PTC Therapeutics Stock

PTC Therapeutics, Inc. (PTC) operates as a science-driven global biopharmaceutical company.

The company focuses on the discovery, development and commercialization of clinically differentiated medicines that provide benefits to patients with rare disorders.

The company’s strategy is to leverage its strong scientific and clinical expertise and global commercial infrastructure to bring therapies to patients.

Pipeline

The company has a portfolio pipeline that includes several commercial products and product candidates in various stages of development, including clinical, pre-clinical and research and discovery stages, focused on the development of new treatments for multiple therapeutic areas for rare diseases relating to neurology, metabolism and oncology.

Global Commercial Footprint

Global DMD Franchise – The company has two products, Translarna (ataluren) and Emflaza (deflazacort), for the treatment of Duchenne muscular dystrophy, or DMD, a rare, life threatening disorder. Translarna has marketing authorization in the European Economic Area, or EEA, for the treatment of nonsense mutation Duchenne muscular dystrophy, or nmDMD, in ambulatory patients aged two years and older and in Russia for the treatment of nmDMD in patients aged two years and older. Translarna also has marketing authorization in Brazil for the treatment of nmDMD in ambulatory patients two years and older and for continued treatment of patients that become non-ambulatory. Emflaza is approved in the United States for the treatment of DMD in patients two years and older.

Upstaza (eladocagene exuparvovec) – Upstaza, a gene therapy for the treatment of Aromatic L-Amino Decarboxylase, or AADC, deficiency, a rare central nervous system, or CNS, disorder is approved for the treatment of AADC deficiency for patients 18 months and older within the EEA and the United Kingdom. The company expects to submit a biologics license application, or BLA, for Upstaza for the treatment of AADC deficiency in the United States to the United States Food and Drug Administration, or FDA, in the first half of 2023.

Tegsedi (inotersen) and Waylivra (volanesorsen) – The company holds the rights for the commercialization of Tegsedi and Waylivra for the treatment of rare diseases in countries in Latin America and the Caribbean pursuant to its Collaboration and License Agreement with a subsidiary of Ionis Pharmaceuticals, Inc. Tegsedi has received marketing authorization in the United States, European Union, or EU, and Brazil for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hereditary transthyretin amyloidosis, or hATTR amyloidosis. The company began to make commercial sales of Tegsedi for the treatment of hATTR amyloidosis and Waylivra for the treatment of familial chylomicronemia syndrome, or FCS, in Brazil in 2022. Waylivra is also approved in Brazil for the treatment of familial partial lipodystrophy, or FPL.

Evrysdi (risdiplam) – Evrysdi, a treatment for spinal muscular atrophy, or SMA, was approved by the FDA for the treatment of SMA in adults and children of all ages and by the European Commission for the treatment of 5q SMA in patients two months and older with a clinical diagnosis of SMA Type 1, Type 2 or Type 3 or with one to four SMN2 copies. Evrysdi has also received marketing authorization for the treatment of SMA in Brazil and Japan. The company expects the EMA to make a regulatory decision on approval for a label expansion for Evrysdi to include infants under two months old with SMA in 2023. Evrysdi is a product of the company’s SMA program and its collaboration with F. Hoffman-La Roche Ltd. and Hoffman-La Roche Inc., which the company refers to collectively as Roche, and the Spinal Muscular Atrophy Foundation, or SMA Foundation.

Diversified Development Pipeline

Splicing Platform – In addition to the company’s SMA program, its splicing platform includes PTC518, which is being developed for the treatment of Huntington’s disease, or HD. The company initiated a Phase 2 study of PTC518 for the treatment of HD in the first quarter of 2022, which consists of an initial 12-week placebo-controlled phase focused on safety, pharmacology and pharmacodynamic effects followed by a nine-month placebo-controlled phase focused on PTC518 biomarker effect. Enrollment in the Phase 2 study remains active and ongoing outside of the United States. Enrollment within the United States is paused as the FDA has requested additional data to allow the Phase 2 study to proceed; discussions are ongoing with the FDA to allow the resumption of the U.S. enrollment. The company expects data from the initial 12-week phase of the Phase 2 study in the second quarter of 2023.

Bio-e Platform – The two most advanced molecules in the company’s Bio-e platform are vatiquinone and utreloxastat. The company initiated a registration-directed Phase 2/3 placebo-controlled trial of vatiquinone in children with mitochondrial disease associated seizures in the third quarter of 2020. The company anticipates results from the Phase 2/3 trial to be available in the second quarter of 2023. The company also initiated a registration-directed Phase 3 trial of vatiquinone in children and young adults with Friedreich ataxia in the fourth quarter of 2020 and anticipates results from this trial to be available in the second quarter of 2023. The company initiated a Phase 2 trial of utreloxastat for amyotrophic lateral sclerosis, or ALS, in the first quarter of 2022 and enrollment is ongoing.

Metabolic Platform – The most advanced molecule in the company’s metabolic platform is sepiapterin. The company initiated a registration-directed Phase 3 trial for sepiapterin for phenylketonuria, or PKU, in the third quarter of 2021 and now expect results from Part 2 of this trial to be available in May 2023 as the trial is overenrolled and additional time is required for the entirety of the primary analysis population to complete the study.

