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Monday, October 17, 2022

CTI started at Buy by Leerink

 

  • SVB Leerink initiated coverage on CTI Biopharma Corp  with an Outperform rating and a $13 price target
  • CTIC is a commercial-stage biopharmaceutical company launching Vonjo — a differentiated, next-generation JAK inhibitor for myelofibrosis.
  • SVB thinks Vonjo will transform the treatment paradigm and offer blockbuster sales potential. 
  • "In contrast to other targeted oncology launches, we think Vonjo will surpass expectations based on results from our proprietary MEDACorp survey of myelofibrosis-treating physicians, indicating a surprising potential for off-label usage," the analyst writes.
  • The price target indicates upwards of 170% upside from current levels, which can be realized as the commercial story unfolds over the next several years.
  • While CTIC represents a SMID-cap company launching a product against large commercial players like Incyte Corp  and GSK Plc , the analyst thinks the competition has weaknesses. 
  • Incyte remains distracted with its dermatology launches, while Jakafi combination approaches remain multiple years away from market entry. 
  • GSK's momelotinib will likely not enter the market until mid-2023 and has safety concerns.

'New England risks winter blackouts as gas supplies tighten'

 New England power producers are preparing for potential strain on the grid this winter as a surge in natural-gas demand abroad threatens to reduce supplies they need to generate electricity.

New England, which relies on natural-gas imports to bridge winter supply gaps, is now competing with European countries for shipments of liquefied natural gas, following Russia’s halt of most pipeline gas to the continent. Severe cold spells in the Northeast could reduce the amount of gas available to generate electricity as more of it is burned to heat homes.

The region’s power-grid operator, ISO New England Inc., has warned that an extremely cold winter could strain the reliability of the grid and potentially result in the need for rolling blackouts to keep electricity supply and demand in balance. 

The warning comes as executives and analysts predict power producers could have to pay as much as several times more than last year for gas deliveries if severe weather creates urgent need for spot-market purchases.

"The most challenging aspect of this winter is what’s happening around the world and the extreme volatility in the markets," said Vamsi Chadalavada, the grid operator’s chief operating officer. "If you are in the commercial sector, at what point do you buy fuel?"

Power producers in New England are limited in their ability to store fuel on site and face challenges in contracting for gas supplies, as most pipeline capacity is reserved by gas utilities serving homes and businesses. Most generators tend to procure only a portion of imports with fixed-price agreements and instead rely on the spot market, where gas prices have been volatile, to fill shortfalls.

"Anybody who is depending on the spot market for their natural-gas supply is probably going to have a pretty significant sticker shock," said Tanya Bodell, a partner at consulting firm StoneTurn who advises energy companies in New England.

New England has been grappling with fuel-supply challenges for more than a decade because the region has limited pipeline capacity. Imports of LNG can make up more than a third of the region’s natural-gas supply during periods of peak demand, according to the Energy Information Administration. The Jones Act, a law restricting the movement of ships between U.S. ports, makes maritime delivery of domestic supplies nearly impossible, so the region relies on gas produced abroad.

Now, intense competition for LNG cargoes driven by European demand makes securing supply ad hoc a costly proposition. This summer, the European benchmark price for natural gas topped $100 per million British thermal units. Gas prices in New England, by comparison, rarely reach much above $30, said Eugene Kim, a research director at energy consulting firm Wood Mackenzie—a differential that encourages suppliers to provide gas to Europe rather than New England.

This summer, the governors of New England states sent a letter to U.S. Energy Secretary Jennifer Graholm citing high natural-gas prices as a reason to waive the Jones Act and allow for domestic LNG imports to the region. They also requested more coordination with the federal government to ensure energy reliability and help modernizing New England’s heating-oil reserve.

New England residents are facing some of their largest electricity bills in years and are likely to pay even more this winter because of higher gas prices. Utilities purchase electricity from generators on the wholesale market and recoup those costs from customers.

Thad Hill, chief executive of Calpine Corp., which operates several plants in the region, said he expects fuel supplies this winter to be sufficient but expensive. The circumstances, he said, might warrant the need for the grid operator to implement stronger incentives for power producers to store or contract for firm supplies ahead of winter.

"The goal should be to put in place a market mechanism that’s actually durable for all but the most egregious situations," he said.

New England’s challenges are becoming more acute as older coal, oil and nuclear-fueled generators shut, leaving gas-fired ones to serve a greater percentage of demand. Since 2013, about 5,200 megawatts of that capacity has retired, according to the New England ISO, an amount equal to roughly a quarter of peak winter demand. Some older plants risk closing faster than they can be replaced by renewable-energy projects, which account for the majority of new capacity proposed for the region.

The changes to the region’s power mix have left it increasingly reliant on imports of gas as well as oil to power the remaining plants, and Russia’s invasion of Ukraine has roiled the global markets for both commodities. Similar to gas, fuel oil is used for home heating and power generation, creating a tight market for the resource on cold days.

