Story in O Magazine about woman with Lewy body dementia

LBD folks –

Apparently the March 2011 issue of O Magazine (O for Oprah) has an article titled “Before I Forget” by Beth Macy about a woman with Lewy Body Dementia.  I haven’t seen the article yet; it’s wonderful that LBD is getting some attention in the popular press.  But I am aware of Beth Macy’s writings in her blog “Intrepid Paper Girl” about this woman, Lynn Forbish.  Beth beautiful writes on the topic of caregiving on rare occasions.

Beth Macy is a writer at the Roanoke Times newspaper.  At a party Beth went to several years ago, a recently retired copy editor from the same newspaper came up to her and said “I have dementia — in case you didn’t know!”  Beth didn’t know.  The retired copy editor, Lynn Forbish, had been diagnosed at 63 with Lewy Body Dementia.  “Sometimes I can’t remember whether to hook my bra in the front or the back,” Lynn told Beth.  Beth writes that “in losing her memory, [Lynn] had regained part of herself.”

I’ve copied below the story Beth wrote in 2007 about Lynn for the Roanoke Times.  Lynn was mad that former co-workers didn’t visit her any more.  Lynn joked that she’d like to send them a Christmas card that read:  “I have dementia, not f—-g herpes!”

Robin

http://www.roanoke.com/health/wb/wb/xp-115806

Dementia causes one to lose her edge
Once, Lynn Forbish was sharp, witty, mercilessly precise. Now a fast-moving form of dementia has changed her life, and in some unexpected ways.
By Beth Macy
The Roanoke Times
Sunday, May 06, 2007

For someone whose livelihood depended on her mastery of language, it troubled Lynn Forbish when she’d struggle to extract an everyday word from memory — “cafeteria,” say — only to have “mess hall” pop out instead.

Later, as the fuzzy thinking worsened, it was her bra that gave her fits: Did the damn thing hook in the front or the back? Just whose idea was it for women to wear these things anyway?

A year ago when she was diagnosed with Lewy body dementia, Lynn could still articulate what it felt like to lose her mind. In the straight-up way of a veteran journalist who knows better than to pussyfoot around the truth, she’d look you in the eye and say:

“I retired because I have dementia … in case you didn’t know!”

She would still correct you if you used “farther” instead of “further” — a holdover from the decades she spent manning newspaper copy desks.

She could still describe the scores of celebrities she’d interviewed in her prime, down to the details on Liberace’s rings.

Those abilities are gone now. In many ways, so is the old Lynn.

She’s been replaced by a softer version of herself — one who no longer teaches her grandchildren four-letter words. One who relies on her son and daughter-in-law to handle her finances, take her to the doctor and cut the meat on her dinner plate.

At 64, the new Lynn has found something the old Lynn never dreamed possible: In losing her memory, she’s found a part of herself.

‘I hate people’

“I work the Sunday New York Times crossword puzzle in ink,” she had boasted in her 1993 letter of application for the chief copy editor job at The Roanoke Times. “I play Scott Joplin rags and Chopin waltzes on an old upright piano that belonged to my great-grandmother.”

Her resume listed decades of experience as a reporter, editor and page designer, including at papers much larger than The Roanoke Times. But the newspaper’s editors had no idea how tough she’d had to be to pull it all off.

She was a single mother in the mid-’60s; her husband left when her son and daughter were 2 years and 6 months old, respectively. Later, he had their marriage annulled so he could remarry in the Catholic Church.

It was an experience Lynn never really got over, friends and family members say.

Her parents helped. But Larry Forbish recalls his mom’s supplementing her newspaper wages — at a department store and a drugstore, working three jobs at once — to pay for his braces. He remembers her hauling pails of cloth diapers to the Laundromat after long shifts at work.

At her hometown paper in Janesville, Wis., Lynn worked her way up from clerk-typist to reporter, covering police and school beats and writing features, too. She wrote essays, including a series about her own efforts to quit smoking: “I used to smoke three packs a day. Now I chew three packs a day.

“Gum, that is. I hate Doublemint gum. I hate people.”

