Multiple IPF drugs are being rushed into Phase III based on early-stage signals of efcacy and safety presented at the ATS meeting. Scrip spoke with the University of Pittsburgh's Kevin Gibson about the candidates, trial design, combination therapy and limitations of current therapy.
A bevy of early-stage IPF candidates showed preliminary signals of efcacy and safety in several sessions during the American Thoracic Society (ATS) International Conference in San Diego May 18-23 and now the drugs are in a race to Phase III.
Some of the presentations were updates from top-line data, but there also were new data to support later- stage programs. Scrip spoke with Kevin Gibson, medical director for the Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease at the University of Pittsburgh, who spoke in various venues at the conference. Gibson was moderator for one of the sessions, a Journal of the American Medical Association (JAMA) editorialist for the simultaneous publication of one of the trials, and a presenter or investigator for other studies.
Gibson told Scrip that while the efcacy signals in these early trials were encouraging, the drugs still are just "a few feet off the beach and have not gotten into the deep water yet." At this early stage, he felt the safety signal was the most important.
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"All of these are incredibly exciting," Gibson said, "primarily because of the preclinical data that suggests efcacy. I'm particularly interested in the Biogen study [of BG00011, for which he was also an investigator], as that has broad implications for our understanding of IPF." BG00011 targets TGF-beta activation, and "if that doesn't work, then we really don't understand IPF ... since almost everything revolves around TGF-beta activation in some form or fashion."
However, Gibson said, "I don't think anyone who has been in the eld long enough would pick a winner at this stage – we're just excited that there's a race. We've learned that no one can pick a winner at this stage." He pointed to Gilead Sciences Inc.'s anti- LOXL2 monoclonal antibody simtuzumab, which many had thought was promising, but then "failed miserably." (Also see "Another Simtuzumab Failure For Gilead" - Scrip, 6 Jan, 2016.)
The Rush To Phase III: But Clinically Meaningful Is Not Necessarily Clinically Useful
While several of the companies have announced that they plan to move to Phase III, one question that came up was whether there were enough patients. "I think there's enough to handle ve or six or eight Phase III clinical trials," Gibson said. However, he added, particularly with the experience of Gilead, "moving from a proof-of-concept study to Phase III is hazardous; it's too expensive," so other companies are wary.
Biogen Inc., for example, started with a Phase IIa trial looking at biomarkers, and is looking to start a 290- patient Phase IIb trial, and about half of the patients are expected to be on background therapy with Roche's pyridone Esbriet (pirfenidone) or Boehringer Ingelheim GMBH's kinase inhibitor Ofev (nintedanib).
Gibson said there are pitfalls with combination therapy, but Biogen's design is probably the best way to go. He said companies can be concerned that they may not be able to nd enough patients who are not on approved agents, but that is not the case, given limitations with current therapies.
"I've had people tell me you cannot do a placebo-controlled trial. Yes, you can," he said. "We have the largest center probably in the country, and I would say two-thirds of my patients say they don't want the [approved drugs], when they look at the side effect prole. It’s a quality of life issue."
Gibson noted that the approved therapies may not take away their cough or give patients energy, and while they can slow the decline of forced vital capacity (FVC), patients can be skeptical.
This is not just an issue for approved drugs, but also for those in the pipeline, though some of these may have an advantage of lower side effects. In the JAMA editorial for the pentraxin 2 study presented at ATS, Gibson and Daniel Kass, director for the Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease, wrote that in this new era with two approved drugs available, "sole reliance on a 10% change in FVC and a trend toward improved survival (as suggested by the FDA) as the primary outcome measure will leave the pulmonary community without clear and coherent guidelines for treatment."
Gibson and Cass also noted that current clinically meaningful endpoints may not necessarily be clinically useful, and while they emphasized that there should be more discussion of endpoints, given the unprecedented interest from pharma companies, they did not have a simple solution. On the one hand, a multi-year trial powered to detect a survival benet is not feasible. On the other, there has been diminished enthusiasm for measures like the six-minute walk distance (6MWD).
However, they did feel that researchers and clinicians should establish a composite endpoint "to address change in pulmonary function as well as other endpoints for which treated patients will experience tangible benets. These include, but are not limited to exercise capacity, quality of life, or survival to transplant ... an IPF therapy that improves or at least stabilizes exercise capacity would be attractive and clinically useful." Such Phase III trials will serve as a "bellwether for the conduct of trials in a post-treatment era in IPF."
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Combination Therapy At Your Own Peril
In data for Prometic Life Sciences Inc.'s PBI-4050 at the ATS meeting, patients who were also on Esbriet had a decline in FVC that was much more dramatic than those also on Ofev or not on either of the approved therapies. The company concluded that was due to drug-drug interactions.