The New England ISO expects that the grid can weather a mild-to-moderate winter without significant reliability challenges. However, it has warned that electricity demand could threaten to surge beyond available supply after multiple sustained periods of severely cold weather, which would result in calls for conservation similar to those issued in California in September during a regionwide heat wave.

LS Power Development LLC has been working to prepare its two gas-fired power plants in New England, one of which can run on oil as backup. Nathan Hanson, the company’s senior vice president of energy and commercial management, said the company is filling the one plant’s backup tanks with oil and has an option to procure for the other plant an emergency supply of gas for use during peak demand.

"The grid overall is in a much tighter position," he said. "If we get a sustained cold period in New England this winter, we’ll be in a very similar position as California was this summer."

https://www.foxbusiness.com/energy/new-england-risks-winter-blackouts-gas-supplies-tighten

Is Brain Insulin Important for Whole-Body Metabolism?

 Data from animal models showed that animals who didn't have any insulin in their brain developed a type 2 diabetes–like phenotype. We wondered if this is true in humans. Can it be that insulin acts in the human brain? Is this important for metabolism in the entire body? This is how I became interested in studying how insulin acts in the human brain.

What we've learned so far is that, indeed, insulin acts in the human brain. This happens in many persons, but there's a substantial number of persons who are insulin resistant in their brain. In these individuals, the brain no longer responds to insulin.

We've learned that proper insulin action in the brain is important to coordinate your metabolism after food intake. It suppresses glucose production from the liver and stimulates glucose uptake in the periphery. Over time, these processes contribute to the regulation of body fat distribution. This determines where in the body fat and energy are stored.

If insulin action in the brain is good, your body stores energy in the subcutaneous compartment. In the case of brain insulin resistance, these processes are disturbed. The brain can't control peripheral metabolism, and in the long run, this leads to an accumulation of visceral fat.

This is where you don't want to have fat because visceral fat is a risk factor for not only type 2 diabetes but also cardiovascular diseases and even some types of cancer. Insulin resistance of the brain leads to a phenotype that's very unfavorable. You don't want this.

What we've done over the last couple of years was to try to find out if brain insulin resistance is something that can be treated or if it is fixed forever.

Our first treatment approach was with the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin. We studied persons with prediabetes who were overweight or obese and treated them with the SGLT2 inhibitor over 8 weeks. These 8 weeks of SGLT2 inhibition were sufficient to totally restore insulin responsiveness of the hypothalamus. This was the first study to show that brain insulin resistance is something that you can treat in humans.

Interestingly, this improvement in hypothalamic insulin action in response to SGLT2 inhibition was closely linked to improvements of peripheral metabolism and to a reduction of liver fat content. That's speculation, but I believe that improved hypothalamic insulin action could contribute to the clinical benefits that we know of this substance class that are present after a long time and really hard clinical endpoints.

The second treatment approach that we tested was exercise. Here, we included sedentary persons who were overweight or obese, and we had them exercise quite heavily over 8 weeks. After 8 weeks of exercise, they didn't lose weight, but it was sufficient to normalize their brain response to a level we normally see in lean persons.

Again, this improved insulin action of the brain after exercise was closely linked to metabolic benefits, underlying that the brain can contribute to metabolic regulation in the body and that this is something that can be restored.

Our next steps will be to better understand how these treatments work, to see what approaches work best, and to determine the mechanisms.

I hope treatment approaches that will improve insulin sensitivity of the brain will not only be beneficial for metabolism, diabetes, and overweight and obesity, but also have beneficial effects on diseases of the brain that are much more frequent in our patients with type 2 diabetes, such as depression and dementia.

I hope we'll learn much more about this in the upcoming years.

Martin Heni, MD

Professor, Division of Endocrinology of Diabetes, Internal Medicine, Ulm University Hospital, Ulm, Germany

Disclosure: Martin Heni, MD, has disclosed the following relevant financial relationships:
Serve(d) as an advisor for: Boehringer Ingelheim
Serve(d) as a speaker or a member of a speakers bureau for: Sanofi; Boehringer; Lily; Novo; Aurjt
Received research grant from: Boehringer; Sanofi

Mark Harmel, MPH, CDCES

Clinical research coordinator; Freelance videographer, Los Angeles, California

Disclosure: Mark Harmel, MPH, CDCES, has disclosed no relevant financial relationships.

https://www.medscape.com/viewarticle/981427

Home-Based Transcranial Stimulation Succeeds for Major Depression

 Home-based transcranial direct current stimulation with real-time supervision significantly improved clinical symptoms of major depressive disorder, based on data from 26 individuals.

Major depressive disorder (MDD) remains a leading cause of disability and a significant predictor of suicide worldwide, Rachel D. Woodham, PhD, of the University of East London and colleagues wrote.

