Alzheimer's Disease: Learning the Lessons Of The Past To Prepare For The Future

No approved treatment has been able to halt the underlying disease processes in the brain in AD patients, and no new treatment has been approved at all in the last decade in this field.Research, and the development of new therapies, has been fraught by a large number of late-stage, high-profile failures in recent years and a vast number of asset suspensions in the earlier stages of development, too.

According to data held by BioMedTracker (BMT), the AD pipeline in the US includes 47 Phase I products that have been suspended or placed on a program hold. Of these 47 drugs, AD was the lead indication for 24 of them. In Phase II (including one Phase IIb program) the picture is similar, as BioMedTracker has 55 AD products listed as suspended.

However, in Phase III, where product failures tend to cause more disruption to wider company strategies, root more financial loss, as well as create higher disappointment to patient populations, BioMedTracker has recorded 13 drug suspensions or program holds (see Exhibit 1). There is also one record for a drug being withdrawn from the market, Pfizer Inc.'s Cognex (tacrine), which was stopped following usage limits on the product due to side effects. Dr Tommy Dolan, vice-president and head of Pfizer's Sandwich site, UK, commented to Scrip, "Neuroscience research is one of the most challenging areas of science not least because, unlike other organ systems, we do not have direct access to the brain – a highly complex organ. We are therefore continually applying learnings from our own research, as well as through important collaborations with industry, academia, advocates and government."

It is here, in late-stage development failures and market pull backs, where Scrip has focused its attention to see what went wrong for these products – but more importantly what lessons were learnt that could influence future AD development programs.

Exhibit 1: Drug failures or suspensions in Alzheimer's disease

Drug Name	Lead Company	Lead Indication	Current Development Stage	Molecule	Target	Drug Classification	Development Phase When Suspended
ABT-126	AbbVie Inc.	N	Suspended	Small Molecule	Nicotinic Acetylcholine Receptor	NME	Phase IIb
Acrescent	H. Lundbeck A/S	N	Suspended	Small Molecule	Serotonin 5-HT3 receptor	Non-NME	Phase III
Avandia	GlaxoSmithKline plc	N	Suspended	Small Molecule	PPAR gamma	NME	Phase III
Bapineuzumab (IV and SQ)	Johnson & Johnson	Y	Suspended	Monoclonal Antibody	Amyloid Beta/Amyloid Plaques	Biologic	Phase III
Bifeprunox	AbbVie Inc.	N	Suspended	Small Molecule	Serotonin 5-HT1 receptor	NME	Phase III
Dimebon	Medivation, Inc.	Y	Suspended	Small Molecule	Mitochondria	NME	Phase III
Flurizan	Myrexis, Inc.	N	Suspended	Small Molecule	Gamma-secretase	NME	Phase III
Gammagard	Baxalta Incorporated	N	Suspended	Protein	Amyloid Beta/Amyloid Plaques	Biologic	Phase III
Lipitor	Pfizer Inc.	N	Suspended	Small Molecule	HMG CoA Reductase	NME	Phase III
Memryte	Voyager Pharmaceutical Corp.	Y	Suspended	Peptide	Gonadotropin-Releasing Hormone Receptor	Non-NME	Phase III
Phenserine	QR Pharma, Inc.	Y	Suspended	Small Molecule	Acetylcholine	NME	Phase III
Risperdal	Johnson & Johnson	N	Suspended	Small Molecule	Serotonin 5-HT2A receptor	NME	Phase III
Semagacestat	Eli Lilly & Company	Y	Suspended	Small Molecule	Gamma-secretase	NME	Phase III
Xaliproden	Sanofi	N	Suspended	Small Molecule	Serotonin 5-HT1a receptor	NME	Phase III
Cognex	Pfizer Inc.	Y	withdrawn from Market	Small Molecule	Cholinesterases	NME	Withdrawn from market

Source: BioMedTracker

Pfizer's Cognex

Developed by Pfizer and later licensed by Japan's Shionogi & Co., Cognex was the first acetylcholinesterase inhibitor (AchEI) to reach the market in 1993 but in 2012 it was discontinued. The drug worked by inhibiting the enzyme acetylcholinesterase based on whether the concentration of acetylcholine in the brain of an AD patient was up to 90% lower than normal. Unwanted side effects appear to be the main reason why this drug was withdrawn from the market.

