12:56 Auxilium: Xiaflex's presence in the blood system could lead to systemic toxicities; immunogenicity concerns remain - experts
Story * FDA advisory panel meeting scheduled for 16 September 2009
* Detecting Xiaflex in the urine indicates that it traveled through the blood system and could affect other organs
* Xiaflex specific for Types I and III collagen, but liver and lungs abundant with these types of collagen
* Even a slight elevation in IgE levels could elicit severe allergic reaction, said an expert
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Auxilium’s (NASDAQ:AUXL) Xiaflex for Dupuytren’s contracture could potentially harm organs in the body, since 7-28% of the collagenase was found in patients’ urine - indicating that the drug enters the blood system, physicians said. The experts interviewed also questioned whether the immune response observed in early clinical trials is negligible.
In a paper titled "Collagen as a Clinical Target: Nonoperative Treatment of Dupuytren’s Disease," which published the data from one of Xiaflex’s Phase II trials, the authors stated that 7-28% of the drug was recovered in patients' urine after 30 to 60 minutes, and claimed that this finding may indicate the kidney’s ability to concentrate collagenase. The paper - which was published in the Journal of Hand Surgery in 2002 - further noted that no collagenase was detected in any of the serum samples collected from one minute to 19.5 hours after the injection was given.
Will Sargent, Auxilium’s vice president of investor relations and corporate communications, also noted that the signal for IgE (immunoglobulin E) – an antibody that plays an important role in allergy – was initially seen in the early development stages of Xiaflex. However, the Phase III results reported that no systemic allergic reactions were noted, despite the fact that the most common adverse events were pain, swelling, bruising and pruritis at the injection site and transient lymph node swelling.
A BLA was recently submitted for Xiaflex and an FDA advisory committee meeting will be held on 16 September 2009.
If 7-28% of collagenase is found in the urine, it means the enzyme must have circulated in the blood plasma and subsequently filtered in the kidney and in the urine, said Dr Erik Ilso Christensen, a professor of anatomy at Aarhus University. Consequently, the collagenase could enter a variety of organs from the blood, notably the liver, he added.
Various PKA studies were done to monitor for systemic exposure but it was very difficult to find evidence, according to Dr Larry Hurst, chief of hand surgery and chair of the department of orthopedics of the Health Science Center at the State University of New York at Stony Brook, and primary investigator of the Phase III CORD trials. The drug "seems to go away," he said.
“How the collagenase got from the Dupuytren’s cord in the hand all the way to the kidney is a mystery if it did not pass through the blood compartment,” said Robert G. Hamilton, PhD, a professor of medicine and pathology at the Johns Hopkins University School of Medicine and the investigator who conducted the pharmacokinetic studies for Xiaflex.
Dr Vijay Vanguri, an instructor in the department of pathology at the University of Massachusetts Medical School, agreed that if collagenase is injected locally into the body, but is detected in the urine, the only way for the drug to appear in the urine is to travel through the bloodstream and filter through the kidneys.
Furthermore, Vanguri noted that the fact the collagenase is circulating through the bloodstream opens the possibility that the drug could affect other organs as well. Collagenase has to be in the blood for some time in order to reach the kidney, added Dr Helmut Rennke, a professor of pathology at Brigham and Women’s Hospital. The time it takes collagenase to travel from the hand to the kidneys provides ample time for the drug to reach other organs in the body, added Rennke.
Sargent noted that Xiaflex is specific for Types I and III collagen, which is not present in nerve bundles. However, Rennke noted that other Types I and III collagen were abundant in other parts of the body.
The liver and lungs could be significantly affected by the type of collagenase that makes up Xiaflex, as both these organs have Types I and III collagen, said Rennke. He also noted that bones have Type I collagen, which could also be "damaged" by the drug.
The company should really test the collagen content in the body, especially in the liver and lungs, to determine whether Xiaflex dramatically decreases the amount of collagen in these organs, Rennke said. A major decrease in collagen content could destruct the structure of these organs, he added.