On weekends, she reviewed entertainers who performed at nearby nightclubs, and later covered similar acts for the St. Petersburg (Fla.) Times, reviewing the likes of Milton Berle, Sammy Davis Jr. and Neil Diamond.

She leveled with Berle in print that he needed to get a new shtick. Of Diamond, she wrote that he would ruin his voice if he didn’t quit singing in that annoying gravelly style.

“She had a reputation for being a nutty madcap when she was here,” recalled Jeanette DeGroot, who worked alongside her in St. Petersburg in the ’70s and ’80s.

But as a night-shift copy editor, Lynn was fierce, priding herself on precision, skepticism and correcting others’ mistakes.

DeGroot recalls her once complaining that someone had tried to break into her apartment, although nothing was damaged or stolen.

How, then, did she know?

One of the plants on her balcony was moved two inches from where she’d put it. “Now that is a classic copy editor for you,” DeGroot said.

Crackerjack editor

About the same time her own mother was diagnosed with vascular dementia, Lynn moved to Roanoke to be near her son, Larry, and his wife, Katie; they were expecting a child.

Concerned about her own family health history, she ate antioxidant-rich foods long before they were the preventive rage. She played bridge, sold antique perfume bottles as a side business and balanced her checkbook in her head.

In journalism circles, the copy desk is known as the “Mount Everest of newsroom discontent,” and in Roanoke, Lynn was ruler of the summit. When she started working at The Roanoke Times in 1993, the paper was lucky to get her, and she didn’t hesitate to let everyone who worked with her know it.

Former business reporter Lois Caliri called her “a real crackerjack. She ran that place at night.”

Longtime reporter Laurence Hammack added: “She saved my butt many a time.”

Former copy editor Mike Kennedy said it was her “command presence” that allowed her to pull off coordinating phones, photographers and reporters when big news broke at night or on weekends.

“We’d sit back-to-back and gripe about things, and they used to call us ‘The Optimism Corner’ because we were so not the optimism corner,” Kennedy said.

Young editorial assistants were warned to tiptoe around her: Don’t turn your desk lamp on; it bothers her eyes. Don’t sit in her chair, or you’ll be ordered to vacate, pronto.

“When new people [editorial assistants] started, we actually had to teach them how to work when Lynn was working,” said Ellen Moseley, a copy editor and page designer. “But that was OK because she … deserved that kind of respect. She was the queen.”

Early in 2005, a computer-system switch was announced, a changeover Lynn dreaded and said so repeatedly. What she didn’t say — and what she’d managed to hide for several months — was her escalating forgetfulness.

Fears unmasked

During a spring trip to Florida, Lynn finally broke down, explaining tearfully to one of her oldest friends that she was having trouble remembering words, finding her car keys and keeping her once-meticulous house neat.

Back in Virginia, she kept her fears to herself. When her visual and spatial abilities began to waver at work — she repeatedly pressed the wrong button to receive a transferred call, for instance — she blamed the phone system.

Once when Moseley summoned the elevator to leave work for the night, she found Lynn inside — trapped, confused and, as she was wont to do in awkward situations: laughing. She hadn’t known which button to push.

Co-workers tried to help her adjust to the new computer system, writing her passwords down, making lists. They even called Larry to express concern.

He didn’t notice his mother faltering until Thanksgiving Day, when Lynn made her usual drive to his Bonsack home — and knocked on the next-door neighbor’s house. At her request, he crunched the numbers on her retirement accounts. She was relieved when he told her she could afford to retire two years early at 63.

“Something’s wrong with my brain,” she finally confided to Nancy Caldwell, a co-worker, just before she voluntarily retired in December 2005.

A few weeks earlier, she had momentarily forgotten what kind of work Caldwell did at the newspaper — when it was Lynn who had trained her in the first place.

Within a month of retiring, Lynn ran into a parked car and lost her driving privileges. When Larry picked her up from the police station, she still couldn’t comprehend what had happened.

“A stop sign just jumped out at me,” she said.

The only thing left to lose was her house.

A new vulnerability

Her home in the Virginia Heights area of Southwest Roanoke was a mess: Papers were stacked everywhere, including on the furniture and stairs. Daughter-in-law Katie Forbish discovered some of the medications Lynn was supposed to be taking mixed in with the cat food.