Tacrine is said to have negative effects on the gastrointestinal tract, hepatic and cardiovascular function and one of the main reasons for its withdrawal was its potential to cause hepatotoxicity. Paul Francis, Professor of Neurochemistry at King's College London and director of Brains for Dementia Research, told Scrip that as well as safety and tolerability issues with tacrine, most of which were temporary, the arrival of compounds which were more tolerable and required less frequent dosing, such as donepezil, meant the use of tacrine was gradually reduced.

Pfizer has had other struggles in late-stage AD development including the Phase III failure of Lipitor (atorvastatin calcium) in 2008 and the collapse of bapineuzumab, of which it was responsible for 50% of development with partner Johnson & Johnson.

GSK's Avandia

In 2009 GlaxoSmithKline plc's AD drug Avandia (rosiglitazone), which targeted PPAR gamma (peroxisome proliferator-activated receptor), was abandoned in Phase III. The study did not present any statistically significant effects of RSG XR (rosiglitazone-extended release tablets) on cognition or global function. Though it is noted the drug was safe and well tolerated, two studies failed to see a benefit of RSG XR in combination with acetyl-cholinesterase-inhibitor (AchEI) therapy.

GSK told Scrip it stopped the development of the drug because the study did not show efficacy. However, Professor Gary Landreth, who holds the patent on the use of PPARG agonists in AD and was also on the writing committee that produced the paper on the outcome of the Avandia Phase III trial, said that it was not clear to him that the "decision to run the Avandia trial was well vetted internally at GSK." He explained that rosiglitazone does not pass the blood brain barrier efficiently in mice and he has yet to come across data which show its CNS bioavailability in humans. As far as Landreth knew, "GSK did little to establish CNS actions of the drug."

"I think the major take home message is that GSK invested $250m in a study whose rationale was not compelling based on normal principles of drug development. The Phase II data were simply over interpreted or misinterpreted. Dr Allen Roses [the person who discovered that apolipoprotein E is a risk factor for AD] was an enthusiast and may have had a disproportionate influence on the decision to go into a large Phase III," Landreth said.

Roses, a neurologist and geneticist, has been called a "controversial character" by some. He is known nowadays for running a number of companies named after wines, for example, he is CEO of Zinfandel Pharmaceuticals – a company still involved in the neurodegenerative space, developing peroxisome proliferator-activated receptors (PPARs) for AD.

Lundbeck/ Allergan's Acrescent

Development of H. Lundbeck's Acrescent, a combination of donepezil and memantine, was suspended in 2013. Francis said that from what he understood, the EMA was not convinced that the combination had any significant advantage over each drug separately.

In 2012 the CHMP expressed its concern that the studies the companies had presented had negative results apart from one study, which the committee also underlined their concerns about as there were flaws in the study's design because it was lacking a control arm for patients.

Though Acrescent didn't progress any further at Lundbeck, a spokesperson for the company told Scrip the research from Acrescent had allowed them to learn more about the challenges of AD for future developments. Lundbeck currently has another AD candidate, selective 5-HT6 receptor antagonist idalopirdine, in Phase III clinical trials; as well as Lu AF20513 in Phase I; and partnered programs for Orlogin (with Neurim Pharmaceuticals Ltd.) and Rexulti (Otsuka Holdings Co., Ltd) in Phase II and Phase III, respectively.

Separately, Lundbeck's former partner on Acrescent, Allergan Inc., has now received FDA approval for Namzaric, which is a fixed-dose combination of donepezil and memantine.

Pfizer/ Medivation's Dimebon (PF-1913539)

First approved in Russia as an anti-histamine and with pre-clinical data showing it may act on NMDA receptors, Dimebon was thrown into trial by Pfizer and Medivation as potential treatment for AD. However, the drug failed to secure statistically significant results for either of its two co-primary endpoints and had no effect in treating the behavioral problems or cognitive decline in AD.

Gary Landreth, Professor of Neurosciences at Case Western Reserve University, told Scrip that this occasion is an example "of the desperation of the field for an effective drug and willingness to invest significantly based on scant data."

Lilly's Semagacestat (LY450139)

Disappointing results from two Phase III studies was what brought development of Eli Lilly's semagacestat to a stand-still in 2010. The drug candidate, a gamma secretase inhibitor aiming to reduce beta amyloid proteins, failed because it worsened cognition and led to detrimental side effects, including the increased risk of skin cancer.

