Lilly brushes off liver tox concerns after Pfizer drops an obesity candidate

Pfizer’s decision to drop an obesity candidate on liver toxicity concerns in June raised a red flag for the analyst community. Could Eli Lilly’s thriving obesity portfolio have similar issues?

Pfizer let go of lotiglipron because of phase 1 and 2 data that showed elevated transaminases, a type of enzyme that can be an indicator of liver dysfunction. The New York-based Big Pharma had been hoping to raise up lotiglipron over more advanced candidate danuglipron because it allowed for once a day dosing—which could have been a bigger threat to Lilly and Novo Nordisk’s offerings. But the safety data took lotiglipron out of the running, leaving the twice-daily danuglipron, which requires a higher dose, as Pfizer’s lead horse heading toward the competitive obesity market.

Lilly, meanwhile, has posted weight loss results for orforglipron showing an astounding 14.7% weight loss at 36 weeks in a phase 2 study published in the New England Journal of Medicine in June. In a second quarter earnings call Tuesday, Lilly Chief Scientific and Medical Officer Dan Skovronsky, M.D., Ph.D., acknowledged a few cases of liver toxicity in the studies for orforglipron. The company had previously said that safety was comparable to other incretin-based therapies.

“There's been more attention on liver safety for orforglipron following the competitor announcement from Pfizer on one of their two oral GLP-1s, so we don't see any read through from that. But of course, we've looked very carefully at liver safety,” Skovronsky said.

Pointing to the data from the journal publication, Skovronsky, who also serves as president of Lilly Research Laboratories, said that there was actually an improvement in liver enzymes when looking at group average data.

“That's not surprising,” he said. “We know that this disease, obesity, is characterized in many patients by excess liver fat, which can cause inflammation and liver abnormalities and when you reverse that, you see an improvement in liver function.”

One of the big questions with the obesity drugs taking the clinic and market by storm is whether patients have to stay on them long term. Skovronsky said that if a patient were to come off orforglipron or any obesity treatment, they could see liver fat and therefore liver enzymes go up again.

Lilly did see a few instances of liver enzyme elevations across the phase 2 trial, but some were in the placebo group. One patient had higher elevations that returned to normal while taking orforglipron.

“That's generally not a pattern that we see in drugs that cause liver injury,” Skovronsky said.

Lilly is advancing orforglipron to phase 3 in obesity and diabetes. Another candidate, retatrutide, also slid into the queue for late-phase testing in the second quarter.

“In phase 3 we'll keep an eye open for all possible safety consequences. I think I've frequently cautioned investors on all of our molecules that phase 3 is really the place where you can get surprised by any new safety findings,” Skovronsky said. “So we'll be watching liver safety closely, but not with any particularly heightened concern versus other adverse events.”

He continued: “And we'll also be watching carefully—this is a new molecule. This is the first time that we're exposing large, large numbers of patients to it for many years, or many, many months, I should say, and we will be monitoring safety carefully.”

https://www.fiercebiotech.com/biotech/lilly-brushes-liver-tox-concerns-after-pfizer-drops-obesity-candidate

Nurse-Delivered Sleep Restriction Therapy Reduced Insomnia Symptoms

 Sleep restriction therapy -- systematically restricting and regularizing time in bed to stabilize sleep -- conducted by a nurse in a primary care setting reduced insomnia symptoms compared with sleep hygiene alone, according to the randomized HABIT trial.

At 6 months, the mean score on the Insomnia Severity Index (ISI) was 10.9 among participants who received nurse-delivered sleep restriction therapy versus 13.9 for those who received a sleep hygiene booklet only (P<0.0001), reported Simon Kyle, PhD, of the Sleep and Circadian Neuroscience Institute at the University of Oxford in England, and co-authors in The Lancetopens in a new tab or window.

Mean adjusted differences in ISI -- which ranges from 0 to 28, with higher scores indicating more severe symptoms -- also significantly favored the intervention at both 3 and 12 months as well:

• 3 months: -3.88 (95% CI -4.66 to -3.10, P<0.0001)
• 12 months: -2.96 (95% CI -3.75 to -2.16, P<0.0001)

In addition, the incremental cost per quality-adjusted life-year (QALY) gained was £2,076 ($2638) with sleep restriction therapy, suggesting that the treatment had a 95.3% probability of being cost-effective based on a £20,000 ($25,412) cost-effectiveness threshold, Kyle and team said.

"Insomnia is a serious condition because it's highly prevalent, has a major effect on quality of life, and increases risk for developing other physical and mental health problems," Kyle said in a statementopens in a new tab or window. "The key issue is that people with chronic insomnia rarely receive evidence-based treatment."

Guidelines suggest that first-line treatment for insomnia should be multi-component cognitive behavioral therapy, "but access is extremely limited worldwide because of inadequate resources and expertise," the authors noted, with patients instead often prescribed hypnotic medication or off-label sedative antidepressants.

Sleep restriction therapy is a principal component of cognitive behavioral therapy, which "counters behaviors that perpetuate insomnia, specifically time-in-bed extension, variability in sleep-wake timing, and daytime napping," Kyle and team explained.

