In April 2021, the USPTO also allowed Patent No. 11,060,128 (the ’128 patent) to our licensor and thereby to us, and this second patent issued on July 13, 2021. The patent is directed to the use of suitable doses of amifampridine to treat patients suffering with LEMS that are slow metabolizers of amifampridine. Any drug product containing amifampridine with a label for the treatment of LEMS, that states the patented dosing regimens and doses in the Dosing and Administration section of a product label, including generic drug product labels, could possibly infringe this patent prior to this patent’s expiration date.
On December 24, 2021, the USPTO allowed continuing application, 11,268,128. On January 3, 2022, the USPTO allowed related continuing application 11,274,332. A further related continuing application, 11,274,331 was allowed on January 7, 2022. All three patents were issued in March 2022 as Patent Nos. 11,268,128, 11,274,332, and 11,274,331, respectively, and extend the coverage of our product that we may be ablepatents to obtain or as to whether payors will agree to cover our product.
The pricinginclude fast metabolizers of pharmaceutical products, in general, and of specialty drugs, in particular, has been a topic of concernamifampridine. These patents are now listed in the U.S. Congress, where hearings have been held on the topic, and a topicOrange Book for FIRDAPSE®.
As part of recent statements madeour transaction with Jacobus Pharmaceuticals, Catalyst also acquired two patents. One of these patents, 10,626,088 issued by the PresidentUSPTO on April 21, 2020, was suitable for listing in the Orange Book and has now been listed in further support of FIRDAPSE®. The other patent, 9,783,497 issued by the PTO on October 10, 2017, is not considered listable under the Orange Book, but, to the extent that it is necessary, Catalyst intends to enforce that patent against infringement as it would any of the United States.Orange Book patents.
We are also pursuing additional patent applications for FIRDAPSE® in an effort to further protect our drug product. There can be no assurance as to how this scrutinythat any additional patents will be issued that provide additional intellectual property protection for our drug product.
There can be no assurance that we do not or will not infringe on pricingpatents held by third parties or that third parties in the future will not claim that we have infringed on their patents. In the event that our products or technologies infringe or violate the patent or other proprietary rights of pharmaceutical products will impact future pricingthird parties, we may be prevented from pursuing product development, manufacturing or commercialization of our products of orphan drugs generally,that utilize such technologies. For example, there may be patents or of pharmaceutical products generally.
While our proposed pricing for Firdapse® has not been established, we recognize the importance of access to our medicines and, if Firdapse® is approvedpatent applications held by the FDA, we expect to work with insurers to gain broad patient access in the U.S. market for the small patient populations of LEMS and CMS. We also expect to introduce and support comprehensive patient assistance programs and charitable access programs to assist eligible patients.
There is a vocal group of neuromuscular physicians who have raised public concerns in a letter to the editor of a medical journal, and some LEMS patients and neuromuscular physicians who have raised public concerns in interviews quoted in articles published in the press,others that LEMS patients may not be able to get amifampridine treatment if we receive an approval of our product. Their overarching concern appears to becontain claims that our product willproducts or operations might be priced too high as an orphan drug ifdetermined to infringe or that may be broader than we arebelieve them to be. Given the first pharmaceutical company to receive an FDA approval for an amifampridine product, thereby giving us the seven-year orphan drug exclusivitycomplexities and the five-year new chemical entity exclusivity for our product. Stories about their concerns have been published in several national publications and some in the press have sought to tie their expectations about the anticipated pricinguncertainties of Firdapse® to stories about perceived abusive price increases of drug products by other pharmaceutical companies. This vocal group has also questioned the appropriateness of the provisions of the Orphan Drug Act that would grant us exclusivity if our product were to be the first amifampridine product approved by the FDA and whether this exclusivity should be eliminated from the law. We have directly responded to these concerns in a letter to the editor in this same medical publication. However,patent laws, there can be no assurance as to the ultimate impact that future patent claims against us may have on our business, financial condition, results of these activities on usoperations, or our products or the extent to which these issues will be raised again in the future.
