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Treatment of ‘terribly disabling’ porphyria complicated by disease rarity, misdiagnosis
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Clinicians are hoping an RNA interference therapeutic targeting aminolevulinic acid synthase 1, known as givosiran, will be the answer for many patients suffering from severe attacks and symptoms related to acute hepatic porphyria.
Patients with this rare family of genetic disorders have limited treatment options.
“It matters if this will be a great prophylactic drug so these patients don’t have attacks,” Samuel M. Silver, MD, PhD, MACP, professor of internal medicine and assistant dean for research at University of Michigan Medical School and HemOnc Today Editorial Board Member, told HemOnc Today. “People’s lives are totally disrupted by these porphyria attacks and, if the drug works, it could change lives.”
Porphyrias are a family of diseases characterized by abnormal functioning of heme biosynthesis enzymes, classified as erythropoietic or hepatic based on the primary site of accumulation of chemicals that produce porphyrins or porphyrin precursors. This buildup of porphyrin precursors and porphyrins can be toxic to many organ systems, such as skin — causing severe rashes — and the nervous system, causing peripheral neuropathy, generalized severe pain, seizures and autonomic dysregulation. They also can affect the liver, causing inflammation, fibrosis and potentially hepatocellular cancer.
“Most are inherited but porphyria cutanea tarda, the most frequent, is actually acquired more often than not,” Silver said.
All forms of porphyria affect fewer than 200,000 individuals in the United States. Based on estimates derived from European studies, the three most prevalent categories of porphyria are porphyria cutanea tarda, occurring in about one of 10,000 individuals; acute intermittent porphyria, with an incidence of one in 20,000; and erythropoietic protoporphyria, estimated to affect one in every 50,000 to 75,000.
The acute hepatic porphyrias are comprised of acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and delta-aminolevulinic acid dehydratase deficiency porphyria. The erythropoietic porphyrias are comprised of hepatoerythropoietic porphyria, congenital erythropoietic porphyria and X-linked protoporphyria.
“They present in multiple ways and are anywhere from rare to extremely rare,” Silver said. “Whether a patient presents to their internist, hematologist, neurologist, gastroenterologist or any other physician they may be seeing, it is unusual enough that the providers often don’t think about it or, if they do, they get the wrong diagnosis.”
Hemin (Panhematin, Recordati Rare Diseases) is the only heme compound approved for treatment of acute porphyria attacks in the United States. The drug’s prescribing information indicates that hemin should be considered after treatment with an alternate therapy, such as glucose. It also is used off-label for prevention of acute attacks.
Experts with whom HemOnc Today spoke said more therapeutics are needed to prevent the chronic symptoms and severe attacks that can sometimes be fatal.
Givosiran (Alnylam Pharmaceuticals) — an investigational RNA interference therapeutic that is administered subcutaneously and targets aminolevulinic acid synthase 1 — is currently in phase 3 development for the treatment of acute hepatic porphyria. By targeting aminolevulinic acid synthase 1, the therapy decreases accumulation of neurotoxic heme intermediates, aminolevulinic acid and porphobilinogen, thus preventing or reducing the occurrence of attacks and controlling overall symptoms.
HemOnc Today spoke with researchers and clinicians about the impact of porphyria, the high likelihood of misdiagnosis, and the need for more tests and treatments made readily available for patients.
Impact of disease
Signs and symptoms of porphyria can range from severe abdominal pain, constipation or diarrhea, and nausea or vomiting to chest pain, mental status changes (eg, confusion, anxiety or hallucinations), muscle weakness that can progress to paralysis, high blood pressure and seizures, and blistering or nonblistering skin rashes.
Acute intermittent porphyria, the most common acute hepatic porphyria, rarely becomes symptomatic due to its genetic enzyme defect. Of 100 patients with the genetic defect, only 10 to 20 patients secrete excess porphyrin precursors, and fewer display symptoms. The disease is most common among women aged younger than 40 years.
