Four years ago, Tom and Karen Hamilton received a devastating diagnosis. A doctor informed them that their nine-year-old daughter’s slight clumsiness—which they’d tried treating with physical and occupational therapy—was neurological, not physical. Specifically, Annie suffered from a rare, progressive, and currently incurable disorder known as Friedreich’s ataxia (FA).

“My wife and I didn’t know anything else to do but to try and attack the problem,” Tom Hamilton recalled. Having recently quit his 25-year Wall Street career to spend more time with Karen, Annie, and Annie’s three siblings, he was able to fully funnel his energy into Annie’s condition. He joined the board of the leading patient advocacy organization, the Friedreich’s Ataxia Research Alliance (FARA). He launched a biotech company, Chondrial Therapeutics, that is already moving a possible therapy—a proprietary protein replacement—into clinical trials. And to continue the fight in translational research, he set up and raised money for a foundation, CureFA, to further propel research.

Now, at the Broad Institute, Hamilton’s latest impactful gift will empower scientists to understand the biological underpinnings of the disease, with the goal of producing more therapeutic possibilities—and ultimately delivering a cure.

                                         Annie, Tommy, Karen, Tom, Catherine, and Gracie Hamilton

                                         Annie, Tommy, Karen, Tom, Catherine, and Gracie Hamilton

FA afflicts 15,000 people worldwide. Their cellular power plants, known as mitochondria, don’t make enough of a protein called frataxin. Insufficient frataxin levels cause energy-hungry cells like neurons to degenerate over time. Balance and coordination weaken. “You lose your ability to walk and know where your limbs are in space,” said Hamilton. Patients often suffer from a host of other conditions, too: scoliosis, diabetes, heart conditions, and vision and hearing loss. Like Annie, most FA sufferers are diagnosed as children. A decade later, they can expect to be wheelchair-bound. The most severe forms of the disease curtail life expectancy.

Luckily, however, FA isn’t a black box. The frataxin gene at the disease’s root was identified in 1998. Since then, scientists have worked to understand its role. Institute Member Vamsi Mootha, co-director of the Metabolism Program and lead scientist on the frataxin effort, wants to lay the foundation for future FA treatments. His team already has a strong starting position: MitoCarta, a blueprint, or what Mootha calls a “wiring diagram,” for the molecular machinery of mitochondria. They’ve already used this resource to gain deep insights into other mitochondrial diseases. Now, they’ve set their sights on FA.

                          Vamsi Mootha

                          Vamsi Mootha

Mootha’s team will combine this mitochondrial map with the Broad’s latest CRISPR genome-editing tools to pick apart the pathways that lie at the root cause of FA. The idea is to learn how loss of frataxin wreaks havoc within the cell. “Our research may provide answers about some mysterious aspects of the disease, for example, why some organs are preserved and others fail. We also hope to reveal novel and unanticipated therapeutic targets,” Mootha said. He is eager to help fulfill Hamilton’s vision. “There’s a parent behind this gift, and there’s a child behind this gift—how can that not motivate you?”

“We feel like we can make a difference in this disease,” Hamilton added. “We’re excited, and we’re full of hope, because we’re going to fix this thing.”

 Learn more about the CureFA foundation here

Chondrial Sets Up Rare Disease Shop With In-Licensed Asset, Series A 

By Marie Powers, News Editor

Three-year-old Chondrial Therapeutics Inc. scored a series A financing of up to $22.6 million and licensed its first asset in a quest to build a pipeline of therapies to treat rare mitochondrial diseases. The financing was led by Deerfield Management. Pharma veteran and former Deerfield adviser Carole Ben-Maimon was named Chondrial’s president and CEO. 

The company’s lead candidate, CTI- 1601, was discovered by Chondrial co-founder R. Mark Payne, professor of pediatric cardiology at Indiana University School of Medicine and director of the Translational Research Training Program of Indiana Clinical Translational Sciences Institute, while he was a scientist at Wake Forest Baptist Medical Center. The asset, targeting Friedreich’s ataxia (FA), was licensed from Indiana University Research and Technology Corp. and Wake Forest University Health Sciences. The Catalyst Fund, a $15 million technology development program of Wake Forest Innovations managed by Pappas Capital, was a minority participant in the A round. 