prospects.Third-Party Reimbursement
Sales of pharmaceutical products depend in significant part on the availability of coverage and adequate reimbursement by third party payors, such as state and federal governments, including Medicare and Medicaid, managed care providers, private commercial insurance plans and pharmacy benefit management (PBM) plans. Decisions regarding the extent of coverage and the amount of reimbursement to be provided for FirdapseUntil FIRDAPSE® are expected to be made on aplan-by-plan, andwas approved in some cases, on apatient-by-patient basis. Particularly given the rarity of LEMS and CMS, we anticipate that securing coverage and appropriate reimbursement from third-party payors will require targeted education. To that end, we expect to hire a dedicated team of field-based market access account managers and reimbursement experts focused on ensuring that clinically-qualified patients have access to our product.
Intellectual property protections for Firdapse®
Under the BioMarin License Agreement, we licensed two pending patents and certain trademarks for Firdapse®. One of the licensed patents is a pending composition of matter patent that, if issued, will protect Firdapse® until February 2027, which includes five years of patent term extension that is expected under the Patent Term Restoration Act. This application was initially rejected following an appeal to the Patent Trial and Appeal Board. The application was refiled with new claims. The new claims were the subject of an office action in which the claims were rejected. A response to the rejection was filed and a final rejection was issued. The application was refiled and is under a final rejection, to which a response is in progress. There can beNovember 2018, no assurance that this patent will be issued. The second patent claims methods of administering Firdapse®. Substantive examination has begun on this patent application and a final rejection has been issued, to which a response is in progress. We may also pursue other patents in order to seek to protect the exclusivity of the drug, dosage forms and methods of administration.
No drug product containing amifampridine for any indication hashad been approved by the FDA such that we received five-year “new chemical entity” exclusivity from the FDA. Therefore, our version of amifampridine, if we are the first to obtain approval of the product in the U.S., will be eligible for five-year newNew chemical entity exclusivity which provides a five-year period of marketing exclusivity for all indications.
We have licensedindications and in the Firdapseabsence of an Orange Book listed patent, precludes a generic from submitting an ANDA until that five year period has expired. Further, when FIRDAPSE® trademark from BioMarin. A trademark application for Firdapse®was allowed, but did not register due to the inability to show use of the mark in interstate shipment. The application was refiled and a Statement of Use was submitted and accepted by the Trademark Office, and the mark was registered in March 2015.
In January 2014, the FDA provisionally approved Firdapse® as a proprietary name for amifampridine phosphate tablets. This provisional approval by the FDA would not prevent the agency from rejecting the name Firdapse®at a later date as part of the NDA review and approval process.
CPP-115
Current status of our development efforts forCPP-115
We aredeveloping CPP-115, a GABA aminotransferase inhibitor that, based on our preclinical studies to date, we believe is a more potent form of vigabatrin, and may have fewer side effects (e.g., visual field defects) than those associated with vigabatrin. We are hoping todevelop CPP-115 for the treatment of refractory infantilespasms. CPP-115 has been granted Orphan Drug Designation by the FDA for the treatment of infantile spasms and Orphan Medicinal Product Designation in the European Union, or EU,LEMS patients, we received seven-year orphan drug exclusivity (ODE) for West syndrome (a form of infantile spasms).
We are currently refining our development plans for this product. We are also working with one or more potential investigators who have expressed an interest in evaluating our product for particular indications (particularly infantile spasms).
We are also continuing our effortsthe treatment of LEMS, precluding a generic filer from receiving final FDA approval until the ODE exclusivity period has expired. Because we have Orange Book listed patents for FIRDAPSE®, potential generic filers were permitted to seek a partnersubmit ANDA filings to work with us in furthering the developmentof CPP-115. However, no agreements have been entered into to date.
There can be no assurance that we will ever successfullycommercialize CPP-115.
Product OverviewFDA starting on the “NCE-1” date (November 28, 2022).
