The FDA has approved oral sulopenem (sulopenem etzadroxil/probenecid), marketed as Orlynvah from Iterum Therapeutics, based on data from a pair of phase 3 trials, SURE 1 (NCT03354598) and REASSURE (NCT05584657), demonstrating its effectiveness against infections caused by Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis.

In the SURE 1 trial, oral sulopenem showed superiority over ciprofloxacin for fluoroquinolone-resistant infections, while the REASSURE trial indicated a better response rate compared with amoxicillin/clavulanate. Experts view this approval as a significant advancement in UTI treatment alternatives, especially amid growing concerns about antimicrobial resistance. The FDA’s Antimicrobial Drugs Advisory Committee highlighted the need for careful post-market monitoring to prevent off-label use.

Corey Fishman, CEO of Iterum Therapeutics, highlighted the importance of Orlynvah in providing new options for patients and addressing antimicrobial resistance in a statment, saying, “We are so pleased to have achieved this historic milestone and would like to thank all the patients, investigators, Iterum colleagues and Iterum consultants and vendors who participated in the development of Orlynvah Orlynvah offers new hope for patients suffering from difficult-to-treat uUTIs. The introduction of novel products, like Orlynvah, is an important way to combat antimicrobial resistance to other approved oral agents and offers a potential solution to patients and physicians. As the first oral penem approved in the US, Orlynvah offers an excellent alternative treatment option for appropriate patients in the underserved uUTI market. With FDA approval and a clear label, we will renew our efforts to achieve a strategic transaction involving Orlynvah with the goal of maximizing value for our stakeholders.”¹

Approximately 40 million uUTI prescriptions are generated annually in the US, with about 1% because of pathogens resistant to standard oral antibiotics. Orlynvah is contraindicated in patients with a history of hypersensitivity to its components and may cause adverse reactions such as diarrhea and nausea.

Earlier this year, in September, the FDA’s Antimicrobial Drugs Advisory Committee (AMDAC) met to discuss the drug’s new drug application,^2,3 focusing on the overall benefits and risks and key considerations for medical providers. The agency did not ask the AMDAC to vote on any matter in the meeting. Fishman noted at the time that the company was “encouraged by the AMDAC’s discussion” and pleased that the AMDAC considered it an important option for certain patients and agreed on its appropriate use.

Key Information From The SURE-1 and REASSURE Trials

SURE 1 trial (NCT03354598)

Oral sulopenem was evaluated against ciprofloxacin in patients with uUTIs, focusing on quinolone-susceptible and nonsusceptible uropathogens. The study enrolled 1671 patients, randomly assigning them to receive either oral sulopenem or ciprofloxacin. In the quinolone nonsusceptible population, sulopenem demonstrated a significantly higher overall response rate of 62.6% compared with 36% for ciprofloxacin.

Clinical success was achieved in 83% of the sulopenem group versus 62.6% in the ciprofloxacin group, while microbiological success was noted in 74.1% of patients treated with sulopenem compared with 49.6% for ciprofloxacin, both with statistically significant differences. In the quinolone-susceptible group, sulopenem met the noninferiority threshold, with an overall response rate of 66.8% compared with 78.6% for ciprofloxacin.⁴

REASSURE trial (NCT05584657)

Further assessed oral sulopenem against amoxicillin/clavulanate (Augmentin) in a cohort of 2222 adult women with uUTIs. Participants were randomly assigned to receive either treatment for five days. The trial’s primary endpoint was the overall response rate at the test-of-cure visit. Sulopenem achieved a response rate of 61.7%, while amoxicillin/clavulanate showed a rate of 55%, with a treatment difference of 6.7%.

Clinical success rates were comparable, with sulopenem at 77.3% and amoxicillin/clavulanate at 76.7%. Microbiological success favored sulopenem at 75.2% compared with 66.7% for amoxicillin/clavulanate, indicating a significant advantage. Both treatments were well-tolerated, with less than 1% of patients discontinuing due to adverse events, and no serious adverse events were reported for sulopenem.⁵ Together, these trials underscore the efficacy and safety of oral sulopenem as a promising treatment option for uUTIs, particularly in populations facing antibiotic resistance.

