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EMA and the US Food and Drug Administration (FDA) are aligned in more than 90% of marketing authorisation decisions for new medicines. This is one of the findings of a joint EMA/FDA analysis comparing decisions on 107 new medicine applications at the two agencies between 2014 and 2016. The study also looked at applications for which the agencies had differing outcomes in terms of type of approval and indication. The most common reason for diverging decisions at the two agencies were differences in conclusions about efficacy. Differences in clinical data submitted in support of an application were the second most common root of divergent FDA and EMA decisions.

“The high rate of convergence in the authorisation of new medicines at EMA and the FDA is the result of expanded investment in dialogue and cooperation since 2003 and has fostered alignment between the EU and the US with respect to decisions on marketing authorisations, while both agencies evaluate applications independently of each other,” said Zaide Frias, head of EMA’s human medicines evaluation division. “Our cooperation clearly supports both agencies in achieving a common goal of maximising patient access to safe, effective and high quality medicines in both regions,” she added.

This is the first analysis by EMA and the FDA that compares the agencies’ decisions related to marketing authorisations.

Some differences were observed in the clinical data due to the difference in timing of submissions (more applications were submitted to the FDA before they were submitted to EMA). Compared to the FDA, EMA often reviewed applications including additional clinical trials or, particularly for oncology medicines, more mature data from the same clinical trial. In those instances, EMA was more likely than the FDA to grant standard approval, a broader indication, or use of a medicine as first-line therapy.

Over the past decade, EMA and the FDA have established joint working groups and several forums for information sharing and collaboration around many aspects of medicine development and regulation, including ‘clusters’ on special topics and therapeutic areas, as well as parallel scientific advice and protocol assistance. These groups bring together experts for example on plans for manufacturing or clinical site inspections, development of medicines for children, oncology products, biostatistics, rare diseases and vaccines. While these groups are not forums for shared decision-making, the strong alignment in decisions on marketing authorisations suggests that they may be contributing to alignment on regulatory science.

Most of the information used for the study was sourced from EMA’s publicly available European Public Assessment Reports (EPARs) and FDA reviews, which contain the agencies’ rationale for their decisions on applications.

The article, entitled “A comparison of EMA and FDA decisions for new drug marketing applications 2014-2016: concordance, discordance and why“, is available through open access in Clinical Pharmacology and Therapeutics.

As sponsors and CROs make increasing use of expert committees — especially Endpoint Adjudication Committees (EAC) and Data Monitoring Committees (DMC), they are asking, “What makes an expert committee successful?”

Who better to answer that question than the experts who have been there?

Respondents to a survey of WCG ACI Clinical’s network of experts had quite a bit to share on the subject of choosing the right committee members. They want their colleagues to have subject-matter expertise, of course. But they also want experience with clinical trials in general and expert committees in particular.

The best committees include members with diverse backgrounds, e.g., statistical, medical, scientific, safety, ethical, etc., respondents said. Each member should possess the requisite expertise in their area of specialty. Each member also should possess an understanding of regulatory framework and ethics as related to committee activity.

Not surprisingly, “ability to work well with others” was a common response. Committee members should understand the roles of other members as well as their own. Other desirable characteristics include flexibility and open-mindedness, being able to analyze risk-versus-benefit variables and a commitment to keeping the patients’ safety top of mind.

The characteristics respondents seek in a fellow committee member were the same one they want in a committee chair, but with particular expertise in dealing with sponsors and regulators. At least one member, usually a chair, should have excellent facilitator knowledge and should know how to listen to all viewpoints and not push his or her own agenda.

Respondents also weighed in on how payment for their committee work is handled. It’s not merely a question of being paid. Eventually, even the slowest payer will compensate committee members. The larger issue, according to respondents, is the hassle factor. Payments are late, or the process for getting paid is onerous. Committee members and their admins don’t need to become “armchair accountants.” They want a streamlined, efficient process that does not require extraordinary effort.

A consistent and clearly identified central point of contact to facilitate activity confirmation and payment was high on the list of characteristics valued by the respondents.