In August 2009,January 2023, we licensedreceived Paragraph IV Certification Notice Letters from three generic drug manufacturers advising us that they had each submitted an Abbreviated New Drug Application (ANDA) to the exclusive worldwide rightsFDA seeking authorization from the FDA to commercialize certain compositionmanufacture, use or sell a generic version of matterFIRDAPSE® in the United States. The notice letters each allege that our six patents relatinglisted in the FDA Orange Book covering FIRDAPSE®are not valid, not enforceable, and/or will not be infringed by the commercial manufacture, use or sale of the proposed product described in these ANDA submissions. Under the FDCA, as amended by the Drug Price Competition and Patent Term Restoration Act of 1984, as amended, we had 45 days from receipt of the notice letters to commence patent infringement lawsuits against these generic drug manufacturers in a new classfederal district court to trigger a stay precluding FDA from approving any ANDA until May 2026 or entry of novel GABA aminotransferase inhibitorsjudgment holding the patents invalid, unenforceable, or not infringed, whichever occurs first, and derivativesin that regard, after conducting the necessary due diligence, we filed lawsuits on March 1, 2023 in the U.S. District Court for the District of vigabatrin. New Jersey against each of the three generic drug manufacturers who notified us of their ANDA submissions.
We intend to develop these compoundsvigorously protect and defend our intellectual property for a broad range of neurological illnesses that could benefit from the inhibition of GABA aminotransferase.CPP-115 is our lead compound from this group of composition of matter patents.
The development efforts ofCPP-115 were led by Dr. Richard B. Silverman, the Patrick G. Ryan/Aon Professor of Chemistry at Northwestern University (Northwestern). Dr. Silverman, who holds 75 patents, is the inventor of pregabalin, also known as LyricaFIRDAPSE®, which is marketed by Pfizer. His goal in inventing the compound that becameCPP-115 was to mimic the mechanism of action of vigabatrin, while making it both more potent and, specific.
CPP-115 works by the same mechanism of action as vigabatrin; that is, the inhibition of GABA aminotransferase, which leads to increased brain GABA levels that reduce epileptogenesis. Due to these similarities, we believe that these two drugs will likely share certain biochemical features related to absorption, metabolism, and elimination, and ourpre-clinical studies ofCPP-115 to date support our expectations. However, based upon ourpre-clinical studies ofCPP-115 to date, we expect that there will be a significant reduction, and possibly elimination, of visual field defects (VFDs) from the use ofCPP-115 compared to vigabatrin. However,although there can be no assurance, that this will ultimately prove to be the case.
Further, based on animal testing to date,CPP-115 has been shown to be at least 200 times more potent than vigabatrin in bothin-vitro and animal model studies. The increased potency could enable the development of dosage forms potentially administrable by other routes of administration compared with the marketed oral, immediate release formulation of vigabatrin, Sabril®. Further, based onnon-clinical testing completed to date,CPP-115 appears to have superior specificity to GABA aminotransferase and we believe that our patents will have a better side effect profile (e.g. less VFDs) compared with Sabrilprotect FIRDAPSE®.
Mechanism from generic competition for the life of action forCPP-115our patents.
We believe thatCPP-115 will be an effective treatment for refractory infantile spasms because it increases endogenous GABA levels inhave also in-licensed the brain throughFIRDAPSE® trademark, and the inhibition of GABA-aminotransferase(GABA-AT).GABA-AT is responsible for the eventual breakdown of GABA and helps to balance its inhibitory effects.
CPP-115 is a GABA analog that is readily absorbed and promptly available to the nervous system, producing effects that last for many hours after a single dose. Due to the fact that this drug is not “receptor active”, its administration does not appear to affect the baseline levels of dopamine, nor those variations in dopamine levels caused by normal stimuli.
