Throughout the five days of the 2015 Alzheimer's Association International Conference, conversation resonated in the hallways about a unique, daylong preconference for some 100 relatives of people with autosomal-dominant AD, who traveled to Washington, D.C., from four continents. The pre-meeting presaged how preventing early-onset AD could, in time, benefit all of Alzheimer’s disease treatment.
100 DIAN Family Members Gather for Their First International Meeting
“My life feels like I am visiting in someone’s house and hear a grandfather’s clock ticking. I fight back by being in DIAN and speaking publicly. It’s the control I have over my genetic destiny.” Brian Whitney, 44.
“I’ve never before met another family who has the same problem.” At-risk daughter, 19.
Brian Whitney knows he has inherited a presenilin-2 mutation that has decimated his extended family for generations and now threatens him—and perhaps his 5-year-old daughter. With his parents, Whitney joined 99 other people from Australia, Canada, Colombia, Puerto Rico, the United Kingdom, and across the United States for a historic, face-to-face meeting of families of the Dominantly Inherited Alzheimer Network (DIAN). Held July 18 in Washington, D.C., in conjunction with the Alzheimer’s Association International Meeting, the Autosomal-Dominant AD (ADAD) Family Conference brought together participants who are certain they will become symptomatic with others who already are. People who have learned their genotype spent the day with people who have not. At-risk teenagers mingled with baby boomers who lost their spouses to ADAD and are now fighting to save the lives of their adult children. Also there were members of the Colombian pedigree with the PS-1 Paisa mutation that has inspired the Alzheimer’s Prevention Initiative (API), who have moved to the United States and plan to join DIAN.
This in-person meeting grew out of repeated requests from DIAN participants, said the network’s leader, Randy Bateman of Washington University, St. Louis. Since the DIAN observational study started in 2008, its participants and researchers have gradually gotten to know each other by way of teleconferences, Webinars, an online forum, and a Facebook group restricted largely to ADAD family members. Families planned the day with DIAN-TU (Trials Unit) staff members including Washington University’s Ellen Ziegemeier (email@example.com) and Alzheimer Association staff. The Colombian API project builds cohesion in similar ways, said Francisco Lopera of the University of Antioquia, who received a standing ovation at the ADAD Family Conference for his work. His project invites participating families for biannual research updates in July and to celebrate Christmas, drawing about 300 each time.
After a multilingual meet-and-greet the night before, the families settled in for a day of lectures and intensive talks with each other and with researchers within and outside of DIAN. They discussed how to handle their genetic risk. They grilled pharma scientists about why they haven’t produced a new AD drug in more than a decade. They made impassioned pleas that their symptomatic relatives get access to investigational drugs. They heard an update of the ongoing clinical DIAN-TU trial of solanezumab and gantenerumab. They exchanged tips on how to solve the practical and financial problems that arise when dementia strikes in the prime of life. They shared how they are dealing with their genetic test results. In telling their stories, family members brought pharma, academic, and regulatory scientists to tears.
By the end of the day, the information and emotion together created a collective sense of being part of something unique, of a movement larger than even autosomal-dominant AD itself. “In 2050, 135 million cases of Alzheimer’s disease are predicted worldwide unless we change the course of history. You are empowered to do that,” Jeffrey Cummings of the Cleveland Clinic Lou Ruvo Center for Brain Health in Las Vegas told an energized audience. The families—whose children have become symptomatic since their parents in the 1990s helped discover APP and presenilin— broke into spontaneous applause when Cummings declared, “We cannot lose another generation to Alzheimer’s disease.”
The work of DIAN and its clinical trials unit, DIAN-TU, is drawing attention beyond the Alzheimer’s field. “You should be proud of what you have pulled off. I am stunned at what is being done in this area. It is cutting-edge, and it is the right thing to do,” said Janet Woodcock, who heads the center for Drug Evaluation and Research (CDER) at the Food and Drug Administration (FDA). “This is going to be big for other diseases, as well. The cancer field is watching what you are doing,” said Maria Isaac of the European Medicines Agency based in London. Throughout the five subsequent days of the AAIC, this family conference resonated in scientific sessions and hallway discussions.
This series summarizes selected presentations; paraphrased audience questions and answers by speakers or other DIAN researchers are interspersed throughout as Q&As. To respect the privacy of families, names of DIAN participants have been removed except for those few who already advocate publicly. Part 1 focuses on genetic testing for an autosomal-dominant gene, Part 2 on news about funding care and research. Part 3 features family stories and debate about the DIAN-TU trial; and a final story summarizes ADAD research results presented at AAIC itself.
