Aduhelm: FDA ( Paradigma) se reafirma y lo justifica...

 

FDA leaders offer perspective on accelerated approval of Biogen’s Aduhelm 

Leaders maintain that Aduhelm fits into the regulatory paradigm of the FDA’s accelerated approval pathway

In a viewpoint posted on JAMA Network, US Food and Drug Administration (FDA) leaders have offered their perspective on the controversial approval of Biogen’s Aduhelm for the treatment of Alzheimer’s disease.

Billy Dunn, director of the FDA’s office of neuroscience, Peter Stein, deputy director of new drugs at the FDA’s Centre for Drug Evaluation (CDER) and Patrizia Cavazzoni, director of the CDER, wrote the article to explain the rationale for the FDA’s decision to grant Aduhelm (aducanumab) an accelerated approval.

In the post, they explained that although evidence from the Aduhelm programme was suggestive of clinical benefit, they came to the conclusion – alongside the FDA’s Peripheral and Central Nervous System Advisory Committee – that the trial data was not adequate to ‘convincingly demonstrate’ a clinical benefit in reducing clinical decline for Alzheimer’s patients.

Despite coming to this conclusion, they said that Aduhelm fits into the regulatory paradigm of the FDA’s accelerated approval pathway.

In explaining the choice to approve Aduhelm via this pathway, the FDA leaders highlighted the seriousness of Alzheimer’s and the expectation that Aduhelm’s mechanism of action may provide meaningful benefit over available therapy.

They also noted that Aduhelm reduced amyloid-beta plaques in both phase 3 trials – this is a key pathological marker and defining characteristic of the disease.

“In listening sessions, we heard from patients and their families about the devastating toll the disease has taken and their desire for a treatment to stop or delay functional losses,” the authors wrote.

“Many made it clear that they are willing to accept the trade-off of some uncertainty about clinical benefit in exchange for earlier access to a potentially effective drug, which is the exact premise and intent of accelerated approval,” they added.

Earlier this week, the FDA’s acting commissioner Janet Woodcock called for an independent review into the agency’s approval of Aduhelm.

Woodcock has asked for the process for review of Biogen’s biologics licence application (BLA) for Aduhelm to be investigated. This will include an ‘ongoing focus on interactions’ between Biogen and FDA staff during the review process.

The independent review will aim to determine if any of those interactions were inconsistent with FDA policies and procedures.

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Aduhelm: FDA 'probably the worst drug approval decision in recent US history'

 

(CNN) Dr. Aaron Kesselheim had been on an advisory committee for the US Food and Drug Administration for a half-dozen years, but he had never been to a meeting like this one.

The FDA establishes advisory committees to assist the federal agency with one of its most important duties: deciding whether to approve the distribution of new drugs. The stakes of these decisions are enormous. Based on the outcome of the FDA's deliberations, patients may gain access to lifesaving medicines, and manufacturers may reap billions in profits. Kesselheim, a professor at Harvard Medical School, was one of the members of this committee because of his expertise on pharmaceuticals that address diseases of the brain, including Alzheimer's, the irreversible, progressive brain disorder that destroys memory and thinking skills, and eventually causes death. Alzheimer's is the sixth leading cause of death in the United States.

The public meeting, conducted as an all-day video call on November 6, 2020, concerned the application for aducanumab, a drug that would be marketed under the name Aduhelm by the company Biogen, which is based in Cambridge, Massachusetts. Aduhelm, if effective, would address one of the most pressing needs in modern medicine: to slow the symptoms of Alzheimer's disease. 

Research into Alzheimer's treatments has long been an exercise in frustration, with no new drugs approved since 2003. The field of Alzheimer's research had proved so difficult that it was dubbed by some with the macabre nickname of the "Valley of Death."

In light of this record, and the need to improve it, Kesselheim was looking forward to examining the prospects for Biogen's new drug. "The great thing about advisory committees is that they are independent, and they don't have a stake in the outcome," he said. "We were just an independent group providing their opinion."

As in all advisory committee meetings, this one included several representatives of the FDA and of the applying pharmaceutical company. Dr. Billy Dunn, the director of neuroscience at the FDA, spoke at length on the call, and Samantha Budd Haeberlein, a senior vice president of Biogen, led the representatives for the company. What was unusual about this meeting, though, according to Kesselheim, was the apparent relationship between the FDA and company representatives.

"There was a strange dynamic, compared to the other advisory committee meetings I've attended," Kesselheim said. "Usually there's some distance between the FDA and the company, but on this one the company and the FDA were fully in line with each other in support of the drug."

