Drug Repurposing 'Fast Track' to New Medicines for Obesity, Diabetes

 Researchers have developed a computer program to identify drugs for other diseases that might be repurposed to treat type 2 diabetes and/or obesity by targeting genetic pathways for these two conditions.

The scientists identified four pathways with known drug targets for type 2 diabetes and five with known drug targets for obesity.

Their findings suggest that:

• Palbociclib (used to treat breast cancer) and cardiac glycosides (used to treat heart failure and heart rhythm disorders) might be repurposed to treat type 2 diabetes.

• Baclofen (a muscle relaxant) and carfilzomib (a chemotherapy) could potentially be used to treat obesity.

• Fostamatinib (used to treat thrombocytopenia), sucralfate (used to treat stomach ulcers), and regorafenib (used to treat cancer) might be used to treat type 2 diabetes and obesity.

• Baclofen and sucralfate would have favorable safety profiles as repurposed treatments.

Sahar El Shair, a PhD student at the Faculty of Health and Medicine, University of Newcastle, New South Wales, Australia, presented the research on October 15 during an oral session at the International Congress on Obesity 2022 (ICO), the biennial congress of the World Obesity Federation, in Melbourne, Australia.

"New treatments with higher activity and specificity are urgently needed to tackle a pandemic of chronic illness associated with type 2 diabetes and obesity," senior co-author Murray Cairns, PhD, said in a press release from the ICO.   

"Our technology harnesses genetically informed precision medicine to identify and target new treatments for these complex disorders," said Cairns, from the School of Biomedical Sciences and Pharmacy at the University of Newcastle.

Matchmaking Between Individual, Their Genetic Traits, and Drugs

Cairns and senior co-author William Reay, PhD, also from the School of Biomedical Sciences and Pharmacy, have co-founded a company called PolygenRx.

The company website explains that they have developed a propriety platform termed the pharmagenic enrichment score (PES), which is "essentially a matchmaking service between patients and drugs, allowing treatment to be optimized for each individual using their unique combination of genetic risk factors."

It is important to note the genetic risk from complex traits, such as type 2 diabetes and obesity, "are quite different [from] the rare genetic disorders caused mostly by a devastating mutation in a single gene," Cairns explained in an email to Medscape Medical News.

"Complex traits," he noted, "are associated with thousands of [genetic] variants that are common in people and have a cumulative effect."

For this specific research, the investigators obtained genetic data from genome-wide association studies of obesity and type 2 diabetes.

"By using very large cohorts (hundreds of thousands of individuals) and comparing the frequency of millions of genetic variants in subjects with these conditions, with controls, these studies have revealed regions of the genome and genes associated with the condition," Cairns noted.

The pharmagenic enrichment score integrates a person's genetics with drug pharmacology to determine if a person would respond more readily to a certain drug.

"We are investigating the potential of thousands of drugs across a broad spectrum of complex traits (the list is almost endless)," Cairns explained.

From the PES score, "we have an estimate of each individual's likelihood of a positive response to said drug," he noted. "We all have variants that increase (and decrease) the risk of these conditions to various degrees as they are common (high frequency) genetic variants."

With this research, "we can implement this precision medicine strategy to match the right [repurposed] drugs for individuals based on their specific burden of genetic risk" for obesity and type 2 diabetes.

"Drug repurposing can be a fast track to new medicines because there is existing knowledge about their safety and activity in humans," he said.

Next Steps: Raising Funds for Clinical Trials

"We would like to progress some of these compounds to preclinical and clinical trials," Cairns said, "but need to raise the funds for this expensive research. With limited government research funding opportunities, we have recently spun out a startup company to attract commercial investment in our platform and the development of new drug candidates."

The authors have reported no relevant financial relationships. Reay and Cairns are co-founders of PolygenRx.