The ADAD family day started around genetic testing. Meagan Cochran, a genetic counselor at the University of Alabama at Birmingham, said that in 2011 the American College of Medical Geneticists and the National Society for Genetic Counselors jointly issued guidelines to standardize predictive testing for Alzheimer’s disease (see Goldman et al., 2011). Before then, local practices varied, with some people finding out their genotype directly through a local physician and others going through a lengthy counseling protocol borrowed from Huntington’s disease (see Genetic Testing for Early Onset Familial AD). The guidelines emphasize the need for a structured process that involves genetic counseling, a multidisciplinary assessment to gauge the person’s ability to cope with knowing their genotype, and post-test counseling and follow-up. Cochran said building a long-term relationship with the family, and involving a support person who is not at risk in the process, has proven helpful to avoid depression or other bad outcomes of predictive testing.
Q: Why can’t I just get tested?
A: I am not trying to make you jump through hoops. There is a lot of value in this protocol. Having the multidisciplinary people involved empowers you to give truly informed consent. It is still your decision, but a much better-informed decision.
Q: Who pays for the test?
A: If you do not want insurance to have this information, you have to pay out-of-pocket or be part of a research study. The DIAN and DIAN-TU support some genetic testing.
Q: When should educating minors begin?
A: It is never too early to start talking to kids. If you don’t, then they know something is going on, but not what. Some kids think it is something they are doing wrong, especially with the personality changes in the affected. But don’t over-share. Do not do a one-time, sit-down, big family meeting that is stressful, but incorporate age-appropriate bits and pieces into the life course. Stop when you have answered a child’s question. Create a new normal.
Q: What age do you suggest for testing?
A: It depends on the person. Some 18-year-olds are mature about these things; some 25-year-olds are not. It is important to know if the family has spoken about it before. Also, what personality type are you? Are you Type A and plan everything? Then test earlier. Would knowing drive you crazy? Then don’t.
Even though a consensus framework to guide the process is now in place, ethical dilemmas crop up, Cochran said. For example, a mutation found in a very young adult who insists on testing will “out” a parent who may not wish to know. A grandson who pursues testing of a deceased grandmother’s autopsy tissue to determine whether there is a family mutation would raise the specter of autosomal-dominant inheritance for all her descendants.
During a breakout session, discussion about how to handle genetic information continued among 45 at-risk people. About 40 percent knew their gene status. The hour seemed too short for many, and avid conversation continued afterward. In the anonymous excerpts below, successive answers to a given question are from different people.
Q: When you knew, whom did you tell?
A: I told most people, including my boss. It helps me.
Q: My genetic counselor said by telling you burden people.
A: That is true. I did not tell my mom because she is a worrier and lives with us. She would second-guess my every sentence if she knew I had the gene.
A: You do burden people by essentially forcing them to give you more empathy. I thought long and hard about whom to tell, but those I did tell have become my closest support network.
Q: I don’t know my status. How did knowing affect those here who do?
A: I did it to stop the constant worrying. Now that I know I am positive, I still worry when I forget something, but I am glad I did it.
A: I found out for my family’s sake because I am my mom’s caregiver. Now I know our options and can plan. For me it’s better that way.
A: For me it was practical. I found out this year. Now I am thinking I may not be functioning in a decade, so should I really gun for this promotion? It changed how I live my remaining good years.
A: I passed up a higher-paying job that would have put me on the road and instead am spending more time with my family.
A: I am close to my family’s age at onset by now. We live abroad but decided to return home and live near our extended family so there is help when I become symptomatic.
Q: Does anyone here regret having found out? [Most heads shake, but ...]
A: It depends on the day. Some days I am blue and regret I brought a child into this risk.
A: No, but I strongly suggest getting genetic counseling. DIAN will find a counselor for you. I just looked up a geneticist and was in and out in 30 minutes. He asked: "Do you want to come back for the result or get a phone call?" I said a phone call. It was the most horrible pain. I was at work. My wife was not with me. I stood there and cried. No follow-up. For three years, I was up and down with depression and weight gain. I never spoke with a counselor. I just don’t reach out. I eventually got on an antidepressant and that helped. Don’t do it like this.
A: As a spouse, I say to those who are considering testing: Do not think only about tomorrow and planning. Think about today and how you will live. This can eat you up.
Q: Why not plan for the future without knowing? I can take out long-term care insurance, etc. I plan as if I am positive, and still live not knowing my status.
A: I hear you: Let me live in well-prepared, blissful ignorance. But I found it did not work for me. At one point I just had to know.
Q: I will find out at some point. But when?
