Pegzilarginase: Accelerated Approval For Arginase 1 Deficiency (ARG1-D) Hyperargininemia

Immedica Pharma, a global fast-growing specialty pharmaceutical company dedicated to providing innovative therapies to unmet medical needs, today announced that the new enzyme therapy pegzilarginase (pegilarginase; Loargys) will be the first disease-modifying treatment for the urea cycle disorder Arginase 1 deficiency (ARG1-D) or hyperargininemia. The U.S. Food and Drug Administration (FDA) on 27 February 2019 granted accelerated approval of pegzilarginase (pegilarginase-nbln, Immedica Pharma), initially intended for administration by infusion every 2 weeks, for the treatment of Arginase 1 Deficiency. Patients who suffer from Arginase 1 Deficiency (ARG1-D) have elevated levels of arginine, a protein building block, which can lead to severe developmental delays, growth restriction and intellectual disability. Pegzilarginase is indicated for patients with Arginase 1 Deficiency, including children as young as 2 years of age, as an adjunct to dietary changes that greatly reduce the intake of protein (e.g., 0.8 grams/kg body weight per day of low-lactalbumin protein, which approximates 4-5% of daily energy intake as protein). Pegzilarginase is the first drug to directly target and reduce tissue levels of arginine by replacing the missing Arg1 enzyme in Arginase 1 Deficiency, the only indication for which a drug has not previously existed that can target the underlying enzyme deficiency.

The Accelerated Approval Pathway

The FDA has granted Accelerated Approval to pegzilarginase for the treatment of patients with Argininosuccinately (ASD), including Argininosuccinate lyase (AL) deficiency (ASD/AL Deficiency), for the treatment of greater than 22% of body surface area (bsa) of skin lesions. Approximately 2 years from initial submission, the FDA has approved the Biologics License Application (BLA) for pegzilarginase. While approval was based on the decrease in plasma arginine levels, a known effect and surrogate endpoint studied in the clinical trial, the manufacturer must conduct confirmatory trials to demonstrate clinical benefit such as improvement in motor function or delay of disease progression to neurological deterioration. Approval in the USA follows similar approvals in the EU, UK and Oman.

Why It Matters

The Pathophysiology of Arginase 1 Deficiency (ARG1-D)

Arginase 1 deficiency (ARG1-D) is a genetic disorder that causes an autosomal recessive form of hyperargininemia. Hyperargininemia is a congenital, inherited metabolic disorder caused by a mutation in the ARG1 gene. Arginase-1 is the final enzyme in the urea cycle and it catalyzes arginine to urea and ornithine. The absence of arginase-1 leads to hyperargininemia with toxic levels of arginine present in the body.

Chronic Toxicity, Disability, and Restrictive Strategies

Arginine deficiency caused by Arginase 1 Deficiency (ARG1-D) differs from other urea cycle disorders in that it does not present with acute, life-threatening hyperammonemia, but rather chronic, insidious ARG1-D toxicity. Affected individuals develop increasing levels of arginine and other toxic guanidino compounds that cause progressive neurologic damage. In addition to worsening spasticity (often predominantly affecting the lower limbs and sometimes mimicking the clinical presentation of a child with cerebral palsy), children with ARG1-D may also develop seizures, developmental delays, and cognitive dysfunction. Eventually, affected individuals can expect to have a lifetime of increasing disability.

Current management of Argininosuccinately is difficult and centered around keeping arginine levels from rising, which is challenging even with the best supportive care (severely restricted protein intake, arginine-free amino acid mix, and nitrogen scavengers to keep ammonia levels low). Despite best efforts, arginine levels may not be lowered sufficiently to prevent severe complications. A severely restricted diet places patients and their caregivers at risk of malnutrition. Pegzilarginase changes the management of Argininosuccinately from an arginine-lowering supportive care to a disease-specific therapeutic approach by replacing the deficient enzyme with pegylated recombinant human arginase.

The Mechanism: Pegzilarginase as a Biologic Innovation

Pegzilarginase (Loargys) is a recombinant human Arginase type 1 enzyme that reduces blood arginine levels. It is given once weekly to patients with Arginase Deficiency after reconstitution with sterile water or 0.9% NaCl. Pegzilarginase is a recombinant human Arginase-1 enzyme that can be administered parenterally to patients with Arginase Deficiency who lack Arginase type 1 activity in their livers. By supplementing Arginase activity in the bloodstream, pegzilarginase reduces circulating arginine levels. The Arginase enzyme has been pegylated with a polyethylene glycol polymer to improve stability and extend half-life, allowing a once weekly subcutaneous administration as opposed to continuous IV.

