[ed. note: Michael Jorrin, who I like to call “Doc Gumshoe,” writes about health and medicine for us from time to time. His columns are not generally focused on investments, though this one does include some commentary about a number of specific companies (most are not publicly traded). His words and opinions are his own, and he has agreed to our trading restrictions. Enjoy!]
The campaign to do something about Alzheimer’s disease (I won’t call it a war) moves forward on several fronts – forward, but with pretty frequent setbacks. We have to acknowledge that at this point, after having tried literally thousands of approaches, no drug or treatment modality reverses the course of the disease. That doesn’t mean that reversing or at least stopping disease progression is not the objective of a colossal amount of effort on the part of a great many entities of all types – academic centers, big and not-so-big pharma, biotechs of all sizes, government, foundations, and some individual scientists.
But it does mean that there is also a great deal of research into drugs and treatments that are not disease-modifying, but can to some degree mitigate the effects of Alzheimer’s disease (AD), specifically in the area of cognition. And, because the optimum time to start treating a person with AD would be as early as possible in the course of the disease so as to prevent irreversible cognitive damage, there is also a great deal of research directed at finding markers that could identify AD in the earliest stages.
In a way, the AD landscape resembles what was going on in rheumatoid arthritis treatment when I first started doing projects in that area. As in AD, there were no disease-modifying agents for RA; the best that could be hoped for was managing the patient’s worst symptoms as the disease marched on, leaving many patients severely disabled. Symptom management relied heavily on high-dose aspirin (this was before even ibuprofen became commonly available) with perhaps a steroid shot if Grandma wanted to get out on the dance floor at her grand-daughter’s wedding. A major difference is that current understanding of what happens in AD at the cellular and molecular level is far ahead of what was known about RA in those bygone days.
The short take is that even though there are no Alzheimer’s disease-modifying drugs available yet, the picture is not bleak. There are options that to some degree mitigate or delay cognitive decline in AD patients, and there are some strategies that appear to affect what are at least assumed to be some of the underlying causes. So there is hope!
How is treatment benefit in AD measured?
I trust that doesn’t sound like a dumb question. I can imagine loud answers from all quarters, amounting to, “If the treatment slows or reverses dementia, that’s a clear positive.” Yes, of course, I agree with that. A question is, are there any really objective and accurate ways of measuring the degree of dementia? And, yes, of course, when the husband fails to recognize his wife, that’s not so good (but remember that excellent book by Oliver Sacks, The Man Who Mistook His Wife for a Hat). But what about finer distinctions?
What they use in clinical trials to assess dementia, or the absence of dementia, are “validated instruments,” – i.e., the Mini Mental State Examination (MMSE), the Clinical Dementia Rating – Sum of Boxes (CDR-SB), and the Alzheimer’s Disease Assessment Scale – cognitive subscale (ADAS-cog). These, and others, are widely used and widely accepted. However, what is missing is an independent, objective measure. When an infection is being treated, it’s one thing when the symptoms go away, but you can always test to see if the pathogen has been vanquished. Currently, there is no such test in AD. Brain scans can detect the presence of amyloid plaque and analyses of cerebrospinal fluid can test for amyloid beta (Aβ) and tau protein, and these tests certainly provide valuable corroborative evidence, if not definitive proof. Also, many of the early-stage studies are not in humans, but in laboratory animals. There are supposedly ways of testing the cognitive capacities of mice – do they remember where the cheese is hidden? – but I hope I can be forgiven for questioning their reliability.
So let’s start out by checking on developments regarding the eleven pharmaceutical companies that I described in my 2013 piece, “Current Clinical Trials in Alzheimer’s Disease.” I am listing them by sponsor rather than by the name of the agent, mostly because several of the agents don’t have names as yet. And, as you’ll see, for several of these outfits, the news is not good, or, in some cases, there’s no news at all. I’m including the whole list as witness of the stuttering progress of investigational drugs for AD.
Broomfield, CO 80021
Accera’s AC-1202 is a medium-chain triglyceride that is metabolized into ketone bodies which provide nutrients to the brain. One of the hallmarks of AD progression is that the brain is prevented from using blood glucose for energy; AC-1202 is supposed to compensate for that. It’s marketed as a pharmaceutical under the name Ketasyn, and as a nutritional supplement as Axona. An agent with a similar mechanism, AC-1204, has enrolled about 75% of 480 subjects in a Phase 3 clinical trial, NOURISH-AD. Another Phase 3 trial is in the works.
