GLYC: GlycoMimetics Analysis and Research Report
2018-05-07 - by Asif , Contributing Analyst - 63 views
GlycoMimetics is a clinical-stage biotechnology company focused on the discovery and development of novel glycomimetic drugs to address unmet medical needs resulting from diseases in which carbohydrate biology plays a key role. Glycomimetics are molecules that mimic the structure of carbohydrates involved in important biological processes. The company's proprietary glycomimetics platform is based on its expertise in carbohydrate chemistry and its understanding of the role carbohydrates play in key biological processes. Using this expertise and understanding, GlycoMimetics is developing a pipeline of proprietary glycomimetics designed to inhibit disease-related functions of carbohydrates, such as the roles they play in inflammation, cancer and infection. The company believe this represents an innovative approach to drug discovery to treat a wide range of diseases.
Most human proteins are modified by the addition of complex carbohydrates to the surface of the proteins. The addition of these carbohydrate structures affects the functions of these proteins and their interactions with other molecules. The company's initial research and development efforts have focused on drug candidates targeting selectins, which are proteins that serve as adhesion molecules and bind to carbohydrates that are involved in the inflammatory component and progression of a wide range of diseases, including hematologic disorders, cancer and cardiovascular disease. Inhibiting specific carbohydrates from binding to selectins has long been viewed as a potentially attractive approach for therapeutic intervention. The ability to successfully develop drug-like compounds that inhibit binding with selectins, known as selectin antagonists, has been limited by the complexities of carbohydrate chemistry. The company believe its expertise in carbohydrate chemistry enables it to design selectin antagonists and other glycomimetics that inhibit the disease-related functions of certain carbohydrates.
GlycoMimetics is focusing its initial efforts on drug candidates for rare diseases that the company believe will qualify for orphan drug designation. The company's first drug candidate, rivipansel, is a pan-selectin antagonist being developed for the treatment of vaso-occlusive crisis, or VOC, a debilitating and painful condition that occurs periodically throughout the life of a person with sickle cell disease. GlycoMimetics has entered into an agreement with Pfizer Inc., or Pfizer, for the further development and potential commercialization of rivipansel worldwide. Rivipansel has received fast track designation from the U.S. Food and Drug Administration, or FDA, as well as orphan drug designation from the FDA in the United States and from the European Medicines Agency, or EMA, in the European Union. The company believe the clinical progress of rivipansel provides evidence of the significant potential of its lead program and its proprietary glycomimetics platform.
Building on its experience with rivipansel, GlycoMimetics is developing a pipeline of other glycomimetic drug candidates. The company's second glycomimetic drug candidate, GMI-1271, is a specific E-selectin inhibitor, which GlycoMimetics is developing to be used in combination with chemotherapy to treat patients with either acute myeloid leukemia, or AML, or multiple myeloma, or MM, both of which are life-threatening hematologic cancers, and potentially other hematologic cancers as well. GlycoMimetics has completed an initial Phase 1 trial in healthy volunteers for GMI-1271 and in May 2017 the company completed enrollment in a Phase 1/2 clinical trial in defined populations of patients with AML. In December 2017, at the annual meeting of the American Society of Hematology, or ASH, the company presented clinical data from this Phase 1/2 clinical trial that showed high remission rates and suggested a favorable safety, pharmacokinetic, or PK, and biomarker profile for GMI-1271.
In March 2018, the company announced its design for a randomized, double-blind, placebo-controlled Phase 3 clinical trial to evaluate GMI-1271 in individuals with relapsed/refractory AML, which design is aligned with guidance received from the FDA. Based on consultations with the FDA, the single pivotal trial is planned to enroll approximately 380 adult patients at 30 to 40 centers in the United States, Canada, Europe and Australia, with enrollment expected to begin in the third quarter of 2018. The primary efficacy endpoint will be overall survival; importantly, the FDA has advised it that data on overall survival will not need to be censored for transplant in the primary efficacy analysis, meaning that patients who proceed to transplant will continue to be included as part of the survival analysis. All patients will be treated with standard chemotherapy of either MEC (mitoxantrone, etoposide and cytarabine) or FAI (fludarabine, cytarabine and idarubicin), with some of the patients randomized to receive GMI-1271 in addition to chemotherapy. Patients receiving GMI-1271 will be dosed for one day prior to initiation of chemotherapy, twice a day through the chemotherapy regimen, and then for two days after the end of chemotherapy, which was the same regimen as in the Phase 2 trial. The dose regimen will be fixed, rather than weight-based, which the company believe will simplify administration. The company plan to offer multiple cycles of consolidation therapy in both arms of the trial for patients who achieve remission. The company believe that multiple cycles of treatment in patients who respond may drive an even deeper response in patients treated with GMI-1271. If this is the case, it could lengthen the duration of remission with potential for additional benefit on survival. Key secondary endpoints of the Phase 3 trial will include the incidence of severe mucositis and remission rate, which will be assessed in a hierarchical fashion to provide supportive data. The company expect preliminary results from this trial to be available by the end of 2020.
