Corante

About this Author
DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

Chemistry and Drug Data: Drugbank
Emolecules
ChemSpider
Chempedia Lab
Synthetic Pages
Organic Chemistry Portal
PubChem
Not Voodoo
DailyMed
Druglib
Clinicaltrials.gov

Chemistry and Pharma Blogs:
Org Prep Daily
The Haystack
Kilomentor
A New Merck, Reviewed
Liberal Arts Chemistry
Electron Pusher
All Things Metathesis
C&E News Blogs
Chemiotics II
Chemical Space
Noel O'Blog
In Vivo Blog
Terra Sigilatta
BBSRC/Douglas Kell
ChemBark
Realizations in Biostatistics
Chemjobber
Pharmalot
ChemSpider Blog
Pharmagossip
Med-Chemist
Organic Chem - Education & Industry
Pharma Strategy Blog
No Name No Slogan
Practical Fragments
SimBioSys
The Curious Wavefunction
Natural Product Man
Fragment Literature
Chemistry World Blog
Synthetic Nature
Chemistry Blog
Synthesizing Ideas
Business|Bytes|Genes|Molecules
Eye on FDA
Chemical Forums
Depth-First
Symyx Blog
Sceptical Chymist
Lamentations on Chemistry
Computational Organic Chemistry
Mining Drugs
Henry Rzepa


Science Blogs and News:
Bad Science
The Loom
Uncertain Principles
Fierce Biotech
Blogs for Industry
Omics! Omics!
Young Female Scientist
Notional Slurry
Nobel Intent
SciTech Daily
Science Blog
FuturePundit
Aetiology
Gene Expression (I)
Gene Expression (II)
Sciencebase
Pharyngula
Adventures in Ethics and Science
Transterrestrial Musings
Slashdot Science
Cosmic Variance
Biology News Net


Medical Blogs
DB's Medical Rants
Science-Based Medicine
GruntDoc
Respectful Insolence
Diabetes Mine


Economics and Business
Marginal Revolution
The Volokh Conspiracy
Knowledge Problem


Politics / Current Events
Virginia Postrel
Instapundit
Belmont Club
Mickey Kaus


Belles Lettres
Uncouth Reflections
Arts and Letters Daily
In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

« Clinical Trial Fraud Uncovered | Main | Aveo: The Rubble Continues to Bounce Around »

July 12, 2013

Lilly Goes All In on Solanezumab

Email This Entry

Posted by Derek

So Eli Lilly is going to double down on solanezumab, their antibody treatment for Alzheimer's that did not show impressive results in earlier trials. The company is going into an even bigger Phase III, with a more carefully selected patient population, in hopes of showing a benefit.

Yikes. On one level, I sort of admire this - it's a decision that takes a lot of nerve to make, will cost a huge amount of money, and is attacking one of the most intractable clinical problems we have. But on that ever-present other hand, what are the odds? If I'm an investor in Lilly stock, am I happy about this move, or not? The only thing I can see to calm the nerves this time, if there's such a thing in an Alzheimer's clinical trial, is better diagnostic criteria from the start:

Eric Siemers, senior medical director of Lilly's Alzheimer's program, said an estimated 25 percent of patients in the two earlier Expedition trials might not actually have had beta-amyloid deposits or Alzheimer's disease, so solanezumab could not have helped them.

He said many patients were enrolled in those trials on the basis of symptoms, without undergoing sophisticated diagnostic procedures now available to confirm the presence of beta-amyloid deposits.

In the new study, Lilly's recently approved radioactive imaging agent, called Amyvid, will be used to screen patients, Siemers said. Biochemical measures in the spinal fluid can also help assess whether patients have Alzheimer's, he said.

I'll say this for them: this trial, you'd think, is going to be the answer. It's going to cost hundreds of millions by the time it's all over, but by gosh, Lilly (and the rest of us) should know if solanezumab is of any use in Alzheimer's. Unless, of course, another bath of equivocal coulda-maybe-worked numbers come out of this one, too. But that's also an answer. Under these conditions, "sort of worked" is going to mean "did not work". I don't see what else is left.

And given Lilly's patent positions and sales forecasts, it looks like they are, to a significant extent, betting the company on this. Drama, this industry could do with less drama. But we seem to be stuck with it.