A: You will know. I took care of my mom and she passed, and I still did not want to. Her death was life-changing, I went back to a new normal for some years, but then it came back and hit me. You will feel it when the time is right.
A: For me, it was starting to forget things. Every time that happened, it was, “OMG, I am getting AD!” I realized that either I will be a happy 50-year-old who knows AD is coming, or I’ll go crazy. That was it.
A: My wife would have to be a caregiver, so when our kids were in their teens it just felt right to find out.
Q: What’s it like for the people here who tested negative?
A: I feel a survivor’s guilt, but more in a sense of responsibility for the others, not as a psychological burden.
A: Knowing I do not have the gene helped me just pour love on my sister who died of it. My cousin has four children and they all have the gene. She had to provide for and take care of all four of them. She needs help from someone who understands.
A: My brother is negative. As someone who is positive, I am glad he found out because I can give him power of attorney.
A: Some of us are getting tested solely for our children because they are hitting 18 and want to know.
A: In our family, onset is 35. I was past that but chose to get tested because my 23- year-old was talking about having kids. I said let me get tested so maybe you do not have to. I was negative, but my three siblings all have it. I am relieved for her, but it’s still complicated.
A: My dad was 47 when he died but it was never talked about. So when my sister got it, it took us five years of diagnosis to find out what she had. Taking care of her, my nephew, my niece, is almost more than I can bear. I do it because I love them, and I can do it because I don’t have the gene. —Gabrielle Strobel
- At DIAN Family Meeting, Funding News Caps Talk of Inadequate Services
- Families Challenge DIAN Scientists to Do Even More, Faster
- New Data on Autosomal-Dominant Alzheimer’s Point to Early Fissures in the Brain’s Microarchitecture
Book page Citations
- Goldman JS, Hahn SE, Catania JW, Larusse-Eckert S, Butson MB, Rumbaugh M, Strecker MN, Roberts JS, Burke W, Mayeux R, Bird T, . Genetic counseling and testing for Alzheimer disease: joint practice guidelines of the American College of Medical Genetics and the National Society of Genetic Counselors. Genet Med. 2011 Jun;13(6):597-605. PubMed.
No Available Further Reading
At DIAN Family Meeting, Funding News Caps Talk of Inadequate Services
The first Autosomal-Dominant AD Family Conference of the Dominantly Inherited Family Network (see Part 1) showcased gaps in legal, financial, and caregiver-support systems. On a more hopeful note, the families heard that the chronic low tide of federal funding for Alzheimer’s research may be slowly turning as the Alzheimer’s Accountability Act starts to take hold.
In May 2008, President George W. Bush signed into law the Genetic Information Non-Discrimination Act to prohibit discrimination in health coverage and employment based on genetic information. GINA sets a federal minimum standard for genetic privacy, though some states have put stronger protections in place (see NHGRI; GINA & You). The families quizzed speakers about the things to which GINA does not apply—e.g., life, disability, and long-term care insurance—and how to navigate testing and insurance. Besides insurance, obtaining disability benefits and legal protection presents a struggle for many families with ADAD. Sheri Abrams, an attorney who specializes in social security disability law and special-needs planning, took questions about how to navigate the bureaucratic process. Her advice included screening medical records before submitting them, never understating problems at home during doctors’ visits, and applying for disability benefits before the gene carrier becomes symptomatic and, potentially, laid off. A common problem for people from families with ADAD is that between caring for a parent in their 20s and becoming symptomatic themselves in their 40s, they have not worked enough years to qualify for social security disability, which is based solely on work history.
Q: When to apply for insurance—before or after testing?
A: Before. Consider long-term care insurance first. You need that because most people with AD spend years in assisted living before entering a nursing home, and Medicaid only covers nursing home care, not assisted living.
Q: My husband got tested years ago, but it is not in his medical records yet. What do I check on the insurance application?
A: The genetic diagnosis alone is not the “condition” yet, so you can check no. Once he has a diagnosis of the symptoms you have to be truthful, otherwise insurance may deny you when you claim a benefit. They may investigate and find out if you hid a pre-existing condition.
Q: What are shadow charts?
A: In the context of genetic testing, it’s when your test provider creates a medical record with a number or initial separate from your primary medical record. Shadow charts have fallen out of favor, though. Say you have a positive test and 10 years later get symptoms and see a neurologist. Then it is difficult to retroactively incorporate the genetic test into your medical record to clarify that that is what is going on with you now, and you have to repeat the test. It’s better to keep a paper record of the test under your real name but store it separately from your electronic record.
Q: Am I required to tell the insurance provider that I participate in research?
Q: To get social security disability, you have to show decline. For those of us who are asymptomatic, can we use the DIAN records for that?