GlycoMimetics is also conducting a Phase 1 multiple ascending dose-escalation trial of GMI-1271 in defined populations of patients with MM and plan to continue enrollment of the trial in 2018. The company anticipate initial topline data in the first quarter of 2019 in this trial.
GMI-1271 received orphan drug designation from the FDA in May 2015 for the treatment of patients with AML. In June 2016, GMI-1271 received fast track designation from the FDA for the treatment of adult patients with relapsed or refractory AML and elderly patients aged 60 years or older with AML. In May 2017, GMI-1271 received Breakthrough Therapy designation from the FDA for the treatment of adult patients with relapsed or refractory AML. In May 2017, the European Commission, based on a favorable recommendation from the EMA Committee for Orphan Medicinal Products, granted orphan designation for GMI-1271 for the treatment of patients with AML.
In February 2018, the company entered into an agreement with the Haemato Oncology Foundation for Adults in the Netherlands, or HOVON, to initiate clinical trial startup activities to evaluate GMI-1271 in adults with newly diagnosed AML but who cannot tolerate intensive chemotherapy, as well as in patients with myelodysplastic syndrome, or MDS, with a high risk of leukemia. The HOVON trial will be the first to evaluate GMI-1271, together with decitabine, in this underserved population of AML and MDS patients; these two populations represent a significant potential indication expansion opportunity for GMI-1271. HOVON intends to enroll approximately 140 patients in the clinical trial, including a control arm. Patients will be evaluated after three cycles of therapy, and key efficacy endpoints will include remission rate, disease-free survival and overall survival. The trial is expected to be conducted in five countries across Europe.
GlycoMimetics is also developing an additional drug candidate, GMI-1359, that simultaneously targets both E-selectin and a chemokine receptor known as CXCR4. Since E-selectin and CXCR4 are both adhesion molecules that keep cancer cells in the bone marrow, the company believe that targeting both E-selectin and CXCR4 with a single compound could improve efficacy in the treatment of cancers that affect the bone marrow such as AML and MM, and solid tumors that often metastasize to bone such as breast and prostate cancer, as compared to targeting CXCR4 alone. GMI-1359 is currently being evaluated in a Phase 1 single-dose escalation trial of GMI-1359 in healthy volunteers. In this trial, volunteer participants receive a single injection of GMI-1359, after which they are evaluated for safety, tolerability, PK and pharmacodynamics. The randomized, double-blind, placebo-controlled, escalating dose study is being conducted at a single site in the United States.
In addition to its programs described above, GlycoMimetics is also advancing other preclinical-stage programs. These programs include small-molecule glycomimetic compounds that inhibit the protein galectin-3, which the company believe may have potential to be used for the treatment of fibrosis, cancer and cardiovascular disease.
The company commenced operations in 2003, and its operations to date have been limited to organizing and staffing its company, business planning, raising capital, developing its glycomimetics platform, identifying potential drug candidates, undertaking preclinical studies and conducting clinical trials of rivipansel, GMI-1271 and GMI-1359. To date, GlycoMimetics has financed its operations primarily through private placements of its securities, upfront and milestone payments under its collaboration with Pfizer, the net proceeds from its IPO in January 2014 and additional public offerings of common stock in 2016, 2017 and 2018, as well as proceeds from sales of common stock under at-the-market sales facilities with Cowen and Company LLC, or Cowen. GlycoMimetics has no approved drugs currently available for sale, and substantially all of its revenue to date has been revenue from the upfront and milestone payments from Pfizer, although GlycoMimetics has received nominal amounts of revenue under research grants.