Dunn in particular was outspoken in his support for the effectiveness of the drug, calling some of the evidence in its favor a "home run," while opponents of approval described the same evidence as inconclusive or worse. Dunn noted further that the FDA "has determined that it is appropriate to exercise the broadest flexibility in applying the statutory standards for these conditions."

From a regulatory perspective, drugs can work in two ways: They can work to treat disease or they can address a surrogate measure for the disease. Take heart attacks, for example. A drug can directly reduce the chances of heart attack or it can address a surrogate for heart attack -- like cholesterol.

At the November meeting, according to Kesselheim, the issue was treatment of Alzheimer's itself, not any surrogate. "The discussion at the committee related to the clinical benefits of the drug" -- that is, whether it slowed the cognitive decline of Alzheimer's patients, he said.

Most of the meeting was devoted to analysis of Biogen's own studies of the effectiveness of Aduhelm. The results were not promising in terms of clinical outcomes. Indeed, two of Biogen's major studies of people taking Aduhelm had been shut down before they were completed because they showed no significant benefit to patients. (Aduhelm, which is injected intravenously, also caused significant side effects, including brain swelling in about a third of patients. Brain swelling, at a minimum, can produce painful headaches as well as more serious problems, including, in rare cases, death.)

In light of this, the advisory committee voted, with one member voting uncertain but no one dissenting, to recommend that the FDA reject the drug.

Seven months later, in June, the FDA gave Biogen final approval to treat patients with Aduhelm in all stages of Alzheimer's disease. Reflecting the confidence in its judgment, the agency even acted on an accelerated basis. 

 

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The financial implications are huge as well. Aduhelm will be extremely expensive, as an intravenous treatment that will cost about $56,000 per year, plus several thousand more in related expenses. Given the number of Alzheimer's patients in the United States, the cost for widespread use of this treatment could quickly run into the many billions of dollars -- much of which would go to Biogen and its partner in the project, Eisai, a Japanese pharmaceutical company. If Aduhelm is approved as a treatment by Medicare, which is currently weighing the issue, the taxpayers will pay much of the tab.

At its core, though, the controversy about Aduhelm raises a fundamental question: Did the FDA approve a drug that doesn't help people -- and if so, why?

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BIOGEN: Aduhelm "borra" también las expectativas y previsiones de ventas

 

Biogen readies fight to reverse preliminary CMS coverage decision for Aduhelm

Biogen executives on Thursday pledged to try to reverse a draft decision by the US Centers for Medicare and Medicaid Services (CMS) that would sharply limit Medicare coverage of its Alzheimer's disease drug Aduhelm (aducanumab). 

The "coverage with evidence development" proposal would only cover Alzheimer's amyloid antibody treatments for patients who are enrolled in approved clinical trials, a decision that threatens to further erode Aduhelm's already struggling sales.

Biogen had expected roughly 50,000 patients would begin treatment with Aduhelm in 2022. However, CEO Michel Vounatsos estimates that only a small number, possibly in the hundreds, who have the resources and time to travel to major hospitals conducting the trials, would now get access to the drug under the CMS rule

Stakeholders urged to voice disapproval

The draft proposal is currently in a 30-day public comment period, with Alisha Alaimo, president of Biogen's US business, saying it is "really, really important" for stakeholders to express their view about the policy. Vounatsos also urged patients to "make their voice heard" during the period to allow for a "broader and more equitable access" to the therapy. After that period closes, Biogen executives said there is likely to be a 30-day period when CMS officials will meet with interested companies and advocacy groups.

Vounatsos indicated that he has had no dialogue with CMS during an initial Medicare coverage review process last year, other than a call with the administrator at the review's outset. In the near future, the CEO hopes that he and his team can meet with CMS officials to share the company's perspective. He also anticipates the final decision, due by April 12, will look different than the "dramatic" CMS proposal that was issued this week.

Most cost-cutting on the way? Meanwhile, the drugmaker recently announced plans for $500 million in cost-reduction measures in 2022, and company officials suggested Thursday that more could be on the horizon if Medicare's final decision does not go its way. "We are engaging very closely with our board on tactical shorter measures, but also strategic options," remarked Vounatsos, although he did not provide specifics.

Biogen previously said that the healthcare system has been "a major bottleneck" to uptake of Aduhelm, which was awarded an accelerated approval by the FDA in June despite doubts over its safety and efficacy .

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The drug's original annual cost of $56,000 per patient also raised concerns over the toll it might take on the Medicare programme. Last month, the company slashed Aduhelm's list price by about half to $28,200 per year . Biogen has indicated that it was banking on the pending Medicare decision to provide "clarity on reimbursement" to help drive sales.

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Aduhelm: Crónica de un fracaso anunciado...