This brief nurse-delivered therapy can be both effective in treating insomnia disorder and improving certain aspects of mental health and functioning for these patients, they pointed out, adding that their study results could have implications for clinical practice in primary care settings because it is cost-effective without major increases in demands on nursing time.

"Future research is needed to understand how the nurse-delivered program could be implemented in the NHS, for example as part of a stepped care approach to insomnia management, and whether this may lead to reduction in prescriptions for sleep medication," Kyle said.

In an accompanying commentaryopens in a new tab or window, Annemieke van Straten, PhD, of Vrije Universiteit Amsterdam in the Netherlands, and co-authors, agreed that this approach could become an important therapy option for patients with insomnia.

"The study by Kyle and colleagues shows that sleep restriction therapy is a simple and effective treatment for at least part of the population of people with chronic insomnia and can be carried out by nurses in primary care," they wrote.

Just 1% of these patients typically receive the preferred treatment of cognitive behavioral therapy for insomnia, despite research that has suggested that the disorder may be prevalent in up to 50% of patients who visit their primary care physicians, they noted.

"This is an important contribution in tackling the public health burden of insomnia," they concluded. "Urgent efforts are needed to adapt treatments for underserved populations and to educate primary care staff in recognizing insomnia."

This pragmatic, superiority, open-label trialopens in a new tab or window enrolled 642 patients from 35 general practices across England from August 2018 to March 2020 and randomly assigned them 1:1 using a web-based randomization program to either four sessions of nurse-delivered sleep restriction therapy plus a sleep hygiene booklet or a sleep hygiene booklet only.

Mean participant age was 55.4 years (range 19-88 years), 76.2% were women, and 97.2% were white.

Overall, 25.4% were currently taking prescribed sleep medications, and 49.2% had a Patient Health Questionnaire-9 score ≥10, indicating depressive symptoms.

The primary outcome was a self-reported insomnia severity score at 6 months, using the seven-item ISI for assessing night- and daytime symptoms of insomnia.

In total, 64.5% of participants in the sleep restriction therapy group attended all four sessions, with a mean total therapy duration of 85.5 minutes.

Of the included patients, 90.3% provided data on a minimum of one outcome measurement.

Eight patients in each group experienced serious adverse events, but none of these events were deemed to be related to the intervention.

Disclosures

This study was funded by the National Institute for Health and Care Research Health Technology Assessment Program.

Kyle reported non-financial support from Big Health in the form of no-cost access to the digital sleep improvement program, Sleepio, for use in clinical research, outside the submitted work. Co-authors reported consultancy fees from Mementor DE and being cofounder of and shareholder in Big Health.

van Straten and a co-author developed the online insomnia intervention i-Sleep, which contains cognitive behavioral therapy for insomnia. van Straten also holds IP in the i-Sleep intervention, which is commercially available to healthcare professionals. The authors did not receive any income from this collaboration.

Primary Source

The Lancet

Source Reference: opens in a new tab or windowKyle SD, et al "Clinical and cost-effectiveness of nurse-delivered sleep restriction therapy for insomnia in primary care (HABIT): a pragmatic, superiority, open-label, randomised controlled trial" Lancet 2023; DOI: 10.1016/ S0140-6736(23)00683-9.

Secondary Source

The Lancet

Source Reference: opens in a new tab or windowvan Straten A, et al "How to boost implementation for insomnia treatment in primary care?" Lancet 2023; DOI: 10.1016/ S0140-6736(23)01040-1.

https://www.medpagetoday.com/psychiatry/sleepdisorders/105901

Natera Lung Transplant Assessment Test Granted Medicare Coverage

  Natera, Inc. (NASDAQ: NTRA), a global leader in cell-free DNA (cfDNA) testing, today announced that it has received confirmation that its Prospera Lung donor-derived cfDNA (dd-cfDNA) transplant assessment test has met coverage requirements from the Centers for Medicare & Medicaid Services’ (CMS) Molecular Diagnostics Services Program (MolDX).

The MolDX technology assessment program has determined that Prospera Lung will be covered under the existing Medicare Local Coverage Determination for Molecular Testing for Solid Organ Allograft Rejection for use in the surveillance setting in lung transplant patients.

Lung transplantation has a five-year survival rate of 59%, the lowest rate of all transplanted organs. Moreover, in the last 20 years, there has been limited improvement in recipient survival.¹ This is primarily driven by acute rejection (AR) and chronic lung allograft dysfunction (CLAD), which is the leading cause of mortality among lung transplant recipients

https://www.biospace.com/article/releases/natera-s-prospera-lung-transplant-assessment-test-granted-medicare-coverage/

MEI starts Phase 1b trial of Avastin combo in colorectal cancer

  MEI Pharma, Inc. (NASDAQ: MEIP), a clinical-stage pharmaceutical company focused on advancing new therapies for cancer, today announced the dosing of the first patient in a Phase 1b study evaluating ME-344 in combination with bevacizumab (AVASTIN®) in patients with previously treated metastatic colorectal cancer.