Her longtime neighbor Lisa Wade noticed lights on at odd hours. When she invited her to dinner, Lynn ate only a piece of bread, saying that food tasted metallic. She had lost 40 pounds.

“Lynn, honey, if you don’t start eating, you’re going to die,” Wade told her.

In February 2006, doctors at the Carilion Center for Healthy Aging diagnosed her with Lewy body dementia, which is rarer than Alzheimer’s disease — and progresses twice as fast. Patients last an average of five to seven years.

Larry was shocked. He knew she was having problems, but had chalked it up to retirement-related depression. “I felt guilty that I didn’t see earlier how bad she was getting. But the doctors shot the hell out of my denial.”

Such a reaction is not uncommon among children of dementia patients, according to Lynn’s geriatrician, Dr. Michael Berry. “When you start out being such a bright person, you have to come down a lot farther on the scales before it becomes obvious” to family members.

His mother, Berry explained, was now reading at a fifth-grade level, and her spatial and manipulative skills — the ability to work a puzzle or draw a simple diagram — scored in the mental retardation range. Protein lumps, called Lewy bodies, were in the nerve cells of her brain, causing it to shrink and impairing her ability to form new memories.

It was no longer safe for her to live at home alone. She needed to socialize and live among people. And she should make a record of her life soon — while she could still remember it.

Lynn had never been especially close to her daughter-in-law, but Katie Forbish put their history aside as she dug into researching Lynn’s disease — and finding her a new home. She interviewed directors of some 20 assisted-living facilities before choosing Ridgewood Gardens, now called Summerville.

“Her tongue was always her enemy,” Katie said. “But God has done a lot of healing with all of us.”

For the first time in decades, Larry added, she’s at peace.

When Lynn can’t think of a word, she no longer snaps at people for “patronizing” her by trying to finish her sentence.

Instead she laughs, a lot and often. In her lucid moments, she even jokes about her condition: “I kind of like this,” she said recently, when a friend arrived with a treat.

“Hey, maybe I’m just making all this dementia stuff up so I can be waited on!”

Though she hadn’t been to church regularly since childhood, Lynn began attending Baptist services with her family and asked Katie to buy her a large-print Bible. She started giving money to a myriad of charities — not just the ones targeted toward diseases that she might get.

“I think probably she is a very tender, loving person who just couldn’t let her hurts go,” Katie says.

“But now the hurts are being let go for her.”

Sometimes hints of the “old” Lynn still resurface: Last year, she threatened to send her former co-workers a Christmas card chastising them for not visiting her more. She joked that the card would read:

“I have dementia, not [expletive] herpes!”

Love interest

The woman who used to coordinate coverage of shootings and plane crashes can no longer dial a phone. She can’t put her sweater on by herself.

She has help, though, at Summerville, thanks to attendants and to her boyfriend, Don Memmer, a retired lawyer who lives down the hall and has a different, milder form of dementia. “He still drives!” Lynn brags. “And he has a car!”

Neither of them can operate the CD player or the VCR anymore, and Lynn looks despondently at her massive movie collection, trying to recall her favorite actor’s name. “It was the guy who played Columbo. … No, it was, it, it, it … Oh, dammit.”

It was Peter Sellers. It comes to her later, in the middle of another conversation.

Lynn and Don watch television mostly, and sometimes venture out in his car — although a recent trip to attend the Cat Fanciers Association Cat Show near Valley View turned into a joy ride instead. They drove around for three hours and never found the show.

Parkinson’s-like tremors have begun to settle into Lynn’s hands, apropos of Lewy body, and occasionally Lynn sees people who are not there. Nothing scary, usually: A pair of girls are lost and in her room, and Lynn calls Katie, asking her to help them find their way.

Moments of lucidity are increasingly rare but spot-on and classic Lynn: “Nobody’s gonna give you a medal or anything for being depressed, so you might as well laugh,” she said recently.

And: “I have no idea what happens to me when I go. But, see, now I don’t worry about that so much, so I guess it’s a blessing.”