Comments (31) + TrackBacks (0) | Category: Alzheimer's Disease | Clinical Trials


COMMENTS

1. Lane Simonian on July 12, 2013 2:20 PM writes...

There is a thin line between guts and stupidity and Eli Lilly may have just crossed it. The fact that they also have a patent on an amyloid imaging agent seems to be further fueling their desire to prove the amyloid hypothesis correct at all costs despite the negative results so far.

Amyloid oligomers or plaques are not the best biomarkers for Alzheimer's disease. Some people with Alzheimer's disease have neither. The best biomarker for the conversion from Mild Cognitive Impairment to Alzheimer's disease is high levels of myo-inositol (Myo-inositol, N-Acetylaspartate are sensitive biomarkers for clinical conversion from MCI to Alzheimer's disease). Myo-inositol levels are high in people with Down syndrome, with high glucose levels, and high blood pressure due to high sodium levels--all of which increase the risk for Alzheimer's disease.

The pathway to Alzheimer's disease is most likely the following: High levels of myo-inositol, high levels of phosphatidylinositol 4,5 biphosphate, high phospholipase c gamma or beta activity, high levels of protein kinase C activity, p38 MAPK activation, activation of NADPH oxidase (superoxide anion) and of Nuclear factor kappa-B (inducible nitric oxide), and peroxynitrites.

In many people with Alzheimer's disease protein kinase C activity slows down as the disease progresses (for those in which it does not hallucinations become a major problem). The principal route to peroxynitrite formation at this point is the following: Peroxynitrite-mediated nitration of NMDA receptor, calcium entry, phosphorylation of the Calcium/Comodulin Dependent Kinase II, phosphorylation of cyclic AMP, phosphorylation of p38 MAPK, and peroxynitrite formation. The combination of p38 MAPK inhibitors with peroxynitrite scavengers may help treat Alzheimer's disease.

The evidence that peroxynitrites are the prinicipal cause of Alzheimer's disease include the following: polyphenols and Omega 3-fatty acids which impede peroxynitrite formation appear to delay the onset of Alzheimer's disease, mice bred with APP and presenilin-1 mutation but without the gene for inducible nitric oxide synthase basically do not develop Alzheimer's disease (Protection from Alzheimer's like disease in mice by genetic ablation of inducible nitric oxide synthase), and peroxynitrite scavengers have partially reversed Alzheimer's disease in small-scale human clinical trials (eugenol in rosemary essential oil, eugenol and ferulic acid in lemon balm--Melissa officinalis--essential oil, and ferulic acid, syringic acid, and vanillic acid in heat-processed ginseng).

The role of amyloid plaques in Alzheimer's disesae is rather minor. Protein kinase C processes the amyloid precursor protein. Phospholipase C triggers the release of intracellular calcium which stimulates the enzymes that cleave the amyloid precursor protein into oligomers. Intracellular calcium release further stimulates protein kinase C activity. However, it is possible to have high levels of protein kinase C activity and subsequently high levels of peroxynitrites without intracellular calcium release. In other words, it is possible to have Alzheimer's disease without amyloid oligomers or plaques.

Early on amyloid oligomers play a role in the reformation of peroxynitrites and later on amyloid plaques play a role in the increased production of peroxynitrites, but neither substantially slow down the production of peroxynitrites, and thus are not very good targets for treating Alzheimer's disease.

Amyloid oligomers by attracting copper and zinc increase the production of hydrogen peroxide (via superoxide dismutase). Peroxynitrite scavengers convert peroxynitrites into a nitrite anion (ONOO- + 2H+ + 2e-= NO2- + H20). Hydrogen peroxide combines with the nitrite anion to reform peroxynitrites (H202 + NO2-= ONOO-+ H20). Catalase and glutathione peroxidase convert hydrogen peroxide into water. Water is a de-nitrating agent: tyrosine-NO2 + H20= tyrosine-H + H+ + NO3-. The iron in or around plaques can also oxidize nitrite anions in nitrite which can directly nitrate tyrosine and other compounds. In Alzheimer's disease the antioxidant balance becomes overwhelmed by the excessive production of peroxynitrtites. Lowering oligomer levels or chelating out copper, zinc, and iron may only buy some extra time without in the end stopping the progression of the disease.

