Citius Pharmaceuticals, Inc. (CTXR) is a specialty pharmaceutical company focused on the development and commercialization of proprietary formulations of already-approved drugs which target large and growing markets. By reformulating, patenting and expanding the indicated uses of drugs that have previously been approved by the FDA, Citius avoids much of the cost, time and risk (of regulatory failure) that is associated with developing drugs from scratch. A key component of CTRX's strategy is their focus on therapies that can leverage more expedited and (oftentimes) less-stringent regulatory pathways and procedures, such as FDA's 505(b)2 pathway and Fast Track designation.
The company's current pipeline consists of Mino-Lok, which is in a large, multi-site phase 3 study for the treatment of catheter-related bloodstream infections (CRBSI), and a mid-stage lidocaine/corticosteroid candidate which aims to be the first and only FDA-approved prescription therapy for hemorrhoids. Meaningful development-related milestones are upcoming for both – including what should be a fairly regular stream of updates from Mino-Lok’s phase 3 study and status/design updates of anticipated phase 2b study for their lidocaine/corticosteroid (severe hemorrhoids) candidate.
Mino-Lok, a proprietary formulation incorporating the widely-used antibiotic, minocycline (in addition to edetate and ethyl alcohol), is being developed as a central venous catheter (CVC) disinfectant, otherwise known as an antibiotic lock therapy. Mino-Lok is protected by a patent portfolio with expiration out to 2024. Minocycline is used for a variety of infection-fighting applications including as an antimicrobial agent with anti-infective catheters.
View Exhibit I - Central Venous Catheter
CRBSI Is a Significant Complication Associated with CVCs…
A central venous catheter (also known as a ‘central line’) is a flexible plastic tube that is inserted into a vein for the purpose of delivering drugs and fluids over an extended (and often repeated) period of time. The other end of the tube, called a lumen, remains outside of the body. CVCs, which can remain in place for many months, provide the benefit of avoiding repeated puncture of veins that would otherwise be required with long-term injections.
While catheters are widely-used and an integral part of modern medicine, their prolonged outside-the-body exposure lends themselves to infection. Of the approximately 7M CVCs used in the United States each year, approximately 500k will get infected. CRBSI is a significant problem associated with the use of central venous catheters, which "pose a greater risk of device-related infections than any other types of medical device and are major causes of morbidity and mortality" (Gahlot R, et al).
These infections can be difficult to treat, particularly those that are acquired intraluminally (i.e. inside the lumen). These central line-associated bloodstream infections (CLABSI) can be difficult to eradicate as pathogens quickly multiply within the lumen, forming colonies and creating antibiotic resistant biofilm.
View Exhibit II - Microbial Source of Catheter-Related Blood Stream Infections
Blood infections are serious and costly to the healthcare system. If not promptly and effectively addressed, they can rapidly impair a persons’ health to the point of potential death. According to the CDC (Guidelines for the Prevention of Intravascular Catheter-Related Infections. O’Grady N, et al), between 12% and 25% of central line associated blood-stream infections result in death. Moreover, the report found that each CVC-associated infection adds as much as $50k, on average, of incremental cost to the healthcare system. Given the high cost in terms of both patients’ health and financial expenditures, the CDC recommends the implementation of new strategies to reduce the incidence of CVC infections.
CRBSI Standard-of-Care Comes with Risks…
Standard protocol to address CRBSI is to remove the catheter, treat the infection with antibiotics and replace the CVC. CVC insertion, by itself, carries not insignificant risk. And those risks may have even greater significance when the procedure is performed on a patient with a blood infection and whose health may be that much more compromised.
The use of CVCs is associated with risk of certain complications. Mechanical complications (such as arterial puncture and hematoma) occur in approximately 5% to 19% of CVC procedures, infectious complications in 5% to 26% and thrombotic complications in 2% to 26% of cases (McGee, D. , Gould M.).
So, for a patient with a CVC which has contracted CRBSI, they are put at significant risk of potentially serious complications when standard-of-care (i.e. CVC removal and replacement) is employed. Citius’ Mino-Lok, which is in a multi-site phase 3 study, may offer an effective and less-risky alternative.
Mino-Lok Treats CRBSI Without Removing CVC…
Citius has exclusive worldwide rights to the Mino-Lok technology, which was initially developed at the University of Texas MD Anderson Cancer Center. Mino-Lok treats blood infections without having to remove and reinsert the CVC, thereby avoiding the associated risks. Instead of replacing the (intraluminally) infected catheter, Mino-Lok is instilled into the catheter lumens (lumens are clamped to prevent Mino-Lok from entering the body) which breaks down bacterial biofilms and kills the offending bacteria. Mino-Lok is intended to be used for two hours per day for five to seven days.
