Ravulizumab Showed Preclinical Promise for ALS. What Happened?

 Ravulizumab (Ultomiris), a terminal complement C5 inhibitor, did not improve functional status and survival in patients with amyotrophic lateral sclerosis (ALS), the phase III CHAMPION-ALS trial

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No significant difference between ravulizumab and placebo emerged in Combined Assessment of Function and Survival (CAFS) scores at week 50 (mean difference of 5.5 points, 95% CI -15.7 to 26.6 points, P=0.61), reported James Berry, MD, MPH, of Massachusetts General Hospital in Boston, and co-authors.

The trial was terminated for futility, the researchers said in JAMA Neurology

opens in a new tab or window. Safety profiles of ravulizumab and placebo were similar.

Ravulizumab is designed to inhibit complement activation by binding to the C5 terminal protein. "There was a clear rationale for testing ravulizumab as a treatment for ALS based on preclinical and clinical evidence suggesting that C5 may be involved in disease progression," Berry and colleagues wrote.

Elevated plasma levels of active fragments of C5opens in a new tab or window have been found in patients with ALS, they noted. Moreover, the expression of complement components, including C5, was dysregulated in regions surrounding motor neuron death in an ALS mouse modelopens in a new tab or window.

In CHAMPION-ALS, pharmacodynamic data confirmed target engagement, the researchers observed, and it's unclear why inhibiting C5 didn't lead to clinical benefit in humans.

Ravulizumab has successfully inhibited C5 in trials of several complement-mediated diseases and recently received FDA approval to treat adults with generalized myasthenia gravis. It has two other approved indications: paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome unrelated to E. coli infection. The drug labelopens in a new tab or window carries a warning for serious meningococcal infections.

CHAMPION-ALS randomized 382 people with ALS to receive ravulizumab (255 participants) or placebo (127 participants) from March 2020 to October 2021. Mean age in the ravulizumab group was 59, and 37% were women. Mean age in the placebo group was 58, and 46% were women.

Participants had a minimal pre-study ALS Functional Rating Scale-revised (ALSFRS-R) progression score of -0.3 points per month. ALSFRS-R scores range from 0 (no ability) to 48 (normal abilities).

All participants were vaccinated against Neisseria meningitidis within 3 years before the study or once treatment started. Participants could enter the trial while receiving ALS standard of care including riluzole (Rilutek) and edaravone (Radicava).

Participants received a loading dose of intravenous ravulizumab (2,400, 2,700, or 3,000 mg, based on body weight) or placebo at baseline, then maintenance doses of ravulizumab (3,000, 3,300, or 3,600 mg) or placebo on day 15 and every 8 weeks thereafter. Dose adjustments were made for participants whose weight dropped below 40 kg.

The primary outcome was the CAFS score, which was based on the change from baseline in ALSFRS-R total score on or before week 50 and time to death. A pre-planned interim futility analysis was conducted when 33% of participants had completed week 26; a conditional power of less than 10% would stop the study.

Mean change from baseline in ALSFRS-R at week 50 was -14.67 points for ravulizumab and -13.33 points for placebo (mean difference of -1.34 points, 95% CI -4.21 to 1.53 points). Secondary endpoints, including changes in serum neurofilament light concentrations, showed no differences between groups.

Incidence rates of treatment-emergent adverse events (TEAEs) were similar in the ravulizumab (80%) and placebo (85%) groups. Serious TEAEs occurred in 16.1% of the ravulizumab group and 18.9% of the placebo group. Headache, fall, and constipation were the most frequent TEAEs. Respiratory failure was the most frequent serious TEAE.

Patient advocacy groups improved the CHAMPION-ALS study design to allow participants to consider other treatment options quickly if the trial failed, Berry and colleagues pointed out.

This included the "decision to proceed directly to a properly powered phase III study with a robust interim futility analysis without first conducting a phase II study, participant selection criteria, and placebo group decline modeling," they wrote.

"The 50-week primary evaluation period ensured sufficient time to characterize effects on multiple functional and survival endpoints," they added. "This time frame allowed for a rigorous assessment of ALSFRS-R and supported survival analysis, which may take longer to demonstrate than the ALSFRS-R."

CHAMPION-ALS was conducted during the COVID-19 pandemic, which may have influenced the findings, the researchers said. The study was limited to people with a minimal pre-study ALSFRS-R progression score of -0.3 points per month; how patients with other rates of disease progression would have responded is unknown.

