Abstract
Last year, Pfizer and GlaxoSmithKline (GSK) announced the creation of new business units devoted to orphan drug discovery, development, and commercialization. And even some pharma giants without such units are showing more interest, and sometimes success, in bringing rare-disease drugs out of the laboratories into clinics and the market.
Two reasons go far toward explaining much of the recent orphan drug activity by big pharma.
“One, the science is catching up, so that frequently, another disease is described genetically. And clearly, our ability scientifically, to develop drugs against diseases, and especially diseases where we know the target, or know potential targets, has never been greater. And then, the unmet need. Clearly, all of pharma needs to replenish their pipelines, and these diseases have been neglected for a while. So there is clear unmet need there,” said Ed Mascioli, M.D., Pfizer's vice president, BioTherapeutics Research and Development, and head of the company's Orphan and Genetic Diseases Research Unit.
Donna Francher, a Global Product Vice President at AstraZeneca (AZ), offers a third reason: “When it comes to orphan drug R&D, there appears to be growing interest within the patient community to participate in clinical trials for rare diseases. This is important, as it is difficult to recruit clinical trial participants when the potential patient population is so small.”
Unlike Pfizer, AZ does not have a specialized rare-disease drug development unit, nor has it announced specific collaborations for rare disease research. However, the company in April began marketing its first orphan drug, vandetanib, for U.S. patients for the treatment of medullary thyroid cancer (MTC) that cannot be removed by surgery or that has spread to other parts of the body, soon after winning U.S. Food and Drug Administration (FDA) approval.
AZ briefly pursued approval for vandetanib 100 mg plus chemotherapy for advanced non–small cell lung cancer (NSCLC). But in October 2009, the company withdrew applications submitted four months earlier to the FDA and the European Medicines Agency (EMA), based on an updated analysis that demonstrated no overall survival advantage, plus preliminary feedback from the agencies that the current package with progression-free survival (PFS) as the primary end point may not be sufficient for approval.
“It is not unusual to study a drug candidate in one patient population, only to learn that the science points to another patient population,” Ms. Francher said.
Ms. Francher and Dr. Mascioli were among executives or spokespeople from four pharmaceutical companies that recently shared insights on the topic with Human Gene Therapy.
Dr. Mascioli's unit has about 10 different projects underway. One is aimed at developing a recombinant protein for hereditary emphysema that would replace current plasma protein therapies. Three projects aim to fight muscular dystrophies with new drugs that help muscles grow, and get stronger. Then there's the program targeting cystic fibrosis, funded over 5 years from the Cystic Fibrosis Foundation starting in 2007. That funding was committed to FoldRx, now a wholly-owned Pfizer subsidiary.
In April, Pfizer announced a $210 million collaboration with Zacharon Pharmaceuticals (San Diego, CA) to treat orphan diseases, including lysosomal storage disorders, using Zacharon's platform for developing small-molecule drugs targeting specific carbohydrate polymers or glycans. The collaboration aims to develop a small-molecule drug that could be taken as a pill, to replace current therapies based on taking complex proteins intravenously.
“We're also active in looking at other opportunities in biotech companies across the country and in Europe as well, and hopefully soon we'll announce another collaboration,” Dr. Mascioli said.
The Pfizer orphan drug unit's most advanced lead candidate is a new factor for patients with hemophilia, either A or B. Because some of those patients have inhibitors to the replacement factor they have been given, Dr. Mascioli said, they have formed antibodies against drugs they have been given, causing them not to work.
“So instead of giving Factor 8 or Factor 9, we're developing a Factor 7 to help these patients,” Dr. Mascioli added. “We hope it will be in the clinic for testing in about a month or so.”
Pfizer's Orphan and Genetic Diseases Research Unit (Cambridge, MA) has some 25 to 30 people, about two-thirds of whom are researchers. But the number of Pfizer staffers working on orphan drugs is much larger because the unit interacts with other groups in the company, such as chemistry, toxicology, and complex drug design and manufacturing, Dr. Mascioli said. Orphan disease researchers also work with partner academic medical centers at the Centers for Therapeutic Innovation (CTI) created by the company in four cities. The company announced its fourth center in August, at University of California, San Diego Health Sciences; the others are in San Francisco, New York, and Boston.
The Boston CTI, announced in June, will carry out translational research partnerships with eight institutions, including Children's Hospital Boston.
“As the only pediatric hospital in the CTI to date, we're optimistic that some of the projects supported through this program will lead to treatments for pediatric genetic conditions, particularly because Pfizer's recently created Orphan and Genetic Disease Unit will be represented in our CTI partnership,” Nurjana Bachman, business development manager at Children's, said in a post on the hospital's clinical and innovation blog Vector (
“Children and people with rare diseases have largely been ignored in the past by the commercial preference for large market opportunities, but when incentives are aligned in a collaborative effort, the chances of success are dramatically increased,” Bachman added.