View Exhibit III - Mino-Lok Instructions for Use
Ph2b Study Demonstrates Superiority to SOC…
A phase 2b study, conducted at the MD Anderson Cancer Center, evaluated Mino-Lok against standard of care in cancer patients with CVC-related bloodstream infections. Results showed Mino-Lok was able to salvage 100% (n=30) of catheters while eradicating the infection, resulting in a 0% complication rate. This compares to an 18% complication rate in the control arm (n=60), which followed standard-of-care (including removal and replacement of the CVC).
View Exhibit IV - Mino-Lok 0% Complications vs. SOC 18% Complication Rate
FDA Fast Tracks Mino-Lok, Multi-Site Ph3 Study Ongoing…
Mino-Lok and Citius’ development program have been granted Qualified Infectious Disease Product designation and Fast Track status by FDA. Fast Track is a designation that is reserved for investigational therapies that address serious or life-threatening conditions and which fill an unmet need. Among other benefits, these allow for more frequent interaction with FDA and a significantly shorter review time. And, while perhaps more subjective, they also provide some early and substantive validation towards the unmet need for the product.
A phase 3 study, which was initiated in late-2016, is ongoing and is expected to enroll 700 patients across 50 institutional sites in the U.S. The randomized (1:1), open label, assessor-blind study will assess efficacy and safety of Mino-Lok compared to standard-of-care antibiotics (which will also be used as an antibiotic lock) in patients diagnosed with CRBSI/CLABSI. Primary endpoint is the proportion of subjects with ‘Overall Success’ at study-end which, among other measures, is defined as a lack of all-cause mortality at Week 8 and lack of catheter removal. Essentially, the goal of the study is to demonstrate the ability of Mino-Lok to reduce complication rates associated with CRBSI by reducing (or eliminating) the need to remove and replace CVCs.
View Exhibit V - Phase 3 Mino-Lok Study
Participating institutions include several world-renowned research universities and medical centers. As of July 9th (per CTRX’s status update), 12 sites were actively enrolling including MD Anderson, Henry Ford Health Center and Georgetown University Medical Center, among others. Another 13 sites were on-deck (although not yet recruiting) and another 13 were in “feasibility stage”. The company anticipates that all 50 sites will be activated by the end of September 2018.
Mino-Lok Could Be First FDA-Approved Lock for CRBSI…
Interim analysis of the phase 3 study will be done at 50% and 75% enrollment, which might provide additional insight into the effectiveness of Mino-Lok in addressing CVC-related infections. If successful in this phase 3 study and subsequently approved by FDA, Mino-Lok could be the first antibiotic lock approved for the treatment of CRBSI. And with nearly 500k of the 7M CVCs used in the U.S. each year becoming infected and an unmet need for a catheter-salvaging therapy, uptake of Mino-Lok could be robust immediately upon launch.
Hydro-Lido is a topical formulation of hydrocortisone (3%) and lidocaine (5%). All currently available hemorrhoid treatments are sold over the counter (OTC) and none have been evaluated in robustly designed clinical trials. If approved, Citius’ lidocaine/corticosteroid candidate could be the first and only FDA-approved product to treat hemorrhoids. With more than 10M Americans suffering from hemorrhoids and 20M units of hemorrhoid products sold in the U.S. each year, it is a sizeable market.
Phase 2a Study…
Results of as phase 2a multi-site, randomized, double-blinded study indicated Hydro-Lido was superior to placebo, hydrocortisone-alone and lidocaine-alone in the treatment of Grade I and II hemorrhoids. The study enrolled 210 patients with Grade I and II hemorrhoids who were treated twice daily for 14 days with placebo or two concentrations each of either Hydro-Lido (3%/5%, 0.5%/1.0%), hydrocortisone-alone (3%, 0.5%) or lidocaine-alone (5%, 1%).
Primary endpoint was Global Score of Disease Severity Scale (GSDS). Secondary measures included assessment of individual signs and symptoms of hemorrhoids. While Citius noted that the study was not powered for statistical significance, the data showed a trend favoring Hydo-Lido and suggests it was more effective than the comparator arms in reducing the severity and symptoms of hemorrhoids. Results are expected to be used to support design of follow-on studies.
View Exhibit VI - Results
Higher Potency Corticosteroid…
In March 2018 Citius announced that they expect to move forward with a higher potency corticosteroid in combination with lidocaine and held a Type C meeting with FDA to discuss the formulation change in the context of a phase 2b study. Clearly the impetus is to target an indication related to more severe hemorrhoids (i.e. Grade II and higher). Presumably Citius’ rationale may be that it may be difficult to compete with OTC hemorrhoid treatments (such as Preparation H) in the lower-grade hemorrhoid market and that the lack of FDA-approved options presents a greater opportunity in more severe indications. Citius expects to be able to use the 505(b) FDA pathway, which could allow them to use safety and effectiveness data “from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference.” In other words, they may be able to use already-established evidence of safety and efficacy of the component APIs of their formulation – which could significantly reduce the cost and time to approval.
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