On 7 June shares in Biogen, a US biotechnology company, soared by 64%. America’s Food and Drug Administration (FDA) had just approved Biogen’s Aducanumab, the first drug for Alzheimer’s disease to be admitted to the market for 18 years. The US Alzheimer’s Association noted that the “historic approval of Aducanumab ushers in an exciting new era in Alzheimer’s and dementia treatment and research”. Aducanumab, to be marketed as Aduhelm, was submitted for approval in the EU and Japan in 2020 and FDA approval makes the other regions more likely to follow suit.
Alzheimer’s: a global scourge
More and more people are being diagnosed with serious neurodegenerative diseases such as Alzheimer’s and Parkinson’s; people are living longer and we have become better at diagnosing them. In this article we concentrate on the main neurodegenerative diseases, Alzheimer’s, Parkinson’s and Huntingdon’s. The good news is that the FDA’s approval of Aducanumab will galvanise research in this subsector and bring forward successful treatments.
Alzheimer’s is the most serious neurodegenerative condition. There are 6.2 million people in the US with the disease and this number will rise to at least 14 million by 2050. The World Health Organisation (WHO) estimates that 50 million people worldwide are suffering from dementias (Alzheimer’s accounts for two-thirds of them), with ten million new cases being diagnosed each year. These are probably substantial underestimates because of poor diagnosis in many countries. The prognosis for Alzheimer’s sufferers is grim. The few drugs previously available merely alleviated certain symptoms.
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But the Alzheimer’s Association says that “Aducanumab addresses the disease in a way that has never been done before. This therapy slows progression of the disease rather than just addressing symptoms”. Biogen’s two 18-month long double-blind phase-III trials (the last stage of clinical trials before approval) involved 3,285 volunteers in 20 countries. (In a double-blind trial neither the patient nor the researchers know which patients are given drugs and which placebos.)
Results showed that there were both dose-dependent and time-dependent reductions in amyloid plaques and tau tangles in the brain when Aducanumab was dispensed. Amyloid plaques and tau tangles are both key signs of Alzheimer’s. The plaques are clumps of protein that gather between neurons and disrupt cell function.
The tangles are abnormal collections of protein inside neurons that spread through the brain once the level of amyloid plaques reaches a tipping point. The highest doses of the drug showed reductions in clinical decline by about a quarter, measured both by cognitive tests and clinical assessment of daily function and behavioural abilities.
Bear in mind that Aducanumab’s approval was accelerated, or fast-tracked; the regulator occasionally speeds through the approval process if a drug can address a serious unmet medical need. The FDA’s approval is primarily based on the drug’s ability to reduce amyloid plaques in the brain. Approval could be revoked, however, if new studies do not affirm the promise shown in the first trials. The FDA is requiring Biogen to conduct a new trial to verify the drug’s clinical benefit (reduced cognitive decline); if benefit is not verified, the FDA could start proceedings to withdraw approval.
A big boost for Biogen
Aducanumab is expected to be most effective if patients are started on it during the very early stages of Alzheimer’s disease. However, even if only early-stage patients are treated, the drug is still likely to provide a large new revenue stream for Biogen, which says it can supply over one million patients a year. The price is $56,000 per year, although there will be discounts for bulk purchases.
Around 500,000 new Alzheimer’s cases are diagnosed in the US each year, so giving Aducanumab to, say, 30% of newly diagnosed US patients (those with confirmed amyloid plaques) could raise up to $8.4bn in the first year, rising to $16.8bn in the second. Compare these figures with Biogen’s 2020 revenue of $13.4bn. Sales in Europe, Japan and other advanced economies could double these sums.
Improved early diagnosis of Alzheimer’s could increase the estimate of 500,000 new cases per year since many cases of mild cognitive impairment are really cases of early-stage Alzheimer’s. In the short term some doctors may want to await the results of Biogen’s further trial.
But doctors taking this view may find that their patients are very unhappy. Jeff Borghoff, now a spokesman for the Alzheimer’s Association, has been lobbying hard. He was enrolled on Biogen’s clinical trial and credits Aducanumab with giving him extra time. He was diagnosed with Alzheimer’s at age 51 and has been on Aducanumab for six years. He initially feared steep mental decline, but says that “to date that has not been the case”.
A strong Alzheimer’s drugs pipeline
But Aducanumab is only one of Biogen’s potential Alzheimer’s drugs. It also has BAN2401 in phase-III trials, BIIB092 in phase-II trials with BIIB076 and BIIB080 in phase-I trials. In April 2021 Biogen’s encouraging phase-II clinical trial results on Lecanemab (BAN2401) showed consistent reductions in both amyloid plaques and clinical decline at the highest doses. The FDA deems it a “breakthrough therapy” and phase-III trials are under way.
Among the other large companies, America’s Eli Lilly stands out with Solanezumab in phase-III trials, Donanemab (which shows evidence of reducing clinical decline) and Zagotenemab in phase II, and two others in phase I.