Researchers of the observational prospective EXPLORE trial — results of which were presented at this year’s European Association for the Study of the Liver Annual International Liver Congress — sought to characterize the natural history, clinical management and quality of life of 112 patients with acute hepatic porphyria. Patients in the study experienced at least three attacks a year or received hemin or gonadotropin-releasing hormone analogue to prevent attacks.
Researchers found that not only did patients suffer from acute attacks, but 65% also experienced chronic symptoms between attacks, thus disrupting quality of life.
The annual attack rate was 3.7 events, which included the 46% of patients taking hemin as prophylaxis. Mean attack duration was 7.3 days. Seventy-six percent of attacks were treated in a health care facility or with hemin.
“These patients are having recurrent attacks, and they not only suffer from these terribly disabling attacks, but also from debilitating symptoms between attacks,” Amy R. Simon, MD, senior director of clinical development at Alnylam Pharmaceuticals, told HemOnc Today. “These people don’t have a lot of good therapeutic options and need a therapeutic that will both help prevent attacks as well as help alleviate the disease manifestations — most commonly pain, nausea and fatigue — in between attacks.”
Potential for misdiagnosis
The most common porphyria is porphyria cutanea tarda, an iron-related disease associated with alcohol and hepatitis C virus infection and HIV infection, as well as hereditary hemochromatosis. It is usually recognized by dermatologists and readily treated with phlebotomy or hydroxychloroquine, an antimalaria drug.
Conversely, acute intermittent porphyria is easily misdiagnosed, potentially leading to devastating consequences for patients.
Porphyria is diagnosed through blood, urine and stool tests. Not all individuals who inherit porphyria have or show symptoms. Thus, porphyria can go years without being diagnosed.
There often is a delay in diagnosis of acute intermittent porphyria because symptoms are very nonspecific and neurological, according to Karl E. Anderson, MD, FACP, associate director of the General Clinical Research Center and professor of preventive medicine and community health at The University of Texas Medical Branch.
“It doesn’t present with a hematological problem, but rather as abdominal pain and neuropathy, often leading to acute hospitalization,” Anderson told HemOnc Today. “Primary care physicians and gastroenterologists would be the primary ones to diagnose it.”
In other cases, patients may be diagnosed with porphyria when they do not, in fact, have the disorder.
“A lot of these patients don’t wind up getting appropriately treated or, equally as bad, they are misdiagnosed as having this and inappropriately treated when they don’t have the disease,” Silver said.
A typical misdiagnosis is based on elevated porphyrin levels.
“Porphyrins are elevated in many other conditions, so sometimes people think if the porphyrins are elevated it is porphyria, and it’s not,” Anderson said. “It can also be misdiagnosed as another disease when people really have it.”
In order to be properly diagnosed, the correct tests need to be performed.
Silver recommends that patients who experience symptoms of the acute porphyrias go home and urinate in a cup, cover it and protect it from sunlight, and bring it to the office next business day so it can be sent to an experienced lab for quantitation of porphobilinogen.
“Because this is rare, when a clinician sees a high porphyria level, especially a high urinary coproporphyrin level — which you can get from a number of medications, and not necessarily from porphyria — it is suddenly an automatic diagnosis of porphyria, and may not be correct,” Silver said.
The wait for a diagnosis can be frustrating for patients.
“It’s a diagnostic journey that is quite fraught for patients and often is a very painful part of their lives,” Simon said. “They can be told the disease is only in their mind, be accused of seeking opioid medications or undergo medical procedures that are ultimately unnecessary, such as endoscopy or laparoscopy.
“Of course, this negative treatment isn’t intentional by medical providers, but this is a rare disease with symptoms and signs that can seem out of proportion to findings on the physical exam, and the initial diagnostic tests are often unrevealing,” Simon added. “It is important to keep top of mind that, though the diagnostic pathway for patients with an acute hepatic porphyria can be challenging, it is very simple to identify whether patients have porphyria by sending a spot urine test for the porphyrin precursors aminolevulinic acid and porphobilinogen.”
