Amicus snaps back on positive data from Pompe Disease study

Amicus Therapeutics (FOLD +6.5%) rebounds on heavy volume a day after dropping to fresh two-year lows before ultimately netting a gain for the day.

FOLD yesterday reported additional “positive” results from a Phase 1/2 clinical study investigating AT-GAA in adult patients with Pompe disease; the Food and Drug Administration previously granted Breakthrough Therapy Designation to AT-GAA for the treatment of late onset Pompe disease based on clinical efficacy results the study.

The company says it will present the results tomorrow at the International Annual Congress of the World Muscle Society.

https://seekingalpha.com/news/3503847-amicus-snaps-back-positive-data-pompe-disease-study-gaa

Japan drug price reforms risk hurting investment: Bristol-Myers CEO

Japan’s “overly restrictive” drug pricing policies risk diverting foreign direct investment to China and other markets, the chief executive of Bristol-Myers Squibb said on Thursday.
The Japanese government made reforms in 2018 that change how its national health system pays for new and innovative drugs.
But those changes are not science-based and favor large domestic drugmakers over foreign and smaller players, Giovanni Caforio told a news conference in Tokyo.
“The world is very competitive, and countries such as China have made it a priority to develop a biopharmaceutical innovation-focused industry,” Caforio said at an event organized by the Japan office of PhRMA, the main U.S. drugmaker lobby.
Caforio was announced as chairman of PhRMA last month.

Japan’s government is seeking ways to squeeze savings from its national health care system as the population ages. The number of working-age people in Japan compared to those over the age of 65 is 1.8, the lowest in the world, according to a 2019 United Nations report.
Japan is the world’s second-largest market for innovative drugs such as gene-based therapies and cutting-edge cancer drugs. As a wealthy country with one of the fastest ageing societies, it remains an attractive market for global pharmaceutical makers.
Japan is also a major center for pharma research, producing drugs such as Opdivo, a blockbuster cancer drug licensed globally by Bristol-Myers.
The rules announced last year evaluate drugs and their makers for innovation to determine how much the government will pay for treatments.

The rules would also subject drugs to annual reviews starting from 2021, as opposed to biannual reviews now. Caforio said he met with senior government officials to press for more discussion on the regulations.
“These decisions could impact whether the strong investment patterns in Japan continue and whether new medicines are rapidly available for Japanese patients in the future,” he said.
https://www.reuters.com/article/us-bristol-myers-japan/japan-drug-price-reforms-risk-hurting-investment-bristol-myers-ceo-idUSKBN1WI0UR

Catalyst Bio reports positive trial update on blood disorder drug

Catalyst Biosciences (CBIO +20%) spikes higher following a positive update on its Phase 2 study of dalcinonacog alfa ((DalcA)), a next-generation subcutaneously administered Factor IX therapy being developed for the treatment of hemophilia B.

CBIO says two subjects have completed dosing and washout, and Factor IX levels in the subjects exceeded the trial efficacy endpoint of greater than 12% activity and no anti-drug antibodies were detected.

The trial is expected to enroll up to six completing subjects who will receive a single intravenous dose, followed by daily subcutaneous doses of DalcA for 28 days; CBIO expects to report final data in H1 2020.

https://seekingalpha.com/news/3503837-catalyst-bio-reports-positive-trial-update-blood-disorder-drug

Gilead’s Descovy gains PrEP indication

The FDA approves Gilead’s (GILD +0.2%) Descovy for a pre-exposure prophylaxis indication.

Descovy for PrEP is indicated to reduce the risk of sexually acquired HIV-1 in adults and adolescents weighing at least 35 kg who are HIV-negative and at-risk for sexually acquired HIV, excluding those at-risk from receptive vaginal sex.

https://seekingalpha.com/news/3503833-gileads-descovy-gains-prep-indication

First Guideline to Say Colon Cancer Screening Is Not for All

For the first time, a guideline recommends that screening for colorectal cancer should not be routinely recommended for all adults aged 50 to 79 years, but instead should be limited to individuals with an elevated level of risk.
The new guideline, from an international panel of experts, goes against the grain. At present, many countries recommend routine screening for all older individuals, and recently some groups have even lowered the starting age to 45 years.
The new guidelines were published online October 2 in BMJ.
Screening should be recommended for adults with a cumulative cancer risk of 3% or more in the next 15 years, the point at which the balance between benefits and harms favors screening, say the authors, led by Lise Helsingen, MD, Clinical Effectiveness Research Group, University of Oslo in Norway
Screening is not recommended when cumulative risk is below 3%.
Risk calculation (over 15 years) can be made using the free online QCancer calculator, advises the panel. “The optimal choice for each person requires shared decision-making,” Helsingen commented in an email to Medscape Medical News.
A risk-based approach is “increasingly regarded as the most appropriate way to discuss cancer screening” and is already used with patients in prostate and lung cancer screening, writes Philippe Autier, PhD, International Prevention Research Institute, Lyon, France, in an accompanying editorial.
The National Comprehensive Cancer Network (NCCN) said the new guide does not change their screening recommendation.

