BiopharmIQ Biotech Business & Corp Dev INSIGHTS
Last week Esai and Biogen (Esai/BIIB) moved a step closer to getting full approval for their Alzheimer Disease (AD) therapeutic, Leqembi (lecanemab), with a vote of confidence from an FDA Advisory Committee (AdCom).^1
Some Anti-Beta Amyloids slow Alzheimer's:
Leqembi is the second beta amyloid antibody that received accelerated conditional approval by the FDA for the treatment of AD. The first beta amyloid antibody to receive accelerated approval by the FDA, Esai/BIIB's Aduhelm turned out to be a commercial and public relations disaster for BIIB and the FDA, and to a certain extent, beta amyloid antibodies for the treatment of AD. However, Leqembi's recent Phase 3 data report outs, as well as Phase 3 data released by Eli Lilly on its competing amyloid beta antibody therapeutic, donanemab, appear to establish that at least some beta amyloid antibodies can slow the progression of AD in patients with mild to moderate disease (See FIG. 2 below (from Esai FDA AdComm Briefing doc June 2023).
But there is increased risk of brain swelling/bleeds:
Amyloid beta therapeutics come with an increased risk of brain swelling (ARIA-E) and bleeding (ARIA-H), which can be serious, and occasionally is fatal. The current prescribing information for lecanemab includes a warning for the risk of ARIA and provides recommendations for monitoring and dose management guidelines.^2 It also describes the increased risk of ARIA in ApoE ε4 homozygotes compared to heterozygotes and noncarriers (See FIG. 10 below from the Esai AdComm presentation), and the need to exercise additional caution when considering the administration of antithrombotics or a thrombolytic agent with lecanemab.
Benefits Outweigh Risks:
However, at least the FDA and its recent Leqembi AdCom appear convinced that at least for Leqembi, the benefits outweigh the risks.
The likely full approval of Leqembi by the FDA later this month, and the possible approval of donanemab over the next year or so if things go as planned for LLY with their FDA review, should be game changers for the use of these drugs by AD patients.^3 This is because CMS has acknowledged that unlike conditionally approved beta amyloid drugs, they will cover the majority of the cost of beta amyloid drugs if they get full approval for U.S. Medicare patients. Thus, it is expected to 1,000s and likely 10,000s of U.S. AD patients will likely be taking lecanamab or donanemab in the coming years, generating billions of dollars of revenue for these drugs. This will be the start of a new and exciting era in the treatment of AD with the first widely used drugs that slow the progression of this debilitating disease.
New Era = New Opportunities:
This new era for AD treatment, opens up a set of opportunities for antibody development companies, biotherapeutics companies, clinical diagnostics companies, clinical research organizations, and patient recruitment companies.
Here are 10 of these opportunities and some target customers/partners for each:
CROs and Patient Recruitment Companies/Organizations:
1. Ex-U.S. CROs and patient recruitment companies:
With Medicare reimbursement for early AD patients likely for Leqembi within the coming weeks/months, and donenamab in the coming year or so, it will be more difficult for companies developing AD therapeutics to recruit patients, especially for companies developing better anti-beta amyloid drugs or other AD drugs that can also increase the risk of severe ARIA. Thus, ex-U.S. CROs and patient recruitment will become more important than ever.
2. Recruitment of earlier and later stage AD patients into anti-beta amyloid trials
With the success of Leqembi, donanemab, and to a certain extent Aduhelm, in AD patients with mild to moderate disease, sponsors will be looking even more closely at anti-amyloid beta therapeutics in other AD patient populations, such as earlier stage or later stage AD, to determine whether these therapeutics are effective in those settings too. Acumen is one company with anti-amyloid beta therapeutic that is focusing on earlier stage AD who likely will be initiating a Phase 2 or Phase 3 trial within the next year.
3. Recruitment for subcutaneous delivery trials:
Several companies are developing next generation anti-amyloid beta therapeutics that have similar binding properties to intravenous drugs that have positive Phase 3 data. Trials in later stage development are underway for Eli Lilly, and will be starting for Prothena, assuming their Phase 1 data later this year looks good.