The same is probably also true of amyloid plaques.
Peroxynitrites mediate the nitration of oligomers which results in their aggregation into plaques. The plaques entomb copper and zinc which means that almost all of the superoxide anions combine with inducible nitric oxide to form peroxynitrites. Chelating out copper and zinc or dissolving the plaques would have only a limited effect on peroxynitrite formation, though.

The very lukewarm results from anti-amyloid drugs make sense and starting earlier is likely not to make any difference.

Permalink to Comment

2. MoBio on July 12, 2013 2:46 PM writes...

Lane: there are many who would dispute your statements regarding the pathogenesis of AD.


Permalink to Comment

3. Nate on July 12, 2013 2:47 PM writes...

Let's give them the benefit of the doubt and assume the beta amyloid hypothesis is correct. How about the elephant in the room? Solanezumab is a monoclonal antibody which is restricted to the central compartment. The beta amyloid plaques are located behind the blood-brain barrier. This therapy will only work if somehow it can indirectly affect the plaques in the brain. I have heard of an "equilibrium" theory which does not convince me whereby acting on whatever is in the central compartment can affect the brain. But I would have a VERY hard time justifying a big clinical spend on such an iffy hypothesis.

Permalink to Comment

4. David M. on July 12, 2013 3:24 PM writes...

Unfortunately post #1 does not take into account the fact that dominantly inherited Alzheimer's has certain genes in the amyloid cascade that are nearly 100% predictive of the early onset type. While we have not ruled out gene linkage in the same chromosomal region, this is indicative that PS1/PS2 or APP mutations associated with dominantly inherited AD

Additionally, the Icelandic mutation recently identified is associated with a significantly and epidemiologically meaningful reduction in the incidence of AD within that carrier population.

Omega-3 fatty acids have never been shown to reduce the onset or decline of AD in well-powered, prospective trials utilizing a time-to-event analysis (onset of AD), or change in the slope of decline in cognition or function; these would be the gold standard for evidence-based medicine. Moreover, for true disease modifying trials, the FDA has indicated a randomized start design is the optimal approach, which has never been attempted in AD, let alone with omega-3's.

However, it is entirely possible that another factor such as peroxynitrites cause cellular damage through multiple pathways, and also increase the enzyme velocity of beta and gamma secretase.

Peroxynitrites could also cause the equilibrium to shift toward the production of AB 1-42, in which case the presence of certain mutations would increase the probability of developing AD, but not in a Mendelian based inheritance manner. The cellular environment may therefore act on risk genes and produce an increased probability of developing AD.

It is therefore not improbable that AD requires "A" and "B" events that interact to occur:

A: A certain level of cellular/metabolic disturbance to be present for X years
B: The presence of risk genes for AD

If the dominant mutations are extremely sensitive to cellular/metabolic disturbances, then having one of them would guarantee development of AD in a Mendelian pattern.

If the genes associated with the late onset AD are *less* sensitive to cellular/metabolic disturbances it may take much, much longer for AD to develop, and the environment may therefore play a key role, thus drifting away from Mendelian inheritance.

We have to explain ALL the data we have and not just dismiss amyloid and genes.

Permalink to Comment

5. David M. on July 12, 2013 3:25 PM writes...

Unfortunately post #1 does not take into account the fact that dominantly inherited Alzheimer's has certain genes in the amyloid cascade that are nearly 100% predictive of the early onset type. While we have not ruled out gene linkage in the same chromosomal region, this is indicative that PS1/PS2 or APP mutations associated with dominantly inherited AD

Additionally, the Icelandic mutation recently identified is associated with a significantly and epidemiologically meaningful reduction in the incidence of AD within that carrier population.

Omega-3 fatty acids have never been shown to reduce the onset or decline of AD in well-powered, prospective trials utilizing a time-to-event analysis (onset of AD), or change in the slope of decline in cognition or function; these would be the gold standard for evidence-based medicine. Moreover, for true disease modifying trials, the FDA has indicated a randomized start design is the optimal approach, which has never been attempted in AD, let alone with omega-3's.

However, it is entirely possible that another factor such as peroxynitrites cause cellular damage through multiple pathways, and also increase the enzyme velocity of beta and gamma secretase.