References

1. Iterum Therapeutics receives U.S. FDA approval of ORLYNVAH (oral sulopenem) for the treatment of uncomplicated urinary tract infections. News release. Iterum Therapeutics. October 25, 2024. Accessed October 25, 2024. https://www.iterumtx.com/news/press-releases/detail/136/iterum-therapeutics-receives-u-s-fda-approval-of

2. September 9, 2024: Meeting of the Antimicrobial Drugs Advisory Committee Meeting Announcement. Updated September 19, 2024. Accessed October 25, 2024. https://www.fda.gov/advisory-committees/advisory-committee-calendar/september-9-2024-meeting-antimicrobial-drugs-advisory-committee-meeting-announcement-09092024

3. Iterum Therapeutics Provides Update on FDA Advisory Committee Discussion of Oral Sulopenem for the Treatment of uUTI in Adult Women. News release. Iterum Therapeutics. September 10, 2024. Accessed October 25, 2024. https://www.iterumtx.com/news/press-releases/detail/133/iterum-therapeutics-provides-update-on-fda-advisory

4. Dunne MW, Das A, Akinapelli K, Zelasky MT, Boucher HW, Aronin AI. Efficacy and safety of oral sulopenem etzadroxil/probenecid versus oral ciprofloxacin in the treatment of uncomplicated urinary tract infections (uUTI) in adult women: Results from the SURE-1 trial. Presented at: ID Week 2020. October 21, 2020. https://d1io3yog0oux5.cloudfront.net/_c686b74a40042109ff06b21eccc8f678/iterumtx/db/395/2729/pdf/SURE+1+Slide+Presentation+IDweek+2020+19OCT_final.pdf

5. Iterum Therapeutics announces positive topline results from its phase 3 REASSURE clinical trial of oral sulopenem in uncomplicated urinary tract infections. News release. Iterum Therapeutics plc. January 30, 2024. Accessed October 25, 2024. https://www.prnewswire.com/news-releases/iterum-therapeutics-announces-positive-topline-results-from-its-phase-3-reassure-clinical-trial-of-oral-sulopenem-in-uncomplicated-urinary-tract-infections-302047483.html

Since the start of the COVID-19 pandemic, the persistence or appearance of neurologic symptoms after clearance of SARS-CoV-2 infection has become a serious health challenge for patients and clinicians worldwide. The effects of post-acute sequelae of SARS-CoV-2 infection (PASC), commonly known as Long COVID, can be debilitating and persist for months after infection. Some of these symptoms can include fatigue, neuropsychiatric sequelae, sleep disturbances, sensorimotor symptoms, cognitive impairment/brain fog, hypoguesia/hyposmia, hearing loss, and ocular symptoms.

As emphasized by the research and experts in the field, currently there are no specific tests for the diagnosis of Long COVID, and clinical features such as laboratory findings and biomarkers may not specifically relate to the condition. It is important to develop and validate biomarkers for the prediction, diagnosis, and prognosis of Long COVID and its response to therapeutics. Regardless of age or preexisting health conditions, Long COVID can affect anyone, highlighting that this condition is not restricted to any specific demographic and does not discriminate, even against the healthiest individuals.

In Episode 3 of our Long COVID roundtable collaboration with NeurologyLive, clinicians discussed treating Long COVID patients, highlighting that care often relies on strategies used for other chronic illnesses.

Our panel of clinicians includes:

• Ravindra Ganesh, MD, MBBS, FACP, Dip ABOM, general medicine doctor at the Mayo Clinic and leader of their Long COVID clinic.
• Svetlana Blitshteyn, MD, FAAN, clinical associate professor of neurology at the University at Buffalo Jacobs School of Medicine and Biomedical Sciences, director of the Dysautonomia Clinic.
• Monica Verduzco-Gutierrez, MD, physical medicine and rehabilitation physician, professor, and chair of rehabilitation medicine at UT Health, leader of the Long COVID clinic.

Ganesh, Verduzco-Gutierrez, and Blitshteyn emphasized the complexity of the condition, noting the absence of FDA-approved therapies and the importance of individualized care. They highlighted the necessity of tailoring interventions based on patient phenotypes, which can include a range of symptoms and underlying issues. With ongoing research into various treatments and the need for comprehensive education among healthcare providers, they collectively advocated for more therapeutic options and better local care to address the multifaceted challenges faced by Long COVID patients.

Transcript edited for clarity.

Ganesh: Nothing is FDA-approved, and everything we use is pieced together from our understanding of other chronic illnesses. Generally, I tend to phenotype people to see which conditions their Long COVID most closely resembles, and we devise therapeutic interventions based on that. For example, in patients with more of a ME/CFS phenotype, historically, the most helpful treatments have included things like low-dose naltrexone and low-dose Abilify. We’ve also tried various supplements. Pacing is critical, getting people to avoid overexertion and the subsequent crash. We help people understand how to minimize and mitigate stresses and exposures in their daily lives, like excessive exposure to stimuli can be highly triggering. We also help them with the accommodations they need for work. Often, people either can’t work or need a significantly reduced schedule. My patients with orthostatic intolerance may need to sit for most of the day.

