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More proof that many Alzheimer's researchers still believe Amyloid-Beta (ultimately leading to neuronal death) is the cause of Alzheimer's Disease.
"The accumulation of amyloid beta is thought to trigger a neurotoxic cascade, leading to plaque formation, phosphorylation of tau protein, formation of neurofibrillary tangles, inflammation, synaptic loss and eventually neuronal death."
https://www.cell.com/current-biology/fulltext/S0960-9822(18)30552-9
While the focus is still on Amyloid-Beta, it is now believed that anti-Amyloid drugs must be given much earlier in the disease process, BEFORE neurons die.
The excerpt below reveals many researchers flawed logic in the cause of AD: research shows a strong correlation between mutation of AD genes and amyloid deposition. Therefore, amyloid deposition must be the cause of AD. Note that lack of synaptic density is also mentioned as a sequelae of amyloid deposition--not the cause of AD, as hypothesized by Dr. Alkon.
"There has been a substantial amount of skepticism towards the amyloid hypothesis ever since its first description in the 1980s. Critics often claim amyloid precursor protein (APP) has neurotropic effects, sharing similar structural features with the precursor of epidermal growth factor, suggesting that increased expression of APP and subsequent increases in amyloid deposition are a response to neuronal injury rather than a pathological driver of the disease. The large amount of failed therapeutic trials targeting amyloid deposition is often used as confirmation of this theory. However, the strong correlation between mutations in the PSEN1, PSEN2 and APP genes and trisomy 21, which all lead to increased accumulation of amyloid plaques and the development of early-onset familial Alzheimer’s disease, strongly supports the amyloid hypothesis. PSEN1 and PSEN2 are important components of the ?-secretase complexes responsible for the cleavage and release of Aß. The APP gene is located in chromosome 21 and mutations in the gene itself or trisomy 21 result in increased levels of amyloid beta. Also Aß42 peptides isolated from late-onset Alzheimer’s disease human brains cause memory deficits, long-term synaptic depression and decreased synapse density when injected to rodent brains, thereby providing further support for the amyloid hypothesis."
Really good thoughts there, Coach.
You are right--without knowing the individual data, it's hard to determine why we didn't get 2-tailed statistical significance in the subgroup analysis. And, in the absence of that detailed information, the only thing that sticks out is that non-memantine placebo performed better than expected and better than overall placebo, and in a small sample size to boot (11 patients). Thanks for pointing that out.
What we all should hope for in the confirmatory phase 2 is that both Bryostatin and placebo groups perform as we expect. That is, we hope to see very few in the Bryostatin group that are non-performers, and we hope to see very few in the placebo group that see an improvement in MMSE score. This is what I'm really getting at with my previous posts today. I'd love to see "normal" data with very few outliers in the Bryostatin and placebo groups. If that is the case, we should pass with flying colors.
In the end, it comes down to trust, and I like that they've brought in stats experts to sign off on their trial design.
I think it comes down to 2 questions:
What percentage of the patients in our confirmatory trial are expected to not have Alzheimer's?
Can Bryostatin successfully treat those dementias included in our confirmatory trial that are not AD (but look similar to AD on neuroimaging)?
---------------
These questions are absolutely crucial to how well our confirmatory trial is designed.
On sub-group analysis, there were patients in the non-memantine Bryostatin group who did not respond to treatment. I expect that will happen in the confirmatory trial, as well.
Increasing the number of patients will certainly help the statistical analysis in the confirmatory trial. (The sub-group analysis had 25 patients; the confirmatory trial will have 100)
But, if we get an imbalance of patients in the Bryostatin group who don't respond to treatment, it will adversely affect the outcome.
Thanks--it seems like they're doing neuroimaging, as well. But this leads to a "probable" diagnosis. There still may be 10-20% in our trial who don't actually have Alzheimer's.
I wish the PKC-e skin test was far enough along to definitively diagnose AD.
I just looked up the inclusion criteria for the last Phase 2 trial:
https://clinicaltrials.gov/ct2/show/NCT02431468?term=bryostatin&rank=2
The inclusion criteria does require imaging to confirm probable Alzheimer's:
"Neuroimaging (computerized tomography (CT) or Magnetic Resonance Imaging (MRI)) within the last 24 months consistent with a diagnosis of probable Alzheimer's disease (AD)"
One statistic from this article that I find interesting, in relation to our trial:
"In 60% to 80% of dementia cases, the cause is Alzheimer’s disease."