Gene Therapy Platform – In addition to Upstaza, the company’s gene therapy platform includes an asset targeting Friedreich ataxia. The company continues to work towards initiating a clinical study for this program. Additionally, the gene therapy platform includes the company’s program targeting Angelman syndrome. The company continues to work towards submitting a filing in the support of the first-in-human study for this program.

Oncology Platform – Unesbulin is the company’s most advanced oncology agent. The company initiated a registration-directed Phase 2/3 trial of unesbulin for the treatment of leiomyosarcoma, or LMS, in the first quarter of 2022 and enrollment is ongoing. The company expects to initiate a registration-directed Phase 2/3 trial of unesbulin for the treatment of diffuse intrinsic pontine glioma, or DIPG, in the fourth quarter of 2023.

Multi-platform Discovery

The company continues to invest in its pre-clinical product pipeline across all of the company’s platforms by committing significant resources to research and development programs and business development opportunities within the company’s areas of scientific expertise, including potential collaborations, alliances, and acquisitions or licensing of assets that complement the company’s strategic mission to provide access to best-in-class treatments for patients who have an unmet medical need.

Marketing Authorization Matters

Translarna for the Treatment of Nonsense Mutation Duchenne Muscular Dystrophy

European Economic Area

The company received marketing authorization from the European Commission in August 2014 for Translarna for the treatment of nmDMD in ambulatory patients aged five years and older in the member states of the EEA, subject to annual renewal and other conditions. In July 2018, the European Commission approved a label-extension request to the company’s marketing authorization for Translarna in the EEA to include patients from two to up to five years of age. In July 2020, the European Commission approved the removal of the statement ‘efficacy has not been demonstrated in non-ambulatory patients’ from the indication statement for Translarna.

The marketing authorization is subject to annual review and renewal by the European Commission following reassessment by the EMA of the benefit-risk balance of continued authorization, which the company refers to as the annual EMA reassessment. In June 2022, the European Commission renewed the company’s marketing authorization, making it effective, unless extended, through August 5, 2023. In February 2023, the company submitted a marketing authorization renewal request to the EMA.

In September 2022, the company submitted a Type II variation to the EMA to support conversion of the conditional marketing authorization for Translarna to a standard marketing authorization, which included a report on the placebo-controlled trial of Study 041 and data from the open-label extension. The company expects an opinion from the Committee for Medicinal Products for Human Use, or CHMP, in the first half of 2023.

Marketing authorization is required in order for the company to engage in any commercialization of Translarna in the EEA, including through participation in the market access process and related pricing and reimbursement negotiations, on a country-by-country basis with each country in the EEA, and is also required to make Translarna available under early access programs, or EAP programs.

As the marketing authorization holder, the company is obligated to monitor the use of Translarna for nmDMD to detect, assess and take required action with respect to information that could impact the safety profile of Translarna and to report this information, through pharmacovigilance submissions, to the EMA. Following its assessment of these submissions, the EMA can recommend to the European Commission actions ranging from the continued maintenance of the marketing authorization to its withdrawal.

The United States

Translarna is an investigational new drug in the United States. During the first quarter of 2017, the company filed a New Drug Application, or NDA, for Translarna for the treatment of nmDMD over protest with the FDA. In October 2017, the Office of Drug Evaluation I of the FDA issued a Complete Response Letter, or CRL, for the NDA, stating that it was unable to approve the application in its current form. In response, the company filed a formal dispute resolution request with the Office of New Drugs of the FDA. In February 2018, the Office of New Drugs of the FDA denied the company’s appeal of the CRL. In its response, the Office of New Drugs recommended a possible path forward for the company’s ataluren NDA submission based on the accelerated approval pathway. This would involve a re-submission of an NDA containing the current data on effectiveness and safety of ataluren with new data to be generated on dystrophin production in nmDMD patients’ muscles. The company followed the FDA’s recommendation and collected, using newer technologies via procedures and methods that the company designed, such dystrophin data in a new study, Study 045, and announced the results of Study 045 in February 2021. Study 045 did not meet its pre-specified primary endpoint. In June 2022, the company announced top-line results from the placebo-controlled trial of Study 041. Following this announcement, the company submitted a meeting request to the FDA to gain clarity on the regulatory pathway for a potential re-submission of an NDA for Translarna. The FDA provided initial written feedback that Study 041 does not provide substantial evidence of effectiveness to support NDA re-submission. The company recently had an informal meeting with the FDA, during which the company discussed the potential path to an NDA re-submission for Translarna. Based on the meeting discussion, the company plans to request an additional Type C meeting with the FDA in the near future to review the totality of data collected as of December 31, 2022, including dystrophin and other mechanistic data as well as additional analyses that could support the benefit of Translarna.

