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.

U.K. DIAN families with researcher Nick Fox of University College London (fourth from left). [Courtesy of Ellen Ziegemeier, Washington University.]

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.

Audience Q&A

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

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References

News Citations

  1. 100 DIAN Family Members Gather for Their First International Meeting
  2. At DIAN Family Meeting, Funding News Caps Talk of Inadequate Services
  3. As DIAN Plans Trial Number Two, the Goal Is to Go Big
  4. London: Europe-U.S. Regulators Mull Prevention Trial in Familial AD

Therapeutics Citations

  1. Solanezumab
  2. Gantenerumab
  3. Aducanumab
  4. Crenezumab

Other Citations

  1. Part 3

External Citations

  1. Right to Try laws
  2. 21st Century Cures Bill

Further Reading

No Available Further Reading