This approach does not address the underlying disease process in AD, but likely has merit in slowing dementia. Researchers are looking into the possibility of using nasal insulin to boost glucose utilization in the brains of persons with AD, and the nutritional supplement faction has been quick to point out that the medium-chain triglycerides in Ketasyn and Axona are also present in coconut oil, so that might be a helpful dietary supplement.
"reveal" emails? If not,
just click here...
Alzheimer’s Disease Cooperative Study (ADCS)
(in cooperation with the National Institute of Aging)
San Diego, CA
The resveratrol trial that I mentioned back in 2013 now has results, and they are at least somewhat promising. Resveratrol’s supposed mechanism is that it stimulates the activity of a class of enzymes called sirtuins, which are thought to mimic the anti-aging effects that caloric restriction has demonstrated in animals. This was supposedly why red wine drinkers (red wine, you certainly know, contains resveratrol) get a survival benefit – although the amount of resveratrol contained in red wine is nowhere near the amount that has been used in clinical trials. The Phase 2 trial enrolled 119 subjects with mild-to-moderate AD and assessed levels of amyloid beta (Aβ) 40 and 42 as well as tau protein in the cerebrospinal fluid. As you may remember from my previous piece, a higher proportion of Aβ42 to Aβ40 is associated with the progression of AD dementia. In this trial, patients taking up to 2000 mg of resveratrol per day maintained higher levels of Aβ40 (which we might dub “the good amyloid beta”) in proportion to Aβ42. There were no differences in tau protein, nor in the mini-mental state exam, but the treated subjects performed better on the activities of daily living scale. All in all, these results, published in September 2015, encourage further research.
Bellus Health, Inc
Laval, Quebec, Canada, H7V4A7
Bellus’s principal candidate is Alzhemed, which is also marketed as a neutraceutical under the name Vivimind. Alzhemed is also known as tramiprosate and as homotaurine, and sometimes as 3APS. The supposed mechanism of action is that it binds to soluble Aβ, inhibiting formation of the sheet formations of Aβ that are found in Alzheimer’s patients. Clinical trials in this agent have failed to show any benefit thus far. Vivimind and another related agent, BLU8499, were licensed to a US company, Alzheon, in late 2013.
[ed. note: Bellus Health is tiny but publicly traded, BLU in Canada, and BLUSF OTC in the US.]
Biogen Idec (BIIB)
In March 2015, Biogen’s AD drug, formerly BIIB037, now aducanumab, reported positive interim results in the PRIME study, a Phase Ib trial. What is particularly arresting about these results is that BIIB037/aducanumab is the first AD agent that has demonstrated both significant symptomatic benefit and significant benefit with regard to one of the presumed physiologic causes of AD, namely the deposition of amyloid plaque. BIIB037/aducanumab is a human recombinant monoclonal antibody (mAb) that targets aggregated forms of Aβ. The original antibodies on which the mAb is modeled came from the brains of individual donors who were thought to have successfully overcome AD.
The trial enrolled 166 patients with mild forms of the disease and followed them for one year. The symptomatic measures employed were the MMSE and the CDR-SB. Four dosage levels of BIIB037/aducanumab were assessed, and at the highest dose, subjects lost 0.58 points on the MMSE, while subjects on placebo lost 3.14 points. On the CDR-SB the scores were 0.59 points for BIIB037 versus 2.04 for placebo. Both differences were statistically significant.
Amyloid plaque deposition was measured by PET scans using the radiotracer florbetrapir 1, which binds to amyloid. In the two highest BIIB037 dose levels, 6 and 10 mg per kg of body weight, the differences in plaque deposition compared with placebo were both considered highly significant, P < 0.001.
Another trial in the 6 mg/kg dose failed to reach clinical significance, which was considered a setback in the development program for aducanumab. Assessing dose levels lower than the 10mg/kg dose is important, because of a dose-related adverse effect called ARIA (amyloid-related imaging abnormalities) which can result in potentially dangerous swelling of the brain. The ARIA effect was more common in APOε4 carriers, who are also more likely to develop AD.
Two Phase III studies in aducanumab are currently under way, with results not expected until sometime in 2020.
