Gunilla Osswald describes her final act at AstraZeneca in a quiet voice. After 28 years trying to develop treatments for brain disorders patients, she was given the “sad task” of closing a large Swedish Research and Development site in 2012. She made 1,300 employees redundant.
Ten years ago, the Anglo/Swedish pharmaceutical company cut its investments in neuroscience. Not only was it the case. GSK, Pfizer, and Bristol Myers Squibb are among the other large pharmaceutical companies who stopped searching for treatments to some of mankind’s most mysterious diseases. Alzheimer’s was viewed as a hopeless, expensive cause at the time. Investors preferred to see companies pursue larger profits in other areas, such as cancer.
Osswald, peering across a conference table at Stockholm, admits that neuroscience is a risky area for drugmakers. It’s a challenging area. “But the benefits can be huge if you have a successful product,” she says.
Osswald didn’t give up after AstraZeneca shut down its site. She instead became the leader for a BioArctic start-up with just 20 people dedicated to fighting Alzheimer’s and recruited others from AstraZeneca. They wanted to develop a drug which would be the first to slow down the progression of Alzheimer’s disease.
They have made progress on that front. The Food and Drug Administration (the US regulator) will decide this week whether or not to approve BioArctic’s first commercially-available drug candidate, lecanemab. This drug was created in collaboration with Japanese drugmaker Eisai and US Biogen. Lecanemab was granted emergency approval by the FDA in January based on data showing that it slowed cognitive decline among early-stage Alzheimer’s sufferers by 27%, a modest but statistically significant outcome. The FDA’s full approval will allow a greater number of patients to have access to the drug. It is the first opportunity for people with Alzheimer’s to be able take something that can slow down the progression of the disease.
“It’s a huge step forward,” Osswald says, explaining that drugs before could only relieve some symptoms and not address the cause of the condition.
Not everyone is in agreement. Researchers and clinicians worry that the reduced rate of cognitive decline during the late stage drug trial will not be “clinically significant” as many patients won’t feel any impact.
The trial revealed that the drug could cause swelling and blood clots in the brain. Intravenously administered drug will need to be closely monitored by the patient. At least three Alzheimer’s sufferers have died after taking lecanemab since the end of the 1,795-patient trial, including two who were taking blood thinners. Eisai stated that the drug was not directly linked with the deaths.
Around 55mn people suffer from dementia worldwide, and up to 70% of them have Alzheimer’s disease — a condition that robs the patient of their memories and ability to communicate. The Alzheimer’s Association in the UK estimates that the disease costs the UK government £25bn per year. It is a debilitating disease for both patients and their family members, and costly for health systems that are overstretched in countries with an ageing population.
Osswald is careful not to overpromise desperate patients. “It is not a miracle cure. “But it can hopefully help them get a longer period of time when they are relatively healthy,” says she.
Lecanemab, a new Alzheimer’s treatment with promise, is not the only one. BioArctic’s results from last autumn were quickly followed by promising results from a trial of a drug from Eli Lilly, donanemab.
The drugs could save money on healthcare by allowing people to stay healthier longer. They will, however, create massive upfront costs. Lecanemab’s official US price will be $26,500 per year. However, insurers can negotiate discounts to make it more affordable. Medicare, a government-backed senior’s insurance program in the US, has agreed to cover its cost if it is approved. The European regulator is expected make a decision on the matter in the first quarter next year.
Lecanemab gives hope to big pharmaceutical companies like Bristol Myers Squibb, GSK and others who are investing in neuroscience, partnering up with startups, or trying to revive failed drug candidates.
According to research by the University of Nevada, there are more clinical trials than ever for Alzheimer’s drug. Drugmakers have increased the number of clinical trials they sponsor in the last year by almost 8 percent. AstraZeneca has a small group of neuroscience researchers with several products under trial, including a product for Alzheimer’s disease in an early study.
Scientists speculate that after a decade of oncology treatment, where mortality rates have fallen for many cancer types, Alzheimer’s disease could be treated with drugs targeted at subgroups of patients.
Lecanemab, while not a perfect medicine, is the result of years of research. It is the culmination a long and frustrating trial-and-error process that has begun to yield results. John Hardy is a professor at University College London and says that academics and pharmaceutical companies now understand the role a drug can play in combating the disease. He says, “We are no longer operating in the darkness.”
