Clinical Trials on Repurposed Treatments for Immediate Incorporation into Clinical Use
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The document discusses repurposing drugs to treat rare diseases through immediate clinical trials. It provides 6 case studies as examples. Case study 1 discusses a collaboration between government, academia, and non-profits to identify new drugs for chronic lymphocytic leukemia. Case study 2 discusses crowdfunding efforts to fund a clinical trial for a rare genetic disease. The document advocates for connecting stakeholders through an online platform called CureAccelerator and explores social finance models like social impact bonds to fund repurposing research.
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Clinical Trials on Repurposed Treatments for Immediate Incorporation into Clinical Use
- 1. Clinical Trials on Repurposed Treatments for Immediate Incorporation into Clinical Use CORD Rare Disease Day Conference 2015 Dr. Bruce Bloom President and Chief Science Officer Cures Within Reach
- 2. Outline •Why repurposing? •How POC clinical trials drive patient impact •Six illustrative examples •CureAccelerator™ •Social Finance 2
- 3. Rare Disease Healthcare Outcome and Funding Crisis •>6000 rare diseases worldwide with no universally effective therapy •Globally impacts >50M people creating significant healthcare costs •Pharma generates 20-30 expensive new medical solutions per year 3
- 4. The Repurposing Opportunity •Clinically testing drugs, devices and nutriceuticals human approved for one disease indication, to create a “new” treatment in a different disease indication •66% of researchers and 25% of clinicians have a scientifically based Repurposing Research idea ready for a pilot clinical trial validation 4
- 5. Why Repurposing? •Faster from idea to patient use •Affordable and safe research •Often the only economical solution for rare diseases •High likelihood of success •Off-label use or market approval options •Improve outcomes and reduce healthcare costs for both patients and payers 5
- 6. Repurposing Roadblocks •Poor/no economic incentives for repurposing •Strong science but weak IP •Inexpensive generic drugs widely available •Hard/expensive to find patients for research •Global issue, local solution 6
- 7. What is special about Medical Research Non-Profit Organizations? •Support research not typically funded by industry, and maybe not be government •Repurposing, rare diseases, acute diseases •Diseases of poor populations •Closer relationship with patients •First to hear of anecdotal successes/failures •Able to catalyze patients for trials •Closer relationship with Researchers •Government funds ideas •NPOs fund people and ideas 7
- 8. What is special about Medical Research Non-Profit Organizations? •Nimble •Address translational/clinical opportunities •Raise additional funds as needed •Reliable source of funds •For new ideas and researchers •For high-risk research •Getting more organized •Unite with other NPOs for advocacy/policy •New business models 8
- 9. Case Study #1 Bringing Stakeholders Together 9 •The Learning Collaborative - Government, Academia, Non-Profit - University of Kansas - Leukemia & Lymphoma Society - NCATS TRND - Identify new drug therapies for patients with CLL - Rare disease with small therapeutic window - CLL not especially attractive to industry
- 10. Case Study #1 Bringing Stakeholders Together 10 •The Learning Collaborative - Strategy - Drug screening - Select repurposed compound, if found - Derisk via POC clinical trial - Repurposing Auranofin for Refractory CLL - Currently in Clinical Trial - Auranofin manufacturer hiccup - LLS buying rights to manufacture
- 11. Case Study #2 From Rare to Common 11 •DevelopAKUre Nitisinone Trial -Rare disease with no treatment -NIH repurposing discovery -Failed NIH clinical trial -Started with a parent on a mission -AKU Society initiation/organization -Looked impossible
- 12. Case Study #2 From Rare to Common 12 •DevelopAKUre Nitisinone Trial -Grassroots crowdfunding campaign -European Commission-£4.8m in funding -£3.2m in co-financing from •European consortium including 13 hospitals •Pharmaceutical companies, universities, biotech companies, AKU patient groups •Help with admin/recruitment
- 13. Case Study #3 From Common to Rare 13 •Repurposing ketorolac to reduce breast cancer recurrence -Researchers from 5 countries -Up to 80% reduction in recurrence -No economic incentive -Nigerian Government to fund -Could create info for use in rare cancers
