Titan Pharmaceuticals
Overview
Titan Pharmaceuticals (TTNP) is a pharmaceutical company developing proprietary therapeutics for the treatment of serious medical disorders. The company's product development programs utilize its proprietary long-term drug delivery platform, ProNeura™, and focus primarily on innovative treatments for select chronic diseases for which steady state delivery of a drug provides an efficacy and/or safety benefit.1
Probuphine®, its first product candidate based on the ProNeura platform, was approved by the FDA in May 2016 for the maintenance treatment of opioid dependence in patients who are stable on low to moderate doses of daily sublingual buprenorphine treatment. The company licensed development and commercialization rights of Probuphine for the U.S. and Canadian markets to Braeburn Pharmaceuticals, Inc., or Braeburn.
In the first quarter of 2017, Braeburn commenced a full commercial launch of the product. However, as with the launch of any new method of medical treatment in the current reimbursement environment, progress has been slow and for the year ended December 31, 2017 the company had royalty revenues of $215,000. While Probuphine sales grew modestly from the first to the second quarter of 2017, this trend reversed in the third quarter and royalty revenues to Titan showed a marked decline during the second half of the year.
Based on feedback from Braeburn and key opinion leaders, the company believe that access to care for patients has been negatively impacted by issues related to the timing and amount of reimbursement to patients and their doctors from insurance providers, as well as the requirements of the Risk Evaluation and Mitigation Strategy, or REMS, program. Although the opioid addiction epidemic continues to be a major concern for the United States, the hurdles to penetrating the market and growing sales of Probuphine have been considerable. The company believed that the Camurus weekly and monthly depot injection products licensed by Braeburn would enable clinicians and patients to become accustomed to longer duration procedure-oriented treatment, thereby encouraging the potential use of Probuphine during the maintenance treatment stage. However, in January 2018, the FDA did not approve the NDA for these products causing a substantial delay in the regulatory approval process. Consequently, Braeburn substantially reduced its field sales force and medical liason personnel hampering any efforts to commercialize Probuphine. Titan Pharmaceuticals is in discussions with Braeburn management to more fully understand the current status of Probuphine, including Braeburn’s interactions with the FDA regarding the post-approval clinical requirements, and the possible return of the commercialization rights. In light of the difficulties encountered to date, the company cannot predict either the timing or the degree to which Probuphine will be accepted by the U.S. medical community.
Titan Pharmaceuticals has continued to make progress in the efforts to advance potential commercialization of Probuphine outside of the U.S. and Canada. During the first quarter 2017, the European Medicines Agency, or EMA, granted eligibility for Probuphine to follow the centralized review and approval process for its Marketing Authorization Application, or MAA. Subsequently the company met with the review teams of the two EMA member countries appointed as rapporteur and co-rapporteur to familiarize them with the development of Probuphine and the safety and efficacy data set, as well as receive their advice on the MAA preparation and presentation. The MAA was submitted to the EMA on November 6, 2017. In October 2017, the company received a notice of allowance from the European Patent Office for a patent covering methods of use claims for treating opioid dependence with a subdermal implant containing buprenorphine. On March 21, 2018, the company entered into an Asset Purchase, Supply and Support Agreement, or Purchase Agreement, with L. Molteni & C. Dei Frattelli Alitti Società Di Esercizio S.P.A., or Molteni, pursuant to which Molteni acquired the European intellectual property related to Probuphine, including the MAA, and will have the exclusive right to commercialize the Titan supplied Probuphine product in Europe, as well as certain countries of the Commonwealth of Independent States, the Middle East and North Africa. Titan Pharmaceuticals is working with Molteni in connection with the regulatory approval process, including interacting with the EMA and providing full support to address questions received from the EMA.
The company believe that its ProNeura long term drug delivery platform has the potential to be used in the treatment of other chronic conditions where maintaining stable, around the clock blood levels of a medication may benefit the patient and improve medical outcomes.
