Semaglutide Shines as Weight Loss Therapy

 In conjunction with lifestyle management, once-weekly semaglutide helped people with obesity lose a significant amount of weight, the Semaglutide Treatment Effect in People with Obesity (STEP) 1 study found.

In a double-blind trial of 1,961 adults with a body mass index (BMI) of 30 or higher, adults on 2.4 mg of weekly semaglutide lost an average 14.9% of baseline body weight after 68 weeks of treatment versus only 2.4% for a group on placebo and lifestyle intervention alone (treatment difference -12.4%, 95% CI -13.4 to -11.5, P<0.001), reported Robert Kushner, MD, of Northwestern University Feinberg School of Medicine in Chicago, and colleagues.

A total of 86.4% of adults on semaglutide were able to cut at least 5% of their baseline body weight during the trial compared with only 31.5% of those adhering to lifestyle intervention alone, the researchers wrote in the study online in the New England Journal of Medicine.

Beyond that, almost 70% of those on semaglutide plus lifestyle intervention achieved a 10% or more weight loss, and more than half were able to lose 15% of their baseline body weight.

In total, adults on semaglutide treatment lost an average 33.7 lb (15.3 kg) by week 68, while those in the placebo/lifestyle intervention group saw only a modest 5.7 lb (2.6 kg) weight loss (estimated treatment difference -30 lb [-12.7 kg], 95% CI -13.7 to -11.7).

Within only the first 4 weeks of treatment initiation, those on semaglutide had more than a 2% reduction in body weight, and continued to lose weight throughout the 68-week trial.

In addition to weight loss, semaglutide also improved cardiovascular risk factors including greater reductions in waist circumference, BMI, systolic and diastolic blood pressures, HbA1c, fasting plasma glucose, C-reactive protein, and fasting lipid levels, as well as physical functioning scores and quality of life.

"I was surprised and gratified to see the unprecedented results from the medication," Kushner told MedPage Today. "The fact that 50% of participants were able to lose at least 15% of initial body weight and one-third lost at least 20% body weight is a game changer."

"Semaglutide is by far the most effective drug intervention we have seen for weight management," he continued. "We know that a lot of the health concerns we see in people who struggle with their weight, such as type 2 diabetes, hypertension, GERD [gastroesophageal reflux disease], and arthritis of the weight-bearing joints, are improved by losing at least 10% of their body weight. In this study, nearly 70% of participants were able to achieve this 10% weight loss threshold by taking semaglutide."

As for the next steps, Kushner said it's all about putting this into practice: "We now need to explore how to encourage and educate healthcare providers to provide obesity care in the primary care setting."

The STEP 1 trial included 1,961 adults with a BMI of 30 or greater, or those with a BMI of 27 or greater with at least one weight-related comorbidity, randomized in a 2:1 fashion. All participants were free of diabetes at baseline -- although 40% had prediabetes -- and about 75% of the cohort were female and white.

Those who received semaglutide were started on a dose of 0.25 mg once weekly for the initial 4 weeks, which was subsequently titrated up every 4 weeks until the maintenance dose of 2.4 mg was achieved by week 16.

Both study groups received individual diet-related counseling sessions every 4 weeks aimed at encouraging a 500-kcal deficit per day paired with a goal of 150 minutes of physical activity per week.

Adverse events were similar to what has already been demonstrated with semaglutide, with gastrointestinal side effects being the most common, the team said.

Overall, about 74% of those on semaglutide reported at least one gastrointestinal side effect -- mostly nausea, diarrhea, vomiting, or constipation -- versus 48% of those on placebo. About 4.5% of those on semaglutide ended up discontinuing treatment due to gastrointestinal events vs 0.8% of those on placebo.