Katie and Larry have read the statistics on caregivers — the soaring depression and high rates of divorce. “Sunday is Nana day,” Katie said, the day they take Lynn to church, then eat out. At Olive Garden, her favorite restaurant, they cut her food and help her when she tries to eat her fettuccine with a knife.

If it’s a nice day, sometimes Larry drives her to Rocky Mount where she tries to go over her inventory of antique perfume bottles and art-deco prints in the antique-mall booth Larry helps her maintain.

Katie talks to her on the phone for an hour every night. “It can consume your life if you let it,” Katie said. “When Katelyn was little, we’d get a baby sitter and then go out to dinner and talk about nothing but Katelyn. Now, we talk about Nana.”

Lynn can still be exasperating. When she misplaces an item, she insists that her housekeeper must have thrown it away. Not long ago, she accused Katie of stealing her favorite sweater.

No, Katie corrected, and located it for her.

Later that afternoon, Lynn apologized for the slight:

“I’m sorry I was such a poop-head today,” she said.

AD Presenting as CBS (2006)

CBS folks –

Probably half of the people I’ve helped with brain donation who had a clinical diagnosis of CBS (or CBD) ended up with a confirmed diagnosis of Alzheimer’s disease (AD) upon brain autopsy. The case of someone recently was the same. One clue in that case was that the person experienced myoclonus which, surprisingly, is more associated with AD than CBD. The Mayo Clinic neuropathology report in this recent case gave the citation to a 2006 article as a reference item. This post is about that 2006 article.

That 2006 article is a case report of a 60-year-old man presenting with “slowly progressive left hemi-Parkinsonism, left hand apraxia, myoclonus, dystonia, visuospatial disturbances, and alien limb phenomenon, resembling corticobasal syndrome.” The man died 8 years after symptom onset. Neuropathological analysis showed that the man had Alzheimer’s Disease. The authors say that the “CBS-like presentation in AD is rare.” Four years later, I don’t think researchers would make the same statement. Indeed, in late 2009, researchers from Mayo, led by Dr. Hu, published research in which 11 of 16 clinical CBS cases ended up having Alzheimer’s Disease upon brain autopsy. One thing I learned from that late 2009 article was that alien limb is not a significant syndrome when differentiating between CBD and AD.

I’ve copied the abstract below.

Robin

Movement Disorders. 2006 Nov;21(11):2018-22.

Alzheimer’s disease presenting as corticobasal syndrome.

Chand P, Grafman J, Dickson D, Ishizawa K, Litvan I.
Department of Neurology, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA.

Abstract
A 60-year-old man presented with slowly progressive left hemi-Parkinsonism, left hand apraxia, myoclonus, dystonia, visuospatial disturbances, and alien limb phenomenon, resembling corticobasal syndrome. Eight years later, neuropathology revealed features of Alzheimer’s disease, with asymmetrical (right more than left) cortical tau burden with image analysis. The videotaped clinical features, neuropsychological aspects, and neuropathological correlates are presented and discussed.

PubMed ID#: 16977625 (see pubmed.gov for the abstract only)

Davunetide Research Update (2/8/11 webinar)

I listened to Dr. Morimoto’s presentation yesterday during the CurePSP webinar. My notes are copied below. I thought the background he gave on animal studies (transgenic mice) was fascinating. Otherwise, there wasn’t anything new for me. I was surprised he didn’t mention the pilot study at all. If any of you listened in and found something interesting, please share!

You can find a video/audio recording of the presentation on the CurePSP website here:
http://curepsp.na5.acrobat.com/p92435146/

You can find a PDF of the slides on the CurePSP website here:
http://www.psp.org/file_download/a84748 … 52e9e8ccf8

Of course the slides won’t contain the Q&A.

Robin

Davunetide Research Update
Presenter: Bruce Morimoto, PhD, Vice President, Drug Development, Allon Therapeutics, Inc.
2/8/11 Webinar

[I didn’t take notes on the background he gave on Allon Therapeutics.]

Drug development is a highly regulated and lengthy process:
Preclinical: lab and animal research
Phase I: early clinical safety testing
Phase II: patient safety; early efficacy
Phase III: efficacy; safety
Ends in new drug application, FDA review, and FDA approval

Description of PSP:
* A degenerative disease involving the brain stem, basal ganglia, and cerebellum. These regions control movement.
* Clinical symptoms (movement problems, cognitive impairment) are the apparent result of the underlying tau pathology in the brain region controlling those functions.

