Searching to cure the incurable

A discovery that Eric Hoffman made as a postdoctoral researcher has inspired his career: working to find a cure for patients suffering from various forms of muscular dystrophy — a group of diseases caused when gene mutations interfere with a person’s ability to form healthy muscle, causing progressive weakness and loss of muscle mass.

While a postdoctoral researcher at Boston Children’s Hospital and Harvard Medical School, Hoffman discovered the defect protein — dystrophin — that causes the most common and most severe fatal form of muscular dystrophy known as Duchenne (DMD). He’s been working on it ever since, trying to translate research advancements into therapeutics.

“Just finding out what causes a disease doesn’t really help the patients,” says Hoffman, associate dean for research and professor of pharmaceutical sciences at Binghamton University’s School of Pharmacy and Pharmaceutical Sciences.

Because the dystrophin gene is carried on the X chromosome, females have two copies of the gene and can serve as asymptomatic carriers, whereas males have one copy that, when mutated, causes DMD, which affects about one in every 5,000 males worldwide.

DMD symptoms generally begin between ages 3 and 5. Patients often require assistance with most activities of daily living by their 20s and die early.

Another form of the disease, known as Becker muscular dystrophy (BMD), is caused by mutations to the same gene, but results in a less severe form of muscle failure that strikes later in life, though it can still rob an individual of strength in his legs and pelvis by his early 20s.

“DMD is the most common, lethal, genetic disease worldwide,” says Hoffman. “It affects all world populations equally because it’s the largest gene by far — with 2.3 million DNA bases — when the typical gene has 30,000 DNA bases. DMD and BMD are probably so common because the gene that causes them is a big target for mutations.”

Hoffman and his colleagues work at the molecular level — he says the best way to think of it is as systems biology, which looks at ways to decipher biological systems, using a cookbook of genes that creates all life as we know it.

“While a single change in the DNA disables the dystrophin gene, downstream of the mutation there are a lot of things happening; we need to understand how muscle reacts to missing dystrophin as the boy ages and why DMD is a progressive disease,” Hoffman says. “Many therapeutic approaches are working to replace the missing dystrophin in patient muscle, but equally important is to prevent the downstream, progressive aspects of the disease that drive patient disability, quality of life and early death.”

One approach to understanding and intervening in the disease progression is through the study of blood biomarkers. The struggling skeletal muscle sends materials into the blood, and deciphering these in the laboratory can lead to interpretation of how the muscle is changing as the patient ages. Scientists in Binghamton’s pharmaceutical sciences laboratories have identified biomarkers for DMD and are at work doing the same for BMD.

“Through these studies, working with patients and physicians worldwide, we were able to show that a patient’s muscle became very upset with absence of dystrophin soon after birth — years before clinical symptoms would emerge,” Hoffman says. “It was as if the muscle thought it was infected with a virus. It would launch immune system responses to fight a virus that wasn’t there.”

This work led to the development of a new drug, vamorolone, which is in clinical trials in eight countries. The drug shows promise in helping the muscle better interpret dystrophin deficiency and slowing down the disease progression. “We’re in Phase 3 of trials now, and the patients seem to be getting better over time, rather than deteriorating,” Hoffman says. “Some of them have been treated for 2½ years now, and families and physicians seem very happy with the treatment.”

Funding drug development

By all accounts, the cost of drug development is skyrocketing — one August 2018 report published by BioPharma Dive puts R&D spending on drug research and development at $71.4 billion in 2017. And NPR science correspondent Richard Harris, in his recent book, Rigor Mortis: How Sloppy Science Creates Worthless Cures, Crushes Hope, and Wastes Billions (2017), writes that the average American household spends $900 a year to support biomedical studies.

But Hoffman and colleagues have developed a model to speed at least part of the development process as they search for drugs that can reduce symptoms of DMD and other life-altering or fatal diseases.

He and Kanneboyina Nagaraju, professor and founding chair of the Department of Pharmaceutical Sciences at Binghamton University, have collaborated for years, including at Children’s National Medical Center in Washington, D.C., where they set up a highly collaborative, interdisciplinary research center that is being replicated at Binghamton.

“Working with for-profit companies, their responsibility is to their shareholders and return on investment, not always on what makes sense in terms of patients and science,” Hoffman says.

As someone committed for decades to these families searching for answers, Hoffman says the focus on profit can be distressing at times.

When Nagaraju, Hoffman and their chemistry colleague John McCall conceived of vamorolone, they took the bold step of committing to developing the drug themselves — from beginning to end, from discovery through approval — without venture capital or typical for-profit business models.

They established ReveraGen BioPharma based in Rockville, Md., in 2008. The company developed vamorolone and currently operates clinical trials for the drug, all supported by a funding model that, Hoffman says, keeps the focus on stakeholders, not stockholders.

Collaborative funding model

“We’ve pulled in $55 million to date with no stock sales, but from funding pieced together from U.S. and European governments and foundations,” Hoffman says. “We have to apply for a lot of grants, but we’re collaborating with everyone in Europe — the European commission for funding clinical trials had about 400 applications for 10 slots, and we got one of them, worth $7 million. We’re building consensus at an international scale.”

In 2013, Hoffman and Nagaraju established a second company, AGADA Biosciences in Halifax, Nova Scotia, also to facilitate orphan drug development for industry, nonprofits and academic-based organizations.

NPR’s Harris says that grants from the National Institutes of Health are “still the big money in the room,” but it can take several years to get through the process. “You can’t say, ‘Let’s just find out,’ he says. “If you have an idea and want to try it in very short order, these other sources of funding make a huge difference.”

“And we’re making so many innovations in the whole process,” Hoffman adds. “We’re not risk-averse because we’re being funded by foundations and parent groups and others who say, ‘Take what risks you wish to move the needle.’ FDA and the European equivalent, EMA, have been highly interactive and supportive. We are there in meetings with them to represent stakeholders, not stockholders. Everything is transparent, really constructive and a lot of fun.”

Part of the beauty of this model, says Hoffman, is the synergy it creates with academia.

The value of such a collaborative model isn’t lost on Harris. “I think collaboration can make a real difference in reproducibility,” he says. “It makes science less competitive and focused on getting the right answers rather than getting ahead.”

And for Hoffman, Nagaraju and their colleagues, that is the end goal.