In December 2017, the GLP-1 receptor agonist was first approved in a 0.5 mg and 1 mg injectable dosing sold under the trade name Ozempic, which is indicated for type 2 diabetes and risk reduction of major cardiovascular events including heart attack, stroke, and death in adults with type 2 diabetes with known heart disease. And in September 2019, an oral form of semaglutide was approved in 7 and 14 mg tablets, sold under the trade name Rybelsus, likewise indicated for type 2 diabetes.

Novo Nordisk's other GLP-1 receptor agonist agent, liraglutide -- sold under the trade name Victoza (1.2 or 1.8 mg/day) for type 2 diabetes in 2010 -- was also approved under the name Saxenda (3 mg/day) for chronic weight management in adults with a BMI of 30 or over, or with a BMI of 27 or more and at least one weight-related medical condition in 2014.

Despite the positive results, the authors of an accompanying editorial, NEJM editors Julie Ingelfinger, MD, and Clifford Rosen, MD, called the gastrointestinal side effects concerning and noted that oral semaglutide has been associated with pancreatitis and with thyroid C-cell tumors in rodents.

"In the real world, it seems unlikely that once-weekly subcutaneous administration would be a palatable or cost-effective solution in the long run," Ingelfinger and Rosen wrote; instead, daily oral semaglutide might be a more "appealing" option to patients. They suggested that future head-to-head trials compare oral GLP-1 agonists with SGLT-2 antagonists, and also compare these pharmacologic therapies with bariatric surgery to assess long-term outcomes.

Kushner noted that the 5-year Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity (SELECT) trial is currently underway, and that additional trials will explore other important questions related to semaglutide in patients with obesity.

Based on the results of the phase III STEP program, Novo Nordisk is now seeking U.S. marketing approval for 2.4 mg semaglutide for chronic weight management.

Disclosures

The trial was funded by Novo Nordisk.

Kushner reported a relationship with Novo Nordisk; co-authors also reported several disclosures.

Primary Source

New England Journal of Medicine

Source Reference: Wilding J, et al "Once-weekly semaglutide in adults with overweight or obesity" N Engl J Med 2021; DOI: 10.1056/NEJMoa2032183.

Secondary Source

New England Journal of Medicine

Source Reference: Ingelfinger J, Rosen C "STEP 1 for effective weight control -- another first step?" N Engl J Med 2021; DOI: 10.1056/NEJMe2101705.

https://www.medpagetoday.com/primarycare/obesity/91146

Sensei Biotherapeutics Closes IPO

 Sensei Biotherapeutics, Inc., a clinical-stage immunotherapy company focused on the discovery and development of next generation therapeutics for cancer, today announced the closing of its initial public offering of 7,000,052 shares of its common stock on February 8, 2021, as well as the issuance of an additional 1,030,243 shares pursuant to the exercise by the underwriters of their option to purchase additional shares on February 10, 2021, at a public offering price of $19.00 per share. The gross proceeds to Sensei from the two closings, before deducting underwriting discounts and commissions and other offering expenses payable by Sensei, were approximately $152.6 million. All of the shares in the offering were offered by Sensei. Sensei’s common stock is listed on the Nasdaq Global Market under the ticker symbol “SNSE.”

Citigroup, Piper Sandler & Co. and Berenberg acted as joint book-running managers for the offering. Oppenheimer & Co. acted as the lead manager for the proposed offering.

https://www.biospace.com/article/releases/sensei-biotherapeutics-announces-closing-of-initial-public-offering/

Terns Pharma Closes IPO, Full Underwriters’ Option Exercised

 Terns Pharmaceuticals, Inc. (“Terns” or the “Company”) (Nasdaq: TERN), a clinical-stage biopharmaceutical company developing a portfolio of small-molecule single-agent and combination therapy candidates for the treatment of non-alcoholic steatohepatitis, or NASH, and other chronic liver diseases, today announced the closing of the Company’s initial public offering of 7,500,000 shares of common stock at a public offering price of $17.00 per share, along with   the exercise in full by the underwriters of their option to purchase an additional 1,125,000 shares of common stock. The exercise of the underwriters’ option to purchase additional shares is expected to close on February 12, 2021, subject to customary closing conditions. After giving effect to the full exercise by the underwriters of their option to purchase additional shares, aggregate gross proceeds to the Company are expected to be approximately $146.6 million, before underwriting discounts, commissions and estimated offering expenses. All of the shares in the offering were offered by Terns. Terns’ common stock is listed on the Nasdaq Global Select Market under the ticker symbol “TERN.”

