Objective
Our objective is simple. People with T1D face two issues: 1) autoimmunity, which destroys beta cells; and, 2) inadequate numbers of insulin-producing pancreatic beta cells. Great progress is being made in autoimmunity, exemplified by the recent approval of teplizumab, but replacing lost beta cells has only been possible through expensive and invasive procedures like pancreas transplant, islet transplant and stem cell transplants, which are unlikely to reach the millions of people with T1D in the world. In 2015, we discovered a drug called harmine, isolated from plants, that is able to make human beta cells regenerate, and can be given as a simple pill. Our work has been replicated by many academic and commercial research organizations around the world. Here, we want to move a novel, next-generation, superior DYRK1A inhibitor called Compound 2-2c as rapidly as possible through the FDA process for approval to study its effects in people with diabetes.
Every drug that is approved by the FDA for use in humans must be shown to be effective and safe. We already have received FDA approval to test a single dose of harmine in normal people (a Phase 1 single rising dose trial), based on initial animal and human safety data. Since restoring human beta cell mass to normal levels with DYRK1A inhibitors is expected to require a minimum one month and perhaps several months of treatment, we now want to perform longer studies (one month) in people with T1D as the next step in DYRK1A inhibitor development. Before permitting human studies longer than one day, the FDA requires that new drugs must first be shown to be safe and effective in small and large laboratory animals, typically rats and dogs. They must also be characterized with respect to doses, drug metabolism, interference with other drugs used by the same people, which organs remove the drugs, how efficiently they are absorbed from the intestine, and many other kinds of safety and analytical testing studies. These kinds of studies are collectively known as “preclinical studies” and are required for same duration of dosing planned for humans. Thus, in this application, we request support to perform these standard preclinical IND-enabling studies on Compound 2-2c in our own laboratories and in outside commercial laboratories (Contract Research Organizations or CRO’s) which routinely perform these studies for biotech companies and large pharmaceutical companies. The specific kinds of testing we require is detailed in the body of the application and in the Confidential Technical Abstract.
Successful completion of these “FDA Checklist” studies will allow us to perform the first human trials for efficacy in people with diabetes. Since 2-2c pills can be produced cheaply, and easily administered by mouth, this therapy will be far less expensive, simple to administer, and will reach millions more people with T1D than stem cell or other transplant approaches.
Background Rationale
In people with T1D, beta cell mass is reduced. Knowing exactly how much beta cell mass remains in a given person with T1D is impossible (there are currently no x-rays, CT-scans, MRIs that can measure beta cell mass in living people), but autopsy studies suggest that beta cell mass is reduced by 30 to 98% in people who die with T1D. These findings, together with inadequate insulin production in T1D, provide the rationale for pancreas transplant, pancreatic islet transplant, and stem cell transplant therapies currently in use and/or in development. Since these therapies are, and will remain, extremely expensive and technically challenging, we have sought to find simpler, cheaper, and more scalable beta cell regenerative therapies. With this goal in mind, we used a robotic high-throughput screen to study 102,000 different known and unknown drugs and found 1, harmine, that makes human beta cells regenerate. We next synthesized ~1000 novel DYRK1A inhibitors. Among these, compound 2-2c displays the most efficacy, highest selectivity and potency, and like harmine can be given to humans and animals by mouth as a pill.
We have shown that DYRK1A inhibitors make adult human beta cells regenerate, increasing their numbers by 300% in three months, and reverses diabetes. When small, ineffective numbers of human organ donor beta cells are transplanted into diabetic mice, human insulin production is increased by 4-fold, diabetes is reversed, and all of this occurs with only low doses of harmine. We have also shown that harmine is safe, does not cause tissue damage, proliferation, or other adverse effects in mice treated for 3 months at the effective doses. We have further shown that harmine can be safely administered to normal human volunteers in single doses in excess of 200 mg, far above the dose required to restore human beta cell mass and function and reverse diabetes in mice. We have also shown that increases in beta cell mass are sustained when harmine is withdrawn. Our current goal is to take compound 2-2c which by all measures is superior to harmine, through preclinical safety studies so we can begin to study it in humans.