Respondents also value consistency in the planning of committee meetings. Committee members want regular, predictable meetings placed on the calendar well in advance. But that’s just the start.

Providing the right data in the right format at the right time is critical. Data and meeting presentation materials should be sent reasonably early to allow members to prepare. For EACs, adjudication systems that have a clear case package prepared are much easier to work with.

If possible, schedule some in-person meetings. It’s particularly useful at the beginning to schedule a face-to-face meeting to outline the roles, duties and responsibilities of the members. A committee, wrote one respondent, “needs to operate as one critical body.” Building this relationship among committee members is key.

Regardless of whether meetings are in person or remote, they need to be paced appropriately; long intervals between meetings require too much review of previous issues and data. “It’s nearly like starting over each time,” one expert respondent said. Touch-point communication and setting up obvious points of contact for committee members in between scheduled meetings is also helpful and practical to ensure smooth function.

And don’t overlook the admins. Ensuring good relationships with the experts’ internal support staff will foster smooth interactions with the experts.

Finally, respondents named several factors that contribute to efficient committee management, including:

• Set expectations: Give committee members detailed guidance on roles, responsibilities and operating procedures, all of which should be in the committee charter. Follow up with clear, timely communication.
• Make expectations clear: To avoid misunderstanding and to ensure expectations are met, it’s critical that members understand them before the first meetings. As one respondent noted, “Some issues could have been avoided if there had been training on the roles and expectations of a DMC.”
• Respond promptly: Experts want clear communication about what’s to be done when. Timely support and responsiveness from the management team is incredibly helpful in avoiding delays and meeting important timelines.
• Limit changes: Keep protocol changes to a minimum, especially when they pertain to inclusion/exclusion criteria and definition of outcomes. (The exception: adaptive design trials.)
• Think small(er): Many experts reported that, in their estimation, smaller committees function better than large ones.
• Provide support: Strong administrative and/or secretarial support for the committee is key to effective committee functioning, according to many respondents.

Sponsors expect a lot from expert committees, and the committee members expect a lot from sponsors. Managed well, these committees enhance trial integrity, improve efficiency, mitigate risks and ensure patient safety.

Amy Ghelardi is vice president of client services, and Bill Stedman is manager of member services at WCG ACI Clinical.

By Amy Ghelardi and Bill Stedman

QPS, a contract research organization (CRO), continues to expand its global footprint with new clinics in the Netherlands and India and a new bioanalytical facility in China.

QPS Netherlands recently celebrated the grand opening of a second clinic, which is ideally positioned on the grounds of the Medical Center Leeuwarden (MCL). While initial studies will focus on neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease, the clinic will ultimately be open to studies in a wide variety of disease states. According to Izaak den Daas, PhD, Director of Patient Studies at QPS Netherlands, “From 2017 onwards, discussion between QPS and medical staff and management of MCL resulted in the mutual agreement of the establishment of a dedicated clinical pharmacology patient unit on the premises of MCL in close vicinity of the policlinic stations of the medical specialists.”

Consisting of adaptable function rooms and eight comfortable bedrooms for overnight stays, the facility was specifically designed to address the safety and security needs of elderly patients with Alzheimer’s and Parkinson’s disease. The first patient study will start on September 15, 2019.

In addition, QPS India opened a new early-phase clinical facility in Hyderabad, India, with a 138-bed capacity spread over four clinical units. The facility is ready for Phase I healthy volunteers as well as Phase II/III patient populations. It also includes a dedicated area for women and is easily accessible, ensuring the health and safety of all volunteers.

QPS India is located in a prime area, which makes it accessible to many pharmaceutical companies performing clinical research. One of the most experienced clinical and bioanalytical service providers in India, QPS India delivers comprehensive CRO services across a broad range of therapeutic areas.