 

La primera fase de la revolución contra el alzhéimer ha acabado en una vía muerta. Solo 11 meses después de que la Administración de Alimentos y Medicamentos de Estados Unidos (FDA, por sus siglas en inglés) aprobara el Aduhelm (aducanumab), el primer tratamiento que ataca las supuestas causas de la enfermedad, la farmacéutica Biogen ha anunciado que abandona los esfuerzos previstos para convertir este anticuerpo monoclonal en un superventas y que prepara el relevo de su máximo ejecutivo, Michel Vounatsos. 

En el tiempo que ha estado en el mercado, el Aduhelm ha sido un fracaso clínico y comercial. La compañía apenas ha ingresado cinco millones de euros con un tratamiento que lanzó a un precio de 56.000 dólares por paciente y año (casi 53.000 euros) y que no ha logrado convencer a la clase médica ante la falta de evidencias sobre su efectividad y el riesgo de efectos secundarios.

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En un comunicado dirigido a sus inversores con los resultados del primer trimestre del año, Biogen informó el pasado martes de que se dispone a “desmantelar la estructura comercial creada para apoyar al Aduhelm”, una medida que supondrá un ahorro de 475 millones de euros. 

La salida de Vounatsos, que ha permanecido cinco años en el cargo, se produce cinco meses después de que el responsable de investigación y desarrollo, Alfred Sandrock, fuera despedido. La compañía solo mantendrá la producción del fármaco para seguir con las investigaciones abiertas y atender a los pocos pacientes en tratamiento.

La caída en desgracia del Aduhelm ha sido vertiginosa. Su aprobación generó el pasado junio una oleada de ilusión en el mundo al ser el primer tratamiento autorizado en dos décadas contra el alzhéimer, una enfermedad que afecta a 50 millones de personas (800.000 en España). La decisión abría también la puerta a una nueva familia de medicamentos que elimina las placas de amiloide de las neuronas de los enfermos, una de las principales hipótesis del origen de la dolencia.

Pero la polémica fue también inmediata. La FDA aprobó el fármaco en contra del criterio de su grupo de expertos, tres de los cuales dimitieron. Las aseguradoras estadounidenses se negaron a financiar el tratamiento y cuando este llegó a la Agencia Europea del Medicamento, se topó con un contundente rechazo.

El portavoz de la Sociedad Española de Neurología, David Pérez, recuerda que la aprobación se basó en dos ensayos “que la propia Biogen había interrumpido por falta de evidencia”, Pero luego “reinterpretó” datos y “concluyó que apuntaban hacia una mejora”. El experto añade que “el proceso se hizo por la vía acelerada”, basándose en el descenso de las placas de amiloide, “que aún no sabemos si aporta un beneficio para el paciente”. “Esto es una llamada de atención a la industria y la FDA de que no vale todo para aprobar un fármaco”, concluye.

El Aduhelm ha sido una de las grandes apuestas de los últimos años de Biogen y los acontecimientos de los últimos meses han dejado su huella en bolsa. La aprobación de la FDA disparó un 40% el precio de sus acciones por las posibles ventas de un tratamiento que solo en Estados Unidos tiene un mercado potencial de seis millones de pacientes. La cotización, sin embargo, ha perdido desde entonces lo ganado y un 20% adicional.

Repercusiones

Lo ocurrido ha tenido también un notable impacto en el terreno de la investigación. Tras 20 años de fracasos, el sector conseguía al fin poner en el mercado un nuevo tratamiento contra el alzhéimer y parecía confirmar una de las premisas con mayor peso en las enfermedades neurodegenerativas de las últimas décadas: la hipótesis amiloide. Esto es, en palabras del científico Miguel Medina, “la suposición de que reducir la carga de esta proteína en el cerebro producirá un beneficio clínico para los pacientes”. El director científico adjunto del Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas explica que esta ha sido “una de las principales líneas de investigación durante años”, aunque aún no está demostrada.

La aprobación por la vía rápida del Aduhelm solo con la evidencia de que es capaz de retirar el amiloide del cerebro, sin confirmar si esto mejora la evolución para los enfermos, abría la puerta a que otros fármacos similares en desarrollo también pudieran adelantar su salida al mercado. La pregunta ahora es si el fracaso del primero puede comprometer el futuro de los demás, que son el gantenerumab, de Roche; el donanemab, de Lilly; y lecanemab, de la japonesa Eisai y también Biogen. 

Medina opina: “No creo que perjudique. Con cautela, porque son datos de las compañías pendientes de publicar, parece que están obteniendo mejores resultados clínicos. Si esto es así, lo ocurrido no tiene por qué afectar a los otros fármacos. Lo que sí se ha visto cuestionado es el recurso a la vía rápida de aprobación”.