A: No. Cognitive test results from DIAN are used for research purposes only, and are not shared with participants or outside groups. To show decline in your social security disability application, it’s best to visit a doctor after your long-term care insurance is in place. That provides a start date to later show decline. DIAN’s refusal to share research data protects you in other situations, for instance if an insurance company calls to ask about a participant. Importantly, when medical information comes up during the assessments—for example, a tumor or an aneurysm—that information is shared with the participant.
Families with ADAD can tap certain support services, but some fall between the cracks of a patchwork of federal and state programs. For example, many symptomatic carriers who get laid off are too young for Medicare but not poor enough to qualify for Medicaid. Robert Kramer, the associate director of public policy for the Alzheimer’s Association, told the audience that as a consequence of the Affordable Care Act many states have broadened eligibility for Medicaid, which covers the cost of diagnosis, treatment, and some home- and community-based services.
Federal funds to provide support services to caregivers are disbursed to states for their discretionary spending under the Older Americans Act. The Act's authorization ran out in 2010, and though the U.S. Senate passed a reauthorization bill on 16 July 2015, that bill awaits action in the House. As it is, the law is underfunded and prioritizes services for people over the age of 60, Kramer said. The PACE program delivers comprehensive care for people with ADAD, but is not available everywhere in the United States and excludes people under 55. The Senate has passed a pilot bill to expand PACE, but the House has not yet acted on it, Kramer said.
In the course of AAIC, there was new momentum in Washington to fund both care services and research. On 16 July 2015, the Alzheimer Caregiver Support Act, originally introduced in 2013 by California Democrat Maxine Waters, was reintroduced as part of a legislative package on Alzheimer’s disease (see press release).
The bigger news occurred around federal funding for research. It was brewing right when the families were meeting. ADAD families are well aware of the longstanding disparity between big killers such as cancer ($5.5 billion in fiscal year 2015), HIV ($3 billion), and Alzheimer’s ($580 million). During their trip to Washington, some DIAN participants visited Capitol Hill to advocate for more funding. At the family conference, Neil Buckholtz of the National Institute on Aging (NIA) reminded the families that in June the House and Senate Appropriations Committees approved increases for fiscal 2016 of $300 million and $350 million, respectively.
Better yet, Buckholtz explained, for fiscal 2017 the NIA is preparing the so-called Professional Judgment Budget mandated by the Alzheimer’s Accountability Act. This type of budget process estimates how much money will be needed to realize research milestones set out in the National Plan to Address Alzheimer’s Disease (NAPA) and defined in more detail in recommendations from the NIH AD Research Summit (see May 2015 news). The idea is to calculate the amount of money that can be put to immediate use based on the current state of the science. Importantly, this type of budget, also called a bypass budget, goes from the NIH director straight to the president, bypassing some of the usual bureaucratic channels where it could be cut. (Others in the department of Health and Human Services can review and comment on the bypass budget, but cannot change it.) Bypass budgets are rare: Only cancer and HIV have gotten them previously, indicating that Congress is starting to put Alzheimer’s on an equal footing. It is more than a one-off: The NIH will prepare an annual bypass budget for the next 10 years.
On July 27, news broke that the professional judgment budget had recommended an additional $323 million be spent on AD research in fiscal year 2017 (see Bypass Budget Proposal). The budget specifically mentions the Dominantly Inherited Alzheimer Network and other secondary prevention initiatives. For individual family stories and debate with pharma and regulatory scientists, see Part 3 of this series.—Gabrielle Strobel
- 100 DIAN Family Members Gather for Their First International Meeting
- Research Summit 2015 Recommendations Released
No Available Further Reading
Families Challenge DIAN Scientists to Do Even More, Faster
On the morning of July 18, 100 participants in the Dominantly Inherited Alzheimer’s Network (DIAN) spent four hours cooped up in a windowless hotel meeting room talking about the genetic, financial, and legal complications of life with autosomal-dominant AD (ADAD) (see Part 1 and Part 2 of this series). In the afternoon, this first international ADAD conference opened its doors to include the principal investigators at DIAN’s 15 sites, the DIAN Trial Unit’s 26 sites, scientists at government regulatory agencies in Europe and the United States, scientists from the two currently participating pharma companies and the DIAN-TU Pharma Consortium, funders, and some reporters. The family conference took place the day before the Alzheimer Association International Conference began.