Prior to its IPO, the company raised an aggregate of $86.6 million to fund its operations, of which $22.5 million was an upfront payment under its collaboration with Pfizer and $64.1 million was from the sale of its convertible promissory notes and convertible preferred stock. The IPO provided it with net proceeds of $57.2 million, and the company received a non-refundable milestone payment from Pfizer in May 2014 of $15.0 million. In August 2015, the company received another non-refundable milestone payment from Pfizer of $20.0 million following the dosing of the first patient in the Phase 3 clinical trial of rivipansel. The company received an additional $19.7 million in net proceeds from its public offering in June 2016, $86.8 million in net proceeds from its public offering in May 2017 and approximately $128.4 million in net proceeds from its public offering in March 2018. During the years ended December 31, 2016 and 2017, the company received an aggregate of $30.5 million of net proceeds from sales of its common stock pursuant to its sales agreements with Cowen.
Since inception, GlycoMimetics has incurred significant operating losses. GlycoMimetics has generated cumulative revenue of $58.6 million since its inception through March 31, 2018 primarily consisting of the $22.5 million upfront payment from Pfizer in 2011, the $15.0 million non-refundable milestone payment in May 2014 and the $20.0 million non-refundable milestone payment in August 2015. The company had an accumulated deficit of $163.8 million as of March 31, 2018, and the company expect to continue to incur significant expenses and operating losses over at least the next several years. The company's net losses may fluctuate significantly from quarter to quarter and year to year, depending on the timing of its clinical trials, the receipt of milestone payments, if any, under its collaboration with Pfizer, and its expenditures on other research and development activities. The company anticipate that its expenses will increase substantially as we:
- initiate and conduct its planned clinical trials of GMI-1271 and GMI-1359;
- continue the research and development of its other drug candidates;
- seek to discover and develop additional drug candidates;
- seek regulatory approvals for any drug candidates other than rivipansel that successfully complete clinical trials;
- ultimately establish a sales, marketing and distribution infrastructure and scale up external manufacturing capabilities to commercialize any drug candidates other than rivipansel for which the company may obtain regulatory approval;
- maintain, expand and protect its intellectual property portfolio;
- hire additional clinical, quality control and scientific personnel; and
- add operational, financial and management information systems and personnel, including personnel to support its drug development and potential future commercialization efforts.
To fund further operations, the company will need to raise capital. The company may obtain additional financing in the future through the issuance of its common stock, through other equity or debt financings or through collaborations or partnerships with other companies. The company may not be able to raise additional capital on terms acceptable to it, or at all, and any failure to raise capital as and when needed could compromise its ability to execute on its business plan. Although it is difficult to predict future liquidity requirements, the company believe that its existing cash and cash equivalents, together with interest thereon, will be sufficient to fund its operations at least through its receipt of preliminary results from its planned Phase 3 clinical trial of GMI-1271 in individuals with relapsed/refractory AML. However, its ability to successfully transition to profitability will be dependent upon achieving a level of revenues adequate to support its cost structure. The company cannot assure you that the company will ever be profitable or generate positive cash flow from operating activities.
The company's Collaboration with Pfizer
In October 2011, the company entered into the license agreement with Pfizer under which the company granted Pfizer an exclusive worldwide license to develop and commercialize products containing rivipansel for all fields and uses. The license also covers specified back-up compounds along with modifications of and improvements to rivipansel that meet defined chemical properties. Pfizer is required to use commercially reasonable efforts, at its expense, to develop, obtain regulatory approval for and commercialize rivipansel for sickle cell disease in the United States. Under the terms of the agreement, the company received a $22.5 million upfront payment. GlycoMimetics is also eligible to earn potential milestone payments of up to $115.0 million upon the achievement of specified development milestones, including the dosing of the first patients in Phase 3 clinical trials for up to two indications and the first commercial sale of a licensed product in the United States and selected European countries for up to two indications, up to $70.0 million upon the achievement of specified regulatory milestones, including the acceptance of its filings for regulatory approval by regulatory authorities in the United States and Europe for up to two indications, and up to $135.0 million upon the achievement of specified levels of annual net sales of licensed products. GlycoMimetics is also eligible to receive tiered royalties for each licensed product, with percentages ranging from the low double digits to the low teens, based on net sales worldwide, subject to reductions in specified circumstances.