ME-344 is a novel mitochondrial inhibitor targeting energy production through the OXPHOS pathway, which is important for supporting tumor cell survival and proliferation for many forms of cancer, including colorectal cancer. Bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, and other antiangiogenics, increase reliance on mitochondrial energy production, thereby providing an important opportunity to evaluate a combination with a mitochondrial inhibitor like ME-344 to inhibit energy production in tumor cells and induce an antitumor effect.

https://www.biospace.com/article/releases/mei-pharma-announces-first-patient-dosed-in-clinical-study-evaluating-me-344-plus-bevacizumab-avastin-in-patients-with-previously-treated-metastatic-colorectal-cancer/

Novo Nordisk Is Keeping Danish Rates Lower, Danske Bank Says

 Novo Nordisk's hugely popular weight-loss drugs are helping to keep interest rates in the country lower, according to Danske Bank director Jens Naervig Pedersen.

"We see a direct link between the growing role of the pharmaceutical industry in the Danish economy and upwards pressure on the currency and lower policy rate," he said in a note on Wednesday.

Denmark's currency is pegged to the euro so the central bank fine-tunes its monetary policy to that of the ECB through a combination of currency-market interventions and interest-rate adjustments to keep the krone stable against the euro.

Danmarks Nationalbank has already raised rates less than the ECB this year to weaken the export-driven strength in its currency, but the growing pharmaceutical industry may force it to widen the spread to the ECB's policy rate beyond the current 40 basis points over the medium term, Pedersen noted.

Surging demand for Novo Nordisk's drugs to treat obesity has sent the company's shares 73% higher this year and has turned it into Europe's second-most valuable company by market capitalization, behind luxury giant LVMH Moet Hennessy Louis Vuitton. If its popularity continues, which Pedersen believes the market is expecting, Danish exports will strengthen further, pushing the currency higher and forcing the central bank to keep interest rates lower.

https://www.marketscreener.com/quote/stock/NOVO-NORDISK-A-S-1412980/news/Novo-Nordisk-Is-Keeping-Danish-Rates-Lower-Danske-Bank-Says-44629994/

Hedge funds dumped Chinese stocks in August, says Goldman

 Global hedge funds "aggressively" sold Chinese stocks amid heightened concerns over the country's property sector and a weak batch of economic data, a Goldman Sachs report on Tuesday showed.

All types of stocks were sold in early August, but A-shares, those listed in the domestic stock market, led the sell-off, comprising 60% of it, the bank said.

"Hedge funds have net sold Chinese stocks in eight of the last 10 sessions on the prime book through 8/14," it said, adding its clients divested both their long and short positions.

This is the largest net selling in Chinese equities over any 10-day period since Oct 2022 and one of the steepest moves in the past five years.

Hedge funds sold 70% of what they bought in the first 5 days post the July 24 Politburo meeting on stimulus hopes, Goldman Sachs estimates.

New York listed - KraneShares CSI China Internet ETF , which offers exposure to China's largest internet companies such as Tencent and Alibaba, slumped 12% in August, the biggest monthly decline since February.

Goldman Sachs, as one of the biggest providers of lending and trading services through its prime brokerage unit to investors, is able to track hedge funds' investment trends.

Global investors have raised concern about China's economy as a confluence of recent events has darkened its economic outlook, and the policy response is viewed as insufficient.

On Tuesday, a broad array of Chinese economic data highlighted intensifying pressure on the economy from multiple fronts, prompting Beijing to cut key policy rates to shore up activity.

Chinese property giant Country Garden is seeking to delay payment on a private onshore bond and a major Chinese trust company that traditionally had sizable exposure to real estate, Zhongrong International Trust Co, has missed some repayment obligations.

Hedge funds are increasingly wary of their exposure to China. A raft of U.S.-based hedge funds, including Coatue, D1 Capital and Tiger Global, cut their positions in Chinese stocks in the second quarter, as the country's economic prospects already seemed to wobble and geopolitical tension increased, securities filings showed on Monday.

U.S. President Joe Biden's executive order to prohibit some U.S. technology investments in China also caused some investors to further reduce their exposure to the world's second largest economy.

A UBS report on Monday showed China's semiconductor sector has been sold significantly by hedge funds in the past two weeks.

https://www.marketscreener.com/quote/stock/THE-GOLDMAN-SACHS-GROUP-12831/news/Hedge-funds-dumped-Chinese-stocks-in-August-says-Goldman-44622909/

Bristol-Myers: Phase 1/2 Trial Updates Show Durable Efficacy Benefits in Lung Cancer

 Repotrectinib continued to demonstrate high response rates and durable responses, including robust intracranial responses, in patients with ROS1-positive locally advanced or metastatic non-small cell lung cancer who were TKI-naïve or previously treated with one TKI and no chemotherapy

Median duration of response and progression-free survival to be disclosed for the first time in the pooled Phase 1/2 population alongside updated results at the IASLC 2023 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer

https://finance.yahoo.com/news/updated-data-trident-1-trial-141900500.html