- 14. Case Study #4 Taking Risks, Finding Success 14 •FD Now and Cures Within Reach • Familial Dysautonomia • Ultra-rare • Almost uniformly fatal disease • Monogenetic autosomal recessive • Strong division in research and clinical community • Hard to create clinical trials • Natural history and epidemiology
- 15. Case Study #4 Taking Risks, Finding Success 15 •Dedicated lab at Fordham University • Working since 2001 when discovered the genetic cause • 2002 discovered the pathway and defective protein • 2003 found 5% functional protein and 2 nutriceuticals that could upregulate • 2005 found the cause of autonomic dysfunction • 2008 third compound brings circulating protein=35% • 2010 discovered dysbiosis impact • 2012 two additional compounds=100%
- 16. Case Study #5 Utilizing Various Exit Strategies 16 •CWR off-label Use POC clinical trials • Autoimmune Lymphoproliferative Syndrome • Repurpose sirolimus-6 patients clinical trial • 5 of 6 in complete remission/still working • 6 more pediatric autoimmune disease POC trials • 85% of patients in 5/6 diseases in remission • Considering trials in 2 more diseases
- 17. Case Study #5 Utilizing Various Exit Strategies 17 •CWR commercialization POC clinical trials • Creation of Rediscovery Life Sciences • 4 projects, including “jurisdictional repurposing” project using old drug for rare acute kidney injury • Working with other commercial partnerships • Pharma • Venture Philanthropy • Social Finance
- 18. Case Study #6 Consortium Development 18 •Multiple Myeloma Research Foundation • Started MMRC 10 years ago • Boston Consulting Group • 6 of the top myeloma centers in North America • Best practices, patient data and IP sharing • Now 16 institutions
- 19. Case Study #6 Consortium Development 19 •Multiple Myeloma Research Consortium • Thalidomide, small POC clinical trial, used off-label, then approved • Six new drugs received FDA approval in 10 years • All have been used off-label in other rare diseases • Clinical trials for drugs in three approved classes plus agents in many new classes
- 20. Connectivity-put it all together 20 Bringing Stakeholders Together CureSparking Taking Risks, Finding Success Leveraging Global Assets Venture Philanthropy Consortium Development
- 21. Connectivity-put it all together 21 The world’s first interactive, online platform dedicated to Repurposing Research •All key stakeholder groups • MR NPOs, pharma, academia, MDs, gov’t PAGs, philanthropy • Pushing transparency and collaboration
- 23. CureAccelerator-put it all together 23 Beta launch in progress Public Launch 1 June, 2015 http://cureaccelerator.org
- 24. Social Finance Any financial investment method that intentionally delivers both a social dividend and an economic return. 24
- 25. Why Social Finance? 1. Sometimes industry and/or non-profit organizations are not creating enough social return using the capitalism or philanthropy models, and 2. The government is not able or willing to raise taxes to fund new programs for social impact or has been unable to create the social return through existing programs 25
- 26. Social Impact Bond Benefits •Attract new forms of capital •Gov’t only pays for effective services •Shift $ risks from gov’t to investors •Opportunity for greater and more vigorous ongoing evaluation •Independent evaluation creates transparency •Feasible for small projects and patient populations 26
- 27. Rare Disease SIB Diagram 27 Investors Cures Within Reach Gov’t or other payer Repurposing Clinical Trials Repurposing Clinical Trials Repurposing Clinical Trials Improved lives Lower costs Social Impact Bond Pays Investors provide repurposing research funding Investors receive return CWR finds and manages rare disease repurposing research Cost savings meets payer’s goals Investors fund more repurposing research
- 28. Rare Disease SIB Calculator 28 Scenario1A-RepurposingResearchSIBROI for an Orphan Disease with esclatingsavingsand number of patients Total Repurposin gResearch Costs Average cost per clinical trial # of clinical trials Potential success rate # of "new" treatments created Average # of patients whohave a disease with a "new" treatment Projected annual healthcare $ saved/ average patient Total potential 5 year savingsfor all patientswith these diseases %patients actually usingthe "new" treatments Total actual savingsfor patientsusingthe "new" treatment healthcare $ saved on thissub- populationof patientsAFTER repayinginvestors 5 year ROI on $50M investment $50,000,000 250,000 200 10% 20 2500 $2,500 $125,000,000 70% 87,500,000 $37,500,000 75.00% $50,000,000 250,000 200 15% 30 5000 $5,000 $750,000,000 70% 525,000,000 $475,000,000 950.00% $50,000,000 250,000 200 20% 40 10000 $10,000 $4,000,000,000 70% 2,800,000,000 $2,750,000,000 