This means 20-40% of patients with dementia don't have Alzheimer's disease.
Does anyone know if everyone who are entered into the Bryostatin trials are verified to have Alzheimer's?
The reason I ask this is because I have discussed the non-memantine subgroup data (14 on Bryostatin and 11 in placebo) with another poster here offline, and we believe there were some non-responders in the Bryostatin group of 14 patients, which brought down the overall scores of the Bryostatin group.
Is it possible that some people with dementia, but not Alzheimer's, were/will be entered in our trials?
Great article. Thanks
Cyosol:
I agree--it's very likely they will raise money before data release next year.
Could be through a partnership, but more likely by selling shares.
At what price is anyone's guess.
We had 2b data released last May, but that data didn't quite meet the standard .05 cutoff for approvable data. Many investors moved on to other biotech stories after the data release; stock price collapsed.
In the 5-6 months leading up to the data last May, we had a runup in price from about $8 to $29, and then back to $15 right before data release.
There was an update at a London conference last fall, and then we got a further update last winter that there was a drug-to-drug interaction between Memantine and Bryostatin, and this new info caused the share price to move from about $4 to $8. However, this new info is considered post-hoc data and can't be used for approval. But it can be used to design a new trial, which has just recently been completed. Further, this new post-hoc data didn't meet the .05 cutoff, but because the data was only on about 40(?) patients, management consulted statistics experts to help design the new confirmatory trial. These statistics experts have signed off on a confirmatory trial of ~100 patients (not sure if this number includes dropouts?). This is intriguing, in that it is assumed that these statistics experts have reviewed every aspect of the data, and concluded that ONLY 100 patients is all that is needed to reach statistical significance. I assume there is some room for error built into this new study with 100 patients. (I believe the memantine confirmatory trial required 200 patients?)
And here we are, about to start the confirmatory phase 2 trial.
So, what happens to the share price from here?
IMO: a partnership would increase the share price, but how much depends entirely on the details. I have seen some AD partnerships fetch $500M upfront. Our market cap is $72 million, so that kind of partnership could increase our share price 5-fold. If it's a more modest partnership, share price might only increase 50%. Will we get a partnership before the data release on the confirmatory trial next summer? No guarantees, but it could happen.
Before the data release last May, the share price tripled in anticipation of the data release, before dropping back to a double just before the data release. Will that happen again? No guarantees, but it could happen.
Will some family members publicly post positive anecdotal stories about their family members who are taking Bryostatin in this new confirmatory trial? No guarantees, but any positive anecdotal information could cause the share price to increase.
Will some tout sheet pick up on the Bryostatin story and convince their subscribers to buy NTRP stock, causing a significant increase in the share price? No guarantees, but it could happen.
Will there be sell-side analysts who give high price targets for NTRP stock over the next several months? No guarantees, but it will probably happen.
-------------
If statistically significant data is released next summer, what should NTRP stock trade for? There was another company that had released positive phase 2 data, and had a market cap of ~$2B before releasing disappointing phase 3 data. My guess is that NTRP should trade with a market cap somewhere north of $500M within a few months, if positive data is released next summer.
The best advice anyone can give is to go in with a plan. My guess is there will be some sort of runup over the next year, assuming we don't have a market meltdown in the interim. Not a bad idea to sell some of your shares into any share price runup so that you lower your cost basis.
Everyone wishes they had done what runncoach did: buy when there's blood in the streets at $4/share. But we don't all have the foresight/guts to do what he did. :)
The other risk in waiting for non-memantine results is missing a possible deal with a large biotech, either for a region (Japan?) or for a distinct indication (MS?).
If a deal contains significant upfront cash (> $50M) and large milestones, then cash is no longer a concern and several new trials can be started.
I could see the share price easily doubling with a partnership that brings in significant cash.
Great to see confirmational research! There's some fascinating info in there about how the brain naturally compensates for deficits in early stages. Eventually, however, the brain is overwhelmed by the disease in later stages.
A few comments:
- We seem to be further advanced in research in other diseases. We've seen research on a disease (fragile-X?) where the shape of dendrite can be brought back to normal with Bryostatin. That might be one of the cascade portions where Bryostatin has an advantage over this compound.
