4D pharma announces topline results from Blautix(R) Phase II trial in irritable bowel syndrome (IBS)

• Positive trends seen in primary efficacy endpoint of the study of overall response in both IBS-C and IBS-D subgroups
• Statistically significant impact on overall response in combined IBS-C and IBS-D group 
• Blautix was well tolerated, with a safety profile comparable to placebo
• Phase II trial results provide strong foundation for the continued development of the first therapeutic with potential to treat both major subtypes of IBS

Leeds, UK - October 7, 2020 - 4D pharma plc (AIM: DDDD), a pharmaceutical company leading the development of Live Biotherapeutics, today announces encouraging topline results from its Phase II BHT-II-002 trial of Blautix(R), a single strain Live Biotherapeutic to treat irritable bowel syndrome (IBS).

Consistent with FDA guidance on the clinical evaluation of treatments for IBS, 4D pharma plc (‘4D’) investigated the effect of Blautix on both bowel habit and pain as a composite response endpoint. 4D pharma also investigated the treatment across both IBS-C (constipation predominant) and IBS-D (diarrhoea predominant) clinical subtypes, as Blautix has potential to treat both major subtypes of the disease, unlike other approved products which act only on symptoms associated with either subtype of IBS.

The Phase II trial showed that Blautix treatment resulted in:

• A statistically significant increase in overall response in pre-planned analysis of the combined IBS-C/D group compared to placebo;
• A positive, though non-significant, increase in overall response in both IBS-C and IBS-D cohorts;  
• Safety profile of Blautix was comparable to placebo, contrasting with many existing therapies which have significant side effect profiles limiting their utility; and
• Positive data trends in population sub-groups within both disease subtypes that warrant further analysis and investigation.

The results of the study demonstrated that Blautix has levels of activity in both IBS-C and IBS-D that are comparable to other drugs approved solely in either indication. The randomised Phase II study was designed to generate data to guide the pivotal development phase of the Blautix program and the results shown give the Company confidence and the necessary data for the design of a Phase III pivotal programme.

The commercial opportunity provided by Blautix could be substantial, given the need for a safe and effective treatment across IBS-C and IBS-D populations.

“IBS is a common and important condition that can have a significant impact on patients’ quality of life. The prospect of a treatment that could equally benefit both IBS-C and IBS-D with a strong safety profile is very compelling,” said Prof. Eamonn Quigley, Head of Gastroenterology and Hepatology at Houston Methodist Hospital and the Study’s Chief Investigator. “I am impressed with the improvement in bowel habit that was observed for Blautix in both IBS-C and IBS-D in the current trial, and believe that it is deserving of further study as it could provide an attractive treatment option in the future.”

“We are very pleased with the outcome of the Blautix Phase II study, demonstrating not only that Blautix has an effect in both IBS-C and IBS-D, but that it has a favourable safety profile. This is very relevant in a condition where all approved treatments only have activity in either IBS-C or IBS-D, and many have treatment-limiting side effects. Blautix could provide a highly differentiated option for patients and physicians,” said Dr. Alex Stevenson, Chief Scientific Officer of 4D pharma. “Uniquely for a single agent, the Blautix Phase II study has generated combined data across both sub-types of IBS. The effect shown by Blautix across both sub-types indicates it may potentially provide a solution to IBS-M patients whose symptoms fluctuate between IBS-C and IBS-D. These patients, who account for around 30 percent of all IBS patients, currently have no approved treatment options. This reflects the broad potential of Blautix as a completely new, safe, flexible therapeutic approach to treating all forms of the condition. The Phase II results provide signals that are highly encouraging and supportive of regulatory engagement around the design of a Phase III pivotal study to provide new therapeutic options to cover the considerable unmet medical need of people suffering from IBS.”

Blautix Study Design and Results

The Blautix Phase II study (ClinicalTrials.gov identifier: NCT03721107) is a multicentre, randomised, placebo-controlled study that enrolled a total of 353 patients with IBS-C or IBS-D with eligible baseline data (158 and 195 patients respectively). Patients in each cohort were randomised 1:1 to receive either Blautix or placebo; in total, 76 IBS-C patients and 94 IBS-D patients received Blautix treatment. Blautix or placebo was administered orally as two capsules, twice daily for 8 weeks.  

The primary efficacy endpoint of the trial was based on whether or not a subject, from either the IBS-C or IBS-D cohorts, was considered an overall responder. For a subject to be classed as an ‘overall responder’ they must have reported an improvement in their weekly (cohort specific) symptoms (abdominal pain intensity and stool frequency or consistency) for greater than or equal to 50 percent of the treatment period. The primary efficacy endpoint was also investigated in the combined IBS-C/D group as part of the planned analysis of the study. 

The randomised Phase II study was designed to generate data in both IBS-C and IBS-D that could be used to guide the subsequent pivotal development phase of Blautix. As such, statistical testing of the primary efficacy endpoint was one-sided and performed at the 0.10 significance level for each individual cohort. No correction for multiple analyses was applied. The power of the study to detect a difference vs placebo was based on a placebo response rate of 40 percent and Blautix response rate of 55 percent. This represents a relative risk (RR) vs placebo of 1.37.