German biopharma group MorphoSys has Swiss giant Roche as a partner in developing Gantenerumab, now in phase-III trials for early Alzheimer’s with the expectation of an FDA filing for approval in 2022. AstraZeneca has a treatment in phase-I trials. There are also several small biotechs working on Alzheimer’s treatments. One small, unlisted biotech – Atalanta Therapeutics – is partnering with Biogen and Genentech (a division of Roche) on its proprietary gene-based therapies for Alzheimer’s, Parkinson’s and Huntingdon’s diseases.
The Alzheimer’s Association reports that of 121 experimental drugs in trials designed to change, slow, or delay the progress of Alzheimer’s, 29 are in phase III. A combination of two or more drugs may well prove to be the most effective treatment.
Finding an effective blood test
Alzheimer’s disease is often diagnosed rather late through observations of memory loss and cognitive impairment. However, drugs such as Aducanumab are most effective when given early, since the amyloid plaques and tau tangles that develop in the brain during the early stages can be more easily reversed if caught quickly. Positron emission tomography (PET) scans can reveal if amyloid plaques or tau tangles have formed and successive scans can show if they have grown.
However, PET scans are expensive and thus not very useful for widespread testing. An alternative is cerebrospinal fluid (CSF) testing. CSF is the watery fluid that surrounds the brain and spinal cord. A sample of CSF is taken from the spine and tested for the presence of amyloid and tau proteins. But the goal of the research and development (R&D) department in Roche’s diagnostics division (and other testing companies) is to develop a blood test to detect amyloid and tau proteins so that doctors can determine whether symptoms of mild cognitive impairment are due to early-stage Alzheimer’s.
Another possible approach pioneered by a team at London’s Queen Mary University is a cheap, sensitive smell test using an aromatic oil. This could provide early identification of Alzheimer’s and Parkinson’s disease. For example, more than 90% of Parkinson’s patients suffer from loss of smell, so a sensitive smell test could identify the disease up to ten years before symptoms appear. Of course, loss of smell is also a feature of Covid-19, so other causes of losing a sense of smell must be eliminated first.
A promising pipeline for Parkinson’s
Parkinson’s disease is less prevalent than Alzheimer’s, but there are still over one million cases in the US and over six million worldwide. Parkinson’s is progressive, with the main symptoms being tremors, rigidity and slowness of movement followed by mild memory and cognitive problems. My father died of Parkinson’s so I have seen at first-hand how serious it is in the later stages.
The main treatment is Levodopa, introduced in the 1970s. It controls symptoms to some extent, but neither halts nor cures the disease. Several other drugs have been approved for use in combination with Levodopa. US biopharma AbbVie is carrying out a phase-III trial of a Levodopa/Carbidopa combination. Biogen is developing new treatments for Parkinson’s too, with Cinpanemab in phase-II clinical trials and BIIB092 and BIIB122 in phase-I trials.
AbbVie has ABBV0805 in phase-I trials for Parkinson’s, while Roche has Prasinezumab in phase-II trials. Eli Lilly’s PR001 gene therapy and AstraZeneca’s MEDI1341 are both in phase I trials for Parkinson’s.
Huntingdon’s disease (HD) is much rarer than Parkinson’s, but there are still 30,000 cases in the US with another 200,000 people at risk of developing it. It is a genetic disease characterised by uncontrollable muscle movements, loss of cognitive ability, personality changes and depression. In 2008, Tetrabenazine, made by a firm called Lundbeck, was the first drug for HD to be approved by the FDA. It helped control the involuntary movements characteristic of HD.
Deutetrabenazine, made by Israel’s Teva Pharmaceuticals, a similar but longer-acting drug, was subsequently approved for HD. Roche has a phase-III clinical trial of Tominersen for HD.
However, the independent data-monitoring panel recommended ceasing the dosing of clinical trial patients with Tominersen on 30 March 2021, based on its assessment of the drug’s benefit-risk profile. This is a blow for HD patients who were hoping to see a new treatment approved.
The core-and-satellite investment strategy
Investors wishing to gain exposure to biopharma companies likely to be launching new drugs for neurodegenerative diseases should adopt a core-and-satellite strategy.
The core companies will be large, low-risk biopharmas with a diverse range of approved and pipeline treatments that include several promising pipeline drugs for Alzheimer’s and Parkinson’s diseases. The satellites will be smaller biotech companies that offer higher risks, but higher rewards.
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For decades, Dr Mike Tubbs worked on the 'inside' of corporate giants such as Xerox, Battelle and Lucas. Working in the research and development departments, he learnt what became the key to his investing. Knowledge which gave him a unique perspective on the stock markets.
Dr Tubbs went on to create the R&D Scorecard which was presented annually to the Department of Trade & Industry and the European Commission. It was a guide for European businesses on how to improve prospects using correctly applied research and development.
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