Biotech Strategy Blog

Commentary on Science, Innovation & New Products with a focus on Oncology, Hematology & Cancer Immunotherapy

Posts tagged ‘Alzheimer’s Drug Development’

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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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

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.

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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