The scientists first heard from six family members about how ADAD tore into their families. It was raw testimony compared with the dispassionate presentation of data usually heard in the abstract remove of a scientific conference. The personal stories had the audience discreetly reaching for tissues, then rising in spontaneous applause. Next up were leading clinicians from outside and inside DIAN, as well as scientists at the U.S. and European regulatory agencies and the two pharma firms whose investigational drugs are being evaluated in the ongoing DIAN-TU trial. They all took questions in an extensive Q&A. Below are excerpts from the talks and the ensuing discussions.
Joanne Harrigan: “I live in a small mining community in the U.K., the fourth generation of my family to be born in the same village. I have one sister but my mother was one of seven. Her father died with dementia when I was 12. Mom was intelligent and always reading, so when we noticed that she was becoming forgetful and doing random silly things we knew something was wrong. She was 50. At the first visit to our general practitioner, he told us mom was depressed. At that time my mother’s sister returned home from living abroad. She was ill and placed in a home, where dementia was diagnosed but attributed to alcohol use. We knew this wasn’t right. We went back to our doctor in 2001 to ask if there is a reason for the family pattern. We were told categorically that there is no genetic form of Alzheimer’s, even though genes had been found years earlier. We pushed a long time, and finally got referred to a memory clinic.
“The disease struck again in another of mom’s sisters. At that point my mom and my aunt were diagnosed with early onset Alzheimer’s, at 53 and 55. Finally, we had an answer, but it brought back the genetics question, and we learned that our family are PS1 mutation carriers. My sister and I are at risk. We both have children.
“Mom became angry and aggressive, my auntie depressed. My dad was mom’s full-time carer. The hardest part to me was her vacant look when I called her ‘mom’ and she asked dad why a strange girl would call her that. In 2013, we had a crisis. Dad was overwhelmed and services were limited because of mom’s young age. She became completely incontinent. On August 15, 2012, mom passed away at 59.
“We still have our auntie with us. She is 64, and though in final stages, still smiles. We participate in research at University College in London. We donated mom’s brain and learned that she declined so fast because she had AD and mixed dementia with Lewy bodies and vascular pathology. Now our hope is that our children do not have to see what we have seen."
Mary Salter: “Unraveling what once was—that is what early AD did to my family. The death of my mother-in-law, Martha, at 40, left five children: Butch, Johnny, Bill, Bobby, Eric. Her disease was never discussed, but when Butch got sick we could not ignore it any more. We unsealed Martha’s records and found out. I was thinking, this can’t keep happening to us. One day I found my husband Bobby in the closet with a gun in his hand. I took it from him and held him, saying, ‘You won’t get it.’ I was wrong. Bobby lost his job as an accountant when his symptoms started at 36. He became unable to feed or dress himself, and died at age 43. Within nine years, four brothers were gone.
“My oldest son, Brad, convinced that he would get this too, had a troubled youth. My second-born, Bryan, dropped out of performing-arts school. My youngest, Carrie, was devastated. I spoke with Dr. Bateman—finally a place that understood this disease and its family dynamics. My kids all decided to join DIAN. Bryan was first to find out his status. My heart beat out of my chest when he told me, ‘I have the gene.’ He is 35. Brad decided to get tested the next year. As we sat there, I felt sick. The counselor said the test is negative but I had mixed emotions. How could I feel happy for one child knowing I would lose another? Last December, Carrie traveled to Birmingham, Alabama, for her results. Waiting for her call, I answered to hear a soft, whimpering cry. ‘It’s not good,’ said her voice. My sister took the phone as I fell. Carrie is 34, with three kids, and here today.
“I am their lawyer and will be their caregiver. Which of my grandchildren will get it? I am not defeated, but despairing. I can’t do this by myself. Please, no more red tape, fund the search for a cure now. We need to stop the unraveling!”
Tal Cohen: “My wife, Giedre, is here. She is 37, her mom’s only surviving child. I have been anguished, watching her become symptomatic. Giedre was among the first patients to be enrolled in the solanezumab arm of the trial. I applaud your compassion in designing the trial such that pooling the placebo groups increases the odds she may be on drug. Still, every time she gets her infusion I worry that it might just be placebo.
“Giedre participated in the DIAN observational study. She endured a lot in doing so. She did so to improve understanding of AD. It is time to give something back to her. I do not know if solanezumab or gantenerumab, or aducanumab or crenezumab, will help my wife or anyone else. I do know they are all being tested, and I ask you to ensure Giedre did not participate in DIAN for years and never got more than placebo.
“Twenty-four states have passed Right to Try laws, 19 more have introduced such laws. I urge DIAN to seize the opportunity to incorporate such laws into your trials. Build compassionate-use access into DIAN-TU. Do it in a meaningful way. I get some opposition when I say this, but I believe AD is even more devastating when it manifests in a person’s 30s than when they have lived a full life. We are talking about a small number of people. Please take uncommon measures to alleviate our suffering.”
