Evolution of the Bacterial Trade
Although the inception of probiotics dates back to more than a century,1 it is only in recent years that scientific milestones have come to harness the potential of symbiotic relationships between microbiota and the human host. In fact, the beneficial impact conferred on the human host set a historical antecedent for what has come to be known as modern day probiotics more than a decade before the time of Fleming’s discovery of penicillin.1 And, 2012 research endeavors championed by a consortium of members to the Human Microbiome Project finally mapped out the normal microbial make-up of the human body.2
Partners to the National Institutes of Health spanned a variety of multi-disciplinary backgrounds, including allergy and infectious disease, arthritis, musculoskeletal and skin diseases; dental and craniofacial research; cancer, diabetes, digestive and kidney diseases.2 With support from the NIH Common Fund, DNA sequencing techniques, and metagenomics, the bacterial contribution for 81-99% of genera identified and their metabolic capabilities has become much appreciated.2
Dr. James Anderson, Director of the NIH Division of Program Coordination, Planning and Strategic Initiatives announced for the first time, “We now have a very good idea of what is normal for a healthy Western population and are beginning to learn how changes in the microbiome correlate with physiology and disease.2”
“We are all walking condominiums of bacteria3”
The benefits of this research and understanding the role of microbiota are much geared at the development of disease-specific therapies. This is reflected in a proliferation of the probiotics market with success contingent upon making the leap to product development and promoting consumption.1
For example, 2013 research findings from University of Maryland Baltimore (NIH-funded probiotics grant) reported the following “skyrocketing” statistics: no studies prior to 1991; 5 studies from 1995-1997; 384 from 2007-2009, and 430 from 2010-2012.4 And, according to the World Gastroenterology Organisation Global Guidelines, the strongest science behind the marketing potential involves gut health and immune function,1 with the intestine described to be “the body’s most important immune related organ” and home to approximately 60% of the body’s immune cells.1
The gut is the most heavily colonized site,5 with 100 trillion microbes that translate to virtually one to two kilograms of our weight.5 In addition, the provision of 600,000 genes to each human1 serves vital roles among energy production, barrier functions, vitamin synthesis, biotransformation of drugs and other functions for maintaining healthy equilibrium state.5
And, it makes sense for immunologic, digestive and metabolic functions5 to be of focused interest. This is much evidenced by the innovative platforms of various biotech companies in the strive to better understand what happens when there is disruption to that commensal state. For example, Trayer Biotherapeutics, dedicated to leveraging this trailblazing research with delivery of novel therapies, is among three companies taking the lead for the rare, genetic disorder, phenylketonuria (PKU), a liver enzyme deficiency and inability to metabolize the essential amino acid, phenylalanine (phe). PKU patients are among a finite number of inborn errors of metabolism (with incidence of 1 in 12,000 – 15,000 births).6
The disease manifestations due to the accumulation of toxic phe on neurological, psychological and mental health (that can ultimately result in mental retardation) have required early and lifelong intervention with a severely restricted therapeutic diet. As of date, patients within the continuum of this complex disease spectrum have limited to no FDA-approved treatment options demonstrative of clinical superiority for preventing such devastating outcomes and mitigating disease other than through dietary manipulation.
At a recent July 2016 conference hosted by the National PKU Alliance, attendees learned of the pre-clinical strategies for a genetically modified probiotic to treat PKU which have now been licensed to Trayer Biotherapeutics for clinical development. The implications for better understanding the PKU microbiome are profound on both a physiological and regulatory level. It is hypothesized that characterization through human trials not only leads to targeted drug development, but there is potential to revolutionize existing regulatory probiotic framework with PKU as the first-ever probiotic biologic drug used in the treatment of this orphan disease.
PKU Patented Technology
The research efforts lead by Dr. Katherine Durrer-Deming and University of North Texas Health Science Center team have been described as pHENOMMenal7 in the field of genetically engineered probiotics and much facilitated by the advances of molecular technologies. The studied bacteria in typical probiotics encompass Lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus and other strains8 and are commonly found in yogurt and fermented food products.
Because probiotic use is often intended for the general population, it should be noted clinical food studies have been quite limited in exploratory role of probiotics as clinical agents4 for which randomized, clinical, controlled trials have been the FDA gold standard for demonstration of efficacy.4
While the definition put forth by Joint FAO/WHO expert consultation deems probiotics as “live microorganisms which when administered in adequate amounts confer a health benefit on the host,4” the absence of any statutory or regulatory definition4 and shortcomings to existing regulatory framework paradoxically pose unique challenges for the commercial development of a first in its class and lend opportunity to customize the pathway for a novel, orphan therapy.
The molecular technologies used in the genetic manipulation of probiotic bacteria for PKU have become manifest in the SA-412 prototype. The description offered by Marc Tewey of Trayer Biotherapeutics on SA-412 illustrates the qualities of a recombinant live biotherapeutic product (LBP). SA-412 is composed of L. acidophilus that has been genetically modified by purposeful addition of a gene shown to express phenylalanine ammonia lyase (PAL), an enzyme which catabolizes phenylalaline3 and is different to the deficient enzyme in the PKU population.