BioArctic’s co-founder, a doctor-turned-scientist called Lars Lannfelt, travelled to the end of the earth to find the clue that led to his drug breakthrough.
Lannfelt became a household name in dementia research in the 1990s when he found a mutation of the gene producing a protein known as amyloid beta in Alzheimer’s sufferers. Alzheimer’s is thought to be caused by a buildup of amyloid, which forms sticky plaques within the brain. Not all researchers are in agreement with the “amyloid hypotheses”. Many therapies that were intended to reduce plaques in the brains of patients have failed in clinical trials, sowing doubts. Lannfelt made his discovery — christened “the Swedish mutation” — after long and slippery drives to faraway communities in his Volvo, which, he laments, lacked power steering.
In his quest for a treatment, he even went further. He flew to Umea, in Northern Sweden, and drove a rental car into a remote village of people who were suffering from Alzheimer’s due to their genetic mutation. The “exaggerated” forms of Alzheimer’s were more severe in these people, with symptoms appearing earlier than the average age and a quicker decline. Blood tests and brain scans made it easier to see what was going on in the brain.
“My thought was that if we didn’t know the cases of mutation, we would never be able to understand the commoner forms.” Lannfelt explains that you should start with the simplest thing.
Lannfelt found that the patients of the Arctic community did not have the sticky plaques. They had amyloid beta, but in a form that is soluble called protofibrils. Lannfelt began to suspect that the protofibrils were the first cause of the disease. The soluble protofibrils are not like plaques. They can move about the brain, clogging up neurons, and ultimately causing them to die.
He thought that protofibrils would be an even safer target. Amyloid beta is found in various forms throughout the body. Only the brain contains protofibrils. The drugs that target amyloid beta in general could latch on to unintended areas, causing serious side effects.
Lannfelt, his BioArctic co-workers and Lannfelt approached Eisai in 2003. Eisai was a larger company that had experience with clinical trials for Alzheimer’s. Eisai, unlike many other pharmaceutical companies of the time was equally determined to find a cure for Alzheimer’s. Haruo Nairto, the chief executive of Eisai, led its discovery lab at the time that Eisai developed their first therapy to treat symptoms of Alzheimer’s. He stayed in touch with patients and families. Alexander Scott, executive Vice-President of Integrity, said that Naito was aware of the “tremendous need” patients had.
The Japanese pharmaceutical company Eisai acquired the lecanemab licence in 2007 and signed a deal with Biogen for the joint development and commercialisation of the drug.
Lannfelt has studied Alzheimer’s disease since 1992. BioArctic’s new approach worked better than expected. He was confident that it would work. The study showed that patients who took the drug declined 27% slower than those taking a placebo on a cognitive-functional scale. The amyloid buildup in the brains of study participants was likely 20-25 years old. Scans revealed a significant reduction in 18 months.
Lannfelt: “I was shocked that the effect was so powerful.”
Investors too were surprised. BioArctic stock soared by more than 240 percent on the day that the first results were released. Analysts at Swedish bank Carnegie predicted that sales would peak at $13bn by 2035. BioArctic will receive a $1.1bn royalty in that year. It stands to gain billions in total. Much of that money will be invested into the search for better drugs.
It is clear that this drug has a different approach from the previous Alzheimer’s drug, which was hailed as a major breakthrough. After a controversial US approval in 2021, Medicare refused to cover Biogen’s and Eisai’s aduhelm. Aduhelm was not as effective, and after one trial failed, scientists questioned the validity of Aduhelm’s trials. The initial price was $56,000 per year. Later, it was reduced to $26,500.
There are now two drugs that have more promising prospects. Eli Lilly in Indianapolis was an exception to Big Pharma’s initial exodus away from neuroscience. It persisted even after other Alzheimer’s medications failed. Ron DeMattos is the senior vice-president, chief scientific officer and head of Lilly’s neurobiologics division. He says that Lilly’s decision to pursue a drug which reduces amyloid was a leap of faith.
Lilly, unlike BioArctic targeted the solid amyloid beta plaques. Donanemab, its molecule, slowed disease progression by 35 percent in 1 182 patients – a smaller group than the lecanemab trial. The trial showed that there were also side effects such as brain swelling and bleeding. The full results of the trial have yet to be published.