Disclosures

The CHAMPION-ALS study was funded by Alexion, AstraZeneca Rare Disease.

Researchers reported relationships with Alexion, Amylyx, Rapa Therapeutics, Mitsubishi Tanabe Pharma America, and the Hospital for Special Care.

Primary Source

JAMA Neurology

Source Reference: opens in a new tab or windowGenge A, et al "Efficacy and safety of ravulizumab, a complement C5 inhibitor, in adults with amyotrophic lateral sclerosis: a randomized clinical trial" JAMA Neurol 2023; DOI: 10.1001/jamaneurol.2023.2851.

https://www.medpagetoday.com/neurology/generalneurology/106283

Novel System Gets FDA Approval for Severe Peripheral Arterial Disease

 The FDA approved the LimFlow system designed to stave off amputation for people with chronic limb-threatening ischemia (CLTI) and no treatment alternatives, device maker LimFlow SA announced

opens in a new tab or window Tuesday.

This puts the first device for transcatheter arterialization of the deep veins, also known as percutaneous deep vein arterialization, on the market for CLTI patients deemed not suitable for other endovascular or surgical revascularization options who are at risk of major amputation.

LimFlow was approved under the FDA's 510(k) pathway based on the PROMISE II study

opens in a new tab or window that showed the LimFlow procedure was safe and led to limb salvage and wound healing. With the operation successful in all but one of 105 trial participants, the device was associated with a 66.1% rate of amputation-free survival at 6 months. An estimated 76% of patients avoided above-ankle amputation.

In PROMISE II, the subgroup of people with dialysis had worse outcomes, however: they had a 36.8% amputation-free survival rate at 6 months and 36.2% died.

"With LimFlow, we now have an option for the sickest patients who were previously consigned to limb loss and the downward spiral that accompanies it," study investigator Daniel Clair, MD, of Vanderbilt University Medical Center in Nashville, Tennessee, said in the company's press release.

"Using this new treatment, we have seen many patients whose limbs have been saved, whose pain has been reduced or resolved, whose chronic wounds are healed or healing, and who can now look forward to happier and more active lives," Clair added.

The LimFlow is a minimally invasive device that restores perfusion to the ischemic foot using ultrasound-guided catheters and covered nitinol stents. The system works by turning a vein into an artery that can send oxygenated blood to ischemic tissues.

This strategy bypasses a limitation of conventional revascularization for critical limb ischemia, which is that it requires a landing point -- an unobstructed vessel in the lower leg or foot -- that may be unavailable in people with distal arterial disease.

CLTI is the most severe form of peripheral arterial disease (PAD) often accompanying diabetes, coronary artery disease, obesity, or high blood pressure. PAD is caused by atherosclerosis and becomes more prevalent with older ageopens in a new tab or window.

https://www.medpagetoday.com/cardiology/peripheralarterydisease/106294

DEA Gets an Earful About Telehealth Prescribing of Controlled Substances

Should the Drug Enforcement Administration (DEA) require a prior in-person visit before allowing clinicians to prescribe controlled substances via telemedicine? That was one of the issues that DEA officials heard conflicting testimony on during a "listening session"opens in a new tab or window Tuesday.

"Arbitrary one-time in-person evaluation requirements do not prevent abuse and diversion," said Helen Hughes, MD, medical director of the Office of Telemedicine at Johns Hopkins Medicine, in Baltimore. "Telemedicine controlled substance prescribing happens in a variety of settings across Johns Hopkins Medicine, often without a previous in-person encounter," such as pediatric patients being prescribed attention deficit-hyperactivity disorder (ADHD) medications and elderly patients who are receiving palliative care.

"The ability for these providers to prescribe controlled substances and use their medical judgment for telemedicine without a prior in-person visit allows patients to receive clinically appropriate, essential care via a convenient and patient-centered modality, and we strongly believe the in-person medical requirement should be removed in its entirety," she said. "While the proposed rule would prevent or limit prescribing in the above scenarios, it does nothing to prevent a provider who saw a patient one time in person -- even 10 years ago -- from recklessly prescribing controlled substances via either telemedicine or in-person care."

Two-Day Session

Dan Reck, CEO of MATClinics, an opioid use disorder treatment company that uses mainly buprenorphine products, disagreed. "Without proper oversight of patients prescribed controlled substances, including regular in-person visits combined with definitive toxicology testing, there is no reason to believe that some telemedicine-only providers won't become buprenorphine mills, just as painkiller mills once flourished," he said. "We are concerned that the consequences of unregulated buprenorphine will contribute further to the already deadly opioid epidemic."

