IDRA : Idera Pharmaceuticals Stock Analysis and Research Report

2017-10-23 - by Asif, Contributing Analyst

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Idera Pharmaceuticals is a clinical-stage biopharmaceutical company focused on the discovery, development and commercialization of novel oligonucleotide therapeutics for oncology and rare diseases. Idera Pharmaceuticals use two distinct proprietary drug discovery technology platforms to design and develop drug candidates: its Toll-like receptor, or TLR, targeting technology and its third-generation antisense, or 3GA, technology. Idera Pharmaceuticals developed these platforms based on its scientific expertise and pioneering work with synthetic oligonucleotides as therapeutic agents. Using its TLR targeting technology, Idera Pharmaceuticals design synthetic oligonucleotide-based drug candidates to modulate the activity of specific TLRs. In addition, using its 3GA technology, Idera Pharmaceuticals is developing drug candidates to turn off the messenger RNA, or mRNA, associated with disease causing genes. Idera Pharmaceuticals believe its 3GA technology may potentially reduce the immunotoxicity and increase the potency of earlier generation antisense and RNA interference, or RNAi, technologies.

Its business strategy is focused on the clinical development of drug candidates for oncology and rare diseases characterized by small, well-defined patient populations with serious unmet medical needs. The company believe the company an develop and commercialize these targeted therapies on its own. To the extent the company seek to develop drug candidates for broader disease indications, the company has entered into and may explore additional collaborative alliances to support development and commercialization.

TLR Modulation Technology Platform

TLRs are key receptors of the immune system and play a role in innate and adaptive immunity. As a result, the company believe TLRs are potential therapeutic targets for the treatment of a broad range of diseases. Using its chemistry-based platform, the company has designed TLR agonists and antagonists to act by modulating the activity of targeted TLRs. A TLR agonist is a compound that stimulates an immune response through the targeted TLR. A TLR antagonist is a compound that inhibits an immune response by blocking the targeted TLR.

Its TLR agonist lead drug candidate IMO-2125 is an agonist of TLR9. its TLR antagonist lead drug candidate is IMO-8400, which is an antagonist of TLR7, TLR8 and TLR9.

Idera Pharmaceuticals is evaluating IMO-2125 for the treatment by intra-tumoral injection of multiple oncology indications both in combination with checkpoint inhibitors and as monotherapy. the company is developing IMO-8400 for the treatment of a rare disease called dermatomyositis.

Intra-tumoral IMO-2125 Development Program in Immuno-oncology

Advancements in cancer immunotherapy have included the approval and late-stage development of multiple checkpoint inhibitors, which are therapies that target mechanisms by which tumor cells evade detection by the immune system. Despite these advancements, many patients fail to respond to these therapies. For instance, approximately fifty percent of patients with melanoma fail to respond to therapy with approved checkpoint inhibitors. Current published data suggests that the lack of response to checkpoint inhibition is related to a non-immunogenic tumor micro environment. Because TLR9 agonists stimulate the immune system, Idera Pharmaceuticals believe there is a scientific rationale to evaluate the combination of intra-tumoral injection of its TLR9 agonists with checkpoint inhibitors. Specifically, Idera Pharmaceuticals believe intra-tumoral injection of its TLR9 agonists activates a local immune response in the injected tumor, which may complement the effect of the systemically administered checkpoint inhibitors. In studies in preclinical cancer models conducted in its laboratories, intra-tumoral injection of TLR9 agonists has potentiated the anti-tumor activity of multiple checkpoint inhibitors in multiple tumor models. These data have been presented at several scientific and medical conferences from 2014 through 2017. Idera Pharmaceuticals believe these data support evaluation of combination regimens including the combination of a TLR9 agonist and a checkpoint inhibitor for the treatment of cancer.