Landreth described this particular situation as an example of the "myopia of the neuroscience community in general and neurodegeneration investigators in particular". Though the preclinical data were compelling, the lack of focus on the disease endpoints meant there was not enough attention on other possible targets of the drug. "The rationale was quite clear if you think that gamma secretases only work on amyloid precursor protein (APP) in the brain. Some of this couldn't have been anticipated as this drug had never been extensively tested in humans. Nice idea – didn't work," Landreth said.

Targeting Amyloid Beta

Semagacestat is not the only amyloid beta-targeting drug to hit the wall in AD research, there have been a number of products with the same mechanism that have struggled to get positive results in large studies. Some products still in development for the treatment have seen more success using the amyloid beta pathway, but the jury is still out on the viability of this approach – with many suggesting much more research is needed into its true potential in AD therapy.

Two late-stage failures Scrip has picked for further exploration in this area are Johnson & Johnson/Pfizer's bapineuzumab (intravenous) and Baxalta Inc.'s Gammagard, both of which are biologic products.

J&J announced a Phase III trial failure for bapineuzumab in the third quarter of 2012. The product's inability to provide adequate evidence for efficacy and safety to support a regulatory filing was a huge disappointment and reignited debate surrounding the appropriateness of targeting beta amyloid in cases where plaques are already present in AD patients.

The decision to discontinue development of bapineuzumab IV in mild to moderate Alzheimer's disease was based on co-primary clinical endpoints not being met in two Phase III studies. According to top-line results of Study 301, announced on August 6, 2012, bapineuzumab IV failed to show any impact on cognitive or functional performance compared to placebo in patients with mild to moderate AD who do not carry the ApoE4 genotype. This followed the July 23, 2012 announcement that a Phase III trial (Study 302) of bapineuzumab IV in ApoE4 carriers – who tend to have a higher risk of developing AD earlier – also failed to meet its co-primary endpoints.

Forbes reported at the time of bapineuzumab's failure, "Evidence to support pivotal trials of any future anti-amyloid drug candidates should be consistent across subgroups and prospectively defined. R&D dollars are precious and should not be wasted on wishful thinking."

There are also arguments to be made for the claims, clinically mild-to-moderate Alzheimer's patients are "too far gone" for an anti-amyloid drug to have an impact. Daniel Chancellor, lead analyst at Datamonitor Healthcare comments, "AD pathology is known to start several years, if not decades before, the onset of the first dementia symptoms. There is mounting evidence that amyloid-targeting drugs have no clinical effect in moderate AD and that you need to investigate as early as you possibly can in order to tease out any efficacy signal."

Similar to bapineuzumab, in 2013 Baxalta Inc.'s Gammagard was suspended following failures in two large-scale Phase III AD trials. The drug, which includes natural antibodies that are directed against forms of beta amyloid, is already approved for the treatment of primary immunodeficiencies and multifocal motor neuropathy. Gammagard did not meet its co-primary endpoints of reducing cognitive decline and preserving functional abilities in patients with mild to moderate AD in the Gammaglobulin Alzheimer's Partnership (GAP) trial, conducted by Baxter (now Baxalta) in collaboration with the Alzheimer's Disease Cooperative Study (ADCS).

The trial was labelled at the time by Dr Norman Relkin, GAP principal investigator, as "unequivocally negative for the primary endpoint". Furthermore, none of the secondary measures of subgroup analysis were corrected for multiple comparisons show it was considered that post-hoc analysis from the trial should be viewed as negative too.

However, Relkin defended that something could be learnt from the failed Phase III program from study signals in predefined subgroups. But while there were some positive signals in E4 carriers and moderate subgroups, analysts at BioMedTracker said, "it is best to not to over-interpret these findings".

Other notable blowups for drugs targeting amyloid beta include Elan's AN1792, Axonyx's phenserine, and Myriad Genetics' Flurizan.

Arguably Lilly's solanezumab, which is currently being tested in a new Phase III trial, could also be listed in this category. The drug initially failed to meet primary endpoints in Phase III studies but the data enabled Lilly to design a better program and take a second shot at goal with this product.