A couple of sources also questioned whether the lack of collagenase in the tested blood actually indicated that the drug did not circulate through the body. “I suggest that the best analytical assays we had available to measure collagenase were most likely too insensitive to detect the administered level of collagenase that was diluted by the total blood volume of five liters,” said Hamilton. He added that it was possible that the time when the blood was collected was not ideal to catch the bolus of collagenase in the blood.
If the level of collagenase found in the blood is low, but is found in the urine, this indicates that tissues must have absorbed the drug as it flowed through the blood system, added Rennke. “To me, this is evidence that organs take up the collagenase,” he said.
Physicians also questioned whether the immunogenicity response seen in the clinical trials could be considered a negligible response. “Truth be told, even though Xiaflex is injected into the cord in the hand, there is sufficient inflammation at the site to allow effective antibody responses to be detected,” said Hamilton.
He also mentioned that although Auxilium stated that low levels of IgE were detected among patients, the conclusion that there would be no allergic response could not be drawn. As an example, Hamilton noted that very low levels of IgE anti-venom in combination with a honeybee sting could elicit a severe allergic reaction in a predisposed individual.
Because the collagenase used for Xiaflex comes from a bacterial source, there will always be a concern that patients would form an immune complex, said Rennke. A serious immune response, such as serum sickness, could cause serious complications, he added.
Serum sickness is an allergic reaction to proteins derived from a foreign source, such as an animal. A patient with serum sickness will experience hypocomplementemia, which is the condition where proteins cease to function or perform poorly.
Dr Bo Yu, a former researcher at Advance Biofactures, a subsidiary of Biospecifics Therapeutics (NASDAQ:BSTC) - the innovators of collagenase for Dupuytren's contracture – who is familiar with the pharmacokinetic studies of Xiaflex, also agreed that immunogenicity is a potential problem with collagenase.
Rennke further noted that the fact that Xiaflex is given intermittently could greatly decrease the drug's efficacy. The amount of time in between each injection allows patients to form antibodies against the drug, which would make them immune to the collagenase, he said.
Dr Roy Meals, a clinical professor of orthopedic surgery at the University of California, Los Angeles and an investigator for Xiaflex, noted that Xiaflex is a foreign protein so patients can develop an allergic reaction, but such reactions have not been observed. Some patients in the Phase II and III trials had as many as eight injections over a year, and there were no allergic responses. The expression of antibodies was not an issue, he added.
Dr F. Thomas Kaplan, a surgeon at the Indiana Hand Center, noted that blood work was performed throughout the trial for immunogenicity testing, but the results were not provided to the investigators. Investigators were initially concerned about the immunogenicity of Xiaflex because it is a large protein, but the immune response has been studied and it is not an issue, according to Hurst, who has personally done over 300 injections and only seen one episode of hives that was treated with a shot of Benadryl. Lymph node swelling decreased rapidly, he said.
When asked if an immune response would be mechanistically linked to collagenase or if it were specific to Xiaflex itself, Dr Roy Kulick, associate professor of orthopedic surgery at Albert Einstein School of Medicine and director of orthopedic hand surgery at Montefiore Medical Center in New York, noted that mast cells are not activated by collagen breakdown. Mast cells are involved in allergic and anaphylactic response.
With regards to the upcoming advisory panel, the FDA has only requested total antibody data, according to Sargent. He also noted that Savient Pharmaceutical's (NASDAQ:SVNT) advisory panel for its gout drug Krystexxa demonstrates the fact that the FDA Arthritis Advisory Committee does not focus on IgE and only looks for clinical events.
Xiaflex treats Dupuytren’s Contracture – a condition where the hand is constantly in a contracted position - by dissolving the collagen in the contracted cord in the hand. The collagenase that makes up Xiaflex is purified from the bacteria clostridia.
Auxilium has a market cap of USD 1.25bn.
by Jacqueline Kwong and Elizabeth Krutoholow
Source Pharmawire
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