Idera Pharmaceuticals is initially developing IMO-2125 for use in combination with checkpoint inhibitors for the treatment of patients with anti-PD1 refractory metastatic melanoma. Idera Pharmaceuticals believe, based on internally conducted commercial research, that in the United States, by 2025, approximately 20,000 people will have metastatic melanoma and approximately 13,000 of those people will have metastatic melanoma that is anti-PD1 refractory. Idera Pharmaceuticals also believe TLR9 agonists may be useful in other tumor types that are unaddressable with current immunotherapy due in part to low mutation load and low dendritic cell infiltration. These tumor types include non-small cell lung cancer, head and neck cancer, renal cell cancer and bladder cancer. Idera Pharmaceuticals believe, based on internally conducted commercial research, that in the United States, by 2025, approximately 160,000 people will have tumor types that are addressable with current immunotherapy and approximately 70,000 of those people will have tumor types that are anti-PD1 refractory.

In June 2015, Idera Pharmaceuticals entered into a strategic research alliance with the University of Texas, MD Anderson Cancer Center, or MD Anderson, to commence clinical development of IMO-2125 in combination with checkpoint inhibitors. In December 2015, the company initiated a Phase 1/2 clinical trial to assess the safety and efficacy of IMO-2125, administered intra-tumorally, in combination with ipilimumab, a CTLA4 antibody marketed as Yervoy® by Bristol-Myers Squibb Company, in patients with metastatic melanoma (refractory to treatment with a PD1 inhibitor, also referred to as anti-PD1 refractory). Idera Pharmaceuticals subsequently amended the trial protocol to enable an additional arm to study the combination of IMO-2125 with pembrolizumab, an anti-PD1 antibody marketed as Keytruda® by Merck & Co. in the same patient population. In the Phase 1 portion of this clinical trial, escalating doses of IMO-2125 ranging from 4 mg through 32 mg in the ipilimumab arm and ranging from 8 mg through 32 mg in the pembrolizumab arm are being administered intra-tumorally into a selected tumor lesion, together with the standard dosing regimen of ipilimumab or pembrolizumab, administered intravenously. The primary objectives of the Phase 1 portion of the trial include characterizing the safety of the combinations and determining the recommended Phase 2 dose. A secondary objective of the Phase 1 portion of the trial is describing the anti-tumor activity of IMO-2125 when administered intra-tumorally in combination with ipilimumab or pembrolizumab. The primary objectives of the Phase 2 portion of the trial are to characterize the safety of the combinations and determine the activity of the combinations utilizing immune-related response criteria. Additionally, a secondary objective of the Phase 2 portion of the trial is to assess treatment response using traditional RECIST criteria. Serial biopsies will be taken of selected injected and non-injected tumor lesions to assess immune changes and response assessments. Idera Pharmaceuticals anticipate that the entire Phase 1/2 trial may enroll approximately 60 to 80 patients across both ipilimumab and pembrolizumab arms.

In September 2016, the company disclosed early clinical results from the 4 mg and 8 mg dosing cohorts of the Phase 1 ipilimumab combination portion of the trial in which three of six evaluable patients demonstrated clinical responses (one complete response and two partial responses). The company also disclosed that the drug was well tolerated through the initial dosing of the 16 mg dosing cohort. The company has completed enrollment in the dose escalation phase in the ipilimumab arm of the trial as well as the 8 mg dosing cohort in the pembrolizumab arm of the trial. The company presented available translational, efficacy and safety data findings from the 4 mg, 8 mg and 16 mg dosing cohorts in the ipilimumab arm during an oral presentation at the Society for Immunotherapy of Cancer (SITC) Annual Meeting in November 2016. In February 2017, the company provided a further update in a poster session at the joint meeting of the American Society of Clinical Oncology (ASCO)-SITC Meeting where the company disclosed that the drug was well tolerated through the initial dosing of the 32mg dosing cohort in the ipilimumab arm as well as through the initial dosing of the 8mg cohort in the pembrolizumab arm.

In April 2017, the company initiated enrollment in the Phase 2 portion of the trial with the 8mg dose of intratumoral IMO-2125. The Phase 2 portion of the trial utilizes a Simon two-stage design to evaluate the objective response rate of IMO-2125 in combination with ipilimumab, compared to historical data for ipilimumab alone in the anti-PD-1 refractory metastatic melanoma population. The ipilimumab arm of IMO-2125-204 has already met the pre-specified futility assessment to advance immediately into the second stage of the Phase 2 portion of the trial given that two patients treated at the Phase 2 dose experienced confirmed responses, including one complete response. In June 2017, the company began dosing patients in the second stage of the Phase 2 portion of the trial. The company anticipate that the Phase 2 portion of the trial will enroll a total of 21 patients dosed at the 8mg dose. Additionally, the Phase I dose escalation of IMO-2125 in combination pembrolizumab is ongoing. The MD Anderson Cancer Center will continue to lead the trial and will be joined by additional centers.