The listening session -- which will last for 2 days -- came about because of the large volume of comments the agency received on two proposed regulations, DEA administrator Anne Milgram, JD, said at the start of the proceedings. "This past March, in concert with the Department of Health and Human Services, DEA issued two sets of proposed telemedicine regulations

opens in a new tab or window," she explained. "Those regulations would have allowed for telemedicine prescribing of certain controlled substances subject to safeguards, and would have imposed an initial limit on telemedicine prescriptions to a 30-day supply. To prescribe more ... the prescribing practitioner generally would have been required to evaluate the patient in person."

"We received over 38,000 public comments in response to those proposed regulations, and we read every single one," she continued. "We believe that it is among the highest number of comments we have gotten in the DEA's history. A significant majority of those comments expressed concerns that the proposed regulations place limitations on the supply of controlled substances that could be prescribed prior to an in-person evaluation. After evaluating these comments, DEA wanted to reopen this conversation about telemedicine prescribing and to allow for a public listening session."

Psychiatrists' Concerns

Psychiatry groups were among those concerned about the proposed 30-day prescribing limit. "The 30-day initiation period would not be adequate given the current wait times" for psychiatric care in many places, said Shabana Khan, MD, a psychiatrist who spoke on behalf of both the American Psychiatric Association and the American Academy of Child and Adolescent Psychiatrists. She noted that 55% of counties in the U.S. have no psychiatrists and 70% of counties have no child psychiatrists.

The psychiatry groups also oppose a DEA proposal to require telemedicine prescribers to note on the prescription that it was accessed via telemedicine. "[Designating] prescriptions as telemedicine increases pharmacist hesitancy to fill the medications without good reason," Khan said. "We are already finding this in our practice. So adding that telemedicine indication on there could potentially make it even more difficult for our patients to access care."

Sterling Ransone, MD, past president and current board chair of the American Academy of Family Physicians, said that while telemedicine has worked very well at his practice when it comes to treating established patients, the academy had concerns about the way in which use of telemedicine-only companies can lead to fragmentation of care. "I practice in a rural area with my wife, who's a pediatrician, and we frequently will have patients come in to see us for follow-up" after a visit with a telehealth-only provider; the patients have no record of the other provider's diagnosis or treatment plan, he said.

"We'll see these folks coming in on antibiotics or other substances which we personally wouldn't have used because we know these patients ... plus we know the bacteria that are in our area," Ransone continued. "I ask, 'What did they do?' 'Well, they put me on a white pill.' 'Do you have it with you?' Usually they don't bring it, and then I'm scrambling trying to figure out what medication they were placed on, so that I don't do harm by prescribing a medication that might interact with the drug that they've been given ... So that fragmentation of care -- the fragmentation of care has been quite concerning for us."

Exceptions Proposed

Other speakers argued for exceptions to the proposed rules. David Hoffman, JD, assistant professor of bioethics at Columbia University in New York City, urged the DEA to treat terminally ill patients differently than other patients when it comes to prescribing controlled substances to treat pain

"If all the DEA had to be concerned about was elimination of opportunities for drug diversion, then the proposed ban on telemedicine for first-prescribing of narcotics might make some sense," he said. "But the interests of patients in need of relief from pain and suffering, particularly those patients with terminal illnesses -- and therefore limited ability to travel to doctor's appointments -- must be considered a strong balancing consideration."

Robert Krayn, CEO of Talkiatry, a telemedicine provider specializing in psychiatry, suggested that hospitals and nonprofit healthcare entities be exempt from some of the data reporting requirements in the proposed rule.

"They have limited resources on the nonprofit side, and when you look at the potential for diversion, it really stems from people who are gaining a profit from making the prescriptions and with a lot of not-for-profits, that is just simply not the case," he said. "The data reporting requirements are cumbersome, and for certain doctors who work at multiple, not-for-profit organizations treating many patients, those records are scattered everywhere; they do not have the money, the resources, or the technology know-how to make this an easily reportable component."

https://www.medpagetoday.com/publichealthpolicy/healthpolicy/106305

Nuvectis Starts NXP900 Phase 1a Clinical Trial

 Nuvectis Pharma, Inc. (NASDAQ: NVCT) ("Nuvectis" or the "Company"), a clinical-stage biopharmaceutical company focused on the development of innovative precision medicines for the treatment of serious conditions of unmet medical need in oncology, today announced the initiation of a Phase 1a dose escalation clinical trial of NXP900, its novel inhibitor of the SRC/YES1 kinase family (“SFK”). The study is designed to evaluate the safety, tolerability and pharmacokinetic properties of NXP900 in patients with advanced solid tumors.