Looking Back To See The Future

While the last 15 years of Alzheimer's R&D have failed to produce a new drug candidate, this investment has not been wholly lost. Arguably it is advances in diagnostics that will facilitate the first disease-modifying drug, as companies such as Biogen, Eli Lilly, and Roche Holding AG can now confirm AD pathology in participants in their clinical trials before dosing drugs specifically designed to target the amyloid pathway. Previously, it had been estimated that up to 20% of patients enrolled in trials actually did not have any AD pathology and that their dementia was due to other causes. This seriously jeopardized the likelihood of clinical trials meeting primary endpoints.

Furthermore, data accumulated by Lilly in its technically failed Phase III EXPEDITION program of solanezumab have forced companies to reconsider the appropriate patient group to target. There is now a large amount of evidence suggesting that the pathology of moderate AD is too far progressed for a disease-modifying drug to work, and that it is early AD, including patients before the onset of dementia, that is the right target. There are even preventative trials in progress, whereby amyloid-targeting drugs are being tested in healthy individuals with a genetic predisposition toward AD.

As these latest clinical trials read out in the second half of this decade, the AD research community will finally be able to either celebrate a desperately needed therapeutic breakthrough, or finally lay the amyloid hypothesis to rest. Irrespective of how this unfolds, there can also be hope that Lundbeck's development of idalopirdine will produce a new treatment that offers additional symptomatic benefit on top of the current standard of care.

Progress In Alzheimer's: Predicting The Future

Despite decades of disappointments in the field of Alzheimer's disease (AD) drug development the pipeline for new AD medicines is rich and prosperous.

The risks and obstacles for companies working in AD are vast, but so too, potentially, are the rewards. According to Datamonitor Healthcare, the global market for AD drugs was worth a combined $4.1bn in 2014, although there are a large number of patients at the earliest stages of disease, before the onset of dementia, currently undiagnosed and untreated. As drug development shifts toward these prodromal AD patients, likely with premium-priced biologic therapies, the market will expand considerably.

But who could reap the rewards of this open-market of opportunity? "The number of candidates in development for AD is at its highest ever level, despite the pipeline's collective inability to produce a new chemical entity since Namenda (memantine) in 2002," notes Datamonitor Healthcare's Chancellor.

According BioMedTracker, this breaks down into 51 candidates in Phase I or I/II clinical trials for the treatment of AD. Of these early stage clinical programs, 29 of the products are targeting AD as their lead indication. In Phase II, II/III or IIb there are 43 drugs being developed for the disease, of these 28 have AD listed as their primary indication. Later down the pipeline there are 15 drugs in Phase III clinical studies, eight of which have AD as the lead indication.

This pipeline overview shows that despite some investors' loss of appetite for AD in light of its difficulties and high risk factor, there is still an important amount of drug development action ongoing. This summary also doesn't include the 10-plus investigator initiated studies at various stages of clinical development recorded by BioMedTracker.

However, the jump down from 43 opportunities in Phase II to only 15 in Phase III highlights the problem of getting new treatments in AD over the final hurdles to market. Professor Gary Landreth told Scrip: "The main problem with developing drugs for AD is our profound ignorance of its biology. This can only be fixed with a concerted basic science effort. The narrow focus of pharma's drug development effort remains problematic and their risk aversion has prevented innovative approaches to therapy".

Still, Chancellor predicts that the next five years "may herald much needed breakthroughs" in AD. As such, Scrip has selected four promising Phase III AD drugs with different modes-of-action that could make it to the finish line that is market approval in the next few years.

