2020-10-16| In-DepthR&D

With its AAT Deficiency Therapy Biting the Dust, Vertex Pins Hope on Second Drug

by Ruchi Jhonsa
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By Ruchi Jhonsa, Ph.D.

Vertex is putting an end to its treatment, VX-814, for a rare genetic disorder after the drug caused an abnormal increase in the levels of liver enzymes in a Phase 2 study. This rare genetic disorder causes changes in the SERPINA1 gene that produces alpha-1 antitrypsin protein. Mutation in the gene causes the production of defective AAT protein, which gets trapped inside the cells instead of floating in the blood. Low blood AAT levels promote lung inflammation, and the accumulation of defective protein in liver cells results in liver damage.

Vertex is well known for its cystic fibrosis portfolio and boasts of three USFDA approved CF drugs, Kalydeco, Orkambi, and Symdeko. While vertex is filling its pocket heavily from the sales of these three, it is also diversifying its portfolio to capture other markets. This was when it started working with AAT therapies. What helped them kickoff with the AAT therapy so easily was their prior knowledge of the protein folding correction therapies they developed for cystic fibrosis.



Vertex’s therapy VX-814 was a small molecule-based therapy designed for correcting the protein-folding defect in AAT protein. The company had been testing the drug in about 50 patients with the deficiency to boost the levels of AAT protein. However, in between the study, investigators noted elevated liver enzymes (AST/ALT) in several patients, and four of them had spikes “greater than eight times the upper limit of normal,” the company said in a statement on October 14th.

On top of that, only low levels of the drug reached the target tissue. While those cases resolved or are still resolving, the company decided to scrap the trial altogether as it would never be able to make a sufficient amount of the drug reach the target tissue without increasing the dosage. That also means more damage to the liver. After the news, Vertex’s stocks dropped 9% in after-hours trading.

Investors had a lot of hope from Vertex’s AAT drug that also received fast track designation from the FDA last year. However, now they are questioning whether Vertex can move beyond CF fame and develop drugs for other conditions. However, not all hope is lost. Vertex has another drug, VX-864, in its pipeline, which targets the same disorder.

The company is proceeding with the Phase 2 trial of this drug, which was initiated in July this year. Similar to the Phase 2 study of VX-814, this study would evaluate pharmacokinetics and safety of the drug in 40 participants and test its ability to ramp up the production of AAT protein over 28 days of dosing. The data from the Phase 2 trial is due in 2021. Why does the company think this drug will work? This drug is “structurally distinct from the one that failed and many times more potent, which might work in its favor.


Competition in the Neighborhood

Currently, AAT deficiency has no cure, and patients rely on augmentation therapy-supplementation of plasma-derived AAT protein-to slow lung damage. If successful, Vertex’s therapy would have been the first one to claim the win. However, with this failure, Vertex might be pushed behind others who are active in the space.

Just a week back, Takeda signed up a $300 million pact with Arrowhead for its RNA interference treatment for liver disease linked to AATD. Unlike Vertex’s small molecule treatment, this works directly at the RNA level, bringing down the mutant protein levels. Last month, Arrowhead reported that after 24 weeks of treatment, four patients saw their serum and liver mutant AAT protein go down by up to 93% and 95%, respectively.

The drug is currently in Phase 2/3 pivotal trial, and thanks to these remarkable results, it might well become the first to reach the market. Dicerna also joined the race in April this year by forming a pact with Alnylam, where the two will pool their respective RNAi drugs for treating AAT deficiency. Both their drugs, ALN-AAT02 and DCR-A1AT, are in Phase 1/2 trial at the moment- slightly behind their rival from Arrowhead/Takeda.

Related Article: Takeda Collaborates with Arrowhead to Overcome Inherited Disorder via RNAi Therapy



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