Biotech Strategy Blog

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Posts from the ‘Alzheimer’s’ category

Can we use immunotherapy to treat or delay Alzheimers Disease?

Berlin Wall Museum

Preserved section of the Berlin Wall

I have a personal interest in Alzheimers Disease, my mother Audrey died from it three years ago back in 2014.

Since then, I’ve watched with fascination and excitement the progress made in using the body’s own immune system against cancer. There’s still a long way to go, but a revolution in treating cancer is underway, as we’ve been documenting on this blog and the Novel Targets Podcast.

In recent years in the United States we’ve also seen grand initiatives targeting cancer such as Vice President Biden’s Moonshot, as well as large philanthropic support e.g. the creation of the Parker Institute for Cancer Immunotherapy.

Sadly, we’ve not seen the same level of interest in targeting dementia or funding research into new treatments for Alzheimers disease.

In the United States, the media doesn’t talk much about Alzheimers (compared to cancer), unlike for example, in the United Kingdom where any promising data is heralded with headlines that frequently deliver “hype over hope.”

Alzheimers is an insidious disease that removes the ability of the person to advocate and care for themselves, instead placing the burden on families and caregivers, often for extended periods of time. Ultimately many people end up in supported living or nursing homes.

As we debate healthcare insurance in the United States, who is going to pay for the cost of dementia care as the population grows older? Caring for dementia is arguably the greatest public health challenge that the western world faces.

Which is why I was excited to talk with a researcher who is thinking outside of the box and leading the way in how we could use our immune system against Alzheimers.

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Yumanity hopes to impact humanity – an interview with Dr Susan Lindquist

Yumanity logoWe recently wrote about Syros Pharmaceuticals, one of whose founders, Dr Rick Young is based at the Whitehead Institute of MIT in Cambridge MA.

Another biopharma start-up company being spun out from research done at the Whitehead Institute for Biomedical Research is Yumanity Therapeutics.

The company recently launched with Tony Coles as CEO and Ken Rhodes as Chief Scientific Officer. Their focus is on transforming drug discovery for neurodegenerative diseases caused by protein misfolding.

The scientific founder is Dr Susan Lindquist, who spoke with Biotech Strategy Blog about her research and the Yumanity approach to drug development.

The company is committed to “improving human conditions. That’s why we call it Yumanity. The Y is for yeast, but it really is focused on humanity,” said Lindquist.

Dr Linquist started her interview by noting that as we live longer, we are more likely to get neurodegenerative diseases, starkly noting the reality of the lack of progress in drug development in this area:

“There is really, right now, nothing that we can do about them. We just do not understand how to move the needle on these and it’s really becoming an absolute crisis and it is taking a very substantial section of our healthcare budget as it is. As we continue to make better inroads against cancer and HIV and all of the other ills of mankind, it’s just going to get worse, I think. Everybody is beginning to appreciate that there is going to be an economic disaster and that we are going to ruining the next generation in a way that, at this point, is going to be tragic.”

So what is the approach Yumanity is taking, in the hope of succeeding where others have failed?

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Healthcare Innovation in Action: Designing for Dementia

Healthcare innovation can take many forms. It can be a breakthrough in our understanding of the biology of cancer, or a disease that allows new drugs to target it in an effective way, for example. We also see it with advances in medical technology such as implants that can help restore vision or imaging techniques that may allow faster and more accurate diagnoses.

However, one area that I had not thought about until recently was how innovation in a building’s design can impact the delivery of healthcare.

We interact with design every day without thinking much about it. Advertisers use design in brand marketing all the time to create instantly recognizable logos that we automatically associate with a product.

Listeners to Roman Mars’ outstanding podcast, 99% Invisible, will already be familiar with the power of design in everyday life. This podcast is well worth a listen!

Currently, I’m in Liverpool in the North West of England for personal and professional reasons, and while here I’m looking at some of the innovative work being done in the area around dementia care.

Last week I visited Everton FC who, in partnership with Mersey Care NHS Trust, use their facilities to engage and provide support to local people in the community who have dementia.

Since then I have also been to Liverpool City Councils’ Sedgemoor Dementia Support Centre in Norris Green.  The Centre recently won a national design award at the health care equivalent of the Oscars (Best Care Complex at the Healthcare Design Awards).