Image from Williams and Lees; Lancet Neurology 2009;8:270-279. Location of pathology in Richardson’s Syndrome. Pathology in upper regions gives rise to cognitive impairment. Pathology in lower regions gives rise to movement problems.

In response to both disease and injury, the brain produces a protein called ADNP (activity dependent neuroprotective protein). Image on right side shows nucleotide sequence.

Davunetide has other names, including:
NAP
NAPVSIPQ Peptide
AL-108
AL-208

Davunetide protects and repairs the cell’s scaffolding (cytoskeleton/microtubules). The image on the right shows that davunetide protected a cell from zinc chloride toxin.

Microtubules form the scaffold within the cell. Microtubules are essential for the neuronal structure and function. As the cell becomes sick through neurodegenerative, the microtubules fall apart. As that happens, you lose the structure of the neuron and the function. It begins to die. Then the tau protein becomes chemically modified and starts clumping up. This gives rise to the pathology of PSP. Images from Stamelou, et al; Brain 2010:133;1578-1590.

Animal model for tau pathology:
* Created mice which progressively develop tau pathologies and spatial memory deficit. (Both a cognitive impairment as well as tau pathology.)
* Transgenic (Tg) mice given two human tau mutations. These mutations are associated with a severe FTD phenotype. (PSP is a type of FTD.)

In a study, animals were administered davunetide intra-nasally. The chemical modification associated with tau protein was analyzed. The study’s conclusion: restoration of normal tau phosphorylation levels. The level of tau went down with davunetide. This was the first hint that davunetide might affect this pathology.

Also analyzed the tangle pathology in the mice brains. The study’s conclusion: davunetide treatment reduces the number of NFTs (neurofibrillary tangles). This means that the total amount of pathology is reduced. It’s a modest improvement but is statistically significant. Shiryaev et al (2009) Neurobiology of Disease 34, 381.

While it’s important that the treatment reduces the pathology, it’s more important that the treatment improves symptoms. The tau double mutant mice, once given davunetide, showed improved learning and memory in the Morris water maze. The tau double mutant mice performed nearly as well as normal mice.

Through these studies, we see that davunetide is having an effect on:
1- the pathway that is leading to the development of the pathology
2- the level of pathology
3- behavior

Human testing of davunetide:
1) Phase 1 clinical safety studies done in (a) healthy young, middle-aged and elderly adults, and (b) Alzheimer’s Disease
2) Phase 2 clinical safety and efficacy studies done in: (a) amnestic MCI (pre-cursor to AD). After 3-month treatment, there was memory improvement. And (b) chronic cognitively-impaired schizophrenia patients. After 3-month treatment, improvement in functional capacity (everyday activities) and possible improvement in memory.

Side effects observed in previous davunetide studies:
* nasal passage complaints such as runny nose, nasal or sinus congestion, throat or sinus pain. These were potentially related to the intranasal administration.
* headache
* dizziness. Note that many PSP patients already have gait instability, episodic dizziness, and/or history of falls.
* nausea
* excessive sweating

Rationale for study of AL-108-231 in PSP:
1) In preclinical (animal) studies, davunetide reduces the tau pathology that is seen in PSP. And reducing the pathology in animals results in an improvement in behavioral outcomes.
2) In clinical studies, davunetide is: well-tolerated with modest side effects; gets into brain; improved memory in aMCI patients (pre-Alzheimer’s Disease); and improved ability to conduct daily tasks in cognitively-impaired schizophrenia patients.