The families’ pleas set the stage for a discussion about the DIAN-TU trial. Scientists essentially asked the families to give DIAN-TU time to succeed. John Morris of Washington University, St. Louis, reminded the audience that the current trial is the first of its kind. “You hear about prevention studies, but there really have not been prevention studies of AD with what we would call disease-modifying drugs. The DIAN-TU trial is the first,” Morris said. Randy Bateman, also of WashU, added that DIAN-TU exists to redress the prior exclusion of families who had contributed so much to research before. “Many of the investigational drugs you hear about have been developed on the mutations that you have in your families. You are young, you do not have other diseases mixed in, we can find you at the preclinical stage, so the chances of success of these drugs might be highest in you,” Bateman said.
DIAN-TU’s goal is to find highly effective drugs, much as statins work profoundly better in young people who have genetic forms of high cholesterol than in the typical older person. “These young people are essentially cured and live full and complete lives. I hold this up as a model of what DIAN aims to do for ADAD,” Bateman said.
As of August 2015, the first DIAN-TU trial is two-thirds full; it plans to complete enrollment this fall. So far, all participants are undergoing the lumbar punctures and MRI assessments. PET completion stands at 99.8 percent, retention at 99 percent. “Those numbers are unheard of,” Bateman said; typically, some 20 to 30 percent of patients drop out of Alzheimer trials and completion rates of biomarkers range from 10 to 30 percent. Because the trial is blinded until the end, no one knows about the effectiveness of Lilly’s solanezumab or Roche’s gantenerumab, the two drugs currently in the trial. The DIAN scientists know more about the antibodies’ safety, because adverse events get reported and monitored along the way. ‘The trial has gone very well from that perspective,” Bateman said. Because the trial thus far has an extremely low adverse event profile, either because of age or the pure form of ADAD being treated, DIAN-TU is actively discussing how to do better with a higher dose, Bateman added.
The current trial will proceed to a biomarker readout at two years, and the therapy (or therapies) that look promising at that point will continue on to a cognitive readout at four years. In the meantime, new trials could be started up or treatment arms added (see April 2015 news).
Two regulatory scientists addressed the family community. Janet Woodcock heads the Center for Evaluation of Neurological Drugs (CEDR) at the Food and Drug Administration (FDA), and Maria Isaac is at the European Medicines Agency (EMA). Woodcock began by commending the DIAN families and team. “The observational study, the use of multiple agents in the trial, the staggered approach to evaluating these therapies—these things are not present in many very serious diseases,” she said. This is the way forward, according to Woodcock. “Having a systematic, results-oriented approach to evaluating new treatments—this is the way this disease will get treated. You should be confident that you are using all available methods to evaluating drugs better,” Woodcock said.
She told the families that a drug for ADAD mainly has to show that it is effective and that the company can produce it to a consistent standard. Safety is a lesser consideration for ADAD. “We understand that you trade some safety for benefit in this form of AD. Do we have the same safety standard here as for a headache medicine? Not at all. The difficult question to answer is, does the drug work?” Woodcock said.
Isaac pointed to a 2010 meeting at the EMA to help get trials and DIAN-TU going (see Nov 2010 news). Isaac noted that presymptomatic trials require new methods and assessments. She told the families that her and Woodcock’s teams have biweekly phone calls to incorporate those into the approval process as the trial unfolds so that once a drug proves effective, the submission for approval can be as similar and swift as possible on both sides of the Atlantic. The EMA operates differently from the FDA, in part because it is a network of 28 member countries with different languages and cultures. Isaac told the families that their project is resonating beyond ADAD. “You are challenging the whole system of drug evaluation by what you are doing in DIAN,” she said.
Eric Siemers of Eli Lilly and Company reviewed why it typically takes 17 years of development for a drug to be approved. Solanezumab, one antibody being tested in DIAN, is no different: It has been in clinical trials since 2004, and the last dose in the current Phase 3 trial for mild late-onset AD will be dispensed in October 2016. One way to speed things up is to partner with academia in ways that tap academia’s strength in science and industry’s strength in honing the molecule and running Stage 3 trials. “The DIAN-TU is a perfect example where we have good collaboration between academia and industry,” Siemers said. In particular, DIAN-TU can streamline development because two drugs are tested simultaneously, and their combined placebo group boosts statistical power to answer whether either drug works.