“At this time, NCCN continues to endorse screening for colorectal cancer in average risk individuals age 50-75,” said Dawn Provenzale, MD, Duke Cancer Institute, Durham, North Carolina, in an email to Medscape Medical News. She is chair of the NCCN Guidelines Panel for Colorectal Cancer Screening.
Provenzale said that the NCCN “will continue to monitor” the risk-based, personalized approach to colorectal cancer screening.
The new guideline is based on research that includes a systematic review of screening trials — including new data from three randomized trials of one-time sigmoidoscopy.
Results from those three trials, recently published after 15 to 17 years follow-up, are what spurred the new guideline, which is part of the BMJ‘s “Rapid Recommendations” initiative. The journal aims to “accelerate” the creation of guidelines based on new evidence.
“It can take years for new research evidence to filter into new treatment guidelines,” the BMJ states on its website.
Duke’s Provenzale acknowledged that her NCCN panel has yet to review the sigmoidoscopy trials data but plans to do so at their next meeting, to be held November/December 2019.
The NCCN’s chief executive officer, Robert Carlson, MD, countered the idea that Rapid Recommendations are the only fast-moving guideline entity.
“When scientifically significant and practice changing information emerges between the planned yearly [NCCN guideline] updates. . . , NCCN initiates a process to develop interim updates of the involved guideline(s) . . . within 2 weeks of released knowledge,” he told Medscape Medical News in an email.

Consideration of Risk Factors

The new recommendations apply to men and women with no prior screening, no symptoms of colorectal cancer, and a life expectancy of at least 15 years.

In the new guide, individual cumulative risk is computed using sex, age, body mass index, physical activity, familial history, and presence of disease predisposing to colorectal cancer. Gender as a risk factor came under new scrutiny as two of the three above-mentioned sigmoidoscopy trials reported a reduction in colorectal cancer mortality and incidence with sigmoidoscopy screening in men, but only a small or no reduction in women (Holme et al [Ann Intern Med. 2018;168:775-82] and Senore and Arrigoni [Lancet Gastroenterol Hepatol. 2019;4:192-93]).
Most colorectal cancer screening guidelines recommend screening for everyone age 50 and over, regardless of individual risk. At this age, the cumulative risk of developing bowel cancer over the next 15 years ranges from 1% to 7% for “most people” considered in the new guideline, say the authors.

Screening Options

The new guideline looked at evidence and made recommendations on screening for four screening options: fecal immunochemical test (FIT) every year, FIT every 2 years, one-time sigmoidoscopy, or one-time colonoscopy.

For individuals with an estimated 15-year risk above 3%, the panel suggests screening with any of the four above approaches.
Because of the absence of randomized trials on FIT and colonoscopy screening, the guideline panel also used results of microsimulation models in their analysis and recommendations.
Overall, there was “substantial uncertainty” regarding the 15-year benefits and harms of screening. All four screening options resulted in similar colorectal cancer mortality reductions, the authors said.

However, FIT every 2 years “may have little or no effect” on cancer incidence over 15 years, but FIT every year, as well as sigmoidoscopy and colonoscopy, may reduce cancer incidence, they comment.
The magnitude of the benefits is dependent on the individual risk, they add.
Serious gastrointestinal and cardiovascular adverse events caused by screening are “rare,” the authors note.
The guideline authors and the editorialist agree that the recommendations to screen are based on “weak” evidence. “We cannot give strong recommendations for screening,” summarized Helsingen.
In his editorial, Autier points out that a personalized approach is in “sharp contrast” with traditional approaches to colorectal cancer screening. He says that institutions typically give the message everyone should get screened and that not doing so endangers one’s health.
“What matters is the uptake, and, to maximize uptake, messages tend to overstate benefits of screening and to downplay any undesirable consequences,” Autier writes.
A personalized approach has multiple benefits, says Autier. For example, prioritizing higher risk individuals is likely to optimize screening effectiveness.
The colorectal cancer screening panel emphasized that everyone invited to screening should be able to accept or decline the invitation based on the benefits and harms they might personally expect from screening.
The new panel was assembled by the MAGIC group, a nonprofit guidelines initiative, in collaboration with BMJ. Panel members included patients, clinicians, content experts and methodologists. The international group hailed from Norway, the United States, Switzerland, Canada, Saudi Arabia, the United Kingdom, and the Netherlands. Other Rapid Recommendations have included prostate cancer screening, corticosteroids for sore throat, and oxygen therapy for acute illness.
Helsingen, Autier, Carlson, and Provenzale have disclosed no relevant financial relationships.
BMJ. Published online October 2, 2019. Full text, Editorial
https://www.medscape.com/viewarticle/919325#vp_1