- I agree that PKC-e biomarker (skin test?) will be key to our success in earlier treatment of AD. If/when our trial proves successful, the PKC-e theory will be viewed as a working model, and then we need to fully develop the skin test for this biomarker.
- This research focuses on early stages of AD, but NTRP has shown that reversal is also possible in late-stage disease.
- "causes of sporadic form still unknown and not yet understood". If PKC-e theory is proven, Alkon/NTRP understand it. I believe Alkon is spot-on with PKC-e theory, but it's just a theory for now.
- They comment that the first detection of neuroinflammation and oxidative stress is in advanced AD. I could be wrong, but just like AB plaques and Tau, I believe these are later-stage SYMPTOMS of AD, not the CAUSE of AD.
- Fascinating discussion of synaptophysin, total synaptic area, and compensation in early stages of AD.
- Overall, I think these guys are onto something in that they are looking heavily at the "compensation" stage of AD. However, they still don't understand the CAUSE of AD (pkc-e deficiency theory). Could be developed into a possible treatment, assuming it's safe and crosses the BBB and can be dosed properly.
- Since they are working in earlier stage AD, unless they can come up with a biomarker to shorten the duration of the trial, their trials will take 2-3 years to complete. IMO, it was good strategy by Dr. Alkon to take late-stage AD patients, as the trials can be of shorter duration.
"The decision was made at the recommendation of an independent data monitoring committee, which reviewed a futility analysis of a phase 3 trial, Prothena said. In addition, a phase 2b study didn't meet its primary or secondary endpoints. The decision "comes as an early negative surprise," said RBC Capital Markets analyst Kennen MacKay."
I agree with the thread.
If Bryostatin only HALTS the progression of AD (safely) over the long haul, this will get bought out for $10B+
If Bryostatin consistently and safely IMPROVES the scores of AD patients AND treats some or all of the other diseases (Fragile-X, Niemann-Pick, TBI, MD, etc), the buyout price will be $20B+.
To be clear: there's still significant risk in NTRP, and it will take 3-5 years and a lot of work to get to either of these buyout prices. But if successful, the payday will be enormous.
Rarely is actual interim data released by a company. Some trials have a Data Safety Monitoring Board review interim results (at a predetermined time) for futility and safety issues, both of which are reasons that a trial can be halted. But it's extremely rare to see a trial halted because the drug arm is so much better than the placebo arm.
I don't anticipate a DSMB interim review of our data for the upcoming trial. I don't think we had an interim look during the last trial, and the safety is pretty well established.
---------------------------
Cyosol: thanks for the extract of info from the 10k report.
Good insights.
The article is definitely worth a read.
There was an important discussion in the article about why large pharma and industry analysts are skeptical of small cap bio results in AD:
ACAD recently ran trials on Nuplazid (pimavanserin) in AD psychosis. They reported positive results in a trial, but while the NPI-NH scores were statistically significant at week 6, they weren't significant at week 12. (According to the Endpoints article, 12 weeks is an industry standard for success; explains why Bryostatin injections are run for 12-15 weeks.) Later, when all the clinical endpoints were revealed, the statistical significance at week 6 was due to a drop in placebo at week 6.
Below is a link to an interesting Endpoints article on AD (You can sign up for a free account to access the entire article):
https://endpts.com/special/the-alzheimers-rd-odyssey-comes-to-another-fork-in-the-road/
Key takeaways from this article for me:
- There is a good summary of recent trial failures in AD, as well as current trials and research.
- There is still HUGE money flowing into AD research, even though some large pharmas are bailing entirely (PFE). Millions of AD patients will flock to any treatment that can change the downward trajectory of AD symptoms (cognition and function). A useful drug in AD will be worth multi-billions.
- The failures keep pummeling pharma industry, and the industry is downtrodden. So, they are now looking at combo therapies (ABeta, Tau, neuroinflammation, etc) and treatment with same drugs at an earlier stage of disease. (My opinion: don't seem to be looking at new ideas like PKC-epsilon theory)
- The ENDPOINTS writers, in my view, are on top of the industry trends and research, and also various trials by large companies. Their focus seems to be large pharma and a few smallcap bios that are spinoffs from large cap companies. (My opinion: smallcap spinoff bios leads to inbreeding of hypotheses on AD instead of new research on AD, such as NTRP)
- They (industry and industry analysts) are still mostly clueless about the possibility that there is one multi-modal drug that can potentially treat all aspects of the disease (such as Bryostatin).