4. Recruitment at clinical sites with excellent brain MRI capabilities:
Since brain swelling and bleeding is an important adverse events to be monitored in anti-beta amyloid trials, clinical sites that have sophisticated brain imaging (e.g. MRI) facilities are important. Furthermore, clinical sites with the knowledge and facilities to differentiate mild, moderate, and severe AD is important. Trials, such as Aduhelm Phase 3 trials, have shown that difficulties in differentiating different mild and moderate patients are believed responsible for different placebo rates in the 2 Phase 3 trials, potentially leading to a successful and a failing Phase 3 intent to treat result (See e.g., Knopman et al. (2020) “Failure to demonstrate efficacy of aducanumab…”.
Contract Manufacturing Organizations:
5. GMP Antibody Production:
With the approval and likely treatment of 10,000s of Alzheimer’s patients with anti-beta amyloid antibodies, there will be a growing need for large scale antibody production at GMP facilities.
Top target sponsor companies for CROs, CMOs, and Clinical sites:
Anti-beta amyloid sponsors: Esai, Biogen, Eli Lilly, Acumen, Prothena, and Roche/Genentech.
Other companies developing antibodies to treat AD: AC Immune SA, Tiziana Life Sciences, Vaccinex
Alzheimer’s vaccine companies: Prothena, Alzamed (cell-based vaccine)
Private, small molecule anti-amyloid companies: Priavoid and Alzheon
6. Apolipoprotein E (ApoE) genetic testing of AD patients:
Apolipoprotein E (ApoE) ε4 homozygote people are not only more likely to develop late onset Alzheimer's ^4, but such patients have an increased risk of developing ARIA if they are treated with Leqembi (and possibly other anti-beta amyloids) (See FIG. 10 above). Thus, Alzheimer's patients should be genetically tested to identify their ApoE allele(s) before they can decide with their physician whether to take an anti-beta amyloid therapeutic, and such patients should be monitored more often for signs of sever ARIA.^2A It has been reported that that APOE4 genetic testing has more than doubled from a year ago.^2B
7. Earlier detection and monitoring of brain bleeds and swelling:
ARIA can be fatal. Thus, earlier detection of ARIA and/or methods to identify those at increased risk for serious or even fatal ARIA will be even more valuable with anti-beta amyloid drugs in wide use.
8. Improved detection, diagnosis and staging of cerebral amyloid angiopathy (CAA):
Further to above, patients with CAA are more likely to develop ARIA. Most Alzheimer's patients are believed to have CAA. Although imaging analysis can be used to detect probable CAA, there is no current definitive test for CAA except post-mortem analysis.^5 Tests that can not only detect and diagnose CAA, but determine the extent of a patients CAA, could prove extremely valuable to identify patients who are much more or much less likely to develop ARIA when taking an anti-beta amyloid therapeutic.
Top potential Alzheimer’s Dx partners:
Molecular Dx companies such as Roche/Genentech, Abbott Dx, Foundation Medicine, Illumina.
Gadolinium suppliers such as Bayer; GE Healthcare; Guerbet LLC; Bracco Diagnostic Inc.; Mallinckrodt Inc.
Alzheimer’s Dx companies such as Eli Lilly
9. Improved anti-amyloid beta therapeutic antibodies
Many different anti-beta amyloid antibodies targeting different epitopes and forms of beta amyloid with different dissociation rates have been developed and used in the clinic (See ACU193 Position and Comparative Profiles Figures below). And see Lecanemab-specific binding figure. These differences in binding properties for different antibodies appear to be very important for whether these therapeutic antibodies passed or failed clinical trials. Thus, there is a need and opportunity for the development and testing of additional beta amyloid antibodies.
(Note: Figure above and below from Acumen corp slide deck May 8 2023.)
For example, Leqembi binds to soluble and protofibrils (See FIGs. below).