Collectively, this is all very good news for the T1D world. For example, if a person with recent onset T1D or at high risk, as in the teplizumab study, had a 50% deficit in beta cell mass, a 300% increase would be too much! If a longer term person with T1D had a “beta cell tank” that was 30% full, a 300% increase in three months would fill the “beta cell tank”.
Description of Project
In this proposal, an experienced team of investigators with extensive experience in human beta cell biology, in regenerative drug discovery, in pharma-based drug design and medicinal chemistry, and in human drug development, requests support to accelerate the translation to humans with Type 1 diabetes of a novel class of drugs they have discovered, the DYRK1A inhibitors, for beta cell regeneration. The team has already shown that one member, harmine, is safe and well tolerated in mice in three month studies, increases human beta cell mass by 300-700% over three months, reverses diabetes, and can be safely administered by mouth in a single dose to normal people. The team has already obtained approval by the FDA to perform human Phase 1 Single Rising Dose Studies in normal healthy volunteers, through funding from the National Institutes of Health. This Phase 1 study is in progress, and has already made it clear that the lead member of the DYRK1A inhibitor class, a natural drug isolated from plants called harmine, is well tolerated in normal people in doses that are >150-fold higher than those required to make human beta cells regenerate.
These early results in mice demonstrating diabetes reversal through beta cell mass expansion are comparable or superior to results from stem cell, islet or pancreas transplant studies, which ultimately will reach only a small minority of people with T1D. In contrast, the availability of a simple, once per day harmine oral pill would be scalable to millions of people with T1D at a fraction of the cost of islet, pancreas or stem cell transplant therapies.
What we seek here is support for gathering additional necessary safety, pharmacologic and other standard preclinical data required by the FDA drug regulatory agency to move a next-gen DYRK1A inhibitor called compound 2-2c through the pre-clinical development and Investigational New Drug (IND) approval process, so that we can begin human trials in people with diabetes.
Anticipated Outcome
As described in other sections, we have developed a drug family that can dramatically expand human beta cell mass for people with T1D. Our goal is to bring this class of drugs through the FDA approval process to people with T1D as rapidly as possible. We are already in Phase 1 human trials with the original compound, harmine, and by the end of year 2 of this proposal should be ready for Phase 2 studies in people with T1D. Our goal here is to bring Compound 2-2c – which by all measures is likely to prove superior to harmine - along in preclinical studies so we can subsequently study it in people with diabetes.
DYRK1A inhibitor drug family members can be administered as a simple daily pill and expands human beta cell mass in only 3 months. The practical implications of this approach are extraordinary: pancreas transplant, islet transplant, stem cell replacement therapies, represent wonderful advances, but because of their cost, the intensity if patient care, the limited numbers of organ donors, will never be accessible and affordable for more than a handful of the 1.6 million people in the US and the 20 million people in the world with T1D. In contrast, simple daily oral dosing of inexpensive pills containing harmine and related drugs will be affordable, accessible and scalable to the large millions of people with T1D.
Relevance to T1D
The relevance to people with T1D is clear. We are proposing to bring a simple, once-a-day pill treatment to people with established and recent onset T1D. We have the drugs, we have the team, and we have the expertise to bring harmine to people with T1D. What we request from the JDRF is financial support to check all of the regulatory boxes required to bring the first class of effective beta cell regenerative drugs to people with T1D. We also believe that while harmine is an attractive compound, success with harmine and 2-2c will lead to a competitive environment in which multiple next-generation versions of drugs in this class will become available to people with T1D including improved versions of harmine from our lab. These proof-of-concept studies will set the stage for later stage Phase 3 efficacy studies required for regulatory approval for all patients for T1D.