Drug Information Association (DIA): Improving Clinical Trial Sampling for Future Research: An International Approach

PHILADELPHIA  – Drug companies want better access to study participants’ genes.

Pharmacogenomic analyses have become a key part of state-of-the-art drug trials, to better hunt down the causes of adverse events or poor drug responses, but the pharmaceutical companies funding and organizing those trials have often been stymied in collecting and using genetic specimens from study participants.

The problem has grown so acute that in September a core group of research facilitators from drug companies together with representatives from academia and regulatory agencies met for a 2-day workshop so that these barriers in the United States, Europe, Japan, and the rest of the world could be better understood and participants could brainstorm solutions.

"Clinical trial sample collection for future research is vital. It provides resources to answer regulatory questions on safety and efficacy, perform testing to elucidate unexpected clinical responses during trials, and allows pharmacovigilence testing of marketed compounds. High [specimen] collection rates that are representative of clinical trial populations and informed consent for broad sample use is essential to insure that the [trial] results broadly apply to all people in the study population," said Amelia Wall Warner, Pharm.D., head of clinical pharmacogenomics and clinical specimen management at Merck in North Wales, Pa., and chairwoman of the meeting.

Despite this, trial organizers at Merck and many other companies have encountered resistance or restrictions on specimen collection and use from regulatory authorities, academic institutions, and the institutional review boards (IRBs) and ethics committees that oversee trials.

The problem may be resolving in the United States through recent actions of the Food and Drug Administration.

"There is a fine line between ethics committees that protect their populations but prevent us from fully investigating the safety and efficacy of a drug in a population," Dr. Warner said. "Health authorities will allow collections, but narrow the scope of their use. Regulatory authorities often require adequate representation of their country’s population for a drug’s approval, but because of genetic variations across populations, the sample size must be representative. Adequate statistical power is needed, but collection of optimal DNA samples for a high percent of patients enrolled in industry clinical trials is still a challenge.

"We use specimens to investigate adverse events and nonresponders, which ultimately benefits patients. Distrust is what we have to overcome. But it’s not patients who [generally] don’t want to participate, it’s the investigators," she said in an interview. "Many patients agree to participate" with specimen collection once a trial receives approval and patients understand the goals of the trial and the reasons for specimen collection, she noted.

Although workshop attendees came up with a list of ways to try to resolve the problem and acknowledged that in an era of global trials solutions need tailoring to the diverse range of barriers that often differ from country to country, the solutions largely boil down to two main strategies – better education and trust building – participants said repeatedly during the sessions.

The problem may also already be resolving in the United States through recent actions of the Food and Drug Administration, a development that may have global impact if regulatory bodies and IRBs in other countries follow the U.S. lead. Last February, the FDA issued draft guidance on clinical pharmacogenomics in clinical studies.

The draft guidance "is very supportive" of DNA specimen collection and analysis, said Gilbert J. Burckart, Pharm.D., associate director for regulatory policy in the Office of Clinical Pharmacology, Center for Drug Evaluation and Research at the FDA. "Sample collection is critical to what you do," he told the industry representatives at the workshop. "You don’t have the science unless you do it, and do it properly." He noted that work on the guidance began in 2008, with the finalized version of the guidance due out soon. The FDA received more than 200 comments on the draft, with the comment period now closed.

The draft says that pharmacogenomic information collected during both drug development and postmarketing studies "can improve the effectiveness and safety of drugs." The draft also notes that "an important prerequisite to successful use of genetic information in drug development is the appropriate collection and storage of DNA samples from all clinical trials ... Plans for general DNA sample collection should be prespecified ... even if these samples are studied only at a later time, during, or after the study. It then becomes possible to seek explanations for differences in exposure, efficacy, tolerability, or safety not anticipated prior to beginning the study."