Epilepsy and Infantile Spasms
Epilepsy is a brain disorder in which clusters of nerve cells, or neurons, in the brain sometimes signal abnormally. In epilepsy, the normal pattern of neuronal activity becomes disturbed, causing strange sensations, emotions, and behavior or sometimes convulsions, muscle spasms, and loss of consciousness. Epilepsy is a disorder with many possible causes. Anything that disturbs the normal pattern of neuron activity - from illness to brain damage to abnormal brain development - can lead to seizures. Epilepsy may develop because of an abnormality in brain wiring, an imbalance of nerve signaling chemicals called neurotransmitters, imbalance of sensitivity to neurotransmitters, or some combination of these factors. We intend to focus our development efforts forCPP-115 on its use as a treatment for refractory infantile spasms.
An infantile spasm is a specific type of seizure seen in an epilepsy syndrome of infancy and childhood. The onset of infantile spasms is usually in the first year of life, typically between4-8 months. The seizures primarily consist of a sudden bending forward of the body with stiffening of the arms and legs; some children arch their backs as they extend their arms and legs. Spasms tend to occur upon awakening or after feeding, and often occur in clusters of up to 100 spasms at a time. Infants may have dozens of clusters and several hundred spasms per day. Infantile spasms usually stop by age five, but may be replaced by other seizure types.
In complex partial seizures, consciousness is altered. Patients may exhibit automatisms (automatic repetitive behavior) such as walking in a circle, sitting and standing, or smacking their lips together. Often accompanying these symptoms are the presence of unusual thoughts, such as the feeling of déjà vu, uncontrollable laughing, fear, visual hallucinations, and experiencing unusual unpleasant odors. These symptoms are thought to be caused by abnormal discharges in the temporal lobe.
According to the Epilepsy Foundation, there are about 3.0 million epilepsy patientstrademark was registered in the United States with approximately 150,000 new cases diagnosed in the U.S. each year. Worldwide, 65 million people are estimated to have epilepsy. The incidence of epilepsy appears to depend somewhat on the age of the individual. The risk of epilepsy from birth through age 20 is approximately 1%. Within this group, incidence is highest during the first year of life and increases somewhat at the onset of puberty. From age 20 to 55 it decreases again, but increases after age 55.
Anti-epileptic drugs work through a variety of mechanisms, including inhibition of sodium ion channels and the enhancement of GABA mechanisms. Although the different types of epilepsy vary greatly, in general, available medications can only control seizures in abouttwo-thirds of patients.CPP-115, like vigabatrin, is aGABA-AT inhibitor, and we are developing it for refractory infantile spasms. Based on the historic use of vigabatrin in treating epilepsy, we believe thatCPP-115 may ultimately work best as an adjunct therapy to existing drugs.
Vigabatrin has been marketed for decades in over 30 countries by Lundbeck and Sanofi-Aventis and their predecessors and licensees under the brand names Sabril®, Sabrilex® and Sabrilan® (hereinafter referred to as “Sabril®”) as an adjunct(add-on) treatment for adult epilepsy and as a primary treatment for the management of infantile spasms. The composition of matter patents for Sabril® in the U.S. expired many years ago. On August 21, 2009, the FDA approved two NDAs for Sabril® for the treatment of infantile spasms and as an adjunctive therapy for adult patients with refractory complex partial seizures who have failed treatments with several other anti-epileptic drugs. The NDAs are for different formulations of Sabril® and both NDAs are held by Lundbeck. Due to the risks of visual field damage associated with vigabatrin, Sabril®was approved under anFDA-mandated Risk Evaluation and Mitigation Strategy (REMS) program and is only available through a special restricted distribution program approved by the FDA. In 2016, the FDA authorized changes to the REMS program for Sabril® to make it less onerous and to make it easier for patients to obtain their medication.
In chronic use for the treatment of epilepsy, vigabatrin has been generally well tolerated with lower than average neurological side effects compared to other approved epilepsy therapies. The most common side effects reported have been drowsiness and fatigue. However, one clearly established adverse side effect is the development of peripheral visual field defects, or VFDs. These VFDs are manifest as a constriction of the peripheral field of vision (i.e., “tunnel vision”). VFDs occur in approximately 33% of users when cumulative dosage levels of vigabatrin approach approximately 1,500 grams.