My mother, Audrey, had Alzheimer’s disease – a form of dementia – and spent the last two years of her life in a nursing home.  While the carers were wonderful people, I always found it rather depressing to visit.  She spent everyday sitting in a standard care home chair in a lounge area that had little cognitive stimulation other than a TV blaring in the background, high up on the wall, just creating mindless noise.

While Audrey’s memory was a bit like a Swiss cheese, she was able to engage in a conversation and had moments of great lucidity. As Tommy Dunne (@TommyTommyTee18), who has early onset Alzheimer’s told me at Everton FC: he has dementia, but he’s not demented!

I was curious to know what was innovative about the Sedgemoor dementia support centre; can design really make such a difference in the delivery of health care to those with dementia?  You can judge for yourself after watching the audio slideshow from my visit.

Sedgemoor shows what can be done in the public sector. Like many examples of successful innovation it had a champion with a vision, willing to take risks, think outside the box and break from the norm of what might otherwise have been a utilitarian oblong box.

That champion with a vision is Liverpool City Council’s Joy McDonnell, a qualified architect who was the client lead. Joy spent two hours giving me a guided tour of Sedgemoor, explaining how each part of the building, even down to the fixtures and fittings, was designed to afford the maximum benefit to users with dementia. I was blown away.

Since it was going to be impossible for me to do justice to a two-hour visit as part of a 6-minute radio documentary I’m producing for a journalism course, I’ve taken some of the pictures from my visit and matched these with the sound I recorded to create an audio slideshow:

What I hope is that Sedgemoor is not just an isolated example, but sets a precedent for future buildings. This is how more dementia care facilities could be designed. If Liverpool City Council can create a publicly funded building like this for the same price as they would an oblong box, why can’t others repeat it around the country?

I would have loved the nursing home my Mother ended up in to have had many of the design features I saw at Sedgemoor.  I could see how this would have improved her quality of life, helped stimulate her memories and keep her more active and engaged.

For anyone who has a chronic long-term illness, such as cancer or dementia, it’s not just about how long you live, but having a good quality of life while you are alive. That is something we should all aspire to for our loved ones and ourselves.

I would like to thank Liverpool City Council, and in particular the press office and dementia support lead, Phil Wong, for making my visit happen. Thanks also to Sedgemoor Manager Mary Plumpton for a warm welcome. Joy McDonnell was not only generous with her time, but gave of herself to bring Sedgemoor to life for me. Thank you, Joy!

If you have come across some innovative programs in the dementia or Alzheimer’s area, do feel share them in the comments section below.

Update June 5, 2014: listen to Living well with dementia – a personal journey

My research into designing for dementia was undertaken while on a BJTC accredited diploma in radio journalism course based at Radio City in Liverpool. You can listen via SoundCloud to the documentary I produced on living well with dementia – a personal journey:

UPDATE November 20th, 2014: BJTC Awards by @maverickny

I’m delighted to announce that Pieter’s fantastic work on dementia won the BJTC 2014 Award for Best Radio Documentary!

Thank goodness for Twitter and being able to follow the live event in Birmingham, UK remotely…

BJTC Awrd 2014

Everton FC leads the way in community dementia support

Dementia care is a “quiet crisis” that already touches many families and will touch many more as we live longer in our old age and the huge baby boomer population reaches retirement age.

The Alzheimer’s Research Trust estimate that 1 in 3 over the age of 65 will have dementia by the time they die. Alzheimer’s disease is one type of dementia.

To cope with this explosion, more care will need to be provided in the community.

Mersey Care NHS Trust, who provide mental health care in Liverpool, Sefton and Kirby, have partnered with Everton FC, an English Premier League Club to support members of the local community with dementia.

Everton v Crystal Palace April 16 2014

Everton FC vs Crystal Palace at Goodison Park on April 16, 2014.

The innovative program called “Pass on the Memories” (Twitter: @efc_potm) helps more than 120 people with memory loss through activities that take place two days a week at Goodison Park. Support is offered via facilitators in the club and health professionals from Mersey Care.

The meetings help trigger sporting memories, but also engages participants in group social activities and visits, thereby keeping them mentally active and engaged.

When I visited, members of the group were about to head off for a visit to the Museum of Liverpool, which would no doubt stimulate powerful memories for many.