- FDA is rewriting trial guidelines to help AD companies in assessing biomarkers and drugs that may help early onset of AD. Focus on cognition decline, which occurs earlier in the disease than functional decline.
lol...
Can you go a bit further into the future, say several months, and link us to Neurotrope's PR telling us the results of the next trial? :)
Thanks for posting.
Seems to be a recent interview (date on article is April 1, 2018). Good to see they still anticipate starting the trial in 1st half of 2018.
"Dr. Ryan added that Neurotrope expects to begin the confirmatory study in the first half of 2018."
Thanks Coach:
~ minute 5:20 : "...next confirmatory trial, which will start in the first half of this year, where we would replicate what we've done and extend it out to 30 weeks."
Not sure if this has changed since mid-February, but it sounds like the company is anticipating going for 30 weeks in the confirmatory trial.
Coach:
You are correct RE: their last tallied score counts. Just one caveat: they have to get at least one score after the initial baseline in order to carry forward this patient's score in the final statistics.
IMO, this tremendously helped the trial statistics of a drug like Namenda. This is because (based on the graph) the drug helps for the first few months (or first few checkup scores), but then the scores decline in a similar trajectory as placebo. So carrying forward these higher scores was a tremendous help for Namenda in the final statistical analysis.
In the case of a drug like Bryostatin, this carry-forward will not help for obvious reasons. Patients that are on-drug who drop out early will conceivably have lower interim scores than if they continued the trial to completion. So the lower carry-forward scores of dropouts would actually HURT the final statistics.
In any case, I'm sure there are a lot of internal discussions, as well as discussion with the FDA on how to handle the high expected dropouts.
PRTA signs a licensing agreement with CELG for Tau preclinical drug candidate + other drug candidates:
http://ir.prothena.com/releasedetail.cfm?ReleaseID=1061508
- Prothena to receive a $100 million upfront payment and a $50 million equity investment by Celgene, with potential license payments and regulatory and commercial milestones, plus additional royalties on net sales from licensed programs
- Collaboration focuses on preclinical programs targeting proteins implicated in several neurodegenerative diseases, including tau, TDP-43 and an undisclosed third target
----------------------------
In spite of failures in Tau and A-Beta, companies are still willing to put up significant money for preclinical candidates in AD.
Can't wait to see what they will pay for a drug candidate ready for Phase 3. :)
That IS paying up.
Roth Capital started coverage of NTRP with a buy rating, target $15.
Maybe someone trying to jump start the stock with the "news"?
No, I didn't skip the 2nd sentence:
It is believed believed to be a significant causative factor for CNS impairment.
Being associated with a disease doesn't necessarily mean it is the cause or even a contributing factor of that disease. Oxidative stress could be present in AD but not the cause of AD. As an example: it was once thought Amyloid beta oligomers were the cause of AD, but after many decades and billions of dollars spent, I think it can be safely stated that it is only associated with AD.
Your definition of multimodal is different than the context that I'm using it: "characterized by several different modes of activity or occurrence."
PKC-epsilon has several different modes of activity on the causes of Alzheimer's, the primary one being synapse loss.
grich:
I agree.
I haven't looked too closely at his articles, but it seems like he believes strongly in this oxidative stress theory.
My questions would be: is oxidative stress a cause of Alzheimer's or is it a symptom of AD? Is it only associated with one aspect of AD (Tau or A-Beta, etc)?
As we know from Dr. Alkon's presentations, Bryostatin is a multi-modal treatment, improving all aspects of AD: Tau tangles, A-Beta, synapse regeneration, neuronal protective, etc.
Oxidative stress may only be associated with one aspect of AD, and improving the oxidative stress may only help that one aspect of AD. This may slow the disease process, but not halt or reverse AD. With Bryostatin, we hope to reverse AD.
I know...I'm preaching to the choir, and everyone here already knows this!.
Thanks coach for that link. Amazing to see that even phase 1 data can be used for breakthrough.