Efforts to advance its next product candidate, the ropinirole implant for the treatment of Parkinson’s disease, have continued and the Investigational New Drug application, or IND, was cleared by the FDA in August 2017. The Phase 1/2 clinical study was initiated shortly thereafter with the first patient treated in early October. This study is being conducted at three clinical research sites in the U.S. that specialize in the treatment of Parkinson’s disease. The trial is an open-label, sequential, dose escalation study that will enroll approximately 20 subjects with idiopathic Parkinson's disease. The primary objectives are to characterize the pharmacokinetic profile of the ropinirole implants, to evaluate their safety and tolerability, and to explore potential signals of efficacy using established disease-specific assessment scales. Patients on a stable dose of L-dopa plus oral ropinirole will have their oral ropinirole switched to ropinirole implants for three months of treatment. Initial data from the first cohort of patients is expected in the first half of 2018 and further progress will depend on the data and available resources.
The company's goal is to expand its product pipeline using the ProNeura implant platform, and Titan Pharmaceuticals has been opportunistically evaluating other drugs for use with this technology in potential treatment applications where conventional treatment is limited by variability in blood drug levels and poor patient compliance.
ProNeura Continuous Drug Delivery Platform
The company's ProNeura continuous drug delivery system consists of a small, solid rod made from a mixture of ethylene-vinyl acetate, or EVA, and a drug substance. The resulting product is a solid matrix that is placed subdermally, normally in the inside part of the upper arm in a simple physician office based procedure, and is removed in a similar manner at the end of the treatment period. The drug substance is released continuously through the process of dissolution. This results in a steady rate of release generally similar to intravenous administration. The company believe that such long-term, almost linear release characteristics are desirable by avoiding fluctuating peak and trough levels of oral dosing that may pose problems for many disease settings.
The ProNeura platform was developed to address the need for a simple, practical method to achieve continuous long-term drug delivery, and, depending on the characteristics of the compound to be delivered, potentially can provide treatment on an outpatient basis over extended periods of up to 12 months. The company believe that the benefits of this technology have been demonstrated by the clinical results to date with Probuphine, and the development and regulatory process have been affirmed by the FDA approval of this product. Titan Pharmaceuticals has been evaluating opportunities to develop this drug delivery platform for other potential treatment applications in which conventional treatment is limited by variability in blood drug levels and poor patient compliance and where existing therapeutic compounds have sufficient potency to be effective at low doses.
Product Pipeline
Probuphine
The company developed Probuphine for the maintenance treatment of opioid dependence. Upon subdermal insertion in a patient, Probuphine is designed to release medication continuously and maintain a stable, around the clock blood level of the drug buprenorphine, an approved agent for the treatment of opioid dependence. Probuphine has been shown to provide six months of medication following a single treatment and was approved by the FDA in May 2016 for the maintenance treatment of opioid dependence in clinically stable patients who are receiving treatment with an oral formulation of buprenorphine at a dose of 8mg/day or less.
The development and commercialization rights to Probuphine for the U.S. and Canada were licensed to Braeburn and pursuant to the agreement, as amended to date, the company received a $15 million milestone payment upon FDA approval of the Probuphine NDA in mid-2016, and are entitled to receive royalties on net sales of Probuphine based on a tiered structure ranging in percentage from the mid-teens to the low twenties. Following approval of Probuphine Braeburn first focused on training and certification of health care providers under the FDA approved REMS program, and by the end of 2016 had certified more than 2400 health care providers for prescribing and/or administering the product. In the first quarter of 2017, Braeburn commenced a full commercial launch. As with the launch of any new method of medical treatment in the current reimbursement environment, progress during the year was slow and the company received royalty revenues of only $215,000 for the year ended December 31, 2017.