J.P. Morgan, Goldman Sachs & Co. LLC and Cowen are acting as joint book-running managers for the offering.

https://www.biospace.com/article/releases/terns-pharmaceuticals-inc-announces-closing-of-initial-public-offering-and-exercise-in-full-of-underwriters-option-to-purchase-additional-shares/

FDA Gives Nod to Sanofi-Regeneron Advanced Basal Cell Carcinoma Treatment

 The U.S. Food and Drug Administration (FDA) has approved Regeneron and Sanofi’s PD-1 inhibitor Libtayo® (cemiplimab-rwlc), a fully-human monoclonal antibody, for the treatment of patients with advanced basal cell carcinoma (BCC) with a history of treatment with a hedgehog pathway inhibitor (HHI) or in patients with advanced BCC who are considered ineligible for an HHI.

Overall, the FDA granted full approval for patients with locally advanced BCC, while accelerated approval was granted for patients with metastatic BCC. Libtayo targets the immune checkpoint receptor PD-1 on T-cells and has been demonstrated to block cancer cells from utilizing the PD-1 pathway to suppress activation of T cells.

"Today's FDA approval of Libtayo will change the treatment paradigm for patients with advanced basal cell carcinoma," according to a statement made by Karl Lewis, M.D., Professor in the Division of Medical Oncology at the University of Colorado and a study researcher. "Advanced basal cell carcinoma is a persistent, painful and highly disfiguring cancer. While the primary systemic treatment options are hedgehog inhibitors, many patients will eventually progress on or become intolerant to this therapy. With Libtayo, these patients now have a new immunotherapy option that has demonstrated clinically meaningful and durable anti-tumor responses."

In May, Sanofi and Regeneron announced topline data from a Phase II trial showing Libtayo featured clinically meaningful and durable responses in patients with advanced BCC who have either progressed on or could not tolerate HHI.

Compared with other investigational agents, Libtayo represents the first therapy to demonstrate a clinical benefit in patients with advanced BCC following HHI therapy in a pivotal clinical trial.

Full approval of Libtayo in locally advanced BCC was based on a primary analysis of a clinical trial, while the accelerated approval of the drug in metastatic BCC was based on an interim analysis of another trial. Additional data from another trial that verify the therapy’s clinical benefit may contribute to future approval of the drug in metastatic BCC.

"With today's approval, Libtayo is now approved for both advanced cutaneous squamous cell and basal cell carcinomas, building a strong foundation in dermato-oncology," said Regeneron’s Israel Lowy, M.D., Ph.D., Senior Vice President, Translational and Clinical Sciences, Oncology, in a statement. "Beyond skin cancers, we also continue to investigate the potential of Libtayo in other difficult-to-treat cancers, starting with non-small cell lung cancer where an FDA decision is expected by the end of February."

The new approval is the second approval in line for Libtayo and was predominantly based on FDA Priority Review. This review process is used for treatments that would meet significant needs, if approved, in treating serious conditions safely and effectively. Libtayo was first approved in 2018 for the systemic treatment of adults with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC ineligible for curative radiation or curative surgery.

While Libtayo has been shown to be effective for the approved indications, research has suggested the treatment is associated with immune-mediated adverse reactions, which could be severe or fatal, in any organ system or tissue.