Other Territories

Translarna received marketing authorization for the treatment of nmDMD in Israel and South Korea in 2015, Chile in 2018, Brazil in 2019 and Russia in 2020, in addition to approvals from other countries, and these licenses are active. Many territories outside of the EEA, including Israel, South Korea and Chile, reference and depend on the determinations by the EMA when considering the grant of a marketing authorization. It is unlikely that the company would be able to maintain the company’s marketing authorizations in these regions in the event the EMA decides not to renew or otherwise modifies or withdraws the company’s marketing authorization in the EEA. The marketing authorization for Translarna in Brazil and Russia are subject to renewal every five years. The company has been pursuing and expects to continue to pursue marketing authorizations for Translarna for the treatment of nmDMD in other regions.

Emflaza for the Treatment of Duchenne Muscular Dystrophy in the United States

Emflaza, both in tablet and suspension form, received approval from the FDA in February 2017 as a treatment for DMD in patients five years of age and older in the United States. In June 2019, the FDA approved the company’s label expansion request for Emflaza for patients two to five years of age.

Emflaza has a seven-year exclusive marketing period in the United States for its approved indications, commencing on the date of FDA approval, under the provisions of the Orphan Drug Act of 1983, or the Orphan Drug Act.

Upstaza

Upstaza is a gene therapy for the treatment of AADC deficiency, a rare CNS disorder arising from reductions in the enzyme AADC that results from mutations in the dopa decarboxylase gene. In July 2022, the European Commission approved Upstaza for the treatment of AADC deficiency for patients 18 months and older within the EEA. In November 2022, the Medicines and Healthcare Products Regulatory Agency approved Upstaza for the treatment of AADC deficiency for patients 18 months and older within the United Kingdom. The company is also preparing a BLA for Upstaza for the treatment of AADC deficiency in the United States and the company expects to submit a BLA to the FDA in the first half of 2023.

Upstaza is an adeno-associated virus, or AAV, gene therapy, which has been assessed in two completed clinical trials, and one ongoing trial. The two completed trials include a total of 18 children with severe AADC deficiency who were treated with a one-time total dose of 1.8 x 1011 vg of Upstaza during a single procedure in which the gene therapy was administered directly to the region of the brain, called the putamen, where dopamine is made and released.

The two completed clinical trials, AADC-1601, a trial in which patients were enrolled under individual compassionate use consents, and AADC-010, were both single-arm, open-label, interventional trials that enrolled a total of 18 patients. The primary and secondary objectives of these trials were to assess the safety and efficacy of Upstaza administered via bilateral putaminal-infusions in patients with severe AADC deficiency at a total one-time dose of 1.8 x 1011 vg. Study enrollment required a diagnosis of AADC deficiency, defined as decreased homovanilic acid, or HVA, and 5-hydroxyindoleacetic acid, or 5-HIAA, and elevated levels of L-DOPA in the cerebrospinal fluid, or CSF, the presence of more than one DDC gene mutation, and the presence of clinical symptoms of AADC deficiency (including developmental delay, hypotonia, dystonia, and oculogyric crisis), and a patient age of older than 2 years.

The ongoing clinical trial, AADC-011, is a single-center, open-label trial to assess the efficacy and safety of Upstaza in patients with AADC deficiency. The primary outcomes for this trial include assessing a change in the PDMS-2 score and measuring the change in the neurotransmitter metabolite HVA or 5-HIAA in the cerebrospinal fluid. 10 patients have been enrolled and treated as of December 31, 2022. With these 10 patients, the company has 28 patients from its three trials being evaluated in safety and efficacy studies.

An end-of-phase 2 meeting was held with the FDA in July 2017, and the clinical, non-clinical and chemistry, manufacturing and control, or CMC, data available as of December 31, 2022 from the two completed clinical trials were reviewed. The FDA provided feedback indicating that the clinical and non-clinical data available as of December 31, 2022 were sufficient to support the submission of a BLA without undertaking additional trials or studies at this time. In a late 2019 interaction with the FDA, the agency requested additional information concerning the use of the commercial delivery system for Upstaza in young patients. In response to the FDA’s request, the company provided additional information concerning the use of the commercial cannula for Upstaza in young patients. In October 2022, the company held a type C meeting with the FDA to discuss the details of a potential submission package for Upstaza. At such meeting, the FDA asked for additional bioanalytical data in the support of comparability between the drug product used in the clinical studies and the commercial drug product. The company has completed these analyses and provided the results to the FDA for review. The company expects to submit a BLA to the FDA in the first half of 2023.

Upstaza for the treatment of AADC deficiency has orphan drug designation in the United States and EU, and rare pediatric disease designation in the United States, and upon BLA approval the FDA may grant the company a priority review voucher.

Due to its orphan medicinal product designation by the EMA, the company relies on a ten-year exclusive marketing period for Upstaza in the EEA, which may potentially be extended for two additional years if the company receives approval for a pediatric exclusivity incentive. If Upstaza for the treatment of AADC deficiency receives FDA approval, the company expects that Upstaza would have a twelve-year exclusive marketing period in the United States for the approved indication, commencing on the date of FDA approval, under the provisions of the Biologics Price Competition and Innovation Act of 2009, or BPCIA, as well as a concurrent seven-year exclusive marketing period, which would commence on the date of FDA approval, under the provisions of the Orphan Drug Act. The company expects to rely on the twelve-year BPCIA regulatory exclusivity and concurrent seven-year Orphan Drug Act exclusivity to commercialize Upstaza in the United States, if it is approved.

