Proteostasis Puts Best Face On Unspectacular CF Combo Data
Executive Summary
With data showing a lung function and sweat chloride benefit for its proprietary CFTR-modulating triplet, Proteostasis says it’s moving ahead. But analysts and investors are concerned the effects are less than seen with Vertex drugs.
Proteostasis Therapeutics Inc. sees the early data on its proprietary triple combination of CFTR-modulating drugs in cystic fibrosis as supporting a move into Phase II this year, and Phase III next, but the lung function data in particular pales in comparison to sector-leader Vertex Pharmaceuticals Inc. – a cause for concern for analysts and investors. Proteostasis finished the trading day March 25 down more than two-thirds of its value.
While Vertex has staked a dominant lead in CF with Kalydeco (ivacaftor) and multiple combination products anchored by that compound – all of based on the concept of modulating the cystic fibrosis conductance regulator (CFTR) gene – Proteostasis is furthest advanced among companies trying to claim a share of the CFTR space. On March 25, it presented 14-day data for both its proprietary triple therapy – the third-generation CFTR corrector PTI-808, novel CFTR potentiator PTI-801 and CFTR modulator amplifying agent PTI-428 – and for two of those compounds as add-on therapy to Vertex’s combo Symdeko (tezacaftor/ivacaftor).
The triplet showed ability to increase percent predicted forced expiratory volume at one second (ppFEV1) ranging from 4% to 8% from baseline compared to placebo, but multiple analysts pointed out that Vertex’s Phase III triple combinations have demonstrated ability to improve FEV1 by about 14%. On March 6, Vertex unveiled data showing that a triplet combining its novel CFTR corrector VX-445 with Symdeko showed a mean absolute improvement of 13.8% in placebo-controlled FEV1, while a combination of VX-659, another new CFTR corrector, plus Symdeko yielded a 14% mean absolute improvement on that measure of lung function. (Also see "Vertex Stuck Between A Good Place And A Better Place" - Scrip, 6 Mar, 2019.)
Vertex’s triplet studies used a four-week duration of treatment for their endpoint, while Proteostasis so far has studied its combos over two weeks. Proteostasis tested two dosing regiments in its triplet study – one incorporating 600 mg of PTI-801, 150 mg of PTI-808 and 30 mg of PTI-428, the other 200 mg of ‘801, 300mg of ‘808 and ‘30 mg of 428. The regimen including 600 mg of PTI-801 showed the better efficacy.
Vertex’s ivacaftor is a CFTR potentiator, while its other CF candidates are all CFTR correctors. Proteostasis CEO Meenu Chhabra noted on a March 25 investor call that her firm’s PTI-428 is the only CFTR modulator amplifier in development. The Boston biotech, however, has been dogged by assertions that PTI-428 has demonstrated minimal benefit if any to date – a follow-on public offering planned for early 2019 had to be postponed for about seven months due to short-selling tactics by Kerrisdale Capital. (Also see "Finance Watch: The Curious Case Of Proteostasis' Short Attack" - Scrip, 22 Mar, 2018.)
Still Reason To Question PTI-428’s Benefit
While Proteostasis is going ahead with its proprietary triplet that incorporates the amplifying agent, the candidate’s activity did not gain much validation from the add-on therapy data the company reported. Neither a trial testing PTI-428 with Symdeko nor one pairing PTI-801 with the Vertex combo showed significant benefit compared to patients dosed with Symdeko alone.
Proteostasis needed to eliminate the sickest patients – those predisposed to rapid pulmonary decline – from its triplet study to come up with a subpopulation that showed an 8% improvement in FEV1 from baseline compared to placebo. That the sicker patients were included in the study in the first place indicated the challenging clinical development environment in CF, one analyst noted, as trial participants strongly prefer to participate in Vertex-sponsored studies.
“Proteostasis’ triple study utilized a ‘broader’ entry criterion by including patients with lung colonization status (e.g. rapid FEV decliners) due to limited patient availability, which 'confounded' the results and made 'interpreting' the data challenging,” Jefferies analyst Michael Yee said in a March 25 note.
Chhabra cited two main arguments for her company’s triplet on the investor call – the treatment effect did not plateau at 14 days, suggesting a greater effect might be achieved with longer study, and her sense that the cystic fibrosis community wants greater choice among therapies and drug makers.
“We have also learned a great deal about what the CF community’s needs throughout this period are, and the answer isn’t a new, high bar on one endpoint measured over 14 or 28 days, but rather choice,” the exec said. “The choice of different modulators to test their performance and customize treatment, not unlike essentially every disease category.
“All the market research and interaction we’ve had with the CF community has taught us a lot, including that there is clear, urgent need for more therapeutic options driven not just by unmet medical need but as importantly by issues of access, tolerability and the overall heterogeneity of this disease,” Chhabra continued. “A second entrant into the current $3bn CFTR modulator market would have significant impact, not the least of which being that it would trigger negotiation of current pricing, reimbursement and access arrangements for payers.”
Proteostasis Plans Trio Of 28-Day Studies
To test out the hypothesis that longer duration of therapy might show a greater benefit on lung function, Proteostasis plans to launch three 28-day studies – the triplet in patients with two copies of the F508del mutation (homozygous), the PTI-801/PTI-808 doublet in F508del homozygous patients and that doublet in CF patients with one copy of the F508del mutation (heterozygous).
In a note discussing how the data would impact Vertex, SVB Leerink analyst Geoffrey Porges conceded that Proteostasis’ theory on longer duration therapy could have merit. “It is possible that increased efficacy could be achieved by the high-dose PTI-801 triple after a longer dosing interval,” he wrote March 25. Overall, however, he predicted that Vertex has a “free and clear CF monopoly after mediocre Proteostasis data.”
Proteostasis remains on track to initiate a Phase III program by the middle of 2020, Chhabra added. She compared the company’s progress to the rate of clinical development Vertex saw, noting that in three years Proteostasis has studied three proprietary CFTR modulators in 500 patients across 10 trials, including 240 CF patients.
Porges’ SVB Leerink colleague Joseph Schwartz, reviewing the data from Proteostasis’ perspective, noted that the company has cash sufficient to fund operations into the second quarter of 2021, perhaps sufficient to get to Phase III data. The company eventually grossed $74.3m in its delayed FOPO last October. (Also see "Finance Watch: Rough US Stock Market Doesn't Stop Biopharma IPOs As Six More Go Public" - Scrip, 31 Oct, 2018.)
“The update today highlights that going forward, the CF competitive landscape will likely get more challenging as Vertex gets ready for their [triple combination] filing,” he said. “However, the triplet data not plateauing at day 14 suggests that with a longer duration, higher FEV is possible and that could provide patients more therapy options.”
Proteostasis shareholders, for the most part, did not see much merit in this upside argument, as the firms’ stock finished the day down 68% to $1.31 per share.