If NTRP management felt they could get Breakthrough status based on this upcoming trial, they could start the paperwork now, and be virtually ready to submit to the review process when the trial is complete. That article says FDA review process takes a minimum of 6 months even with priority review. There is also the possibility of doing a rolling submission, which allows submitting individual sections of the NDA paperwork for review as they are completed. I would guess that companies with drugs designated breakthrough designation can use the rolling submission.
I assume that the Stanford group is working on the FDA process to get CGMP approval for the manufacturing plant.
It would be great to see job postings by NTRP that pertain to the FDA review process. Might show what mgt is thinking about their expectations of trial outcome and if they think the FDA will view it as breakthrough data.
The ideal (fastest) path to approval for Bryostatin would be accelerated approval.
From Wikipedia:
The [US FDA] initiated the FDA Accelerated Approval Program in 1992 to allow faster approval of drugs for serious conditions that fill an unmet medical need. The faster approval relies on use of surrogate endpoints.[1] Drug approval typically requires clinical trials with endpoints that demonstrate a clinical benefit, such as increased survival for cancer patients. Drugs with accelerated approval can initially be tested in clinical trials that use a surrogate endpoint, or something that is thought to predict clinical benefit. Surrogate endpoints typically require less time, and in the case of a cancer patient, it is much faster to measure a reduction in tumor size, for example, than overall patient survival.
Drugs approved under the FDA Accelerated Approval Program still need to be tested in clinical trials using endpoints that demonstrate clinical benefit, and those trials are known as phase 4 confirmatory trials. If the drug later proves unable to demonstrate clinical benefit to patients, the FDA may withdraw approval.[2][3]
The example above is for accelerated approval for cancer drugs. Most accelerated approvals involve completing at least 1 phase 3, but there are rare cases of approvals after phase 2.
As it relates to Bryostatin for Alzheimer's, if the phase 2 is well-designed and if the results significantly exceed the 95% confidence interval, I could see the POSSIBILITY of accelerated approval for Bryostatin after the upcoming Phase 2 trial. Alzheimer's disease is a serious condition with an unmet need, and one could view the surrogate endpoint as improvement at 15 weeks (typical phase 3 AD drug trials last at least 6 months). The separate "phase 4" trial, conducted after approval, could prove out the 6 months statistically significant improvement, and may extend up to a year to clear up any lingering concerns about long-term safety.
Assuming the FDA agrees to accelerated approval based on the phase 2, the approval process would still take at least 15 months (6 months to prepare paperwork for filing, 6 months to review and then a PDUFA date is set).
Further, the manufacturing site needs CGMP approval by the FDA, which could take at least 1 year (can be done in parallel with paperwork).
Most drug companies will (wisely) allow ONLY very limited access for compassionate-use, typically for those who have already been in a trial (to continue the drug beyond the end of the trial). Agreeing to compassionate use for those who have NOT been in Bryostatin drug trials can be perilous: What if bad outcomes happen with patients who aren't closely followed and monitored? What if patients aren't seeing the benefits, because the drug isn't being administered correctly in a well-controlled trial?
While I would love to see patients get Bryostatin as quickly as possible, I would not be keen to see widespread use of Bryostatin (compassionate-use) until it is approved. Getting approval of Bryostatin should be the focus.
Interesting:
"...for use in the treatment of central nervous system disorders, lysosomal storage diseases, stroke, cardioprotection and traumatic brain injury..."
"Lysosomal storage diseases (LSDs; /?la?s?'so?m?l/) are a group of about 50 rare inherited metabolic disorders that result from defects in lysosomal function. Lysosomes are sacs of enzymes within cells that digest large molecules and pass the fragments on to other parts of the cell for recycling."
I wonder if Bryostatin can be used to treat some of the symptoms associated with LSD, such as (1) delay in intellectual development and (2) seizures.
Yes, I agree. Intriguing the positive effect it has on the side-effects of MS: "reverses neurologic deficits after EAE onset".
I also like the highlight of Bryostatin safety: "These findings suggest the potential for bryo-1 as a therapeutic agent in MS, particularly given its established clinical safety."
That is interesting pre-clinical data.
Biogen (BIIB) could get a 2-for-1 by partnering with Neurotrope on Bryostatin for Alzheimer's and Multiple Sclerosis:
https://www.benzinga.com/analyst-ratings/analyst-color/18/02/11216071/argus-downgrades-biogen-on-trial-delays-competition-in-
If the PKC-e theory is proven out in trials, and if there is a low-cost test developed to determine abnormal PKC-e levels (biomarker) in patients, this could open the door for a path to treat the moderate and mild populations with Bryostatin.
