVP)
The Muscular Dystrophy Association initiated the Venture Philanthropy program (MVP) in 2011 as a means of funding the development and commercialization of new treatments for neuromuscular diseases. vamorolone was an inaugural awardee of the MDA VP program in 2011 with a first round award. ReveraGen successfully accomplished all phase 1 objectives, and was awarded a second round contract in 2012. All milestones of the second round contract have also been accomplished. A third round contract was awarded in 2014 for support of the Phase 1 clinical trials of vamorolone; these studies were completed in 2015. Through the three MDA contracts, a total of ~$2.5M has been provided in support of the vamorolone drug development program.
Save Our Sons
Save Our Sons a charity organization in Sydney Australia that was founded in 2008 by Elie Eid and Vice President Bass Abboud. Their goal is to raise funds and awareness to help find a cure for Duchenne Muscular Dystrophy (DMD). Save our Sons has provided funding for toxicology studies of vamorolone.
Joining Jack
Joining Jack is a newly organized UK-based foundation focused on translational research to bring therapeutics to DMD boys. Joining Jack and ReveraGen entered a venture philanthropy relationship in 2014 in support of the Phase 1 clinical trials of vamorolone.
DRF (Duchenne Research Fund)
DRF is a UK-based charity, formerly known as the GM Trust, incorporated in 2007 to fund research in therapies for Duchenne muscular dystrophy. DRF has provided venture philanthropy funding for the Phase 1 clinical trials of vamorolone.
Duchenne UK
In 2016, Joining Jack and DRF united to create Duchenne UK.
Duchenne Children’s Trust
Duchenne Children’s Trust was founded in 2011 as a UK-based charity focused on support of research towards therapeutics of DMD. The Trust has provided venture philanthropy funding for Phase 1 clinical trials.
Duchenne Alliance Research Foundation
The Duchenne Alliance is a consortium of foundations focused on research and therapeutics development for Duchenne muscular dystrophy. Their primary funding arm is through the Duchenne Dashboard. The Duchenne Alliance has funded ReveraGen for a new GMP drug synthesis (3.0 kg), establishing the Phase 2a clinical trial infrastructure, and a murine mdx/DBA biomarker and efficacy pre-clinical trial. Foundations contributing to this include Pietro’s Fight (NY), Michael’s Cause (NY), Alex’s Wish (UK), Ryan’s Quest (NJ), and Save Our Sons (Australia).
Parent Project Muscular Dystrophy (PPMD)
Parent Project Muscular Dystrophy’s mission is to end Duchenne. They accelerate research, raise voices in Washington, demand optimal care for all young men, and educate the global community. In 2014, they initiated the ‘Xcelerate’ program to facilitate clinical trials of the most promising drugs in DMD. Vamorolone was one of two awardees in this program, receiving $750,000 in venture philanthropy in support of chronic toxicology studies.
Action Duchenne
Action Duchenne, initially called Parent Project UK, was set up in 2001 and seeks support from all parts of the Duchenne community including researchers, clinicians, physicians, pharmacological companies, and other Duchenne charities. Action Duchenne provided funding to ReveraGen in 2015 to support biomarker studies.
Defeat Duchenne Canada (formerly Jesse’s Journey)
Defeat Duchenne Canada (formerly Jesse’s Journey) is a Canadian foundation based in Ontario that is focused on supporting Duchenne muscular dystrophy research to “Defeat Duchenne – Change Lives”. In 2020, Defeat Duchenne Canada provided funds to initiate a clinical trial of vamorolone in a broad age range of Duchenne boys (2 years to 18 years); the funds will be earmarked for Canadian clinical trial sites, and is provided under a venture philanthropy agreement (repayment to 4x based on later drug sales milestones). The clinical trial is VBP15-006, and is anticipated to being enrolment in 2021.
European Commission (EC)
In 2014 the EC issued a call for proposals entitled Horizons 2020, where drug development applications for orphan disease were invited. Newcastle University (Kate Bushby, Michela Guglieri) took the lead on a vamorolone application to fund Phase 2b clinical trials in DMD boys throughout Europe. This application was successful, with reviewers noting innovations in clinical trial design, use of blood biomarkers, and business models. ECRIN and TRiNDS are academic-focused CROs that aid in management of the trials, anticipated to begin in 2017.
National Institutes of Health – NIAMS, NINDS
Two institutes within the US National Institute of Health (NIH) are supporting clinical trials of vamorolone in DMD boys in the US. The National Institutes of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provided a clinical trial planning grant for the Phase 2a clinical trials of vamorolone in the US to Dr. Paula Clemens (University of Pittsburgh). The National Institutes of Neurological Disorders and Stroke (NINDS) then provided key funds to carry out the Phase 2a and Phase 2a extension studies in the US through a small business grant (Direct to Phase II SBIR). The NINDS grant was renewed in August 2018 to provide support for the Phase 2b study (VBP15-004). In 2019, NINDS provided supplemental funding specifically for an ethics substudy of the vamorolone clinical trial. In this ethics study, ReveraGen developed mechanisms to report back data on participants in the vamorolone trials to the patient families at their request. This approach is innovative in providing centralized return of participant-level data, and comparison of the participants data to others in the trial, directly to families that request this. Suzanne Gaglianone and Laurie Conklin have activated this program and manage the return of data to families. In 2020, NINDS awarded a $3.4M Commercialization Readiness Pilot SBIR award to ReveraGen to prepare the FDA NDA and EMA MAA filings expected in 2021 and 2022, respectively. In 2021, FDA awarded ReveraGen a grant to support a pilot Phase 2 study in Becker Muscular Dystrophy (NCT05166109).