SFKs are aberrantly activated in various cancer types and they are central mediators of various oncogenic processes such as proliferation, survival, cell adhesion, invasion, and angiogenesis. NXP900 is a potent and highly selective SFK inhibitor, including low nanomolar IC₅₀ against YES1 and SRC (0.5nM and 2.4nM, respectively) that demonstrated robust single agent anti-cancer activity against several solid tumor types in preclinical models.

https://www.biospace.com/article/releases/nuvectis-pharma-announces-initiation-of-the-nxp900-phase-1a-clinical-trial/

AbbVie SKYRIZI Met All Primary, Secondary Endpoints V. Stelara in Head-to-Head Study in Crohn's

 

• SEQUENCE, a Phase 3 head-to-head study (study drug open-label and efficacy assessment blinded) compared risankizumab to ustekinumab for the treatment of adult patients with moderately to severely active Crohn's disease who have failed one or more anti-TNFs¹
• Risankizumab met both primary endpoints of non-inferiority for clinical remission (Crohn's Disease Activity Index [CDAI]) at week 24 and superiority of endoscopic remission at week 48 versus ustekinumab
• All secondary endpoints achieved statistical significance for superiority versus ustekinumab
• Safety results were consistent with the overall safety profile of risankizumab, with no new safety risks identified

https://www.biospace.com/article/releases/abbvie-s-skyrizi-risankizumab-met-all-primary-and-secondary-endpoints-versus-stelara-ustekinumab-in-head-to-head-study-in-crohn-s-disease/

Procept: FDA Investigational Device Exemption for Aquablation® Therapy for Prostate Cancer

 PROCEPT BioRobotics Corporation (NASDAQ: PRCT) (“PROCEPT BioRobotics”), a global leader in surgical robotics, announced today the Investigational Device Exemption (IDE) approval from the U.S. Food and Drug Administration (FDA) to investigate the safety and efficacy of Aquablation therapy for prostate cancer.

The IDE approval allows PROCEPT BioRobotics to initiate a single-arm feasibility study in the United States. The data generated from this IDE study will support future research and regulatory applications in the United States. The study will enroll patients with localized prostate cancer at three prestigious cancer centers, Keck Medical Center of USC, Perlmutter Cancer Center at NYU Langone Health, and Mount Sinai Tisch Cancer Center.

https://finance.yahoo.com/news/procept-biorobotics-receives-u-fda-120000969.html

FDA warns CVS, Walgreens about marketing of unapproved eye products

 The U.S. Food and Drug Administration this week warned CVS Health Corp. (CVS), Walgreens Boots Alliance Inc. (WBA) and several smaller consumer products companies about marketing unapproved eye products. "The FDA is particularly concerned that these illegally marketed, unapproved ophthalmic drug products pose a heightened risk of harm to users because drugs applied to the eyes bypass some of the body's natural defenses," the FDA said in a release Tuesday. In a letter to Walgreens dated Monday, the agency said several eye-drop products offered on the company's website, including drops for allergies and pink eye, are unapproved new drugs whose delivery through interstate commerce may violate federal law. The FDA's letter to CVS contained similar warnings about "CVS Health Pink Eye Relief Drops" offered through the CVS website. Both letters also raised concerns about the manufacturing practices of contract manufacturers producing the products. The FDA asked the companies to notify the agency of steps taken to correct the violations within 15 working days. CVS said in a statement that on receipt of the FDA letter it stopped the sale of the CVS Health brand pink-eye relief drops at stores and online, and customers who purchased the product can return it for a full refund. "We're committed to ensuring the products we offer are safe, work as intended and satisfy customers," CVS said. Walgreens also said late Tuesday that it would pull the products in question "out of an abundance of caution," and customers who purchased the products can return them for a full refund. CVS shares gained 2.6% Tuesday, while Walgreens stock was up 1.4%.

https://www.morningstar.com/news/marketwatch/20230912891/fda-warns-cvs-walgreens-about-marketing-of-unapproved-eye-products