The primary efficacy endpoint was analysed in the Full Analysis Set (FAS) of all randomised subjects, including those who had protocol violations deemed to impact the assessment of efficacy.

A summary of the results for the FAS (n equals 353) is given below, showing Blautix achieved:

• In the IBS-C/D combined group (n equals 170), a statistically significant overall response rate of 24.1 percent compared to 17.5 percent for placebo (n equals 183) (p equals 0.0625), representing an RR of 1.38 (95 percent confidence interval: 0.913, 2.083);
• In IBS-C patients (n equals 76) a numerically superior but statistically non-significant overall response rates of 25 percent compared to 17.1 percent for placebo (n equals 82) (p equals 0.152), representing an RR of 1.46 (95 percent confidence interval: 0.791, 2.711); and
• In IBS-D patients (n equals 94) a numerically superior but statistically non-significant overall response rate of 23.4 percent compared to 17.8 percent for placebo (n equals 101) (p equals 0.216), representing an RR of 1.31 (95 percent confidence interval: 0.753, 2.290). 

The response rate was also assessed for those patients who completed the 8-week treatment period without any major protocol deviations, the Efficacy Evaluable Analysis Set (EEAS). The EEAS typically represents the patient population with greatest level of study compliance and better represents the effect of the treatment.  In the EEAS population, Blautix treatment compared to placebo demonstrated an increased statistically significant overall response rate in the combined IBS-C/D group, a nominally statistically significant effect in the IBS-C cohort, and an increase in overall response rate in IBS-D.

Blautix also showed a highly favourable safety profile, with a total of 58 adverse events (AEs) in 177 (32.8 percent) subjects compared to 68 AEs in 188 (33.0 percent) subjects receiving placebo. There was 1 serious adverse event (SAE) in the Blautix treated (0.6%) and 1 SAE in the placebo treated group (0.5 percent).  Neither SAE was deemed to be treatment related. 

The Company is currently undertaking further analysis of the study results, including investigation of sub-groups with signals of higher levels of overall response, in order to define the future pivotal clinical development strategy.

A presentation describing the Phase II results in more detail can be found on 4D pharma’s website at https://www.4dpharmaplc.com/en/investors/reports-presentations.

About Blautix(R) 

Blautix is a single strain Live Biotherapeutic product (LBP), being developed as a treatment for both IBS-C and IBS-D. Pre-clinical studies demonstrated its ability to address visceral hypersensitivity and other symptoms of IBS and increase microbiome diversity. A Phase I study in healthy volunteers and IBS patients showed that Blautix was well tolerated and an improvement in symptoms was also reported relative to placebo. The Phase II BHT-II-002 trial demonstrated an impact on overall response with regards to bowel habit and abdominal pain in IBS-C and IBS-D. Blautix was well tolerated, with a safety profile comparable to placebo. Further information on the Phase II study can be found at ClinicalTrials.gov Identifier: NCT03721107.

About IBS

Irritable bowel syndrome (IBS) has an incidence in the US of 10-15 percent of the population. IBS is clinically defined to different subtypes - constipation-predominant (IBS-C), diarrhoea-predominant (IBS-D) and mixed phenotype (IBS-M), which comprise in the US 38.5 percent, 32.5 percent and 29.0 percent of diagnosed cases respectively. Existing approved treatments are focused on addressing the specific symptoms of disease subtypes, rather than the underlying disease, and often have only modest levels of efficacy and significant side effects. Research indicates that the microbiome is altered in IBS patients compared to healthy controls, but that the alteration is consistent across the different subtypes, suggesting the possibility that a microbiome-based intervention could address multiple subtypes.

About 4D pharma

Founded in February 2014, 4D pharma is a world leader in the development of Live Biotherapeutics, a novel and emerging class of drugs, defined by the FDA as biological products that contain a live organism, such as a bacterium, that is applicable to the prevention, treatment or cure of a disease.  4D has developed a proprietary platform, MicroRx(R), that rationally identifies Live Biotherapeutics based on a deep understanding of function and mechanism.

4D's Live Biotherapeutic Products are orally delivered single strains of bacteria that are naturally found in the healthy human gut. The Company has six clinical studies in progress, namely a Phase II clinical study of Blautix(R) in Irritable Bowel Syndrome (IBS), a Phase I/II study of MRx0518 in combination with KEYTRUDA(R) (pembrolizumab) in solid tumours, a Phase I study of MRx0518 in a neoadjuvant setting for patients with solid tumours, a Phase I study of MRx0518 in patients with pancreatic cancer, a Phase I/II study of MRx-4DP0004 in asthma, and a Phase II study of MRx-4DP0004 in patients hospitalised with COVID-19. Preclinical-stage programs include candidates for CNS disease such as Parkinson's disease and other neurodegenerative conditions. The Company has a research collaboration with MSD, a tradename of Merck & Co., Inc., Kenilworth, NJ, USA, to discover and develop Live Biotherapeutics for vaccines.

For more information, refer to https://www.4dpharmaplc.com.