Ionis Pharmaceuticals, Inc. Common Stock FDA announcement

Thank you to everyone joining us today as we discuss ZANVASTRO, which is now the first and only FDA-approved disease-modifying therapy for the treatment of Alexander disease. Please be sure to visit the investor section of the Ionis website to see the press release Ionis has issued earlier today, along with the slides accompanying today's webcast. Before we begin, I would like to remind you that our discussion today will contain forward-looking statements that are based on our current expectations and beliefs. Such statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors contained in our SEC filings for additional detail. With me on the call today are Brett Monia, Chief Executive Officer, Holly Kordasiewicz, Chief Development Officer, and Kyle Jenne, Chief Global Product Strategy Officer.

Our agenda today will be as follows: Brett will provide opening remarks. Holly will provide a brief review of the unmet need associated with Alexander disease, as well as the data that support the approval and label of ZANVASTRO. Kyle will review our launch strategy for ZANVASTRO, which represents Ionis' first independent commercial launch in neurology. After Brett's brief conclusion, we will open the call for your questions. With that, I'll turn the call over to Brett.

Thanks, Wade. Good morning, and thanks everybody for joining us on today's call. Today is a landmark day for people with Alexander disease and Ionis, as the FDA has approved ZANVASTRO, the first and only disease-modifying treatment for this ultra-rare, progressive, and often fatal neurological disorder. The FDA approves ZANVASTRO with a broad label enabling treatment of both children and adults with Alexander disease. With today's approval coming nearly three weeks early, we are positioned to bring ZANVASTRO to patients even sooner than anticipated. ZANVASTRO was approved based on positive data from our pivotal study in children and adults with Alexander disease. The study achieved a statistically significant and clinically meaningful benefit on the primary endpoint measuring motor function. Additionally, trends favoring ZANVASTRO across key symptom domains were also observed, along with a favorable safety and tolerability profile.

For Ionis, this approval builds on our long history of discovering and developing first-in-class treatments for rare neurological diseases such as SPINRAZA, first therapy ever approved to treat SMA, and QALSODY, the only disease-modifying treatment approved for a genetic form of ALS. ZANVASTRO builds on our legacy of innovation and reinforces the transformational power of our technology. As the first independent launch from our industry-leading neurology pipeline that today includes eight wholly owned medicines addressing similarly challenging diseases like Dravet syndrome, Prion disease, and Angelman syndrome, ZANVASTRO provides a strong foundation to support these potential future launches. Furthermore, as Ionis' third wholly owned commercial medicine, ZANVASTRO joins TRYNGOLZA and DAWNZERA in demonstrating our ability to successfully capitalize on the opportunities from our rich and growing pipeline. We were pleased to receive a Rare Pediatric Disease Priority Review Voucher from the FDA in connection with ZANVASTRO's approval.

This voucher provides an opportunity to accelerate the FDA review of a future Ionis medicine and potentially accelerate our ability to bring it to patients sooner. In addition to launching in the U.S., we are also expanding access to ZANVASTRO to people with Alexander disease outside the U.S. through our commercial partner Recordati, which remains on track to file for approval in the EU and Japan next year, with additional submissions to follow. Before I turn the call over to Holly, I want to extend my sincere thanks to the Alexander Disease community, including the patients, families, investigators, advocacy organizations, and research partners who helped make this approval possible. I also want to recognize the Ionis team for their innovation, dedication to patients, and commitment in bringing this important medicine forward. With that, I'll turn the call over to Holly.

Thank you, Brett. Before I begin, I would also like to thank the Alexander Disease community for their partnership and support that made the approval of ZANVASTRO possible. It is a powerful, determined community, and it has been a privilege to work with them. Alexander disease is an ultra-rare, progressive, and severe neurological disease caused by pathogenic variants in the GFAP gene. Because it affects the brain's white matter, Alexander disease can involve multiple regions of the brain and present with complex symptomatology. While symptoms often present first in infancy or childhood, onset can occur at any age, with most patients experiencing progressive motor and cognitive dysfunction, loss of mobility and independence, and difficulty controlling the muscles needed for swallowing, airway protection, and purposeful movement. Sadly, it is almost always fatal. Alexander disease is estimated to affect approximately 1 in 1 million to 3 million people worldwide.

