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Horizons
DRUG DEVELOPMENT

By Wendy Wolfson

 On the map: Art Mellor plans to compile all available information about MS into a Cure Map for researchers and the public. 
August 13, 2003 | At 37, Art Mellor was a successful entrepreneur. After graduating from MIT, he co-founded three companies in succession. But in June 2000, working at his computer, he felt a burning patch of skin on his shoulder.

The diagnosis was multiple sclerosis (MS). Literally termed "multiple scars" for the progressive damage it wreaks on the brain and spinal cord, MS results in double vision and numbness, eventually rendering most sufferers unable to walk. Although there are five drugs available, there is no known cause, and no cure.

A wiry, iconoclastic man, Mellor is a born problem solver. "I thought, OK, I'll find out who is working on the cure," he recalls. "I was surprised that there wasn't a focused effort going on." Indeed, drug companies currently spend more on marketing existing MS drugs than they do on researching cures. So in conjunction with his doctor, Tim Vartanian of Beth Israel Deaconess Medical Center, Mellor created a new company — a nonprofit biotech called Boston Cure Project — to save himself and others.

Affecting 400,000 people in the United States and 2 million worldwide, MS borders on orphan disease status (defined by the FDA as diseases that affect fewer than 200,000 Americans). Other fatal neurodegenerative diseases affect even smaller populations. Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, affects 30,000 Americans, with 8,000 new cases diagnosed yearly; Huntington's disease is a dominantly inherited disorder that affects 30,000 patients, inexorably depriving them of bodily control and reason.

Mellor is one of a coterie of entrepreneurs transferring expertise from the private sector to speed cures for orphan diseases — unattractive markets for drug companies. "The government is not going to solve this problem," he says.

Academic scientists gain career advancement by publishing peer-reviewed articles and securing grants. Pharma companies exist to benefit their shareholders by developing drugs on a large scale. "The only people who are responsible for curing a disease are people who are affected by the disease," Mellor says. "I have a problem to solve, and that is my primary motivation. My background is in starting companies and organizing skill sets."

"The model isn't visionary," Mellor insists. "If you look at any major human achievement that involves complexity, it involves two aspects: a lot of hard work by people who know what they are doing, and management, direction, and goals."

Inspired by massive ventures in complex problem solving, such as the Apollo space program, he articulated a project-management framework that oversees all the administration, so researchers can concentrate on finding a cure.

Mellor is assembling all information known about MS to make a Cure Map, open to researchers, MS patients, and their families. "Finding a cause gives you a definitive diagnosis. Some people have gone from neurologist to neurologist saying that it is all in their head ... which it was," he says mordantly. "The prognosis is related to the cause. We don't have a good animal model for MS, which makes testing treatments more difficult. Knowing the cause makes testing easier."

Boston Cure Project is negotiating with Genomics Collaborative to build a pilot MS blood and tissue bank for distribution to researchers. The plan is to ramp up to thousands of samples, while Genomics Collaborative takes care of the kits, storage, databanks, and manages the relationship with clinics.

This planned MS tissue and data bank for researchers would collect thousands of high-quality samples: blood and cerebrospinal fluid, and brain and spinal cord tissue from deceased donors.


Brotherly Love 
In 1999, James Heywood's 29-year-old brother, Stephen, was stricken with ALS. To help his brother, Heywood started the ALS Therapy Development Foundation (ALS-TDF), a nonprofit biotechnology company, in his family's basement in Newton, Mass. ALS-TDF now employs more than 40 scientists and staff, who pick FDA- approved drugs and screen them for potential therapeutic value in ALS. The organization has collaborated with 28 commercial companies and academic researchers to screen more than 50 drugs, finding two therapeutic targets in ALS and four lead drug candidates.

Heywood echoes Mellor's opinion that pharma and biotech's goals are only marginally aligned with the public good. He is offering them incentives to get closer. Heywood is compiling a massive ALS knowledge-management system for researchers and patients. "We don't know what we know and what we don't know," Heywood says. "What are the models of the disease? How do you develop targets? By structuring the data, the problems pop out."

Heywood admires J. Craig Venter, whom he credits with revolutionizing gene discovery by automating gene sequencing. "Yes, there is much automation in the pharmaceutical industry, but it is mostly focused on the early stage of drug screening in cell or protein assays," Heywood says. "We automate the discovery of new treatments for ALS from target to clinical application."

Heywood is dangling the ALS information database and intellectual property that ALS-TDF generates in its drug-screening program in animal models to lure pharmas to commit to further drug development and clinical trials. "Pharmaceutical companies can evaluate entering the $300-million ALS market for the cost of a $100,000 study in our program, rather than building their own multimillion-dollar ALS program," Heywood says. "We are lowering their cost of drug development ... but really, lowering the cost of making that go/no-go decision."

One of Heywood's mentors, Alex d'Arbeloff, chair of the MIT Corporation, told him the key questions to ask to benchmark results: What have you done to improve your process? What have you done to confirm your strategy? How have you improved the alignment of your patients' and your partners' goals?

