Could the amyloid hypothesis have scored its first success? The European Medicines Agency (EMA) is poised to approve a drug that acts by blocking amyloid formation in a rare inherited disease, familial amyloid polyneuropathy (FAP). The disease attacks the peripheral nervous system, kidneys, and heart, robbing people of the ability to walk and leading to death within 10 years. FAP is caused by mutations in transthyretin that make the protein’s normal tetrameric state unstable, causing it to fall apart into monomers that then clump into amyloid (see, e.g., Colon et al., 1996). The new drug, tafamidis, acts by stabilizing the transthyretin tetramer, preventing it from dissociating. In clinical trials, people who took the drug maintained whatever leg strength and sensation they started with, showing only minimal deterioration over 30 months, and their autonomic nervous system function seemed to improve. The outcomes are in sharp contrast to the normal rapid deterioration seen with the disease. If the drug is approved as expected, it will become the first therapy to successfully treat an amyloid disease by interfering with amyloidosis.

Other scientists in the field hailed the development. “This is a proof of principle that the act of stabilizing a protein by a drug may have therapeutic benefit,” Gregory Petsko at Brandeis University, Waltham, Massachusetts, told ARF. “Because there are a large number of diseases where proteins are destabilized, I think this gives great encouragement to people like myself, who are trying to apply the same principle to other diseases.” For example, the approach might be applicable to some forms of amyotrophic lateral sclerosis (ALS), as well as to Parkinson’s disease and Lewy body dementias.

The drug, trade name Vyndaqel, is the culmination of some 20 years of work on transthyretin by researchers led by Jeff Kelly at the Scripps Research Institute, La Jolla, California. In 2004 Kelly founded the company FoldRx, which developed tafamidis under the direction of CEO Richard Labaudiniere. FoldRx is now a subsidiary of Pfizer Inc., which will market the drug. In July, the EMA Committee for Medicinal Products for Human Use issued a positive opinion on tafamidis, and the agency is expected to follow its recommendation and approve the drug within 60 days, at which point it will be immediately available by prescription in Europe. In the U.S., Pfizer is currently submitting a new drug application to the Food and Drug Administration. The approval process will probably take a year but is not expected to require new trials, Kelly told ARF.

FAP is most common in Portugal, Sweden, and Japan. This devastating disease typically strikes somewhere between ages 30 and 60, depending on the exact transthyretin mutation and the ethnic background. The disorder causes pain, muscle weakness, and sensory loss. Affected people lose the ability to walk, and they also develop autonomic nervous system problems, including gastrointestinal issues that lead to drastic weight loss. Late in the disease, amyloid deposits affect the heart and kidneys, causing organ failure and death. Transthyretin, a secreted protein that normally carries the thyroid hormone thyroxin, is made by the liver. Liver transplants have been the only available treatment to slow the course of the disease.

Tetramer dissociation is the rate-limiting step in transthyretin amyloid formation, Kelly told ARF. More than 100 transthyretin mutations are known, the majority of which weaken the tetramer and cause amyloidosis. The most common is a valine to methionine swap at position 30 (V30M). Intriguingly, a Portuguese family with the V30M mutation also carried a protective transthyretin mutation that stabilized tetramers; people who inherited both mutations did not develop the disease. Kelly and colleagues embarked on a search for drugs that had the same effect (see, e.g., ARF related news story on Hammarström et al., 2003; Green et al., 2005; Johnson et al., 2008). The scientists found that the weakest interface in the tetramer is the dimer-dimer interface, where thyroxin normally binds. Tafamidis binds at this site and, in effect, glues the tetramer together, raising the energy barrier for dissociation so high that it cannot happen under physiologic conditions, Kelly said. Petsko compares the mechanism to adding a tiny piece of Scotch tape to an Origami figure to hold it together.

The Phase 2/3 trial, conducted at sites throughout Europe, involved about 120 people with early to moderate FAP, all symptomatic. For 18 months, half the participants took 20 milligrams of tafamidis daily, while the rest got placebo. An open-label extension trial continued to 30 months, with all participants taking tafamidis. Since mobility is one of the first casualties of the disease, the main outcome measure was muscle strength, sensation, and reflexes in the legs. The slope of deterioration was dramatically different in the two groups, Kelly said, with patients taking tafamidis from the get-go experiencing little loss of function over 30 months. In addition, when people switched from placebo to drug, deterioration leveled off, showing that the drug is also beneficial when taken later in the disease course. Gastrointestinal function seemed to improve for people on the drug, as they regained lost weight. Once switched to drug, those who had been on placebo caught up to treatment group weights by month 30. “That really got the physicians’ attention,” Kelly said. Adverse events were mild and did not differ between the treatment and placebo arms, Kelly added. Trial results have been submitted for publication.

Although the Phase 2/3 trial participants carried the V30M mutation, an open-label study demonstrated that tafamidis also works for several other common mutations, and the EMA is likely to approve it for use with multiple mutations, Kelly said. It is possible that there are rare mutations for which the drug will not work, suggested Per Hammarström at Linköping University, Sweden, who did postdoctoral training in Kelly’s lab. One example might be a very rare form of FAP that affects the brain, he said. In this case, the mutation makes transthyretin so unstable that the protein does not get secreted, and stabilizing it could cause problems by allowing transthyretin to get out of cells and spread through the body. Kelly agreed tafamidis should not be prescribed for this class of patients.