In the meantime, Biogen has two more AD drugs in much earlier stages of development. One, labeled BAN2401, targets Aβ before it has aggregated into the forms that characterize AD. The other, E2609, is a β-secretase enzyme inhibitor (BACE), which targets the amyloid cascade upstream of Aβ peptide generation. Eight Phase 1 trials evaluating the safety and pharmacology of E2609 in nearly 500 healthy volunteers and people with early AD have been completed. The single oral ascending-dose study of 5 to 800 mg drug showed a reduction of Aβ levels in plasma; a 14-day ascending-dose study of 25 to 400 mg showed a dose-dependent reduction of up to 80% in Aβ levels in cerebrospinal fluid.
Biogen is a major contender in the Alzheimer’s sweepstakes and is putting upwards of $2.5 billion on the line, with the expectation – or hope? – of a big-time payback, perhaps in the not-too-distant future.
Raleigh, NC 27614
Curaxis has declared bankruptcy and its stock is valued at much less than a penny a share. So it goes. I have seen no recent news about their AD drug, VP4896; it’s possible that they have licensed it to another biotech. VP4896 decreases the amount of luteinizing hormone released by the pituitary. There does appear to be evidence supporting the role of this hormone in both the cognitive deficits and molecular pathology that characterizes AD.
Now Perrigo (PRGO),
One of their AD drugs is ELND005, which prevents the aggregation of Aβ clusters. A Phase III trial at 62 locations failed to attain clinical significance, and in January, 2014 all further Phase III trials were suspended. Another Elan/Perrigo AD drug is bapineuzumab, which has been licensed to Janssen, a Johnson & Johnson subsidiary. Two Phase III trials in bapineuzumab have been conducted, only one of which reported any significant benefit. Bapineuzumab targets the accumulation of amyloid plaque, and in carriers of the APOε4 gene, PET scans demonstrated highly significant (P = 0.004) differences between patients who received bapineuzumab infusions compared with those who received placebo. There was no observed difference between treatment and placebo groups in patients without the APOε4 gene. Also, the treatment effect was more pronounced in patients with mild disease compared with those with moderate disease. However, no effects on either functional or cognitive outcomes were found, and all subsequent Phase III trials were suspended.
The bapineuzumab experience raises a serious and fundamental question. If a drug really does reduce the accumulation of amyloid plaque in at least a subset of patients, but this has no observable effect of symptoms, does this not imply that perhaps amyloid plaque is not the culprit? My skeptical nature prevents me from saying “yes” to that proposition. For one thing, as we have already learned, not all amyloid is the same. Assessing the differences between the two forms of Aβ – the 40 and 42 amino acid varieties, with Aβ42 dubbed “the bad amyloid” – was not part of the protocol. And it’s also possible that earlier intervention might have made a difference. In any case, bapineuzumab appears to have taken its place in the growing list of AD dead ends. Of the 14 clinical trials with bapineuzumab, 8 have been terminated, and 6 are completed. None are currently under way.
Now Forum Pharmaceuticals
Waltham, MA 02451
EvVivo became Forum Pharmaceuticals in 2014. Clinical trials of their leading drug, EVP-6124, also called encenicline, are on hold due to a small number of serious gastrointestinal side effects, which caused the FDA to instruct Forum to interrupt their three ongoing AD studies. Encenicline is an alpha 7 nicotinic receptor agonist, which supposedly boosts neurotransmitter function, enhancing memory and executive function. Previous small trials with this agent had reported highly significant improvements in global cognitive function compared with placebo. Forum is currently making a case to the FDA to move forward with the planned Phase III trials. We should note that encenicline is not intended to be a disease-modifying agent, but may find a robust niche among the very few drugs that have a positive effect in terms of delaying the progress of AD-related dementia. Forum, by the way, at present is privately held.
Now Roche Pharmaceuticals (RHHBY)
Roche’s motivation in acquitting Memory was to participate in the development of Memory’s AD drug, then dubbed MEM-3454 and now called RO5313534. It is a nicotinic acetylcholine receptor agonist, perhaps similar to Forum’s encenicline mentioned above. Acetylcholine is a neurotransmitter with a number of functions, one of which is enhancing cognitive processes in the brain. Early studies in this agent reported highly significant (P < 0.001) improvement in cognitive function as early as 8 hours post dosing. The results of a trial evaluating the effectiveness of this drug used on combination with donepezil, which is one of the very few drugs approved for treating the cognitive symptoms of AD, have not been announced as of 2 November 2015. Whether this is Roche keeping their cards close to their chest, or, alternatively, clamping the lid on the garbage can, is hard to know. In any case, even though RO5313534 is not a disease-modifying drug, it could well secure a prized space in the limited AD marketplace.