Tegsedi and Waylivra

In August 2018 the company entered into a Collaboration and License Agreement with Akcea Therapeutics, Inc., or Akcea, a subsidiary of Ionis Pharmaceuticals, Inc., or Ionis, for the commercialization by the company of Tegsedi, Waylivra and products containing those compounds in countries in Latin America and the Caribbean, or the PTC Territory.

Tegsedi

Tegsedi, a product of Ionis’ proprietary antisense technology, is an antisense oligonucleotide, or ASO, inhibitor of human transthyretin, or TTR, production. Tegsedi is the world’s first RNA-targeted therapeutic to treat patients with hereditary transthyretin amyloidosis, or hATTR amyloidosis. In October 2019, it received marketing authorization from ANVISA, the Brazilian health regulatory authority, for the treatment of stage 1 or stage 2 polyneuropathy in adult patients with hATTR amyloidosis in Brazil. The company’s marketing authorization for Tegsedi in Brazil is subject to renewal every five years. It has also received marketing authorization in the United States and EU for the same indication. The company began to make commercial sales of Tegsedi for the treatment of hATTR amyloidosis in Brazil in the second quarter of 2022 and the company continues to make Tegsedi available in certain other countries within Latin America and the Caribbean through EAP programs.

Waylivra

Waylivra is an ASO that has received marketing authorization in the EU for the treatment of FCS, subject to certain conditions. The United States and EU regulatory agencies have granted orphan drug designation to Waylivra for the treatment of FCS. In connection with the marketing approval for Waylivra in the EU, the European Commission is requiring Akcea to provide results of a study based on a registry of patients to investigate how blood checks and adjustments to frequency of injections are carried out in practice and how well they work to prevent thrombocytopenia and bleeding in FCS patients taking Waylivra. In August 2021, ANVISA approved Waylivra as the first treatment for FCS in Brazil and the company began to make commercial sales of Waylivra in Brazil in the third quarter of 2022 while continuing to make Waylivra available in certain other countries within Latin America and the Caribbean through EAP programs. The company’s marketing authorization for Waylivra in Brazil is subject to renewal every five years.

Additionally, the company received approval of Waylivra for the treatment of FPL in Brazil in December 2022.

Evrysdi

Evrysdi was approved by the FDA in August 2020 for the treatment of SMA in adults and children two months and older and by the European Commission in March 2021 for the treatment of 5q SMA in patients two months and older with a clinical diagnosis of SMA Type 1, Type 2 or Type 3 or with one to four SMN2 copies. Evrysdi also received marketing authorization for the treatment of SMA in Brazil in October 2020 and Japan in June 2021. In May 2022, the FDA approved a label expansion for Evrysdi to include infants under two months old with SMA and the company expects the EMA to make a regulatory decision on approval for a label expansion for Evrysdi to include infants under two months old with SMA in the 2023. Evrysdi is a product of the company’s SMA program and its collaboration with Roche and the SMA Foundation.

Using the company’s splicing technology and in collaboration with the SMA Foundation and Roche, the company identified highly potent small molecule splicing modifiers that, in non-clinical studies in cultured cells derived from patients with SMA, increased both the inclusion of exon 7 in the SMN2 messenger RNA, or mRNA, transcript and the levels of SMN protein produced by the SMN2 gene. Importantly, in studies in transgenic mice carrying only the SMN2 gene, these orally bioavailable compounds penetrated the blood-brain barrier and increased the levels of full-length SMN2 mRNA and protein in brain, spinal cord, muscle and other tissues. In these same mouse studies, treatment with these compounds resulted in increased survival, restoration of body weight, prevention of motor neuron loss and improved motor function.

Diversified Development Pipeline

The company’s pipeline has a number of development programs in the clinical stages. These include splicing, Bio-e, metabolic, gene therapy and oncology programs, as well as studies in the company’s current commercial products for maintaining authorizations, label extensions and additional indications.

Splicing Platform

The company’s splicing platform focuses on the development of innovative therapies for diseases, such as SMA, that involve regulation of mRNA splicing in the cell.

In addition to Evrysdi and the company’s SMA program, its splicing platform includes PTC518, which is being developed for the treatment of HD. HD is a neurodegenerative and progressive brain disorder caused by a toxic gain-of-function triplet repeat expansion in the Huntingtin gene resulting in uncontrolled movements and cognitive loss. There are no disease-modifying therapies approved to delay the onset or slow the progression of HD. PTC518 is an orally bioavailable molecule with broad central nervous system and systemic distribution that has been designed to target Huntingtin protein expression with high selectivity and specificity. The company announced the results from its Phase 1 study of PTC518 in healthy volunteers in September 2021 demonstrating dose-dependent lowering of huntingtin messenger ribonucleic acid and protein levels, that PTC518 efficiently crosses blood brain barrier at significant levels and that PTC518 was well tolerated. The company initiated a Phase 2 study of PTC518 for the treatment of HD in the first quarter of 2022, which consists of an initial 12-week placebo-controlled phase focused on safety, pharmacology and pharmacodynamic effects followed by a nine-month placebo-controlled phase focused on PTC518 biomarker effect. Enrollment in the Phase 2 study remains active and ongoing outside of the United States. Enrollment within the United States is paused as the FDA has requested additional data to allow the Phase 2 study to proceed; discussions are ongoing with the FDA to allow the resumption of the U.S. enrollment. The company expects data from the initial 12-week phase of the Phase 2 study in the second quarter of 2023.

