Bellerophon Therapeutics, Inc. (NASDAQ:BLPH) is a clinical development-stage medical therapeutics company focused on the development and commercialization of INOpulse, a novel nitric oxide therapy which, if successfully developed and approved for sale, will address serious and terminal chronic cardiovascular diseases with high unmet needs. The company has several mid-to-late stage clinical studies ongoing in three distinct clinical indications (PH-ILD, PH-COPD and PH-Sarcoidosis), all of which lack effective treatment options. Their PH-ILD program, which is evaluating the safety and effectiveness of INOpulse in the treatment of Pulmonary Hypertension associated with Interstitial Lung Disease (PH-ILD), is the furthest along and represents a potential commercial opportunity worth in excess of $2B per year.
Last week BLPH announced additional positive data from Cohort 1 of its ongoing Phase 2/3 study of INOpulse in PH-ILD. This builds on earlier data releases from this same cohort which included statistically significant improvement in multiple clinically meaningful activity parameters – encouraging as the proposed Phase 3 (pivotal) study is expected to use the same measures as its primary endpoint. With Cohort 1 data continuing to look highly promising and Cohort 2 (higher dose group) topline data anticipated later this year, the likelihood for near-term value-inflection opportunities (from this study alone) appears to be increasing.
New Compelling Phase 2/3 Data Further Supports Utility of iNO in PH-ILD
On October 23rd Bellerophon announced new positive data from its ongoing Phase 2/3 clinical trial in PH-ILD. This data, which relates to Cohort 1 (the initial of three cohorts in this Ph2/3 PH-ILD study), continues to support the effectiveness of iNO in this indication and follows on the heels of similarly encouraging results announced in January and May of this year.
Importantly, the new data appears to largely confirm prior results, including superiority of INOpulse in improving patients’ ability to perform daily activities (degradation of which is a primary symptom of PH-ILD and predictor of survival and death) and the durability (i.e. lasting effect) of INOpulse treatment. The data is particularly encouraging as these are measures that have already been validated by regulators as appropriate pivotal trial endpoints. They also represent real-world, clinically important measures and are likely to be used by insurers and physicians to make reimbursement and adoption decisions, respectively.
The most recent results, which were unveiled last week as a late-breaking oral presentation at the American College of Chest Physicians (CHEST) 2019 Annual Meeting (New Orleans), includes additional positive responder (i.e. 15% increase or decrease from baseline) data related to the key activity measures including the primary endpoint (moderate to vigorous physical activity, or MVPA) as well updated positive results from the open label extension portion of the study.
New Cohort 1 Data
The responder data comes from the randomized, double blind, placebo controlled (RCT) portion of the study while the Open Label Extension data relates to those patients that, following completion of the RCT, volunteered to continue to be followed for another 27 weeks. Below we provide additional background on the study design and previously announced Cohort 1 data.
‣ Any improvement from baseline: results showed that while only 15% of subjects treated with placebo showed any improvement (although none met the threshold of ‘clinically meaningful’) on all three activity measures (MVPA, non-sedentary activity and overall activity), of those patients treated with INOpulse 46% experienced improvement in MVPA, 39% experienced improvement in non-sedentary activity and 62% experienced improvement in overall activity
‣ Clinically meaningful change from baseline: for the change in these outcome measures to be considered ‘clinically meaningful’ it must differ from baseline by at least 15%. Clinically meaningful change (on both improvement and decline) also favored the INOpulse arm
◦ Improvement: Results showed that while 0% of placebo patients experienced a clinically meaningful improvement from baseline in all three activity measures (i.e. MVPA, non-sedentary activity and overall activity), of those patients treated with INOpulse 23% experienced clinically meaningful improvement in MVPA, 8% experienced clinically meaningful improvement in non-sedentary activity and 15% experienced clinically meaningful improvement in overall activity
◦ Decline: Of the patients in the placebo arm 71%, 43% and 21% experienced a clinically meaningful decline (i.e. degradation of activity as compared to baseline) as measured by MVPA, non-sedentary activity and overall activity, respectively. This compares to the INOpulse arm which had a lower proportion of patients in each of the three activity measures experiencing clinically meaningful declines – specifically 39%, 23% and 15% experienced a clinically meaningful decline of MVPA, non-sedentary activity and overall activity, respectively.
