Monoclonal antibodies for Alzheimer’s disease: questionable clinical benefit at a high price

With novel treatments for Alzheimer’s disease dominating the headlines, the most recent being donanemab with the FDA requesting an independent advisory committee to review its safety and efficacy[1], questions remain about their clinical benefit. As the number of patients with Alzheimer’s disease in the US is projected to grow in the coming years, so does the need for a paradigm-changing treatment. However, our model finds that the new monoclonal antibodies offer little clinical innovation over the old standard of care, donepezil. Leaving aside price, their disadvantages in safety/tolerability and dosing outweigh their modest efficacy gains.  

Despite remaining on the market, unlike its ill-fated predecessor Aduhelm, Leqembi shows negative clinical innovation over donepezil of -10.0% in our framework. This is little better than Aduhelm, which shows -11.0% clinical innovation vs. donepezil. As shown above, much of the negative clinical innovation is driven by convenience. Leqembi is given as a one-hour IV infusion every two weeks, compared with donepezil’s once-a-day pill. While Leqembi offers an efficacy benefit measured by standard measures of cognitive decline in AD, this pales in comparison to the inconvenience of the regimen, combined with high cost, high prevalence of potentially serious side effects and a black box warning for amyloid-related imaging abnormalities (ARIA). Questions also remain about how clinically meaningful the improved efficacy is: it is unclear how much patients and their families can appreciate a slowing in cognitive decline of about 6 months for the fraction of patients that experience it.[2]

Even though little separates Leqembi from Aduhelm in our framework, Leqembi has managed to achieve modest sales – around $10.1 million in 2023, still well below the original Eisai projections of $28 million for the year.[3] This is despite the fact that the Institute for Clinical and Economic Review (ICER) deemed its current annual WAC price of around $26,000 to offer low long-term value for money, suggesting a more appropriate price is around $10,000 annually.[4]

In spite of these equivocal results, in-class Eli Lilly drug donanemab was originally expected to be approved this year, with some analysts projecting blockbuster sales of more than $1 billion by 2025.[5] However, our model suggests donanemab will offer slightly lower clinical innovation than Leqembi or Aduhelm, owing to a poorer safety/adverse event profile and higher rates of ARIA.

Leqembi is currently trialing in subcutaneous form, as is donanemab.  More convenient dosing would improve the outlook for these agents, but they will still face the headwinds of modest efficacy and significant safety concerns, as well as burdensome monitoring/imaging requirements. With all these considerations, it is difficult to believe that Eisai will hit its revenue target of $8.8 billion by 2032.[6]

[1] Edited to note 3/8/24 New York Times article

[2] https://memory.ucsf.edu/lecanemab

[3] https://www.biopharmadive.com/news/eisai-leqembi-alzheimers-target-revenue-earnings/706668/, https://www.pharmalive.com/eisai-sees-dramatic-increase-in-leqembi-uptake-following-full-fda-approval/, https://www.reuters.com/business/healthcare-pharmaceuticals/eisai-expects-alzheimers-drug-rake-revenue-665-mln-by-march-2023-11-07/

[4] https://icer.org/wp-content/uploads/2023/04/ICER_Alzheimers-Disease_Final-Report_For-Publication_04172023.pdf

[5] https://www.investors.com/news/technology/eli-lilly-stock-why-version-alzheimers-treatment-could-become-a-blockbuster-in-2025/

[6] https://www.fiercepharma.com/pharma/eisai-dials-sales-ambitions-alzheimers-med-leqembi-amid-launch-growing-pains

Evrysdi: A Potential Game-Changer for SMA Type 1 Patients

Spinraza was the first effective treatment option for Spinal Muscular Atrophy (SMA) Type 1.  Zolgensma and Evrysdi are reshaping the market because of their superior efficacy.

SMA Type 1 is a rare, debilitating genetic disorder, affecting about 1 in 10,000 live births, with symptoms beginning before six months of age. Historically, infants born with this disorder could not sit without support.  Most were expected to live two years or less.

The FDA approval of Spinraza (nusinersen, Biogen) in 2016 finally offered hope to families. The ENDEAR trial of Spinraza had such positive results that it was terminated early to give all participants access to Spinraza in an open-label extension (SHINE). Since then, Zolgensma (onasemnogene abeparvovec, Novartis, approved 2019) and Evrysdi (risdiplam, Roche, approved 2020) have emerged as alternative treatment options.

Like Spinraza, Evrysdi is a chronic treatment. However, it offers several benefits over Spinraza. In infantile-onset, symptomatic SMA Type 1 patients less than two years old, Evrysdi has noticeably higher efficacy (event-free survival and motor milestone response). These gains reduce mortality and morbidity. Evrysdi is a daily oral therapy, more convenient than Spinraza’s intrathecal bolus route.

Evrysdi is dosed by kg/bodyweight, with an annual price cap not to exceed that of treating a 44 lb child, complicating any simple cost comparison. However, even at its maximum price, the annual cost of Evrysdi is less than that of maintenance Spinraza.

In the Equinox model, Evrysdi offers 15.1% clinical innovation versus Spinraza. Historically, drugs that have scored >10% clinical innovation have become market dominators, and so far, annual sales of Evrysdi have trended in this direction.

One way that Spinraza has an edge over Evrysdi is its quantity of supporting data, since Evrysdi has not been around as long to establish a track record.

Zolgensma is another promising treatment option for SMA type 1. Unlike Spinraza and Evrysdi, Zolgensma is a single-dose gene therapy. At approximately $2.25 million 2023 USD (WAC, Micromedex), its price tag has been criticized in the past. However, Novartis offers different payment plans, including outcome-based and over-time payment plans, both up to 5 years.

Spinraza and Evrysdi (at maximum dose) overtake that $2.25 million mark after about 5 and 6 years of treatment, respectively. However, this calculation ignores other direct costs (such as hospitalization) and the potential for additional therapies if the initial treatment is insufficient. This added cost is worth considering since recent data shows that 7.5 years after dosing, almost one-third of Zolgensma-treated patients had received follow-up treatment. Unlike Spinraza and Evrysdi, a patient cannot simply switch off of Zolgensma if it does not perform as expected. Discounts, negotiations, and payer willingness to sponsor an expensive one-time therapy like Zolgensma also complicate the picture.

In summary, in a head-to-head comparison against Spinraza, Evrysdi is the clear winner. This sets it up to become a future standard-of-care as data continue to accumulate. Zolgensma is also innovative over Spinraza. However, it will likely continue to face challenges as payers continue to negotiate the best way to finance an expensive one-time treatment where a cost-effective outcome cannot always be guaranteed.