As some readers of the blog may know, my mother Audrey (who died recently at age 89) had Alzheimer’s disease.  It’s a progressive disease with no known cure.  I watched her memory slowly but surely deteriorate over several years.  A keen dancer, she reached a point where she couldn’t remember how to dance anymore.

What Everton FC is doing by lending their support to the Pass on the Memories scheme, is something that sporting clubs around the world should all consider in their communities.

Goodison Park home of Everton FC

Sporting clubs derive considerable support from local communities and have facilities that are vastly underused outside of games. Many of their fans will sadly develop dementia. Engaging the local community in this way is a tremendous way of giving back.

As social services continue to be cut back in Liverpool due to budget cuts, I’m impressed by the way Mersey Care and Everton FC are helping those with dementia have the best quality of life they can through this type of local partnership.

If it didn’t exist, I expect many people would end up just sitting at home all day with little mental stimulation or interaction.

Henry Mooney Everton FCDuring my visit to Goodison Park, I spoke with Everton FC Community Engagement Manager, Henry Mooney (@HMooney23) who plays a key role in running the Pass on the Memories program at the club. He told me you don’t have to be an Everton fan to participate. 🙂

Living with Alzheimer’s disease is not easy.  Unlike a physical disability, you can’t readily tell if someone has dementia, they look normal much like the rest of us.

Tommy Dunne

Tommy Dunne, 61, was diagnosed with early stage Alzheimer’s disease three years ago. He told me that just because he has dementia, does not mean he is demented. Raising awareness of dementia and getting rid of the stigma associated with it is something we all can help with.

As the number of people with dementia grows, those who provide services (shops, transport etc) will need to be educated on how they can help people with dementia maintain their independence and undertake the activities of daily living that we all take for granted.

I was pleasantly surprised and pleased to see that Tommy is active on Twitter (@TommyTommytee18). It’s a great way to share his experiences.

I’ve included excerpts of the interviews I did with Tommy and Henry Mooney in the radio documentary on dementia that I produced – you can listen via the embedded SoundCloud at the end of this post or using this link.

If you are in the Liverpool area and have a family member with dementia, I encourage you to find out more about this innovative program.

Taking a more strategic view, I’m still shocked by how little progress there has been in drug development to tackle dementia, and in particular Alzheimer’s disease.

In comparison to oncology where research is focused on multiple new targets for drugs, as well as novel biomarkers that can help predict who are more likely to respond, dementia research seems like a record stuck in the groove.

Focusing on one target has failed to yield an effective Alzheimer’s drug despite spending hundreds of millions on clinical research.

More needs to be done to understand the biology of Alzheimer’s disease and generate new insights into potential new targets that at the very least delay the progression of a disease that many of us will possibly end up with in the future.

Update April 30, 2014: Everton FC write up my visit on their Community news site

I was thrilled to hear that John Howard, (@JHowEFC08) Media Officer for Everton in the Community has written about my visit to the Pass on the Memories program. He’s published a really well written post on the Everton FC community website that goes into more detail about the program.

Pieter Droppert interviewing Tommy Dunne. Picture Credit: John Howard, Everton FC

Here’s the link to John’s piece if you are interested in more information: Pieter’s views on Pass on the Memories

Update May 19, 2014: Talking about Dementia on BBC Radio Merseyside Daybreak show

At the start of Dementia Awareness Week in the UK, I was very grateful for the opportunity to go on the May 18, 2014 edition of BBC Radio Merseyside’s Daybreak show, produced by Helen Jones.

I talked about my late mother, Audrey and some of the innovations in dementia care that I’ve written about on the blog. If you have the chance do listen to an excerpt from the show:

Update June 5, 2014: listen to living well with dementia – a personal journey

My research into Everton’s Pass on the Memories program was undertaken while on a BJTC accredited diploma in radio journalism course based at Radio City in Liverpool. You can listen via SoundCloud to the documentary I produced on living well with dementia – a personal journey:

Using CSF Biomarkers for Differential Diagnosis of Neurological Diseases

Drug development for neurodegenerative brain diseases such as Parkinson’s or dementia, of which Alzheimer’s is the most common form, needs to focus on patients early in the disease, not those where brain damage has already occurred.