Exhibit 2: The AD drug development pipeline

Drug Name	Lead Company	Target	Current Phase	Lead Indication	Likelihood of Approval	Molecule
Gantenerumab	Roche Holding AG	Amyloid Beta/Amyloid Plaques	II/III	Y	9% (43% Below Avg.)	Monoclonal Antibody
Albutein + Flebogamma DIF	Grifols, S.A.	Amyloid Beta/Amyloid Plaques	II/III	Y	52% (Same As Avg.)	Protein
AZD3293	AstraZeneca PLC	Beta-secretase (BACE)	II/III	Y	52% (Same As Avg.)	Small Molecule
BAN2401	Eisai Co., Ltd.	Amyloid Beta/Amyloid Plaques	IIb	Y	16% (1% Below Avg.)	Monoclonal Antibody
NIC5-15	Humanetics Corporation	Gamma-secretase	IIb	Y	17% (Same As Avg.)	Small Molecule
Sembragiline	Evotec AG	Monoamine oxidase B (MAO-B)	IIb	Y	7% (10% Below Avg.)	Small Molecule
Aducanumab	Biogen, Inc.	Amyloid Beta/Amyloid Plaques	III	Y	53% (1% Above Avg.)	Monoclonal Antibody
ALZT-OP 1	AZTherapies, Inc.	Amyloid Beta/Amyloid Plaques	III	Y	52% (Same As Avg.)	Small Molecule
Crenezumab	Roche Holding AG	Amyloid Beta/Amyloid Plaques	III	Y	45% (7% Below Avg.)	Monoclonal Antibody
Solanezumab	Eli Lilly & Company	Amyloid Beta/Amyloid Plaques	III	Y	16% (36% Below Avg.)	Monoclonal Antibody
MK-8931	Merck & Co., Inc.	Beta-secretase (BACE)	III	Y	53% (1% Above Avg.)	Small Molecule
Masitinib	AB Science S.A.	Fibroblast Growth Factor Receptor (FGFR)^ KIT/c-KIT^ Platelet-derived growth factor receptor (PDGFR)	III	N	52% (Same As Avg.)	Small Molecule
Encenicline	FORUM Pharmaceuticals, Inc.	Nicotinic Acetylcholine Receptor - a7 subtype <br>(a7 nAChR)	III	N	51% (1% Below Avg.)	Small Molecule
AVP-786	Otsuka Holdings Co., Ltd.	NMDA Glutamate Receptor	III	N	52% (Same As Avg.)	Small Molecule
Actos	Takeda Pharmaceutical Company Ltd	PPAR gamma	III	N	52% (Same As Avg.)	Small Molecule
Azeliragon	vTv Therapeutics Inc.	Receptor for Advanced Glycation End Products (RAGE)	III	Y	52% (Same As Avg.)	Small Molecule
Rexulti	Otsuka Holdings Co., Ltd.	Serotonin 5-HT2A receptor	III	N	52% (Same As Avg.)	Small Molecule
Idalopirdine	H. Lundbeck A/S	Serotonin 5-HT6 receptor	III	N	56% (4% Above Avg.)	Small Molecule
RVT-101	Axovant Sciences, Inc.	Serotonin 5-HT6 receptor	III	Y	55% (3% Above Avg.)	Small Molecule
LMTX	TauRx Therapeutics Ltd.	Tau proteins	III	N	49% (3% Below Avg.)	Small Molecule
AC-1204	Accera, Inc.	Tricarboxylic Acid (TCA) Cycle/Citric Acid Cycle (CAC)	III	Y	52% (Same As Avg.)	Small Molecule

Source: BioMedTracker

Lilly's Solanezumab

Eli Lilly & Co is expected to start giving analysts and investors some color on its AD program for solanezumab (LY2062430), an antibody against beta-amyloid, by the end of 2016 – and the results are highly anticipated by experts in the field. While Lilly's overall CNS portfolio is in decline, high hopes are held for its AD drug which is currently leading the race to be the first disease-modifying drug available to treat AD patients.

After two Phase III failures already though, solanezumab has not been immune to the perils of AD drug development. However, Lilly is conducting a third trial of solanezumab in mild AD, known as EXPEDITION3, having finally identified the most appropriate patients for its drug. Its developmental hurdles mean that any regulatory approval will be delayed until at least 2018 for the product.

Lilly's drug would represent the first disease-modifying AD therapy that could theoretically find widespread use and change the treatment landscape. A disease-modifying drug could be used to alter the rate of cognitive and functional decline. It would be used as an adjunct to the existing cholinesterase inhibitors, which are actually able to improve the symptoms of patients, albeit over a finite time period. Taken together, this approach could provide short-term symptomatic benefits and slow the progression of the underlying disease, with the ultimate goal of delaying the time until hospitalization and extending life expectancy.

Lundbeck's Idalopirdine Vs. Axovant's RVT-101

H. Lundbeck's AD candidate idalopirdine (Lu AE58054) is the leader of a new class of AD drugs, 5-HT6 receptor antagonists. A number of pharma companies have managed to get their 5-HT6 targeting products into large, late-stage clinical trials. Lundbeck's offering and Axovant Sciences's product in the same class, RVT-101, are both in Phase III trials. Meanwhile, Pfizer Inc. and Suven Life Sciences also have 5-HT6 receptors in Phase II for the treatment of AD. AbbVie is a bit further behind with a Phase I candidate.