ICO 2022. Abstract LB022. Presented October 15, 2022.  

https://www.medscape.com/viewarticle/982691

Reaction Is Overdone For PTC: Cantor

 

• Earlier today, the FDA requested additional data to allow a 12-week portion of the Phase 2 PIVOT-HD study evaluating PTC Therapeutics Inc's 
  PTCT-8.64%+ Free Alerts
   PTC518 for Huntington's disease.
• The additional requirement comes for the trial in the U.S.
• Cantor Fitzgerald reiterates its Overweight rating and price target of $69. 
• After speaking with management, Cantor believes that the stock reaction was likely knee-jerk, and the company highlighted that the situation was not a clinical hold. 
• PTCT was also confident around potential timelines, guiding for 12-week data in 1H of 2023.
• The analyst still sees potential value-creating catalysts in the near term and believes that PTCT has a mix of commercial- and clinical-stage opportunities.
• "We believe multiple clinical opportunities could be future revenue drivers for PTCT. Additionally, management has guided multiple data readouts, including Phase 3 data for PTC923 in phenylketonuria by YE22, which we view as a key investor focus," the analyst added in the note.

https://www.benzinga.com/analyst-ratings/analyst-color/22/10/29328891/reaction-is-overdone-for-ptc-therapeutics-pausing-huntington-trial-enrollment-analy

1 in 7 Community-Living Seniors Die in the Year After Major Surgery

 Roughly one in seven community-living older adults in the U.S. died in the year after a major surgery, and the risk was far higher for those with frailty or probable dementia, according to a national population-based estimate.

Based on findings from nearly 1,000 community-living Medicare beneficiaries who underwent a major surgery from 2011 to 2017, the population estimate for mortality within 1 year of surgery was 13.4%, reported Thomas Gill, MD, of the Yale School of Medicine in New Haven, Connecticut, and colleagues.

Mortality at 1 year grew to 27.8% among the individuals with frailty (adjusted hazard ratio [aHR] 2.18, 95% CI 1.40-3.40) and 32.7% for those with probable dementia (aHR 4.41, 95% CI 2.53-7.69), the authors wrote in JAMA Surgery.

Major surgery is common in this population, Gill's group explained, with a 5-year cumulative risk of 13.8% that represents nearly 5 million people. Individuals with frailty comprise 12.1% of this population, while those with probable dementia comprise 12.4%.

"These values, combined with the mortality estimates reported in the current study, highlight the public health relevance of major surgery in an aging society, and suggest that policies, resources, interventions, and programs aimed at optimizing the care and outcomes of older U.S. adults undergoing major surgery may have utility," wrote Gill and colleagues.

In an accompanying editorial, Jennifer Perone, MD, and Daniel Anaya, MD, both of the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, noted that the mortality rates in the frail and dementia populations "suggest that there is a break in the system where goals of surgery are often not accomplished following surgery."

"These findings are likely to have an even more drastic effect on patients in the assisted-living setting, with clear unmet needs for those most vulnerable," they continued. "The cumulative mortality extending along the first year suggests that death is not associated with surgery alone but also with chronic conditions (and changes derived from surgery) and the overall life expectancy of the population."

For their study, Gill and colleagues examined data on 1,193 major surgeries from 992 community-living older adults enrolled in the National Health and Aging Trends Study (NHATS), including 661 elective and 532 non-elective surgeries. All patients were fee-for-service Medicare beneficiaries, and major surgeries and mortality were identified by linking to data from the Centers for Medicare & Medicaid Services. Information on dementia and frailty came from NHATS assessments.

Mean patient age was 79 years, and 56% were women. Over three-quarters were white and 16.6% were Black. The mean number of chronic conditions was 2.8, which included frailty in a fourth of patients, pre-frailty in about half, possible dementia in 10.6%, and probable dementia in 12.5%. The most common surgeries were musculoskeletal (40%), followed by abdominal (18%) and vascular (12%) surgeries.

Those who underwent elective surgery tended to be younger and have better education compared to those undergoing non-elective surgery, and were also less likely to be eligible for Medicaid, frail, or have possible or probable dementia.

At 1 year of follow-up, 206 patients died, representing 872,097 survey-weighted deaths. Median time to death was 96 days for all major surgeries (169 days for elective and 62 days for non-elective surgeries).

Non-elective surgery was associated with a nearly threefold higher mortality risk compared with elective or planned surgery (22.3% vs 7.4%, respectively; aHR 2.75, 95% CI 1.85-4.08). Additionally, Black race was associated with a higher mortality risk compared with white race (aHR 1.73, 95% CI 1.06-2.80) as was male sex (aHR 1.51, 95% CI 1.08-2.13).

Not surprisingly, risk of 1-year cumulative mortality increased with age and was significantly higher in the three oldest age groups (compared to patients ages 65-69):

• Age 80-84: aHR 2.50 (95% CI 1.34-4.66)
• Age 85-89: aHR 3.03 (95% CI 1.48-6.19)
• Age ≥90 and up: aHR 6.56 (95% CI 3.19-13.5)

"Large mortality differences were readily apparent within the first month after major surgery for the two oldest age groups and for persons who had frailty and probable dementia," the study authors noted. "These differences, which were comparable to that observed between elective and nonelective surgery, persisted over the following 11 months, suggesting the potential short-term and long-term prognostic value of these factors."