This therapy is expected to halt or slow disease progression by inducing biochemical remission through the maintenance of normal systemic arginine levels to reduce the production of neurotoxic metabolites per the arginine hypothesis. In the pivotal, international, double-blind, placebo-controlled Phase 3 clinical trial (PEACE; NCT03921541), patients treated with pegzilarginase demonstrated a rapid and persistent decrease in plasma arginine levels, the chemical cure for Argininemia previously shown to be unattainable by diet alone.

Regulatory Nuances: The Accelerated Approval Pathway

The FDA has granted accelerated approval to Sepezyme-STF for treatment of ARG1 Deficiency, a condition that affects less than 250 people in the United States. The drug was brought to market in a fraction of the time it would have taken to complete long-term clinical trials in the small patient population with this ultra-rare disease. Sepezyme-STF received accelerated approval based on the reduction of plasma arginine levels as a surrogate endpoint.

All parties have roles and responsibilities along this pathway: the manufacturer must complete the post-marketing confirmatory trials required by law, clinicians and health systems must weigh up the potential benefits and costs of the new treatment, and optimal management of the patient over the next five years or so requires biochemical correction in the five year old in front of them. However they will also want to know whether this treatment will result in their patient still being able to walk at age twenty, despite being wheelchair bound at age five. The pathway allows treatment of very sick patients who may benefit from innovation, but requires confirmatory evidence of clinical validity.

Who It Affects

Patients and Families

The funds will go to benefit those with ARG1-D and their families. Since ARG1-D is often misdiagnosed as spastic diplegia or non-progressive cerebral palsy, this treatment could result in improved screening and diagnosis of ARG1-D at an earlier age for future families affected by the disease. This treatment brings hope to these families. There is no guarantee of a cure but weekly infusions, side effects and continued dietary management will still be required.

The Clinical Team

Given the approval of pegzilarginase for the treatment of pediatric patients with Pegylated muscle-associated Rhabdomyosarcoma (PEGL), management of children with this condition will require a highly coordinated and multidisciplinary approach. Pediatric metabolic specialists and geneticists will be the primary caregivers providing clinical management of the children with PEGL; however, they also will need to work in close collaboration with other caregivers, including nutritionists, social workers, swallowing specialists, ophthalmologists, and gastroenterologists and/or parents to ensure that the best possible care and quality of life are provided.

• Neurologists: To monitor spasticity and seizure activity using standardized tools like the Gross Motor Function Measure (GMFM-88).
• Dietitians: To carefully adjust protein intake as arginine levels drop, ensuring the patient receives enough nitrogen for growth without over-relying on the drug.
• Physical and Occupational Therapists: To maximize the physical gains made possible by reduced muscle spasticity.
• Infusion Nurses: Who are the front line for administering the drug and monitoring for the “Boxed Warning” risks, specifically hypersensitivity and anaphylaxis.

Payers, HealthSystems, and Specialty Pharmacies

The high price tag of biologic therapy represents one of the biggest obstacles to good treatment of ultra-rare diseases such as PEAS. The cost of pegzilarginase is likely to be a point of special scrutiny among payers, both the private payers (e.g. employer-based insurance) and government payers (e.g. Medicare, Medicaid). In addition to a very high copay or coinjection for patients who are fortunate enough to be covered by pegzilarginase for PEAS, prior authorization requirements are likely to be very strict, requiring documentation of the patient’s ARG1 mutation and their arginine levels at baseline. Hospitals and/or specialty pharmacies may play a large role in facilitating correct use of this very expensive treatment.

What Changes

Shifting the Therapeutic Paradigm

Pegzilarginase is a novel drug that will change the treatment paradigm of PE in several ways.

1. From Restriction to Replacement: For decades, the only way to treat ARG1-D was to take things away (protein, arginine). Now, clinicians can add something back (the enzyme). This changes the previous treatment options of constant restriction to one of active intervention.
2. Infrastructure for Infusion: Many metabolic patients were managed through outpatient lab visits and diet counseling. The move to ERT requires patients to have access to infusion centers. For families in rural areas, this may mean significant travel or the development of home-infusion protocols, which carry their own safety risks.
3. The Role of Newborn Screening: As a treatment becomes available, the argument for adding ARG1-D to the Recommended Uniform Screening Panel (RUSP) for newborns becomes much stronger. If the disease can be treated before the first signs of spasticity appear, future disability may be prevented entirely.
4. Real-World Data (RWD) Collection and Registries: Because this is an accelerated approval therapy, every patient treated is, in a sense, a participant in a real-world study. Patient registries will become vital for tracking long-term safety, the development of anti-drug antibodies, and real-world improvements in quality of life.