A la espera de estos resultados, David Pérez abre otras opciones: “Existe el riesgo de que estemos insistiendo en la diana equivocada. Hay una corriente hacia otras líneas de investigación que ponen el foco en lo infeccioso e inflamatorio o en los problemas de irrigación del cerebro, aunque están en fases más prematuras. La hipótesis amiloide era puntera hace 20 años, pero no se consigue demostrar”.

En su escrito a los inversores, Biogen afirma que tiene previsto volver a solicitar por la vía rápida a la FDA este mismo trimestre la aprobación de su segundo fármaco contra el alzhéimer, el lecanemab, mientras espera tener en otoño los resultados del ensayo Clarity AD para intentar obtener “la aprobación completa de la FDA en el primer trimestre de 2023”.

Lilly también tiene previsto solicitar la aprobación del donanemab por la vía rápida ante la FDA, lo que aspira a lograr a principios del próximo año, mientras Roche ha optado por completar los ensayos en marcha y acumular evidencias de la mejora clínica de los pacientes antes de hacerlo, para lo que aún no tiene fecha decidida.

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FDA aprueba Aduhelm / Biogen, nuevo tratamiento para Alzheimer

 

The Food and Drug Administration on Monday approved the first new treatment for Alzheimer’s disease in nearly two decades, a landmark decision that has been eagerly awaited by millions of Americans diagnosed with the condition but that will be hotly contested by some in the scientific community who doubt the drug’s effectiveness.

While other drugs treat symptoms of Alzheimer’s, the new medicine, called Aduhelm, is the first to attack what some believe is an underlying cause of the disease and slow cognitive decline, albeit marginally. It does so by eliminating clumps of a toxic protein believed to destroy neurons and cause dementia.  

Aduhelm is not a cure for Alzheimer’s, and it doesn’t reverse the disease’s progression.

The drug — which just two years ago was declared a stunning failure — is now expected to generate billions of dollars in revenue for its maker, Biogen.

“This historic moment is the culmination of more than a decade of groundbreaking research in the complex field of Alzheimer’s disease,” Biogen CEO Michel Vounatsos said in a statement. “We believe this first-in-class medicine will transform the treatment of people living with Alzheimer’s disease and spark continuous innovation in the years to come.”

But the approval of Aduhelm, also known by its scientific name aducanumab, is all but sure to become one of the most controversial and disputed decisions on a drug application in recent years. The FDA granted marketing clearance to the drug over the strong objections of a panel of independent experts it convened in November. Those advisers reviewed Biogen’s clinical data and concluded overwhelmingly that there was insufficient evidence that the treatment had significant benefits for patients. They argued the drug should not be approved, as have many outside experts. Others saw enough evidence of efficacy — and a desperate need for new treatments.

Instead of judging Biogen’s treatment solely on its effects on cognition, the FDA granted a conditional approval based on Aduhelm’s ability to clear the toxic proteins, called beta-amyloid. In order to continue marketing the drug, Biogen will need to complete a large clinical trial to confirm that removing the plaque has cognitive benefits, the FDA said. If that study fails, the FDA has the authority to rescind its approval.

In approving the drug on a conditional basis, the agency departed from decades of regulatory precedent, setting a new bar for treatments with considerable potential but unproven benefits — a standard that could also be applied to other devastating diseases.

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Biogen said the yearly cost for a maintenance dose of Aduhelm, based on an average patient’s weight, would be $56,000. That’s a list price, not the net price or the price paid by patients with insurance. The out-of-pocket cost for patients with insurance will vary depending on their coverage. Analysts had expect it to cost between $10,000 and $25,000 per year, which would have already placed it among the most expensive medicines marketed to primary care physicians. The company expects to start shipping the drug in about two weeks. 

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FDA desconfia de Aduhelm

 

La FDA abre una investigación sobre el fármaco del alzhéimer 

ABC 

Ante las numerosas críticas y denuncias que despertó el fármaco para combatir el alzhéimer, la Administración de Alimentos y Medicamentos de Estados Unidos (FDA) ha abierto una investigación médica sobre el medicamento. Aduhelm, de Biogen, recibió una «aprobación acelerada» en junio, a pesar de que un panel de expertos independientes que asesoró a la agencia no encontró pruebas suficientes de sus beneficios, señaló la FDA.

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«Desde que la agencia aprobó Aduhelm, los prescriptores y otras partes interesadas han expresado confusión con respecto a la población a la que está destinado al tratamiento», señaló el portavoz de la FDA, Michael Felberbaum, en un comunicado a medios de comunicación, como la agencia Afp. «Era importante aclarar específicamente que es apropiado iniciar el tratamiento en pacientes con deterioro cognitivo leve o etapas de demencia leve de la enfermedad de alzhéimer», agregó. 

