Therapies

About Primary Immunodeficiency Disease (PIDD)

PIDD is a class of inherited genetic disorders that causes an individual to have a deficient or absent immune system due to either a lack of necessary antibodies or a failure of these antibodies to function properly. PIDD patients are more vulnerable to infections and more likely to suffer complications from these infections. According to the World Health Organization, there are over 250 different presentations of PIDD. As patients suffering from PIDD lack a properly functioning immune system, they typically receive monthly, outpatient infusions of IVIG therapy. Without this exogenous antibody immune support, these patients would be susceptible to a wide variety of infectious diseases. PIDD has an estimated prevalence of 1:1,200 in the United States, or approximately 250,000 people.

Leading a New Paradigm in Immunotechnology: RI-002

We are currently developing our lead product candidate, RI-002, for the treatment of PIDD, and have completed a pivotal Phase III clinical study. RI-002 is derived from human plasma blended from normal donors and donors tested to have high levels of neutralizing antibody titers to respiratory syncytial virus (RSV). RI-002 is manufactured using a process called fractionation, which purifies immune globulins, or IgG, from this blended plasma pool resulting in a final IVIG product containing naturally occurring polyclonal anti-pathogen antibodies (e.g., streptococcus pneumonia, H. influenza type B, cytomegalovirus or CMV, measles, tetanus). We use our proprietary RSV microneutralization assay to test for standardized levels of neutralizing antibodies to RSV in the final drug product.

Study Design

The RI-002 pivotal Phase III clinical trial was conducted as a single-arm study in which patients were treated approximately once per month for a period of 12 months plus 90 days for follow up. Fifty-nine patients were enrolled in 9 treatment centers in the United States.

The pivotal Phase III primary end point followed published FDA industry guidance, which provides for a reduction in the incidence of serious bacterial infections to less than 1 per year in each patient receiving IVIG. The secondary outcome was safety and included other pharmacokinetic (PK) data collection points, including antibody titers to certain pathogens, such as RSV, Streptococcus pneumoniae, Haemophilus influenzae type B, cytomegalovirus, measles, and tetanus.

Study Results

RI-002 demonstrated positive results in the Phase III study in patients with PIDD, meeting its primary end point of no serious bacterial infections (SBI) reported. RI-002 was administered for a total of 793 infusions with zero serious adverse events to 59 patients in 9 treatment centers throughout the United States. These results, included in the Biologics License Application (BLA) we have submitted to the FDA, meet the requirement specified by FDA guidance of <1 SBI per patient-year.

On February 22, 2015, at the 2015 American Academy of Allergy, Asthma & Immunology Annual Meeting, scientific investigators reported on the secondary outcomes that included: a total of 93 days, or 1.66 days per patient per year lost from work or school due to infection; one hospitalization due to an infection of only 5 days duration in the entire study and IgG trough levels above those required by the FDA for IVIG products. Additionally, there was a marked increase in all of the measured specific anti-pathogen antibodies in patients enrolled in the PK arm of the study (n=31). The mean of maximum fold increases in specific antibody levels after infusion of RI-002 ranged from 1.9 fold (S. pneumonia type 19A) to 5.3 fold (RSV), which were statistically significant fold increases from the pathogen's specific measured baselines. The majority of patients in this study did not experience any infusion-related AEs or complications. There were no SAEs reported during the trial attributable to the study drug. There was a low incidence of adverse infusion reactions, with a total of 31 events experienced by 18 patients.

Rationale for the potential Evaluation in RSV-Infected Patients

RSV is a common virus that ordinarily leads to mild, cold-like symptoms in healthy adults and children. In high-risk groups, such as the PIDD population and the other immunocompromised populations, RSV can lead to a more serious infection and may even cause death.

Additional Research Findings

We previously conducted a randomized, double-blind, placebo-controlled Phase II clinical trial to evaluate RI-001, RI-002’s predecessor product candidate, in immunocompromised, RSV-infected patients. This trial was conducted with 21 patients in the United States, Canada, Australia, and New Zealand. The Phase II dose-ranging trial demonstrated a statistically significant improvement in the change from baseline RSV titers to day 18 in the high-dose and low-dose treatment groups when compared with placebo (P=0.0043 and P=0.0268, respectively). The mean fold increase in anti-RSV neutralizing antibody in the high dose group was 9.24 (95% CI 4.07, 21.02) and the observed mean fold increase in the low dose group was 4.85 (95% CI 2.22, 10.59). The mean fold change for placebo treated patients was 1.42 (95% CI 0.64, 3.17). In addition, more patients in the high dose (85.7%) and low dose (42.9%) groups experienced greater than a 4-fold increase from baseline to day 18 in RSV titer levels compared to placebo (0%). There were no serious drug-related adverse events reported during the trial.