Until today, in the absence of any approved disease-modifying treatments, care for people with Alexander disease has largely focused on symptom management and support as the disease progresses. Given the small size of this population and the urgent need for treatment, with the support of the FDA and Alexander Disease community, we took an innovative approach in designing our ZANVASTRO registrational trial. We combined first-in-human dose finding and pivotal studies into one controlled integrated trial protocol, which provided the results that supported today's approval. The ZANVASTRO trial enrolled 54 people, ages 2 to 53, the majority of whom were under the age of 18 at enrollment, reflecting the real-world Alexander disease population. The primary objective of this study was to evaluate ZANVASTRO's impact on stabilization of gross motor function in children and adults with Alexander disease.

The primary endpoint in the study measured stabilization of gait speed in participants aged 5 and up using the 10-meter walk test, a commonly used measure of gross motor function in neurological diseases. The study also measured gross motor function in younger participants, as well as a number of secondary and exploratory endpoints aimed at capturing the constellation of Alexander disease symptoms. The approved dosage of ZANVASTRO is 50 milligrams and is administered quarterly by intrathecal injection, the same well-established route of administration as our other approved neurology medicines. We initially tested a lower 25 milligram quarterly intrathecal dose in a small cohort of patients, which enabled us to establish ZANVASTRO safety and pharmacokinetic profile. Once complete, we tested the approved ZANVASTRO 50 milligram dose in a larger cohort of patients, which represented the pivotal portion of the trial.

The study met its primary endpoint, showing a statistically significant and clinically meaningful stabilization of gait on the 10-meter walk test in participants treated with ZANVASTRO 50 milligrams. This was a very exciting outcome as it represented the first time a medicine demonstrated disease-modifying benefit in this patient population. Secondary and exploratory endpoints also consistently favored ZANVASTRO. In participants aged 2 to 4, ZANVASTRO improved gross motor function compared with control on the Gross Motor Function Measure-88 or GMFM88, a well-established measure appropriate for this age group. ZANVASTRO also substantially reduced plasma GFAP compared with control, providing evidence that ZANVASTRO engaged the intended target and is modulating the underlying mechanism of Alexander disease in ZANVASTRO-treated patients. ZANVASTRO also demonstrated a favorable safety and tolerability profile in the trial.

Most adverse reactions observed in the trial were mild to moderate in severity, and serious adverse reactions occurred less frequently with ZANVASTRO compared to control. These efficacy and safety results supported a broad label for children and adults reflecting the real world Alexander disease population. Importantly, we believe ZANVASTRO is well positioned to become an important new treatment option and the standard of care for people living with Alexander disease. With that, I'll turn the call over to Kyle.

Thank you, Holly. We are thrilled to bring ZANVASTRO, the first disease modifying treatment for Alexander disease, to people in the U.S. who are living with this ultra rare progressive neurological disorder. This represents an important new medicine for a community with significant unmet need. We are launching ZANVASTRO with a broad label enabling children and adults diagnosed with Alexander disease to access treatment. We are working quickly to get product into the channel so we can bring this important treatment to patients in need shortly. With our customer facing team already in the field, we are ready to launch ZANVASTRO. Although exact prevalence is not well understood, we estimate that approximately 300 people in the U.S. are living with Alexander disease, approximately half of whom have been identified through medical claims.

Among the patients who currently receive supportive treatment for their disease, many do so at one of the approximately 12 leukodystrophy Centers of Excellence in the U.S. At launch, our team will focus on these centers to ensure identified patients can gain access to ZANVASTRO if appropriate. In parallel, we will work to reach treaters in neurology centers outside this concentrated network in an effort to identify new patients who may benefit from ZANVASTRO. We will do this strategically leveraging omnichannel resources as needed to extend our team's reach. We have four initial launch priorities. First, the team will work to transition patients currently receiving ZANVASTRO in the clinical study and expanded access program to commercial drug while ensuring continuity of care for these patients throughout the process.

Second, we will work to get patients who have already been diagnosed with Alexander disease and identified through ICD 10 codes and patient registries on treatment. Third, we will work to raise disease awareness among physicians who care for people with this rare neurological disease to drive new patient identification. Finally, we will work with payers to ensure coverage and access for ZANVASTRO. We have also tailored Ionis Every Step Patient and HCP support program to meet the unique needs of the Alexander community. For healthcare providers and site staff, we have adapted our Access and Reimbursement Support services specifically for ZANVASTRO, which is intrathecally administered, dosed quarterly, and will be reimbursed mostly under the patient's medical benefit. For patients and families, they will have access to a comprehensive suite of education and reimbursement support services designed to help patients start and stay on treatment.