Aduhelm, un anticuerpo monoclonal aplicado por vía intravenosa, también conocido por su nombre genérico aducanumab, se probó en dos ensayos en humanos de etapa tardía, conocidos como ensayos de fase 3. 

Mostró de manera convincente una reducción en la acumulación de una proteína llamada beta-amiloide, que crea una placa en el tejido cerebral en los pacientes con la dolencia. Pero no se sabe con certeza si esto se correlacionó con una reducción en el deterioro cognitivo: un estudio sugirió que sí, mientras que otro concluyó lo contrario.

Aduhelm "side effects"...layoffs

 

The axe has started to fall at Biogen. Among the first to feel its wrath: the commercial team for the biotech’s beleaguered Azlheimer’s drug Aduhelm.

As part of a previously announced plan to achieve $500 million in cost cuts, the biotech on Wednesday notified some employees that their positions were being eliminated.

“These changes will help the company remain flexible so additional investments can be made in our pipeline and other strategic initiatives,” read an emailed statement shared by Biogen’s communications team. “We appreciate the contributions of our departing colleagues, who will be eligible for severance and support services as they transition out of the company.”

While the company declined to disclose an exact number of layoffs, multiple news reports provided some detail. Among more than 100 people let go as of Thursday, pink slips were issued to two-thirds of the Alzheimer’s commercial team and all of the company’s Alzheimer’s field leaders, Endpoints News reported, citing senior company officials. Salespeople on older brand Spinraza, a treatment for spinal muscular atrophy, were also impacted, according to STAT News.

Biogen announced the restructuring scheme in December along with a 50% cut on Aduhelm’s list price, from $56,000 to $28,200 per patient. The pricing move came just ahead of a Centers for Medicare and Medicaid decision on Medicare’s reimbursement for the drug, in which the federal payer said it will only cover Aduhelm when used in a clinical trial.

In response, Biogen said the CMS proposal would effectively limit coverage to a mere 1,000 to 2,000 patients in a trial. The drugmaker had hoped to start 50,000 patients on the treatment this year. A final CMS decision is due next month.

Meanwhile, Biogen has had trouble convincing commercial payers to cover the drug and doctors to prescribe it. Skepticism among the medical and scientific community has run high since the drug’s June approval, which came via the FDA’s accelerated approval pathway despite mixed clinical data.

With the launch hobbled by these issues, sales have suffered. Aduhelm revenue for the fourth quarter totaled just $1 million, prompting Biogen leadership to start cutting costs.

An earlier STAT report had noted that more than 1,000 jobs — representing about 10% of Biogen’s staff — were set to be terminated this year through layoffs, voluntary resignations and the elimination of open positions. The Biogen spokesperson said that the $500 million cost savings will not entirely be driven by reductions in head count and that some employees will be able to apply for open positions.

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ADUHELM: Biogen "tira la toalla"...

 

Biogen is giving up its ownership of Aduhelm, the Alzheimer’s disease treatment whose 2021 approval led to scrutiny and outrage, turning the page on a tempestuous chapter in the company’s long history.

Neurimmune, the Swiss company that invented Aduhelm, will regain full rights to the intravenous medicine, Biogen said Wednesday. Biogen will also terminate an ongoing clinical trial meant to prove the treatment’s benefits for patients in the early stages of Alzheimer’s.

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Aduhelm es un "milagro"?

 

Is the new Alzheimer’s ‘wonder drug’ really such a miracle? 

Research shows Aduhelm may not improve symptoms – and there are worrying side-effects. So what’s the best hope... and what can you do now to protect yourself? As far as holy grails in medicine are concerned, you don’t get one much more significant than a cure for dementia. It’s the condition many of us fear most, surveys consistently show, as the disease slowly but inexorably obliterates the mind.

We’ve been waiting for a breakthrough treatment for decades, yet despite billions spent on drug development and research by governments and companies worldwide, the majority of candidates have fallen by the wayside.

Some experimental medicines have even had the opposite effect of the intended effect, actually worsening brain function.

And the only drugs currently available simply tackle specific symptoms of mild to moderate dementia — there is nothing that can slow down the disease or prevent it.

So understandably there was huge excitement and hopeful headlines recently after the first new medicine for Alzheimer’s (the most common type of dementia) in two decades was approved by the U.S. regulator, the Food and Drug Administration. 