The draft also cites three recent, real world examples where pharmacogenomic data proved critical in understanding and refining treatment challenges with certain drugs:

• Abacavir (Ziagen), an HIV drug, produces a hypersensitivity reaction in about 5%-8% of patients. About 3-4 years after abacavir receive marketing approval, pharmacogenomic research identified a HLA allele (HLA-B*5701) that appeared associated with the reaction. A prospective trial, PREDICT-1, assessed the relationship between this HLA marker and abacavir hypersensitivity, resulting in revised labeling in 2008 that included a strong recommendation for HLA screening of patients before prescribing the drug (N. Engl. J. Med. 2008;358:568-79).

• Clopidogrel (Plavix), an antiplatelet drug widely used to reduce thrombotic events in patients with cardiovascular disease. Clopidogrel is a prodrug that requires multiple cytochrome P450 enzymes for conversion into its active form. Postmarketing studies of clopidogrel showed that a genetic allele of CYP2C19 linked to reduced production of the active metabolite and poorer clinical responses in patients. This led to revised clopidogrel labeling in 2009 and again in 2010 for patients with reduced CYP2C19 function.

• Warfarin, a widely used antithrombotic drug, requires ongoing monitoring of the coagulation state of patients receiving the drug. Variations in the cytochrome P450 enzyme CYP2C9 and in the VKORC1 gene, which encodes the vitamin K epoxide reductase, account for a substantial part of the variability in warfarin’s effect in patients. In 2010, the FDA updated the labeling for warfarin to include a table to guide initial dosing with the drug based on CYP2C9 and VKORC1 genotypes.

"The FDA guidance will make significant headway for U.S.-based studies, and our hope is that potentially the ICH [International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use] will pick up the topic and talk about harmonization of at least the collection of future-use specimens across the United States, Europe, and Japan," Dr. Warner said at the meeting, sponsored by the Drug Information Association. Even now, before the finalized version of the guidance, "communicating the FDA draft guidance has helped." The draft guidance "already seems to be [affecting] decisions" made by trial oversight groups both in the United States and elsewhere, she noted. "When an IRB has questions about the scope of research, we [Merck] have sent them the FDA’s draft guidance, and we’re getting positive responses."

Recent cancer-drug development stands in sharp contrast, having largely avoided the pharmacogenomic issues. "Oncology is often considered an exception. Pharmacogenomics has been most beneficial [to date] in oncology." Cancer drug development has already undergone "a paradigm change," that embraced pharmacogenomics, Dr. Warner said in an interview.

Some recent examples of the now tight link between clinical specimen collection, pharmacogenomic analysis, and cancer-drug development include vemurafenib (Zelboraf), a recently approved drug that specifically acts against cases of advanced melanoma that feature a mutation in the BRAF gene, and crizotinib (Xalkori), which is particularly active against advanced-stage lung cancer that features an ALK fusion mutation.

Other steps the workshop participants agreed on included having companies and industry associations formalize best practices for specimen collection and use, partnering with patient advocacy groups, and, above all, better education aimed at all parties – government authorities, academic institutions, researchers, ethics committees, and IRBs – on why specimens are collected, how they’re handled, and the safeguards in place to ensure confidentiality and proper use. Another development that should ease restrictions going forward is the increasing integration of pharmacogenomics into routine medical practice, and the resultant increased familiarity and comfort that physicians and patients have with these analyses.

"There has been frustration that [drug companies] have identified subpopulations [defined by pharmacogenomics] that hasn’t yet translated yet into clear dosing strategies," Dr. Warner said. The drug industry "needs to do better defining dosing strategies [when physicians] collect pharmacogenomic information.

"Industry needs to build trust for how we collect, store, and use specimens for research. We need to make transparent our processes and how we put them into practice to ensure patient protection and ensure we use specimens responsibly. A realistic goal is a global success rate [for clinical-specimen collection 5 years from now] of 80%. A goal of more than 90%" would be ideal, but probably is not realistic given current issues and challenges, she said.

"Pharma is moving toward more trials in developing countries, where there is more restriction and concern about specimen collection and storage, which will hold us back from a 5-year goal of more than 90%. We’re going to have to make targeted efforts in key countries, such as China. Local storage and analysis [of specimens] will be the strategy that most companies will need to implement."

Dr. Warner is an employee of Merck. Dr. Burckart said he had no disclosures.

PHILADELPHIA  – Drug companies want better access to study participants’ genes.