Among the limitations were that data were unavailable for individuals with Medicare Advantage, a growing population where enrollment rates are expected to increase from the 25% in the current analysis to 42% by 2028.

Disclosures

This study was supported by the NIH via the National Institute on Minority Health and Health Disparities. The NHATS was funded by the National Institute on Aging.

Gill disclosed funding from the NIH. Coauthors did not disclose any competing interests.

Perone and Anaya reported no conflicts of interest.

Primary Source

JAMA Surgery

Source Reference: Gill TM, et al "Population-based estimates of 1-year mortality after major surgery among community-living older US adults" JAMA Surg 2022; DOI: 10.1001/jamasurg.2022.5155.

Secondary Source

JAMA Surgery

Source Reference: Perone JA, Anaya DA "Patient experience following surgery in the geriatric population -- increased relevance and importance of longer-term surgical outcomes" JAMA Surg 2022; DOI: 10.1001/jamasurg.2022.5156.

https://www.medpagetoday.com/surgery/generalsurgery/101300

Surface, Immutep and Corbus Move Beyond Anti-PD-1/PD-LI with New Targets

 Initially, anti-PD-1/anti-PD-L1 therapies offered the hope of curing cancer. Experience showed that despite truly amazing results in some patients and the approval of five such therapeutics in the United States and Europe, they elicited a response in less than one-third of those receiving them.

PD-L1 expression, while still an important biomarker, is not the static, “yes/no” predictor of tumor response for which researchers hoped.

The challenge for PD-1/PD-L1 checkpoint inhibitors is the tumor microenvironment (TME). It is such a complicated mass of cells and proteins that no single therapy is likely to cure all or even many types of cancers in all patients.

Now companies are pursuing other targets, often as adjuvants to moderate the TME and thus expand the efficacy of anti-PD-1/anti-PD-L1 therapies.

IL-27 and CD-39

Surface Oncology, for example, is in the clinic with programs against IL-27 and CD-39.

IL-27 is a cytokine that helps immune cells communicate with one another. It seems to be important in lung, liver and kidney cancer. Although it’s not present in most tumors, when it is there “it has a profound suppressive effect on both the innate and the adaptive immune system – the T cells and NK cells,” said Rob Ross, M.D., oncologist and CEO of Surface in an interview with BioSpace.

SRF388, a fully human anti-IL-27 antibody, breaks this cellular communication so the immune system can attack the tumor. Early indications suggest it can shrink tumors alone or in combination with pembrolizumab, an anti-PD-1 therapy.

Surface’s second program targets CD-39, an enzyme that is important in the adenosine axis, breaking down ATP, a metabolite inside healthy cells that acts as an immune stimulant.

“When ATP is found outside the cells, it means the cells have been broken apart,” Ross said, triggering the immune system to act.

“When ATP later is broken down into adenosine, that suppresses the immune system,” he continued. CD-39 is the protein that breaks-down ATP into AMP, which then is broken down into adenosine, Ross explained. “Cancer would love to be surrounded by adenosine, so the cancer cells up-regulate CD-39.”

Surface’s candidate, SRF617, inhibits CD-39, decreasing immune suppressions around the tumor.

Currently, SRF617 is a systemic technology, although more targeted delivery may emerge. “For the most part, if you have cancer, CD-39 is most active at the site of the tumor because you don’t have a lot of other areas of active inflammation,” Ross said.

“In the clinic, we’re pursuing both SRF388 and SRF617 in combination with anti-PD1 therapies,” he shared. 

“What I expect is that in the future, patients with tumor types that respond to PD-1 at least sometimes will have combinations that combine anti-PD-1 therapies with drugs like ours,” Ross said. That will pave the way for more robust responses and, perhaps cures based upon turning on the immune system.

Leveraging LAG-3

In Australia, Immutep is developing eftilagimod alpha (dubbed ‘efti’) to modulate the lymphocyte activation gene-3 (LAG-3) immune control mechanism. Efti is a combination therapy with standard of care, currently in a trial for non-small cell lung cancer. A late-breaking abstract will be presented in November at the Society for Immunotherapy of Cancer (SITC) Annual Meeting.