Transcranial direct current stimulation (tDCS) has demonstrated effectiveness as a noninvasive therapy for MDD, but requires frequent sessions, and repeat visits to treatment centers are a barrier for many patients, they noted. The tDCS procedure involves delivery of a weak direct electric current via placement of electrodes, usually with the anode over the left dorsolateral prefrontal cortex and the cathode over the right dorsolateral prefrontal cortex, suborbital, or frontotemporal region.

"The current changes neuronal membrane potential and facilitates discharge," but "in contrast to rTMS and ECT, tDCS does not directly trigger an action potential," the researchers wrote. The most common side effects reported with tDCS are tingling, itching, burning sensation, skin redness or headache.

The researchers proposed that tDCS could be provided at home under real-time remote supervision.

In an open-label feasibility study published in the Journal of Psychiatric Research, they recruited 26 adults with MDD in current depressive episodes of moderate to severe severity. In addition to maintaining their current treatment regimens of medication, psychotherapy, or cognitive behavioral therapy, participants used tDCS at home in 30-minute sessions, for a total of 21 sessions over 6 weeks. A researcher was present in person or on a real-time video call for each at-home session.

The primary outcome of Hamilton Rating Scale for Depression (HAMD) score improved significantly, from a mean of 19.12 at baseline to 5.33 after 6 weeks. At 3 months, the mean HAMD score was 5.65, and 78.2% of patients met the criteria for clinical remission (HAMD score less than 9). At 6 months, patients maintained this improvement, with a mean HAMD score of 5.43 and 73.9% of the participants in clinical remission. The majority of participants (24 of 26) completed the full 6-week treatment.

Clinical assessments were conducted at baseline, at the end of the 6-week treatment period, at 3 months, and at 6 months, and included not only the HAMD, but also the Hamilton Anxiety Rating Scale (HAMA), Sheehan Disability Scale (SDS), Patient Health Questionnaire–9 (PHQ-9), and Young Mania Rating Scale. All participants showed significant improvements in HAMA, SDS, and PHQ-9 scores from baseline that endured from the end of the treatment period to the 6 months' follow-up.

The tDCS involved a bilateral frontal montage, F3 anode, F4 cathode, 2mA, and two different devices were used.

All participants reported the acceptability of at-home tDCS as either "very acceptable" or "quite acceptable."

The results were limited by the open-label feasibility design and lack of a sham control treatment; therefore, the findings of efficacy are preliminary, the researchers emphasized. "Having real-time supervision for each session likely contributed to symptom improvement."

However, the results support the feasibility of at-home tDCS to improve outcomes both short- and long-term in patients with moderate to severe MDD, the researchers said. Larger, sham-controlled trials are needed to show efficacy, and additional assessment of feasibility should include the use of app-based devices, which may be more feasible for individuals with lower socioeconomic status.

The study received no outside funding. The study was supported by the Rosetrees Trust. The researchers had no financial conflicts to disclose.

https://www.medscape.com/viewarticle/982529

Solid Biosciences Touts Encouraging Preclinical Data From Potential Duchenne Gene Therapy

 

  • Solid Biosciences Inc  presented additional data characterizing AAV-SLB101, a novel adeno-associated virus (AAV) vector designed for improved transduction efficiency and biodistribution to muscle cells. 
  • In studies in wild-type mice, the mdx mouse model of Duchenne (DMDmdx) and non-human primates (NHPs) AAV-SLB101 demonstrated superior transduction efficiency compared with AAV9.
  • In DMDmdx mice, the biodistribution of AAV-SLB101 to the quadriceps was significantly increased, and biodistribution to the liver and brain was decreased compared with AAV9.
  • In DMDmdx mice, microdystrophin protein expression was significantly higher with AAV-SLB101 than with AAV9.
  • Across multiple mouse studies, muscle tissues treated with SGT-003 showed approximately 2- to 3-fold higher levels of microdystrophin protein. 
  • The company says the AAV-SLB101 capsid may be a superior candidate for muscle-targeted gene therapies, with the potential to achieve higher levels of efficacy with lower total doses.
  • The company expects to submit an investigational new drug application (IND) for SGT-003 in mid-2023 and, subject to IND clearance, initiate patient dosing in late 2023. 

Relmada: Point72 stake up to 7.3%

 

CUSIP No. 75955J402
(1) Names of reporting persons    Point72 Asset Management, L.P.
 
(2) Check the appropriate box if a member of a group
(a)
(see instructions)
(b)X
(3) SEC use only
 
(4) Citizenship or place of organization Delaware
 
Number of shares beneficially owned by each reporting person with:
 
(5) Sole voting power                  0
 
(6) Shared voting power              2,081,300 ** (see Item 4)
 
(7) Sole dispositive power           0
 
(8) Shared dispositive power       2,081,300 ** (see Item 4)
 
(9) Aggregate amount beneficially owned by each reporting person
 
2,081,300 ** (see Item 4)
 
(10) Check if the aggregate amount in Row (9) excludes certain shares
 
(see instructions)
 
(11) Percent of class represented by amount in Row (9) 7.3% *** (see Item 4)
 
(12) Type of reporting person (see instructions) PN