For those with a different autonomic phenotype, there are other interventions. I use nerve stimulators for patients with hyperadrenergic dysautonomia post-COVID. We also have medications for Postural Orthostatic Tachycardia Syndrome (POTS), including beta blockers and fludrocortisone, which can be very effective depending on the patient. Then, we have many non-pharmacological interventions. Patients without post-exertional malaise can tolerate some degree of physical activity, especially if it’s not vertical. There are activities that can help them regain muscle tone without being too challenging. It’s a mixed bag of symptoms and treatments.

In terms of ongoing trials, there are several. The RECOVER trials are looking at treatments like IVIG and Paxlovid. There are also studies on sleep and cognitive dysfunction. Non-RECOVER trials are also of interest, like the REVERSE-Long COVID trial with baricitinib. I’m eager to see the results.

Verduzco-Gutierrez: There isn’t a magic cure or pill yet, but figuring out the phenotype is key because symptom management is possible for many patients. For example, so many patients have POTS or some other form of dysautonomia, and there are both pharmacological and non-pharmacological interventions that can help control their symptoms. While it may not eliminate everything, we can manage a lot. There’s sometimes hesitation around starting medications like beta blockers when they’re needed, but I encourage people to try these treatments.

It’s also crucial to screen patients for post-exertional malaise because if they have it, we need to identify their energy envelope and ensure they don’t overdo it, which could lead to a crash. Studies show that exercising certain populations can worsen their condition, sometimes causing muscle necrosis. We need to listen carefully to each patient and decide: “Does this person need to pace themselves, or can they increase activity?” It’s essential to tailor an activity modification program based on how the patient responds. Some patients may need to decrease their activity, while others may be able to gradually increase it.

We also see patients with dysfunctional breathing patterns, which are part of the autonomic nervous system. For them, breath work can be very helpful. It helps retrain the diaphragm and allows them to breathe deeply again. Long COVID manifests in many ways, and if a patient has migraines or sleep disorders, we treat those conditions too, sometimes more aggressively than before. Even though there isn’t one medication or treatment that will fix everything, symptom management can still make a big difference.

Blitshteyn: That’s a very thorough and appropriate approach. I do want to caution that I often have patients who come to me from various Long COVID clinics, and the treatment they’ve been offered is frequently insufficient. Often, they’re referred to physical therapy, psychotherapy, or a sleep evaluation, but for many patients, that’s not enough. Long COVID is an umbrella term covering multiple phenotypes, so focusing solely on simple interventions isn’t going to work for most patients, many of whom need medications.

We have to learn how to manage these patients, even if we’ve never treated POTS or neuropathic pain before. Education across specialties is going to be critical to improving patient care. While guidelines exist and continue to be published, they won’t help if specialists aren’t reading them. The old pattern for post-infectious syndromes, checking bloodwork, which usually comes back normal, and then suggesting cognitive behavioral therapy or exercise, won’t cut it for Long COVID. While those treatments are helpful, we need to address the underlying issues like viral persistence, immunologic abnormalities, autoimmunity, and hypercoagulability. You can’t exercise or diet your way out of those.

Ganesh: If you asked me for my wish list for Long COVID patients, besides finding a cure and understanding the pathology, I would wish for better local care. It’s not fair that patients must go to a territory or quaternary care center just to get diagnosed, or try a treatment. When I send them home, it’s often difficult to maintain their care because many physicians won’t continue the treatments. I’ve heard doctors say, “I’ve never used this, it’s not FDA-approved, and I’m not going to use it off-label.” We need better uptake of treatments in primary care across the country.

Verduzco-Gutierrez: I still face resistance from some clinicians who don’t even believe Long COVID is a real disease. Just had a colleague today say one of the patients she saw was told “Long COVID is not real. You’re just depressed.”

Blitshteyn: Ultimately, we need more therapeutic tools because there won’t be a one-size-fits-all solution. Some patients will respond well to oral medications, others will need infusions, and some may need immunotherapy or antivirals. This is my wish list as well, more options, from over-the-counter remedies to heavy-duty immunotherapies, all FDA-approved and accessible to our patients.