The company’s splicing platform clinical development program also includes several studies evaluating Evrysdi in a broad SMA patient population covering the ages from newborns to 60 years old that remain ongoing. In addition to the Firefish (infantile onset SMA; age at enrollment of one to seven months) and Sunfish (later onset SMA; age at enrollment of two to 25 years) studies that established the safety profile of Evrysdi, the Jewelfish (patients who previously received other SMA targeted therapies; age at enrollment of six months to 60 years) and Rainbowfish (pre-symptomatic patients; age at enrollment of newborns to 6 weeks) studies may potentially be used to support future applications for label extensions.

Jewelfish, an open-label study investigating the safety, tolerability, pharmacokinetics, and pharmacokinetics/pharmacodynamic relationship of Evrysdi in patients aged from 6 months to 60 years with SMA previously treated with one of several experimental or approved SMA therapies, initiated in the first quarter of 2017. Also, Evrysdi was well tolerated, with no drug-related adverse events leading to withdrawal from the study. The study has completed recruitment.

Rainbowfish is an open-label, single-arm, multicenter study, investigating the efficacy, safety, pharmacokinetics and pharmacodynamics of Evrysdi in babies, from birth to six weeks of age (at first dose) with genetically diagnosed SMA who are not yet presenting with symptoms. The study has completed recruitment. Interim data from Rainbowfish showed that 80 percent of pre-symptomatic infants with SMA treated with Evrysdi for at least 12 months achieved motor milestones such as sitting without support, rolling, crawling, standing unaided, and walking independently.

Bio-e Platform

The company’s Bio-e platform consists of small molecule compounds that target oxidoreductase enzymes that regulate oxidative stress and inflammatory pathways central to the pathology of a number of CNS diseases. Oxidation-reduction, or redox, reactions are an essential component of the generation and regulation of energy in living systems. These reactions are regulated through a set of enzymes known as oxidoreductase enzymes that uniquely require the transfer of an electron, or a redox chemical reaction, to affect their biological activity.

One of the advanced molecules in the company’s Bio-e platform is vatiquinone. Vatiquinone is a small molecule orally bioavailable compound that has been in development for inherited mitochondrial diseases and related genetic disorders of oxidative stress. Vatiquinone targets 15-lipoxygenase, or 15-LO, a key regulator of oxidative stress, lipid-based neuro-inflammation, alpha-synuclein oxidation and aggregation and cell death. In the third quarter of 2020, the company initiated a registration-directed Phase 2/3 randomized, placebo-controlled trial of vatiquinone in approximately 60 children with mitochondrial disease associated seizures, called MIT-E. The company has completed enrollment in this trial after previously experiencing delays in enrollment due to the COVID-19 pandemic. All subjects were followed for one month to ensure a baseline seizure frequency, and have been randomized to receive vatiquinone or placebo for six months. The company anticipates results from the Phase 2/3 trial to be available in the second quarter of 2023. Mitochondrial disease associated seizures is a highly morbid condition of refractory seizures in patients with inherited mitochondrial disease. The company estimates that there are approximately 20,000 patients with mitochondrial disease associated seizures globally. The clinical rationale for the MIT-E trial is based on reports of decreased seizure frequency, disruption of status epilepticus and reduced mortality risk and disease-associated morbidity recorded through compassionate use studies of vatiquinone in mitochondrial disease patients conducted in the United States and EU.

Additionally, the company initiated a registration-directed Phase 3 trial of vatiquinone in approximately 120 patients with Friedreich ataxia in the fourth quarter of 2020, called MOVE-FA. The MOVE-FA trial is an 18-month parallel arm, placebo-controlled study evaluating vatiquinone versus placebo in children and young adults with Friedreich ataxia. The company has completed enrollment for the MOVE-FA trial and the company anticipates results to be available in the second quarter of 2023. Vatiquinone has previously been studied in Friedreich ataxia patients in a Phase 2 trial that included a six-month placebo-controlled phase followed by an 18-month open label extension. In this trial, long-term vatiquinone treatment (18-24 months) was associated with an improvement in overall disease severity and neurological function relative to natural history. Vatiquinone has been dosed in over 500 subjects and has been generally well-tolerated in the clinic.

The other advanced molecule in the company’s Bio-e platform is utreloxastat, a small molecule orally bioavailable compound that targets 15-LO and is in development for the potential treatment of adult CNS patients. In the third quarter of 2021, the company completed a Phase 1 trial in healthy volunteers to evaluate the safety and pharmacology of utreloxastat. Utreloxastat was found to be well-tolerated with no reported serious adverse events while demonstrating predictable pharmacology. The company initiated a Phase 2 trial of utreloxastat for ALS in the first quarter of 2022 and enrollment is ongoing.