In general, Gibson said, "the problem with combination therapy is that in order to do it well you need to make sure two drugs don't have adverse interactions or don't enhance side effects, so simply administering two drugs together in a [proof-of-concept] study is not a good idea." One issue is that "it is hard to argue for an additive benet when you don't know how [Esbriet and Ofev] work" and there is the risk that they may interfere with the actions of each other. Moreover, "you may double the side effects without any evidence whatsoever that you are doubling the benet," he said.
Of course, with high-priced orphan drugs, reimbursement would also be a signicant issue for combination therapy.
Another strategy, instead of combination therapy, is replacing current options. Gibson noted that Esbriet and Ofev "make people sick with diarrhea and fatigue. Any drug that doesn't have [that adverse effect] prole is going to do better in terms of prescription."
Galapagos' Early POC For GLPG1690
In updated data from a 23-patients Phase IIa proof-of-concept (POC) trial, daily doses of Galapagos NV's oral autotaxin inhibitor GLPG1690 did not show any important safety or tolerability issues and numerically stabilized FVC compared to placebo both in on-site measures (ITT population: +25 mL versus -70 mL, +3.7% versus -2% percent predicted) and in home spirometry measures. (Also see "Galapagos' FLORA: Highly Positive Hints In IPF, But More To Prove" - Scrip, 11 Aug, 2017.)
While there was a signal of efcacy, it was not statistically signicant, though that could be due to the small size of the study. Autotaxin is involved in the production of lysophosphatidic acid (LPA), and both are elevated in IPF and various inammatory conditions. The study also demonstrated target engagement, with a reduction in LPA.
In an accompanying Lancet, Respiratory Medicine article, Toby Maher and colleagues implied a more benign side effect prole than currently approved Esbriet or Ofev, which were not allowed in the study and are known to have tolerability issues, while acknowledging rm conclusions could not be drawn.
The study was notable for providing support for the drug with a relatively small number of patients and short duration. Gibson pointed out to Scrip that one of "the challenges these smaller proof-of-concept trials have is trying to gure out a population of patients who will likely change during a very limited period of observation so that they can see a signal to justify proceeding forward."
He also lauded the use of home FVC measurements, which he said could prove to be a tool for POC trials in the future and useful for identifying patients who decline. Another potential tool will be biomarkers. "There are a lot that have been looked at that at least can stratify patients at high risk of decline, so that should be a useful tool down the road," Gibson said, though he noted that the change in biomarkers should come before the change in FVC, or there is not as much rationale for their use.
Galapagos is jumping to Phase III, which is expected to start in the second half of 2018.
Promedior's Partnered Pentraxin 2
New data from a 117-patient Phase II study of pentraxin 2 (PRM-151) – a recombinant form of the human pentraxin 2 protein developed by Promedior Inc. with Bristol-Myers Squibb Co. – showed statistically signicant benet on change in percent predicted FVC (-2.5% versus -4.8% for placebo), though both groups showed a
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decline, with patients receiving pentraxin 2 declining at a slightly slower rate than in the placebo group after week 12.
The magnitude of the benet on FVC was of similar magnitude in the 78% of patients on Esbriet/Ofev as those not on these drugs, though in both arms, those on concomitant drugs declined more than those not on other treatments.
Pentraxin 2 also had a statistically signicant and more pronounced impact on 6MWD (-0.5m versus -31.8m), with relative stability compared to a decline for placebo. Ganesh Raghu, director of the Interstitial Lung Disease/Sarcoid/Pulmonary Fibrosis Program at the University of Washington, Seattle, and colleagues noted in the simultaneous JAMA publication that a difference of 24m to 45m has been reported to be clinically important in IPF and a decline of 25m or more has been independently associated with one-year mortality. However, they also acknowledged that the nding is only weakly correlated with other respiratory measures and symptoms.
Gibson's accompanying JAMA editorial, called the
6MWD ndings intriguing, but elaborated on the investigators' views that there has been diminished enthusiasm for the measure, at least as a primary endpoint, due to the weak correlation and other confounders.
However, no signicant benet was seen on several other efcacy endpoints in the study. One drawback was the drug was given intravenously, though only every four weeks. On safety, pentraxin 2 patients did have more cough (18% versus 5%), about 4% of patients had infusion reactions (though none were deemed serious), and there were several cases of elevated liver enzymes, which also are seen with approved drugs.
Pentraxin 2, or serum amyloid P, is a naturally occurring inhibitor of monocyte differentiation into pro- inammatory macrophages and production of TGF-beta1. Gibson told Scrip this was particularly interesting, because it is replacing something that is decient in human IPF, reintroducing a molecule thought to be protective against pulmonary brosis. That could also mean it turns out to have fewer side effects.