Diagnosing and treating patients more effectively earlier will, even if you aren’t able to instigate a cure, offer the ability to modify the disease progression and slow or delay when brain damage occurs.  In the case of Alzheimer’s, once the amyloid plaques (tangles of misshapen proteins) have accumulated in nervous tissue, it has so far been impossible to untangle or remove them.

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Last year, I interviewed Dr Todd Sherer, (then the Chief Program Officer) and now the CEO of the Michael J. Fox Foundation, who told me that: “biomarkers are a real focus of the foundation.” Sherer went on to say that:

“Parkinson’s is a difficult disease to diagnose, there is no definitive diagnostic test, so it ends up a clinical diagnosis.  Getting a biomarker that could help better confirm the diagnosis would allow people to get the correct treatment earlier in their disease”

Which is why I was interested to see new research published earlier this week in the journal Archives of Neurology (online first, August 27, 2012), by Sara Hall and colleagues at Lund University, University of Gothenburg and Skåne University Hospital in Malmo, Sweden.

Hall and colleagues describe how a panel of five cerebrospinal fluid (CSF) biomarkers allowed the differential diagnosis of common dementia from Parkinsonian disorders:

  • Beta-amyloid 42
  • Total tau
  • Phosphorylated tau
  • Alpha-synuclein
  • Neurofilament light chain

Patients with early symptoms of neurodegenerative diseases can be hard to diagnose.  Misdiagnosis can occur, which means patients may not respond to treatment or they could be enrolled into a clinical trial, and end up skewing the results.

Ensuring that we have the right patients in clinical trials is important as we seek to alter disease progression.  In other words it’s important to see whether new drugs or treatments are impacting the disease course.  If you have a wrongly diagnosed patient in a trial, then the drug may show no effect, not because it’s not effective, but that patient’s disease is not responsive.

Multivariate analysis indicated that the panel of 5 CSF biomarkers could accurately differentiate Alzheimer’s disease (AD) from Parkinson disease with dementia (PDD), and dementia with Lewy bodies (DLB). The Neurofilament light chain biomarker alone could differentiate PD from atypical Parkinson disease, Hall and colleagues noted.

Whilst the panel was not able to distinguish all forms of dementia, in an accompanying editorial Richard J. Perrin MD, PhD from the University of Washington, stated that this research “represents a significant step forward.” Perrin concluded that:

“Implementation of CSF biomarker panels such as this one should improve the efficiency of clinical trials and accelerate the evaluation and discovery of new effective treatments for neurological diseases.”

Summary

Developing biomarkers that assist in the ability to diagnose Alzheimer’s, Parkinson and dementia patients correctly, and then be able to monitor their subsequent disease progression, should be a key focus of those biotechnology and pharmaceutical companies that want to do innovative and rational drug development.

References

ResearchBlogging.orgSara Hall, MD, Annika Ohrfelt, PhD, Radu Constantinescu, MD, Ulf Andreasson, PhD, Yulia Surova, MD, Fredrik Bostrom, MD, Christer Nilsson, MD, PhD, Hakan Widner, MD, PhD, Hilde Decraemer, Katarina Nagga, MD, PhD, Lennart Minthon, MD, PhD, Elisabet Londos, MD, PhD, Eugeen Vanmechelen, PhD, Bjorn Holmberg, MD, PhD, Henrik Zetterberg, MD, PhD, Kaj Blennow, MD, PhD, & Oskar Hansson, MD, PhD (2012). Accuracy of a Panel of 5 Cerebrospinal Fluid Biomarkers in the Differential Diagnosis of Patients With Dementia and/or Parkinsonian Disorders Arch Neurol. DOI: 10.1001/archneurol.2012.1654

Richard J. Perrin, MD, PhD (2012). Cerebrospinal Fluid Biomarkers for Clinical Trials Arch Neurol. (August 27 Online First) DOI: 10.1001/archneurol.2012.2353

Repetitive brain injury from high impact sports generates similar pathophysiology to traumatic brain injury in soldiers blown up by IEDs

Several retired American Football stars have ended up with chronic traumatic encephalophy (CTE), previously known as dementia pugilistica. It’s similar to Alzheimer’s disease in that the brain ends up with neurofibrillary tangles.