Our previous clinical andnon-clinical studies ofCPP-115
On November 1, 2010, we announced key results for our initial series of safety and efficacy evaluations in a number of animal andin-vitro laboratory studies. These results included superior visual safety ofCPP-115, compared to vigabatrin, pharmacokinetic data supporting oral administration ofCPP-115, pharmacologic target specificity, metabolic profile, and an absence of genotoxic, cardiovascular, respiratory, and liver enzyme side effects. It was also shown to be effective in multiple animal models for epilepsy and cocaine addiction.
On May 22, 2012, we reported positive results from a Phase 1a double-blind, placebo-controlled clinical trial evaluating the safety, tolerability and pharmacokinetic profile ofCPP-115. The study evaluated single ascending doses ranging from 5 mg to 500 mg (a dose greater than ten times the predicted effective dose of15-30 mg/day derived from animal data) ofCPP-115 solution administered orally to 55 healthy volunteers.CPP-115 was found to be well tolerated with no side effects, rapidly absorbed and eliminated, and exhibited linear, dose dependent pharmacokinetics.
In December 2015 we announced top line results from a Phase 1b double-blind, placebo controlled safety and tolerance study ofCPP-115 in six normal healthy adult male volunteers. The results showed significant increases in brain levels of the surrogate marker for potential efficacy, gamma-aminobutyric acid (GABA), a mechanism known to effectively treat epilepsy and infantile spams. The main adverse effect of prolonged elevated brain GABA, somnolence, was also observed.
While the primary objective of this study was to obtain safety and tolerance data forCPP-115 administered over 14 days, brain GABA levels were measured as a surrogate marker of potential efficacy, sinceCPP-115 is a second generation GABA aminotransferase inhibitor. Specifically, this study examined GABA levels in both the POC (Parietal-Occipital Cortex), a grey matter rich region thought to be associated with epilepsy, and which was previously studied for vigabatrin. The maximum brain GABA increases, in both brain regions, ranged from about 150% to over 200% of baseline levels, as measured by magnetic resonance spectroscopy (MRS).
Previous clinical andpre-clinical studies ofCPP-115 undertaken by others
An animal study reporting positivepre-clinical efficacy in a “rat multiple hit model” in which the use ofCPP-115 was evaluated for the treatment of infantile spasms was published in the January 2014 issue of the journal,Epilepsia, The study was authored by Stephen W. Briggs, Tomonori Ono, MD, PhD, Solomon L. Moshe, MD and Aristea S. Galanopoulou, MD, PhD of the Saul R. Korey Department of Neurology, Dominick P. Purpura Department of Neuroscience, Laboratory of Developmental Epilepsy, The Comprehensive Epilepsy Center (CEC) at Montefiore Medical Center / Albert Einstein College of Medicine of Yeshiva University, Bronx, New York. The study concluded that(i) CPP-115 suppresses spasms in themultiple-hit model of infantile spasm, with onset of effect as early as the day after the first dose; (ii) the therapeutic doses ofCPP-115 were well tolerated in developing rat pups; and(iii) CPP-115 showed efficacy for a longer duration at lower doses that were better tolerated than the previously tested therapeutic vigabatrin doses.
In September 2016, the Journal of Epilepsy & Behavior Case Reports published a case report of a child treated withCPP-115 in an investigator-sponsored, investigational new drug protocol. Based on treatment withCPP-115, this particular child experienced a significant reduction of seizures, with no evidence of retinal dysfunction. According to the case report, prior to treatment withCPP-115, the patient had failed ten drugs and the ketogenic diet, and had approximately 100 seizures per day. One year after startingCPP-115 and coming off of clobazam and vigabatrin, the patient’s reported seizures have seen a marked reduction in frequency and his cognition and behavior have improved.