Verduzco-Gutierrez: Exactly, and some patients may have more than one underlying pathophysiology. It’s like a ship with multiple anchors. You might remove one anchor, like autoimmunity, but they could still have others, hypercoagulability or mitochondrial dysfunction. We have to figure out what’s driving each patient’s symptoms and tailor treatments accordingly.

Blitshteyn: We need to study this population to understand the genotypes and phenotypes that predispose them to post-infectious syndromes. For example, we know that joint hypermobility is a predisposing factor. Hopefully, we’ll identify the genes responsible for these post-infectious syndromes that are so disabling.

Stay tuned for future episodes in the coming weeks.

Clarametyx Biosciences, Inc has announced the initiation of the Phase 2a trial for its antibody therapy, CMTX-101, following the successful completion of Phase 1b. This new stage will further evaluate CMTX-101 as an adjunct treatment for chronic pulmonary infections in patients with cystic fibrosis (CF).

At IDWeek, David Richards, CEO of Clarametyx Biosciences, highlighted the company’s commitment to tackling bacterial biofilms, which significantly contribute to antibiotic resistance. “Our technology platform is all about bacterial biofilms, which are a key component of bacterial defense that drive recalcitrance and resistance to antibiotic action. Our lead effort is CMTX-101, which is a therapeutic monoclonal antibody. This antibody targets the DNA b2 binding protein, which is a bacterial-only protein that has a critical intracellular function. But for our purposes, it binds an extracellular DNA lattice that stabilizes this bacterial biofilm, and the only thing our drug does is bind that protein, resulting in rapid collapse of the biofilm. This is important because it enables innate immune effectors and antibiotics to do their job better.”

Trial Details:

• Phase 2a Structure: The trial is structured as a double-blind, randomized, placebo-controlled study assessing the safety, tolerability, pharmacokinetics, and immunogenicity of CMTX-101 when used alongside standard antibiotic therapies. The study aims to enroll up to 41 adults diagnosed with CF, with results expected in 2025. Preliminary data from earlier phases indicated no safety concerns associated with the use of CMTX-101.

Richards further detailed the clinical progress, saying, “We’ve been steadily making progress in the clinic to prove out this novel technology and mechanism. With respect to CMTX-101, we first completed a Phase 1a in 20 healthy volunteers in 2023. Recently, in Q1 2024, we began a Phase 1b trial focused specifically on individuals with cystic fibrosis who are chronically infected with Pseudomonas aeruginosa. This study involved 41 subjects, and we just completed the Phase 1b portion, having dosed our first patient in the 2a trial just yesterday. This study is not only looking at safety but also early signals of efficacy regarding bacterial load and sputum. Additionally, we have recently completed our Phase 1b study in bacterial pneumonia, which combined safety assessments with our Phase 1a findings. The topline results showed not only safety but also encouraging trends in key inflammatory biomarkers, including IL-6, PCT, and CRP. While this was a small study, we are encouraged by the results.”

Looking forward, Richards elaborated on the broader implications of their therapeutic approach: “The beauty of this approach, to reiterate, is that it targets a highly conserved protein across bacterial species. With a single therapeutic like CMTX-101 or a vaccine with CMTX-301, we have the potential to cover a wide range of pathogens. Initially, with CMTX-101, we’re focusing on the chronic respiratory space. We believe we can intervene in bronchiectasis, which is common in cystic fibrosis and non-CF bronchiectasis, as well as in anti-M lung disease. By addressing chronic bronchial infections—an integral part of the vicious cycle that leads to lung function decline and increased mortality—we aim to improve outcomes and reduce therapy regimens in these patients. We see potential for this approach to extend to other bacterial infections, including prosthetic joint infections and skin diseases.”

In conclusion, Richards emphasized the transformative potential of their research, stating, “We think we have a truly novel category of therapy and vaccine that, if our preclinical data translates, could really change treatment paradigms in the clinic.” Clarametyx’s dedication to combating bacterial biofilms aligns with its strategic mission to address chronic infections. The company has also recently completed a study of CMTX-101 for community-acquired bacterial pneumonia, which yielded promising safety and efficacy data.

Reference

Clarametyx Biosciences Announces Progress on Study of Antibody Therapy CMTX-101 for Infections Associated With Cystic Fibrosis. BioSpace. October 17, 2024. Accessed October 24, 2024. https://www.biospace.com/news/clarametyx-biosciences-announces-progress-on-study-of-antibody-therapy-cmtx-101-for-infections-associated-with-cystic-fibrosis