For the past two years NIH has been trying to double its funds for developing orphan drugs. But the FY 2012 budget offered more of the same, as in the same $24 million of annual funding set aside for NIH’s Therapeutics for Rare and Neglected Diseases (TRND) program since its creation in 2009. The institute had sought $50 million for TRND this year and last.
If there is any comfort to be taken, it comes from Congress agreeing to a restructuring of NIH. This brought funding for the rare and neglected disease program to one place. TRND will now be financed directly as part of the National Center for Advancing Translational Sciences’ (NCATS’) division of preclinical innovation. Previously, TRND was funded through assessments cobbled together from the budgets of some of NIH’s institutes and centers.
The restructuring capped a busy year for TRND. The organization approved 10 disease drug development programs. TRND’s next solicitation is expected to result in approval of four to six projects. While no specific date for the solicitation has been set, “we’re shooting for probably April,” John C. McKew, Ph.D., chief of NIH’s Therapeutics Development Branch, which includes TRND, told GEN.
“One of the key things is transformational care,” Dr. McKew commented. “We’re particularly interested where there are no therapeutic modalities available for a patient population. Or if there is something on the market for them, we want to have a real clear distinction from what’s out there.”
TRND doesn’t fund projects directly but helps academic and industry organizations access drug development capabilities that include high-throughput screening, medicinal chemistry, and toxicology. Thus far TRND has approved 14 projects overall, not including a Schistosomiasis collaboration with Rush University that was halted after it failed to achieve milestones.
Two TRND projects, one on sickle cell disease (SCD) and the other on chronic lymphocytic leukemia (CLL), have advanced to clinical trials: Phase I testing on Aes-103, a candidate for SCD, started December 21, 2011. Plans call for another patient trial at the NIH Clinical Center starting in March. The only drug approved for SCD is the anticancer agent hydroxyurea. It is currently sanctioned for adults only, is of modest efficacy, and has undesirable side effects.
For the CLL project, TRND joined with Kansas University’s Institute for Advancing Medical Innovation, the Leukemia and Lymphoma Society (LLS), and the hematology branch within NIH’s National Heart, Lung and Blood Institute to form The Learning Collaborative. The consortium is repurposing auranofin for relapsed CLL. LLS provides a clinical trial matching service through its Information Resource Center, which assists patients in finding clinical trials to participate in, explained Louis J. DeGennaro, Ph.D., evp and chief mission officer for LLS.
“The CLL trial has enrolled its first patient at the University of Kansas Medical Center,” Dr. DeGennaro told GEN. “Further recruiting is under way. Two other clinical trial sites are expected to open in 2012.”
Pending final data packages, two other TRND projects could advance to clinical evaluation, Dr. McKew noted. One is the development of a therapy for Niemann-Pick type C1 (NPC1) disease, for which there are currently no FDA-approved therapies. The other project is the development of DEX-M74 (ManNAc) as a treatment for hereditary inclusion body myopathy (HIBM), an adult-onset neuromuscular disorder for which no cure exists. The National Human Genome Research Institute filed a patent application to use DEX-M74 for HIBM as well as an IND application with the FDA in 2007. However, FDA issued a hold, saying additional preclinical studies were needed.
Discussing what it’s like to work with TRND, Dr. DeGennaro remarked, “LLS and TRND factor out the need for a financial return on investment and thus allow therapies to advance for rare diseases with small patient populations. Our efforts will effectively de-risk molecules and allow biotech and pharma to pick them up at a later stage of development with more confidence in success.”
For cash-strapped companies scrambling to find investors, TRND could prove to be a valuable partner. “For investigators who are trying to do work, or really tiny companies that need money, that can’t get interest from big pharma or other biotech, they have another option in TRND,” Emil Kakkis, M.D., Ph.D, president of the EveryLife Foundation for Rare Diseases, told GEN. “I look at them as working in parallel. I don’t think it’s going to increase competition.”
At least half of the collaborations going forward are with small companies looking to collaborate with researchers within NIH, joined sometimes by investigators from outside the agency, Dr. McKew said. “Obviously, they need funding, and that’s why they came to us. Other people will have to invest in them, whether they’re a bigger company buying into the project, or a venture cap investing in a small company that exists.”
Patient groups represent another category of potential partners in rare disease development, notes Pat Furlong, founding president and CEO of Parent Project Muscular Dystrophy (PPMD). Two of TRND’s projects focus on DMD. One examines the AVI Biopharma exon 50-skipping drug, AVI-4038; the other examines ReveraGen Biopharma’s lead compound, VBP-15. The latter has attracted funding partners that include Congressionally Directed Medical Research Programs, which in FY 2012 will spend $3.2 million on the Duchenne Muscular Dystrophy Research Program, as well as ReveraGen BioPharma, MDA Venture Philanthropy, and The Foundation to Eradicate Duchenne.
“As often as small rare disease groups do drug development with biotechs, the biotechs typically don’t have sufficient money to take that drug through the process, so they raise a little, initiate the target tranches, and then come back at lead optimization, and they have more money. It’s a stop-start, stop-start kind of approach,” Furlong told GEN. “We feel that the TRND program offers a more efficient, streamlined process.”
TRND’s challenge “is actually doing drug development, because as we know, it’s actually not that easy,” added Dr. Kakkis, who heads Ultragenyx Pharmaceutical. “There’s a pretty uphill battle for TRND to get to that level of capability to really successfully drive development through. But Francis Collins has clearly committed to doing it, and they’re picking some good projects to work on,” Dr. Kakkis said.
“I think if anything, what the TRND program will do is highlight the viability of some small projects and make them more plausible for a big company to pick up and develop. That will be a benefit to the system.” According to Dr. McKew, one TRND project is far enough along to initiate talks with prospective commercial partners this year. Timing of project hand-offs to partners will vary from case to case.
The future of TRND and just how much it will benefit orphan drug development is linked to the evolution of NCATS. As the new center tries to justify itself, TRND could serve to validate NCATS’ focus on translational medicine. This focus will likely grow as a priority for NIH no matter what the next few years hold for the agency in terms of congressional support.
Another key benefit of TRND could be forging closer ties between the traditionally very separate cultures of NIH and FDA when it comes to rare disease drug development. All that looking ahead, however, will likely have to take a back seat to the most basic challenge NIH faces for bolstering TRND’s activities—ensuring it has adequate funding to do the required R&D work for orphan diseases, starting with the FY 2013 budget.