Hillhurst Biopharmaceuticals, Inc.

Throwback Thursdays: Q2 2023 We completed the last patient’s last visit in our U.S. Phase 1 clinical trial of HBI-002, an oral low-dose carbon monoxide therapeutic developed to treat sickle cell disease (SCD). The main objective of the trial was to investigate HBI-002's safety, tolerability, and pharmacokinetics in healthy adult subjects. The study involved both single and multiple ascending dose cohorts, aiming to validate HBI-002's positive safety profile. This milestone brought us closer to advancing to Phase 1b/2a, which targets the prevention of vaso-occlusive crises in SCD patients. Other potential disease targets included conditions associated with inflammation and cell death, such as Parkinson's disease. As Edward Gomperts, Co-founder, Chairman, and acting Chief Medical Officer of Hillhurst, noted, "With the treatment protocol for our final enrolled participant complete, we look forward to reviewing the data and advancing development plans for HBI-002 as an innovative treatment for sickle cell disease.”

Throwback Thursdays: Q3 2022 We were excited to receive a notice of award for a $5 million HEAL Initiative® grant from the National Institutes of Health. This grant allowed us to continue our research into HBI-201, a preclinical drug with the potential to be used in pain management without the need for opioids. Inhaled Nitrous Oxide gas had long been approved and used as an analgesic agent in the treatment of acute pain conditions such as sickle cell disease and kidney stone pain. However, delivery challenges had prevented N2O from being used as a home therapy to treat acute pain. Orally dosed HBI-201 could potentially allow N2O to be used as a therapeutic in the home setting, avoiding the challenges of inhaled administration. The Helping to End Addiction Long-term® (HEAL) Initiative is dedicated to addressing the national opioid public health crisis by finding new ways to prevent and treat pain. We were honored to be part of this important effort. This was a critical area of research, as the ongoing opioid epidemic has underscored the urgent need for safer and more effective pain management options. With over 100,000 deaths from drug overdose in the US in 2021 alone—a nearly 100% increase since 2015—we are hopeful that HBI-201 has the potential to make a significant impact in the field of pain management. We look forward to continuing our work to bring patients a non-opioid alternative for acute pain management.

Throwback Thursdays: Q3 2022 We received a notice of award for our first Parkinson’s disease-focused grant, targeting the heme oxygenase-1/carbon monoxide pathway. This grant, from the National Institute of Neurological Disorders and Stroke (NIND), provided $630K in support to us and our collaborators. “Because there are no approved neuroprotective drugs for the treatment of Parkinson’s disease, the NIH rightly recognized that new drug products were a high priority. This funding gave us the opportunity to advance our HBI-002 drug product in this important clinical indication with substantial medical need,” said Edward Gomperts, MD, Chairman of Hillhurst. The resources provided by the NIH grant for Parkinson’s Disease were further enhanced by significant non-dilutive funding from private foundations. At the time, we had four additional active small business grants from the NIH, including one for Sickle Cell Disease. We continued to actively seek non-dilutive funding with several other grants submitted and in preparation, covering a variety of therapeutic indications and drug products from both government and foundation sources.

Throwback Thursdays: Q1 2022 Hillhurst Biopharmaceuticals was awarded a late-stage NIH Phase 2b Small Business Innovation Research (SBIR) grant of three million dollars. The proceeds from this grant were allocated to fund our planned Phase IIa clinical study in sickle cell disease patients. We believe that HBI-002 has the potential to be a breakthrough treatment, with the ability to prevent pain crises and offer fewer side effects than current treatments. Our goal is to improve the lives of the hundreds of thousands of people suffering from this debilitating disease. In addition to improving patient outcomes, we see potential for our treatment to significantly reduce the cost of hospitalizations and lessen the burden on the healthcare system. We are grateful for the support of the NIH SBIR program and excited to continue working toward bringing new and innovative treatments to patients in need. With this funding, we move one step closer to realizing our goal of improving the lives of those affected by sickle cell disease, and we eagerly share our progress as we moved forward.