Peroxynitrites could also cause the equilibrium to shift toward the production of AB 1-42, in which case the presence of certain mutations would increase the probability of developing AD, but not in a Mendelian based inheritance manner. The cellular environment may therefore act on risk genes and produce an increased probability of developing AD.

It is therefore not improbable that AD requires "A" and "B" events that interact to occur:

A: A certain level of cellular/metabolic disturbance to be present for X years
B: The presence of risk genes for AD

If the dominant mutations are extremely sensitive to cellular/metabolic disturbances, then having one of them would guarantee development of AD in a Mendelian pattern.

If the genes associated with the late onset AD are *less* sensitive to cellular/metabolic disturbances it may take much, much longer for AD to develop, and the environment may therefore play a key role, thus drifting away from Mendelian inheritance.

We have to explain ALL the data we have and not just dismiss amyloid and genes.

Permalink to Comment

6. David M. on July 12, 2013 3:26 PM writes...

Unfortunately post #1 does not take into account the fact that dominantly inherited Alzheimer's has certain genes in the amyloid cascade that are nearly 100% predictive of the early onset type. While we have not ruled out gene linkage in the same chromosomal region, this is indicative that PS1/PS2 or APP mutations associated with dominantly inherited AD

Additionally, the Icelandic mutation recently identified is associated with a significantly and epidemiologically meaningful reduction in the incidence of AD within that carrier population.

Omega-3 fatty acids have never been shown to reduce the onset or decline of AD in well-powered, prospective trials utilizing a time-to-event analysis (onset of AD), or change in the slope of decline in cognition or function; these would be the gold standard for evidence-based medicine. Moreover, for true disease modifying trials, the FDA has indicated a randomized start design is the optimal approach, which has never been attempted in AD, let alone with omega-3's.

However, it is entirely possible that another factor such as peroxynitrites cause cellular damage through multiple pathways, and also increase the enzyme velocity of beta and gamma secretase.

Peroxynitrites could also cause the equilibrium to shift toward the production of AB 1-42, in which case the presence of certain mutations would increase the probability of developing AD, but not in a Mendelian based inheritance manner. The cellular environment may therefore act on risk genes and produce an increased probability of developing AD.

It is therefore not improbable that AD requires "A" and "B" events that interact to occur:

A: A certain level of cellular/metabolic disturbance to be present for X years
B: The presence of risk genes for AD

If the dominant mutations are extremely sensitive to cellular/metabolic disturbances, then having one of them would guarantee development of AD in a Mendelian pattern.

If the genes associated with the late onset AD are *less* sensitive to cellular/metabolic disturbances it may take much, much longer for AD to develop, and the environment may therefore play a key role, thus drifting away from Mendelian inheritance.

We have to explain ALL the data we have and not just dismiss amyloid and genes.

Permalink to Comment

7. David M. on July 12, 2013 3:28 PM writes...

Unfortunately post #1 does not take into account the fact that dominantly inherited Alzheimer's has certain genes in the amyloid cascade that are nearly 100% predictive of the early onset type. While we have not ruled out gene linkage in the same chromosomal region, this is indicative that PS1/PS2 or APP mutations associated with dominantly inherited AD

Additionally, the Icelandic mutation recently identified is associated with a significantly and epidemiologically meaningful reduction in the incidence of AD within that carrier population.

Omega-3 fatty acids have never been shown to reduce the onset or decline of AD in well-powered, prospective trials utilizing a time-to-event analysis (onset of AD), or change in the slope of decline in cognition or function; these would be the gold standard for evidence-based medicine. Moreover, for true disease modifying trials, the FDA has indicated a randomized start design is the optimal approach, which has never been attempted in AD, let alone with omega-3's.

However, it is entirely possible that another factor such as peroxynitrites cause cellular damage through multiple pathways, and also increase the enzyme velocity of beta and gamma secretase.

Peroxynitrites could also cause the equilibrium to shift toward the production of AB 1-42, in which case the presence of certain mutations would increase the probability of developing AD, but not in a Mendelian based inheritance manner. The cellular environment may therefore act on risk genes and produce an increased probability of developing AD.