Oral Contraceptives Tied to Depressive, Psychiatric Symptoms in Teens

Use of oral contraceptives is associated with an increased risk for depressive and other psychiatric symptoms in young women, new research shows.
A large prospective cohort study showed that individuals who took oral contraceptive pills (OCPs) reported experiencing more crying, eating problems, and hypersomnia compared to their counterparts who did not take OCPs.
Such symptoms, the investigators note, can affect quality of life and can lead to nonadherence, potentially resulting in an unwanted pregnancy.

Dr Hadine Joffe

It is important to monitor for depressive symptoms in these teens, study investigator Hadine Joffe, MD, executive director, Connors Center for Women’s Health and Gender Biology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, told Medscape Medical News.
“Young women should know that if they have a mood issue when on the Pill, it can be addressed so it doesn’t interfere with their functioning, with their relationships and their schoolwork or their ability to take the medicine, if that’s the treatment of choice,” she added.
Joffe suggested that young, sexually active teens need to be made aware of alternatives to oral contraception.
The study was published online October 2 in JAMA Psychiatry.

A Reproductive Right

Many teens and young women are sexually active, and their access to birth control is “an important reproductive right,” said Joffe.

Discussions about contraceptive choice should include information regarding the risks and benefits of the various options. Benefits of OCPs include period regulation, control of painful periods, and prevention of unwanted pregnancy. Potential risks include worsening mood and, although rare in young people, blood clots and increased blood pressure.
Researchers used data on 1010 persons from the Tracking Adolescents’ Individual Lives Survey (TRAILS), a Dutch population survey that investigates the psychological, social, and physical development of adolescents.
Study participants were recruited from primary schools. Participants underwent a baseline assessment; the mean age of the participants at the time of baseline assessment was 11 years. Follow-up assessments were conducted at median ages of 13, 16, 19, 22, and 25 years. For all follow-up assessments, retention rates were 80% or higher.
The study included girls and young women aged 16 to 25 years. On at least one occasion during the study period, each participant filled out a form that assessed use of oral contraceptives and depressive symptoms.
Researchers used well-validated instruments to assess depression. For participants aged 16 years, the researchers used the DSM-IV–oriented affective problems scale of the Youth Self-Report, a version of the Child Behavior Checklist.
At ages 19, 22, and 25 years, the investigators used a scale that includes two additional items: indecisiveness and feeling unable to succeed.
The researchers conducted all analyses both with and without adjusting for age, socioeconomic status, and ethnicity.

As a whole, OCP use was not associated with higher adjusted mean scores on depressive symptoms (β coefficient, 0.006; 95% confidence interval [CI], -0.013 to 0.025; P = .52).

Age Dependent

However, at age 16, girls who used OCPs had higher depressive symptom scores compared to those who did not use OCPs (mean score, 0.40 vs 0.33; β coefficient, 0.075; 95% CI, 0.033 – 0.120; P < .001).
For participants in this age group, compared to nonuse of OCPs, OCP use was associated with more crying (odds ratio [OR], 1.89; 95% CI, 1.38 – 2.58; P < .001), eating problems (OR, 1.54; 95% CI, 1.13 – 2.10; P = .009), and hypersomnia (OR, 1.68; 95% CI, 1.14 – 2.48; P = .006).

“This study showed that these girls ― whose brains are still developing, so they’re at a different state than a 22-year-old or 25-year-old ― appear to have more of a connection with these mood symptoms than the girls who aren’t on the Pill,” said Joffe.
Anhedonia and sadness, which are symptoms required for the diagnosis of depression, were unaffected. The authors note that in contrast to adult depression, the diagnosis of which focuses more on anhedonia, the emphasis in teen depression is more on vegetative or physical disturbances, such as loss of energy, as well as changes in weight, appetite, and sleep.
For 16-year-old girls, the association was weakened after adjusting for depressive symptoms before use of OCPs, but the findings remained significant. This suggests that the relationship between OCP use and depressive symptoms could be bidirectional.