Based on feedback from Braeburn and key opinion leaders the company believe that access to care for patients with Probuphine has been negatively impacted by issues related to the timing and amount of reimbursement to patients and their doctors from insurance providers, as well as the requirements of the REMS program. Although the opioid addiction epidemic continues to be a major concern for its country, the hurdles to penetrating the market and growing sales of Probuphine have been considerable. Advice from its consultant in this field indicates that a more focused commercialization strategy is necessary for success. These include re-segmenting target customer markets and focusing on academic institutions with addiction residencies and fellowships, MAT-supported residential treatment programs, physicians with long-term recovery oriented treatment programs and expansion of the specialty pharmacy network to better utilize the third party payor system. Additionally, the company believe Probuphine can benefit from the trend of opioid addiction treatment’s move towards extended release formulations, such as one month depot injections, the first of which was approved by the FDA at the end of 2017. These products will enable clinicians and patients to become accustomed to longer duration procedure-oriented treatment, which may encourage the potential use of Probuphine during the maintenance treatment stage. However, in January 2018, the FDA did not approve the NDA for the injectable products Braeburn had in-licensed causing a substantial delay in the regulatory approval process. Consequently, Braeburn substantially reduced its field sales force and medical liason personnel hampering any efforts to commercialize Probuphine. Titan Pharmaceuticals is in discussions with Braeburn management to more fully understand the current status of Probuphine, including Braeburn’s interactions with the FDA regarding the post-approval clinical requirements, and the possible return of the commercialization rights. However, in light of the difficulties encountered to date, the company cannot predict either the timing or the degree to which Probuphine will be accepted by the medical community.
Titan Pharmaceuticals has made considerable progress in the efforts to advance potential commercialization of Probuphine outside of the U.S. and Canada. In order to enable regulatory clarity for product approval in Europe, the company sought scientific advice and met with the U.K. regulatory agency, MHRA, and the German regulatory agency, BfArM, and based on feedback from these meetings the company submitted an application to the EMA seeking eligibility for Probuphine to follow the centralized review and approval process for its MAA. In early March 2017, the company received confirmation from the EMA that Probuphine is eligible for a centralized review and approval process. While the preparation of the MAA was in progress, the company met with the review teams of the two EMA member countries appointed as rapporteur (Ireland) and co-rapporteur (United Kingdom) to familiarize them with the development of Probuphine and the safety and efficacy data set, as well as receive their advice on the MAA preparation and presentation. The MAA was submitted to the EMA on November 6, 2017. Titan Pharmaceuticals was also granted Small Manufacturing Entity, or SME, status in Europe, which provides for some monetary benefits during the application process and commercialization. In October 2017, the company received a notice of allowance from the European Patent Office for a patent covering methods of use claims for treating opioid dependence with a subdermal implant containing buprenorphine. Upon issuance, this patent is expected to provide protection for Probuphine in Europe into 2023.
In late November 2017, the company announced that the company had entered into a binding term sheet with Molteni for commercialization of Probuphine in Europe and certain other territories. On March 21, 2018, the company announced that the company had entered into the Purchase Agreement pursuant to which Molteni acquired the European intellectual property related to Probuphine, including the MAA, and will have the exclusive right to commercialize the Titan supplied Probuphine product in Europe, as well as certain countries of the Commonwealth of Independent States, the Middle East and North Africa, or the Molteni Territory. The Purchase Agreement superseded the license arrangement contemplated by the term sheet. The company received an initial payment of €2.0 million (approximately $2.4 million) upon execution of the Purchase Agreement and Titan Pharmaceuticals is entitled to receive milestone payments totaling €4.5 million (approximately $5.5 million) upon the achievement of specified regulatory and product label milestones. Additionally, Titan Pharmaceuticals is entitled to receive earn-out payments for up to 15 years on net sales of Probuphine in the Molteni Territory ranging in percentage from the low-teens to the mid-twenties. Titan Pharmaceuticals is working with Molteni in connection with the European regulatory approval process, including addressing questions that have been posed by the EMA.