It is therefore not improbable that AD requires "A" and "B" events that interact to occur:

A: A certain level of cellular/metabolic disturbance to be present for X years
B: The presence of risk genes for AD

If the dominant mutations are extremely sensitive to cellular/metabolic disturbances, then having one of them would guarantee development of AD in a Mendelian pattern.

If the genes associated with the late onset AD are *less* sensitive to cellular/metabolic disturbances it may take much, much longer for AD to develop, and the environment may therefore play a key role, thus drifting away from Mendelian inheritance.

We have to explain ALL the data we have and not just dismiss amyloid and genes.

Permalink to Comment

8. David M. on July 12, 2013 3:31 PM writes...

Unfortunately post #1 does not take into account the fact that dominantly inherited Alzheimer's has certain genes in the amyloid cascade that are nearly 100% predictive of the early onset type. While we have not ruled out gene linkage in the same chromosomal region, this is indicative that PS1/PS2 or APP mutations associated with dominantly inherited AD

Additionally, the Icelandic mutation recently identified is associated with a significantly and epidemiologically meaningful reduction in the incidence of AD within that carrier population.

Omega-3 fatty acids have never been shown to reduce the onset or decline of AD in well-powered, prospective trials utilizing a time-to-event analysis (onset of AD), or change in the slope of decline in cognition or function; these would be the gold standard for evidence-based medicine. Moreover, for true disease modifying trials, the FDA has indicated a randomized start design is the optimal approach, which has never been attempted in AD, let alone with omega-3's.

However, it is entirely possible that another factor such as peroxynitrites cause cellular damage through multiple pathways, and also increase the enzyme velocity of beta and gamma secretase.

Peroxynitrites could also cause the equilibrium to shift toward the production of AB 1-42, in which case the presence of certain mutations would increase the probability of developing AD, but not in a Mendelian based inheritance manner. The cellular environment may therefore act on risk genes and produce an increased probability of developing AD.

It is therefore not improbable that AD requires "A" and "B" events that interact to occur:

A: A certain level of cellular/metabolic disturbance to be present for X years
B: The presence of risk genes for AD

If the dominant mutations are extremely sensitive to cellular/metabolic disturbances, then having one of them would guarantee development of AD in a Mendelian pattern.

If the genes associated with the late onset AD are *less* sensitive to cellular/metabolic disturbances it may take much, much longer for AD to develop, and the environment may therefore play a key role, thus drifting away from Mendelian inheritance.

We have to explain ALL the data we have and not just dismiss amyloid and genes.

Permalink to Comment

9. mad on July 12, 2013 3:33 PM writes...

This is why there are so many layoffs in pharma research...clinical people waste millions on these "hail mary" studies when they should have done their job and stopped the development so the money could go back into R&D

They push it too far and suck away all the cash-- post hoc data anysis in basic reseach is ok but in clincal trial its getting really risky and really expensive

Permalink to Comment

10. bad wolf on July 12, 2013 3:55 PM writes...

Unfortunately posts #4-8 do not take into account the fact that there is a time delay between pushing "post" and going up, and pushing "post" a few more times just ends up looking silly.

Permalink to Comment

11. drug_hunter on July 12, 2013 4:03 PM writes...

Does Lilly have a 2% chance of this working? If so, then a $200M investment might be justifiable .... we can all make fun of stupidity at the C-level, and we know that Lilly is panicking a bit these days, so maybe this is a Bad Decision ... but I think one could argue that it would be an equally gutsy move to NOT run this trial.

Permalink to Comment

12. Lane Simonian on July 12, 2013 4:59 PM writes...

I have fallen to the time delay, too, but David M. makes some good points. Peroxynitrites can shift production to AB42 (Modification of y-secretase by nitrosative stress links neuronal aging to sporadic Alzheimer's disease). Nitration has been identified as one of the main causes of plaque aggregation (Nitration of tyrosine 10 critically enhances amyloid B and plaque formation).

Genes which inhibit the phosphatidylinositol 3 kinase/Akt increase the production of amyloid precursor proteins and peroxynitrites because they increase the substrate for phospholipase C (phoshatidylinositol 4,5 biphosphate). Because presenilin genes do so almost completely, they ensure the onset of Alzheimer's disease whereas other genes which do so less thoroughly (the APOE4 gene, for instance)simply increase the risk for Alzheimer's disease.