Science Translational Medicine Cover May 16CTE has also been seen in soldiers who have experienced blast induced traumatic brain injury (bTBI) from improvised explosive devices (IEDs). I previously wrote on this blog about how nanotechnology may revolutionize the detection of TBI using a nanomaterial that changes color.

Research published in the May 16, 2012 issue of Science Translational Magazine by Lee Goldstein and colleagues from the Molecular Aging and Development Laboratory at Boston University & other institutions, compared CTE neuropathology in blast-exposed military veterans and athletes with repetitive concussion injury.

For the first time they have shown similarities in what happens to the brains of soldiers when they are blown up and to athletes in sports that have repeated head impacts.

The reseachers looked at 8 post-mortem brains, 4 military veterans aged 22 to 45 with a history of blast exposure were compared to 4 athletes aged 17 to 27 who were either American Football players or, in one case, a wrestler. Despite the small sample size, the results showed similar brain trauma in the two groups:

“the effects of blast exposure, concussive injury, and mixed trauma (blast exposure and concussive injury) were indistinguishable.”

It is worth noting that the brain neuropathysiology seen was different from that seen with Alzheimer’s disease (AD).

The researchers went on to develop a mouse model that could be used to investigate the link between blast exposure, brain neuropathology and behavior.  I encourage you to read the STM paper for full details on this.

Some of the key findings of their mouse experiments were:

  • Blast exposure induces traumatic head acceleration in a blast neurotrauma mouse model
  • Single-blast exposure persistently impairs axonal conduction and long-term potentiation of activity-dependent synaptic transmission in the hippocampus
  • Single-blast exposure induces long-term behavioural deficits that are prevented by head immobilization during blast exposure.

The authors conclude that their results “provide compelling evidence linking blast exposure to long-lasting brain injury.”

What this research suggests to me is:

  • An ongoing need to design safer head protection for athletes and soldiers
  • The need to monitor and detect traumatic brain injury (I wrote last year about how nanomaterials were being developed to monitor blast exposure)
  • Need to identify those genetic factors (e.g. carrying the APOE e4 allele leads to a high risk of developing Alzheimer’s disease) that may lead to a heightened risk of developing dementia or CTE.

The paper by Goldstein and colleagues in STM is well worth reading if you have an interest in this area and the debate about the safety of young people in high-contact sports.

Reference

ResearchBlogging.orgGoldstein, L., Fisher, A., Tagge, C., Zhang, X., Velisek, L., Sullivan, J., Upreti, C., Kracht, J., Ericsson, M., Wojnarowicz, M., Goletiani, C., Maglakelidze, G., Casey, N., Moncaster, J., Minaeva, O., Moir, R., Nowinski, C., Stern, R., Cantu, R., Geiling, J., Blusztajn, J., Wolozin, B., Ikezu, T., Stein, T., Budson, A., Kowall, N., Chargin, D., Sharon, A., Saman, S., Hall, G., Moss, W., Cleveland, R., Tanzi, R., Stanton, P., & McKee, A. (2012). Chronic Traumatic Encephalopathy in Blast-Exposed Military Veterans and a Blast Neurotrauma Mouse Model Science Translational Medicine, 4 (134), 134-134 DOI: 10.1126/scitranslmed.3003716

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AACR 2012: Promising CML & PI3K compounds from Indian company Piramal Healthcare

India to me conjures up thoughts of curry, cricket and call centers.  When I think about the Indian pharmaceutical industry, global manufacturers of generics such as Ranbaxy, Natco and Dr Reddy’s Laboratories come to mind.

AACR 2012 Annual Meeting Posters Piramal Healthcare

Photo: Pieter Droppert/Biotech Strategy Blog

What I don’t associate India with, is pharmaceutical drug discovery and the development of new drugs.

Pharmaceutical R&D is not only expensive, but requires a high-degree of expertise and comes with a high risk of failure.

Companies in the United States, Europe and Japan still develop most new drugs.

However, that may change in the future as the emerging economies in Brazil, Russia, India and China (BRIC) start to fund innovation and invest in drug discovery.

If we expect the economies of the BRIC group of countries to overtake the economies of the G-6 countries in the next 40 years, then it’s likely they will start developing their own pharmaceutical drugs.

Early signs of this were on show at the recent annual meeting of the American Association for Cancer Research (AACR) in Chicago.