Robert Lasser of Roche leads that company’s team for gantenerumab, the other antibody currently in the DIAN-TU trial. Thanking the families for “the incredible amount of information we are gaining about Alzheimer’s disease because of your participation,” Lasser recounted how having a few more years of quality life would have allowed his grandfather to teach Lasser’s young son to play drums before he died of Alzheimer’s. He said that many researchers in industry and academia have lost family members to AD, if not ADAD. “We feel the pressure and are pushing within our company bureaucracies for faster change,” Lasser said. Development of a drug not only takes many years but also a billion dollars, hence even a large pharma company advances only a few such projects in parallel for a given disease. And AD is harder than other diseases. While the industry average of success—i.e., getting an investigational drug approved—stands at 4.1 percent, for Alzheimer’s that number is 0.5 percent, Lasser said.
Q: Can our symptomatic relatives get active drugs through compassionate use?
Woodcock: I understand your point of view: “The drug is safe enough, why can’t we get it?” The main problem is when a lot of people just take drugs and we open access, then we cannot show that there is a real effect. Once a treatment is available it’s harder to get people into placebo-controlled trials. We can open access more once trials are enrolled and we can be confident that we will get an answer. The major tension is between opening access and getting an answer to whether a drug works.
Siemers: The antibodies are relatively safe, but no drug is like water. If there was a drug that was purely for ADAD, then we could have those regulatory discussions. But we are talking about drugs that are about LOAD [Late-Onset Alzheimer’s Disease] as well. We have not proven efficacy. We are just not there yet. In the Expedition 1 and 2 trials we had a statistical effect, but it was in a secondary analysis. In AD, we do not have a surrogate biomarker that is reasonably likely to predict clinical benefit. In HIV, drugs were given early on compassionate-use basis, but it was more straightforward because viral load predicted efficacy.
Lasser: This is a company-by-company decision. Some companies are quicker than others, some are more open than others. We internally have to come to that balance of safety, i.e., how many people have been treated, versus giving it to people.
Q: Then will you consider dynamic assignment, where some patients would be allowed to transition to active drug before the placebo-controlled phase is over? You understand the urgency of people in this room.
Siemers: We spend a lot of time talking about open-label and compassionate use. In terms of open-label extensions, or what we call delayed start, we offer that not just to act ethically but also to learn more. We found that when we offer drug to people at the end of the placebo-controlled phase, 95 percent chose to do so. But to give the drug for compassionate use outside of a trial, for that we feel we have too little data showing it works. Another worry is that once you make it available on compassionate use, then people will drop out of the trial. So we hope participants will make it through the blinded portion and then go on open label.
Woodcock: In cancer trials, when a patient gets worse, they switch over to another drug. Of course, in cancer there are other drugs. In AD it’s different. Progression is seen gradually with very subtle changes and there may not be another drug.
Q: What exactly are our options for access?
Woodcock: The FDA has access programs through which people have been treated. We have many such available, but there are complexities to it. All groups with serious diseases struggle with these access issues.
Q: Can you provide incentives for companies to make drugs available?
Woodcock: The best thing regulators can do is to provide a very clear path to the market. That stimulates activity because companies can make clear decisions. DIAN is helping here because it is providing biomarker evidence that will show us the right pathway to quickly and effectively evaluate a candidate drug.
Q: Have there been trials before that use historical data instead of placebo so that everyone in the trial can get the drug? Is this doable in DIAN?
Woodcock: You take a huge risk if you do not do a placebo-controlled randomized trial. You want to answer as quickly as possible the question of, does this drug benefit disease? The issue is you might miss an effect. If your drug has a moderate effect, then you will not see that with historical controls only. If you had a drug that cures disease, fine. With a cure, like penicillin, you do not need a control group at all. But for most drugs, you do need a proper control group.
Q: What more can DIAN do?
Isaac: What DIAN is doing is aggressive and a good way to go. They can get even more aggressive once they have more confidence in the biomarkers.
Q: Will DIAN-TU use data from the observational study to strengthen controls?
Bateman: Yes, we are planning to use it, though in practice there are constraints to how this kind of data can be applied.
Q: How does DIAN choose the drugs to be tested?
Bateman: We have a drug-evaluation committee that receives nominations. The members of the DIAN-TU Pharma Consortium have nominated 21 drugs. We class them: category 1 is ready for immediate evaluation in a trial, category 2 is of interest but has remaining questions, category 3 is of no interest. The committee deliberates and rates each nomination based on all available information.
Q: Why has there been so little success?
Lasser: The drug failures in the past decade have placed the theories under a lot of stress. We had hints of what is going on in AD, but only had the tools to measure properly in humans in past five to 10 years or so. We are putting the plane together as it flies.