5500.00% $50,000,000 250,000 200 25% 50 20000 $20,000 $20,000,000,000 70% 14,000,000,000 $13,950,000,000 27900.00% $50,000,000 250,000 200 30% 60 100000 $50,000 $300,000,000,000 70% 210,000,000,000 $209,950,000,000 419900.00% Scenario 1-RepurposingResearch SIBROI for an Ultra-Orphan Disease with small $ savingsand minimal patient use Total Repurposin gResearch Costs Average cost per clinical trial # of clinical trials Potential success rate # of "new" treatments created Average # of patients who have a disease with a "new" treatment Projected annual healthcare $ saved/average patient Total potential 5 year savingsfor all patientswith these diseases %patients actually usingthe "new" treatments Total actual savingsfor patientsusingthe "new" treatment healthcare $ saved on thissub- population of patientsAFTER repayinginvestors 5 year ROI on $50M investment $50,000,000 250,000 200 10% 20 2500 $10,000 $500,000,000 10% 50,000,000 $0 0.00% $50,000,000 250,000 200 15% 30 2500 $10,000 $750,000,000 10% 75,000,000 $25,000,000 50.00% $50,000,000 250,000 200 20% 40 2500 $10,000 $1,000,000,000 10% 100,000,000 $50,000,000 100.00% $50,000,000 250,000 200 25% 50 2500 $10,000 $1,250,000,000 10% 125,000,000 $75,000,000 150.00% $50,000,000 250,000 200 30% 60 2500 $10,000 $1,500,000,000 10% 150,000,000 $100,000,000 200.00%
- 29. Current Development of Repurposing Research SIB •England Pilot Project SIB-2106 Rare Disease Day Launch •Early discussions with Canadian partners •MaRS Centre for Impact Investing (Canada) undertaking a feasibility study funded by the Mindset Foundation •Contacting WHO and World Bank 29
- 30. Questions & Answers Contact: Dr. Bruce E. Bloom 847-745-1245 Bruce@cureswithinreach.org www.cureswithinreach.org 30
Editor's Notes
- Reference for 7000 diseases without an effective therapy: http://www.irdirc.org/?page_id=34 References for about 30 new drugs per year: http://www.fda.gov/drugs/developmentapprovalprocess/druginnovation/default.htm
- Nonprofit organizations can support alliances that typically would not be supported through public investments, such as with for-profit companies. They can bridge disciplines, institutions, and ideas when the opportunity arises and in record time. With financial incentives, they can change the culture and structure of research. Even though private contributions cannot match those of the federal government or industry, nonprofit disease research organizations play a special role. Because of their close relationships with the patient communities, their ability to move quickly to address emerging translational and clinical opportunities, and their capacity to leverage public investment, these organizations can catalyze and jump-start innovation. Moreover, they can serve as a reliable source of funds for novel, high-risk research that might not be able to compete successfully for public funds. Because they are closer to the patients and therefore closer to the problems needing solutions, innovative nonprofit funders have heightened awareness of the importance of translational and clinical research programs. Increasingly, they are forming a unified advocacy front on key public policy issues affecting the pace of research, such as privacy regulations, intellectual property challenges, and the resolution of ethical issues.
- Nonprofit organizations can support alliances that typically would not be supported through public investments, such as with for-profit companies. They can bridge disciplines, institutions, and ideas when the opportunity arises and in record time. With financial incentives, they can change the culture and structure of research. Even though private contributions cannot match those of the federal government or industry, nonprofit disease research organizations play a special role. Because of their close relationships with the patient communities, their ability to move quickly to address emerging translational and clinical opportunities, and their capacity to leverage public investment, these organizations can catalyze and jump-start innovation. Moreover, they can serve as a reliable source of funds for novel, high-risk research that might not be able to compete successfully for public funds. Because they are closer to the patients and therefore closer to the problems needing solutions, innovative nonprofit funders have heightened awareness of the importance of translational and clinical research programs. Increasingly, they are forming a unified advocacy front on key public policy issues affecting the pace of research, such as privacy regulations, intellectual property challenges, and the resolution of ethical issues.