The late Mark A. Smith was one of the most noted proponents for the peroxynitrite hypothesis of Alzheimer's disease. Here is a quote from his research.

In brain tissue from cases of Alzheimer's disease, we found increased protein nitration in neurons, including but certainly not restricted to those containing neurofibrillary tangles (NFTs). Conversely, nitrotyrosine was undetectable in the cerebral cortex of age-matched control brains. This distribution is essentially identical to that of free carbonyls. These findings provide strong evidence that peroxynitrite is involved in oxidative damage of Alzheimer's disease. Moreover, the widespread occurrence of nitrotyrosine in neurons suggests that oxidative damage is not restricted to long-lived polymers such as NFTs, but instead reflects a generalized oxidative stress that is important in disease pathogenesis.(Widespread peroxynitrite-mediated damage in Alzheimer's disease)

He used to say about his detractors that he always asked them to prove him wrong and they never could. That may seem to involve a lack of humility, but I think it was because of his confidence in the link between peroxynitrites and all the major features of Alzheimer's disease. I would add that anti-amyloid drugs have essentially failed to produce signigicant results three times in the last year whereas peroxynitrite scavengers from in vitro studies to human clinical trials have worked each time.

Permalink to Comment

13. 5-HT on July 12, 2013 5:50 PM writes...

The EXPEDITION I and II results look real enough to me, and I'd say there is at least a 50/50 shot they hold up in this new trial. I think it's real, but the effect size is very small. So the question in my mind is how many people are going to put up with an infusion every 4 weeks if they and their caregivers have little evidence the product is working.

Permalink to Comment

14. Esteban on July 12, 2013 6:15 PM writes...

@13: A real effect, per the FDA, no matter how small can more than pay for the cost of development, given the huge unmet need of AD.
Aricept made billions and was only shown to give a modest boost in cognition. Hard endpoints, like delaying entry into a nursing home, never panned out, which is why the British Health Service wouldn't pay for it.

Permalink to Comment

15. SteveM on July 12, 2013 7:45 PM writes...

Lilly is only following the now normative Pharma business model. Develop a weakly effective therapy against a severe medical condition. Recruit desperate patients and family members to make registration and insurance reimbursement a political issue. Saturate the media with biased DTC hope-against-hope messaging to pump up demand from those same poor, desperate people.

And price the product at 200 Grand per patient before they expire little better off from using the drug.

When your pipeline stinks, you go with what you got - smoke and mirrors...

Permalink to Comment

16. bank on July 13, 2013 2:25 AM writes...

If I understand correctly, Lilly are hoping that by excluding the 25% of patients who potentially did not have AD a beneficial effect of solanezumab will become apparent. Without access to their numbers I can only hope that they estimate correctly. Otherwise, it would seem that any beneficial effect must be very small in order to have been "statistically swamped" by these 25%. So in either case it seems as if the hopes pinned on solanezumab are misguided, whatever the underlying causative mechanisms of AD.

Permalink to Comment

17. Starlie Wiggel on July 13, 2013 10:01 AM writes...

@Bank and @SteveM, you're completely missing the story and the point of this trial. This is all about playing Washington to get regulatory change, not making patients healthier. SteveM is partially right, there will be a strong patient advocacy aspect to this, but the success of any good lie is a kernel of truth, and there's a pretty decent chance this drug will do nothing, or worse. Success needs to depend on more than statistical good fortune generating spin-able results.

The real ground game here is influencing the agency, most likely via malleable legislators. See this?

http://www.nytimes.com/2013/03/14/health/fda-to-ease-alzheimers-drug-approval-rules.html?_r=0

This will save Lilly and make a few people in building 73 (and K-Street) very rich in the process. AD patients will die anyway, and as long as the lid can be kept on the patients who die because of the treatment, you've got at least the next generation of Donepezil. Even a well-advertised placebo means billions in sales in the AD market.

Permalink to Comment

18. SteveM on July 13, 2013 10:55 AM writes...

Re: Starlie Wiggel "SteveM, you're completely missing the story and the point of this trial.