ProNeura-Ropinirole for Parkinson’s Disease
Parkinson’s disease, or PD, is a disease of the central nervous system characterized by the loss of dopaminergic neurons, which leads to increasing activity in the brain region that influences movement and motor function. According to the Parkinson’s Disease Foundation, more than one million people in the U.S. suffer from PD, and this number is projected to double by 2030. Early stage PD patients are treated with daily doses of drugs designed to replace dopamine in the brain. However, these therapeutics typically lose their benefits after several years of chronic treatment, and trigger serious side effect. About one-third of the treated patients develop motor response fluctuations and/or drug-induced dyskinesias within only three to five years of treatment, and these symptoms are present in almost all patients after 10 to 12 years. Clinical and nonclinical research indicates that these motor side effects arise from the pulsatile dopaminergic stimulation resulting from current oral treatment. Continuous dopaminergic stimulation, or CDS, by subcutaneous infusion has been shown to palliate these motor complications, as well as to delay or prevent the onset of dyskinesias. The company believe its ProNeura drug delivery technology provides a clinically-validated platform to safely and conveniently provide CDS for several months from a single treatment. Further, the subdermal placement of these implants eliminates many of the device-related complications associated with existing treatment modalities.
Based on these principles the company designed an implant to deliver the drug ropinirole and conducted appropriate non-clinical studies, including a non-clinical study in an MPTP Parkinsonian primate model and demonstrated that a sustained non-fluctuating plasma level of ropinirole could be delivered safely for several months following implantation and could control PD symptoms without triggering dyskinesias in severely lesioned primates. Following further optimization of the implant and completion of the IND enabling non-clinical studies, the company submitted the IND application to the FDA in early 2017 and it was cleared in August 2017 for commencement of the proposed Phase 1/2 clinical study. The trial is an open-label, sequential, dose escalation study that will enroll approximately 20 subjects with idiopathic Parkinson's disease. The primary objectives are to characterize the pharmacokinetic profile of the ropinirole implants, to evaluate their safety and tolerability, and to explore potential signals of efficacy using established disease-specific assessment scales. Patients on a stable dose of L-dopa plus oral ropinirole will have their oral ropinirole switched to ropinirole implants for three months of treatment. This study is being conducted at three clinical research sites in the U.S. that specialize in the treatment of Parkinson’s disease. The first patient was treated in October 2017 and initial data from the early patients in the study is expected in the first half of 2018. The company will evaluate this data for appropriateness of the dose and the blood level of the drug, and further progress in the study will be determined based on these findings, as well as the availability of funds.
Other ProNeura Product Feasibility Programs
The company's goal is to expand its product pipeline using the ProNeura implant platform, and Titan Pharmaceuticals has been opportunistically evaluating other drugs and disease settings for use with the ProNeura platform in potential treatment applications where conventional treatment is limited by variability in blood drug levels and poor patient compliance. Together with Opiant Pharmaceuticals, Inc., or Opiant, the company began conducting a feasibility assessment of a subcutaneous implant using its proprietary ProNeura™ sustained release technology to administer an opioid antagonist. A product that may deliver non-fluctuating, therapeutic levels of an opioid antagonist continuously for up to six months may be ideally suited for the prevention of opioid relapse and overdose. Titan Pharmaceuticals is targeting to complete this assessment in the first half of 2018 and, if appropriate, seek support from agencies such as the National Institutes of Health for advancing a product candidate. Titan Pharmaceuticals is collaborating with the Walter Reed Army Institute of Research, or WRAIR, and the Southwest Research Institute in the early non-clinical evaluation of the ProNeura platform in malaria prophylaxis. The early data from this collaboration is encouraging and has been presented by the WRAIR staff at several conferences, and WRAIR is now seeking additional funding from the Department of Defense to continue the program with additional non-clinical testing of the implant formulations in large animal studies. Early non-clinical testing is being conducted for the development of a kappa opioid receptor agonist implant for the treatment of chronic pain. If successfully developed and approved, this would offer a potential non-addictive opioid analgesic for the treatment of chronic pain. Formulation studies and early in vitro testing is being conducted for the potential development of an implant with a currently approved peptide for the treatment of adult type 2 diabetes mellitus. Also, in 2017 the company completed early non-clinical development focused on formulation optimization of an implantable triiodothyronine (T3) product for the treatment of hypothyroidism. Any further development will depend on availability of resources and interest from partners.