Piramal Healthcare, part of an Indian conglomerate with $900 million of turnover in FY2011, presented four posters at the meeting on promising early-stage drug development compounds, including:

  • P7170, a Phosphoinositide 3-Kinase (PI3K)-mammalian Target of Rapamycin (mTOR) and Activin Receptor-Like Kinase 1 (ALK1) inhibitor.
  • P2745, an orally bioavailable molecule effective in imatinib resistant chronic myeloid leukemia cell lines including those with the T315i mutation.

P2745 is currently in Phase 1 drug development in India, and could be a potential competitor to Ariad’s Ponatinib in relapsed/refractory CML, given that it also inhibits the T315i mutation.

A few days after the AACR annual meeting, Piramal announced that they had acquired the molecular imaging portfolio of Bayer Pharma AG, including the rights to Florbetaben, a PET tracer for the detection of beta-amyloid plaque, a hallmark of Alzheimer’s disease.

The first presentation of the phase III trial results for florbetaben will take place tomorrow in the emerging science session at the annual meeting of the American Academy of Neurology (AAN) in New Orleans.

Piramal estimates the global market potential for PET imaging agents for Alzheimer’s disease to be $1.5 billion.

“We plan to build a promising portfolio in the pharma space, including our newly acquired Molecular Imaging assets, which will help us create a global branded pharma business”

said Ajay Piramal, Chairman of the Piramal Group in a press release.  The rise of the Indian pharmaceutical industry looks set to continue.

A personal perspective on Alzheimer’s: my mother doesn’t dance anymore

My mother has Alzheimer’s disease – I first suspected some form of dementia when her friends told me that she didn’t dance anymore.  Of course she insisted she did, but it was clear she had “forgotten” the steps in a way that was beyond the forgetfulness of getting older.

As a European snow bird she would travel to Malta each year to escape the damp, grey English winters.  One year when I visited her in Malta, I noticed when she went up to the hotel dinner buffet, she could not “remember” where to return to.

With a blank and vacant look she would gaze out hoping to find a clue that jarred her memory.  Friends gently directed her to the right table and diffused the embarrassment with humor.

Sadly during my visit I saw that she could no longer remember the names of people she had holidayed with for 10 years each winter, or what clothes she had worn the day before.  Her holiday companions and the hotel treated her with kindness, but it was the beginning of a decline, and her last winter in Malta.

At home, she has struggled to manage activities of daily living and the need for care has increased.   As a family, we’ve endeavored to support her independence for as long as possible, but a nursing home is now in the not too distant horizon.

Which is why I have a personal interest in Alzheimer’s disease.  It’s an area where innovation needs to catch up with demand for treatment and therapies, not to treat it when it’s happened – it’s too late to untangle the damage, but to delay it’s occurrence in those at risk.

This week in the New England Journal of Medicine (NEJM), research showed that continued treatment of moderate to severe Alzheimer’s disease with donepezil (Aricept) provides modest cognitive and functional benefits.

By the time moderate to severe disease has set in, the damage has already been done, and the train has left the station metaphorically speaking.  Those with this status require the support of caregivers.  This study was undertaken in community-dwellings i.e. some form of nursing home or care facility.

In their NEJM paper, Robert Howard of the Institute of Psychiatry & UK colleagues assessed changes in Standardized Mini-Mental State Examination (SMMSE) & Bristol Activity of Daily Living (BADLS) scores in moderate to severe Alzheimer’s patients who received donepezil or memantine in a double-blind, placebo controlled trial.

Patients continued to decline over the course of the study, so what the study showed was that by giving a cholinesterase inhibitor, the rate of decline was slowed.  The functional benefit was equivalent to 32% of the total deterioration seen over 12 months.

However, dramatic as this significant benefit sounds, the author’s rightly caution that the improvements in cognition and function were small relative to the overall decline in cognitive and functional status seen in all patients.

While this paper offers evidence-based medicine for the continuation of donepezil in those with moderate to severe disease, this treatment does not lead to a cure or restoration of function.

A study sample size of 430 was estimated to give a 95% power to detect a 1.0 point difference in SMMSE scores between donepezil and placebo groups, and 90% power to detect a 2.0 point difference.  In the end a total of 295 participants were enrolled.