No, I get the point exactly. Regulatory relief is but one tactic in this Pharma business model of marketing marginal value, but very high cost drugs to desperate patients.

The current media blitz for Provenge illustrates the DTC arm of the strategy.

When dozens of these niche drugs are on the market priced at a couple hundred grand a year for treatment, something eventually has to hit the fan.

Permalink to Comment

19. bank on July 13, 2013 12:23 PM writes...

@Starlie,

I understand what you say and agree. It's a very cynical move.

Permalink to Comment

20. Lane Simonian on July 13, 2013 2:29 PM writes...

Yes, there are two prongs to this strategy. One is to try to find a way to give the drug earlier perhaps even before the onset of Alzheimer's disease (using their amyloid imaging agent as the starting point) and the second is to get the drug approved without demonstration of clear clinical efficacy. To declare failure a partial success is still a risky strategy.

Eli Lilly is engaging in a tautology. Amyloid plaques are the cause of Alzheimer's disease so if you don't have plaques you don't have the disease. This is not the case:

Alzheimer's disease without amyloid plaques

Amyloid plaques have long been thought to be the cause of neuron loss in Alzheimer’s disease. Now researchers report that excess of mutated amyloid precursor protein (APP) inside the neurons is sufficient to induce neuron death. The report challenges the notion that amyloid deposits outside of the cells are necessary for neuron death in Alzheimer’s disease.

Protein kinase C regulates the secretion of the amyloid precursor protein and via p38 MAPK leads to the formation of peroxynitrites, but the formation of amyloid plaques requires intracellular calcium release (Buxbaum, Calcium regulates processing of the amyloid precursor protein in a protein kinase C-dependent manner). If the release of intracellular calcium is inhibited or blocked by various compounds, but protein kinase C is activated, a person can have the amyloid precursor protein and peroxynitrites, but not amyloid plaques. Everyone with Alzheimer's disease has signs of peroxynitrite-mediated damage; not everyone with Alzheimer's disease has amyloid plaques. And even for those who do, the anti-amyloid drugs have only a minimal effect on the production of peroxynitrites and thus only a minimal effect on the progression of Alzheimer's disease.

Eli Lilly should have gone back to the drawing board rather than doubling down. With the current mindset of pharmaceutical companies and the apparently obliging nature of the FDA a really effective treatment for Alzheimer's diseae may indeed not be available for decades.

Permalink to Comment

21. Lane Simonian on July 13, 2013 2:34 PM writes...

The correct title for the article is Calcium regulates processing of amyloid precursor protein in a protein kinase C-independent manner.

Permalink to Comment

22. pgwu on July 14, 2013 10:31 AM writes...

A big chunk of the few hundreds mil might end up in private equity's pocket who invested in CROs. Andy Parrett has an interesting article in the April issue of Applied Clinical Trials where a pharma executive is the emperor with a new cloth and some large CROs are the tailors.

Permalink to Comment

23. Harrison on July 15, 2013 1:51 PM writes...

The people who decide reimbursement for the gov't announced that Lilly's pet ligand will not be reimbursed for most patients because there is no treatment option specific to amyloid. Lilly needs to run this study to show there is a reason to reimburse AV-45. It's still risky, but they have been backed into a proverbial corner.

Permalink to Comment

24. Starlie Wiggel on July 15, 2013 8:12 PM writes...

Someone needs to call animal control. Lilly's pet ligand is off its leash again.

Permalink to Comment

25. Rich Rostrom on July 20, 2013 10:59 AM writes...

"Lilly Goes All In on Solanezumab...

So Eli Lilly is going to double down on solanezumab..."

The gambling metaphors are badly mixed. One "goes all in" in poker; one "doubles down" in blackjack.

The two actions are also very different in effect. An "all in" bet puts the player's entire stock of chips at risk; if he loses, he's broke. "Doubling down" means doubling the amount at risk, but is not related to the player's resources.

So - is Lilly investing its entire capital in solanezumab? If solanezumab fails, will Lilly be broke?

Or is Lilly doubling its investment, preparing to spend as much again as previously invested?