Myriad Pharmaceuticals, now Myrexis (MYRX)
Salt Lake City, UT 84108
The last time I peeked, Myriad Pharmaceuticals had been spun out from test developer Myriad Genetics, and then changed its name to Myrexis, Inc. Their lead drug is flurizan or MPC-7869, which is the R-enantiomer of flurbiprofen, an NSAID similar to ibuprofen. Enantiomers are chemically identical but mirror image versions of the same molecule; the R-enantiomer is the right-handed version and the L-enantiomer is the left handed version. The two can behave differently because of how they fit to their targets; imagine a key cut to the same contours, but with the grooves on the opposite side – it just wouldn’t slide into the lock. Flurizan had been tested and failed in prostate cancer, but had shown promise in delaying cognitive decline in AD patients. However, more recent studies have reported that it does not pass the blood-brain barrier at sufficient concentrations for clinical use. So there’s another one that bites the dust.
San Diego, CA 92130
Sonexa is a very small private biotech with one product, ST101, aimed squarely at AD. ST101 is a small molecule that acts as a T-type calcium channel activator. In the brain, T-type channels regulate neuronal firing patterns. They open in response to negative membrane potentials, and are thus suited for regulating neuronal activity. Investigators at the University of California Irvine found that that ST101 induces cleavage of amyloid precursor protein (ABB) at a novel site, generating an APP cleavage product that does not appear to be a substrate for either of the enzymes that cleave APP forming amyloid beta (Aβ) and thus does not lead to formation of Aβ. ST101 is orally active, efficacious at low doses, and improves memory function in mice and non-human primates. Two preliminary efficacy and safety studies in ST101 have been completed, one in conjunction with donepezil; results have not yet been published. From where I sit, this one is still alive and kicking.
Vivus, Inc (VVUS)
Mountain View, CA 94050
Vivus is a small pharmaceutical company with a couple of FDA approved agents and others in development in a number of treatment areas besides AD. Their AD drug is VI-1121, which targets acetylcholine release by altering the balance of two enzymes that regulate acetylcholine balance. The proposed mechanism is interesting – AD patients have a higher proportion of the enzyme butyrylcholinesterase (BuCheE) in proportion to acetylcholinesterase (AChE); thus targeting the former may increase the availability of acetylcholine, which is vital to cognitive function. But it doesn’t appear as though VI-1121 is going to do the trick; trials in VI-1121 have been discontinued.
What’s the score?
Of the 11 sponsors and their candidate drugs, none so far have hit the bulls-eye, meaning sufficiently robust Phase III clinical trial results to warrant an FDA submission, let alone fuel speculation of an early FDA approval. Six of the 11 are in the “maybe” category. Five are dead in the water. In the AD area, this is not a bad average at all, although what will happen to the six “maybe” candidates going forward is anyone’s guess. Biogen obviously has an edge because of their deep pockets, but deep pockets alone won’t be the deciding factor. Some of the “maybes” have interesting and possibly promising mechanisms, and even if they themselves don’t hit the jackpot, other agents using the same or similar mechanism may work a bit or even a lot better.
When I did my first Doc Gumshoe Alzheimer’s pieces way back in 2013, those 11 agents were the most promising ones I had spotted. They could be taken as a fairly representative sample of the universe of AD drug development, covering a range of mechanisms, including both disease-modifying and symptom-alleviating mechanisms. And what has happened with those development programs is very representative of what is going on in the AD world. There have been no clear wins.
A common phenomenon in drug development is that many drugs in the early phases show promise. The biotechs and pharma outfits that are conducting the research evince optimism, but the stumbling blocks are multitudinous, and outright failure looms. Some of the smaller biotechs, for financial reasons, can only take the development program so far, and investors as well as Big Pharmas are understandably cautious. But the potential yields are huge. A small biotech scores good Phase II results, or even Phase Ib, and gets bought out by a Big Pharma. Then, even if later studies don’t pan out, investors can make a tidy profit. I won’t go on about that – as I’ve often said, that’s not my department.