- Approximately 15,000 people in the United States are diagnosed each year with a rare blood cancer called chronic lymphocytic leukemia (CLL). Patients ultimately become resistant to current chemotherapies, and their disease recurs — leading to death. Working with the NCATS Chemical Genomics Center, the lead investigator found that the drug auranofin selectively kills CLL cells. Auranofin was previously approved by the Food and Drug Administration (FDA) as a treatment for rheumatoid arthritis. The goals of this TRND project are to develop auranofin as a treatment for refractory CLL and to develop a novel collaborative paradigm that is broadly applicable to repurposing drugs for rare diseases. The Institute for Advancing Medical Innovation at the University of Kansas, the Leukemia & Lymphoma Society (LLS), and the NCATS TRND program have formed a collaboration known as The Learning Collaborative (TLC). The goal of this collaboration is to identify new drug therapies for patients with rare blood cancers such as CLL. CLL is a blood and bone marrow disease that usually occurs in middle-aged adults and progresses over a long period. Currently, therapeutic options for CLL patients are limited and few therapies are under development. There is an important need for new medical treatments. To find compounds that selectively kill CLL cells versus normal donor lymphocytes, TLC carried out a high-throughput screen of a library of known drugs using a cell proliferation assay. The arthritis drug auranofin was identified as a potent, selective cytotoxic agent. A cooperative research and development agreement (CRADA) has been established to conduct the necessary pre-clinical and clinical proof-of-concept studies to determine the potential benefit of auranofin in treating individuals with relapsed CLL. The development strategy for repurposing the therapeutic use of auranofin for CLL capitalizes on available pre-clinical and clinical experience with a known, previously approved, therapeutic drug to accelerate clinical testing of the same drug for a new medical indication (CLL). The goal is to complete pre-clinical through clinical trial studies, at which time an industry partner will be engaged.
- Approximately 15,000 people in the United States are diagnosed each year with a rare blood cancer called chronic lymphocytic leukemia (CLL). Patients ultimately become resistant to current chemotherapies, and their disease recurs — leading to death. Working with the NCATS Chemical Genomics Center, the lead investigator found that the drug auranofin selectively kills CLL cells. Auranofin was previously approved by the Food and Drug Administration (FDA) as a treatment for rheumatoid arthritis. The goals of this TRND project are to develop auranofin as a treatment for refractory CLL and to develop a novel collaborative paradigm that is broadly applicable to repurposing drugs for rare diseases. The Institute for Advancing Medical Innovation at the University of Kansas, the Leukemia & Lymphoma Society (LLS), and the NCATS TRND program have formed a collaboration known as The Learning Collaborative (TLC). The goal of this collaboration is to identify new drug therapies for patients with rare blood cancers such as CLL. CLL is a blood and bone marrow disease that usually occurs in middle-aged adults and progresses over a long period. Currently, therapeutic options for CLL patients are limited and few therapies are under development. There is an important need for new medical treatments. To find compounds that selectively kill CLL cells versus normal donor lymphocytes, TLC carried out a high-throughput screen of a library of known drugs using a cell proliferation assay. The arthritis drug auranofin was identified as a potent, selective cytotoxic agent. A cooperative research and development agreement (CRADA) has been established to conduct the necessary pre-clinical and clinical proof-of-concept studies to determine the potential benefit of auranofin in treating individuals with relapsed CLL. The development strategy for repurposing the therapeutic use of auranofin for CLL capitalizes on available pre-clinical and clinical experience with a known, previously approved, therapeutic drug to accelerate clinical testing of the same drug for a new medical indication (CLL). The goal is to complete pre-clinical through clinical trial studies, at which time an industry partner will be engaged.