Axovant and Lundbeck will be battling it out to gain the all-important first-to-market status for this class of AD drugs. They will both also be fighting, against Lilly's slightly delayed drug, to be the first AD therapy to reach the market in over a decade.

Axovant, a wholly owned subsidiary of Roivant Sciences, picked up RVT-101 from GlaxoSmithKline for just $5m, via a licensing agreement, in December 2014. At the time, some saw this as GSK losing faith in the product, which in July 2011 reported poor results in two failed six-month trials. Both of these trials missed their primary endpoints of significant improvement in cognition. GSK determined the product didn't warrant the R&D spend required to take it to market. However, others believed the drug just fell victim of cost-cutting. Axovant has since touted statistically significant analyses from the existing Phase II program, taking forward the drug into Phase III testing on the back of its $315m initial public offering.

According to the paper 5-HT6 receptors and Alzheimer's Disease by Maria Javier Ramirez, published on the US National Library of Medicine (Part of the National Institutes of Health) in April 2013, the 5-HT6 receptor, a member of the 5-HT receptor superfamily, is involved in affective disorders, anxiety and depression, epilepsy, and obesity. Initially, interest in the 5-HT6 receptors was triggered by evidence showing that certain anti-psychotics are able to bind to these receptors.

Ramirez says, "Overall, several 5-HT6-targeted compounds can reasonably be regarded as powerful drug candidates for the treatment of Alzheimer's disease."

However, Ramirez pointed to the failure of Pfizer and Medivation's Dimebon (dimebolin) as a warning that as with all areas of AD research and drug development, there are still issues. Dimebon showed a good affinity for 5-HT6 receptors in earlier clinical studies but in a multinational Phase III study known as CONCERT it produced no improvements in AD patients. Pfizer and Medication disbanded their partnership following the failure of the CONCERT trial.

She says, "The crucial point regarding compounds acting on 5-HT6receptors is the intracellular pathways activated after the interaction of the compound with the receptor. Therefore, perhaps it is a question not only of developing an agonist or antagonist with good affinity but also of developing compounds able to activate the necessary mechanisms for the pro-cognitive effects."

Merck's verubecestat

Merck & Co's verubecestat, formerly known as MK-8931, a beta amyloid precursor protein site-cleaving enzyme (BACE) inhibitor, is being developed for the treatment of mild cognitive impairment (MCI) due to AD and mild to moderate AD. Datamonitor Healthcare notes that BACE inhibition involves the modulation of amyloid precursor protein (APP) cleavage, reducing the formation of all beta amyloid species. "This distinguishes BACE inhibitors from the unsuccessful gamma secretase inhibitors, which do not lower total amyloid but rather shift its production in favor of shorter, less neurotoxic proteins," notes Chancellor.

While this mode of action is aimed at pre-emptive treatment, as Merck is positioning verubecestat as a treatment option to slow or stop the conversion into dementia, the company is also researching the drug in patients with mild to moderate AD. The company believes that drug treatment may be viable to improve or slow the decline of symptoms of patients already suffering from dementia. Should verubecestat achieve market approval in both settings Merck would be positioned strongly against competitors that might also get to market in the next five years.

Verubecestat now represents the most advanced BACE inhibitor in the AD pipeline.BioMedTracker has given the product a 53% likelihood of approval rating, a modest 1% above the average for a similar product at the same stage of development.

The Road Ahead

The need for new AD therapies has grown in parallel with the world's aging population, as such, a number of AD focused funding initiatives have sprouted globally. These enterprises, which include US president Barack Obama's BRAIN initiative and the UK's Alzheimer's Research Discovery Fund, may well speed up the process of finding the cure to the most common type of dementia which contributes to 60-70% of cases.

The development of disease-modifying drugs for AD is recognized as a worldwide necessity. This set of drugs will modify, either by stabilizing or slowing, the molecular pathological steps leading to neurodegeneration and finally dementia. While the road to discovering new therapies for AD is proving to be a rocky one there are currently 15 promising new drugs in late-stage development allowing the future to look a bit bright for the whole disease pipeline; particularly Scrip's handpicked four that all have the potential to shake up the AD environment.