Metabolic Platform

The company’s metabolic platform seeks to identify potential treatments for metabolic disorders. The most advanced molecule in the company’s metabolic platform is sepiapterin, a precursor to intracellular tetrahydrobiopterin, which is a critical enzymatic cofactor involved in metabolism and synthesis of numerous metabolic products. Sepiapterin has been pursued as a possible treatment for orphan metabolic diseases associated with defects in the tetrahydrobiopterin biochemical pathways, including PKU.

In December 2019, the company was announced that the Phase 2 trial for sepiapterin as a potential treatment for PKU met its primary and secondary endpoints, achieving statistically-significant and clinically-meaningful reduction in blood Phe levels compared to both baseline and an active control group. The company initiated a registration-directed Phase 3 trial for sepiapterin for PKU in the third quarter of 2021 with the primary endpoint in the study of achieving statistically-significant reduction in blood Phe level. The primary analysis population includes those patients who have a greater than 30% reduction in blood Phe levels during the Part 1 run-in phase of the trial. In January 2023, the company announced preliminary data from the Part 1 run-in phase of this trial, including that the mean reduction in blood Phe levels in an initial cohort of subjects during the Part 1 would be recognized as clinically meaningful if maintained in Part 2 of the trial. The company expects results from Part 2 of this trial to be available in May 2023 as the trial is overenrolled and additional time is required for the entirety of the primary analysis population to complete the study.

Gene Therapy Platform

The company’s gene therapy platform focuses on the development of innovative therapies for rare, debilitating diseases of the CNS. In addition to Upstaza, the company’s gene therapy platform includes an asset targeting Friedreich ataxia continues to undergo preclinical studies. The company continues to work towards initiating a clinical study for this program. Additionally, the gene therapy platform includes the company’s program targeting Angelman syndrome, a rare, genetic, neurological disorder characterized by severe developmental delays. The company continues to work towards submitting a filing in support of the first-in-human study for this program.

Oncology Platform

Unesbulin is the company’s most advanced oncology agent. Unesbulin is a small molecule inhibitor of tubulin polymerization that is associated with cell cycle arrest. In addition, administration is associated with a hyperphosphorylation of tumor BMI1 protein that subsequently leads to BMI1 protein degradation and reduction in BMI1 protein function. The company has assessed unesbulin in a Phase 1 multi-center study in patients with advanced solid tumors. Unesbulin is also being evaluated in LMS in patients who have relapsed or are refractory to current treatments. Preclinical evaluations suggested that unesbulin had synergistic effects in combination with dacarbazine. The company completed a Phase 1 dose escalation study of unesbulin for LMS in the fourth quarter of 2021. Unesbulin in combination with dacarbazine was found to be well-tolerated and a dose was selected for subsequent trials. The company initiated a registration-directed Phase 2/3 trial of unesbulin for the treatment of LMS in the first quarter of 2022 and enrollment is ongoing.

The company is also assessing unesbulin for the treatment of DIPG. The company completed a Phase 1 dose-escalation trial in DIPG patients in the fourth quarter of 2021. The initiation of the company’s registration-directed Phase 2 trial of unesbulin for DIPG was delayed as the company continued to track the progress of patients in the company’s Phase 1 trial and analyze the corresponding data. The company expects to initiate a registration-directed Phase 2/3 trial of unesbulin for the treatment of DIPG in the fourth quarter of 2023.

While the company has decided to deprioritize the emvododstat program for the treatment of acute myeloid leukemia, or AML, the company is exploring other potential treatments for AML as part of the company’s oncology platform.

As part of the company’s continuous portfolio review, the company has decided to deprioritize its program for emvododstat for the treatment of COVID-19.

Collaborations, License Agreements and Funding Arrangements

The company has ongoing collaborations with Roche and the SMA Foundation for SMA, a license agreement with National Taiwan University, or NTU, for Upstaza, a collaboration and license agreement with Akcea for Tegsedi and Waylivra and a license agreement with Shiratori Pharmaceutical Co., Ltd., or Shiratori, relating to the manufacturing processes and technology for sepiapterin. The company also has received grant funding from Wellcome Trust pursuant to funding agreements under which it has continuing obligations.

Roche and the SMA Foundation

In November 2011, the company entered into a license and collaboration agreement with Roche and the SMA Foundation to further develop and commercialize compounds identified under its SMA sponsored research program with the SMA Foundation and to research other small molecule compounds with potential for therapeutic use in patients with SMA. The research term of this agreement was terminated effective December 31, 2014. The ongoing collaboration is governed by a joint steering committee consisting of an equal number of representatives of the company, the SMA Foundation and Roche.

The company has granted Roche worldwide exclusive licenses, with the right to grant sublicenses, to its patent rights and know-how with respect to such compounds and products. Roche is responsible for pursuing worldwide clinical development of compounds from the research program and has the exclusive right to develop and commercialize compounds from the collaboration.