Pharmacogenomic analyses have become a key part of state-of-the-art drug trials, to better hunt down the causes of adverse events or poor drug responses, but the pharmaceutical companies funding and organizing those trials have often been stymied in collecting and using genetic specimens from study participants.

The problem has grown so acute that in September a core group of research facilitators from drug companies together with representatives from academia and regulatory agencies met for a 2-day workshop so that these barriers in the United States, Europe, Japan, and the rest of the world could be better understood and participants could brainstorm solutions.

"Clinical trial sample collection for future research is vital. It provides resources to answer regulatory questions on safety and efficacy, perform testing to elucidate unexpected clinical responses during trials, and allows pharmacovigilence testing of marketed compounds. High [specimen] collection rates that are representative of clinical trial populations and informed consent for broad sample use is essential to insure that the [trial] results broadly apply to all people in the study population," said Amelia Wall Warner, Pharm.D., head of clinical pharmacogenomics and clinical specimen management at Merck in North Wales, Pa., and chairwoman of the meeting.

Despite this, trial organizers at Merck and many other companies have encountered resistance or restrictions on specimen collection and use from regulatory authorities, academic institutions, and the institutional review boards (IRBs) and ethics committees that oversee trials.

The problem may be resolving in the United States through recent actions of the Food and Drug Administration.

"There is a fine line between ethics committees that protect their populations but prevent us from fully investigating the safety and efficacy of a drug in a population," Dr. Warner said. "Health authorities will allow collections, but narrow the scope of their use. Regulatory authorities often require adequate representation of their country’s population for a drug’s approval, but because of genetic variations across populations, the sample size must be representative. Adequate statistical power is needed, but collection of optimal DNA samples for a high percent of patients enrolled in industry clinical trials is still a challenge.

"We use specimens to investigate adverse events and nonresponders, which ultimately benefits patients. Distrust is what we have to overcome. But it’s not patients who [generally] don’t want to participate, it’s the investigators," she said in an interview. "Many patients agree to participate" with specimen collection once a trial receives approval and patients understand the goals of the trial and the reasons for specimen collection, she noted.

Although workshop attendees came up with a list of ways to try to resolve the problem and acknowledged that in an era of global trials solutions need tailoring to the diverse range of barriers that often differ from country to country, the solutions largely boil down to two main strategies – better education and trust building – participants said repeatedly during the sessions.

The problem may also already be resolving in the United States through recent actions of the Food and Drug Administration, a development that may have global impact if regulatory bodies and IRBs in other countries follow the U.S. lead. Last February, the FDA issued draft guidance on clinical pharmacogenomics in clinical studies.

The draft guidance "is very supportive" of DNA specimen collection and analysis, said Gilbert J. Burckart, Pharm.D., associate director for regulatory policy in the Office of Clinical Pharmacology, Center for Drug Evaluation and Research at the FDA. "Sample collection is critical to what you do," he told the industry representatives at the workshop. "You don’t have the science unless you do it, and do it properly." He noted that work on the guidance began in 2008, with the finalized version of the guidance due out soon. The FDA received more than 200 comments on the draft, with the comment period now closed.

The draft says that pharmacogenomic information collected during both drug development and postmarketing studies "can improve the effectiveness and safety of drugs." The draft also notes that "an important prerequisite to successful use of genetic information in drug development is the appropriate collection and storage of DNA samples from all clinical trials ... Plans for general DNA sample collection should be prespecified ... even if these samples are studied only at a later time, during, or after the study. It then becomes possible to seek explanations for differences in exposure, efficacy, tolerability, or safety not anticipated prior to beginning the study."

The draft also cites three recent, real world examples where pharmacogenomic data proved critical in understanding and refining treatment challenges with certain drugs:

• Abacavir (Ziagen), an HIV drug, produces a hypersensitivity reaction in about 5%-8% of patients. About 3-4 years after abacavir receive marketing approval, pharmacogenomic research identified a HLA allele (HLA-B*5701) that appeared associated with the reaction. A prospective trial, PREDICT-1, assessed the relationship between this HLA marker and abacavir hypersensitivity, resulting in revised labeling in 2008 that included a strong recommendation for HLA screening of patients before prescribing the drug (N. Engl. J. Med. 2008;358:568-79).