Sanofi’s Global Development Head, Oncology and Pediatric Innovation Peter Adamson said Sanofi and Regeneron plan to further develop Libtayo in other clinical trials and settings, such as a monotherapy and in combination with other therapeutic regimens.

https://www.biospace.com/article/fda-gives-thumbs-up-to-meaningful-sanofi-regeneron-treatment-for-advanced-bcc-/

FDA Adcom Gives Merck’s Keytruda a Surprise Thumbs Down

 Merck’s checkpoint inhibitor Keytruda (pembrolizumab) is the dominant player in the immuno-oncology space. In the third quarter of 2020 alone, Keytruda had sales of $3.7 billion, an increase of 21% from the same period the previous year.

But the U.S. Food and Drug Administration’s (FDA) Oncologic Drugs Advisory Committee (ODAC) voted against recommending the drug as neoadjuvant treatment for high-risk, early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy after surgery, at least for now.

It has been approved by the FDA to treat certain forms of bladder cancer, classical Hodgkin’s lymphoma, colorectal cancer, esophageal cancer, kidney cancer, liver cancer, melanoma skin cancer, non-small cell lung cancer, small cell lung cancer and squamous cell head and neck cancer. Keytruda is approved to also treat forms of cervical cancer, Merkel cell cancer, primary mediastinal large B-cell lymphoma, gastric cancer, certain metastatic or unresectable solid tumors, triple-negative breast cancer and endometrial cancer, in addition to pediatric colorectal cancer and other pediatric cancers.

The FDA adcom indicated that the company’s most recent interim analysis of KEYNOTE-522 had not met the pre-specified threshold for statistical significance and “remained immature with 53% of targeted EFS (event-free survival) events having occurred. As a result, the OS (overall survival) endpoint could not be formally tested and is also immature with 32% of the targeted OS events having occurred.”

All 10 panelists supported the FDA’s evaluation that Merck should wait for more definitive data from KEYNOTE-522. Richard Pazdur, the FDA’s cancer head, made a rare public announcement, admonishing Merck for submitting the drug ahead of the data.

Patient representative Natalie Portis agreed, saying, “I’m a little baffled by why the rush here.”

In general, the advisory committee members supported the need for more evidence of survival benefit instead of Merck’s projections. There were high levels of toxicity observed, while Keytruda offered questionable benefit.

It was a bit of an unusual meeting for ODAC. The adcom—as most FDA advisory committees do—typically makes an up or down vote on a drug. In this case, they asked if Merck needed to wait for more mature data. It has caused analysts to wonder why Merck is pressing ahead prematurely on this even though the FDA had been clear they were rushing things.

Deborah Armstrong, one of the committee members, of Johns Hopkins Medicine, said, “I hope that this is a positive study, but at this point in time, it’s premature to start treating patients with this therapy.”

Some have questioned whether it has something to do with the retirement of the company’s chief scientific officer Roger Perlmutter and the recent announcement that chief executive officer Ken Frazier was retiring in the next few months.

In response, the company stated, “Merck filed the application in May 2020, well before Dr. Perlmutter’s recent retirement. We submitted this application because of the significant unmet need for this patient population and because we and other experts in the field firmly believe in the strength of the data. We appreciate the perspective of the FDA advisory committee and will continue to work with the FDA to bring forward additional data to address this grievous disease with a high degree of unmet need.”

To date, no checkpoint inhibitor has been approved for a breast cancer indication outside the metastatic setting. Genentech’s Tecentriq (atezolizumab) has been approved for metastatic TNBC based on data from the IMPassion130 trial, and Keytruda received accelerated approval for the same indication.

In the KEYNOTE 522 trial to date, 1,174 untreated, high-risk, early-stage TNBC patients were randomized 2:1 to receive neoadjuvant therapy with carboplatin-paclitaxel chemotherapy plus Keytruda or a placebo, followed by Keytruda or placebo as adjuvant therapy. The co-primary endpoints are pathologic complete response (pCR) rate and EFS.