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Aduhelm (Biogen): LOWN Institute vs FDA

 

BY Judith Garber | June 14, 2021

This week, the American Food and Drug Administration (FDA) approved a new treatment for Alzheimer’s disease for the first time in nearly two decades. The new drug aducanumab (brand name Aduhelm) was developed by Cambridge, MA pharmaceutical company Biogen and Japanese pharmaceutical company Eisai Co., Ltd. While certain patient advocacy groups such as the Alzheimer’s Association applauded the FDA’s decision, many other experts — including the FDA’s own advisory panel — were dismayed by the drug’s approval. Not only does was the approval of aducanumab based on a very low level of evidence, but the approval has significant implications for future drug trials, health system costs, patient safety, and conflicts of interest.

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FDA aprueba Aduhelm / Biogen, nuevo tratamiento para Alzheimer

The evidence behind the approval

 

The path to approval for aducanumab was anything but straightforward. In 2015, Biogen started two randomized controlled trials, called EMERGE and ENGAGE, to test the effectiveness and safety of aducanumab. At an interim look at the data in 2019, Biogen shut the trials down, declaring that the drug was not proving to be effective, and that further study would be “futile.” However, data continued to come in from trial participants, and a few months later, Biogen did a reanalysis and found that EMERGE was showing positive results for patients taking a high dose of aducanumab.

“These kinds of subgroup and responder analyses should be used to generate hypotheses for further study, not to decide if a drug is safe and effective for treating people with Alzheimer’s disease.”

Dr. Jason Karlawish, in StatNews

Experts were skeptical that this result was enough proof for Biogen to seek FDA approval. For one, the FDA generally requires two controlled trials to approve a new drug, and Biogen had positive results from only one trial. Second, although the trial results were statistically significant, it’s not clear that the results actually show clinical significance– that is, that the drug makes a noticeable difference to patients or their families. 

The primary endpoint of the trials was change on the Clinical Dementia Rating Scale (CDRS). The range for this scale is from 0-18, with a higher score indicating more severity of illness. Among those taking a high dose of aducanumab in the EMERGE trial, the average decrease on the scale was 0.39 points, according to the Institute for Clinical and Economic Review (ICER) report.

Given the negative results of ENGAGE (as well as the many previous negative trials of drugs that similarly target brain amyloid), the positive results of EMERGE may have been due to random chance as much as anything else. But even if the result is “real,” that doesn’t mean we should rush to approve the drug. 

In a recent StatNews op-ed, Dr. Jason Karlawish, professor of medicine at the University of Pennsylvania’s Perelman School of Medicine, argued that “these kinds of subgroup and responder analyses should be used to generate hypotheses for further study, not to decide if a drug is safe and effective for treating people with Alzheimer’s disease.”

After looking at the evidence, the FDA’s own advisory panel voted overwhelmingly that the trials were not “primary evidence of effectiveness of aducanumab for the treatment of Alzheimer’s disease.” It’s not uncommon for the FDA to vote against the recommendation of its advisory panels, but this was the first time in many years that the FDA overruled such a decisive vote by a panel. Many of the panel members were shocked by the FDA’s approval of the drug, and as of June 11, three have resigned. Más

Alzheimer: No Clinical Benefit From Drug Targeting Amyloid (Aduhelm)

 

A recent review article in the Journal of Alzheimer Disease identified 9 compounds targeting amyloid that had failed in phase 3 trials since 2018.

In January 2019, Roche, Genentech’s parent company, announced it was discontinuing 2 phase 3 trials of crenezumab in patients with mild, sporadic Alzheimer disease because preplanned interim analyses concluded that the treatment was unlikely to meet its primary end point of slowing cognitive decline.

And a year before the findings of the Colombia crenezumab trial were reported, the US Food and Drug Administration (FDA) approved aducanumab (Aduhelm), another antiamyloid monoclonal antibody, even though none of the agency’s panel of outside experts had voted “yes” when asked whether clinical trials had shown it to be effective in treating Alzheimer disease.

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The agency granted aducanumab “accelerated approval,” which is based on a surrogate end point—in this case, a reduction in amyloid-β plaque in the brain—that, according to the FDA, “is reasonably likely to predict a clinical benefit to patients.” Aducanumab, the only antiamyloid drug that has ever received FDA approval, is the first Alzheimer therapy designed to modify the underlying disease process and not just treat symptoms.

After the FDA approved aducanumab, the Centers for Medicare & Medicaid Services (CMS) released a national coverage policy for the therapy as well as future antiamyloid antibodies to spur the collection of more information about their safety and effectiveness.

Medicare will cover aducanumab and other such therapies granted accelerated approval based on a surrogate end point, such as amyloid reduction, only for beneficiaries participating in FDA-sanctioned randomized clinical trials to determine clinical effectiveness. Aducanumab isn’t cheap. In January, Biogen cut the drug’s wholesale acquisition cost in half, to $28 200 per year for an average-size patient (dosing is based on patients’ weight).