Permalink to Comment

26. THX1138 on October 2, 2013 12:00 AM writes...

#5 - as for caregivers wiling to bring family members for an infusion every 4 weeks - let me tell you, it's a non-issue. My mom has been taking Solanezumab on open label for 2 years, and double-blind for 18 months prior to that. Is it a drag? Yes. But if there may be some benefit for her - we'd take her once a week. Is it helping to slow the progression of AD? Hard to say. She has gotten worse, but she's also still at home and can converse and is - partially - intact. Side effects seem to be nil for her (one reason we chose the trial in 2010, in consultation with PCP and 2 neurologists), and she's on the drug for sure 2 years now. MRI's and blood labs are every 4-6 months keeping a close watch. I'm not a scientist, but an informed layman who's read all about AD and attended conferences with the 'experts' - it's a very tricky disease, and doubtful there will be one magic bullet - but hopefully with multiple approaches and drugs the pathways of this horrible disease can be delayed and pushed back - a delay of a decade or two of progression will give millions a much better quality of life and avoid so much suffering. Let's hope this is one step in the right direction - especially if given earlier in the pre-clinical phases. I was floored by a recent statement: in the past decade, there has not been ONE NEW DRUG approved by the FDA for Alzheimer's treatment. Zero. That is sad. And frightening. And let's hope that changes soon.

Permalink to Comment

27. THX1138 on October 2, 2013 12:07 AM writes...

Oops meant #13 (not 5) re. caregivers and monthly infusion.

Permalink to Comment

28. petros on October 24, 2013 2:35 AM writes...

Given what we've seen so far on solanuzemab I was surprised to read this comment from a new Decision Resources AD market assessment

"“We expect Eli Lilly’s solanezumab to launch beginning in 2018 and to attain blockbuster status in 2019,” says Decision Resources Senior Analyst Georgiana Kuhlmann. “We anticipate the drug will attain sales of nearly $5.5 billion in 2022, the last year of our current forecast period, across the United States, France, Germany, Italy, Spain, United Kingdom, and Japan.”

Permalink to Comment

29. rudolph nucci on November 16, 2013 8:36 AM writes...

is PBT2 a drug that's on the right track?

Permalink to Comment

30. Marianne on April 19, 2014 8:08 PM writes...

My father has been in this trial since December of 2009. When we started he was starting to decline on a daily bases and was soo afraid that we could not keep him in the house. From the moment the trial began we saw the improvement he started eating again and the fear he was experiencing stopped. Now his memory did not get better but he is able to track a conversation and if he wants to he can respond on point with what is being said. My father may not know how old he is or how many grandchildren he has but he is still living in the house he gave me and in 2009 I didn't think he would be able to for much longer. Everyone is looking for the cure but I believe if this had been available when I first saw the signs which was 2006 that my dad would still have a lot of his memory. Now we had done MRI but not the pats can but what I know is I was watching my father deteriorate in front of my eyes with weigh loss, fear, and no memory of what was going on. Today he looks healthy is not afraid and the mind is working better than it was 4 years ago

Permalink to Comment

31. Marianne on April 19, 2014 8:08 PM writes...

My father has been in this trial since December of 2009. When we started he was starting to decline on a daily bases and was soo afraid that we could not keep him in the house. From the moment the trial began we saw the improvement he started eating again and the fear he was experiencing stopped. Now his memory did not get better but he is able to track a conversation and if he wants to he can respond on point with what is being said. My father may not know how old he is or how many grandchildren he has but he is still living in the house he gave me and in 2009 I didn't think he would be able to for much longer. Everyone is looking for the cure but I believe if this had been available when I first saw the signs which was 2006 that my dad would still have a lot of his memory. Now we had done MRI but not the pats can but what I know is I was watching my father deteriorate in front of my eyes with weigh loss, fear, and no memory of what was going on. Today he looks healthy is not afraid and the mind is working better than it was 4 years ago

Permalink to Comment

POST A COMMENT




Remember Me?



EMAIL THIS ENTRY TO A FRIEND

Email this entry to:

Your email address:

Message (optional):




RELATED ENTRIES
Science Gifts 2014: General Books (and More) on Chemistry
A (Sad) Look Back to 2006 At GSK
Reading Nature For Free
Cambrian Genomics Does It All
Cuts Coming at GSK
Try Some Reactions. Actually, Try Them All.
Holiday Blogging
Reaction Discovery Reviewed