Data for pCR were unblinded after an interim analysis demonstrated a statistically significant absolute difference of 13.6% in favor of Keytruda. The company is still following up on EFS and OS, but meanwhile, the difference in pCR has dropped to 7.5%.

Philip Hoffman, chair of ODAC and of the University of Chicago, stated, “I think that many, if not most, of us believe that this trial may well turn out to be positive, as time goes on with further analyses and as we see what the effect of the pathologic CR rate does in fact lead to. But I think there certainly is consensus among the committee that hasn’t yet been demonstrated sufficiently to warrant going ahead with full FDA approval right now.”

https://www.biospace.com/article/fda-adcom-gives-merck-s-checkpoint-inhibitor-keytruda-a-surprise-thumbs-down/

Pfizer could directly deliver COVID-19 shot to S.Africa vaccination points

 Pfizer said it could deliver its COVID-19 vaccine, which requires ultra-cold temperatures for storage and distribution, directly to points of vaccination in South Africa.

South Africa is scrambling to secure supplies after the AstraZeneca vaccine it planned to use to kick off its immunisation campaign had greatly reduced efficacy against the COVID-19 virus variant now dominant in the country.

Pfizer said it had allocated vaccine doses to South Africa and was currently in discussions with the government.

“We are enabling direct shipment to the point of vaccination in a thermal shipper that will maintain the ultra-low temperature required for up to 10 days unopened,” Pfizer told Reuters in an e-mailed response to questions late on Tuesday.

Pfizer’s COVID-19 vaccine needs to be stored and distributed at around -70 degrees Celsius, requiring countries importing it to have ultra-cold chain capabilities.

That is a potential impediment for countries including those in Africa with weak public health systems.

“We have experience in distributing, storing and administering the vaccine in our Phase 3 trial sites around the world (including South Africa) so we already know that the processes we are using work, and patients are able to be dosed at the points of vaccination,” Pfizer said.

South Africa says it has secured 20 million doses from Pfizer, with deliveries starting in the second quarter. It also expects to receive 117,000 Pfizer shots in the first quarter from the COVAX facility co-led by the World Health Organization.

“The supply that will be sent to South Africa and to COVAX is manufactured at our site in Puurs, Belgium,” Pfizer said.

https://www.reuters.com/article/us-health-coronavirus-safrica-pfizer/pfizer-could-directly-deliver-covid-19-shot-to-south-africa-vaccination-points-idUSKBN2AA132

New York will reopen stadiums with limited capacity

 New York state will allow large stadiums and arenas, such as Citi Field and Madison Square Garden, to reopen for sports and concerts later this month, with sharply limited capacity and other measures to prevent the spread of COVID-19.

Any stadium that can fit more than 10,000 people can stage events beginning on Feb. 23 at 10% capacity so long as the state’s Department of Health signs off on its safety plans, Governor Andrew Cuomo said on Wednesday.

Brooklyn’s Barclays Center has already won approval for a basketball game between the Brooklyn Nets and the Sacramento Kings on that day, Cuomo said.

Some venues, including Yankee Stadium in the Bronx, have already been redeployed as mass vaccination sites. State officials said they would discuss with venue managers how to continue vaccination efforts once sports and concerts return.

The venues must enforce all COVID-19 prevention measures, such as the mandatory wearing of face masks and social distancing, Cuomo said. Attendees must show evidence that they had tested negative for the novel coronavirus within 72 hours prior to the event’s start.

In January, Cuomo allowed a limited number of spectators at a Buffalo Bills NFL playoff game, the team’s first in 24 years.

It was the first time spectators were at a professional sporting event in New York state since the coronavirus brought sports to a halt in mid-March.

About 6,700 fans attended the game at the 72,000-seat Bills Stadium in Orchard Park, a suburb of Buffalo in western New York.

https://www.reuters.com/article/us-health-coronavirus-new-york/new-york-will-reopen-stadiums-with-limited-capacity-idUSKBN2AA2ML