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I wrote about a small company named Pliant Therapeutics (NASDAQ:PLRX) two years ago. Pliant interested me because despite being an under-the-radar company, it had important collaborations, and it worked in fibrotic diseases. In July, Pliant stock went up after data from a phase 2a trial – designed to test safety and tolerability – also showed the drug’s efficacy in improving forced vital capacity or FVC in idiopathic pulmonary fibrosis patients. Although a trial of only 12 weeks may not be enough to convince scientists, and while there was confusion about dose dependent improvements because a smaller dose showed better efficacy than a higher one, Pliant stock has been on the rise. Data from a higher dosage cohort, coming next year, will help remove the confusion. Interestingly, Pliant’s own CEO once doubted that such a small trial will show FVC improvements.
Pliant works in integrin-mediated inhibition of the TGF-β pathway, which reduces fibrosis and is safe. The science is described thus in the 10-K:
We believe that tissue-specific inhibition of TGF-β may hold the key to successfully treating fibrosis. In normal tissues, TGF-β is activated in response to tissue injury which initiates a cascade that results in collagen production and, ultimately, scar formation to heal the tissue. In fibrosis, however, TGF-β signaling becomes dysregulated, with TGF-β being continuously activated, leading to excess collagen deposition, even in the absence of acute tissue injury. TGF-β, while implicated in fibrosis pathophysiology, is expressed, and intermittently activated across all tissue types and plays important, contextspecific roles in tissue homeostasis. Therefore, TGF-β cannot be blocked systemically without disrupting these homeostatic functions and causing significant toxicities. To treat fibrosis more precisely in specific tissues, we believe it is crucial to discover and treat the underlying mechanism causing excess TGF-β activation. Our scientific founders are pioneers in elucidating the role of specific extracellular receptors known as integrins as a key element in the activation of TGF-β.
The company is running trials in Idiopathic Pulmonary Fibrosis or IPF and Primary Sclerosing Cholangitis or PSC. The product candidate is called PLN-74809. These are ongoing phase 2a trials with data to topline next year. Another candidate, PLN-1474, is being developed for NASH-Associated Liver Fibrosis in collaboration with Novartis (NVS).
This year, the company announced data from a proof of concept trial. From the 10-K:
In February 2022, we announced positive results from an expanded PLN-74809 Phase 1b proof-of-mechanism trial. This study evaluated PLN74809’s ability to suppress TGF-β activation in the lungs of healthy volunteers as measured through relative pSmad2 levels in alveolar macrophages collected through bronchioalveolar lavage (BAL) at 6 hours and 24 hours after the last dose. The trial was conducted in two parts. Part 1 evaluated PLN-74809 at doses of 80 mg and 160 mg versus placebo and Part 2 evaluated PLN-74809 at 320 mg versus placebo. PLN-74809 demonstrated clear evidence of on-target biological activity in the lungs of healthy participants. Results showed that PLN-74809 inhibited TGF-β activation by up to 92% and 76% at 6- and 24-hours, respectively, following dosing. PLN-74809 was well tolerated with mostly mild adverse events, and no severe adverse events. There was no dose relationship associated with adverse events, no serious adverse events (SAEs) and no treatment discontinuations due to adverse events. This trial further defines the relationship between plasma exposure of PLN-74809 and TGF-β inhibition in the lung and will guide dose selection in future trials.
Data from a phase 2a trial was also announced, which showed PLN-74809 was well tolerated with strong treatment effect on FVC or Forced Vital Capacity and Quantitative Lung Fibrosis or QLF in IPF patients. 320 mg data is expected in early 2023. Biogen (BIIB) and GSK (GSK) discontinued integrin studies in IPF after safety concerns. Pliant says those particular toxicities were absent in its trials.
IPF has 140,000 US patients, with 30-40,000 new patients every year. Boehringer Ingelheim’s Ofev or Roche’s (OTCQX:RHHBY, OTCQX:RHHBF) Esbriet are two approved therapies which together made $3bn in 2021. However, two things; one, Esbriet has gone off patent and Ofev will go off patent in 2025; and two, neither drug is very effective nor safe. In my opinion, while the second point creates an opportunity for PLRX, the first point actually hurts its prospects.
Financials
PLRX has a market cap of $968mn and a cash reserve of $163mn. After the positive IPF data, the company raised a whopping $230mn from the market in a secondary offering, bringing its cash balance to nearly $400mn. Research and development expenses were $26.3 million this quarter, while general and administrative expenses were $8.3 million. This gives them a cash runway of over 10 quarters at the current rate of expenses. The company also has a $100mn loan facility with Oxford Finance LLC. The company recently received $4mn in milestone payment from partner Novartis after its partnered NASH program moved into the clinic.
Bottomline
PLRX looks like an emerging winner with an important data readout next year. Beyond that, there’s a catalyst desert for a year or more, which may be an attractive opportunity to pick up shares. Right now, though, the boat seems to have sailed off.
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