One mutated gene. One faulty enzyme. A severely protein-restricted diet at best, irreversible brain damage and intellectual disabilities, at worst.Phenylketonuria (PKU) is a disease that is caused by a rare genetic disorder and results in the accumulation of the amino acid phenylalanine in the body, due to a deficiency in the enzyme which normally breaks it down (phenylalanine hydroxylase, or PAH). PKU affects about one in every 15,000 live births in the U.S. and an estimated 50,000 people in the US and Europe.These days, all developed countries test every newborn for the disease. If caught early in life, the most serious symptoms can be avoided by adhering to a specialized diet highly restricted in protein (which contains phenylalanine) -- limiting the variety of foods patients are able to consume and hindering a normal lifestyle. The FDA approved drug sapropterin was the gold standard drug for PKU patients for years, but is only effective in a minority of patients who have some residual PAH activity, as a result of specific mutations. A newly approved drug, Palynziq® (a recombinant, pegylated enzyme that is administered subcutaneously), enables patients to avoid the inconvenient and largely unpalatable restricted diet, but requires daily injections and carries a high risk of anaphylaxis.Patients may soon have another, more convenient and potentially safer option: an orally-administered recombinant phenylalanine ammonia lyase (PAL) enzyme developed by Codexis that acts as a substitute for the patient’s ineffective PAH enzyme. Critically, Codexis’ PAL candidate was engineered to be stable in the gastrointestinal tract, to render it much less susceptible to degradation under the harsh conditions of the gastrointestinal tract, specifically proteolytic attack in the upper intestines.“We were able to use our platform technology to achieve something that scientists had attempted unsuccessfully since the 1970s: develop an enzyme therapy for PKU that can be taken orally and is stable in the gastrointestinal tract,” says Hicham Alaoui Ph.D., Vice President of Biotherapeutics R&D at Codexis. The enzyme has since delivered promising results in clinical trials and was recently in-licensed by Nestlé Health Science for further development towards ultimate commercialization.

Engineering novel proteins to tackle biotherapeutic challenges

The technology Alaoui is talking about is CodeEvolver®, Codexis’ protein engineering platform - a comprehensive and sophisticated approach to fine-tuning natural proteins for specific, desired functions.A leader in protein engineering, the Bay Area company has used its CodeEvolver® platform to develop novel proteins for a range of industries, most notably for small molecule pharmaceutical manufacturing, as well as for food, industrial and diagnostic applications. Biotherapeutic discovery is an increasingly important focus for the company, and provides a welcome challenge for Codexis, including Alaoui and his colleague Kerryn McCluskie Ph.D., Codexis’ Sr. Director of Translational Biology.

Hicham Alaoui Ph.D., Vice President of Biotherapeutics R&D at Codexis. Image credit: CodexisCombined, the two have nearly half a century of experience in drug discovery, but agree that Codexis offers a unique opportunity that neither had been offered before: a truly novel approach to designing the next generation of biotherapeutics. Through use of the CodeEvolver® platform, virtually any protein, including enzymes, can be evolved through a well-honed, rapidly iterating process of high-throughput experimentation and machine learning, until the desired characteristics are achieved. Why, exactly, is this significant?“While I’ve worked in biologics for some time, I realized that most currently approved enzyme replacement therapies are an exact copy of protein sequences found in nature,” explains Alaoui. “But here at Codexis, we go beyond what is provided in nature, and change many amino acids in the human sequences to create new variants that address some of the challenges faced by today’s therapeutics and develop the next generation of more efficacious and safer biologics.”Some of the challenges involved in developing effective and safe biologics include: pharmacokinetics (the movement of a drug through and out of the body); pharmacodynamics (the effect of a drug inside the body); safety (for instance immunogenicity), as well as stability and manufacturability. Neither Alaoui nor McCluskie doubt the ability of the CodeEvolver® platform to tackle and overcome these challenges. One of the reasons McCluskie was drawn to Codexis was the fact that their platform has been proven, multiple times, for PKU and in many other contexts. She welcomes the opportunity to mentor a team through the process of successfully applying the platform for biotherapeutic discovery.

Kerryn McCluskie Ph.D., Codexis’ Sr. Director of Translational Biology. Image credit: Codexis PKU is Codexis’ first such success story in the therapeutic space, marking the start of what Codexis hopes and expects to be a hugely rewarding journey and the foundation for a successful biotherapeutics division. The company is working on developing novel proteins across a variety of indications. To date, the focus has been on monogenic conditions -- those caused by a well-defined genetic defect that results in the deficiency of a single enzyme. From a validation of efficacy standpoint, it is clear: the enzymatic activity missing in the patient is either restored by the developed biologic candidate or it isn’t.However, validation of the CodeEvolver® protein engineering process against these genetic conditions provides an indicator of future successes in the application of the platform to develop treatments for more complex diseases, including non-enzyme proteins and those requiring systemic administration for optimal efficacy.

Success begins with the patient in mind

While the CodeEvolver® platform is the tool driving the biotherapeutic discovery, the patient is an important driver behind Codexis’ early success on what is for the company, a new frontier.“In order to generate highly effective protein therapeutics, it is critical to use the most physiologically relevant assays to interrogate the effect of mutations in the large libraries that we are creating,” says Alaoui. “The protein attributes we look for in the laboratory need to translate to improving the symptoms that patients experience. We start with the patient in mind and then devise strategies to guide protein evolution to give us that highly effective and safe therapeutic.” It is this approach, he says, that is critical to the success of advancing a therapeutic discovery from bench to bedside.Starting with the patient in mind means defining a target product profile for the ideal drug that addresses the symptoms of the disease at its roots, and working from there to generate a highly optimized protein that is ultimately suitable for clinical use. Often times, just talking to patients teaches us important attributes of a potentially successful treatment for a specific disease.“Considering my career in science, and the disease areas I've worked in, there have been various instances where people say ‘these four symptoms really bother the patient,’ but no one has actually talked to the patients to find out if that’s true. But, when you get patients together, you find that actually, there's a fifth symptom that’s much more important from their perspective. You also get their thoughts on what is really impacting their quality of life. So, by talking to the patients early in the drug development process and by being involved with the patient advocacy groups, we really have a much better overall understanding of the real challenges facing these patients and we use that to guide our efforts,” says McCluskie.The close relationship that the Codexis team has fostered with patients and their clinicians is critical for its success, according to McCluskie and Alaoui. It also serves as a tangible reminder of the impact that the Codexis programs may have on patients’ life, specifically, and the treatment of genetic diseases in general. Participating in Rare Disease Day, a global event that strives to increase awareness of rare diseases, is one avenue through which the Codexis team is able to help educate people about the importance of rare disease research and the efforts to finding new therapeutics to treat these often devastating disorders.In a short time, Codexis has made significant strides toward bringing protein design to the forefront of biotherapeutic discovery. The company has broken the mold of the traditional discovery and development process, by addressing challenges that can best be met by going beyond the protein sequences that nature has provided. Welcome to a new era in medicine.Learn more about CodeEvolver® at SynBioBeta 2019 October 1-3 in San Francisco. Dipnath Baidyaroy and Oscar Alvizio of Codexis will be speaking about the commercial success of the platform on Wednesday, October 2, at 12:30pm. Codexis, a conference Gold sponsor, is also sponsoring Wednesday night’s after party.