Mr. Fabio Chianelli reports

PHARMATHER HOLDINGS SUBMITS FAST TRACK APPLICATION TO FDA FOR KETARX(TM) (KETAMINE) FOR THE TREATMENT OF PARKINSON'S DISEASE

Pharmather Holdings Ltd. has submitted a fast-track application to the U.S. Food and Drug Administration (FDA) for Ketarx (ketamine) for the treatment for levodopa-induced dyskinesia in Parkinson's disease (LID-PD).

Fast-track designation aims to expedite the development and review of new drugs that are intended to treat serious or life-threatening conditions and demonstrate the potential to fill unmet medical needs. The purpose is to get important new drugs to patients faster. Filling an unmet medical need is defined as providing a therapy where none exists or providing a therapy which may be potentially better than available therapy. Drugs that are granted this designation are given the opportunity for more frequent meetings with the FDA to discuss the drug's development plan and ensure collection of appropriate data needed to support drug approval; more frequent written communication with FDA about such things as the design of the proposed clinical trials and use of biomarker; eligibility for accelerated approval and priority review, if relevant criteria are met; and rolling review, which means that a drug company can submit completed sections of its new drug application (NDA) for review by the FDA, rather than waiting until every section of the NDA is completed before the entire application can be reviewed. NDA review usually does not begin until the drug company has submitted the entire application to the FDA.

Following its recently announced Type C meeting with the FDA for advancing Ketarx toward phase 3 clinical development, the company is evaluating a phase 3 clinical trial design to align with the FDA's recommendations that would allow for a potential FDA approval. The safety and efficacy results from its previously announced presentation of the phase 1/2 clinical study evaluating ketamine as a potential new treatment for LID-PD will be used to support the investigation of Ketarx in a proposed phase 3 clinical study.

Summary results of the phase 1/2 clinical study:

• Enrolled subjects with moderate to advanced Parkinson's disease with a target infusion rate being 0.30 milligram/kilogram/hour. Data highlight that ketamine was safe, well tolerated and demonstrated that 100 per cent of subjects treated with ketamine had a reduction in dyskinesias as measured by UDysRS (unified dyskinesia rating scale).
• UDysRS showed a 51-per-cent reduction from baseline during infusion 2, 49 per cent at three weeks and 41 per cent at three months postketamine.
• The maximum tolerated infusion rate ranged from 0.20 to 0.30 mg/kg/hr, which was dependent on either discomfort due to dissociation or hypertension. There were no adverse events postinfusion.

Pharmather retains rights to U.S. patent No: 11,426,366 (expires May, 2036), titled "Compositions and Methods for Treating Motor Disorders," which includes claims intended to cover ketamine in the potential treatment of Parkinson's disease and motor disorders that cause involuntary or uncontrollable movement or actions of the body.

Ketamine's potential in Parkinson's disease

Parkinson's disease is a debilitating disorder that affects an estimated one million people in the United States and 10 million people worldwide. The global Parkinson's disease market is expected to grow from $5-billion (U.S.) in 2019 to $7.5-billion (U.S.) by the end of 2025.

Ketamine is an FDA-approved N-methyl-D-aspartate receptor-modulating (NDMA) drug that is widely used as an anesthetic agent either alone or in combination with other anesthetic agents. The possible therapeutic effect of low-dose ketamine on levodopa-induced dyskinesia was noted in a retrospective analysis of Parkinson's disease patients who received ketamine for pain relief. During this analysis, it was observed that the patients experienced an improvement in LID lasting several weeks beyond treatment. These results were corroborated in a phase 1/2 clinical study, and in a rodent LID model, and this possible effect has also been examined in a controlled study. Ketamine may also have additional benefits in the treatment of pain and depression, which are frequent co-morbidities of Parkinson's disease.

About Parkinson's disease

There is currently no cure for Parkinson's disease, although some drug combinations are used to treat the disease symptoms. Although the etiology of Parkinson's disease is not fully understood, it is thought to result from loss of pigmented dopaminergic neurons in the substantia nigra and their striatal projections, leading to dopamine deficiency in the striatum. This ultimately affects the cortico-striatal system that controls movement. As a progressive neurogenerative disorder of the central nervous system that primarily affects the motor nerve system, symptoms of Parkinson's disease may emerge slowly and include tremors, rigidity, bradykinesia and postural instability. Also, patients may experience non-motor symptoms such as autonomic dysfunction (orthostatic hypotension, constipation, bladder dysfunction), psychiatric (depression), cognitive and sensory symptoms (pain). These non-motor symptoms become more common as the disease progresses. Treatments, including levodopa and dopamine agonists, which restore the dopamine deficits in the brain, have been employed for almost 50 years. However, with continued treatment using levodopa, dose-limiting motor side effects often emerge. This includes the emergence of abnormal involuntary movements termed levodopa-induced dyskinesias, which can be identified in about 50 per cent of patients within five years after initiation of levodopa treatment and in almost all patients within 10 years posttreatment initiation. These side effects often limit further dose increases in dopaminergic therapy.

There can be no assurance that the company will proceed with the clinical development toward a phase 3 clinical study and that the FDA will support any potential request for an expedited path to approval, such as fast-track designation, or further development for ketamine in the treatment of Parkinson's disease.

About Pharmather Holdings Ltd.

Pharmather Holdings develops and commercializes specialty pharmaceuticals exhibiting growing adoption and permitting novel delivery methods to enhance patient outcomes and prescriber workflow. The company's lead product is Ketarx (ketamine) to fill the unmet medical needs for anesthesia, sedation, pain, mental health and neurological indications.

We seek Safe Harbor.