QPS India has successfully cleared over 22 regulatory inspections from the U.S. Food and Drug Administration (FDA), Medicines and Healthcare Products Regulatory Agency (MHRA), European Medicines Agency (EMA), World Health Organization (WHO), and Drug Controller General of India (DCGI). In addition, QPS India is a proud partner to several prominent generic pharmaceutical companies and has contributed to first-to-file and 505(b)(2) projects.

“QPS India is well known for quality, compliance, and commitment with a good regulatory track,” says Daniel Rapaka, Deputy General Manager of Business Development at QPS India. “It’s a one-stop solution for all generic bioavailability and bioequivalence (BA/BE) studies and clinical trials.”

Finally, QPS China celebrated the grand opening of a new bioanalytical facility in Suzhou, China, in February 2018. This facility provides critical expertise and bed capacity, helping QPS meet the rapidly expanding need for liquid chromatography-mass spectrometry (LC-MS) and mass spectrometry (MS) laboratories for drug development in China. According to Yongdong Zhu, PhD, Vice President and Head of Bioanalytical Services at QPS Suzhou, “It is a well-equipped, fully GLP-compliant bioanalytical facility.”

With 13 scientists and supporting staff and four cutting-edge LC-MS/MS systems, QPS Suzhou offers a comprehensive array of services. These include method development and validation as well as analysis of drugs and drug metabolites.

Dive Brief:

• Danish drugmaker Lundbeck will acquire Alder BioPharmaceuticals for $1.95 billion, adding a late-stage migraine treatment to its pipeline via a buyout deal the companies announced Monday.
• Alder, a small biopharma headquartered in Bothell, Washington, is essentially a one-drug company centered on the experimental CGRP inhibitor eptinezumab. A decision on the drug’s approval is expected from the Food and Drug Administration by February 2020. 
• Lundbeck will pay $18 per Alder share along with a non-tradable contingent value right worth $2 if eptinezumab wins European approval. The upfront cash translates to a 79% premium over the closing price of Alder stock on Friday. The companies expect the deal to be completed during the fourth quarter of 2019.

• Dive Insight:

  Alder, as a neurology-focused company with a late-stage drug, frequently featured on lists of biotech takeover targets compiled by Wall Street analysts.

  Having advanced eptinezumab through to regulators, Alder was facing the prospect of launching a CGRP inhibitor in a market that already features similar, competing drugs sold by Amgen and Novartis, Eli Lilly and Teva. 

  “We can’t imagine any investor wanted to see Alder launch eptinezumab alone,” Piper Jaffray’s Danielle Brill wrote in a Monday note to investors.

  Instead, the challenge of playing market latecomer will shift to Lundbeck. Company executives said Monday they anticipate eptinezumab growing into a blockbuster product by tapping its pre-existing salesforce and resources.

  Lundbeck’s neuroscience commercial capabilities could address many of the questions facing eptinezumab, RBC Capital Markets analyst Brian Abrahams wrote Monday. That Alder ended up in Lundbeck’s hands is a “missed opportunity” for Biogen, the analyst said, noting that drugmaker could have benefited from acquiring a late-stage neuroscience drug.

  Lundbeck said it anticipates submitting eptinezumab to European regulators in 2020. The drugmaker also plans to continue developing ALD1910, a preclinical migraine treatment designed to inhibit PACAP, or the pituitary adenylate cyclase-activating peptide.

  Since taking over last July, Lundbeck CEO Deborah Dunsire has inked two M&A deals to expand the company’s neuroscience pipeline. In May, for example, the drugmaker finalized an acquisition of Abide Therapeutics for $250 million. A data readout from Abide’s leading drug candidate is expected next year from a Phase 2a trial in Tourette syndrome.

  While patient demand appears high, the market for CGRP drugs has featured rebating and formulary battles as well. Amgen, Lilly and Teva all launched their respective products with free drug programs in a three-way tug-of-war for market share. 

  Even with those issues, Abrahams calculated last month that the therapeutic class is on pace to bring in $1 billion in sales its first full year, indicative of Wall Street expectations that CGRP blockers could eventually sell $5 billion a year in the U.S. 