DeMattos: “I think the field can move beyond all this back-and-forth, amyloid hypotheses or not amyloid hypotheses.” The real question is, how can we continue to benefit patients? How can we improve on our success and continue to make the patient better? Hardy, the neurology professor at UCL, says the real problem with the previous drugs targeting beta amyloid was that they didn’t remove enough of it. “To me, the two [new] drugs look pretty similar, they both remove amyloid, and they both have similar clinical effects,” he says.
Rob Howard, professor of old-age psychiatry at the same institute, disagrees. He acknowledges that amyloid beta has a connection with Alzheimer’s but does not believe it is the cause of its progression. He believes that there is a poor correlation between the amount of amyloid cleared and the clinical benefit in lecanemab patients.
Philip Scheltens who heads the E€260mn LSP Dementia Fund says that since the success of the lecanemab/donanemab trials, Big Pharma has shown a lot more interest in neuroscience biotechs. He says that “we are in an interesting situation because Big Pharma has suddenly gained interest, but does not have a pipeline.”
Scheltens claims that dementia is less well understood despite the fact it affects a similar amount of people. This may be because there are fewer funds available for research. On the online database PubMed there are 4.8mn cancer papers, but only 264,000 dementia papers.
Osswald, who is aware that the global Big Pharma has now taken notice of BioArctic’s tiny company in Stockholm is very tight-lipped when it comes to what else BioArctic works on for Alzheimer’s. The company was inspired by the transformation of oncology. Anders Martin Lof, chief financial officer of the company, said that oncology has been the “big thing”, with more targeted drugs often combined to have a greater impact.
“We are at the beginning of neuro. He says, “I think that we are about to enter a golden age.”
Even if the amyloid buildup is the initial sign of Alzheimer’s disease, there are still other targets that need to be addressed, such as the tau tangles in the brains of patients. Eisai has already tested lecanemab in combination with a tau-targeting drug.
Drugs may be targeted at specific groups as tests become more accurate, and we learn more about what’s happening in individuals. For example, cancer patients are sequenced for mutations that are driving their tumours, and specific drugs prescribed. Some people believe Alzheimer’s will not be a single illness.
BioArctic also looks at ways to more effectively target beta-amyloid. The moonshot project involves a “brain-transporter” that is designed to deliver more drugs into the brain. Only about 1% of a drug is able to cross the blood-brain barriers, which means that patients have to take large doses, and risk side effects. It hopes to access 600km of blood vessel inside the organ by hijacking the system which delivers iron into it.
Zoe Karamanoli is an analyst with RBC Capital Markets who covers BioArctic. She says that brain transporter still has a lot of risk at this point, but it does have “huge potential”. She believes that BioArctic will benefit from its cash windfall resulting from lecanemab royalty payments, but this is not enough for a second successful outcome. It is definitely helpful to have something that works and has been approved in a field as difficult as this. She warns, “Don’t assume that everything will work.
Lecanemab has already been tested in phase 3 for people with lower levels of amyloid and without symptoms.
Some companies want to move earlier. AC Immune was granted FDA breakthrough status last week, allowing it to move quickly through the regulatory process. The company hopes that the “Alzheimer’s” vaccine will help stimulate the immune system and allow it to attack the protein buildup itself.
A Swedish scientist created in 2020 a blood test which can detect early stages of brain buildups, even before any treatment is sought. The test can detect disease up to 10 years in advance of patients showing any symptoms.
Others hope that if less amyloid is stuck to blood vessel walls, the side effects will be reduced.
Scott, who has Alzheimer’s and whose parents both died, compared the use of drugs to combat the disease with the “pretty extreme procedures” some people are willing to undergo to reduce their cancer risk. He says that people will undergo double mastectomy if there is a history of cancer in their family. Angelina Jolie was a good example.
BioArctic can make billions of dollars more if lecanemab preventive use is adopted. Osswald wants to turn BioArctic, a standalone pharmaceutical company that conducts large clinical trials and sells their own drugs worldwide, into a standalone company.
She does not want to see it become the next AstraZeneca, which she believes could be bogged down by bureaucracy. BioArctic is a small company with 85 employees spread across an office, labs and a few floors in Stockholm.
She is not afraid of the competition, as other Big Pharma companies join in on the race to find better treatments for Alzheimer’s. “We don’t fear competition.” “I think it’s helpful for patients,” says she. “The market is huge.”