THERAPEUTIC FOCUS - Sarilumab Approval for Polymyalgia Rheumatica Highlights Enduring Unmet Medical Needs

INTRODUCTION

An IL-6 receptor antagonist, sarilumab (Kevzara^®, mar­keted by Sanofi/Regeneron), recently gained FDA approval for the treatment of polymyalgia rheumatica (PMR). Sarilumab is the vanguard of a few new therapies now being developed by phar­maceutical companies for PMR, a disease long overlooked by the industry despite its high prevalence and debilitating symptoms. Sarilumab’s approval is beneficial for patients with PMR: a new, effective treatment option is now available, promotion of the drug will increase disease awareness, and the success encourages oth­ers in the industry to continue and expand their PMR research. However, the proportion of patients who can benefit from the drug is limited. Significant unmet needs remain for all persons suffering from PMR

OVERCOMING THE CHALLENGES OF TREATING PMR

PMR is the most common autoimmune illness of the elderly and second only to rheumatoid arthritis in prevalence of all rheu­matic diseases. Bilateral shoulder pain is the most frequent pre­senting symptom; hip (also usually bilateral) and neck pain, stiffness, and fatigue are also core symptoms.¹ PMR is uncommon prior to age 50, most often presenting between ages 70 and 80. PMR is about 70% more common in women compared to men. Incidence and prevalence data show a substantial decreasing cline from Northern to Southern Europe, and the disease is un­common or rare in persons of Black or East Asian race.² The US prevalence, based from age-, sex-, and year-specific incidence rates and adjusted to the US White population, was estimated to be 701 [95% CI: 651-750] per 100,000, which translates to ap­proximately 840,000 current persons with PMR in the US.³

PMR can be challenging to diagnose. It’s not unusual that a patient receives a confirmed PMR diagnosis only after achieve­ment of remission with a moderate glucocorticoid (steroid) dose of 12.5-25-mg prednisone equivalent daily. The European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) guideline recommends a taper to 10 mg within 4-8 weeks and a 1-1.25-mg dose reduction every 4 weeks there­after until discontinuation, provided remission is maintained.⁴ The purpose of taper is to avert the various and well-established mor­bidities of steroid use, which can include osteoporosis, difficult-to-control diabetes and hypertension, adiposity, cardiovascular disease, glaucoma, muscle and skin atrophy, and mood, sleep, and cognition deficits. But 43% (29%-56%) of patients relapse within a year, and many are unable to taper to discontinuation – at 1, 2, and 5 years after steroid initiation, 77% (71%-83%), 51% (41%-61%), and 25% (15%-36%) remain on steroids.⁵

For 6 decades, patients with PMR have faced a Hobson’s choice between the symptoms of their disease and the side effects of their medicine. Steroid side effects can be even more impactful for elderly patients – consider the probability of long-term dis­ability associated with fracture in someone in their 70s or 80s compared to younger adults. Patients with PMR, because of their age, are also more likely to have comorbid conditions, such as diabetes, hypertension, and glaucoma that can be exacerbated by steroid use.

Until recently, patients with PMR had no third option: the only approved therapy for PMR was steroids. (Historical note: Steroids were never approved by the FDA for treatment of PMR according to modern standards. The indication preceded the Kefauver-Har­ris Act of 1962.) DMARDs (eg, methotrexate, leflunomide) are used as steroid-sparing agents, but their efficacy has not been demonstrated, and most patients who receive DMARDs still re­quire steroids even if at a lower dose. Several biologics have been tested as steroid-sparing agents, but most failed to show efficacy, for example, tumor necrosis factor blocking agents, which the EULAR/ACR guideline recommends against for the treatment of PMR.

NEW CLINICAL RESEARCH CREATES HOPE

Early signs of a new hope came from two academic clinical trials of the IL-6 re­ceptor antagonist tocilizumab. Low or no disease activity together with a protocol-specified decrease of steroid dose in pa­tients with active PMR was achieved in 33 of 49 treated with tocilizumab and 16 of 51 treated with placebo.⁶ Glucocorticoid-free remission at week 16 in patients with new-onset PMR was achieved in 12 of 19 treated with tocilizumab and 2 of 17 who received placebo.⁷ These results confirmed the pathophysiological role of IL-6 in PMR and have led to off-label prescription of tocilizumab. However, there’s no sign tocilizumab, now subject to biosimilar competition, will gain an indication for PMR.

