Novo bets against Crispr for amyloidosis

Novo moves into amyloidosis not long after Intellia made a splash here.

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On the face of it Novo Nordisk’s purchase of Prothena’s transthyretin amyloidosis project PRX004 yesterday looked odd. The deal is outside the Danish group’s core expertise and there is plenty of competition, including from Intellia’s Crispr project NTLA-2001, which recently caused a stir with results in six patients.

Novo must believe that there will still be room for more conventional approaches like PRX004, an anti-transthyretin antibody, and experience in haemophilia shows that the progress of advanced therapies is not always smooth. And, at just $100m in up front and near-term milestones, PRX004 represents a small bet for Novo.

Disease modifying?

Novo plans to develop PRX004 initially for transthyretin amyloid (ATTR) cardiomyopathy, which is caused by amyloid deposits, made up of abnormal transthyretin protein, building up in the heart. As such, the project will become part of the group’s cardiovascular push, which also includes ziltivekimab, an asset Novo acquired with Corvidia.

A spokesperson for Novo told Evaluate Vantage that the group had been attracted by the high unmet need in ATTR cardiomyopathy, despite therapies being available. She added that today’s standard of care only treated the symptoms of the disorder, while PRX004 could target the underlying cause.

The project is an antibody designed to bind to and clear pathologic transthyretin while sparing the healthy form of the protein.

Thus it works differently from Pfizer’s ATTR cardiomyopathy drug Vyndaqel, which stabilises healthy transthyretin to prevent its breakdown and the build-up of amyloid fibrils.

Meanwhile, RNA therapeutics like Alnylam’s Onpattro prevent the production of transthyretin.

If PRX004 is successful it could therefore be used in combination with other approaches or as a monotherapy.

Only Neurimmune, with its phase 1 antibody NI006, has a similar approach in the clinic, according to Evaluate Pharma.

The ATTR amyloidosis landscape
Product Company Disease subtype Description 2026e sales ($m)
Approved
Vyndaqel Pfizer Wild type/hereditary cardiomyopathy Oral TTR stabiliser 3,628
Onpattro Alnylam Hereditary polyneuropathy (ph3 Apollo-B cardiomyopathy trial to read out mid-2022) IV TTR RNAi therapeutic 742
Tegsedi Ionis Hereditary polyneuropathy SC TTR antisense 589
Filed
Vutrisiran Alnylam Hereditary polyneuropathy (ph3 Helios-B cardiomyopathy trial ongoing) SC TTR RNAi therapeutic 1,813
Phase 3
Acoramidis (AG10) Bridgebio Pharma Wild-type/hereditary cardiomyopathy/polyneuropathy Oral TTR stabiliser 1,195
Eplontersen (IONIS-TTR-LRx) Ionis Wild-type/hereditary cardiomyopathy/polyneuropathy SC TTR antisense 75
Phase 1
NTLA-2001 Intellia /Regeneron Hereditary polyneuropathy/cardiomyopathy IV Crispr-associated Cas9 gene therapy 696
PRX004 Prothena Wild type/hereditary cardiomyopathy IV anti-TTR antibody 34
CRX-1008 Som Biotech/Corino Therapeutics Hereditary leptomeningeal Oral TTR stabiliser -
NI006 Neurimmune Wild type/hereditary cardiomyopathy IV anti-TTR antibody -
Source: Evaluate Pharma & clinicaltrials.gov.

Despite the excitement over NTLA-2001, Vyndaqel remains the big target in amyloidosis. And, like Vyndaqel, PRX004 could have utility in both the hereditary and wild-type forms of the disease; still, PRX004’s phase 1 trial only enrolled hereditary patients.

Novo plans to start a phase 2 study in 2022. However, the spokesperson declined to give more details about that trial’s design, including whether it would include patients with wild-type disease or those with more severe heart failure at baseline.

The latter point is relevant because Prothena has previously said it would target the niche of moderate to advanced ATTR cardiomyopathy, specifically patients with NYHA class III and IV heart failure. The company has noted that Vyndaqel showed little effect in this group in its pivotal trial.

Again, however, PRX004’s phase 1 study only evaluated patients with milder NYHA class I and II heart failure.

In any case, Novo might want to take aim at the broader ATTR cardiomyopathy population, where Prothena has put the number of patients at 400,000 to 1.4 million.

With the Danish group on the hook for up to $1.2bn in total, it will want to make the most of PRX004 should the asset progress.

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