For monoclonal antibodies that receive FDA approval via the conventional pathway, which involves demonstrating clinical benefit, Medicare will still only cover the cost for patients in CMS-approved or NIH-supported studies.

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No matter their opinion about the usefulness of targeting amyloid, dementia experts seem to agree that the complexity of Alzheimer disease calls for a multipronged treatment approach tailored to the particular patient, depending on such factors as the stage of their disease.

“I have a hard time imagining how targeting any single molecule or any single pathology is likely to yield a meaningful clinical benefit,” Gandy said.

 (Sam Gandy, MD, PhD, director of the Mount Sinai Center for Cognitive Health in New York)

Although the final answer on amyloid may not yet be in, researchers are branching out in their search for tools—both drugs and lifestyle changes—that could at least slow the development or progression of Alzheimer disease.

“A decade ago, there wasn’t much in terms of alternative targets” to amyloid, Hodes said. To illustrate his point, he noted that 5 of the 8 late-stage Alzheimer trials funded by the NIA involve antiamyloid therapies. However, Hodes said, only 13 of the 61 phase 1 or phase 2 trials receiving NIA funding target amyloid.

 (Richard Hodes, MD, director of the National Institute on Aging (NIA))

Nonamyloid therapeutic targets include other proteins, such as tau—tau neurofibrillary tangles are a hallmark of Alzheimer disease that haven’t received as much attention as amyloid plaques—TDP-43 (transactive response DNA-binding protein 43), the accumulation of which in the central nervous system is also a feature of other neurodegenerative diseases; and α-synuclein, which appears to interact with tau in neurodegenerative diseases, Hodes said. Besides proteins, other Alzheimer therapeutic targets for which the NIA is funding trials include inflammation, genetics, and vascular system changes, he said.

The NIA is also supporting 131 studies of nonpharmacological interventions focused on cognitive training, sleep, and exercise, among others, Hodes said. One NIA-funded phase 3 trial presented at the Alzheimer’s Association conference evaluated whether regular exercise could benefit people with amnesic mild cognitive impairment (MCI), which primarily affects memory and increases the risk of Alzheimer disease or related dementias.

The trial randomized 296 adults to either moderate-intensity aerobic training or low-intensity stretching, balance, and range-of-motion exercises for 18 months.

Exercise sessions took place at a YMCA 4 times a week for a total of 120 minutes to 150 minutes per week. In the first 12 months, a trainer supervised 2 sessions a week, while the other 2 were unsupervised. All exercise was unsupervised in the last 6 months. Neither group showed significant declines from baseline in the primary measure of cognitive function over 12 months, suggesting that both the moderate- and low-intensity exercise, and, possibly, the socialization participants received with it, stalled cognitive decline, researchers reported at the meeting. In contrast, cognitive function did decline over a year in similar adults with MCI who participated in a large “usual care” observational study.

Approximately 6.5 million people aged 65 years or older in the US are living with Alzheimer disease, and that number is expected to nearly double by 2050, according to the Alzheimer’s Association.

”The stakes are too high just to focus on amyloid,” Reiman said.

(Eric Reiman, executive director of the Banner Alzheimer Institute in Phoenix)

Más

Aduhelm: Ser o...no ser, lo aclara el ICER

 

 

 In summary, we judge that the evidence is insufficient to conclude that the clinical benefits of aducanumab outweigh its harms or, indeed, that it reduces progression of AD.

 Ver:

Aduhelm (Biogen): LOWN Institute vs FDA

 

If blended efficacy results are used from the Phase III trials, our base-case analyses suggest that an annual cost of $50,000 for aducanumab, as has been suggested by market analysts, would not be in alignment with its clinical benefits.

 

 If aducanumab were determined to have no net health benefit, no threshold price could be generated to guide considerations of fair pricing. Más
 

Ver también:

Alzheimer's drug approval: Advocacy group calls for FDA resignations 

FDA: Aprobar por "via acelerada" en cuestionamiento...

El tratamiento contra el cáncer aprobado por "vía acelerada" y retirado no es un caso aislado: es un problema mayor

El día 7 de noviembre, la farmacéutica GlaxoSmithKline (GSK) publicó una nota de prensa en la que reconocía que los ensayos clínicos que estaba llevando a cabo para probar la eficacia del Blenrep, su innovador fármaco contra el mieloma múltiple, no estaban dando los resultados esperados. Si este fuera un caso normal, no dejaría de ser un caso más de medicamentos que no consiguen llegar al mercado.