• Clopidogrel (Plavix), an antiplatelet drug widely used to reduce thrombotic events in patients with cardiovascular disease. Clopidogrel is a prodrug that requires multiple cytochrome P450 enzymes for conversion into its active form. Postmarketing studies of clopidogrel showed that a genetic allele of CYP2C19 linked to reduced production of the active metabolite and poorer clinical responses in patients. This led to revised clopidogrel labeling in 2009 and again in 2010 for patients with reduced CYP2C19 function.

• Warfarin, a widely used antithrombotic drug, requires ongoing monitoring of the coagulation state of patients receiving the drug. Variations in the cytochrome P450 enzyme CYP2C9 and in the VKORC1 gene, which encodes the vitamin K epoxide reductase, account for a substantial part of the variability in warfarin’s effect in patients. In 2010, the FDA updated the labeling for warfarin to include a table to guide initial dosing with the drug based on CYP2C9 and VKORC1 genotypes.

"The FDA guidance will make significant headway for U.S.-based studies, and our hope is that potentially the ICH [International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use] will pick up the topic and talk about harmonization of at least the collection of future-use specimens across the United States, Europe, and Japan," Dr. Warner said at the meeting, sponsored by the Drug Information Association. Even now, before the finalized version of the guidance, "communicating the FDA draft guidance has helped." The draft guidance "already seems to be [affecting] decisions" made by trial oversight groups both in the United States and elsewhere, she noted. "When an IRB has questions about the scope of research, we [Merck] have sent them the FDA’s draft guidance, and we’re getting positive responses."

Recent cancer-drug development stands in sharp contrast, having largely avoided the pharmacogenomic issues. "Oncology is often considered an exception. Pharmacogenomics has been most beneficial [to date] in oncology." Cancer drug development has already undergone "a paradigm change," that embraced pharmacogenomics, Dr. Warner said in an interview.

Some recent examples of the now tight link between clinical specimen collection, pharmacogenomic analysis, and cancer-drug development include vemurafenib (Zelboraf), a recently approved drug that specifically acts against cases of advanced melanoma that feature a mutation in the BRAF gene, and crizotinib (Xalkori), which is particularly active against advanced-stage lung cancer that features an ALK fusion mutation.

Other steps the workshop participants agreed on included having companies and industry associations formalize best practices for specimen collection and use, partnering with patient advocacy groups, and, above all, better education aimed at all parties – government authorities, academic institutions, researchers, ethics committees, and IRBs – on why specimens are collected, how they’re handled, and the safeguards in place to ensure confidentiality and proper use. Another development that should ease restrictions going forward is the increasing integration of pharmacogenomics into routine medical practice, and the resultant increased familiarity and comfort that physicians and patients have with these analyses.

"There has been frustration that [drug companies] have identified subpopulations [defined by pharmacogenomics] that hasn’t yet translated yet into clear dosing strategies," Dr. Warner said. The drug industry "needs to do better defining dosing strategies [when physicians] collect pharmacogenomic information.

"Industry needs to build trust for how we collect, store, and use specimens for research. We need to make transparent our processes and how we put them into practice to ensure patient protection and ensure we use specimens responsibly. A realistic goal is a global success rate [for clinical-specimen collection 5 years from now] of 80%. A goal of more than 90%" would be ideal, but probably is not realistic given current issues and challenges, she said.

"Pharma is moving toward more trials in developing countries, where there is more restriction and concern about specimen collection and storage, which will hold us back from a 5-year goal of more than 90%. We’re going to have to make targeted efforts in key countries, such as China. Local storage and analysis [of specimens] will be the strategy that most companies will need to implement."

Dr. Warner is an employee of Merck. Dr. Burckart said he had no disclosures.

PHILADELPHIA  – Drug companies want better access to study participants’ genes.