- Cambridge, 16th June 2014 – Patients with a rare genetic disease are today starting on a major international clinical trial of a treatment that could dramatically change their lives for the better. Run by the Royal Liverpool University Hospital and patient group the AKU Society, the five-year Phase III trial aims to recruit 140 patients to three centres across Europe, including one in Liverpool. Alkaptonuria (AKU) is caused by a genetic defect that leads to bones and cartilage going brittle and black. It is often referred to as black bone disease. The trial will assess the long-term effectiveness of a potential drug called nitisinone in preventing the progression of the disease. “All patients with alkaptonuria (AKU) are heavily motivated to participate in a trial that could change their lives,” said Dr Nicolas Sireau, Chairman of the Cambridge-based AKU Society and father of two children with AKU. “We have patients ready to start the trial, but if anyone believes someone in their family has the condition we urge them to get in contact with the AKU Society.” The funding for the trial includes £4.8m from the European Commission, with another £3.2m in co-financing from a European consortium including 13 hospitals, pharmaceutical companies and consultancies, universities, biotech companies and national AKU patient groups. Prof Lakshminarayan Ranganath, Medical Director of the AKU Society and Coordinator of the trial, said: “This is the first time patients, clinicians, scientists and industry have collaborated so closely on launching a major trial for such a rare genetic disease. We hope it will serve as a model for other groups trying to develop treatments for rare diseases.”
- Cambridge, 16th June 2014 – Patients with a rare genetic disease are today starting on a major international clinical trial of a treatment that could dramatically change their lives for the better. Run by the Royal Liverpool University Hospital and patient group the AKU Society, the five-year Phase III trial aims to recruit 140 patients to three centres across Europe, including one in Liverpool. Alkaptonuria (AKU) is caused by a genetic defect that leads to bones and cartilage going brittle and black. It is often referred to as black bone disease. The trial will assess the long-term effectiveness of a potential drug called nitisinone in preventing the progression of the disease. “All patients with alkaptonuria (AKU) are heavily motivated to participate in a trial that could change their lives,” said Dr Nicolas Sireau, Chairman of the Cambridge-based AKU Society and father of two children with AKU. “We have patients ready to start the trial, but if anyone believes someone in their family has the condition we urge them to get in contact with the AKU Society.” The funding for the trial includes £4.8m from the European Commission, with another £3.2m in co-financing from a European consortium including 13 hospitals, pharmaceutical companies and consultancies, universities, biotech companies and national AKU patient groups. Prof Lakshminarayan Ranganath, Medical Director of the AKU Society and Coordinator of the trial, said: “This is the first time patients, clinicians, scientists and industry have collaborated so closely on launching a major trial for such a rare genetic disease. We hope it will serve as a model for other groups trying to develop treatments for rare diseases.”
- a report was presented by an anesthesiology group from Brussels including P. Forget and M. De Kock [8]. They retrospectively reviewed the outcome from 327 consecutive breast cancer patients treated at their hospital. Patients were given mastectomy performed by one surgeon and this was followed by conventional adjuvant therapy according to accepted consensus reports. The relapse outcome was presented grouped by what drug was used as analgesia. The surprising development was that one analgesic drug resulted in 5-fold lower relapse hazard 9–18 months post-surgery compared to all the other drugs. The best drug was ketorolac which was the only NSAID out of the six in the group.