  While the three marketed CGRP drugs are all administered subcutaneously, eptinezumab is given as a quarterly intravenous infusion.

  Analysts expect the FDA to approve oral CGRPs next year from Biohaven Pharmaceutical and Allergan, potentially adding more competition to the therapeutic class.

  The deal also will wrap up a relatively short CEO stint for Alder’s Bob Azelby, who joined the company last June after serving as Juno Therapeutics’ chief commercial officer until that company’s acquisition by Celgene.

  Alder’s share price opened Monday at $18.58, up 85% from previous close.

All eyes on DCGI to see if it echoes the alert, since over 180 variants sell in India

First, the alarm was sounded for the presence of a “probable” cancer-causing substance in Valsartan, used to treat blood pressure and heart failure. And now, a similar concern has been expressed by the United States Food and Drug Administration (USFDA) on heart-burn drug Ranitidine.

Over the weekend, the USFDA said that “some Ranitidine medicines, including some products commonly known as the brand-name drug Zantac, contain a nitrosamine impurity called N-nitrosodimethylamine (NDMA) at low levels.” NDMA is classified as a probable human carcinogen (a substance that could cause cancer) based on results from laboratory tests, the regulatory authority said. And while the agency was working with international regulators and industry to determine the source of this impurity in Ranitidine, it did not stop people from taking the medicine and advised them to talk to their doctors if they wished to discontinue it.

In India, Ranitidine has multiple producers, as did Valsartan. And the spotlight is on the Drug Controller General of India (DCGI) to see how it advises doctors prescribing these medicines.

“The impurity is minimal, but the DCGI needs to get it checked and get pharmaceutical companies to submit data on these drugs,” said Ravi Wankhedkar, former President of the Indian Medical Association. There has been no advisory to doctors yet from the drug regulator’s office, he told BusinessLine, adding that the situation was similar with Valsartan. Doctors continue to to prescribe both drugs, he added.

The size of the Ranatidine market is pegged at ₹730 crore a year (including combinations of the drug), with over 180 generic versions in the market, according to data from AIOCD-AWACS. A host of companies including Cadila Pharma, GlaxoSmithKline, JB Chemicals and Zydus Cadila sell versions of the drug. Interestingly, Sanofi, which sells Zantac globally, does not sell it in India.

The USFDA’s red-flag on Valsartan, too, saw several drug regulators issue cautionary directives.

In India, the Valsartan market was pegged at ₹263 crore a year, with over 50 manufacturers, including Novartis, Cipla, Lupin and Torrent, making generic versions and combinations.

Carcinogen alert

NDMA is an environmental contaminant found in water and foods. In the case of Valsartan, the impurity trail seemed to trace back to the active pharmaceutical ingredient sourced largely from China and India. Companies including Hetero and Aurobindo recalled their products.

The FDA action on Ranitidine came about following an investigation of NDMA and other nitrosamine impurities in blood pressure and heart failure medicines called Angiotensin II Receptor Blockers (ARBs) since last year. In the case of ARBs, the FDA has recommended recalls as it discovered unacceptable levels of nitrosamines.

The FDA is evaluating whether the low levels of NDMA in Ranitidine pose a risk to patients. “Patients should be able to trust that their medicines are as safe as they can be and that the benefits of taking them outweigh any risk to their health. Although NDMA may cause harm in large amounts, the levels the FDA is finding in Ranitidine from preliminary tests barely exceed amounts you might expect to find in common foods,” it said.

About 600 industry-sponsored trials were initiated in South Korea in the last 12 months.

Asia-Pacific specialist CRO Novotech has welcomed the South Korean Comprehensive Five-year Plan for the Advancement of Clinical Trials aimed at further establishing the country as a leading research and clinical trial destination in the region and globally.

Novotech identified key points expected effective in 2019 from the Comprehensive Five-year Plan that will be of particular interest to US biotech.