Pharmacogenomic analyses have become a key part of state-of-the-art drug trials, to better hunt down the causes of adverse events or poor drug responses, but the pharmaceutical companies funding and organizing those trials have often been stymied in collecting and using genetic specimens from study participants.

The problem has grown so acute that in September a core group of research facilitators from drug companies together with representatives from academia and regulatory agencies met for a 2-day workshop so that these barriers in the United States, Europe, Japan, and the rest of the world could be better understood and participants could brainstorm solutions.

"Clinical trial sample collection for future research is vital. It provides resources to answer regulatory questions on safety and efficacy, perform testing to elucidate unexpected clinical responses during trials, and allows pharmacovigilence testing of marketed compounds. High [specimen] collection rates that are representative of clinical trial populations and informed consent for broad sample use is essential to insure that the [trial] results broadly apply to all people in the study population," said Amelia Wall Warner, Pharm.D., head of clinical pharmacogenomics and clinical specimen management at Merck in North Wales, Pa., and chairwoman of the meeting.

Despite this, trial organizers at Merck and many other companies have encountered resistance or restrictions on specimen collection and use from regulatory authorities, academic institutions, and the institutional review boards (IRBs) and ethics committees that oversee trials.

The problem may be resolving in the United States through recent actions of the Food and Drug Administration.

"There is a fine line between ethics committees that protect their populations but prevent us from fully investigating the safety and efficacy of a drug in a population," Dr. Warner said. "Health authorities will allow collections, but narrow the scope of their use. Regulatory authorities often require adequate representation of their country’s population for a drug’s approval, but because of genetic variations across populations, the sample size must be representative. Adequate statistical power is needed, but collection of optimal DNA samples for a high percent of patients enrolled in industry clinical trials is still a challenge.

"We use specimens to investigate adverse events and nonresponders, which ultimately benefits patients. Distrust is what we have to overcome. But it’s not patients who [generally] don’t want to participate, it’s the investigators," she said in an interview. "Many patients agree to participate" with specimen collection once a trial receives approval and patients understand the goals of the trial and the reasons for specimen collection, she noted.

Although workshop attendees came up with a list of ways to try to resolve the problem and acknowledged that in an era of global trials solutions need tailoring to the diverse range of barriers that often differ from country to country, the solutions largely boil down to two main strategies – better education and trust building – participants said repeatedly during the sessions.

The problem may also already be resolving in the United States through recent actions of the Food and Drug Administration, a development that may have global impact if regulatory bodies and IRBs in other countries follow the U.S. lead. Last February, the FDA issued draft guidance on clinical pharmacogenomics in clinical studies.

The draft guidance "is very supportive" of DNA specimen collection and analysis, said Gilbert J. Burckart, Pharm.D., associate director for regulatory policy in the Office of Clinical Pharmacology, Center for Drug Evaluation and Research at the FDA. "Sample collection is critical to what you do," he told the industry representatives at the workshop. "You don’t have the science unless you do it, and do it properly." He noted that work on the guidance began in 2008, with the finalized version of the guidance due out soon. The FDA received more than 200 comments on the draft, with the comment period now closed.

The draft says that pharmacogenomic information collected during both drug development and postmarketing studies "can improve the effectiveness and safety of drugs." The draft also notes that "an important prerequisite to successful use of genetic information in drug development is the appropriate collection and storage of DNA samples from all clinical trials ... Plans for general DNA sample collection should be prespecified ... even if these samples are studied only at a later time, during, or after the study. It then becomes possible to seek explanations for differences in exposure, efficacy, tolerability, or safety not anticipated prior to beginning the study."

The draft also cites three recent, real world examples where pharmacogenomic data proved critical in understanding and refining treatment challenges with certain drugs:

• Abacavir (Ziagen), an HIV drug, produces a hypersensitivity reaction in about 5%-8% of patients. About 3-4 years after abacavir receive marketing approval, pharmacogenomic research identified a HLA allele (HLA-B*5701) that appeared associated with the reaction. A prospective trial, PREDICT-1, assessed the relationship between this HLA marker and abacavir hypersensitivity, resulting in revised labeling in 2008 that included a strong recommendation for HLA screening of patients before prescribing the drug (N. Engl. J. Med. 2008;358:568-79).