In the registrational trial for the IL-6 receptor antagonist sarilumab (NCT03600818), patients diagnosed with PMR, at a current steroid dose of 7.5- to 20-mg prednisone equivalent daily, with a history of PMR disease flare at a dose of no less than 7.5 mg, and having recent biochemical evidence of inflammation as­sociated with PMR disease activity were randomized equally to two treatment arms:

• sarilumab injected every other week, prednisone tapered from 15 mg to dis­continuation at week 14, or
• placebo for sarilumab injected every other week, prednisone tapered from 15 mg to discontinuation at week 52

The primary endpoint was the propor­tion of patients who achieved sustained re­mission at week 52 defined by achievement of four components:

• disease remission no later than week 12
• absence of disease flare from week 12 through week 52
• sustained reduction of C-reactive pro­tein to < 10 mg/L from week 12 through week 52
• successful adherence to the defined prednisone taper from week 12 through week 52

Sustained remission was achieved by 17 of 60 patients who received sarilumab and 6 of 58 who received placebo. The package insert shows sarilumab was asso­ciated with numerically higher proportions of patients who achieved each of the four components of sustained remission, as well as substantially lower cumulative steroid dose through week 52.⁸

Consistent with the trial population, sarilumab is only indicated for patients with PMR who have had an inadequate re­sponse to, or cannot tolerate, glucocorti­coids (steroids). Sanofi/Regeneron market research suggests that’s about one-third of patients with PMR. Sarilumab is, therefore, not indicated for the majority of patients with PMR. Furthermore, based on the clin­ical trial results, only about 28% of patients who try sarilumab will achieve sustained steroid-free remission. That is only approx­imately 18% more than what was achieved in the control arm of steroids alone, mean­ing sarilumab has only demonstrated ad­ditional benefit for 18% of one-third of PMR patients, or approximately 6% of all patients with PMR. Finally, sarilumab is only indicated in combination with steroids, so all treated patients continue to be exposed to steroids, which have not been shown to be free of safety risks at any dose or duration.

Sarilumab also carries a black box warning for risk of serious infections and warnings for neutropenia, thrombocytope­nia, elevated liver enzymes, lipid abnor­malities, and gastrointestinal perforation. It’s an injectable product, which many view as less desirable than a pill. And it’s ex­pensive ($57,526 per year; caremark.com accessed June 27, 2023), which limits ac­cess. The bottom line: while sarilumab will undoubtedly help some patients with PMR, it has limited efficacy as well as safety, con­venience, and cost-related challenges. Un­fortunately, all patients suffering from PMR continue to have substantial unmet med­ical needs.

NOVEL THERAPY APPROACHES TO PMR TREATMENT

Patients with PMR might have addi­tional novel therapy choices in the coming years, as the industry has begun to recog­nize the unmet needs of the large popula­tion of patients with PMR. Secukinumab (Cosentyx^®, marketed by Novartis), an anti-interleukin 17A antibody currently in­dicated to treat plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, and non-radiographic ankylosing spondyloarthritis, is in a Phase 3 clinical trial (NCT05767034) as a steroid-sparing agent for treatment of PMR. ABBV-154, an antibody-drug conjugate of the TNFα in­hibitor adalimumab and a novel glucocor­ticoid receptor antagonist, had been in a Phase 2 clinical trial (NCT04972968). However, AbbVie announced in April 2023 that ABBV-154 development was discontinued due to its risk profile.⁹ Others have initiated development of similar an­tibody-steroid conjugates with the aim of using the antibody to target the steroid to immune cells, thereby limiting systemic steroid exposure.

PMR patients need a treatment that is effective, safe, convenient, and accessible. Steroid-sparing biologics, although they can be effective options for some patients, each have their own safety issues, usually still require concomitant steroid use, are not the most convenient form of drug, and collectively represent a large economic burden as the most costly drug class for all of us who pay for them through insurance premiums or taxes. Steroids are highly ef­fective to treat PMR, to the point steroid re­sponse can be the basis for diagnosis of PMR rather than another disease with sim­ilar symptoms. Many patients who don’t respond favorably to steroids probably would with a higher dose or longer dura­tion, both of which are discouraged to protect patient safety.

Rather than another steroid-sparing agent, a novel approach is to develop a steroid side-effect-sparing agent. One company trying this approach is Sparrow Pharmaceuticals. SPI-47 is in a Phase 2 clinical trial as a fixed-dose combination of the steroid medicine prednisolone with SPI-62, an inhibitor of the intracellular en­zyme 11β-hydroxysteroid dehydrogenase type 1 (HSD-1). The HSD-1 inhibitor is in­tended to reduce the side effects of the steroid, thereby allowing for safer treat­ment with the highly effective medicine.