SMA Foundation

In 2006, the company entered into a sponsored research agreement with the SMA Foundation under which the company and the SMA Foundation have collaborated in the research and preclinical development of small molecule therapeutics for SMA. The company is also collaborating with the SMA Foundation and Roche to further develop these compounds.

National Taiwan University

Pursuant to the license and technology transfer agreement, originally entered into between Agilis Biotherapeutics, Inc., or Agilis, NTU and Professor Wuh-Liang (Paul) Hwu, in December 2015, or the NTU Licensing Agreement., NTU granted to the company an exclusive, perpetual license, with the right to grant sublicenses through all tiers, to research and use the intellectual property, data, chemistry, manufacturing and controls, or CMC, records, documents, confidential information, materials and know-how pertaining to the Research, including Upstaza for the treatment of AADC deficiency, under the NTU Collaboration Agreement, or the Technology, and to develop, make, manufacture, use, sell, import and market the Technology and any other products made, invented, developed or incorporated by or with the Technology, or the Licensed Products. Subject to any regulatory delays or issues, the company is obligated to research, use and develop the Technology to manufacture Licensed Products by December 23, 2025. Additionally, the company is obligated to obtain marketing approval of Upstaza for the treatment of AADC deficiency, either by the FDA or by the EMA, by December 31, 2024. In July 2022, the European Commission approved Upstaza for the treatment of AADC deficiency for patients 18 months and older within the EEA, satisfying that obligation. The NTU Licensing Agreement expires on December 23, 2035.

Tegsedi and Waylivra

PTC Therapeutics International Limited, the company’s subsidiary, entered into a Collaboration and License Agreement, or the Tegsedi-Waylivra Agreement, dated August 1, 2018 by and between the company and Akcea, for the commercialization by the company of Tegsedi, Waylivra and products containing those compounds, which the company refers to collectively as the Products, in countries in Latin America and the Caribbean, or the PTC Territory. In addition, Akcea has granted to the company a right of first negotiation, or ROFN, to commercialize AKCEA-TTR-Lrx, a follow-on product candidate to inotersen, on an exclusive basis in the PTC Territory. The company is responsible for all meetings, communications and other interactions with regulatory authorities in the PTC Territory.

Under the terms of the Tegsedi-Waylivra Agreement, Akcea has granted to the company an exclusive right and license, with the right to grant certain sublicenses, under Akcea’s product-specific intellectual property to develop, manufacture and commercialize the Products in the PTC Territory. In addition, Akcea has granted to the company a non-exclusive right and license, with the right to grant certain sublicenses, under Akcea’s core intellectual property and manufacturing intellectual property to develop, manufacture and commercialize the Products in the PTC Territory and to manufacture the Products worldwide in accordance with a supply agreement with Akcea. Akcea has in-licensed certain of the Akcea intellectual property from its parent company, Ionis. Each party has agreed not to, independently or with any third party, commercialize any competing oligonucleotide product in the PTC Territory for the same gene target as inotersen.

Shiratori

In connection with the company’s acquisition of Censa Pharmaceuticals, Inc., or Censa, in May 2020, the company became a party to a license agreement dated as of February 8, 2015, as amended, between Shiratori and Censa, or the Shiratori License Agreement. Pursuant to the Shiratori License Agreement, Shiratori granted Censa the sole and exclusive worldwide right and license, with the right to sublicense, under certain licensed know-how, or the Licensed Know-How, and licensed patents, or the Licensed Patents, relating to manufacturing processes and technology for sepiapterin, to research, have researched, develop, have developed, use, import, export, market, have marketed, offer for sale, sell and have sold, and otherwise commercialize any final pharmaceutical product in finished form containing sepiapterin as an active pharmaceutical ingredient, including sepiapterin, collectively the Sepiapterin Products, covered by the Licensed Patents or using the Licensed Know-How in all countries and territories of the world outside of Japan, or the Sepiapterin Territory.

Intellectual Property

Patents and Trade Secrets

As of January 31, 2023, the company’s patent portfolio included a total of 143 active U.S. patents and 63 pending U.S. non-provisional patent applications, including continuations and divisional applications, that were owned, co-owned, or exclusively in-licensed. The company’s patent portfolio also includes numerous International and ex-U.S. patents and patent applications.

The patent rights relating to ataluren owned by the company include 42 issued U.S. patents relating to composition of matter, methods of use, formulations, dosing regimens and methods of manufacture and multiple pending U.S. patent applications relating to methods of use, formulation, and dosing regimens. The company does not license any material patent rights relating to ataluren to unaffiliated parties. The issued U.S. patents relating to composition of matter are scheduled to expire in 2024 and all U.S. patents that issue from the U.S. patent applications arising from the composition of matter would also be expected to expire in 2024. Issued U.S. patents relating to therapeutic methods of use are scheduled to expire in 2026 and 2027, including patent term adjustment. The company’s patent rights relating to ataluren include granted patents or pending counterpart patent applications in a number of other jurisdictions, including Canada, certain South American countries, Europe, certain Middle Eastern countries, certain African countries, certain Asian countries and certain Eurasian countries. The company owns 15 European patents relating to composition of matter, uses, dosing regimens and methods of manufacture of ataluren, as well as multiple pending European patent applications relating to composition of matter, uses and formulations. Granted European patents will expire in 2024 for those patents drawn to composition of matter, in 2026 and 2027 for those patents drawn to dosing regimen, and in 2027 for those patents drawn to the manufacturing process.