• Clopidogrel (Plavix), an antiplatelet drug widely used to reduce thrombotic events in patients with cardiovascular disease. Clopidogrel is a prodrug that requires multiple cytochrome P450 enzymes for conversion into its active form. Postmarketing studies of clopidogrel showed that a genetic allele of CYP2C19 linked to reduced production of the active metabolite and poorer clinical responses in patients. This led to revised clopidogrel labeling in 2009 and again in 2010 for patients with reduced CYP2C19 function.

• Warfarin, a widely used antithrombotic drug, requires ongoing monitoring of the coagulation state of patients receiving the drug. Variations in the cytochrome P450 enzyme CYP2C9 and in the VKORC1 gene, which encodes the vitamin K epoxide reductase, account for a substantial part of the variability in warfarin’s effect in patients. In 2010, the FDA updated the labeling for warfarin to include a table to guide initial dosing with the drug based on CYP2C9 and VKORC1 genotypes.

"The FDA guidance will make significant headway for U.S.-based studies, and our hope is that potentially the ICH [International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use] will pick up the topic and talk about harmonization of at least the collection of future-use specimens across the United States, Europe, and Japan," Dr. Warner said at the meeting, sponsored by the Drug Information Association. Even now, before the finalized version of the guidance, "communicating the FDA draft guidance has helped." The draft guidance "already seems to be [affecting] decisions" made by trial oversight groups both in the United States and elsewhere, she noted. "When an IRB has questions about the scope of research, we [Merck] have sent them the FDA’s draft guidance, and we’re getting positive responses."

Recent cancer-drug development stands in sharp contrast, having largely avoided the pharmacogenomic issues. "Oncology is often considered an exception. Pharmacogenomics has been most beneficial [to date] in oncology." Cancer drug development has already undergone "a paradigm change," that embraced pharmacogenomics, Dr. Warner said in an interview.

Some recent examples of the now tight link between clinical specimen collection, pharmacogenomic analysis, and cancer-drug development include vemurafenib (Zelboraf), a recently approved drug that specifically acts against cases of advanced melanoma that feature a mutation in the BRAF gene, and crizotinib (Xalkori), which is particularly active against advanced-stage lung cancer that features an ALK fusion mutation.

Other steps the workshop participants agreed on included having companies and industry associations formalize best practices for specimen collection and use, partnering with patient advocacy groups, and, above all, better education aimed at all parties – government authorities, academic institutions, researchers, ethics committees, and IRBs – on why specimens are collected, how they’re handled, and the safeguards in place to ensure confidentiality and proper use. Another development that should ease restrictions going forward is the increasing integration of pharmacogenomics into routine medical practice, and the resultant increased familiarity and comfort that physicians and patients have with these analyses.

"There has been frustration that [drug companies] have identified subpopulations [defined by pharmacogenomics] that hasn’t yet translated yet into clear dosing strategies," Dr. Warner said. The drug industry "needs to do better defining dosing strategies [when physicians] collect pharmacogenomic information.

"Industry needs to build trust for how we collect, store, and use specimens for research. We need to make transparent our processes and how we put them into practice to ensure patient protection and ensure we use specimens responsibly. A realistic goal is a global success rate [for clinical-specimen collection 5 years from now] of 80%. A goal of more than 90%" would be ideal, but probably is not realistic given current issues and challenges, she said.

"Pharma is moving toward more trials in developing countries, where there is more restriction and concern about specimen collection and storage, which will hold us back from a 5-year goal of more than 90%. We’re going to have to make targeted efforts in key countries, such as China. Local storage and analysis [of specimens] will be the strategy that most companies will need to implement."

Dr. Warner is an employee of Merck. Dr. Burckart said he had no disclosures.

PHILADELPHIA – New findings that show T-cell activation plays a critical role in the development of alopecia areata has opened new doors to treatment.