10. Therapeutics to treat brain bleeds:
With 1,000s or 10,000s of patients on anti-beta amyloid therapeutics, there likely will be an increased rate of symptomatic brain bleeds compared to those that spontaneously appear in AD patients who do not take anti-beta amyloid therapies. Thus, there is a need for more effective therapeutics to prevent and/or treat brain bleeds.
The above will be especially true for patients on anti-platelet agents and anti-coagulants, which likely includes many AD patients given the current prevalence of these types of drugs in the aging U.S. population.
11. Oral (small molecule or peptide) to block beta amyloid plaque formation:
A number of companies are developing small molecules that target beta amyloid oligomers. These include the private companies Priavoid, developing the peptide PRI-002 and Alzheon, developing the small molecule ALZ-801, both of these candidates can be delivered orally, and the recent anti-beta amyloid clinical success has invigorated interest in small molecules and peptides that block the formation of beta amyloid plaque formation. Thus, there are renewed opportunities to develop such small molecules and peptides. See “Why Lecanemab's success spells the revival of small-molecule Alzheimer's treatments”
Top target anti-beta amyloid sponsor companies as potential partners for biotherapeutics companies:
Esai, Biogen, Eli Lilly, Acumen, Prothena
12. Genetic Counselors:
There is a growing need for genetic counselors as more molecular markers for AD are discovered. This issue has been identified based on the finding that the U.S. has just 1 genetic counselor for every 82,000 and the UK has just 1 in 193,500 ('It totally backfired': The pitfalls of Alzheimer's genetic testing | Reuters)
^1 The AdCom voted a 6-0 that clinical efficacy was sufficiently demonstrated by Esai/BIIB's Phase 3 trial and in their discussion of genetic factors and safety, appeared to endorse the current label of Leqembi, or something similar. Leqembi was conditionally approved in January under an accelerated pathway using a surrogate marker (removal of beta amyloid plaques).
^2A From current Leqembi label:
“17 PATIENT COUNSELING INFORMATION
Advise the patient and/or caregiver to read the FDA-approved patient labeling (Medication Guide).
Amyloid Related Imaging Abnormalities
Inform patients that LEQEMBI may cause Amyloid Related Imaging Abnormalities or “ARIA”. ARIA most commonly presents as a temporary swelling in areas of the brain that usually resolves over time. Some people may also have small spots of bleeding in or on the surface of the brain. Inform patients that most people with swelling in areas of the brain do not experience symptoms, however, some people may experience symptoms such as headache, confusion, dizziness, vision changes, nausea, aphasia, weakness, or seizure. Instruct patients
to notify their healthcare provider if these symptoms occur. Inform patients that events of intracerebral hemorrhage greater than 1 cm in diameter have been reported infrequently in patients taking LEQEMBI, and that the use of antithrombotic or thrombolytic medications while taking LEQEMBI may increase the risk of bleeding in the brain. Notify patients that their healthcare provider will perform MRI scans to monitor for ARIA [see Warnings and Precautions (5.1)].
Inform patients that although ARIA can occur in any patient treated with LEQEMBI, there is an increased risk in patients who are ApoE ε4 homozygotes, and that there is a test available to determine ApoE ε4 genotype.
Advise patients that the Alzheimer’s Network for Treatment and Diagnostics (ALZ-NET) is a voluntary provider-enrolled patient registry that collects information on treatments for Alzheimer’s disease, including LEQEMBI. Encourage patients to participate in the ALZ-NET registry [see Warnings and Precautions (5.1)].”
‘It totally backfired’: The pitfalls of Alheimer’s genetic testing: Reuter’s - Apr 2023.
^5 The Boston criteria are commonly used when evaluating patients for Cerebral Amyloid Angiopathy. It is a combination of clinical, pathological, and radiographic criteria that are used to assess the probability of CAA. Definitive diagnoses can only be made through a postmortem examination of the brain. However, a “probable CAA” diagnosis can be made during life utilizing imaging or tissue sampling. https://www.ncbi.nlm.nih.gov/books/NBK556105/
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Original published: 6/27/23