License Agreements
In December 2012, the company entered into a license agreement, or the Braeburn Agreement with Braeburn pursuant to which the company granted Braeburn an exclusive right and license to commercialize Probuphine in the United States of America and its territories, including Puerto Rico, and Canada, or the Braeburn Territory. Under the Braeburn Agreement, as amended to date, Braeburn made a non-refundable up-front license fee payment of $15.75 million in 2012 and a milestone payment of $15 million upon FDA approval of the NDA in May 2016. Under the Braeburn Agreement, Titan Pharmaceuticals is entitled to receive royalties on net sales of Probuphine ranging in percentage from the mid-teens to the low twenties. The Braeburn Agreement also provides for up to $165 million in sales milestones and $35 in regulatory milestones, as well as royalties, up to an aggregate of $50 million, on a percentage of sales in the low single digit by Braeburn, if any, of other continuous delivery treatments for opioid dependence and can elect to receive low single digit royalties on sales, if any, by Braeburn of other products in the addiction market in exchange for a similar reduction in its royalties on Probuphine.
In February 2016, Braeburn informed it that it has entered in a sublicense agreement with Knight Therapeutics, Inc., or Knight, a specialty pharmaceutical company, whereby Braeburn has granted to Knight the rights to commercialize Probuphine in Canada.
Intellectual Property
The company's goal is to obtain, maintain and enforce patent protection for its product candidates, formulations, processes, methods and any other proprietary technologies, preserve its trade secrets, and operate without infringing on the proprietary rights of other parties, both in the United States and in other countries. The company's policy is to actively seek to obtain, where appropriate, the broadest intellectual property protection possible for its current product candidates and any future product candidates, proprietary information and proprietary technology through a combination of contractual arrangements and patents, both in the United States and abroad. However, patent protection may not afford it with complete protection against competitors who seek to circumvent its patents.
The company also depend upon the skills, knowledge, experience and know-how of its management and research and development personnel, as well as that of its advisors, consultants and other contractors. To help protect its proprietary know-how, which may not be patentable, and for inventions for which patents may be difficult to enforce, the company currently rely and will in the future rely on trade secret protection and confidentiality agreements to protect its interests. To this end, the company require all of its employees, consultants, advisors and other contractors to enter into confidentiality agreements that prohibit the disclosure of confidential information and, where applicable, require disclosure and assignment to it of the ideas, developments, discoveries and inventions important to its business.
In June 2010, the United States Patent and Trademark Office (“USPTO”) issued a patent covering methods of using Probuphine for the treatment of opiate addiction. Titan is the owner of this patent which claims a method for treating opiate addiction with a subcutaneously implanted device comprising buprenorphine and EVA, a biocompatible copolymer that releases buprenorphine continuously for extended periods of time. This patent will expire in April 2024. A U.S. continuation application is currently pending which includes claims related to Probuphine for the treatment of pain. Related patents covering use of Probuphine with the continuous delivery technology for the treatment of opiate addiction have also been allowed or issued in Australia, Canada, Europe, India, Japan, Mexico and New Zealand. A further Probuphine application is pending in Hong Kong. On March 21, 2018 the company executed the Purchase Agreement with Molteni whereby the European intellectual property covering Probuphine, including the European patent, was acquired by Molteni. Patents covering certain dopamine agonist implants, including ropinirole implant, have already been issued or allowed in the United States, Europe, Japan, China, Australia, Canada, South Korea, Mexico, New Zealand, South Africa, Israel and Hong Kong.
Titan Pharmaceuticals has filed additional patent applications for a heterogeneous implant designed with some unique properties that may provide benefits to the structural integrity of the implants and potentially enhance drug delivery.
Future court decisions or changes in patent law might materially affect the patents or patent applications, including, but not limited to, their expiration dates.
Competition
The pharmaceutical and biotechnology industries are characterized by rapidly evolving technology and intense competition. Many companies of all sizes, including major pharmaceutical companies and specialized biotechnology companies, are engaged in the development and commercialization of therapeutic agents designed for the treatment of the same diseases and disorders that the company target. Many of its competitors have substantially greater financial and other resources, larger research and development staff and more experience in the regulatory approval process. Moreover, potential competitors have or may have patents or other rights that conflict with patents covering its technologies.
