Neuroscience Is The Next Oncology: Why Biogen Is Doubling Down

While other large biopharma companies are withdrawing from CNS research, Biogen is rare in not only staying in, but doubling down. Executives at the company’s 40th anniversary event in Switzerland explained why.

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Biogen sees rapid progress in many aspects of CNS R&D

“What’s happening in neuroscience right now is like nothing we’ve seen before. Neuroscience is at an inflection point. We have seen the signs and Biogen has chosen to step forward and lead.” Michael Ehlers, Biogen Inc.’s executive vice president, R&D, is convinced that the company is in the right place at the right time, but Biogen’s attitude is unusual.

Michael Ehlers

In recent years, other companies – GlaxoSmithKline PLC, Pfizer Inc., AstraZeneca PLC, Novartis AG, Sanofi among them – have chosen to exit or scale back their R&D into disorders of the central nervous system (CNS). Biogen, on the other hand, spun out its hemophilia business in 2017 under former CEO George Scangos. The latter’s strategy to double down on neurology is now being enthusiastically pursued by his successor Michel Vounatsos as the company enters its fifth decade. So what gives Biogen its confidence, and how is it approaching the neuroscience challenge?

According to Ehlers, speaking at an event in Lucerne to mark the Swiss-born biotech’s 40th anniversary, there are “six broad reasons” for the company’s belief that “neuroscience is the next oncology” and “the fastest area of ongoing scientific advance.”

• Firstly, “arguably there’s no area that’s advancing as rapidly as neuroscience in terms of understanding of disease biology.” This growth in knowledge encompasses areas including how the brain develops, how it is affected by aging, and brain plasticity.

• Second is the growing ability to stratify patients by disease pathology.

• Third is the advent of novel technologies to deliver therapeutic agents, for example using cell or gene therapies, or brain penetrative biologics, or intrathecally, like Spinraza (nusinersen), Biogen’s recently launched antisense oligonucleotide treatment for spinal muscular atrophy, which booked sales of $1.25bn in the first nine months of 2018 after winning approval in the US in December 2016 and in the EU, Japan and other markets the following year.

• Fourth is the fact that “the genetics of complex CNS disorders is advancing beyond where it would have been imagined just four or five years ago.”

• Fifth, there is a “real revolution in the ability to interrogate the pathophysiology of neurological disease,” driven by technology-enabled progress in biomarker research. “We see a time that is happening right now where there will be patient stratification and early diagnosis enabled by biomarkers,” stated Ehlers.

• And finally, he highlighted increasing openness on the part of regulators to new ideas: “innovative trial design informed by patient need and experience will allow us to proceed through development more rapidly,” he said.

Still, as the company’s chief medical officer Al Sandrock admitted, “No-one would consider [neuroscience R&D] low-hanging fruit. It’s hard and full of risk.”

Transforming The Medical Role

In recognition of the historically high rate of failure in CNS drug development, Sandrock outlined ways in which Biogen is trying to “greatly improve CNS disease treatment” while doing all it can to de-risk its pipeline work.

Some of that springs directly from a reappraisal of his own role within the company. “I have been CMO at Biogen for quite a number of years but the CMO role has evolved. I used to be in charge of all development, starting from R [research] to D [development] transition all the way to Phase III and post marketing. Now my role is mainly medical, so I’m not directly involved in R&D although I sit on a committee called the product development operating council.”

Al Sandrock, Biogen's chief medical officer

According to Sandrock, “medical is one of the areas in biopharma that’s transforming the most,” notably through the potential to use real-world evidence and big data analytics to quantify clinical experience and “make the clinic more of a place where you can actually learn about disease.”

He is ambitious in this regard. “I am going to turn it into something that I think hasn’t been seen before. Where we really put the patients in the center and we say how can we improve the practice of medicine with the use of our drugs, with the use of diagnostics, with the use of monitoring tools – how can we maximally improve neurological healthcare on behalf of our patients?”

This will involve shifting from simple static diagnosis – running an MRI scan to confirm the suspected presence of a disease like multiple sclerosis, for example – to quantifying, tracking and ultimately providing optimally tailored treatments for individual patients.

“So we’re working with a lot of companies that are doing digital tracking and passive monitoring. Also, in the clinic we have an iPad-based device, for example, where MS patients come into the clinic 30 minutes before their appointment and get their vision, cognition, upper extremity function, ambulation, etc systematically recorded, almost the way we would in a clinical trial. We’re also capturing patient-reported outcomes. And we are working with Siemens to quantify the MRI images. We’re also getting biological data, and we’re combining that with electronic health records,” he explained.

“And if you put all that together, you can really transform how we measure change in these patients. One day I’m hoping that we’ll get to the point where physicians have a decision support device where you put all the data – genetics,  imaging, clinical, wearable data and so on – and you can then say, based on real-world evidence, for this type of patient, they are most likely to respond to drug A versus drug B, and if they don’t respond to drug A, you’d know it quicker, and then you’d know what’s the next best drug.”

Optimizing Neuroscience Drug Development

Back in drug development, when it comes to maximizing the potential of the pipeline, Biogen is spreading its neuroscience bets over a range of areas with a range of therapeutic approaches and partnerships.