Pfizer is one of two big pharma companies to create dedicated orphan drug units last year. The other was GlaxoSmithKline (GSK), which announced its GSK Rare Diseases unit in February 2010, four months before Pfizer released news of its unit.
Of the big pharmaceutical manufacturers, GSK and its predecessor companies had the greatest number (14) of orphan drug designations granted for medicines subsequently approved in the United States between the enactment of the Orphan Drug Act in 1983 and 2010. In addition to building on that orphan-drug heritage, GSK says the rare diseases unit was created to leverage existing partnerships and establish further in-licensing opportunities.
“If you look at orphan drug designations for the last 10 years, the orphan drug designations have gone up quite well. But when you look at FDA approvals for rare disease products, that line has been flat for 10 years. It's still hard to do this, just like any other drug development program,” said Michael Diem, M.D., M.B.A., GSK's director of business development for rare diseases. “Part of our intent at GSK Rare Diseases is to leverage our collective company development and regulatory expertise to improve our odds in getting new medicines approved for these patients.”
The unit focuses on some 200 orphan diseases: “That doesn't mean that that's the only 200 that we would be interested in. It just means that that's where the science is most promising and we believe we can make the most significant contribution to patients affected by rare diseases,” Dr. Diem said.
“If another company is working on something that's not on our list of 200, it doesn't mean we're not interested in it. If it is an area of patient need, they have good data, and they have evidence that they're affecting the disease pathway, or the mechanism of action makes sense, we are certainly open to trying to work with a partner,” he added.
The unit has four assets in late-stage development: • A collaboration with Prosensa Therapeutics (Leiden, The Netherlands) around Duchenne's muscular dystrophy in boys with a dystrophin gene mutation amenable to an exon 51 skip (up to 13% of boys with DMD). The collaboration earlier this year began a phase III clinical study of the antisense nucleotide labeled GSK 2402968 • A collaboration with Italy's Telethon Foundation, and the San Raffaele Scientific Institute in Milan, to study GSK 2696273, an investigational gene therapy for adenosine deaminase severe combined immune deficiency (ADA-SCID), now in a phase III trial • Migalastat HCl for Fabry disease, a treatment that GSK in-licensed from Amicus Therapeutics last fall. Migalastat is in phase III as monotherapy and in phase II in combination with enzyme replacement therapy • A reformulation of FLOLAN, a treatment for pulmonary artery hypertension available in the United States
Among candidates in earlier development phases is an antisense therapy designed to treat transthyretin amyloidosis that has entered phase I studies. The therapy is the first of six planned for development under a collaboration with Isis Pharmaceuticals. GSK agreed to pay $35 million upfront to Isis, which is eligible to receive on average up to $20 million in milestones per program up to phase II proof of concept. If all six drug candidates are developed and commercialized to predetermined sales targets, Isis will be eligible for license fees and milestone payments, totaling nearly $1.5 billion.
GSK's Rare Diseases Unit numbers just under 30 full-time staffers, most of them based in the greater London area. The remainder are scattered internationally, although all report to the company's London headquarters, known as GSK House. U.S. staffers are based in GSK's two U.S. corporate campuses, in Philadelphia and North Carolina's Research Triangle Park.
“We believe that the integrated structure of GSK Rare Diseases, from early discovery through to commercialization, will ensure that we can most effectively and efficiently interact with patient organizations, the small number of specialist physicians and institutions who treat patients with rare diseases,” Dr. Diem said. “We have global heads on the market access and commercial sides. Then we have development heads across four main therapeutic areas. So that would be, immunoinflammation, which includes things like ophthalmology, and bone, and more general inflammatory therapeutic areas. Then we have metabolic and inherited disorders. This is quite broad. And then we have CNS and muscle disorders and then lastly, rare malignancies and hematology.”
Each therapeutic area has its project teams. Each late-stage project has a dedicated medicine development leader who runs the program, as well as the R&D team, including study managers who work closely with the principal investigators conducting the various clinical studies.
“We believe that the unit we have created at GSK will enable us to build on our existing skills, knowledge, and expertise, to really tackle the scientific questions that need to be answered and addressed, and to ultimately deliver medicines to patients. And again, it's an effort that's centered around a business unit, but then taps into the broader expertise of the company around the globe,” Dr. Diem said. “Four things define GSK Rare Disease's approach: an integrated team working from discovery through to commercialisation; clear focus on around 200 priority rare diseases, a global access model and upfront rigor to focus our R&D efforts in the areas where we have the highest probability of leading to medicines of value.”
That expertise includes many of GSK's 11,000 researchers worldwide, Dr. Diem said: “As they're working on different projects for different therapeutic areas, we now have them thinking more and focusing in on the question, ‘What pathways are more applicable to rare diseases?’ whereas in the past, those rare diseases didn't get as much attention given the focus on other indications at the company.”
