Centessa claims a place in the antitrypsin deficiency pipeline

 Vertex lost $6bn in market cap in June after failing in its second attempt in alpha-1 antitrypsin deficiency. Meanwhile, Arrowhead has more than doubled in value, to $6.7bn, since its RNAi approach to the rare disease first showed promise.

There is always more than one driver behind a company’s valuation, of course, but these two examples help illustrate the substantial potential that investors see in a successful AATD treatment. There are only a handful of projects in clinical development, and Arrowhead remains in pole position, though approaching readouts from the likes of Mereo and Inhibrx could firm up the pipeline.

Centessa claimed to join that queue yesterday with the first look at clinical data on its phase 1 project ZF874. A liver toxicity signal means that investors remain to be convinced, however, and for now the biggest bets are being placed on more advanced assets. 

Current market

AATD is an inherited condition causing no or very low levels of a protective enzyme inhibitor, alpha 1 antitrypsin. In its natural form AAT, which is made in the liver, protects the lungs from damage. This means that AATD patients, particularly those who inherit two copies of the malfunctioning gene, are at heightened risk of developing lung diseases like emphysema.

In the liver, mutated or misfolded versions of AAT, sometimes called Z-AAT, build up, causing progressive damage and in rare cases requiring liver transplant. There are no specific treatments available for liver manifestations, although AAT augmentation therapy has been developed for those with severe lung disease.

That treatment involves harvesting normal AAT from blood plasma for infusion, though its benefits have been long debated, and it is not available in all countries. This has not hindered a billion-dollar market, however; it is worth noting that AAT augmentation products are very costly.

Grifols is the dominant player here thanks to a product it acquired with the US biotech Talecris a decade ago; Takeda has a presence thanks to its Shire purchase, which it in turn gained it via Baxter. This explains the Japanese pharma company’s ongoing interest, which last year included cornering certain rights to Arrowhead’s project for $300m up front.

It seems that, should new approaches to AATD make it to market, Grifols has the most to lose.

 Prolastin-C (Grifols): $857m

In terms of the pipeline, RNAi approaches are the most advanced, although these are primarily directed at the liver problems caused by AATD. Arrowhead’s ARO-AAT is considered most promising for now, based on small cuts of data that have been released this year from an ongoing, open-label phase 2 study.

The latest update will emerge at the AASLD meeting this coming weekend. The project, also called TAK-999, works by knocking down production of the mutated Z-AAT protein in the liver. Like most work in this space the focus here is on patients with a homozygous PiZZ mutation, who are most likely to develop severe complications of AATD.

The newly released AASLD abstract describes mean reductions of Z-AAT in the liver of 80-89%, over two cohorts of 16 patients in total, measured at 24 and 48 weeks. Signals of improving liver function and fibrosis have also been seen.

Some analysts reckon ARO-AAT could reach the US in 2022. A more rigorous phase 2 trial called Sequoia is fully enrolled, and should also start generating data next year; how quickly the FDA is prepared to move here is a big question for Arrowhead investors.

Coming behind is Dicerna’s similar RNAi therapy belcesiran, though so far only early results in 18 patients have been reported. These were promising, however, and a larger phase 2 trial, Estrella, has already begun. Alnylam has an option over ex-US rights but, unless a clear safety or efficacy advantage is seen, Dicerna needs to bring on a larger partner if belcesiran is to be considered real competition to Takeda and Arrowhead.

The AATD pipeline
Project	Company	Mechanism	Details
Phase II
TAK-999	Arrowhead/Takeda	RNAi therapeutic	Ph2 Sequoia fully recruited; awaiting plans for pivotal development/filing
Belcesiran	Dicerna (Alnylam option)	RNAi therapeutic	Ph2 Estrella study recruiting
Alvelestat	Mereo (from Astrazeneca)	Neutrophil elastase inhibitor	Ph2 data due by YE 2021 (targeting lung manifestations only)
Phase I
INBRX-101	Inhibrx	Recombinant AAT fusion protein	Ph1 data reported Oct 2021; next update expected H1 2022
ZF874	Centessa	Small-molecule AAT inhibitor	Initial ph1 data reported Nov 2021
Preclinical
AAT gene therapy	Intellia Therapeutics	Crispr/Cas-9 gene therapy	Preclinical work ongoing
AAT research programme	Vertex Pharmaceuticals	AAT correctors	Next-gen programmes to enter clinic in 2022
APB-101	Apic Bio	AAT gene therapy	IND enabling studies ongoing
KB408	Krystal Biotech	Gene therapy	Preclinical data presented Oct 2021
Source: Evaluate Pharma & company statements.

The other mid-stage contender is Mereo, which is aiming at patients with AATD lung disease. Its project, alvelestat, is proposed to work by inhibiting the lung-damaging neutrophil elastase enzyme, a role normally played by AAT.

A phase 2 trial that should yield data before the end of the year primarily measures reductions in desmosine, a biomarker of neutrophil elastase activity. A larger phase 3 trial looking at harder endpoints is a likely next step.

Back further in the pipeline are Inhibrx and Centessa, both of which claim to have the solution for both liver and lung manifestations of AATD.

Centessa

Lying behind Centessa’s efforts is a belief that the disease can be treated by prompting the faulty AAT protein to fold correctly. ZF874 is a pharmaceutical chaperone that, as the company describes it, acts as a molecular patch. Clinical proof of mechanism was claimed yesterday from data in three patients – levels of functional AAT returned to normal in the two who received ZF874.

A toxicity signal in one patient removed the shine, however, and the company’s insistence that a way forward could be found by changing the dosing schedule failed to impress. Centessa’s shares dropped 19% on the update. 

Finally, Inhibrx is pursuing arguably the most straightforward approach with its recombinant AAT-Fc fusion protein, INBRX-101. This could offer a more convenient and cost effective option over AAT augmentation therapy and, according to Inhibrx, complement RNAi approaches.

Shares in the company have advanced 68% since the first look at phase 1 data were released in October. The next update, which will concern a larger patient cohort, is due in the first half of 2022; the attention of bigger players already present in AATD has presumably already been piqued.

That will likely include CSL and Grifols. True, several gene therapies are in preclinical development, but it is easy to understand how INBRX-101 might feel like a surer bet for those with market share to lose.

https://www.evaluate.com/vantage/articles/news/trial-results/centessa-claims-place-antitrypsin-deficiency-pipeline