"We continue to be interested in new modalities, such as gene therapy, and partnering to complement our portfolio"

As well as programs to expand its already strong multiple sclerosis franchise, it is looking at Alzheimer’s disease, Parkinson’s disease and movement disorders, neuromuscular disorders like spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), pain, stroke and more. It has a range of biological, small-molecule, antisense and gene therapies under investigation.

The company told Scrip: “We continue to be interested in exploring new modalities, such as gene therapy, to expand the target space for neurological diseases. In addition, we expect to remain active in exploring partnering opportunities that would complement our portfolio.”

  Biogen's Clinical Development Pipeline

General area	Disease	Program	Partner	Phase
MS and Neuroimmunology	MS	BIIB098 (diroximel fumarate)	Licensed from Alkermes	III
	MS	Opicinumab (anti-LINGO)		II
Alzheimer's disease and dementia	Alzheimer's	Aducanumab (Aβ mAb)	Developed with Neurimmune	III
	Alzheimer's	Elenbecestat (E2609, BACE inhibitor)	Developed with Eisai	III
	Alzheimer's	BAN2401 (Aβ mAb)	Developed with Eisai	II
	Alzheimer's	BIIB092 (anti-tau mAb)	Licensed from Bristol-Myers Squibb	II
	Alzheimer's	BIIB076 (anti-tau mAb)		I
	Alzheimer's	BIIB080 (IONIS-MAPTRx)	Developed with Ionis Pharmaceuticals; option to acquire	I
Parkinson's disease and movement disorders	Progressive supranuclear palsy (PSP)	BIIB092 (anti-tau mAb)	Licensed from Bristol-Myers Squibb	II
	Parkinson's	BIIB054 (anti-α synuclein mAb)	Acquired from Neurimmune	II
Neuromuscular disorders including SMA and ALS	ALS	BIIB067 (IONIS-SOD1-Rx)	Developed with Ionis Pharmaceuticals; option to acquire	I
	ALS	BIIB078 (IONIS-C9Rx)	Developed with Ionis Pharmaceuticals; option to acquire	I
	SMA	BIIB110 (f/k/a ALG-801)	Acquired from AliveGen, Inc.	I
Pain	Trigeminal neuralgia	BIIB074 (vixotrigine)		II
	Small Fiber Neuropathy	BIIB074 (vixotrigine)		II
	Neuropathic pain	BIIB095 (Nav 1.7)		I
Ophthalmology	X-linked retinoschisis	BIIB087 (gene therapy)	Developed with Applied Genetic Technologies Corporation	II
	X-linked retinitis pigmentosa	BIIB088 (gene therapy)	Developed with Applied Genetic Technologies Corporation	II
Neuropsychiatry	Cognitive impairment associated with schizophrenia	BIIB104 (AMPA)	Acquired from Pfizer	II
Acute neurology	Large hemispheric infarction [stroke]	BIIB093 (iv glibenclamide)		III
	Acute ischemic stroke	TMS-007 (plasminogen modulator)	Option to acquire from TMS Co., Ltd.	II
	Drug-resistant focal epilepsy	Natalizumab		II
Other	Lupus	Dapirolizumab pegol (anti-CD40L)	UCB, Inc.	II
	Idiopathic pulmonary fibrosis	BG00011 (STX-100)		II
	Lupus	BIIB059 (anti-BDCA2)		II

 

Source: Biogen

Alzheimer’s R&D

Biogen’s Alzheimer’s pipeline is industry leading, and – with the help of its partnership with Eisai Co. Ltd. – it has four separate programs at Phase II or above, including two advanced monoclonal antibodies against the amyloid-beta (Aβ) peptide (aducanumab and Eisai-led BAN2401) and Eisai-partnered elenbecestat, one of the last remaining BACE inhibitors following the failure of a string of others in the class. But recent trial results for BAN2401 prompted widespread confusion and the future of aducanumab hinges on the results of a Phase III trial which is not due to read out until early 2020. (Also see "Biogen, Eisai Report BAN2401 Seemingly Positive In Alzheimer's; Others Skeptical" - Scrip, 26 Jul, 2018.)

Despite the ongoing uncertainty, Sandrock believes data so far from the company’s double punt on late-stage Aβ-targeting antibodies in Alzheimer’s – another field littered with casualties, including Pfizer/Johnson & Johnson’s bapineuzumab and Eli Lilly & Co.’s solanezumab – suggest it is on the right track.

"If you conduct the studies in a way that you can learn even from the failures, we'll be moving the field forward"

“Aducanumab and BAN2401 are similar antibodies. They don’t bind to the same epitope, but it’s very similar. Not just the epitope, but also the specificity for aggregated forms of Aβ versus monomeric forms of Aβ. So here are two different companies with two different antibodies, showing basically the same result: a substantial reduction in amyloid plaque burden and a slowing of cognitive decline. When I used to work in a lab, the highest form of validation was if a different lab used similar reagents and reproduced the result you got in your own lab. I feel like something similar has happened here.”