On the in vitro level, functional PAL in phe metabolism has been demonstrated through trans-cinnamic acid (metabolite) production by the plasmid carried probiotic, Lactobacillus reuteri 100-23.7
On the in vivo level, studies using oral administration in the murine model have shown an average of 30-40% reduction in plasma phe depending on the length of treatment.7 SA-412 development seeks to perform Phase I/II clinical studies in hopes that a transition of the gene modification to the human specific strain will ideally lead to an alternate or even effective adjunct or combination therapy with introduction of more whole protein to the PKU diet and improved quality of life.3,7
While drawing upon atypical expertise of the Texas researchers and commercializing recombinant techniques for orphan LBP development is in of itself a potential marketing niche, the road to Phase I/II clinical trials is not without uncertainty and risk. The applicable regulations to these pioneering efforts must take into account a number of factors for SA-412 technology to be a future reality. This includes departure from traditional probiotic use (as opposed to foods), the intended population (for patients with rare, genetic disease), and novel drug delivery systems.
Regardless of the pathway, the one constant to the equation in navigating FDA terrain is safety as an imperative. Because the PKU patient is harbor to a complex microbial environment and differs from the norm, the necessity of reliable data for safe and efficacious use really underscores the value of an investigational new drug (IND) submission. There is the possibility that the interaction of LBPs and this environment will be a determinant factor in direction of Phase I/II studies and the implications of this on orphan drug development with low volume products are significant.
Research findings may also bring new questions and slow the progression through an already rigorous pre-market approval process on one of the highest risk categorized products ever to emerge from the FDA pipeline. Questions take money to answer; and with Phase I/II on the horizon for 2017, if the rules of the bacterial trade are not well defined from the start, it is the patients that lose out.
PKU Condominiums & Regulatory Convergence: What Does the Future Hold?
Effective stakeholder engagement early on with the FDA would be beneficial in incentivizing and accelerating the process for filing an IND for PKU. The opportunity for a LBP to tap into a probiotic framework that has been predominantly a “drug oriented, evidence –based medicine paradigm4” and meet FDA standards also has timely coincidence with the imminent threat of medical foods extinction.9 Dietary manipulation of phe with provision of medical foods has been the cornerstone of therapy for PKU since 1951 and is associated with an accumulation of substantial, scientific literature that more than exceeds FDA standards for a minimum of 25 years to establish history of safe use.4”
However, the regulatory burden and new and emerging market entry barriers on the category of medical foods have become significantly more burdensome in recent years. For example, July/August 2016 publication by Nutrition Insightreports there is “reduced access and increased costs to patients in addition to widespread confusion.9” Hence, there is serious unmet need when it comes to treatment options for PKU. And, the biggest failure in current regulatory framework on medical foods ironically constitutes the biggest marketing advantage of a LBP for PKU: “addressing the role of foods in preventing disease, improving health, or possibly treating disease.4”
The burden of proof for introducing novel therapies to the market largely rests with the manufacturer, and the question remains if the commercialization of the potentially first-ever PKU live biotherapeutic product can rise to the challenge of FDA standards and find balance with flexibility in Phase I/II clinical trials.
The preliminary specifications for FDA acceptability and recombinant DNA advisory permission must address many factors in addition to acceptable disease endpoints and functionality of the SA-412. Regulatory considerations for live microorganisms on the path to retail distribution must take into account good manufacturing practices (or GMP) and various control measures. These include quality and consistency, dosage forms, contaminants and purity, stability of the microbial components pre and post-manufacturing (like shelf life), mechanism of action (especially for protection against acidic environment, drug interactions), and others.
Although human applications of SA-412 technology “taking vacation in the mouse gut7”may have limitations, the good news reported by Dr. Durrer-Deming in combatting biopharmaceutical hurdles is that “treating PKU mice with pHENOMMenal did not result in systemic anti-AvPAL IgG7” or immune response to the recombinant L. acidophilus AvPAL gene. Can PKU human condominiums of bacteria find regulatory convergence with trials slated to commence in 2017?
A live biotherapeutic product regulated as an orphan drug for PKU clearly exemplifies one size does not fit all within the existing probiotic framework. The impact of a dynamic scientific, economic and social environment is going to take all stakeholders and collaboration with both the FDA Center for Biologics Evaluation and Research (CBER) and the FDA Office of Orphan Products (OOPD) for finding regulatory purview. While there is no statutory definition affording the safe harbor for this novel orphan therapy PKU patients deserve and need, one thing is conclusive.
Trayer Biotherapeutics is a contentious force in defining its own regulatory pathway and certainly one to watch for driving the competition of microbiome science and unleashing the power of “bacteria, our friends.3”