- In the summer of 2001, Dr. Rubin’s laboratory identified the genetic cause of FD in a gene that makes a protein called IKAP. In 2003, Dr. Rubin noted that FD patients are able to produce SOME functional IKAP protein. This finding prompted an intense screening program to find naturally-derived compounds to increase the amount of functional IKAP produced in FD cells. Two compounds were initially found capable of increasing the amount of functional IKAP protein produced in these cells, a form of vitamin E called tocotrienol and a chemical component of green tea termed epigallocatechin gallate (EGCG). These inexpensive and safe compounds have allowed FD patients to significantly reduce their disease symptoms and have had a dramatic improvement in their length and quality of life. In 2005 the lab reported that FD patients do not have enough of an enzyme called MAO (monoamine oxidase), which is responsible for breaking down a potentially toxic substance called tyramine. The researchers published a tyramine free diet that is helping to avoid life-threatening crises that used to occur frequently in FD patients. In 2008 the research team discovered that vitamin A, as well as the related provitamin A forms, such as beta-carotene, can further increase the production of the functional IKAP in FD-derived and normal cell lines in a manner similar to the effect of the tocotrienols. FD patients can take these vitamin A compounds along with the tocotrienols and EGCG. In 2010 the lab discovered that it was possible for a child to internally produce their own life threatening tyramine through a process called “dysbiosis”, caused by microbial imbalances in the digestive tract. Intestinal dysbiosis produces tyramine from excess protein. The tyramine enters the blood and cause FD crises. Additional investigation revealed that intestinal dysbiosis is encouraged by a condition referred to as hypochlorhydria, which is the reduced presence of stomach acid. Many children with FD, takes medication to reduce the presence of stomach acid. When protein intake has been reduced in the cases where there were no obvious triggers for an ongoing FD crisis and the children were taking advantage of the therapeutic regimens that have been developed, the crisis abated in a day or two. As the children with FD tend to be underweight, the researchers were concerned that the reduction in protein intake might negatively impact their weight. What they found has surprised them. Many of the children who are now being limited to the Recommended Daily Allowance (RDA) of protein have actually put on weight. The children said they are no longer going through periods of nausea and that they are eating more because they are hungry. Researchers are not sure if the weight gain is due to the increased consumption of food or whether the metabolism of those with FD is negatively impacted by an excess amount of protein intake. And in 2012, the biggest discovery of all! Two components of soy, genistein and daidzein, when combined with EGCG, allow kids with FD to produce 100 PERCENT OF THE REQUIRED IKAP PROTEIN! What this means, is that when these children take these compounds, which they can purchase affordably at the pharmacy, they can lead almost normal lives. Their nervous system will function as well as it would if they didn’t have the disease!
- The Alzheimer's Drug Discovery Foundation (ADDF) and the Alzheimer's Society (UK) announced a new partnership that will provide funding for drug-repurposing research in Alzheimer's disease and related dementias. Their stated goal is the acceleration of critical development programs and the bringing of new treatments to patients. Drug repurposing leverages existing scientific evidence and research to accelerate the drug development process. It has a significant advantage over traditional drug development in that the repositioned drug has already passed a significant number of toxicity and other tests. Therefore, its safety is known and the risk of failure for reasons of adverse toxicology are reduced. More than 90% of drugs fail during development,[1] and this is the most significant reason for the high costs of pharmaceutical R&D. In addition, repurposed drugs can bypass much of the early cost and time needed to bring a drug to market. The new partnership intends to fund projects up to $1.5 million each focused on drug repurposing, leveraging existing scientific evidence and research to accelerate the drug development process.
- Reference for nutriceuticals for familial dysautonomia (FD): http://www.fdnow.org/research/treatment-breakthroughs References for Cerezyme for Gaucher’s Disease: http://www.genzyme.com/Patients/Educational-Info/The-Cost-of-Enzyme-Replacement-Therapy.aspx http://www.nytimes.com/2008/03/23/opinion/23sun3.html?_r=0
- Reference for nutriceuticals for familial dysautonomia (FD): http://www.fdnow.org/research/treatment-breakthroughs References for Cerezyme for Gaucher’s Disease: http://www.genzyme.com/Patients/Educational-Info/The-Cost-of-Enzyme-Replacement-Therapy.aspx http://www.nytimes.com/2008/03/23/opinion/23sun3.html?_r=0
- Reference for nutriceuticals for familial dysautonomia (FD): http://www.fdnow.org/research/treatment-breakthroughs References for Cerezyme for Gaucher’s Disease: http://www.genzyme.com/Patients/Educational-Info/The-Cost-of-Enzyme-Replacement-Therapy.aspx http://www.nytimes.com/2008/03/23/opinion/23sun3.html?_r=0
- Reference for nutriceuticals for familial dysautonomia (FD): http://www.fdnow.org/research/treatment-breakthroughs References for Cerezyme for Gaucher’s Disease: http://www.genzyme.com/Patients/Educational-Info/The-Cost-of-Enzyme-Replacement-Therapy.aspx http://www.nytimes.com/2008/03/23/opinion/23sun3.html?_r=0