It’s a question of using the right biomarkers and designing trials to answer the right questions, Sandrock explained. “This in general applies to neuroscience: it’s very risky, but if you use the right biomarkers, conduct the studies in a way that you can learn even from the failures, then I think we won’t be wasting our shareholders’ investment, we’ll be moving the field forward, and then we’ll probably still have failures but at least we’ll learn from them.”

Case Study: Smart Trials To Mitigate Pipeline Risk

Sandrock cites a Phase Ib trial of aducanumab published in Nature in 2016 as an example of how the companies invests in doing trials right from the start to de-risk down the line.

“We used a biomarker for cohort selection. So we knew that patients that entered the trial all had amyloid. It’s expensive and somewhat cumbersome to have to do PET scans on every single patient, but we felt it was important to verify that they actually had amyloid in the brain and therefore actually had Alzheimer’s disease.

“Second is we used the PET scan to know that we got target engagement. All too often, if you look back at clinical trials in neuroscience, we don’t even know that the drug got to the brain and engaged the target. So we’re not even sure if the trial or the drug failed. And we can’t even be certain that we’ve tested any biological hypothesis. So we carefully quantified and we showed that we had a dose dependent reduction in amyloid plaque burden.

“And then we used imaging for safety surveillance. One of the most important side effects with aducanumab is ARIA [amyloid-related imaging abnormalities], so we had regular monitoring by MRI so that we could assess ARIA. Most of the ones we see are asymptomatic, but nevertheless, we used imaging for safety surveillance.

“And then we used the clinical endpoints [to establish] whether or not the biomarker changes we’re seeing in any way correlate with the clinical effects. So if we’re seeing effects on slowing of cognitive decline, does it happen more often in patients who actually had amyloid reduction?”

Combination Possibilities

In the longer term, Sandrock envisages the possibility of combination therapies being developed for Alzheimer’s. “One reason we licensed Aβ and tau [the anti-tau antibody BIIB092 was licensed from Bristol-Myers Squibb Co.] is that we believe combo is the way to go in future. We have plans to do combinations but we want to get monotherapy data first. We are starting to do animal models. I see a day where you do PET scans to see toxic proteins are building up in a patient’s brain. In future we will talk about amyloidopathies,

tauopathies, synucleopathies and so on, and that is how we will treat it.”

And Then...Market Access

If the magnitude of the scientific challenge is daunting when it comes to Alzheimer’s R&D, success would lead into a new challenge: market access and reimbursement. On this front, Biogen is engaging with payers in different ways, Vounatsos said.

Obliquely, it is enhancing its engagement with policy leaders in Europe via the three anti-TNF biosimilars it has launched under its Samsung Bioepis Co. Ltd. joint venture with Samsung BioLogics, which “enhance the value proposition and the sustainability of the system” by enabling large savings for public payers and creating “head room for innovation.”

But it is also engaging early with policy makers in key markets including in Europe, Japan and the US on the specific issue of preparedness for new Alzheimer’s therapies. Vounatsos pointed out that it won’t just be about reimbursement – there will be infrastructure needs to provide early diagnosis and monitoring and potentially new treatment modalities. Nevertheless, the already spiraling costs to society of the disease and “the increasingly progressive attitudes of healthcare systems and regulators give us hope that policy leaders will invest in infrastructure to give access to treatments” – although “the amount of work needed in the next five to seven years is staggering if we want to have a meaningful impact.”

Michel Vounatsos

Staying Ahead

Meanwhile, Biogen cannot bask for long in the remarkable success of its Ionis Pharmaceuticals Inc.-partnered antisense therapy Spinraza. A competitive threat is looming in the shape of the potentially one-time gene therapy treatment AVXS-101 acquired by Novartis in April, which is under FDA review. Unfortunately, an investigational new drug (IND) application for Biogen’s own gene therapy for SMA, under development in partnership with University of Pennsylvania, has been placed on hold by the FDA, after the agency had questions about preclinical data.

Key Biogen Product Sales Nine Months Ended Sep. 30, 2018

Indication	Product	Sales	Change year on year
MS	Tecfidera	$3,164m	+1%
MS	Interferon (includes Avonex and Plegridy)	$1,766m	-12%
MS	Tysabri	$1,400m	-7%
MS	Fampyra	$70m	+4%
SMA	Spinraza	$1,254m	+141%
Inflammatory conditions	Benepali (biosimilar etanercept)	$360m	+42%
TOTAL PRODUCT REVENUES		$8,061m	+5%

 

In its mainstay area of multiple sclerosis, the outlook is challenging in the face of rising competition and reimbursement challenges. Analysts at Leerink in an Oct. 29 note thought Biogen had “the resources and research to remain at the forefront of the category, but it is still likely to lose share and price over time and faces flat-to-declining sales.” Nevertheless, they view Biogen’s pipeline for serious neurological diseases as its “most interesting part” which “could unlock tremendous value.”

With more than a year to go before the next moment of truth in its late-stage Alzheimer’s pipeline, the world’s oldest biotech will need to keep its foot to the pedal on building up its other assets (and potentially building them out with acquisitions and partnerships) if it is to make the most of the brave new world of neuroscience for the years to come.