Existing, future treatments
Porphyria attacks can be severe and may lead to fatalities. However, preventive measures can be taken by individuals to assist in avoiding attacks. These measures include avoiding alcohol and certain drugs — barbiturates, tranquilizers, birth control pills and sedatives — and limiting exposure to sunlight.
It is important to develop new treatments to make porphyria attacks less frequent.
“Some do go on and continue to have many symptoms, so it’s important to treat attacks and find ways to prevent them,” Anderson said.
Although there is no cure for porphyria, there are treatment options for each category of disease.
Meperidine hydrochloride may be given for pain, and glucose is given to maintain carbohydrate levels. Injections of hemin are used to limit the body’s production of porphyrin and porphyrin precursors.
For porphyria cutanea tarda, hydroxychloroquine is used to absorb excess porphyrins in patients who cannot tolerate phlebotomy to reduce the body’s iron and porphyrins.
Increasingly, research is directed toward treating the underlying mechanisms that cause symptoms, as well as developing new therapeutics.
Phase 1/phase 2 open-label extension studies of givosiran — also presented at this year’s Annual International Liver Congress — showed that the safety profile supports continued clinical development, given a greater than 90% decrease in the mean annualized porphyria attack rate and hemin use compared with baseline.
The studies included 16 patients, seven of whom (44%) achieved an annualized attack rate of zero following a mean of 8.5 months on treatment. Conversely, during the prospectively monitored run-in period, these patients had experienced a median annualized attack rate of 15.1 (range, 6.3-34).
These data led to the phase 3 ENVISION clinical trial, for which researchers have randomly assigned 94 patients aged 12 years and older to receive a subcutaneous injection of 2.5 mg/kg givosiran or placebo once a month over 6 months to measure the reduction in neurotoxic heme intermediates, aminolevulinic acid and porphobilinogen, as well as attacks, hemin use, chronic symptoms and quality of life.
Annualized rate of attacks over 6 months serves as the study’s primary endpoint. Secondary endpoints include the reduction of chronic symptoms — such as pain, nausea and fatigue — that impact daily and overall quality of life.
Alnylam Pharmaceuticals expects to report topline study results of the primary endpoint — the annualized attack rate after 6 months of treatment — in early 2019.
“The bottom line for the future is to determine whether givosiran can be effective to prevent acute attacks,” Silver said.
It also remains important to identify other genetic factors that may play a role in porphyria symptoms and acute attacks, because most people who inherit the familial mutation never get sick, Anderson said.
“We need to know why other modifying genes make the disease worse,” he said. “It’s important to figure out what other genetic factors and environmental factors are contributing, so they can be corrected.” – by Melinda Stevens
References:
Ramanujam V-MS and Anderson KE. Curr Protoc Hum Genet. 2015;doi:10.1002/0471142905.hg1720s86.
The following were presented at European Association for the Study of the Liver Annual International Liver Congress; April 11-15, 2018; Paris:
Sardh E, et al. Abstract GS-016.
Gouya L, et al. Abstract PS-143.
For more information:
Karl E. Anderson, MD, FACP, can be reached at University of Texas Medical Branch, 301 University Blvd., Galveston, TX, 77555; email: kanderso@UTMB.EDU.
Samuel M. Silver, MD, PhD, MACP, can be reached at University of Michigan Medical School, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109; email: msilver@umich.edu.
Amy R. Simon, MD, can be reached at Alnylam Pharmaceuticals, 300 Third St., Cambridge, MA, 02142; email: media@alnylam.com.
Disclosures: Silver reports he is a principal investigator on the ENVISION clinical trial, and has received travel support from the American Porphyria Foundation. Simon reports employment with Alnylam Pharmaceuticals. HemOnc Today could not confirm Anderson’s relevant financial disclosures at the time of reporting.