Kadmon's ROCK2 Inhibitor KD025
Kadmon Pharmaceuticals Inc.'s KD025, which inhibits Rho-associated coiled-coiled kinase 2 (ROCK2), had updated data at ATS showing a slowing of FVC decline over 24 weeks: -50 mL versus -175 mL for best supportive care (BSC), as well as a smaller portion with a 5% or more decline (29% versus 55%), though these apparently were not statistically signicant.
Gibson was the presenter, and he showed that the numbers for KD025 at 24 weeks, as well as a subset followed to 45 weeks, were in the range seen in the Phase III studies of Esbriet and Ofev, while the BSC nding was in the range of the placebo groups from those trials.
Though the drug did not appear to perform better than these approved drugs, Gibson told Scrip that he was impressed that patients who previously were on Esbriet/Ofev stabilized so much (-2 mL versus -273 mL),
Bristol's Fibrotic Game Plan: Promedior Buy Hinges On Phase II Data
By Joseph Haas 31 Aug 2015
Already very active in deal-making for brotic disease companies and candidates in the past year, Bristol-Myers Squibb ponied up $150m in upfront cash on Aug. 31 for an option to acquire Promedior Inc. and its mid-stage biologic for myelobrosis (MF) and idiopathic pulmonary brosis (IPF).
Read the full article here
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though there were only two placebo patients to compare. However, that also meant that there was not as large a benet as the overall numbers for those not previously on therapy.
On safety, there were more KD025 patients with elevated liver function tests (20% versus 14%). Still, Dr. Gibson said KD025 appeared more tolerable than currently approved drugs, so even if it had comparable efcacy, it could be a replacement for the current options.
Datamonitor Healthcare's Sultan Khan also told Scrip that "commercial appeal will be buoyed if pharmacodynamic synergy is demonstrated with [FibroGen Inc.'s] pamrevlumab (anti-CTGF antibody). KD025’s ROCK signaling pathway causes a downstream effect on CTGF suggesting possibility to potentiate their effect on brosis when combined." (Also see "FibroGen Hails 'Milestone' IPF Data, Phase III And Partners Beckon" - Scrip, 8 Aug, 2017.)
Khan also said, though, that there were potential pitfalls, since one could be potent enough that the other would have a minimal effect or too much inhibition could lead to unforeseen adverse events.
Gibson said Kadmon had decided to expand the study to 80 patients and then decide whether to proceed further.
In a discussion after the session, one participant said it was odd that all the trials released had such a large decline in the placebo group. Gibson felt part of that was luck, but also there may be a selection bias. Patients may be on Esbriet or Ofev and declining, so they decide to stop the drug and enter a trial instead.
Prometic's PBI-4050 Alone And In Combination
ProMetic's PBI-4050 is a daily oral drug that reduces brosis through GPR40 agonism and GPR84 antagonism, which was tested alone or with Esbriet or Ofev in 41 patients for 12 weeks. While it showed relative stability in FVC alone or with Ofev, patients on PBI-4050 and Esbriet declined substantially (-102mL).
Lyne Gagnon, Prometic's vice president of preclinical research and development, attributed the result for the Esbriet combination to a drug-drug interaction (increased metabolism of pirfenidone and reduced absorption of PBI-4050).
While the lack of a placebo group was a weakness of the study, Gagnon noted that the PBI-4050/Esbriet group performed like the placebo group in other studies. Of course, there also is the possibility that the combination could have made patients worse off than they otherwise would have been. The drug was well- tolerated, though, and impacted a number of biomarkers. Phase III is planned to start in mid-2018.
BG00011 Study Too Short For Pulmonary Data
Biogen's BG00011 is a monoclonal antibody targeting integrin alpha-V beta-6, which modulates TGF-beta – a key mediator in the injury/repair imbalance in IPF. In a placebo controlled, Phase IIa, sequential dose- escalation study presented at ATS, where the drug was given once-weekly for eight doses, the efcacy data primarily involved safety, pharmacokinetics and biologic activity, which was demonstrated by dose- dependent effects on pre-specied genes that paralleled preclinical ndings.
An audience member asked why Biogen did not present pulmonary function test data, but the investigator – the University of Washington's Raghu – said the study was too short for those results to be interpretable.
Dosing at up to 1 mg/kg was well tolerated, but three patients on 3 mg/kg had sustained respiratory declines. The investigator did not know the cause, but said it could be due to over-suppression of TGF-beta, perhaps with an inammatory are up. Another audience member noted, however, that there was appreciable variability in the PK, and asked whether at the lower dose and in a larger study there could be some patients who have too high an exposure. Raghu said they do not believe so, but will be following that carefully in further studies.
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The study did allow investigators to select a 56 mg at dose to carry forward in Phase IIb, which will enroll approximately 290 patients, about half of whom are expected to be on background therapy.