In March 2017, the company initiated a Phase 1 trial with IMO-2125 administered as a single agent intra-tumorally in multiple tumor types. The company is also planning to initiate a Phase 2 clinical trial with IMO-2125 administered intra-tumorally together with other checkpoint inhibitors in multiple tumor types.

In June 2017, the U.S. Food and Drug Administration, or FDA, granted Orphan Drug Designation for IMO-2125 for the treatment of melanoma Stages IIb to IV.

IMO-8400 in Rare Diseases

Idera Pharmaceuticals has initiated clinical development of IMO-8400 for the treatment of rare diseases and have selected dermatomyositis as its lead clinical target for which the company is developing IMO-8400. Idera Pharmaceuticals selected this indication for development based on the reported increase in TLR expression in this disease state, expression of cytokines indicative of key TLR-mediated pathways and the presence of auto-antibodies that can induce TLR-mediated immune responses.

Idera Pharmaceuticals considered that multiple independent research studies across a broad range of autoimmune diseases, including both dermatomyositis and psoriasis, have demonstrated that the over-activation of TLRs plays a critical role in disease maintenance and progression. In autoimmune diseases, endogenous nucleic acids released from damaged or dying cells initiate signaling cascades through TLRs, leading to the induction of multiple pro-inflammatory cytokines. This inflammation causes further damage to the body's own tissues and organs and the release of more self-nucleic acids, creating a self-sustaining autoinflammatory cycle that contributes to chronic inflammation in the affected tissue, promoting disease progression.

Idera Pharmaceuticals believe that it demonstrated proof of concept for its approach of using TLRs to inhibit the over-activation of specific TLRs for the treatment of psoriasis and potentially other autoimmune diseases in a randomized, double-blind, placebo-controlled Phase 2 clinical trial of IMO-8400 that the company conducted in patients with moderate to severe plaque psoriasis, a well-characterized autoimmune disease. In this trial, the company evaluated IMO-8400 at four subcutaneous dose levels of 0.075 mg/kg, 0.15 mg/kg, 0.3 mg/kg, and 0.6 mg/kg, versus placebo, administered once weekly for 12 weeks in 46 patients. The trial met its primary objective as IMO-8400 was well tolerated at all dose levels with no treatment-related discontinuations, treatment-related serious adverse events or dose reductions. The trial also met its secondary objective of demonstrating clinical activity in psoriasis patients, as assessed by the Psoriasis Area Severity Index.

Dermatomyositis is a rare, debilitating, inflammatory muscle and skin disease associated with significant morbidity, decreased quality of life and an increased risk of premature death. While the cause of dermatomyositis is not well understood, the disease process involves immune system attacks against muscle and skin that lead to inflammation and tissue damage. Major symptoms can include progressive muscle weakness, severe skin rash, calcium deposits under the skin (calcinosis), difficulty swallowing (dysphagia) and interstitial lung disease. The company believe, based on internally conducted commercial research, that dermatomyositis affects approximately 25,000 people in the United States, and is about twice as common in women as men, with a typical age of onset between 45 and 65 years in adults. Dermatomyositis represents one form of myositis, a spectrum of inflammatory muscle diseases that also includes juvenile dermatomyositis, polymyositis and inclusion body myositis.

In December 2015, we initiated a Phase 2, randomized, double-blind, placebo-controlled clinical trial designed to assess the safety, tolerability and treatment effect of IMO-8400 in adult patients with dermatomyositis. Eligibility criteria include evidence of active skin involvement. Patients in the trial are randomized to one of three groups to receive once weekly subcutaneous injections of: placebo, 0.6 mg/kg of IMO-8400 or 1.8 mg/kg of IMO-8400, in each case, for a period of 24 weeks. The trial is expected to enroll up to 36 patients and is being conducted at 21 centers in the United States, the United Kingdom and Hungary. The primary efficacy endpoint is the change from baseline in the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI), a validated outcome measure of skin disease. Additional exploratory endpoints include muscle strength and function (which are among the International Myositis Assessment & Clinical Studies Group (IMACS) core set measures), patient-reported quality of life and biochemical markers of disease activity.

