Clinical Trials

Date: 2017-11-02

Type of information: Presentation of results at a congress

phase: 3

Announcement: presentation of results of the ATTR Amyloidosis Meeting

Company: GSK (UK) Ionis Pharmaceuticals (USA - CA)

Product: Ionis-TTRRx - inotersen

Action mechanism:

• antisense oligonucleotide. ISIS-TTRRx, now Ionis-TTRRx is an antisense drug in development with GSK for the treatment of transthyretin (TTR) amyloidosis, a severe and rare genetic disease characterized by progressive dysfunction of peripheral nerve and/or heart tissues. It is designed to inhibit the production of all forms of TTR and could offer an alternative approach to treat all types of transthyretin-related amyloidosis. The FDA has granted ISIS-TTRRx fast track designation and orphan drug status for the treatment of FAP.
• ISIS-TTRRx is part of the Isis-GSK strategic alliance to develop RNA therapeutics for rare and infectious diseases. Isis is eligible to earn an additional $50 million in pre-licensing milestone payments to support the Phase 2/3 study of ISIS-TTRRx. In addition, Isis is eligible to receive regulatory and sales milestone payments and double-digit royalties on sales of ISIS-TTRRx.

Disease: TTR amyloid cardiomyopathy

Therapeutic area: Rare diseases - Genetic diseases

Country: Argentina, Brazil, France, Germany, Italy, New Zealand, Portugal, Spain, UK, USA

Trial details:

• The Phase 2/3 study of ISIS-TTRRx is a randomized, double-blinded, placebo-controlled, international study designed to support an application for marketing approval of ISIS-TTRRx in patients with FAP (Familial Amyloid Polyneuropathy). The fifteen month study will enroll approximately 200 patients randomized 2:1 to receive 300 mg/week of ISIS-TTRRx or placebo and will measure the effects of ISIS-TTRRx on neurological dysfunction and on quality-of-life. (NCT01737398)

Latest news:

• • On November 2, 2017, Ionis Pharmaceuticals announced new data from the Phase 3 NEURO-TTR study, evaluating inotersen in patients with hereditary TTR amyloidosis (hATTR). Results from the study demonstrated early and significant benefit in both co-primary endpoints:  Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) and modified Neuropathy Impairment Score +7 (mNIS+7), a measure of neuropathic disease progression, in inotersen-treated patients compared to placebo-treated. A continued increase in benefit, relative to placebo, was observed in both endpoints through study completion. Statistically significant benefit was also observed in multiple other endpoints in the study, including the SF-36 Health Survey and cardiac measures. The data have been presented at the first annual meeting of the ATTR Amyloidosis Meeting in Paris, France.
• The NEURO-TTR study met both co-primary endpoints, the Norfolk QoL-DN, a validated instrument for physician-assessed quality of life, and mNIS+7, a validated instrument for evaluating hATTR disease severity. Consistent and significant benefit compared to placebo was observed in both co-primary endpoints at both eight months and 15 months. In addition, consistent and significant benefit was observed in both endpoints independent of disease stage, types of mutation, previous use of TTR stabilizers or presence of cardiomyopathy. Compared to placebo-treated patients, inotersen-treated patients experienced substantial and statistically significant benefits, including:
  • A mean 11.68-point and a mean 6.14-point benefit compared to placebo in Norfolk QoL-DN at 15 months and eight months respectively (p=0.0006, p=0.032).
  • A mean 3.59-point clinically meaningful benefit compared to placebo in the SF-36 Health Survey at 15 months (p=0.006). SF-36 is a commonly used and validated QoL instrument for assessing general health status across eight domains of health.
  • A mean 19.73-point and a mean 8.69-point benefit compared to placebo in mNIS+7 at 15 months and eight months respectively (p=0.00000004, p=0.0005).
  • Encouraging benefit compared to placebo in multiple cardiac measures in patients with significant cardiac disease at baseline (interventricular septum thickness, IVS ? 1.5 cm), including left ventricle mass (p=0.0288), IVS (p=0.0150), posterior wall thickness (p=0.0425), and trends in favor of inotersen treatment vs. placebo treatment in global longitudinal strain.
  • Significant benefit compared to placebo in patients with cardiac disease at baseline in both primary endpoints (Norfolk QoL-DN, p=0.036 and mNIS+7, p<0.001) and in the SF-36 Health Survey endpoint (p=0.025) at 15 months.
  Two key safety issues were identified during the study: thrombocytopenia and safety signals related to renal function. Enhanced monitoring was implemented during the study to support early detection and management of these issues. Serious platelet and renal events were infrequent and easily managed with routine monitoring, which has proven effective since implementation. Other serious adverse events were observed in 24.1% of inotersen-treated patients and 21.7% of placebo-treated patients. No cumulative toxicities have been identified with long-term exposure. Adverse events occurring in ?10% of patients and twice as frequently in inotersen-treated patients compared with placebo-treated patients, included thrombocytopenia/platelet count decreases, nausea, pyrexia, chills, vomiting and anemia. Injection site reactions accounted for less than 1% of all injections and were mild or moderate in severity. There were no discontinuations due to injection site reactions. The overall mortality rate in the NEURO-TTR study was 2.9% and was lower than mortality rates reported in other studies in hATTR patients. There was a total of five deaths in the study, five (4.7%) in the inotersen arm and zero in the placebo arm. Four deaths in the inotersen arm were associated with disease progression and considered unrelated to treatment. As previously reported, there was one fatal intracranial hemorrhage in conjunction with serious thrombocytopenia. No serious thrombocytopenia was observed following implementation of more frequent monitoring. • On October 15, 2017, Ionis Pharmaceuticals announced that new data from the Phase 3 NEURO-TTR study with inotersen in patients with hereditary TTR amyloidosis (hATTR) with polyneuropathy were presented at the 142^nd annual meeting of the American Neurological Association(ANA) in San Diego, California. In the study, inotersen-treated patients achieved a mean 19.73-point benefit in the mNIS+7 co-primary endpoint after 15 months of treatment, compared to placebo-treated patients (p = 0.00000004), further demonstrating the clinically meaningful benefit of inotersen treatment. A statistically significant benefit in mNIS+7 was also observed at eight months. Key safety findings of thrombocytopenia and renal events identified during the study were shown to be monitorable and manageable with routine blood and urine testing. • On April 7, 2016, Ionis Pharmaceuticals provided an update on the IONIS-TTRRx program. IONIS-TTRRx is currently being evaluated by IONIS in an ongoing Phase 3 study, NEURO-TTR, in patients with transthyretin (TTR) familial amyloid polyneuropathy. A Phase 3 study, CARDIO-TTR, is also being planned by GSK to evaluate IONIS-TTRRx in patients with TTR amyloid cardiomyopathy. GSK is in the process of finalizing the protocol for the CARDIO-TTR study with the FDA. In that process, the FDA has placed a clinical hold on the CARDIO-TTR study while GSK provides answers to questions about the protocol stemming from Ionis' ongoing NEURO-TTR study. The NEURO-TTR study, which is regulated by a separate division at the FDA, continues as planned and is on track to complete in the first half of 2017.
• • On July 27, 2015, Isis Pharmaceuticals announced preliminary results from an investigator-sponsored study in patients with transthyretin amyloid-related cardiomyopathy that was presented by Dr. Merrill Benson at the 20th World Congress on Heart Disease (WCHD) in Vancouver, Canada. In a presentation titled, "Transthyretin Amyloid Cardiomyopathy Treatment with an Antisense Oligonucleotide Inhibitor of TTR (ISIS-TTRRx)", Dr. Benson reported on preliminary results from his investigator-sponsored open-label study in patients with TTR-related cardiomyopathy. In patients who completed nine months of weekly dosing (n=3) with 300 mg of ISIS-TTRRx, reductions in TTR protein of up to 88% were observed with a mean reduction of 78%. In addition, patients who completed six months of dosing (n=5) were evaluated by echocardiography and showed no increase in left ventricular wall thickness. In this study, patients receive 300 mg of ISIS-TTRRx once weekly for a total of 24 months with a three month follow up period (Abstract 221 p233).
• • On April 22, 2015, Isis Pharmaceuticals announced positive data from an ongoing open-label extension (OLE) study of ISIS-TTRRx in patients with familial amyloid polyneuropathy (FAP). FAP patients completing the ongoing Phase 3 study are eligible to enroll in this OLE study in which all patients receive ISIS-TTRRx. An analysis conducted on the first group of patients to reach three months of treatment in the OLE study showed a reduction in transthyretin (TTR) protein levels up to 92 percent with a median reduction of 78 percent compared to patients' baseline TTR levels at entry into the Phase 3 study. Patients continue to be enrolled as they complete dosing in the Phase 3 study. These data will be presented at the American Academy of Neurology meeting in Washington, DC. In a platform presentation titled, 'A Phase 3 Study to Evaluate ISIS-TTRRx in Patients with Transthyretin Familial Amyloid Polyneuropathy (TTR-FAP): Study Design and Baseline Demographics', Dr. Benson reported that in the first thirteen patients to enter the OLE study, reductions of up to 92 percent in TTR protein after thirteen weeks of treatment with ISIS-TTRRx were observed. Across all patients enrolled in the Phase 3 study, 27 TTR mutations were represented to date, including the Val30Met mutation, which is the most common mutation found in patients with FAP. ISIS-TTRRx is designed to reduce all forms of TTR, including both mutant and wild type, and therefore should provide therapeutic benefit to any FAP patient regardless of that patient's individual TTR mutation.
• • On March 3, 2014, Isis Pharmaceuticals has announced  that it has earned a $1 million milestone payment from GSK related to the initiation of an open-label extension study of ISIS-TTRRx, which is being offered to those patients with familial amyloid polyneuropathy (FAP) who have completed dosing in the Phase 2/3 study of ISIS-TTRRx. Including this milestone payment, Isis has earned $25 million in upfront and milestone payments for advancing ISIS-TTRRx.  This $1 million milestone payment is the third of the $50 million in milestone payments Isis is eligible to earn as the Phase 2/3 study progresses.  In addition, if GSK elects to exercise its option to exclusively license the ISIS-TTRRx program, Isis is eligible to receive a license fee, regulatory and sales milestone payments and double-digit royalties on sales of ISIS-TTRRx.
• • On July 30, 2013, Isis Pharmaceuticals has announced that it has earned a $2 million milestone payment from GSK related to the advancement of the ongoing Phase 2/3 study of ISIS-TTRRx in patients with familial amyloid polyneuropathy (FAP). Isis has earned $20 million in upfront and milestone payments prior to first patient dosed in the ongoing Phase 2/3 study.  The $2 million milestone payment announced is the first milestone of the $50 million in milestone payments Isis is eligible to earn as the Phase 2/3 study progresses.  In addition, if GSK elects to exercise its option to exclusively license the ISIS-TTRRx program, Isis is eligible to receive a license fee, regulatory and sales milestone payments and double-digit royalties on sales of ISIS-TTRRx.
• • On February 19, 2013, Isis Pharmaceuticals has announced that it has earned a $7.5 million milestone payment from GSK related to the initiation of a Phase 2/3 clinical study for ISIS-TTRRx in Familial Amyloid Polyneuropathy. Isis and GSK recently amended the clinical development plan and financial terms relating to ISIS-TTRRx to support this registration-directed Phase 2/3 clinical study on ISIS-TTRRx.

 

Is general: Yes