The results showed that:

“Patients who were assigned to continue taking donepezil, as compared with those assigned to discontinue donepezil, had scores on the SMMSE that were higher (indicating better cognitive function) by an average of 1.9 points (95% CI, 1.3 to 2.5; P<0.001) and scores on the BADLS that were lower (indicating less functional impairment) by an average of 3.0 points (95% CI, 1.8 to 4.3; P<0.001).”

The researchers noted that:

“The severity of dementia at entry significantly influenced the effect of donepezil on SMMSE scores, with larger benefits observed in patients with moderate disease (SMMSE score, 10 to 13) than in those with severe disease (SMMSE score, 5 to 9).”

More information on the study design and detailed results can be found in the published NEJM paper.

My Mother takes donepezil and I’m pleased to see that there’s now some clinical data to support its continued use, as she will no doubt progress.

All those with loved ones who have Alzheimer’s will be pleased with any news that delays the progression of this debilitating disease.

Reference

ResearchBlogging.org
Howard, R., McShane, R., Lindesay, J., Ritchie, C., Baldwin, A., Barber, R., Burns, A., Dening, T., Findlay, D., Holmes, C., Hughes, A., Jacoby, R., Jones, R., Jones, R., McKeith, I., Macharouthu, A., O’Brien, J., Passmore, P., Sheehan, B., Juszczak, E., Katona, C., Hills, R., Knapp, M., Ballard, C., Brown, R., Banerjee, S., Onions, C., Griffin, M., Adams, J., Gray, R., Johnson, T., Bentham, P., & Phillips, P. (2012). Donepezil and Memantine for Moderate-to-Severe Alzheimer’s Disease New England Journal of Medicine, 366 (10), 893-903 DOI: 10.1056/NEJMoa1106668

Preview of 2012 BIO CEO Investor Conference #BIOCEO2012

By on February 10, 2012

The fourteenth annual BIO CEO & Investor Conference takes place next week (February 13-14, 2012) in New York at the Waldorf-Astoria hotel. I will be commuting from New Jersey so will not be experiencing at first hand the charm of staying at this iconic hotel.

BIO-Investor-CEO-Conference-New-York-2012-Waldof-AstoriaThe focus of the meeting is on publicly-traded biotechnology companies, and provides an opportunity for investors, analysts and industry executives to hear company presentations, undertaken one-on-one partnering discussions and listen to pharmaceutical industry leaders present their vision of the future.

Wifi permitting I will be live tweeting from the sessions I attend (@3NT).  I expect others at the conference such as @adamfeurestein to be sharing news and insights.  You can follow the twitter conversation using the (rather long) hashtag #BIOCEO2012.

My focus at the meeting will be on some of the workshops, rather than the company presentations which typically are shared on investor relations websites of publicly traded companies,.  A few that caught my attention include:

Secrets of Oncology Success – Lessons and Trends in Phase II Clinical Trial Outomes

In my opinion, too many companies rush phase II drug development, particularly in oncology.  I recently saw a company go to phase III on the basis of a 14 patient trial.   I will be interested to see what insights the panel offer on what trial designs they liked and which they didn’t and what lessons others can learn from this for new product development.

Speakers in this session include Mohammad Azab, CMO of Astex Pharmaceuticals and Michael Morrissey, CEO of Exelixis.

Neurology: “Alz” Well that Ends Well – Settling the Beta-Amyloid Debate

I doubt very much that this program will settle the debate over the amyloid hypothesis of Alzheimer’s disease, and whether this presents a “real” drug development target.  The challenge in this area is that by the time amyloid deposits can be imaged in the brain, the damage has already been done.

The amyloid load seen in the brain is also only loosely related to cognitive decline, suggesting that even if a therapeutic were able to remove plaque from the brain, it might not alleviate the symptoms of cognitive decline.

Drugs may need to target earlier stages of the disease such as synaptic decline, before beta-amyloid buildup is suggested.  Synaptic proteins have been suggested as a target.

I look forward to hearing the panels views on the current state of Alzheimer’s drug development and what the emerging targets may be.

The 2012 BIO CEO & Investor conference looks to be an interesting meeting in New York next week. If you are attending do let me know as it would be good to meet up if the opportunity presents.