He said the company's global commercialization know-how will also be tapped for orphan drugs. “We are committed to set world class capabilities and to achieve global reach in order to deliver new treatments to those patients who need them most.” In fast-growing “middle income” countries like Brazil, India, and China, GSK will work with governments to get medicines registered and made available there, Dr. Diem said.
Unlike GSK or Pfizer, Novartis does not segregate orphan drug research into its own unit, although development of such drugs is among priorities of the Novartis Institute for Biomedical Research (NIBR; Cambridge, MA).
“Rare disease research is central to our approach to drug discovery. We believe focusing on the patient and following the science yields results,” said Jeff Lockwood, Global Head Communications, NIBR. “Different from the blockbuster model, for which companies can be constrained by marketing consideration, an understanding of molecular pathways allows Novartis to better develop drugs that have potential implications in a variety of disease areas with the ultimate goal of developing therapies that meet the unmet medical needs of patients.”
“Working with a targeted indication, where there is a deep understanding of how the drug works, can lead to better success,” Lockwood added.
NIBR has research projects in more than 40 rare diseases across a broad disease spectrum. Novartis is joining with InCyte to develop the oral Janus kinase (JAK) inhibitor INC424, also known as INCB018424, which is in a phase III study for myelofibrosis. Novartis has licensed the rights to INC424 outside the United States, while InCyte maintains the rights stateside.
If it prevails in clinical trials and enters the market, INC424 would join a roster of Novartis orphan drugs that already includes Gleevec (imatinib mesylate) tablets, approved in the United States for 10 cancer indications; EXJADE (deferasirox), which treats chronic iron overload due to blood transfusions in patients 2 years of age and older; Zometa (zoledronate), a treatment for hypercalcemia of malignancy (HOM); and Ilaris (canakinumab), approved in the United States for the treatment of two forms of cryopyrin-associated periodic syndromes (CAPS): familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS).
In May, the FDA approved Afinitor (everolimus) for the treatment of progressive neuroendocrine tumors of a rare cancer, pancreatic origin (PNET), in patients with unresectable, locally advanced or metastatic disease. Afinitor is already approved in the United States and in Switzerland for the treatment of patients with subependymal giant cell astrocytoma (SEGA).
In addition, NIBR is carrying out early clinical research on drugs that target tuberous sclerosis complex, Muckle-Wells/CAPS, fragile X, medulloblastoma, Cowden's syndrome, spinal muscular atrophy, and Rett's syndrome.
“What makes rare disease research attractive is that we are clearly meeting an unmet medical need and these diseases are mechanistically well understood—making tackling the scientific challenges simpler and the development more efficient,” Lockwood said. “In addition, the mechanisms that underlie these diseases are usually shared by more common diseases, so understanding them can shed light on multiple ailments. Our approach is often to start by developing a drug for a rare disease and then apply it to more common ones later.”
Despite the recent pharma initiatives, skepticism remains concerning the extent to which companies will stay committed to translating orphan drug discoveries into new therapies for the market.
“Large pharmaceutical companies have frequently made a lot of noise about working in orphan space. And, if you ask me, the jury is very much out. Orphan product development has traditionally been dominated by small biopharmaceutical companies that have done amazing things with their very limited resources,” Timothy R. Coté, M.D., M.P.H., who until May served as director of the Office of Orphan Products Development at the FDA, told HGT.
“One of the resources large pharmaceutical companies have is a PR office. They have used that resource exceedingly well,” said Dr. Coté, now chief medical officer for the National Organization for Rare Disorders (NORD) and a faculty member at the Keck Graduate Institute (Claremont, CA).
“What we look at, both at NORD and here at Keck, is the buzz-to-beef ratio: How much buzz is there for how much beef. And when it comes to large pharma right now, there's quite a lot of buzz. And not as much beef as we would like to see.”
He said the measures of “beef” that orphan drug development supporters and others should examine include orphan status designations and product approvals.
“I have every hope for it. I am very, very much courting their involvement. I did so from inside the [FDA]. Every year, I went to every one of those companies, a couple of times. And I was there for four years,” Dr. Coté said. “I'm not from Missouri, but I do want to see it. I haven't seen it yet, but I'm hopeful.”
Pharma executives interviewed by HGT said they and their companies are committed to working to dispel such skepticism. One way pharma companies can do that is obvious: Push safe, effective new drugs past the laboratory and into the clinic, and then into the market. Beyond that, however, big pharma should open up more about its newly expressed commitment to research and development into rare diseases.
Interestingly, none of the four companies interviewed by HGT would disclose how much they spend on orphan-drug R&D, nor would they quantify how much they will increase that spending in coming years. Big pharma has generally shared overall R&D spending trajectories—up or down, depending on the company—for the near future, so any increases in orphan drug development would stand out, especially in companies with shrinking R&D budgets. Although more spending is never a guarantee of success, such increases can raise well-founded hopes for doctors, and especially patients, that all those roughly 7000 orphan diseases will finally become orphan drug indications, followed not too long after by new treatments.