“Because of the way the study was designed, we can’t determine that the Pill caused the depressive symptoms,” said Joffe. “But based on the kind of analysis we did, it looks like the relationship goes both ways, that people who had more mood symptoms earlier in their teen years were more likely to be on the Pill when they were 16, and vice versa; girls who were on the Pill at age 16 were more likely to have mood symptoms.”
The authors pointed to a previous study that showed that worsening of mood among individuals using OCPs was more likely in users who had a history of depression.
The use of OCPs affects hormone levels, including levels of androgens and stress hormones. Some women may be particularly sensitive to the hormonal fluctuations in these contraceptives.
As well, important emotion-related regions of the brain, such as the amygdala, the prefrontal cortex, and the hippocampus, are still maturing during adolescence.
“Teens are dealing with lots of issues, which makes them more sensitive to many things they take that affect their body and their brain,” said Joffe.

IUDs a Better Choice for Teens?

The researchers investigated whether the association between OCP use and depressive symptoms may be explained by preexisting differences.
For instance, 16-year-old OCP users were more sexually active and experienced more stressful events, as well as more menstruation-related pain and acne, than their counterparts in the nonuser group. Analyses showed that all these factors weakened the association, although none diminished it.
The researchers wondered what role, if any, the “healthy survivor effect” played. Women who experience psychological adverse effects may be more likely to discontinue oral contraceptives, which could lead to an underestimation of the association between OCP use and depressive symptoms.
Comparing only first-time OCP users to nonusers strengthened the association between OCP use and depressive symptoms for the whole cohort (β coefficient for first-time OCP use, 0.021; 95% CI, -0.005 to 0.046; P = .11).
“This means that if you remove the group who took the Pill before and maybe went off it because of a side effect, it looks like the pattern was still evident, and the association was even stronger,” said Joffe.
Clinicians should be aware that adolescents who use OCPs may have mood problems, the authors note. Teens may attribute their depressive symptoms to the contraceptives and stop taking them, which could result in an unwanted pregnancy.

To lower this risk, long-acting reversible contraceptives, such as intrauterine devices (IUDs), are recommended as a first-line option. “We definitely encourage consideration of other means of birth control” in this age group, said Joffe.
An advantage of the IUD is that after it is inserted, it can be left in for many years and “doesn’t rely on somebody taking something like a pill consistently and reliably,” she said.
The investigators do not recommend limiting OCP use to counterbalance the risk for depressive symptoms. They point out that OCPs have benefits, including beneficial effects on dysmenorrhea and premenstrual syndrome, and are much safer than pregnancy and associated postpartum depression risks.

This new longitudinal analysis does not provide information about specific OCPs. However, the researchers checked which OCPs were used in a comparable cohort of girls born in the same year and whose addresses included the same postal code as the girls in this study. They found most of these persons were using the same type of progestin.
It is unclear whether the findings are generalizable to the US population, owing to the differences in the acceptability of, and access to, contraception. For example, unlike Dutch teens, not all US teens have access to no-cost contraception, the authors note.

Definite Correlation

Commenting for Medscape Medical News, Maureen Sayres Van Niel, MD, who is president of the Women’s Caucus of the American Psychiatric Association and is a reproductive psychiatrist in Cambridge, Massachusetts, described the study as “important” and “well done.”

“This study collected data over a long period of time, which is exactly the kind of data we need,” she said.
Scandinavian countries and the Netherlands “are better able to do these kinds of studies than the US because they have every person’s medical data on record, beginning at birth and continuing until death,” said Van Niel.
Previous “excellent” studies ― one from Sweden and one from Denmark ― showed a “definite correlation” between use of hormonal contraceptives and depression and antidepressant use later in life, said Van Niel. She noted that this new analysis is different in that it assessed the occurrence of depressive symptoms while girls were actually taking oral contraceptives.
Van Niel agreed that the new results don’t mean that teenage girls should not use OCPs. She noted that the overall incidence of depression in young persons who use OCPs is “still low.”
Van Niel said that although sexually active girls need effective contraception, in her experience, “they are less likely to use a nonoral form of contraceptive that older women use, such as the ring or IUD.”
Some vulnerable young girls may be predisposed to depressive symptoms and may be particularly sensitive to hormonal fluctuations, said Van Niel. Researchers are working on genetic markers and biomarkers to identify such susceptible individuals, she said.
TRAILS has been financially supported by the Netherlands Organization for Scientific Research NOW, the Dutch Ministry of Justice, the European Science Foundation, the European Research Council, the European Science Foundation, Biobanking and Biomolecular Resources Research Infrastructure BBMRI-NL, the Gratama Foundation, the Jan Dekker Foundation, participating universities, and the Accare Center for Child and Adolescent Psychiatry. The authors’ relevant financial relationships are listed in the original article. Van Niel has disclosed no such financial relationships.
JAMA Psychiatry. Published online October 2, 2019. Full text
https://www.medscape.com/viewarticle/919328#vp_1