• Promoting early phase trials: A specific review team is being launched this year – the Clinical Trial Review Division to expedite pre-IND review/ prior-review and streamline IND submission.
• Support IoT based clinical trials : New guideline release for electronic ICF
• Acceptance of GLP data from non-OECD country (e.g. China) : Revision of regulatory requirement for pre-clinical data to allow submission of non-OECD countries’ GLP data if the company has secured credibility through a fact-finding study

Besides the changes in 2019, differentiating approval systems for multi-national phase III trials to have already obtained the nod in major would be applied in 5 years.

According to the Korea Biomedical Review the new Comprehensive Five-year Plan will involve a significant increase in expert staff to support rapid approval processes.

The Five-year Plan will focus on:

• Establishing a clinical trial safety management system, and a patient communication system
• Increasing international competitiveness
• Expanding treatment opportunities including for rare and intractable diseases

Novotech CEO Dr John Moller said:

“South Korea is already a top 10 location globally for clinical trials and the capital Seoul is the top-ranked globally.” He said the new five-year plan will deliver valuable improvements that will attract even more international biotechs.

“We have a strong Novotech CRO team based in Seoul which has grown by over 25% over the past year to accommodate the increasing demand for trials in South Korea – particularly from US biotechs.”

About 600 industry-sponsored trials were initiated in South Korea in the last 12 months.

In an interview with Life Science Leader, KONECT mentioned:

• Sponsors like the speed and quality they get from performing trials in South Korea
• The population density ensures a strong availability of patients
• The Korean healthcare system provides universal coverage via clusters of technologically advanced hospitals concentrated in large cities such as Seoul, Busan, and Incheon
• The hospitals are monitored continuously by the government through accreditation and evaluation programs

“With 66 hospitals per million people, South Korea ranks second among OECD (Organization of Economic Cooperation and Development) members. Rapid recruitment and startup are enabled by optimized recruitment practices and the large volumes of daily patient traffic,” KONECT said.

Novotech, known as the Asia-Pacific CRO, has offices and teams through the region as well as partnerships and long-term relationships with major hospitals that directly benefit clients.

Novotech’s in-country relationships enable a more comprehensive understanding of local regulatory changes, access to leading PIs, strong site connections, and productive patient populations to deliver success for our clients within timelines and budgets.

Novotech was established in 1996, headquartered in Australia with offices in 11 countries across the region, and over 20 site partnerships with major health providers.

US antitrust authorities are coming under pressure from consumer groups and unions to block the proposed $63 billion merger of AbbVie and Allergan, according to a press report.

Reuters reported that around a dozen advocacy groups and unions, including the American Federation of Teachers and Public Citizen, have written to the Federal Trade Commission (FTC) urging it to consider blocking the deal.

Citing a letter also from Consumer Action and various unions, Reuters said the signatories are concerned that the merger would create the fourth largest pharma company in the world.

This would create a powerful force at a time of rising drug prices and widespread concern about the impact of medicine prices on US citizens, who may have to cover all or some of their prescription costs from their own pockets depending on their insurance arrangements.

A four-week supply of the inflammatory diseases drug Humira (adalimumab) costs more than $60,000 a year, with sales reaching $20 billion in 2018.

The organisations said the FTC should go further than identifying product overlaps, which is a common approach taken during antitrust reviews of drug companies.

In many cases the FTC will ask for one of the merging companies to sell off a product where there is an overlap to ensure there is healthy competition, while allowing deals to still go ahead.

The unions signing the letter are also unimpressed with Allergan’s track record on pricing, noting its controversial and bizarre deal in 2017 that transferred patents to its dry-eye drug deal Restasis to a native American tribe, blocking legal challenges from generic rivals.

“These practices should receive careful attention as part of the commission’s investigation into the effects of this proposed merger and if an adequate remedy can not be found, the commission should challenge this acquisition,” the group said in the letter cited by Reuters.

As figures show the UK continues to lag behind other developed countries in cancer survival, a new project aims to create a national database with ambitious goals to challenge the variation in care standards in the NHS and encourage clinical trial research.

