Versus Vertex, Proteostasis' triplet CF data fall short, wilting stock
It’s too little, too late for little Proteostasis Therapeutics.
The Boston drug developer that is looking to take on Vertex Pharmaceuticals — and the company’s entrenched slate of cystic fibrosis medicines — reported data from a mid-stage study testing its own CF triplet on Tuesday. The results failed to impress, sinking the stock $PTI more than 42% to $2.51 in premarket trading.
The trial tested Proteostasis’ dirocaftor (or PTI-808), and posencaftor (or PTI-801) with or without nesolicaftor (or PTI-428) against a placebo in a four-week Phase II study in CF patients. Overall, 28 F508del homozygous and 40 F508del heterozygous subjects were enrolled in the doublet, triplet or placebo arms. CF is caused by a defective and/or missing CFTR protein resulting from certain mutations in the CFTR gene — the F508del mutation is one of the most common.
The homozygous patients that got the triplet combo saw a mean absolute improvement in ppFEV1 of 8 percentage points over pooled placebo at day 28. The percent predicted forced expiratory volume in one second, or ppFEV1, is an established marker of cystic fibrosis lung disease progression.
In people with CF, there is a problem in moving chloride across cell membranes, which means higher concentrations of chloride (as salt) in sweat. In Proteostasis’ trial, sweat chloride concentration in homozygous subjects receiving the triplet demonstrated a mean improvement of -29 mmol/L at day 28, compared to pooled placebo.
On both measures, the triplet induced statistically significant improvements — the doublet data was positive, but not statistically significant, the company said.
The data appears less competitive than Vertex’s Trikafta, Jefferies’ Michael Yee wrote in a note, estimating that Proteostasis’ 8% ppFEV1 benefit over placebo is about 40% lower than Trikafta’s benefit of 13-14%.
Proteostasis must achieve +10% benefit in ppFEV1 and 20mmol decline in sweat chloride with its triplet at 14-28 days to stay competitive as a second entrant, Cantor Fitzgerald’s Elemer Piros wrote in a note in March. Days later, the company underwhelmed investors when its proprietary triplet data showed a ppFEV1 benefit of 5%-8%, depending on the patient group on day 14.
Meanwhile, in the heterozygous population of Proteostasis’ Phase II trial, mean changes in ppFEV1 were not deemed statistically significant, although the improvement in sweat chloride concentration was.
“(T)he PTI combos did not work at all in the heterozygous group, which in our view raises a question about the overall effect and mechanism of PTI’s drugs (which necessarily doesn’t make sense),” Yee said, adding that the results were on very small numbers of patients and that Proteostasis’ Phase II enrolled CF patients with high disease burden or those who had failed prior therapies represent a very niche population, given that 85-90% of the CF market can be treatable (in theory) by a more robust CF VRTX regimen.
Still, with positive data in the homozygous population, Proteostasis will motor on. On Tuesday, the company said it would graduate to a Phase III trial, unveiling plans to launch a late-stage study in CF patients with the common F508del homozygous mutation in 2020.
The cystic fibrosis drugs made by Vertex are the first treatments that address the underlying genetic causes of CF, which is characterized by thick sticky mucus in the lungs, digestive system and other organs that reduces life expectancy. Vertex’s medicines target the cystic fibrosis transmembrane conductance regulator (CFTR) gene and are engineered to designed to correct the malfunctioning protein it makes. The company’s triplet, Trikafta, was approved earlier this year and is engineered to address 90% of the CF population.
Proteostasis drug, nesolicaftor is meant to boost levels of the CFTR protein. The therapy is an add-on treatment for patients with the F508del mutation in the CFTR gene who are already taking an approved CFTR modulator or as part of Proteostasis’ triple combo regimen that includes dirocaftor, a potentiator, and posencaftor, a corrector. Proteostasis is also investigating the use of its drugs in combination with Vertex’s CF therapies.
Last year was tumultuous for Proteostasis, marked by a vicious short attack, a yanked stock offering — but the biotech was given the endorsement of mighty Roche, which seized the rights to potential small molecule modulators with undisclosed targets from the company.