Throwback Thursdays: Q1 2022 We proudly announced the completion of the Single Ascending Dose stage of our Phase 1 clinical trial for HBI-002 in healthy adult subjects. The results demonstrated appropriate safety, tolerability, and pharmacokinetics. HBI-002 was designed to address the delivery challenge of low-dose carbon monoxide (CO), which has been shown to signal a variety of beneficial mechanisms, including anti-sickling, vasodilation, and anti-inflammation. By instilling low-dose CO in an aqueous liquid, enabled by our proprietary GLASS platform, we became the first company to enable chronic home use of this promising therapy. This breakthrough opens the door for HBI-002 to provide a safer and more effective option for the prevention of sickle cell pain crises, offering exciting possibilities for patient care.

Throwback Thursdays: Q1 2022 We were honored to be selected as a San Diego “Cool Company” by CONNECT, a premier innovation company accelerator in San Diego. The Cool Companies program was designed to give San Diego’s top-performing startups direct access to quality venture capital. Up until then, we had been primarily funded through non-dilutive grant funding from both public and private sources. Looking ahead to our Phase 1 clinical study, we invited investors to join us as we prepared to advance to Phase 2a in Sickle Cell Disease. We believed this would unlock substantial value as we collected important efficacy biomarkers from Sickle Cell Disease patients.

Throwback Thursdays: Q1 2022 Hillhurst manufactured HBI-002 drug product in preparation for our phase 1 clinical trial in healthy subjects. HBI-002 is an oral investigational drug product for the treatment of Sickle Cell Disease, designed to deliver low targeted doses of carbon monoxide. Both clinical and preclinical studies with inhaled low dose carbon monoxide support a potential therapeutic role in SCD. However, up to now, no one has ever attempted to deliver CO through the stomach. For the first time we were about to test whether patients can obtain the same beneficial low levels of CO (5% - 10% blood concentration) through the gut.

SAN DIEGO, CA (November 7, 2023) Hillhurst Biopharmaceuticals, Inc. (“Hillhurst”), a clinical-stage biopharmaceutical company focused on developing liquid drug products containing therapeutic gases, today announced the award of an up to $5 million HEAL (Helping to End Addiction Long-term®) Initiative grant from the National Institutes of Health. The NIH HEAL Initiative funds research to find scientific solutions to the opioid public health crisis. The initial $2 million award will fund the preclinical development, and, if awarded, an additional $3 million will fund the clinical development through a Phase 1 clinical study of HBI-201, an oral nitrous oxide therapeutic candidate for patients with sickle cell disease (SCD). HBI-201 is targeted for the treatment of acute pain associated with vaso-occlusive crises (VOC) in SCD. Hillhurst is collaborating on the preclinical portion of this project with Don Simone, Ph.D, and John Belcher, Ph.D., both Professors at the University of Minnesota, whose labs will test HBI-201 in mouse models of SCD pain. “With this award, the NIH HEAL Initiative enables further development of HBI-201with the objective of addressing a significant unmet need for non-opioid pain medications for patients with sickle cell disease,” said Andrew Gomperts, Hillhurst’s Chief Executive Officer. “We believe our novel approach of oral delivery of the analgesic nitrous oxide, approved for use by inhalation, holds great promise for these patients.” About Sickle Cell Disease Sickle cell disease is a genetic disorder that is characterized by recurrent, unpredictable acute pain episodes associated with VOCs. Opioids are one of the primary means of symptomatic management of acute SCD pain, but have substantial drawbacks such as hyperalgesia, tolerance, and potential dependence. About HBI-201 Hillhurst’s product, HBI-201, is an oral drug product candidate of nitrous oxide (N2O), with an administration route designed to enable the home use of N2O for patients suffering from pain associated with VOCs in SCD. The analgesic properties of N2O are well known, and N2O is an FDA-designated medical gas that is used for its analgesic, among other, properties. Other potential disease targets are conditions associated with acute pain. About Hillhurst Hillhurst is a clinical stage company focused on its proprietary GLASSTM platform, which enables novel drug products based on therapeutic gases that, up until now, have been limited by inhaled delivery, including a unique pipeline of novel liquid therapeutic candidates intended to treat patients with acute pain, sickle cell disease, and Parkinson’s disease.