The not-for-profit organisation Health Data Research UK has announced a series of seven new data hubs to encourage research into new medicines.

There are “hubs” covering eye health, inflammatory bowel disease, acute care, clinical trials, respiratory diseases and real world data – but in the light of the new figures published in the Lancet the cancer hub is likely to have a high profile.

Based around a central database run by IQVIA, the cancer hub aims to use oncology data gathered from across the UK to improve patient care, diagnose the disease earlier, and enable people to access innovative new medicines through trials.

The idea is that if hospitals can pool their data, which has been fully anonymised to protect patients’ identity, they can start to tackle a range of issues that have long been holding back cancer care in the NHS.

Drawing on experience and technology from working with 150 hospitals across the EU, IQVIA said the initial focus will be on colorectal cancer and paediatric malignancies.

But Tim Sheppard, senior vice president and general manager for Northern Europe at IQVIA, said the project will move swiftly to other types of cancer after this initial bedding in phase.

Sheppard told pharmaphorum in an interview: “We hope institutions provide data for all of their patients not limited to certain types of cancer.”

By pooling data and working together on the project, hospitals could better understand the information they already hold and begin to work on issues such as variation in care by sharing best practice.

Designing clinical trials and recruiting patients to them is another challenge for pharma companies, or academic institutions, when they are conducting oncology research.

Chris Ball, director of major partnerships at IQVIA, said: “We can identify patients who could benefit from clinical trials and we can take away work from clinicians and accelerate and research.”

IQVIA’s team hopes that this national cancer database will encourage more oncology R&D in the UK, in line with the government’s decision to champion life sciences in its industrial strategy in 2017.

Sheppard said: “The overarching aim involving all four countries is to have an all-inclusive cancer database for the UK. This data set will be a global advantage to the UK in attracting the trials.”

Sheppard said that he had been “pleasantly surprised” by the response so far and IQVIA already has a list of 20 institutions from across the UK interested in taking part.

Figures published by The Lancet this week show that the UK is still lagging behind other comparable countries in terms of five-year survival rates for three common cancers – colon, oesophagus and lung.

In stomach cancer, the progress in the UK has been slow, meaning it is now bottom of the list of countries including Australia, Canada, Ireland, and Denmark based on figures gathered between 1995 and 2014.

One-third of the clinical trials that led to new cancer drugs approved between 2008 and 2018 didn’t report on the race of trial participants — and even studies that did report on race often had far fewer black and Hispanic cancer patients than might be expected, given the makeup of the cancer patient population.

That’s according to a new study, published in JAMA Oncology, that looked at 230 clinical trials that supported oncology drugs approved by the Food and Drug Administration. Of those studies, just 145 reported on at least one race of trial participants. Just 18 broke the data down by the four major racial groups — white, Asian, black, and Hispanic — in the U.S. The study’s authors say their findings highlight the clear need for better reporting and representation in cancer trials sponsored by the drug industry.

“It’s important to recognize that this problem is there and this problem is persisting over the years,” said Dr. Kanwal Raghav, an oncologist at MD Anderson Cancer Center and an author of the study.

For trials that did report on race, there were notable disparities in the makeup of participants. White patients accounted for 76% of study participants, while Asian patients accounted for 18%. But black patients made up just 3% of participants in clinical trials for approved cancer drugs during that time, and Hispanic patients accounted for just 6%. The proportion of black and Hispanic patients in cancer trials did improve somewhat during the decade the study examined, though not considerably.

Black and Hispanic patients, in particular, were underrepresented in trials that led to cancer drug approvals. There were far fewer black and Hispanic patients in cancer clinical trials than would be expected, given the share of cancer patients who are black or Hispanic. Raghav and his colleagues say that’s problematic, particularly for trials that play a pivotal role in patient care.

“When you come across clinical trials that establish FDA approval or standard of care [for a new drug], they should definitely be representative of the population it’s used to treat,” Raghav said.