From April 2009 to February 2011, RI-001 was also administered to 15 compassionate use patients where physicians requested access to the product for treating their patients with documented lower respiratory tract RSV infections due to the fact that these patients had failed conventional therapeutic interventions. Serum samples were obtained from 13 patients. Samples showed that patients demonstrated a 4-fold or greater rise in RSV antibody titers from baseline. Serum samples were not obtained from 2 patients that received palivizumab. All patients (11) who received RI-001 within 4.2 days after the onset of the diagnosis of RSV survived. The drug was well-tolerated in all 15 patients and there were no reports of serious adverse events attributable to RI-001. Data from our Phase II trial, compassionate use experience, and data obtained from the evaluation of RI-002 in the infected cotton rat animal model have been presented at various conferences during 2014, 2015, and 2016.

Based on these results, following FDA approval, if received for PIDD, we plan to evaluate RI-002 for the treatment of patients at risk for, or infected with RSV.

Publications, Abstracts, and Posters

Abstracts

Protection Against Palvizumab Resistant RSV with IVIG Containing High Titer Anti RSV Neutralizing Antibodies

2nd International Primary Immunodeficiencies Congress Budapest Marriott Hotel, Budapest, Hungary, November 5-6, 2015

Results of a Phase III Trial in Patients with PIDD Using an IVIG Containing High Titer Neutralizing Antibody to Respiratory Syncytial Virus (RSV)

CIS Annual Meeting, Immune Deficiency & Dysregulation North American Conference, Hilton Americas, Houston, TX, April 9-12, 2015

Pharmacokinetics of RI-002, an Investigational IGIV Preparation

AAAAI Annual Meeting, Houston, TX, February 20-24, 2015

Treatment of Normal and Immune Suppressed Cotton Rats with IVIG Containing High Neutralizing Titer Anti-RSV Antibody

9th International Respiratory Syncytial Virus Symposium, Stellenbosch, South Africa, November 9-13, 2014

Polyclonal Human Intravenous Immune Globulin (IGIV) with High-Levels of RSV Neutralizing Antibodies: A Summary of Animal and Human Studies

Annual Conference of the Canadian Blood and Marrow Transplant Group (CBMTG), Halifax, NS, June 11-14, 2014

Polyclonal Human Intravenous Immune Globulin (IGIV) with High-Levels of RSV Neutralizing Antibodies: A Summary of Animal and Human Studies

2014 Clinical Immunology Society (CIS) Meeting: Primary Immune Deficiency Diseases North American Conference, Baltimore, MD, April 10-13, 2014

A Summary of the Study of a Polyclonal Human IVIG with Standardized High-Levels of RSV Neutralizing Antibodies

IDSA International Conference, Breaking the Rules! Hyatt Regency Chicago, IL, August 21-24, 2013

Posters

Compassionate Use Experience with High Titer RSV Immunoglobulin (RSV-IVIG) in RSV Infected Immunocompromised Persons

ID Week™, New Orleans Ernest Morial Convention Center, New Orleans, LA, October 26-30, 2016

Protection Against Palivizumab Resistant RSV With An IVIG Containing High Titer Anti-RSV Neutralizing Antibodies

International Primary Immunodeficiencies Congress Budapest, Hungary, November 5-6, 2015

Analysis of Specific Antibody Levels in PIDD Patients Enrolled in a Pivotal Trial with an IVIG Containing High Titer Neutralizing Antibody to RSV

Clinical Immunology Society (CIS) 2015 Annual Meeting, Immune Deficiency & Dysregulation North American Conference, Houston, TX, April 9-12, 2015

Treatment of Normal and Immune Suppressed Cotton Rats with IVIG Containing High Neutralizing Titer Anti-RSV Antibody

RSV 2014, 9th International Respiratory Syncytial Virus Symposium, Stellenbosch, South Africa, November 9-13, 2014

Polyclonal Human Intravenous Immune Globulin (IGIV) with High-Levels of RSV Neutralizing Antibodies: A Summary of Animal and Human Studies

Annual Conference of the Canadian Blood and Marrow Transplant Group, The Westin Nova Scotian, Halifax, NS, June 11-14, 2014

Polyclonal Human Intravenous Immune Globulin (IGIV) with High-Levels of RSV Neutralizing Antibodies: A Summary of Animal and Human Studies

CIS Annual Meeting: Primary Immune Deficiency Diseases North American Conference, Hilton Baltimore, MD, April 10-13, 2014

Use of High Titer RSV Immunoglobulin (RI-001-RSV IVIG) in Immunocompromised Adults

IDSA International Conference, Breaking the Rules! Hyatt Regency Chicago, IL, August 21-24, 2013