A report last year from a genome-wide association study involving 1,054 patients with alopecia areata (AA) and more than 3,000 controls, identified eight genes strongly linked to the disease (Nature 2010;466:113-7). One of the gene’s codes for a ligand, ULBP3, appears in the dermal sheath of hair follicles in patients with AA. The ULBP3 ligand appears responsible for attracting the cluster of T cells that produce the characteristic histopathology of affected hair follicles, Angela M. Christiano, Ph.D., said at the meeting.

©Heidi Frerichs/iStockphoto.com

"Normally the hair follicle is immune privileged, but when the ULBP3 ligand is increased, T cells attack" the follicle and cause its destruction and the hair loss that is pathognomonic for AA, said Dr. Christiano, professor of dermatology and of genetics and development at Columbia University Medical Center in New York.

The ULBP3 finding led to a search for possible treatments that could interfere with the T-cell attack, guiding Dr. Christiano and her associates to the drug abatacept (Orencia). The agent suppresses T-cell activation and activity and is approved for treating rheumatoid arthritis (RA) and juvenile idiopathic arthritis. Study results reported almost a decade ago showed that abatacept worked in a mouse model of AA, she said.

Testing of a drug such as abatacept represents a new direction for AA treatment, which until now has usually been treated with agents developed for psoriasis, a strategy that has been unsuccessful.

Dr. Christiano and her coinvestigators designed a pilot study to test the efficacy of abatacept in patients with moderately severe AA, 6-12 months after diagnosis. They set these parameters because the patients will have established disease that is unlikely to spontaneously remit, but not so severe as to be too advanced to respond to T-cell based treatment.

Their planned study will randomize 56 patients to either a subcutaneous injection of abatacept or placebo at baseline, weeks 2 and 4, and then every 4 weeks for five cycles for a total treatment duration of 6 months. The study’s primary endpoint will be a 30%-40% improvement on the severity of alopecia tool after the first 6 months of treatment, and then after an additional 6 months of untreated follow-up, she said in an interview.

"I don’t think we could have been more shocked by what we found" in the genetic study, said Dr. Christiano at the meeting, sponsored by the Drug Information Association. "We fully expected to be aligned with other skin autoimmune diseases, like psoriasis." Instead, the eight genes linked to AA closely overlapped with type 1 diabetes, RA, and celiac disease, disorders that "we never considered."

But like the ULBP3 ligand found in the hair-follicle dermal sheaths of patients with AA, these autoimmune diseases also feature upregulated ligands that attract T cells to cellular targets and cause the disease: synoviocytes in RA, gut epithelial cells in celiac disease, and pancreatic islet cells in a mouse model of type 1 diabetes.

Dr. Christiano said that she had no disclosures.

PHILADELPHIA – New findings that show T-cell activation plays a critical role in the development of alopecia areata has opened new doors to treatment.

A report last year from a genome-wide association study involving 1,054 patients with alopecia areata (AA) and more than 3,000 controls, identified eight genes strongly linked to the disease (Nature 2010;466:113-7). One of the gene’s codes for a ligand, ULBP3, appears in the dermal sheath of hair follicles in patients with AA. The ULBP3 ligand appears responsible for attracting the cluster of T cells that produce the characteristic histopathology of affected hair follicles, Angela M. Christiano, Ph.D., said at the meeting.

©Heidi Frerichs/iStockphoto.com

"Normally the hair follicle is immune privileged, but when the ULBP3 ligand is increased, T cells attack" the follicle and cause its destruction and the hair loss that is pathognomonic for AA, said Dr. Christiano, professor of dermatology and of genetics and development at Columbia University Medical Center in New York.

The ULBP3 finding led to a search for possible treatments that could interfere with the T-cell attack, guiding Dr. Christiano and her associates to the drug abatacept (Orencia). The agent suppresses T-cell activation and activity and is approved for treating rheumatoid arthritis (RA) and juvenile idiopathic arthritis. Study results reported almost a decade ago showed that abatacept worked in a mouse model of AA, she said.

Testing of a drug such as abatacept represents a new direction for AA treatment, which until now has usually been treated with agents developed for psoriasis, a strategy that has been unsuccessful.