Discovering the cause of Lou Gehrig’s disease

In a letter to the science journal Nature, published online on August 21, 2011, scientists from Northwestern University in Chicago report findings that could help develop drugs for patients with Amyotrophic Lateral Sclerosis (ALS), more commonly known as Lou Gehrig’s disease.

ALS is a progressive, fatal, degenerative motor neurone disease, which results in the inability to walk, get out of bed, move arms, hands, swallow or chew. Unlike Alzheimer’s disease, cognitive functions are not usually impaired, making it a particularly nasty disease when faced with awareness of disease progression.

According to Wikipedia, ALS is one of the most common neuromuscular diseases worldwide, with 1 or 2 people in every 100,000 developing ALS each year.

One of the characteristics of ALS and other neurodegenerative disease is the accumulation of protein aggregates or inclusions. Amyloid-ß plaques and intracellular tau neurofibrillary tangles are common in Alzheimer’s disease, for example.

By contrast, in ALS, a hallmark of the disease pathology is the presence of ubiquitin-positive, protein aggregates in spinal motor neurons.

The new research from Northwestern University shows how a mutation in UBQLN2, the gene that encodes ubiquilin 2, may be the cause of ALS in some patients.

The UBQLN2 mutation results in a failure to properly encode the protein, ubiquilin 2, a member of the ubiquitin-like protein family known as ubiquilins. The result is that normal protein degradation through the ubiquilin pathway is impaired, leading to cellular deposits and abnormal protein aggregation.

How did the team at Northwestern discover this insight?

Using DNA sequencing they looked at a five-generation family with 19 affected by ALS and sought to identify the causative gene in the transmission of this disease.  They found that a mutation in UBQLN2, the gene that encodes ubiquilin 2 was the key difference in those family members with or without ALS.

They subsequently tested the hypothesis that UBQLN2 mutations were causative of ALS using clinical data from 40 individuals in 5 families with UBQLN2 mutations. Interestingly in eight patients with the UBQLN2 mutation and ALS, dementia was also present suggesting a possible link between ubquilin 2 inclusions and dementia.

The team explored this correlation by examining brain autopsy samples of 15 cases without UBQLN2 mutations, of which 5 had experienced dementia as well as ALS. They found no ubiquilin 2 pathology in the hippocampus of the 10 ALS patients without dementia, but did find it in the 5 that had experienced both ALS and dementia. They noted:

The correlation of hippocampal ubiquilin 2 pathology to dementia in ALS cases with or without UBQLN2 mutations indicates that ubiquilin 2 is widely involved in ALS-related dementia, even without UBQLN2 mutations.

They also observed that:

We did not observe obvious differences in the distributions of wild-type and mutant ubiquilin2.

The authors concluded:

These data provide robust evidence for an impairment of protein turnover in the pathogenesis of ALS and ALS/dementia, and possibly in other neurodegenerative disorders as well.

These interesting findings by the Northwestern group were reported in Nature, and while promising, must be treated with caution for several reasons:

  1. It is still early-stage preliminary research on a small group of subjects.
  2. The exact function of ubiquilin 2 is not well understood.
  3. Not all ALS patients have the UBQLN2 mutation
  4. If the UBQLN2 mutation is not present in all ALS patients, then this mutation is not the sole means by which ALS develops.
  5. UBQLN2 may not be the only mutation involved in the pathophysiology of ALS.

The data from Northwestern does, however, offer hope that in the future, gene therapy or new treatments could be developed that stop or slow disease progression. Targeting the ubquilin pathway and the UBQLN2 mutation may, for example, prevent the abnormal protein turnover and aggregation that leads to impaired signaling and loss of function seen in ALS.

Further research into pathogenic pathways could lead to new targets for drug development, not only for the treatment of ALS but also dementia, and other neurodegenerative disorders.

ResearchBlogging.orgDeng, H., Chen, W., Hong, S., Boycott, K., Gorrie, G., Siddique, N., Yang, Y., Fecto, F., Shi, Y., Zhai, H., Jiang, H., Hirano, M., Rampersaud, E., Jansen, G., Donkervoort, S., Bigio, E., Brooks, B., Ajroud, K., Sufit, R., Haines, J., Mugnaini, E., Pericak-Vance, M., & Siddique, T. (2011). Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia Nature DOI: 10.1038/nature10353

Story source:  LA Times & Fierce Biotech

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