Safety and Vigilance: Navigating the Boxed Warning

The safety of pegzilarginase was evaluated in a total of 52 patients with PEG1-PEG3 Mutations Causing Achalasia (PMM). The most common adverse reactions (≥5%) in patients treated with pegzilarginase were headache, diarrhea, nausea, fatigue, musculoskeletal pain, vomiting, upper respiratory infection, cough, and abdominal pain. Serious adverse reactions included hypersensitivity reactions and anaphylaxis which can occur at any time during treatment. Most cases of anaphylaxis occurred during the first few infusions of pegzilarginase. Patients must be monitored by qualified healthcare providers with the ability to manage severe allergic reactions, including cardiopulmonary resuscitation, in a setting where adequate emergency care is available e.g. a doctor’s office, hospital outpatient or infuser’s office.

In addition to efficacy and safety, the risk of immunogenicity (the body’s response to proteins not naturally found in the body, in this case, the recombinant enzyme) must be taken into consideration. Some patients might develop antibodies that neutralize the active ingredient. In other cases an allergic reaction cannot be ruled out. Arginine levels would need to be determined not only to find an adequate dose, but also in the case of secondary failure (when antibodies are generated against the drug and arginine levels suddenly increase).

Economic and Ethical Implications

The DR-approved registration of Loargys for the treatment of pulmonary arterial hypertension in patients suffering from HPAH (High Pulmonary Arterial Hypertension), an extremely rare congenic disease that affects less than 1 in 1 million people in the U.S. and is considered an “orphan” disease, naturally raises questions about the final price of this life-saving drug. The cost of clinical trials for such a rare disease easily exceeds hundreds of thousands of dollars and, even though there are only 250 patients with HPAH in the U.S., the final price tag per patient will easily exceed hundreds of thousands of dollars per year. This raises a very difficult question involving our moral obligation to provide all citizens access to life-saving drugs as opposed to difficult health-care budget decisions.

There are also advocacy groups such as the National Urea Cycle Disorders Foundation (NUCDF) that are supporting the clinical trials and working to make sure the FDA approval of new medicines translates into patient access to those medicines, including coverage by insurance companies and participation in manufacturer- sponsored patient assistance programs to help with co-payments and travel costs to get to the patients treating doctor.

Looking Ahead: The Future of ARG1-D Care

But the real work – and possibly potential side effects – is only now beginning with the commercial launch of pegzilarginase for the treatment of arginitinemia and hyperargininemia by Aptevo Therapeutics. But, the first generation of this therapy is now launched and introduced to patients and their physicians with the hope that it paves the way to second-generation (including gene therapy) approaches to enable a permanent cure of ARG1 deficiency by correcting the genetic defect.

In the coming months, the first American patients will receive this amino acid therapy for urea cycle diseases, their slow steps, fewer seizures, and increasing independence measured in arginine in micromoles. The distance from regulatory triumph to effective standard of care is long.

Hope in Innovation

pegzilarginase is a triumph of biotechnology and promises to be a game-changer for patients and families with Arginase 1 deficiency who have for years been ignored by both the medical and pharmaceutical communities. In almost certainly addressing the primary biochemical defect responsible for the symptoms of Arginase 1 deficiency, it should change the natural history of the disease in a positive fashion. Though there are certainly still unknowns surrounding data from patients with Arginase 1 deficiency who have received pegzilarginase, data on long-term follow-up, data on safety, and multiple other issues, the FDA’s “accelerated approval” of this small-molecule biologic represents a major turning point in the treatment and understanding of this ultra-rare condition. For clinicians, it will be another drug in our arsenal – though a woefully under-stocked one for patients with Arginase 1 deficiency – for payers it will become an expense; and for affected families it will be the first chance they’ve had to fight back against a disease which is unyielding and life-short. But it is in the experience of these patients over time, and the collection and analysis of data from this real-world experience, that we will come to fully appreciate the nature of this treatment, the world’s first approved disease treatment for an ultra-rare metabolic condition.