Tysabri’s failure in a phase II ischaemic stroke trial underscores the fact that very few pharmacological advances have been made in this condition, despite biopharma companies approaching treatment from several different angles.
While stroke incidence and deaths have declined, mortality and disability are elevated among patients who survive the initial event, making new treatments an urgent need. Biogen had hoped that Tysabri could limit harm to the nervous system, an approach the company is also taking with its second stroke project, BIIB093. But the most hyped agent is Athersys’s stem cell therapy Multistem, which is designed to repair damaged tissue (see table below).
Tysabri, which is already approved in multiple sclerosis, is believed to protect the nervous system by inhibiting the inflammatory activity of immune cells. In stroke animal models its mechanism of action, antagonism of α4 integrin, reduced the amount of brain tissue damage.
However, this hypothesis was not borne out by the Action 2 study, which found that Tysabri failed to improve patients’ disability scores versus those receiving placebo.
Next project up
Biogen has quickly pivoted to BIIB093, which targets the Sur1-Trpm4 channel that mediates brain swelling in stroke patients. The agent was known as Cirara before it was bought from Remedy Pharmaceuticals for $120m, and Biogen is preparing to start a phase III trial mid-year.
|Selected projects in the acute ischaemic stroke pipeline|
|Project||Company||Pharma class||Trial ID|
|Multistem||Athersys/Healios||Anti-tumour necrosis factor cell therapy||NCT02961504|
|NA-1||Nono||Postsynaptic density protein 95 inhibitor||NCT02315443|
|Radicava||Mitsubishi Tanabe||Free-radical scavenger||NCT03346538|
|BIIB093/Cirara||Biogen||NC Ca-ATP channel inhibitor||NCT02864953|
|Revacept||Takeda||Platelet aggregation inhibitor||NCT01645306|
|SB623||Sanbio||Mesenchymal cell therapy||NCT02448641|
|S 44819||Servier||Gamma-aminobutyric acid antagonist||NCT02877615|
|ReN001||Reneuron Group||Cell therapy||NCT02117635|
The group must have got excited by Remedy's phase II data, which found that BIIB093 reduced 90-day mortality by 53% in patients with severe strokes. The small trial also showed a numerical benefit in reducing disability, which is no doubt something Biogen will hope can hit statistical significance in a pivotal trial.
However, not everyone shares Biogen’s enthusiasm: Leerink analysts noted that, while BIIB093 “has a certain level of plausibility”, it has not been validated, and they give the project a low probability of success.
On entering phase III, BIIB093 will trail Multistem, Mitsubishi Tanabe Pharma’s Radicava and lesser-known agents like Nono’s NA-1, which is being tested as an emergency drug administered by first responders.
Radicava, a free-radical scavenger, won US approval in amyotrophic lateral sclerosis based on data showing that it slowed decline in motor function – its label states that it is not known how it exerts a therapeutic benefit (Radicava bags approval without a radical benefit, May 8, 2017).
As edaravone, Radicava is approved as an immediate post-stroke therapy in Japan. Curiously, the main stroke trial is also in Japan, so it is unclear what commercial plans Mitsubishi Tanabe has for this asset. NA-1, meanwhile, inhibits postsynaptic density protein 95, which are thought to disrupt a signalling pathway that regulates cell death.
The stem cell approach embraced by Athersys, by Reneuron in the form of its phase II project Ren001, and by Sanbio with SB623, aims to rebuild damaged neurons rather than prevent damage. This could prove important for patients who do not receive immediate tissue plasminogen activator, which can remove the clot blocking blood flow to the brain and thus stop further destruction.
Athersys said in November that its Japan partner Healios had enrolled the first patient into its phase III Treasure trial. A separate study to meet European and US standards, Masters 2, is slated to begin soon, although Athersys has not been specific about timing – the group recently announced an agreement with Aspire Capital Fund for a $100m equity capital facility, which involved a $1m up-front investment.
While the stem cell approach looks like a high-risk gamble, the sellside has the most bullish outlook for Athersys. EvalutePharma’s consensus forecast puts sales of Multistem at $1.1bn in 2022, by far the biggest in this space.
UK-based Reneuron, meanwhile, has received the US FDA’s green light to begin the phase IIb Pisces III study of Ren001, which company executives have said would begin in the first half of 2018. Sanbio, meawhile, in December achieved 85% patient enrolment into its phase II trial of SB623.
Success in reducing or improving disability after a stroke has been elusive. With much of the damage done in the first hours, the focus remains on agents that can be delivered in an early treatment window. A bigger accomplishment would be a product that can help slow or reverse disability for the unlucky patients who do not receive optimal treatment initially.