The patent rights relating to risdiplam co-owned by the company and Roche include 4 issued U.S. patents relating to composition of matter, methods of use, and methods of manufacture and pending U.S. patent applications. The company does not license any material patent rights relating to risdiplam to unaffiliated parties. The issued U.S. patents relating to composition of matter are scheduled to expire in 2033 and 2035. The company’s patent rights include granted patents or pending counterpart patent applications in a number of other jurisdictions, including Canada, certain South American countries, Europe, certain Middle Eastern countries, certain African countries, certain Asian countries and certain Eurasian countries. The company co-owns 2 European patents relating to composition of matter, and uses of risdiplam. The expiration dates of the granted European patents relating to composition of matter are scheduled to expire in 2033 and 2035.

Analogous patent term extension provisions are available in Europe and certain other ex-U.S. jurisdictions to extend the term of a patent that covers an approved drug. One means of patent term extension in Europe after EMA approval is based on obtaining a Supplementary Protection Certificate, or SPC. The company has applied for SPCs for ataluren in all applicable European countries in which it has a European patent and has obtained SPCs or expect to obtain SPCs in all applicable European countries. The maximum patent term extension provided by an SPC is a total of 5 years from the date of patent term expiration.

Manufacturing

The company has a commercial manufacturing services agreement with MassBiologics of the University of Massachusetts Medical School, or MassBio, to provide sufficient quantities of its Upstaza program materials to meet anticipated clinical trial and commercial scale demands.

Sales and Marketing

The company’s product revenue has primarily been attributable to the sale of Translarna for the treatment of nmDMD in territories outside of the United States and to the sale of Emflaza for the treatment of DMD in the United States. The company has employees across the globe, with the largest concentrations being in the United States, Latin America and Europe. In addition, in select territories, the company has engaged full time consultants, marketing partners and distribution partners to assist it with its international commercialization efforts for its products.

Customers

During 2022, the company’s product revenue was primarily attributable to Translarna for the treatment of nmDMD and to Emflaza for the treatment of DMD. Translarna for the treatment of nmDMD was available on a commercial basis or via reimbursed EAP programs in multiple territories outside of the United States. In some territories, orders for Translarna are placed directly with the company and in other territories it has engaged with third-party distributors. As a result, orders for Translarna are generally received from hospital and retail pharmacies and, in some cases, one of the company’s third-party partner distributors.

The company’s third-party distributors act as intermediaries between the company and end-users and does not typically stock significant quantities of Translarna.

Emflaza for the treatment of DMD is available on a commercial basis throughout the United States. The company utilizes six specialty pharmacies to sell and distribute Emflaza to patients. The specialty pharmacies receive prescription orders for Emflaza directly from physicians and ship Emflaza directly to the end-user upon fulfillment of the order.

Government Regulation

After FDA approval of a product is obtained, the company is required to comply with a number of post-approval requirements, including, among other things, establishment registration and product listing, record-keeping requirements, reporting certain adverse reactions and production problems to the FDA, providing updated safety and efficacy information, and complying with requirements concerning advertising and promotional labeling.

The company has received orphan drug designation from the FDA for Translarna for the treatment of nmDMD, Emflaza for the treatment of DMD, Upstaza for the treatment of AADC deficiency, Evrysdi for the treatment of SMA, vatiquinone for the treatment of Friedreich ataxia and treatment of seizures in patients with mitochondrial disease, utreloxastat for the treatment of ALS, PTC-FA for the treatment of Friedreich ataxia, PTC-AS for the treatment of Angelman syndrome, sepiapterin for the treatment of hyperphenylalaninemia, including hyperphenylalaninemia caused by PKU and unesbulin for the treatment of LMS and DIPG.

The company has obtained an orphan medicinal product designation from the European Commission, following an evaluation by the EMA’s Committee for Orphan Medicinal Products, for Translarna for the treatment of nmDMD, Upstaza for the treatment of AADC deficiency, Evrysdi for the treatment of SMA, vatiquinone for the treatment of Friedreich ataxia, utreloxastat for the treatment of ALS, PTC-AS for the treatment of Angelman syndrome, sepiapterin for the treatment of patients with hyperphenylalaninemia, including hyperphenylalaninemia caused by PKU, and unesbulin for the treatment of LMS.

Research and Development

The company’s research and development expense was $651.5 million for the year ended December 31, 2022.

Competition

Waylivra faces competition from drugs like Myalept (metreleptin). Myalept is produced by Novelion Therapeutics, Inc.

Evrysdi, an orally bioavailable treatment, faces competition from treatments that are not orally bioavailable, including Spinraza (nusinersen), a drug developed by Ionis; and Zolgensma (onasemnogene abeparvovec), a gene therapy drug developed by AveXis, Inc., (acquired by Novartis in 2018).

History

PTC Therapeutics, Inc. was founded in 1998. The company was incorporated under the laws of the state of Delaware in 1998.