 In vivo, steroids cycle between active (eg, prednisolone) and inactive (eg, pred­nisone) forms. Inside cells, HSD-1 converts inactive steroids to their active form. The common steroid medicine prednisone is actually an inactive prodrug that requires HSD-1 for activation to prednisolone. What is not well appreciated is that it is the level of active steroids available intracellu­larly that matters most for the unintended side effects of steroids. Circulating levels of either active or inactive steroids are less consequential.

Prednisolone is inactivated to pred­nisone by a different enzyme, HSD-2, in tissues where steroids are acutely toxic, most prominently in the kidney. Circulating prednisone is re-activated to prednisolone intracellularly predominantly in liver and other organs such as adipose, brain, bone, skin, muscle, and eye where steroid excess can lead to known safety problems. Potent inhibitors of HSD-1 lower active in­tracellular steroid levels in several of those tissues, thereby potentially reducing the side effects of steroid use.

In mice, SPI-62 prevented steroid-as­sociated hyperphagia, accelerated weight gain, insulin resistance, increased adipos­ity, and muscle and skin atrophy (submit­ted for publication). In a recent academic clinical trial, the HSD-1 inhibitor AZD4017, when given in combination with prednisolone to healthy adult males, prevented many acute toxicities of the steroid.¹⁰ HSD-1 inhibition prevented suppression of the bone formation biomarkers osteocalcin and procollagen type I N-propeptide, increase of the bone resorption biomarker C-terminal colla­gen type I crosslinks, reduction of insulin sensitivity and glucose disposal measured during an insulin clamp, elevation of triglycerides, and night-time diastolic hypertension. HSD-1 is also expressed at low levels in cells of the human immune system. That expression might contribute to the observations that AZD4017 prevented prednisolone effects on some immune biomarkers but not others. None of the affected biomarkers are understood as relevant to PMR pathophysiology, so the implication of those findings on the efficacy of prednisolone in patients is unclear.

The ongoing Phase 2 clinical trial of SPI-47 in patients with PMR (NCT05436652) aims to determine whether co-administration of SPI-62 can both reverse adverse prednisolone effects (eg, changes on bone biomarkers consistent with an osteoporotic phenotype) and preserve desired effects (ie, symptomatic control of PMR, suppression of cytokines and acute phase bio­markers that have been associated with PMR disease activity). If successful, this trial will provide clinical proof-of-concept for the steroid side effect-sparing approach of HSD-1 inhibition.

CONCLUSION

2023 is a banner year for patients with PMR. After a 6-decade wait, they have a new treatment option – the IL-6 receptor antagonist sarilumab. The pharmaceutical industry has awakened to their enduring unmet medical need, which even with the approval of sarilumab remains substantial. Another steroid-sparing biologic, secukinumab, with a distinct mechanism of action and already available for treatment of other rheumatic diseases, is in a Phase 3 clinical trial. Finally, a novel approach with HSD-1 inhibition has the poten­tial to yield a medicine that shares the same efficacy and convenience as today’s steroids while reducing the safety challenges that currently limit steroid utility.

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Dr. David A. Katz is Chief Scientific Officer of Sparrow Pharmaceuticals. Prior to founding Sparrow, he was a pharmaceutical R&D leader at Abbott and AbbVie, where he led clinical development and drug discovery teams, and was a personalized medicine pioneer. He is dedicated to mentorship of the next generation of life sciences entrepreneurs, currently as an entrepreneur-in-residence at Oregon Health & Science University. He held post-doctoral fellowships in Immunology at Universities of Chicago and Michigan, earned his MPhil and PhD degrees in Molecular Biophysics and Biochemistry from Yale University, and is an alumnus of Pomona College (BA, Chemistry). He has published over 50 peer-reviewed scientific papers.

Robert Jacks is Chief Executive Officer of Sparrow Pharmaceuticals and has 20 years of experience in the biopharmaceutical industry. He has founded or co-founded multiple companies and raised more than $170 million. Previously, he was the President & CEO of Indalo Therapeutics, a clinical-stage biotechnology company developing therapeutics for serious fibrotic diseases, and President, CFO, and Co-Founder of Symbiomix Therapeutics, which was sold after achieving NDA approval for Solosec®. He also previously held the positions of Head of Corporate Development for Tobira Therapeutics, Head of Business Development for ACT Biotech, and Entrepreneur-in-Residence for OrbiMed Advisors. He began his pharmaceutical industry career in finance and product development at Pfizer, where he last worked as the Director of Business Development for Oncology and Infectious Diseases. He earned an MBA from Columbia Business School, an MSE in Civil Engineering from Stanford University, and a BSE in Civil Engineering from Duke University.