The US Food and Drug Administration (FDA) has granted orphan drug designation to Systebryl (PTI-110), a small molecule drug developed by ProteoTech, Inc., as a therapy for immunoglobulin light chain (AL) amyloidosis.1
AL amyloidosis is a rare hematologic disorder characterized by deposits of insoluble amyloid (starch-like) fibrils in the extra-cellular space of various tissues. The fibrils are collections of misfolded immunoglobulin light chain proteins. In AL amyloidosis, plasma cells in the bone marrow spontaneously begin overproducing the defective amyloid proteins, outpacing the body’s ability to eliminate them. Systems may be mild to life-threatening.
Systebryl is believed to work by targeting and disaggregating amyloid deposits, allowing them to be cleared from the body. The company describes Systebryl as a “first-in-class disease-modifying drug” and notes that no other therapies are approved to treat AL amyloidosis.1
The company plans to initiate phase 1/2 proof-of-concept trials later this year.
Although chemotherapy is sometimes used to treat patients with AL amyloidosis, it is ineffective for at least 33% of patients.2
Autologous stem cell transplant may be an option for some patients, but a 2013 review published in Blood
on treatment options for AL amyloidosis notes that the evidence for ASCT is limited, with only 1 randomized trial of ASCT conducted in this patient population. Early diagnosis is associated with better outcomes, but for many patients, diagnosis is often delayed.
With systemic AL amyloidosis, all organs and the peripheral nervous system may be affected, whereas the central nervous system is typically spared (Figure
At diagnosis, two-thirds of patients with AL amyloidosis have classical deposits in the kidneys, and these patients typically present with heavy proteinuria or nephritic syndrome.3
Between 20% and 45% have a reduced glomerular filtration rate. Almost 50% of patients have diastolic heart failure at diagnosis, and 70% or more ultimately experience cardiovascular involvement.2,3
Deposits of amyloid cause the atrial and ventricular walls to thicken, and patients with cardiovascular involvement display varying degrees of muscle weakness, shortness of breath, and fluid retention in their lower limbs.3
Vascular infiltration can also cause serious bleeding complications. Amyloid-related heart disease is considered an independent predictor of death due to heart failure or arrhythmia.
Other more commonly affected tissues include the gastrointestinal tract, liver, and tongue.2,3
Manifestations of AL amyloidosis have been observed in the spleen and lung; some studies describe involvement of these organs as rare, whereas others suggest it may be more common. Some patients also experience skin lesions and joint problems.
ANS, automatic nervous system; PNS, peripheral nervous system.
Rare Diseaes Quick Facts: AL Amyloidosis
Several types of amyloidoses occur, of which AL (primary) amyloidosis is the most common and most severe.3
The disease affects 10,000 to 20,000 people worldwide each year. 4
The average age at diagnosis is 65 years.3
Survival for patients with advanced AL amyloidosis at diagnosis is 4 to 6 months.4
Veterans exposed to Agent Orange may be at risk for AL amyloidosis.5
ProteoTech is granted orphan drug designation for Systebryl (PTI-110) for the treatment of AL amyloidosis [press release]. http://www.businesswire.com/news/home/20150112005166/en/ProteoTech-Granted-Orphan-Drug-Designation-Systebryl%E2%84%A2-PTI-110#.VMav0P54o04. Published January 12, 2015. Accessed January 26, 2015.
Merlini G, Wechalekar AD, Palladini G. Systemic light chain amyloidosis: an update for treating physicians. Blood. 121:5124-5130.
Desport E, Bridoux F, Sirac C, et al. AL Amyloidosis. Orphanet J Rare Dis. 2012;7:54.http://www.ojrd.com/content/pdf/1750-1172-7-54.pdf Accessed January 31, 2015.
Proteotech. Promising therapy for AL (immunoglobulin light chain) amyloidosis. http://www.proteotech.com/pipeline/systebryl.html. Published 2014. Accessed January 26, 2015.
Institute of Medicine. Veterans and agent orange: update 1996. Summary and research highlights. http://www.iom.edu/Reports/1997/Veterans-and-Agent-Orange-Update-1996-Summary-and-Research-Highlights.aspx. Published April 18, 1997. Accessed January 26, 2015.