Chondrial, of Bala Cynwyd, Pa., was founded in 2013 by Payne and Steven Plump, a former official at Indianapolis-based Eli Lilly and Co. A year later, the company collected seed financing of about $1.6 million, according to SEC documents. Thomas Hamilton, a member of the board at the Friedreich’s Ataxia Research Alliance, was the company’s initial sole investor, Ben- Maimon said. 

Early on, Chondrial began working to scale up manufacturing, while board member Hamilton, who had a longstanding relationship with Deerfield, brought the asset to the venture firm’s attention. Serendipitously, in 2015 Deerfield established a $550 million fund targeting early stage science from academic research institutions, with a focus on advancing therapies targeting genetic disorders, cancer and orphan diseases into the clinic. 

Deerfield first asked Ben-Maimon, who was consulting with the venture firm at the time, to conduct due diligence on Chondrial and, later, to step in as CEO. Ben-Maimon previously served as president of Global Pharmaceuticals, the generics unit of Impax Laboratories Inc., and had earlier roles at Barr Pharmaceuticals Inc. and, after its acquisition, by parent Teva Pharmaceutical Industries Ltd. 

“That’s what I love to do – start small companies and develop drugs, so it was a good fit,” Ben-Maimon told BioWorld Today


FA, which occurs in about one in 5,000 people in the U.S. and about twice that number in Europe, is caused by an abnormality in the FXN gene, inherited in autosomal recessive fashion, that is responsible for the production of frataxin. Although the function of frataxin isn’t clearly understood, the protein is known to be active in the mitochondria and to assist with energy production. Individuals with FA have very low levels of frataxin, resulting in the debilitating condition. 

CTI-1601 uses a carrier protein to deliver frataxin, typically produced elsewhere in the cell, to the mitochondria. Chondrial’s research premise is that, by replacing the deficient protein, the mitochondria will resume normal function, resulting in a lessening of symptoms and slowing or curtailment of disease progression. 

“It’s a real challenge to get drugs or proteins of any kind through the extracellular membrane, then through the mitochondrial membrane, and then get them to stay,” Ben- Maimon explained. The carrier protein that Payne selected “worked quite effectively,” she said, solving the transport problem and enabling the protein to “stick” inside the mitochondria. 

The company’s therapeutic hypothesis remains to be proved, Ben-Maimon acknowledged, but she’s confident that Payne’s decades of research in the mitochondrial space stand the company in good stead to advance CTI-1601 into the clinic. Chondrial is completing preclinical work on the asset and plans to initiate a pre-investigational new drug (IND) application meeting with the FDA this year. Based on the agency’s guidance, the company will complete manufacturing and IND-enabling studies before filing an IND application as quickly as possible. 

“Knowing the population of patients that we’re dealing with, the faster we go, the happier we’ll all be,” Ben-Maimon said. “It’s a very bad disease, and it’s progressive. We’re hopeful it’s reversible in the early stages, but we don’t know when that changes so we’re very anxious to get moving. This is our highest priority.” 

FA remains a rare disease space in search of therapeutic options. Patients suffered a crushing blow in December when Horizon Pharma plc, of Dublin, reported the failure of its phase III STEADFAST (Safety, Tolerability and Efficacy of Actimmune Dose Escalation in Friedreich’s Ataxia study), which missed the primary and secondary endpoints in evaluating Actimmune (interferon gamma-1b) to treat FA. (See BioWorld Today, Dec. 9, 2016.) 

Actimmune was the only agent in an active phase III program, according to Cortellis Clinical Trials Intelligence (CTI), so its failure appeared to propel a phase II FA asset to the head of the class. Reata Pharmaceuticals Inc. is advancing omaveloxolone, a close structural analogue of bardoxolone methyl that was developed to improve tissue distribution, in the randomized, placebo-controlled study known as MOXIE, with initial data expected in the first half of this year. (See BioWorld Today, May 27, 2016.) 