A look at a drug with a completely different target
None of those 11 drugs targeted tau protein accumulation, even though the tau protein hypothesis was gaining prominence at the time. To review what was in the previous Doc Gumshoe piece about AD, the essential difference between the amyloid beta and tau protein hypotheses is that the Aβ structures impede communication between neurons by congregating in the synapses, whereas tau protein fibrils lead to neuron death by forming tangles in the axons that are the conduits for nourishment for neurons. In brief, Aβ works its mischief outside the neurons, while tau kills neurons from within.
TauRX Therapeutics, Ltd
TauRX is a biotech spun off from the University of Aberdeen in Scotland, where its clinical trials are being conducted, although its official headquarters are based in Singapore, likely for tax reasons. Their AD candidates are derived from a parent compound, methylene blue, which has been around for decades, and has been used to treat malaria and methemoglobinemia, a blood disease in which normal hemoglobin is replaced by a form containing ferric rather than ferrous iron, which is less able to transport oxygen. TauRX’s first formulation based on methylene blue (methylthioninium chloride) was Rember, which has been replaced by a successor, TRx0237. TRx0237 and Rember have the same mode of action, but TRx0237 is a stabilized, reduced form of the parent compound in order to improve the drug’s absorption, bioavailability, and tolerability.
The most prominent advocate for the tau hypothesis is Prof. Claude M. Wischik, of the University of Aberdeen School of Medicine and Dentistry, and also of TauRX Therapeutics. He is unabashedly scornful of the Aβ hypothesis, and outspokenly positive about the prospects for TRx0237. For a taste of his rhetoric, here’s a bit from his paper in Biochemical Pharmacology (88: 2014):
“A recent meeting hosted by the New York Academy of Sciences had the title: “A Truce in the βAP-tist/Tau-ist War?” A truce only needs to be called when one side no longer sees any hope of outright victory. The extraordinary history of repeated clinical trial failures at phases 2 and 3 based on the β-amyloid hypothesis does suggest a need for βAP-tists to find a way out of an untenable situation. For long-term Tau-ists such as the authors, it is early days in the campaign, as we are only conducting the very first tau-based phase 3 clinical trial. It would be understandable that we would see no need for a truce at this stage.”
Dr Wischik is not content with expressing his support for the tau hypothesis – which, after all, is to a considerable degree his baby. No, he also takes out the cudgels and wallops the Aβ hypothesis. The paper I cited above lists 27 clinical trials targeting aspects of the Aβ hypothesis, and marking most of them as “failed.” Yes, it is true that most of these trials failed to meet their objectives, but that certainly does not put the Aβ hypothesis to rest. A distinct possibility is that by the time the subjects in these trials started treatment, the accumulation of Aβ had reached the point where prevention or slowing of further accumulation would not make much difference. One of the problems with treating AD is that by the time symptoms appear – that is, overt signs of dementia – treatment that addresses Aβ may just be too late. I do not accept Dr Wischik’s premise that the advocates of the Aβ hypothesis need “to find a way out of an untenable situation.”
This is not to say that the evidence for the tau hypothesis is not reasonably good. An exploratory study of TRx0237 in 321 persons with mild/moderate AD reported two types of treatment benefits. In a subset of patients with moderate AD, there was a significant (P = 0.047) difference between subjects treated with TRx0237 and placebo patients. Note, that P value just barely reaches the standard for significance, so this is far from a home run. But also, in a subset of patients with mild AD, there was a highly significant difference (P < 0.001) in cerebral blood flow, which is essential to neuronal function.
While TauRX presses ahead with clinical trials in their proprietary formulation of methylthioninium, researchers are tinkering with the basic molecule to try to find structures that have a better pharmacodynamic profile – i.e., permit better absorption, reach higher concentrations – characteristics that lead to better efficacy. Currently, five clinical trials in TRx0237 are under way, plus one more in methylene blue and AD.
Although TauRX appears to have an inside track with the methylene blue/ methylthionimium-based therapy, they by no means have an exclusive claim on that approach. The parent molecule is not subject to patent, and it wouldn’t surprise me in the least if other biotechs, or even piracy-inclined laboratories anywhere in the world, tried to cash in on what might be a lucrative product.