Siemers: In AD, people have tried all sorts of drugs. There were few serious candidates available, and the need is so great. People did not realize the opportunity cost of evaluating drugs that have only a remote chance of success. It ties up investigators, sites, patients, and creates lots of incidences of failure. We all have a responsibility to not waste time on drugs that have a very low probability of succeeding. That is why it is so important that the DIAN committee choose drugs carefully.
Woodcock: We want the most efficient trial design. We do not want trials that are obscure and in the end nobody knows why it did not work. Part of our problem is the FDA needs money to hire and pay scientific personnel. FDA has had trouble recruiting enough neurologists because we cannot pay them what they make in industry or academy. Congress recognizes that now, and the 21st Century Cures Bill contains some changes in the pay scale.
Isaac: We are all doing science. It is complex and takes time. The work just has to be done. The regulators are not the bottleneck.
Lasser: We never felt that the regulators are the issue. The issue is the science. Another reason why things move slowly is that it takes us two years just to enroll everyone we need for a large trial. Imagine if enrollment took two months.
Siemers: I agree completely. When people receive a diagnosis, or even realize they are at risk, their knee-jerk reaction needs to be, “I have to find a clinical trial.” That would be a huge help.
Q: In the trial, what happens with the first people who complete the four years of the trial?
Bateman: One option is they stop the drug and are followed. One is that they continue blinded. One option is open-label extension and all who finish the study go on drug. Each has pros and cons, and we will have a decision before the first patient finishes trial.
Q: Could accelerated approval be used in this disorder?
Woodcock: Yes. We issued a draft guidance talking about how you could use accelerated approval for AD in general, but in particular for this form of it.
Q: How about orphan-drug approval?
Woodcock: A drug that treats all AD would exceed the 200,000-patient definition for rare diseases. A drug that is only useful for ADAD would be an orphan drug. It is up to the developer what they seek. Whether it has orphan designation, or not, does not change our standard for approval. For you as families, whether a drug has orphan designation makes no difference.
Q: What is the best-case scenario, what is a more likely scenario?
Lasser: That’s tough to say when you do not know what success looks like. Can we slow the disease by years? Can we stop it? At this point, it’s too early to say.
Siemers: Despite the doom and gloom you read in some media, personally I really do think we are on right track with some of the drugs we are hearing about. Will one of them cure this? Probably no. So a likely scenario is that we will be in an in-between zone, where we see some effects but have to find out if they are clinically meaningful. That is where we will really push the envelope with combination therapies.
Q: Is ADAD the same disease process as LOAD? So that someone with ADAD has biomarkers starting in their 20s and someone with LOAD in their 50s? Or is ADAD faster?
Bateman: Our data suggests that the process, the staging, the sequence of events, and the rate appear to be similar between ADAD and LOAD, although final proof is not yet known. To follow a 25-year process you need 25 years, and we have not had those biomarker tools for that long. But we can make predictions even with the shorter intervals of observation that we do have now, five years or so. And those data suggest that ADAD and LOAD are similar.
Q: If DIAN demonstrates a biomarker change and a cognitive benefit, what does that mean for sporadic AD? Can that help approval of the drug for LOAD?
Isaac: At the moment the agencies do not have the data about how similar ADAD and LOAD are. You scientists have that data. I ask you to compare, find out, and tell us. That is very important. Then we can answer your question.
Woodcock: The good news is there are parallel natural history studies in both diseases. If you find a biomarker that is meaningful in both, you can bridge with it. For example, we have been approving drugs for cystic fibrosis. We think of it as one disease, but there are many mutations and they have different consequences. We started by approving the first drug for just 7 percent of cases with a specific mutation and took it from there. We are used to dealing with this question. Show us data on the extrapolation from ADAD to LOAD.
Morris: The growing incorporation of biomarkers has created more optimism in LOAD. The solanezumab Phase 3 trials could have failed because they contained up to 30 percent of people who were misdiagnosed. They did not have the target the drug was to treat. They had something else. Now the next trial requires that everyone in it have a positive amyloid scan.
Siemers: That is a perfect example of how we are learning as we go.
Bateman: In closing, I expect that from this first meeting, real action will follow. Everybody here has families and day jobs, but we all gathered today on Saturday because we believe in this so strongly. Thanks to all.
For research updates on autosomal-dominant Alzheimer’s disease gained in large part with the participation of these families, see Part 3 of our AAIC coverage.—Gabrielle Strobel
- 100 DIAN Family Members Gather for Their First International Meeting
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- As DIAN Plans Trial Number Two, the Goal Is to Go Big
- London: Europe-U.S. Regulators Mull Prevention Trial in Familial AD
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