Edison Pharmaceuticals Inc. also has a phase II asset, EPI-743, an orally bioavailable small molecule that’s a member of the para-benzoquinone drug class targeting the enzyme NADPH quinone oxidoreductase 1. The drug completed a phase IIb trial in FA, and in 2013 privately held Edison inked an R&D and commercialization agreement with Dainippon Sumitomo Pharma Co. Ltd. to advance the lead program EPI-743 in Japan, but the companies have not disclosed additional development, according to Cortellis CTI. (See BioWorld Today, March 29, 2013.) 

The richer FA pipeline is upstream. In all, 17 of 24 disclosed drugs actively targeting FA have yet to move into the clinic, according to CTI. They include assets from established companies such as Biomarin Pharmaceutical Inc., Bioblast Pharma Ltd., Proqr Therapeutics BV and Rana Therapeutics Inc. Newer entrants, in addition to Chondrial, include Agilis Biotherapeutics LLC, Fratagene Therapeutics Ltd. and Voyager Therapeutics Inc., which has a potential $845 million deal with Sanofi SA’s Genzyme unit to pursue treatments for FA and other central nervous system diseases. (See BioWorld Today, Jan. 2, 2014, Aug. 18, 2014, and Feb. 12, 2015.) 

Another company with FA in its sights, Bamboo Therapeutics Inc., was acquired last year by New York-based Pfizer Inc. for $150 million up front and milestone payments of up to $495 million. (See BioWorld Today, Aug. 2, 2016.) 

Chondrial’s series A is designed primarily to advance FA-1601 into a phase I program in FA, but the four-person company also is ramping up R&D efforts in other rare mitochondrial diseases at a newly established laboratory at the Science Center in Philadelphia. 

“We are looking at other assets that target mitochondrial diseases, and we think Deerfield will support that,” Ben- Maimon confirmed. Payne, as chief scientific officer, and Plump, as executive advisor, remain important members of the R&D team, she added. 

Longer term, “we’ll be opportunistic,” Ben-Maimon said. “We definitely want to take CTI-1601 at least through phase I, which will be more than just a safety and tolerability study. We’ll also be looking at some pharmacodynamics in patients. Once we’re comfortable that we have proof of concept that shows this is a viable treatment for Friedreich’s, we’ll move aggressively.” 

Father Hopes NIH Distinction for Indy-Developed Drug Could Save Daughter’s Life

This article posted on by Kylie Veleta, Special Projects Reporter for Inside Indiana Business

Friedreich’s ataxia (FA) is a rare—and especially cruel—disease. Tom Hamilton knows the heartache well; his 11 year-old daughter Annie deteriorates physically with each passing day. He says saving her life is “a race against the clock,” and he’s hopeful Indianapolis-based Chondrial Therapeutics could give his family more years with Annie. The National Institutes of Health (NIH) just accepted the startup’s drug candidate into a prestigious program that will accelerate its development—and perhaps help put time on Annie’s side.

NIH’s Therapeutics for Rare and Neglected Diseases (TRND) program has selected Chondrial Therapeutics’ drug, called TAT-Frataxin, for its highly-competitive program that focuses on speeding development and footing the bill to get the company to Phase 1 clinical trials. It’s the second critical development for TAT-Frataxin; the first came from a father.

Hamilton, who lives in New York, worked on Wall Street for 25 years, but left the industry a few years ago to spend more time with his family. Three months later, doctors diagnosed Annie with FA.

“My wife and I often say we’ve been given a very large dose of perspective,” says Hamilton. “All the things you thought were important—you realize really aren’t.”

“Horrible” is the word Hamilton uses to describe FA, which has no treatment. Parents think they have a healthy child until about the age of 10, when typical adolescent clumsiness becomes so pronounced that they begin to suspect something else may be at play. Annie’s prognosis is the same as the 50,000 other people in the U.S. with the disorder; she’ll likely be in a wheelchair by her teenage years and die in her mid-20s or mid-30s due to cardiovascular complications.