Study design for AL-108-231:
* multicenter, multinational: approximately 300 PSP patients will be treated for 1 year at about 47 clinical sites in US, Canada, Australia, Germany, UK and France.
* Placebo-controlled: 1:1 ratio
* couble-blind

Key patient qualifications:
* probable or possible diagnosis of PSP with no other neurologic disease
* 41 to 85 years old
* reliable caregiver
* patient and caregiver must be fluent in local language so that interviews can be completed
* reside outside skilled nursing home or care facility at the start of the study
* ability to take 5 steps with walker or minor assistance
* parkinson medications must be stable for 90 days and other medications must be stable for 30 days

Study assessments
* Patient and caregiver interviews: safety (adverse events, con meds) and efficacy (disease severity, daily living, cognitive, mood)
* Lab tests including nasal examination, blood tests, MRI scan, lumbar puncture (optional), eye movement (optional at some sites), DNA collection (optional)

31 sites in North America: coordinating center in North America is UCSF. Dr. Adam Boxer is the study physician.

15 sites in Europe: half the sites in Germany are up and running; half the sites in the UK are up and running; the French sites should be up and running in another month or so.

1 site in Australia: Dr. David Williams in Melbourne. Open for recruitment.

For more information:
* see clinicaltrials.gov, study NCT01110720
* contact Allon Therapeutics: Sue Anne Crocker, [email protected]

Q&A: [I re-ordered these]

Question: Do you expect that davunetide will un-do damage that has already been done?

Answer: Our expectation is to prevent additional damage from occurring. We don’t expect to un-do damage that has already been done.

Question: In the 12-week pilot, there was no evidence to suggest efficacy. Does this concern you?

Answer: No. We were not expecting to see any kind of efficacy in the 12-week pilot study. It was a small study: a total of 12 patients. Not only PSP patients but also CBS patients.

Question: Will the drug help eye movements?

Answer: We don’t know. We are including this in the study since one of the distinguishing characteristics of PSP is eye movement problems. How does the eye movement dysfunction relate to some of the other impairments in PSP?

Question: What do we expect in terms of improvements?

Answer: We don’t know. Our best guess is that it’s going to take about 12 months before we see any affect from the treatment. The gains will be modest. We need a large sample size and a lengthy study period to be sure we are seeing improvements.

Question: I infer that only the Richardson’s Syndrome type of PSP patients are included. What can you say to a family dealing with another type of PSP as to the justification for this?

Answer: Inclusion criteria is really looking at the Richardson’s Syndrome type of PSP. In a clinical trial, we need to look at a similar population of patients.

Question: Is the study relevant to FTDs?

Answer: Tau pathology isn’t unique to PSP. CBS and PNFA have tau pathology. Alzheimer’s also has tau pathology.

We need to show that davunetide is effective in PSP before we can look into other conditions.

Question: Are MSA patients included in this study?

Answer: No, PSP only.

Dr. Morimoto’s Comment: Lots of questions about specific situations. Go to clinicaltrials.gov and find the site nearest you. Ask that site about your specific situation.

Dr. Morimoto’s Comment: A number of visits need to be made to the particular site. It’s up to the site to determine if you live close enough or not. Anecdotally, a number of people are travelling a long distance to participate.

[I had a few questions that didn’t get asked. They are: ]

Question: Is it reasonable to think that 47 sites can enroll 6-7 patients each to get to 300 patients? When do you anticipate the 300th patient will enroll?

Question: When might we see published data from this study?

Question: Since the Alzheimer’s market is bigger than the PSP market, why aren’t you testing this first in the AD market?

“Davunetide Research Update” (webinar, 2-8-2011)

CurePSP (psp.org) hosted a webinar yesterday to allow researchers to give an update on the experimental drug davunetide.  The key presenter was Bruce Morimoto, PhD, Vice President, Drug Development, Allon Therapeutics, Inc., the maker of davunetide.

My notes from Dr. Morimoto’s presentation and the question-and-answer session are below.

I thought the background Dr. Morimoto gave on animal studies (transgenic mice) was fascinating.  Otherwise, there wasn’t anything new for me.  I was surprised he didn’t mention the davunetide pilot study at all.  If any of you listened in and found something interesting, please share!

Editor’s Note:  Unfortunately these links are no longer working.
You can find a video/audio recording of the presentation on the CurePSP website here:
curepsp.na5.acrobat.com/p92435146/

You can find a PDF of the slides on the CurePSP website here:
www.psp.org/file_download/a8474849-0fa9-4ed9-8659-9452e9e8ccf8

Of course the slides won’t contain the Q&A.