Northwestern University License Agreement
On August 27, 2009, we entered into a license agreement with Northwestern University (Northwestern), under which we acquired worldwide rights to commercialize new GABA aminotransferase inhibitors and derivatives of vigabatrin which had been discovered and patented by Northwestern. Under the terms of the license agreement, Northwestern granted us an exclusive worldwide license to United States composition of matter patents related to the new class of inhibitors and a patent application relating to derivatives of vigabatrin. This includes U.S. patent number 6,794,413 covering the composition of matter forCPP-115. We have designated the lead compound to be developed under this license asCPP-115.
Under our license agreement with Northwestern, we will be responsible for continued research and development of any resulting drug candidates. We have the right to terminate the agreement in whole or in part upon written notice. As of December 31, 2017, we have paid Northwestern upfront payments, milestone fees and maintenance and patent fees aggregating $424,885 and we are obligated to pay certain additional fees and milestone payments in future years relating to our clinical development activities under this license or payable upon passage of time (the next milestone payment, in the amount of $300,000, is due on the earlier of completion of the first Phase 3 clinical trial ofCPP-115 or August 27, 2018). We are also obligated to pay Northwestern royalties on any products resulting from the license agreement. We also have the right to enter intosub-license agreements, and if we do, a royalty on anysub-license fees will be payable to Northwestern.
Patent protection forCPP-115
In addition to the exclusively licensed U.S. Patent 6,794,413, in March 2015, the U.S. Patent & Trademark Office (US PTO) issued patent 8,969,413 for the method of use patent forCPP-115 for neurological and psychological uses. This patent will expire in 2032, subject to potential extensions allowed under the patent term restoration act. A continuation application was filed to capture additional methods of using CPP for neurological and psychological conditions. This continuation application is undergoing substantive examination. Patents for the same coverage remain pending in the European Patent Office, Japan and Canada. There can be no assurance that the claims of this patent will be allowed, or if allowed, that such claims will provide adequate patent protection forCPP-115.
Generic Sabril®
In September 2015, we announced the launch of a program to develop our version of vigabatrin(CPP-109) as a generic version of Sabril®, which is marketed in the United States by Lundbeck. Lundbeck’s exclusivity for Sabril® expired on April 26, 2017.
As part of our development of this product, we have obtained the reference listed drug and the active pharmaceutical ingredient, entered into an exclusive supply agreement for the vigabatrin active pharmaceutical ingredient with a manufacturer that has submitted a DMF to the FDA, validated the manufacturing process, and prepared a number of batches of vigabatrin for us on a commercial scale in the past, developed and validated quality control and stability test methods, and collected stability data showing thatCPP-109 has an acceptable shelf life in two container closure systems. We are also taking the steps that will be required for us to obtain the rights to commercialize generic versions of this product.
There can be no assurance that we will be successful in these efforts or that any ANDA that we submit for vigabatrin will be accepted for review or approved. There can also be no assurance that any bioequivalence studies that we submit to the FDA in support of an ANDA for this product will be acceptable to the FDA. Finally, any approved generic version of vigabatrin that we are approved to commercialize will, consistent with Sabril®, only be available subject to anFDA-mandated Risk Evaluation and Mitigation Strategy (REMS) program.
We are continuing our efforts to seek a partner to work with us in furthering the development of generic Sabril®. However, no agreements have been entered into to date.
Intellectual Property Rights2015.
Protection of our intellectual property and proprietary technologyregulatory exclusivities is a strategic priority for our business. We rely on a combination of patent, trademark, copyright and trade secret laws along with institutionalknow-how and continuing technological advancement, to develop and maintain our competitive position. Our ability to protect and use our intellectual property rights and regulatory exclusivity in the future development and commercialization of our products, operate without infringing the proprietary rights of others, and prevent others from infringing our proprietary rights, is crucial to our future success. See Item 1A. “Risk Factors —- Risks Related to Our Intellectual Property.”
11