The ALS mouse model is predicated on a rare inherited form of ALS. While there is no guarantee that drugs screened for other diseases will work on ALS, the virtue of the compounds being pre- approved is that if something works, patients can use it off-label and don't need drug companies.


Virtual Collaboration 
Minka vanBeuzekom, managing director of the Cure Huntington's Disease Initiative (CHDI), an offshoot of the Hereditary Disease Foundation founded by Nancy Wexler in 1968, believes that CHDI can slash drug-discovery costs by dispensing with Big Pharma infrastructure. CHDI screens chemical libraries, tests hits, maintains quality control, and facilitates information exchange. Collaboration is done virtually — the foundation doesn't have any labs. Since no real drug targets exist yet, all researchers can do is observe patients and families, and study banks of donated brain tissue.

 "A big company is not going to start a program on Huntington's disease. They will get involved, however, when we come to their doorstep with a molecule in a bottle that works really well in animal models of disease and appears to be nontoxic."

Ross Stein, Harvard Center for Neurodegeneration and Repair 

These organizations can offer lower overhead than Big Pharma for the early stages of drug discovery, primarily because they account for only the drugs that work, run lean teams, and can minimize marketing costs as each possesses a defined community of patients.

However, these nonprofit biotechs are fragmented. They need to collaborate or at least marshal resources. The Multiple Sclerosis Society has a policy that it doesn't work with organizations, but Boston Cure Project communicates with them and other MS organizations, such as The Myelin Project.

Another caveat expressed by academic researchers is that because of their applied focus, the nonprofit biotechs may not have the ability to do the sort of fundamental science necessary to ultimately cure these diseases.

The nonprofit biotech entrepreneurs are betting that if they take on the early-stage risk to present drug targets and IP gift-wrapped to Big Pharma, they can induce them into carrying the drug to fruition. Ironically, under the Orphan Drug Act of 1983, orphan drug development can be profitable for big drug companies; they receive grant funding, tax incentives for clinical research, and seven years' marketing exclusivity after FDA approval. Moreover, they can then charge high prices for the drugs they develop.

The trick is getting them interested.


Race for the Cure 
The Laboratory for Drug Discovery in Neurodegeneration (LDDN) at the Harvard Center for Neurodegeneration and Repair combines academic research and early-stage drug discovery focusing on Alzheimer's disease, ALS, Parkinson's disease, and Huntington's disease. "These neurodegenerative diseases simply are not being worked on by pharma," says LDDN Director Ross Stein.

Affiliated with Brigham and Women's Hospital, LDDN intends to leverage its network of Harvard postdocs and industry researchers to do drug-discovery projects for far less than Big Pharma. LDDN hopes Big Pharma then will take on the initial orphan drug targets that LDDN develops. "We aren't tied to a certain technology ... If somebody does a deal with us, they could do it under very favorable terms, as there are no VCs that have to be paid off," Stein says.

Orphan Products 
The FDA has designated more than 1,000 orphan products and approved more than 200 for marketing.

Read More 
  
LDDN conducts assay development, high-throughput screening, and medicinal chemistry, and plans to do pharmacology and regulatory affairs. Established with a large private donation, the Center hopes to sustain itself with NIH grants and pharma companies. All intellectual property will be shared with collaborating hospitals and drug companies. For now, LDDN is sticking to basic robotic technology for drug discovery, forsaking microfluidics or combinatorial chemistry. "We are very low-tech," Stein says. "I don't like technology because you get caught up in technology and you forget the mission."

Perhaps the real value of an academic lab such as LDDN is to spur the kind of innovation that is not happening in the commercial marketplace. "A big company is not going to start a program on Huntington's disease," Stein says. "They will get involved, however, when we come to their doorstep with a molecule in a bottle that works really well in animal models of disease and appears to be nontoxic. From the conversations I've had with companies, they will take that forward."

Perhaps. Stein recognizes his best chances may rest with larger biotechs such as Genzyme or Biogen. If drug companies don't want to collaborate, the backup strategy is to get further philanthropic funding or NIH backing.

While LDDN can do the sort of basic research that may result in fundamental drug discoveries, Stein admits, "It is hard for us to work with organizations like Art's and Jamie's. Our time frame is different. If we had molecules we had optimized and put through animal models under the Orphan Drug Act, we would need at least five years from the day we opened our door."

The gulf between the people who need to be cured and the companies and institutions researching drugs persists. "I never worked with patients my whole time in industry in 20 years. Not once did I meet a patient — just family members — who was suffering from a disease I was working on," Stein says. "Patient groups ... are disappointed that our timeline is longer than they would like. I understand their point of view, but what we do takes a long time. We probably test 70,000 compounds. Once we discover that we have to do medicinal chemistry, it is a long process. Frankly, the projects we are doing today may not help the patients."

There are signs of incipient cooperation between LDDN and the entrepreneurs. Whether they succeed in their missions, only time will tell. But in the process, they are clarifying what needs to happen to find a cure.



Wendy Wolfson writes about science and technology from Somerville, Mass. She can be reached at wendywolfson@attbi.com.








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