‘Chemical Burns’ Seen as Possible Cause of Vaping Lung Damage

Lung injuries from vaping probably result from direct toxicity or tissue damage caused by noxious chemical fumes, rather than from an accumulation of lipids in the lungs, pathology data suggest.
“We were not surprised by what we found, regarding toxicity,” Brandon T. Larsen, MD, PhD, a surgical pathologist at the Mayo Clinic, Scottsdale, Arizona, and a national expert in lung pathology, said in a news release.
“We have seen a handful of cases, scattered individual cases, over the past two years where we’ve observed the same thing, and now we are seeing a sudden spike in cases. Our study offers the first detailed review of the abnormalities that may be seen in lung biopsies to help clinicians and pathologists make a diagnosis in an appropriate clinical context,” Larsen said.
To learn more about the pathology of vaping-associated lung injury, Larsen and colleagues studied lung biopsy specimens from 17 patients (13 men; median age, 35 years) who reported vaping and who were suspected of having associated lung injuries. Two of the patients were from the Mayo Clinic, and the other patients were from elsewhere in the United States. Most (71%) of the patients vaped with marijuana or cannabis oils.
Larsen and colleagues’ findings were published online October 2 in the New England Journal of Medicine.
All of the patients had bilateral pulmonary opacities; 15 of the patients presented in 2019.
All of the lung biopsy specimens revealed “patterns of acute lung injury, including acute fibrinous pneumonitis, diffuse alveolar damage, or organizing pneumonia, usually bronchiolocentric and accompanied by bronchiolitis,” the authors explain.
Histologic findings were nonspecific, but all cases were characterized by foamy macrophages and pneumocyte vacuolization. Pigmented macrophages were sometimes seen, but these never predominated. There were often prominent neutrophils; eosinophils were seen rarely; and no granulomas were seen.

Bronchioloalveolar lavage fluid was available for two cases. They revealed “abundant foamy macrophages.” Two patients who had diffuse alveolar damage died.
The researchers saw no histologic or radiologic evidence of tissue damage resulting from an accumulation of lipids such as mineral oils, which until now have been a suspected cause of vaping-linked lung injuries.
“While we can’t discount the potential role of lipids, we have not seen anything to suggest this is a problem caused by lipid accumulation in the lungs. Instead, it seems to be some kind of direct chemical injury, similar to what one might see with exposures to toxic chemical fumes, poisonous gases and toxic agents,” Larsen said in the news release.
More than 800 lung injury cases have been linked to vaping during the past several months, and at least 12 patients in 10 states have died. Investigators believe products that contain THC or other cannabis oils such as cannabidiol may be involved.

Some states have temporarily banned the sale of e-cigarettes or the flavored liquids used in the products, pending health investigations. The US Food and Drug Administration is considering banning all nontobacco-flavored vaping liquids. The Centers for Disease Control and Prevention cautions that children, young adults, pregnant women, and adults who don’t currently use tobacco products should not use e-cigarettes, and the American Lung Association says e-cigarettes are not safe and can cause permanent lung injury and disease.
“Everyone should recognize that vaping is not without potential risks, including life-threatening risks, and I think our research supports that,” Larsen warned. “It would seem prudent based on our observations to explore ways to better regulate the industry and better educate the public, especially our youth, about the risks associated with vaping.”
“Although it is difficult to discount the potential role of lipid, we believe that the histologic changes instead suggest that vaping-associated lung injury represents a form of airway-associated lung injury represents a form of airway-centered chemical pneumonitis from one or more inhaled toxic substances rather than exogenous lipoid pneumonia as such, but the agents responsible remain unknown,” the authors conclude.
Larsen has received personal fees from Paraxel and Veracyte outside of this study. One coauthor has received personal fees from Paraxel. The remaining coauthors have disclosed no relevant financial relationships.
N Engl J Med. Published online October 2, 2019. Full text
https://www.medscape.com/viewarticle/919361