Open Label Extension portion:
‣ The major takeaway of the new data from the open label extension portion of the study is that it continues to show the durability pf effectiveness of INOpulse therapy. In other words, results from the OLE study indicate that the improvement to the activity measures that INOpulse patients experienced during the RCT (i.e. blinded) portion appear to be largely maintained through 27 weeks (~6 months) in OLE’s longer follow-up period. In addition, some of the placebo patients which experienced a deterioration in activity during the RCT experienced a reversal after receiving INOpulse treatment in the OLE portion. The ability to improve activity levels of PH-ILD patients and to maintain that improvement has been shown to be critically important given that numerous clinical studies have demonstrated that physical activity is associated with a host of clinically meaningful outcomes and is an independent predictor of survival and death. As such, this durability data, while important from a regulatory standpoint, has direct real-world applicability as well as it relates to improving patient outcomes.
◦ Durability of INOpulse treatment: (per BLPH’s 10/23/19 PR):
• “Collectively, subjects (with an average of 27 weeks of OLE data) demonstrated maintenance of MVPA, overall activity and non-sedentary activity”
• “Subjects randomized to active treatment in the blinded portion of the trial continued to maintain their activity levels when transitioning to OLE over 27 weeks of open-label treatment”
◦INOpulse ‘rescued’ (our word) placebo patients:
• “Subjects randomized to placebo in the blinded portion of the trial transitioned from a decline during blinded treatment to stabilization of activity levels (MVPA, overall activity and non-sedentary activity) over 27 weeks of open-label treatment”
Background on PH-ILD Phase 2/3 Study and Previously Announced Cohort 1 Data
Phase 2/3 Study: positive Ph2 data announced in May, Ph3 to serve as pivotal U.S. study
In January of this year BLPH announced positive initial results from a Phase 2b clinical trial of INOpulse in the treatment of PH-ILD. The company leveraged those compelling results, which we discuss below, to successfully petition FDA on the choice of the primary endpoint and modify the study from a Phase 2b to a Phase 2/3, with the Phase 3 portion expected to serve as a pivotal registrational trial. BLPH announced in early April that FDA concurred.
Results from Cohort 1 (of the Phase 2b portion) were announced in January. The randomized, double-blind, placebo-controlled study (iNO-PF) is evaluating the safety and effectiveness of INOpulse in the treatment of patients with PH associated with ILD and on long-term oxygen therapy (LTOT). Enrollment was initially intended to be 80 patients among three cohorts and across three doses (iNO 30 n=40, iNO 45 n=20 and iNO 75 n=20). However, the update from Ph2b to Ph2/3 modified the design of the Ph2 portion to two cohorts across two doses (iNO 30 = 40, iNO 45 = 40), which will determine the dose to use in the (newly created) Ph3 portion, which is expected to enroll approximately 300 patients. The updated design allows for a seamless transition (without requiring an end-of-Phase 2 meeting with FDA) from Ph2 to P3 (pivotal) studies. The Ph2 portion also includes an open label (‘part 2’) dose-escalation treatment period.
Primary endpoints: The study was initially designed to assess a number of exploratory endpoints including; activity monitoring, right and left ventricular function, (several) oxygen de-saturation measures, 6MWD, QoL (as measured by patient reported outcomes), pulmonary hemodynamics and NT-ProBNP, among others. BLPH announced in April that FDA agreed to their proposal to use ‘improvement in moderate to vigorous physical activity (MVPA) as measured by a medical wrist-worn continuous activity monitor’ (known as actigraphy) as the primary endpoint in the Phase 3 study. BLPH’s proposal to use MVPA as the primary endpoint was motivated by results of Cohort 1 which showed INOpulse patients experienced a statistically significant improvement (of 34%) in MVPA versus patients on placebo.
Importantly, FDA’s decision to accept MVPA as the primary endpoint also confirms that this is considered a clinically meaningful measure (a classification that can be critical in attracting clinician interest and adoption and can also have reimbursement-related significance). This is also supported by numerous clinical studies that have demonstrated that physical activity is associated with a host of clinically meaningful outcomes and is an independent predictor of survival and death, including in patients with various cardiopulmonary diseases. MVPA/actigraphy has also been used as a primary or secondary endpoint in a number of late-stage (drug and device) clinical trials for pulmonary and cardiovascular conditions including as the primary endpoint in Novartis’ ongoing Ph3 study of Entresto (in chronic heart failure) and Actelion’s Ph4 (post-marketing) study of selexipeg in PAH, among others.