Dr KSS and “the Manchurian Candida”
To learn more about this highly interesting and highly speculative theory about the pathology of AD, you will have to join the Irregulars and read Dr KSS’s superb post from a few weeks ago. I will say nothing about it beyond suggesting that it’s at least possible that the culprit referred to invades our poor vulnerable brains after and not before it is damaged by some of the other putative causes of AD.
… and one more for the road
This one’s about the “orange aspirin” that cures – yes, cures!!! – Alzheimer’s. Here’s part of the spiel:
“90 DAY ALZHEIMER’S TREATMENT:
“Could This Be The Biggest Breakthrough Health Experiment Since The Polio Vaccine?
“Research shows New ‘Orange Aspirin’
“Could End Alzheimer’s Disease
“It acts on your brain much like aspirin.
“It’s quick, it’s painless, and it’s cheap…
“Yet what doctors are calling a ‘brain health miracle’ could be the final key to solving the Alzheimer’s mystery.
“Meet Linda — an 83 year old woman who could no longer cook, clean, or use the bathroom without help.
“Worse, she couldn’t remember her late husband or her family members.
“Was her life over? Some doctors would say yes.
“But in a research study, Linda was put on an unusual new treatment. A 90-day Alzheimer’s protocol that ended up generating huge buzz in the research community.
“And something incredible happened.
“After just 12 weeks of taking this ‘orange aspirin’, researchers from the National Center for Biotechnology Information were blindsided.
“As they reported,
“…her agitation, apathy, anxiety and irritability were all relieved. She began to tell about the need to urinate. Furthermore, she came to join in the laughter watching the TV comedy program, began to sing songs and do knitting which she used to do .’
“After one full year on the treatment they reported,
‘She came to recognize her family and remember her late husband. She now lives at home without significant symptoms!’
… and it goes on from there. On and on and on, with more and more miraculous cures, attributed to “orange aspirin,” which some of you already know is curcumin, commonly found in the spice turmeric. Curcumin has been known as an anti-inflammatory for some time, and as such might be effective in preventing inflammation-associated changes in the brain. The “90 Day Alzheimer Treatment” goes on to contrast curcumin supplements, which is what they are touting, with expensive research on the investigational agent J147, derived from molecules found in curcumin, which has lately reported highly positive anti-aging and cognitive effects in mice.
The only problem with the curcumin supplement for AD is that it’s not too easy to sneak it past the blood-brain barrier; thus the need for painstaking research to develop a drug that might have some of those properties but does get past the blood-brain barrier. Of course, Big Pharma is accused of suppressing information about the curcumin supplement out of greed.
As we might expect, the “90 Day Alzheimer Treatment” goes on to pitch their “Little Bible of 77 Censored Health Cures” as well as several newsletters. The source is an outfit called “Natural Health Solutions.”
Doc Gumshoe strongly favors natural health solutions, without the capital letters, as long as they are really health solutions. J147 looks promising, and I’ll keep an eye on it. As for curcumin supplements, I remain, as usual, skeptical.
While I’m in skepticism mode, let me also express doubts that AD is a disease/condition with a unitary etiology, whether Aβ, tau, or any other single culprit. Many factors can cause the buildup of crud in our brains. Maybe we can slow some of them down; maybe we can find ways to continue putting our brains through their paces despite the crud. There’s lots to be learned.
And while working on this piece, I dug up so much more on AD treatment that I couldn’t cram it into this Doc Gumshoe blog. I will share it with you in an upcoming piece.
Forgive me if I pat myself on the back
A study published in JAMA on 17 November has borne out what I’ve been saying for years. Viz, after the U. S. Preventive Services Task Force issued its guidelines that men should not have PSA testing, the number of early stage prostate cancers dropped from 540.8 cases per 100,000 men aged 50 and older in 2008 to 416.2 per 100,000 in 2012. The total reduction in diagnoses of prostate cancer was 33,519 cases. While it’s true that many cases of prostate cancer are non-fatal – most men die with and not of prostate cancer – it’s virtually certain that some of those cases that escaped diagnosis will prove fatal. As with their recommendation that women under 50 should not have mammograms, what these green eyeshade types are doing is making more work for the undertaker.
* * * * * * *
As always, I look forward to receiving your comments. Best to all, Michael Jorrin (aka Doc Gumshoe)