Robin

——————————

Davunetide Research Update
Presenter:  Bruce Morimoto, PhD, Vice President, Drug Development, Allon Therapeutics, Inc.
CurePSP Webinar
February 8, 2011

[I didn’t take notes on the background he gave on Allon Therapeutics.]

Drug development is a highly regulated and lengthy process:
Preclinical:  lab and animal research
Phase I:  early clinical safety testing
Phase II:  patient safety; early efficacy
Phase III:  efficacy; safety
Ends in new drug application, FDA review, and FDA approval

Description of PSP:
* A degenerative disease involving the brain stem, basal ganglia, and cerebellum.  These regions control movement.
* Clinical symptoms (movement problems, cognitive impairment) are the apparent result of the underlying tau pathology in the brain region controlling those functions.

Image from Williams and Lees; Lancet Neurology 2009;8:270-279.  Location of pathology in Richardson’s Syndrome.  Pathology in upper regions gives rise to cognitive impairment.  Pathology in lower regions gives rise to movement problems.

In response to both disease and injury, the brain produces a protein called ADNP (activity dependent neuroprotective protein).  Image on right side shows nucleotide sequence.

Davunetide has other names, including:
NAP
NAPVSIPQ Peptide
AL-108
AL-208

Davunetide protects and repairs the cell’s scaffolding (cytoskeleton/microtubules).  The image on the right shows that davunetide protected a cell from zinc chloride toxin.

Microtubules form the scaffold within the cell.  Microtubules are essential for the neuronal structure and function.  As the cell becomes sick through neurodegenerative, the microtubules fall apart.  As that happens, you lose the structure of the neuron and the function.  It begins to die.  Then the tau protein becomes chemically modified and starts clumping up.  This gives rise to the pathology of PSP.  Images from Stamelou, et al; Brain 2010:133;1578-1590.

Animal model for tau pathology:
* Created mice which progressively develop tau pathologies and spatial memory deficit.  (Both a cognitive impairment as well as tau pathology.)
* Transgenic (Tg) mice given two human tau mutations.  These mutations are associated with a severe FTD phenotype.  (PSP is a type of FTD.)

In a study, animals were administered davunetide intra-nasally.  The chemical modification associated with tau protein was analyzed.  The study’s conclusion:  restoration of normal tau phosphorylation levels.  The level of tau went down with davunetide.  This was the first hint that davunetide might affect this pathology.

Also analyzed the tangle pathology in the mice brains.  The study’s conclusion:  davunetide treatment reduces the number of NFTs (neurofibrillary tangles).  This means that the total amount of pathology is reduced.  It’s a modest improvement but is statistically significant.  Shiryaev et al (2009) Neurobiology of Disease 34, 381.

While it’s important that the treatment reduces the pathology, it’s more important that the treatment improves symptoms.  The tau double mutant mice, once given davunetide, showed improved learning and memory in the Morris water maze.  The tau double mutant mice performed nearly as well as normal mice.

Through these studies, we see that davunetide is having an effect on:
1- the pathway that is leading to the development of the pathology
2- the level of pathology
3- behavior

Human testing of davunetide:
1) Phase 1 clinical safety studies done in (a) healthy young, middle-aged and elderly adults, and (b) Alzheimer’s Disease
2) Phase 2 clinical safety and efficacy studies done in:  (a) amnestic MCI (pre-cursor to AD).  After 3-month treatment, there was memory improvement.  And (b) chronic cognitively-impaired schizophrenia patients.  After 3-month treatment, improvement in functional capacity (everyday activities) and possible improvement in memory.

Side effects observed in previous davunetide studies:
* nasal passage complaints such as runny nose, nasal or sinus congestion, throat or sinus pain.  These were potentially related to the intranasal administration.
* headache
* dizziness.  Note that many PSP patients already have gait instability, episodic dizziness, and/or history of falls.
* nausea
* excessive sweating

Rationale for study of AL-108-231 in PSP:
1) In preclinical (animal) studies, davunetide reduces the tau pathology that is seen in PSP.  And reducing the pathology in animals results in an improvement in behavioral outcomes.
2) In clinical studies, davunetide is:  well-tolerated with modest side effects; gets into brain; improved memory in aMCI patients (pre-Alzheimer’s Disease); and improved ability to conduct daily tasks in cognitively-impaired schizophrenia patients.