The first potential milestone payment under the Pfizer agreement was $35.0 million upon the initiation of dosing of the first patient in a Phase 3 clinical trial of rivipansel by Pfizer. Under the collaboration, Pfizer made a $15.0 million non-refundable milestone payment to it in May 2014, which the company recognized as revenue in May 2014, when earned, and the dosing of the first patient in the Phase 3 clinical trial in June 2015 triggered the remaining $20.0 million milestone payment to it. The company recorded the $20.0 million milestone payment as revenue in June 2015. There were no milestone payments received from Pfizer for the three months ended March 31, 2018 or 2017.
The company entered into a research services agreement with the University of Basel, or the University, for biological evaluation of selectin antagonists. While the scope of work under the research agreement with the University ended in 2017, certain patents covering the rivipansel compound are subject to provisions of the Research Agreement. Under the terms of the Research Agreement, the company owe the University 10% of all future milestone and royalty payments received from Pfizer with respect to rivipansel. There were no payments due to the University for the three months ended March 31, 2018 or 2017.
Research and Development
Research and development expenses consist of expenses incurred in performing research and development activities, including compensation and benefits for full-time research and development employees, facilities expenses, overhead expenses, cost of laboratory supplies, clinical trial and related clinical manufacturing expenses, fees paid to contract research organizations and other consultants and other outside expenses. Other preclinical research and platform programs include activities related to exploratory efforts, target validation, lead optimization for its earlier programs and its proprietary glycomimetics platform.
To date, its research and development expenses have related primarily to the development of rivipansel and its other drug candidates. In April 2013, when the company completed its Phase 2 clinical trial of rivipansel, all further clinical development obligations associated with rivipansel shifted to Pfizer.
The company do not currently utilize a formal time allocation system to capture expenses on a project-by-project basis because GlycoMimetics is organized and record expense by functional department and its employees may allocate time to more than one development project. Accordingly, the company only allocate a portion of its research and development expenses by functional area and by drug candidate.
Research and development costs are expensed as incurred. Non-refundable advance payments for goods or services to be received in the future for use in research and development activities are deferred and capitalized. The capitalized amounts are expensed as the related goods are delivered or the services are performed.
Research and development activities are central to its business model. Drug candidates in later stages of clinical development generally have higher development costs than those in earlier stages of clinical development, primarily due to the increased size and duration of later stage clinical trials. The company expect its research and development expenses to increase over the next several years as the company seek to progress GMI-1271, GMI-1359 and its other drug candidates through clinical development. For example, as the company prepare to potentially submit an application for marketing approval for GMI-1271, the company will incur substantial expenses in scaling up the production and manufacturing of GMI-1271. However, it is difficult to determine with certainty the duration and completion costs of its current or future preclinical studies and clinical trials of its drug candidates, or if, when or to what extent the company will generate revenues from the commercialization and sale of any of its drug candidates that obtain regulatory approval. The company may never succeed in achieving regulatory approval for any of its drug candidates.
The company's proprietary platform is based on its expertise in carbohydrate chemistry and its understanding of the role carbohydrates play in key biological processes. Most human proteins are modified by the addition of complex carbohydrates to the surface of the proteins. The addition of these carbohydrate structures affects the functions of these proteins and their interactions with other molecules. The company's initial research and development efforts have focused on drug candidates targeting selectins, which are proteins that serve as adhesion molecules and bind to carbohydrates that are involved in the inflammatory component and progression of a wide range of diseases, including hematologic disorders, cancer and cardiovascular disease. The ability to successfully develop drug-like compounds that inhibit binding with selectins, known as selectin antagonists, has been limited by the complexities of carbohydrate chemistry. The company believe its expertise in carbohydrate chemistry and its understanding of carbohydrate-protein binding interactions enable it to design selectin antagonists and other glycomimetics (such as galectin antagonists) that may inhibit the disease-related functions of certain carbohydrates in order to develop novel drug candidates to address unmet medical needs.
All of GlycoMimetics’ compounds have been discovered internally, leveraging the company’s specialized chemistry and its in-depth understanding of carbohydrate biology (“glycobiology”).