Another striking finding: Different racial groups were more likely to enroll in different types of trials. White patients were more likely to enter larger, randomized, later-stage trials with multiple arms. Minority groups, on the other hand, were more likely to enter smaller, non-randomized trials with just one arm. It’s not clear why, exactly, that’s the case. But taken together, Raghav said the findings raise questions about what the disparities might suggest about how researchers recruit for and run clinical trials.

“You do a trial of cancer patients across the country, you should see that kind of proportional representation. If it’s not being done, why is it not?” he asked.

About the Author

Megan Thielking

Reporter

Megan writes about health and medicine, with a focus on mental health.

In March 2019, Cambridge, Mass-based Biogen and its collaboration partner, Tokyo-based Eisai, discontinued their global Phase III clinical trials, ENGAGE and EMERGE, of aducanumab in Alzheimer’s patients. Biogen also ended iys EVOLVE Phase II trial and long-term extension PRIME Phase Ib trial of the drug. For many in the industry, it marked the end of what could be called the amyloid-beta era. For several decades, researchers had focused on the prevention and elimination of the accumulation of the protein beta-amyloid in the brains of Alzheimer’s patients. Although the amyloid theory isn’t exactly dead, now most researchers have turned to other approaches after repeated failures with beta-amyloid.

Today marks what is likely to be viewed as yet another nail in the coffin of the beta-amyloid theory. Biogen and Eisai announced they were discontinuing their Phase III trials, MISSION AD1 and AD2, evaluating an investigational oral BACE inhibitor elenbecestat in patients with early Alzheimer’s disease. The Data Safety Monitoring Board (DSMB) ran a safety review and recommended the trials end because of an unfavorable risk-benefit ratio.

BACE stands for beta-site amyloid precursor protein cleaving enzyme, which is responsible for initiating the creation of beta-amyloid. Elenbecestat, like other BACE inhibitors, is designed to stop the creation of beta-amyloid.

The companies’ Phase III elenbecestat program consisted of two global Phase III trials with exactly the same protocols. They were multicenter, placebo-controlled, double-blind, parallel-group Phase III studies to evaluate the efficacy and safety of the drug in a total of approximately 2,100 patients with mild cognitive impairment (MCI) or mild AD, which collectively are dubbed early Alzheimer’s disease. The patients also had confirmed amyloid pathology in the brain.

Patients received either 50 mg of elenbecestat or placebo daily for 24 months. The primary endpoint was the Clinical Dementia Rating Sum of Boxes (CDR-SB).

Another study, the long-term extension of the Phase II clinical trial of elenbecestat (Study 202) is also being discontinued.

The companies plan to continue trials of the anti-amyloid beta protofibril monoclonal antibiody BAN2401 and the Phase III CLARITY AD trial of BAN2401.

“We would like to thank the patients and the families, as well as medical professionals, that participated in the MISSION AD studies,” said Lynn Kramer, chief clinical officer, Neurology Business Group, Eisai. “Without their contributions we would not be able to advance Alzheimer’s disease research. We are very disappointed with the news, and intend to learn from these data and continue engaging with patients and investigators, to pursue the discovery of new medicines for Alzheimer’s disease.”

Although researchers haven’t completely abandoned beta-amyloid as being a component of Alzheimer’s disease, attention and resources are shifting to other aspects of the disease. In particular, new research is suggesting that neuroinflammation and dysfunction of the brain’s immune system are bigger drivers of the disease than amyloid itself.

In a January interview with BioSpace, Rudy Tanzi, Kennedy Professor of Neurology at Harvard University and at Massachusetts General Hospital, said, “I think amyloid and tangles trigger the disease, but they’re not sufficient to cause dementia. In a nutshell, what we’ve learned is that amyloid comes very early, 15 years before symptoms. And all the genetics tells us this disease begins with amyloid.”

Amyloid may kill some neurons, but not enough to create dementia. But the amyloid and tangle-driven neuronal cell death eventually hits a tipping point where the brain’s innate immune system reacts with significant levels of neuroinflammation, leading to more cell death that causes the dementia symptoms.