Study design for AL-108-231:
* multicenter, multinational:  approximately 300 PSP patients will be treated for 1 year at about 47 clinical sites in US, Canada, Australia, Germany, UK and France.
* Placebo-controlled: 1:1 ratio
* couble-blind

Key patient qualifications:
* probable or possible diagnosis of PSP with no other neurologic disease
* 41 to 85 years old
* reliable caregiver
* patient and caregiver must be fluent in local language so that interviews can be completed
* reside outside skilled nursing home or care facility at the start of the study
* ability to take 5 steps with walker or minor assistance
* parkinson medications must be stable for 90 days and other medications must be stable for 30 days

Study assessments
* Patient and caregiver interviews:  safety (adverse events, con meds) and efficacy (disease severity, daily living, cognitive, mood)
* Lab tests including nasal examination, blood tests, MRI scan, lumbar puncture (optional), eye movement (optional at some sites), DNA collection (optional)

31 sites in North America:  coordinating center in North America is UCSF.  Dr. Adam Boxer is the study physician.

15 sites in Europe:  half the sites in Germany are up and running; half the sites in the UK are up and running; the French sites should be up and running in another month or so.

1 site in Australia:  Dr. David Williams in Melbourne.  Open for recruitment.

For more information:
* see clinicaltrials.gov, study NCT01110720
* contact Allon Therapeutics:  Sue Anne Crocker, [email protected]

Q&A:  [I re-ordered these]

Question:  Do you expect that davunetide will un-do damage that has already been done?

Answer:  Our expectation is to prevent additional damage from occurring.  We don’t expect to un-do damage that has already been done.

Question:  In the 12-week pilot, there was no evidence to suggest efficacy.  Does this concern you?

Answer:  No.  We were not expecting to see any kind of efficacy in the 12-week pilot study.  It was a small study:  a total of 12 patients.  Not only PSP patients but also CBS patients.

Question:  Will the drug help eye movements?

Answer:  We don’t know.  We are including this in the study since one of the distinguishing characteristics of PSP is eye movement problems.  How does the eye movement dysfunction relate to some of the other impairments in PSP?

Question:  What do we expect in terms of improvements?

Answer:  We don’t know.  Our best guess is that it’s going to take about 12 months before we see any affect from the treatment.  The gains will be modest.  We need a large sample size and a lengthy study period to be sure we are seeing improvements.

Question:  I infer that only the Richardson’s Syndrome type of PSP patients are included.  What can you say to a family dealing with another type of PSP as to the justification for this?

Answer:  Inclusion criteria is really looking at the Richardson’s Syndrome type of PSP.  In a clinical trial, we need to look at a similar population of patients.

Question:  Is the study relevant to FTDs?

Answer:  Tau pathology isn’t unique to PSP.  CBS and PNFA have tau pathology.  Alzheimer’s also has tau pathology.

We need to show that davunetide is effective in PSP before we can look into other conditions.

Question:  Are MSA patients included in this study?

Answer:  No, PSP only.

Dr. Morimoto’s Comment:  Lots of questions about specific situations.  Go to clinicaltrials.gov and find the site nearest you.  Ask that site about your specific situation.

Dr. Morimoto’s Comment:  A number of visits need to be made to the particular site.  It’s up to the site to determine if you live close enough or not.  Anecdotally, a number of people are travelling a long distance to participate.

[I had a few questions that didn’t get asked.  They are: ]

Question:  Is it reasonable to think that 47 sites can enroll 6-7 patients each to get to 300 patients?  When do you anticipate the 300th patient will enroll?

Question:  What’s the baseline PSP Rating Scale score for those who participated in the pilot?  What’s the baseline MMSE score for those who participated in the pilot?

Question:  I’ve heard that we might see published data from this study in 2013.  Do you think that’s reasonable?  Are we talking the beginning of 2013 or the end of 2013?

Question:  Since the Alzheimer’s market is bigger than the PSP market, why aren’t you testing this first in the AD market?