“Efti works as an antigen-presenting cell (APC) activator. It’s not at all like checkpoint inhibitors,” said Marc Voigt, CEO of Immutep. “We use LAG-3 as a tool to activate the patient’s immune system via its ligand, MHC-II.”

Notably, Efti uses LAG-3 to activate both the innate and adaptive immune systems by binding to APCs like dendritic cells, monocytes and macrophages via MHC II molecules and leads to proliferation of CD4+ and CD8+ T cells.

“We are trying to induce a stronger immune response – especially the CD8+ cytotoxic immune response,” said Frédéric Triebel, M.D., Ph.D., CSO and CMO. There are a few approaches.

“For patients with a hot tumor and many activated T cells at the tumor site, you can block LAG-3 or PD-1, or block both together because the pre-existing T cells will continue proliferating. Or, with a cold tumor where there are few to no pre-existing T cells at the tumor site…you can induce T cells to go there with an APC activator such as efti,” Triebel said.   

To do this, Immutep uses the immunostimulant efti to, in effect, form a new pathway that activates APCs such as the dendritic cells in the lymph nodes, skin, gut and tissues. These APCs present tumor peptides to the T cells and activate them so they can effectively recognize tumor cells and kill them. This approach can be combined with an anti-PD-1 therapy, such as pembrolizumab.

“In our clinical trials, we are not recruiting patients with high levels of PD-L1, which is a marker for T cell activation at the tumor site. Instead, we are recruiting all patients whether they have a hot or cold tumor,” Triebel said. “This expands the target population by more than three-fold.”

Targeting TGFß

At Corbus Pharmaceuticals, and throughout the industry, “We’re recognizing that the subtlety of the cell types in the TME drives responsiveness to PD-1 or PD-L1 therapy,” said Rachael Brake, Ph.D., CSO of Corbus Pharmaceuticals.

Cancer cells have multiple, pernicious ways to prevent the T cells from penetrating the TME. To thwart that, “Corbus is targeting a growth factor – TGFß – that is important in normal homeostasis but that is corrupted significantly in a large number of tumors,” she told BioSpace. When it’s allowed to signal, immunosuppression ensues.

Historically, targeting TGFß systemically hasn’t worked and, in fact, has created harmful target toxicities throughout the body.

“Corbus, therefore, is targeting cell-bound TGFß – which is tethered to the surface of the immune cells or the cancer cells, or to both,” Brake said.

The αvβ8 integrin is of specific interest. “It doesn’t appear to function like the other (20 to 30) members of this integrin family, and is the only integrin that exclusively functions as an activator of TGFß,” she continued.

Corbus’s lead compound, CRB-601, blocks the interaction between cell-bound TGFß and the αvβ8 integrin. Corbus plans to enter the clinic with CRB-601 in 2023, Brake shared.

https://www.biospace.com/article/beyond-anti-pd-1-pd-li-3-companies-swing-for-the-fences-with-new-targets-/

Sartorius Shares Fall After Top-Line Guidance Downgrade

 Shares in Sartorius AG traded lower Wednesday after the company reported results for the nine months of 2022 and adjusted its sales outlook for the current year.

For the first nine months, the German pharmaceutical and laboratory equipment supplier recorded a net profit of 525.7 million euros ($518.3 million) compared with EUR307.8 million a year earlier, on sales that grew to EUR3.11 billion from EUR2.53 billion.

At 0808 GMT, shares were down 12% at EUR341.20.

Earnings before interest, taxes, depreciation, and amortization came in at EUR1.05 billion, up from EUR866.4 million in the same period a year earlier.

The company said it now expects consolidated sales revenue growth in the full year to reach the lower half of the previously guided range of around 15% to 19% , with non-organic growth from acquisitions anticipated to contribute about 2%. It still sees its underlying Ebitda margin reaching about 34%, Sartorius said.

"We are specifying our full-year outlook for 2022 within the range projected so far, but the global political and economic uncertainties remain high," Sartorius Chairman and CEO Joachim Kreuzburg said.

The group hasn't downgraded top-line guidance in quite some time, which is likely to send the stock lower this morning, analysts at Berenberg said in a note. "We remain confident on the underlying momentum of the bioprocess solutions division and note that this is a risk that the group has been actively highlighting since the start of 2022," they added.

https://www.morningstar.com/news/dow-jones/202210192940/sartorius-shares-fall-after-top-line-guidance-downgrade