Third-generation Antisense (3GA)

Third-generation Antisense (3GA) Technology to Target mRNA

Idera Pharmaceuticals is developing its 3GA technology to "turn off" the mRNA associated with disease causing genes. Idera Pharmaceuticals has designed 3GA oligonucleotides to specifically address challenges associated with earlier generation antisense and RNAi technologies.

Its focus is on creating 3GA candidates targeted to specific genes to treat cancer and rare diseases. Its key considerations in identifying disease indications and gene targets in its 3GA program include: strong evidence that the disease is caused by a specific protein; clear criteria to identify a target patient population; biomarkers for early assessment of clinical proof of concept; a targeted therapeutic mechanism of action; unmet medical need to allow for a rapid development path to approval and commercial opportunity. To date, the company has created 22 novel 3GA compounds for specific gene targets that are potentially applicable across a wide variety of therapeutic areas. These areas include rare diseases, oncology, autoimmune disorders, metabolic conditions, single point mutations and others. Its current activities with respect to these compounds range from cell culture through investigational new drug, or IND, application-enabling toxicology.

In January 2017, the company announced that it had selected IDRA-008 as its first candidate to enter clinical development. the company is planning to develop IDRA-008 for a well-established liver target with available pre-clinical animal models and well-known clinical endpoints. The company believe that IDRA-008 has potential for both broad and rare disease applications.

In November 2015, Idera Pharmaceuticals entered into a collaboration and license agreement with GlaxoSmithKline Intellectual Property Development Limited, or GSK, to license, research, develop and commercialize pharmaceutical compounds from its 3GA technology for the treatment of selected targets in renal disease, which agreement the company refer to as the GSK Agreement. Under this collaboration, the company are creating multiple development candidates to address the initial target designated by GSK. From the population of identified development candidates, GSK may designate one development candidate in its sole discretion to move forward into clinical development. Once GSK designates a development candidate, GSK would be solely responsible for the development and commercialization activities for that designated development candidate.

Additional Programs

IMO-9200 for Autoimmune Disease. Idera Pharmaceuticals has developed a second novel synthetic oligonucleotide antagonist of TLR7, TLR8, and TLR9, IMO-9200, as a drug candidate for potential use in selected autoimmune disease indications. In 2015, Idera Pharmaceuticals completed a Phase 1 clinical trial of IMO-9200 in healthy subjects as well as additional preclinical studies of IMO-9200 for autoimmune diseases. In 2015, the company determined not to proceed with the development of IMO-9200 because the large autoimmune disease indications for which IMO-9200 had been developed did not fit within the strategic focus of its company. In November 2016, the company entered into an exclusive license and collaboration agreement with Vivelix Pharmaceuticals, Ltd., or Vivelix, granting Vivelix worldwide rights to develop and market IMO-9200 for non-malignant gastrointestinal disorders, which agreement the company refer to as the Vivelix Agreement.

Collaborative Alliances

In addition to its current alliances, Idera Pharmaceuticals may explore potential collaborative alliances to support development and commercialization of its TLR agonists and antagonists. The company may also seek to enter into additional collaborative alliances with pharmaceutical companies with respect to applications of its 3GA program. The company is currently party to collaborations with Vivelix, GSK, Abbott Molecular, and Merck & Co.

Accumulated Deficit

As of June 30, 2017, the company had an accumulated deficit of $575.0 million. Idera Pharmaceuticals expect to incur substantial operating losses in future periods. The company do not expect to generate product revenue, sales-based milestones or royalties from its development programs until the company successfully complete development and obtain marketing approval for drug candidates, either alone or in collaborations with third parties, which the company expect will take a number of years. In order to commercialize its drug candidates, the company need to complete clinical development and comply with comprehensive regulatory requirements.

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