Dr. Christiano and her coinvestigators designed a pilot study to test the efficacy of abatacept in patients with moderately severe AA, 6-12 months after diagnosis. They set these parameters because the patients will have established disease that is unlikely to spontaneously remit, but not so severe as to be too advanced to respond to T-cell based treatment.

Their planned study will randomize 56 patients to either a subcutaneous injection of abatacept or placebo at baseline, weeks 2 and 4, and then every 4 weeks for five cycles for a total treatment duration of 6 months. The study’s primary endpoint will be a 30%-40% improvement on the severity of alopecia tool after the first 6 months of treatment, and then after an additional 6 months of untreated follow-up, she said in an interview.

"I don’t think we could have been more shocked by what we found" in the genetic study, said Dr. Christiano at the meeting, sponsored by the Drug Information Association. "We fully expected to be aligned with other skin autoimmune diseases, like psoriasis." Instead, the eight genes linked to AA closely overlapped with type 1 diabetes, RA, and celiac disease, disorders that "we never considered."

But like the ULBP3 ligand found in the hair-follicle dermal sheaths of patients with AA, these autoimmune diseases also feature upregulated ligands that attract T cells to cellular targets and cause the disease: synoviocytes in RA, gut epithelial cells in celiac disease, and pancreatic islet cells in a mouse model of type 1 diabetes.

Dr. Christiano said that she had no disclosures.

PHILADELPHIA – New findings that show T-cell activation plays a critical role in the development of alopecia areata has opened new doors to treatment.

A report last year from a genome-wide association study involving 1,054 patients with alopecia areata (AA) and more than 3,000 controls, identified eight genes strongly linked to the disease (Nature 2010;466:113-7). One of the gene’s codes for a ligand, ULBP3, appears in the dermal sheath of hair follicles in patients with AA. The ULBP3 ligand appears responsible for attracting the cluster of T cells that produce the characteristic histopathology of affected hair follicles, Angela M. Christiano, Ph.D., said at the meeting.

©Heidi Frerichs/iStockphoto.com

"Normally the hair follicle is immune privileged, but when the ULBP3 ligand is increased, T cells attack" the follicle and cause its destruction and the hair loss that is pathognomonic for AA, said Dr. Christiano, professor of dermatology and of genetics and development at Columbia University Medical Center in New York.

The ULBP3 finding led to a search for possible treatments that could interfere with the T-cell attack, guiding Dr. Christiano and her associates to the drug abatacept (Orencia). The agent suppresses T-cell activation and activity and is approved for treating rheumatoid arthritis (RA) and juvenile idiopathic arthritis. Study results reported almost a decade ago showed that abatacept worked in a mouse model of AA, she said.

Testing of a drug such as abatacept represents a new direction for AA treatment, which until now has usually been treated with agents developed for psoriasis, a strategy that has been unsuccessful.

Dr. Christiano and her coinvestigators designed a pilot study to test the efficacy of abatacept in patients with moderately severe AA, 6-12 months after diagnosis. They set these parameters because the patients will have established disease that is unlikely to spontaneously remit, but not so severe as to be too advanced to respond to T-cell based treatment.

Their planned study will randomize 56 patients to either a subcutaneous injection of abatacept or placebo at baseline, weeks 2 and 4, and then every 4 weeks for five cycles for a total treatment duration of 6 months. The study’s primary endpoint will be a 30%-40% improvement on the severity of alopecia tool after the first 6 months of treatment, and then after an additional 6 months of untreated follow-up, she said in an interview.

"I don’t think we could have been more shocked by what we found" in the genetic study, said Dr. Christiano at the meeting, sponsored by the Drug Information Association. "We fully expected to be aligned with other skin autoimmune diseases, like psoriasis." Instead, the eight genes linked to AA closely overlapped with type 1 diabetes, RA, and celiac disease, disorders that "we never considered."

But like the ULBP3 ligand found in the hair-follicle dermal sheaths of patients with AA, these autoimmune diseases also feature upregulated ligands that attract T cells to cellular targets and cause the disease: synoviocytes in RA, gut epithelial cells in celiac disease, and pancreatic islet cells in a mouse model of type 1 diabetes.

Dr. Christiano said that she had no disclosures.