Cohort 1 (n=41: iNO=23, placebo=18), was intended to be randomized 1:1 and evaluated iNO 30 dose. A one-week run-in period was followed by eight weeks of treatment. Patients then transfer to open label therapy at iNO 30 x 8 weeks, iNO 45 x 8 weeks, iNO 75 x 8 weeks which is followed by long-term open label therapy. Results, announced in January and (additional data in) May 2019, are discussed below.
Cohort 2 (n=44) is randomized 2:1 and evaluates iNO 45 dose. A one-week run-in period is followed by 16 weeks of treatment. Patients then transfer to open label therapy at iNO 45 x 8 weeks, iNO 75 x 8 weeks which is followed by long-term open label therapy. BLPH announced on August 1st that Cohort 2 completed enrollment. The Ph2 study is expected to complete later this year.
Cohort 3/Phase 3 (n=~300): The optimal dose to be used in Phase 3 will be determined by results of Cohort 1 and Cohort 2. BLPH anticipates Ph3 to begin in 1H 2020 and while the study size has not yet been determined, the company estimates total enrollment of around 300 patients (150/arm) and a completion timeline of 18 to 24 months.
Phase 2 Cohort 1 Results: significant improvement in MVPA, clean safety profile
Results of Cohort 1 (i.e. 8 weeks treatment at iNO 30) were initially announced in January and additional data released in May, which were presented at the American Thoracic Society International Conference. Highlights included statistically significant improvements versus placebo in MVPA and overall activity (illustrated in graph below with distinct treatment vs placebo separation beginning ~week 4) and clinically meaningful improvement in NT-ProBNP as well as oxygen saturation. In summary, INOpulse demonstrated targeted delivery of NO, resulting in oxygen saturation during exercise and significant improvement in key activity measures. iNO therapy was well tolerated, incidence of serious adverse events were low (and similar in both groups) and all SAEs were unrelated to iNO.
- MVPA (primary endpoint): iNO patients saw a statistically significant 34% improvement vs placebo and
o 23% of iNO patients has clinically meaningful improvement in MVPA vs 0% on placebo [‘clinically meaningful’ increase is defined as >15% increase in MVPA from baseline]
o 39% of iNO patients has clinically significant decline in MVPA vs 71% on placebo [‘clinically meaningful’ decrease is defined as >15% decrease in MVPA from baseline]
- Portion of awake time spent in MVPA improved by a statistically significant 38%
- Overall activity improved by a statistically significant 12%
- Calorie expenditure improved by a statistically significant 12%
Data from the open label portion showed that patients continued benefit from iNO treatment and those that transitioned from placebo to iNO experienced a change from deterioration to improvement in both MVPA and overall activity.
- Placebo patients had an average weekly decrease of three minutes per day of MVPA during blinded treatment, which reversed to an average weekly increase of one minute per day during open-label
- Placebo patients had an average weekly decrease of 22 counts/minute in overall activity during blinded treatment, which reversed to an average weekly increase of 15 counts/minute during open-label
- iNO patients remained stable for both MVPA and overall activity during blinded treatment, both of which improved during open-label, with an average weekly increase of 1 minute/week in MVPA and 15 counts/minute in overall activity
Our take: the Cohort 1 results are highly encouraging, particularly achievement of statistical significance on improvement in MVPA versus placebo, which will serve as the primary endpoint in the Phase 3 study. The clean safety profile, while not a surprise given the lack of INOpulse-associated SAEs in prior clinical trials, is equally encouraging. We will be eagerly awaiting results of Cohort 2 and curious to see if the increased treatment period (to 16 weeks) and dose (to iNO 45) results in further separation on the efficacy measures and/or any adverse change in safety. While we would view meeting statistical significance in MVPA in Cohort 2 as a highly positive event, the combination of statistical significance on MVPA and strong evidence of dose response could be particularly compelling as it relates to providing insight into the potential utility of INOpulse in PH-IPF.
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