Minute 13:10 :
"In addition we are going to begin what we hope will be a policy of looking at partnering collaborative programs. One of those is Fragile-X..."
That sounds great to me! This new policy seems to coincide with the arrival of our new president (this week?).
I agree--I'd love to see 3 trials running at once. With an additional $15-20M in cash, they could be doing just that.
Biogen stops testing Tysabri to treat stroke after study fails
https://finance.yahoo.com/news/biogen-reports-top-line-results-123000062.html
Thanks, Cyosol for pointing out the highlights.
I didn't realize it can be given orally. This is great news! Also glad to hear they plan to incorporate the oral administration.
It's also good to hear they are going beyond 15 weeks. Initially, I thought this would add some risk. But since we have long-term safety in cancer trials, and we also have long-term track history with compassionate-use patients, I think this is a risk worth taking.
True...but I think the right course of action now is to raise money (or a small partnership), in order to advance manufacturing synthetic Bryostatin, initiate all of the other trials (Fragile-X, etc), and to continue preclinical work on other PKC-e activators and other routes of delivery.
Long NTRP
I believe we will see NTRP raise money over the next several months. There are several ways to accomplish this:
- A dilutive financing (Perhaps 3M shares at $6.50/share?)
- A partnership for Bryostatin in another country (e.g. Japan) with upfront money
- A partnership on one of the other indications (Fragile-X, APOE4, or TBI) with upfront money
++++++
The most attractive way to raise capital might be a partnership for Bryostatin in a country like Japan, for all indications, for ~$50M upfront and a 10% royalty.
By raising significant capital, we can progress our business development including:
- Trial runs of manufacturing synthetic Bryostatin
- Buildout of manufacturing capacity for synthetic Bryostatin
- Initiate a Phase 1/2 trial in Fragile-X
- Initiate a Phase 1/2 trial in APOE4
- Initiate a Phase 1/2 trial in TBI
- Work on an alternative to IV infusion (either IM or oral delivery)
- Preclinical work on other potential drugs that activate PKC-e, including bryologs
I also think it's important that we complete the proposed phase 2 trial in AD with ~ 1 year of cash in the bank, leaving us in strong cash position for negotiating a partnership with a major pharma next year.
+++++++++++
Does anyone have any insights on the new president's ability to negotiate partnerships?
Dr. Algazi comment (principal investigator of Phase 2b EP IL-12 + Keytruda):
When he was asked what he predicts the ORR would be on the total population, not just patients refractory to anti-PD1 inhibitors, his answer was simply... "75%". (from Twitter--POUNDtheROCK author)
That is, he predicts ORR of tavo + Keytruda will be significantly better than 1st line treatment (Opdivo) in unresectable melanoma.
For comparison, Opdivo results in melanoma:
1st trial: Opdivo vs Dacarbazine (chemo):
Opdivo: Complete Response Rate (CRR): 4%, Objective Response Rate (ORR): 34%
Dacarbazine: CRR: 1%, ORR: 9%
2nd trial: Opdivo+Yervoy vs Opdivo vs Yervoy
Opdivo+Yervoy: CRR: 8.9%, ORR: 50%
Opdivo: CRR: 8.5%, ORR: 40%
Yervoy: CRR: 1.9%, ORR: 14%
Opdivo Label: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125514s012lbl.pdf (pp. 41-44)
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EP IL-12 + Keytruda complete response rate is stunning at >40%
I was mistaken in this statement from my earlier post:
Further, I believe Keytruda has only an 18% complete response rate in first-line melanoma
---------------------------------
In reviewing the Keytruda label document, Keytruda was compared against Yervoy in a phase 3 trial for approval (Yervoy-naive patients):
Keytruda: CRR (Complete Response): 5-6%, BORR (Complete+Partial): 33-34%
Yervoy: CRR: 1%, BORR: 12%
EP IL-12 +
Keytruda: CRR: >40%, BORR: >50%
(Refractory/Relapse, Open Label, Patients predicted to be Keytruda non-responders)
Keytruda label: https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125514s012lbl.pdf
(page 17-18)