Es más, teniendo en cuenta los considerables efectos secundarios de este fármaco en cuestión, sería lo normal. Carpetazo y a otra cosa. Sin embargo, este no es un caso normal: el Blenrep lleva ya más de dos años en el mercado y, de hecho, hace muy poco que España lo acaba de incorporar al Sistema Nacional de Salud. Así que la pregunta es evidente, ¿y ahora qué?

La FDA ha movido ficha. 

En agosto de 2020, la FDA norteamericana había aprobado por la "vía acelerada" (un método más corto y, por tanto, menos costoso) este medicamento. No obstante, al revisar los datos que aportaba GSK, ha ordenado la inmediata retirada del fármaco del mercado estadounidense. Esto no solo ha reforzado las dudas que, en los últimos años, se han levantado en torno a los procedimientos de aprobación de la FDA, sino que ha generado un efecto "bola de nieve" que pone en duda los procedimientos de otras agencias de medicamentos, como la europea.

¿Qué pasa en Europa? 

Lo que ocurre en Europa es que el fármaco también está aprobado desde el verano de 2020, pero a diferencia del procedimiento no contempla una retirada fulminante del producto a no ser que haya "problemas de seguridad". Y en este caso no los hay: simplemente se ha descubierto que el fármaco sencillamente no funciona (como se suponía que lo hacía y, por tanto, no es una opción terapéutica viable). Por ello, Europa tendrá que esperar a principios de 2023, cuando la evaluación programada decida qué hacer con el fármaco.

Se da la circunstancia de que España acaba de incorporar este medicamento a la cartera de la Seguridad Social tras varios rechazos por parte de la Comisión Interministerial de Precios de los Medicamentos por “las incertidumbres respecto a su valor terapéutico y criterios de racionalización del gasto público e impacto presupuestario" en el sistema nacional de salud.

No hay que olvidar que este tipo de medicamentos son muy caros (6.974,48 euros el vial para el caso del Blenrep; es decir, 120.000 al año por paciente) y eso hace que, aunque la EMA los apruebe, la sanidad española se lo tome con calma. La consecuencia directa es que, pese a las críticas de asociaciones de pacientes y de la industria, el 45% de los nuevos medicamentos aprobados por la UE no está disponible en España. Este caso evidencia que la cuestión es más compleja de lo que parece.

Una polémica que va mucho más allá de este medicamento. Porque el caso del Blenrep llega en un momento extraño. El año pasado, se despertó una enorme polémica en el mundo médico porque la FDA aprobó un medicamento contra el Alzheimer, el Aduhelm, contra la opinión de su propio grupo de expertos. Algo que, por cierto, era la primera vez que ocurría. Y no, no es un caso aislado.

Ver:

Todo sobre Aduhelm en PHARMACOSERÍAS

Según publicaba Elisabeth Mahase en The Bristish Medical Journal el año pasado, el 44% de las terapias que desde 1992 ha aprobado por la FDA "por la vía rápida" no lograron demostrar su efectividad. Eso son 112 de 253. Es más, Mahase dejaba bastante claro que la agencia norteamericana permitió que siguieran en el mercado durante mucho más de lo razonable pese a no tener evidencias claras y ser sorprendentemente costosos. No tenemos datos del proceso equivalente de la EMA, pero lo cierto es que ambas agencias suelen ir de la mano en la inmensa mayoría de casos.

¿Está roto el sistema de aprobaciones de medicamentos? 

Yo no iría tan lejos porque en esta crisis confluye muchos factores. El más novedoso es el nuevo interés de la opinión pública en todo lo que tiene que ver con los procesos de aprobación y comercialización de los medicamentos. Un interés que parece heredado de la pandemia y que tiene como resultado que los fallos del sistema sean discutidos con "luz y taquígrafos". Si miramos los estudios, podemos comprobar que los problemas se remontan a mucho antes.

Si uno de los factores cambia, todo debe cambiar. Es decir, no parece razonable que las agencias del medicamento no analicen la cuestión con detalle y desarrollen procesos de aprobación que no comprometan directamente su credibilidad. Porque, como hemos repetido muchas veces, la confianza es un "recurso no renovable" y la revolución biotecnológica de los próximos años no va a hacer, sino aumentar el potencial de los medicamentos disponibles (pero también la incertidumbre y me temo que los precios).

Javier Jimenez / Xataka

Biogen’s reckoning: How the Aduhelm debacle pushed a troubled company and its fractured leadership to the brink

 

The shocking revelation came in a Saturday afternoon email, restricted to a tight circle of top executives within Biogen. 

Al Sandrock, the company’s most prominent scientist and chief of its entire research and development group, was leaving. There was no warning or explanation. After 23 years at Biogen, Sandrock, 64, had apparently decided it was time to retire. Más

Ver

 Biogen Announces Alfred W. Sandrock, Jr. to Retire as Head of Research & Development