Some transthyretin mutations, such as one that occurs in the African-American population, primarily cause cardiomyopathy, a weakening of the heart muscle. Sporadic transthyretin disease can also arise in elderly people, leading to cardiomyopathy. An open-label study suggested the drug will also help these cardiac patients, Kelly told ARF, but a placebo-controlled trial still needs to be done before tafamidis can be used in this population. Pfizer is currently running an extension of the cardio study and is recruiting for another open-label trial of the drug.

In the future, Kelly envisions that tafamidis could be used in pre-symptomatic people with transthyretin mutations, ideally preventing amyloid from ever forming. Kelly noted that in the clinical trial, those patients at the earliest stages of the disease saw the most dramatic benefit from treatment. His hope is that tafamidis could keep people asymptomatic for decades, in the same way that the protective transthyretin mutation prevents disease.

“As far as I know, this is the first pharmacologic evidence that the amyloid hypothesis has some validity,” Kelly said, as it demonstrates that blocking amyloid formation benefits patients. Kelly noted that they have no evidence that previously deposited amyloid is cleared, but the drug’s action does prevent the formation of new monomers and various other intermediates. Kelly speculated that this may be the reason that patients do better, as some previous research has suggested these small intermediates may be the toxic species (see ARF related news story). This idea has also gained popularity for Alzheimer’s disease, where many researchers now believe Aβ oligomers are the most harmful variety (see, e.g., ARF related news story and ARF news story).

Tafamidis represents an interesting approach to an amyloid disease, David Teplow at the University of California, Los Angeles, told ARF. “Most people have focused on how to [directly] block fibril assembly,” he said. This approach instead makes the native molecule more stable by using a pharmacological chaperone. The idea has been around for a while, Teplow said, but this is the first drug to demonstrate that the approach can work.

In many ways, transthyretin was an ideal test case for this method, several commentators pointed out. The protein is secreted, making it easily accessible to drugs, and it folds into a specific shape with a protein-binding site, allowing it to be stabilized. Also, transthyretin is not the main carrier for the hormone thyroxin, so blocking the binding site is not likely to have side effects.

Researchers are investigating pharmacological chaperones for several other diseases. Petsko pointed out that many recessive metabolic disorders, such as Gaucher's disease, Tay-Sachs' disease, and Fabry's disease, are caused by mutations that make proteins fall apart. Biotech company Amicus Therapeutics, based in Princeton, New Jersey, is conducting clinical trials of chaperones for Gaucher's and Fabry's disease. Cases of ALS caused by mutations in superoxide dismutase 1, which forms a native dimer, might also be amenable to this approach.

It is not clear if a chaperone approach could work for Alzheimer’s disease, Hammarström noted, as both the Aβ peptide and tau are disordered, with no folded structure to stabilize. Likewise, the α-synuclein protein that aggregates in Parkinson’s disease and Lewy body dementias has always been considered an unfolded protein. However, new evidence from Petsko’s lab and Dennis Selkoe’s group at Brigham and Women’s Hospital, Boston, Massachusetts, indicates that α-synuclein also forms a tetramer, opening up the possibility of gluing it together with chaperones, though unlike transthyretin, it does not have a native ligand (see ARF related news story). “I view the progress on transthyretin and development of tafamidis as an illustrative example of the route we and others should consider for attempting to find specific physiological synuclein stabilizers,” Selkoe wrote to ARF (see full comment below).—Madolyn Bowman Rogers.


  1. I am familiar with the tafamidis work and the recent recommendation of its approval for FAP. I view the preclinical and clinical science behind this success as an excellent example of a rationally designed, disease-modifying drug for a progressive, ultimately fatal amyloidosis. In a conversation with Jeff Kelly, whose basic research led to tafamidis, we agreed that this agent, which was tailor made to stabilize the physiological transthyretin tetramer, would presumably not bind to and stabilize the α-synuclein physiological tetramer. Nonetheless, I view the progress on transthyretin and development of tafamidis as an illustrative example of the route we and others should consider for attempting to find specific physiological synuclein stabilizers as therapeutics and preventatives for PD and other human synucleinopathies.

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News Citations

  1. NSAIDs and Derivatives Keep Transthyretin in Its Place
  2. Amyloidoses—Native and Synthetic Fibril Formers Offer Clues
  3. Aβ Oligomers and NMDA Receptors—One Target, Two Toxicities
  4. Bad Guys—Aβ Oligomers Live Up to Reputation in Human Studies
  5. An α-Synuclein Twist—Native Protein a Helical Tetramer

Paper Citations

  1. . FAP mutations destabilize transthyretin facilitating conformational changes required for amyloid formation. Ciba Found Symp. 1996;199:228-38; discussion 239-42. PubMed.
  2. . Prevention of transthyretin amyloid disease by changing protein misfolding energetics. Science. 2003 Jan 31;299(5607):713-6. PubMed.
  3. . Genistein, a natural product from soy, is a potent inhibitor of transthyretin amyloidosis. Proc Natl Acad Sci U S A. 2005 Oct 11;102(41):14545-50. PubMed.
  4. . Biochemical and structural evaluation of highly selective 2-arylbenzoxazole-based transthyretin amyloidogenesis inhibitors. J Med Chem. 2008 Jan 24;51(2):260-70. PubMed.

External Citations

  1. positive opinion
  2. Phase 2/3 trial
  3. open-label study
  4. cardiomyopathy
  5. open-label study
  6. cardio study
  7. open-label trial
  8. Gaucher's
  9. Fabry's

Further Reading