“You don’t sleep for about six months [after the diagnosis], and then you realize that doesn’t help anyone either,” says Hamilton. “We try to put our head down and put all of our resources, time and energy toward trying to get a cure for these kids.”

After Annie’s diagnosis, Hamilton contacted the FA Research Alliance, a global organization focused on finding a treatment or cure for the disorder.

“I said, ‘What do you guys need? Tell me therapies that need help that don’t have sponsorship,” says Hamilton. “They said there’s a doctor in Indiana, Mark Payne, and he has a protein therapeutic drug that we think has some legs.”

Hamilton started throwing millions of his own money at the disease; he gave more than $3 million to establish a FA research center at The Children’s Hospital of Philadelphia, and he invested $1.1 million in Chondrial Therapeutics to secure the intellectual property for TAT-Frataxin.

FA is a genetic disorder that limits the production of frataxin, an important protein that functions in the mitochondria, known as the energy-producing factories of the cell. Patients lose sensory nerves in their extremities and, ultimately, develop serious heart conditions.

Payne, who is an Indiana University School of Medicine professor of pediatrics, developed the drug to deliver frataxin to the mitochondria of the cells, allowing the cells to produce energy normally and not die.

“Think of it like giving insulin to diabetics. If you can provide frataxin, you turn a pretty devastating disease into a very manageable, high quality-of-life, chronic disease,” says Chondrial Therapeutics Chief Executive Officer Steven Plump. “While patients need to continue to receive that frataxin over their lifetime, it restores the productivity of those cells and—at least in animal studies to date—extends their life.”

Plump says being selected for the TRND program greatly “de-risks” development expenses and unleashes the power of TRND’s scientists to move TAT-Frataxin to human trials. For Hamilton, the advancements can’t come fast enough; while a treatment wouldn’t reverse Annie’s condition, it will stop the progression, which could mean saving her life.

“It’s heart-wrenching seeing your kid walk down the stairs, and every day, it gets harder. She’s lost some pretty serious neuronal capability, so we have to do it for others; if we can save other kids, that’s worth it as well,” says Hamilton. “I think in five years, there will be a therapy. I’m hoping it’s much sooner. I need it sooner.”

Chondrial Therapeutics Announces Development Milestone

Chondrial Therapeutics announced today the company’s lead drug candidate for the treatment of Friedreich’s Ataxia (FA), TAT-Frataxin (TAT-FXN) has been accepted for further development by Therapeutics for Rare and Neglected Diseases (TRND) program researchers at the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health.

“NCATS seeks to develop new technologies and more efficient paradigms for translation, in the context of important unmet medical needs,” said Anton Simeonov, Ph.D., director of NCATS’ Division of Preclinical Innovation. “Through our TRND program, we look forward to collaborating on this project for its potential to produce a treatment to patients in need.”

NCATS scientists will provide expertise and resources, working with Chondrial Therapeutics. Their goal is to enable an Investigational New Drug (IND) application, advance TAT-Frataxin into Phase I trials, and ultimately deliver a therapy for this debilitating orphan disease.

FA is a rare inherited disease that causes nervous system damage and movement problems. Usually beginning in childhood, it leads to impaired muscle coordination that worsens over time.

 “We are excited about being selected into this prestigious program”, said Steven Plump, CEO of Chondrial. “ It will enable Chondrial to draw upon the diverse drug development talent of the NCATS TRND team and their collaborative network. In addition, it will significantly reduce our development costs and financial risk.”

Mark Payne, M.D.,  CSO of Chondrial, also noted, “This milestone event validates the exciting potential of our lead candidate, TAT-Frataxin, for the treatment of Friedreich’s Ataxia. In addition, it opens the door to leverage our proprietary platform for treatment of other mitochondrial Orphan diseases.”

For more information about this story contact:

Steven Plump

Chondrial Therapeutics LLC