With respect to Probuphine, there are no six-month implant formulations of buprenorphine on the market or in development, and the primary competition it faces comes from Indivior, PLC (formerly the pharmaceutical business of Reckitt Benckiser Group, PLC), which markets globally a sublingual buprenorphine product (tablet and film formulations trade name Subutex and Suboxone) for the treatment of opioid dependence that currently holds the dominant market share of global sales, and recently received FDA approval for a one month depot injection (tradename Sublocade) that became commercially available in the first quarter of 2018. Probuphine also faces competition from two additional proprietary daily dose formulations that have been approved by the FDA; the first is a sublingual tablet called Zubsolv marketed by Orexo and the second is a buccal patch called Bunavail marketed by Bio Delivery Sciences International. Also, during 2013 and 2014, several generic sublingual tablet formulations of buprenorphine similar to Suboxone and Subutex were approved by the FDA that are expected to compete in the opioid addiction treatment market. Other forms of buprenorphine are also in development by other companies, including intramuscular and intradermal one week and one month depot injections which, if approved, will also compete with its product. Braeburn has licensed rights to certain of such potential products and Titan is entitled to a low single digit royalty on net sales of competing products, if commercialized. However, Braeburn received a complete response letter, or CRL, to the depot formulations of buprenorphine (Camurus 2038) and the approval is likely delayed by several months. Alkermes, Inc. also markets Vivitrol®, a one-month depot injection of naltrexone as a maintenance treatment for opioid dependent patients who have successfully gone through a detoxification process and achieved abstinence.
If successfully developed and approved for commercialization, its ProNeura ropinirole product for PD will face competition primarily from numerous daily dose dopamine agonist treatments currently in use that provide symptom relief from disease related immobility, as well as the complications associated with long-term levodopa therapy (e.g. dyskinesias, tolerance). Approved products in the U.S. in addition to Requip XL®, which is marketed by GlaxoSmithKline, include Apokyn® (US WorldMeds LLC), Parlodel® (Novartis Pharmaceuticals Inc.), Mirapex ER® (Boehringer Ingelheim Pharmaceuticals Inc.) and Neupro® (UCB Inc.). There is a strong need for products providing continuous, stable, long term delivery of dopamine and dopamine agonists and the FDA recently approved a product called Duodopa®, the first and only treatment delivered via catheters directly into the duodenum that is capable of providing 16 continuous hours of carbidopa and levodopa for treatment of motor fluctuations in advanced PD. Duodopa is marketed globally by Abbvie. Also, Titan Pharmaceuticals is aware of products in mid-stage clinical development that are capable of short to medium-term subcutaneous and subdermal delivery of levodopa/carbidopa using pumps.
Manufacturing
The manufacturing of Probuphine has primarily been conducted at DPT Laboratories, Inc., or DPT, and Titan Pharmaceuticals has expanded the manufacturing facility at this contract manufacturer to establish commercial scale capability to support the market launch of Probuphine and ongoing demand. Titan Pharmaceuticals has entered into a commercial manufacturing agreement with DPT that governs the terms of the production and supply of Probuphine. During a part of 2017, the company continued to supply and support Braeburn while an agreement between Braeburn and DPT for the supply of Probuphine was being finalized. Pursuant to the Purchase Agreement, Titan Pharmaceuticals is responsible for the manufacture and supply of Probuphine as needed for the Molteni Territory.
To date, Titan Pharmaceuticals has obtained the supply of bupenorphine from Teva Pharmaceuticals, Inc. under a commercial supply agreement similar to the one with DPT.
Sales and Marketing
The company do not currently have any sales and marketing capability. As its licensee, Braeburn has sole responsibility for sales and marketing of Probuphine within the United States and, through its sublicensee, Knight Pharmaceuticals, Inc., in Canada. Molteni has sole responsibility for the commercialization of Probuphine in the Molteni Territory. The company's current plans are to make similar arrangements for the commercialization of any additional products the company may successfully develop based on its ProNeura technology.
