Janney: Amicus Has Significant Upside From Gene Therapy Pipeline

Amicus Therapeutics, Inc. FOLD 3.16% has an extensive portfolio of novel therapies for rare diseases with a focus on lysosomal storage disorders, according to Janney Montgomery Scott.

The Analyst

Janney’s Yun Zhong initiated coverage of Amicus Therapeutics with a Buy rating and $20 fair value estimate.

The Thesis

Galafold, a next-gen enzyme replacement therapy, is well-positioned to gain significant share of the expanding Fabry disease market, Zhong said in the Friday initiation note.

While global ERT sales reached nearly $1.5 billion in 2018, a large number of patients are not receiving treatment — mainly due to the requirement of biweekly IV infusions, the analyst said. Against this backdrop, Galafold offers a highly favorable alternative treatment, as it offers oral dosing with comparable efficacy, he said.

A large number of undiagnosed or misdiagnosed Fabry patients carry mutations, Zhong said, adding that such patients will be more amenable to Galafold treatment.

Expressing optimism regarding the therapy’s rapid penetration due to increased disease awareness and improved diagnostics, Zhong said that Amicus’ $500-million estimate could prove highly conservative.

With the Celenex acquisition, Amicus gained access to one the broadest gene therapy pipelines in the industry, the analyst said. The acquisition, along with the UPenn collaboration and the company’s expertise, could help Amicus build a platform that will support its exponential growth in the coming years, he said.

The company has another ERT in pivotal Phase III clinical development for Pompe disease. Given the strong Galafold launch trend and encouraging Pompe data to date, there seems to be limited downside risk for Amicus, according to Janney.

https://www.benzinga.com/analyst-ratings/analyst-color/19/04/13493975/janney-amicus-therapeutics-has-significant-upside-from-gene-therapy-pipeline

23andMe Breast, Ovarian Risk Test Misses Nearly 90% of BRCA Mutation Carriers

A study led by researchers at Invitae has found that 23andMe’s direct-to-consumer BRCA test, which tests for three common variants in the BRCA1 and BRCA2 genes and is authorized by the US Food and Drug Administration, misses almost 90 percent of BRCA mutation carriers, both in those with and those without a personal or family history of cancer.

In addition, it misses almost 20 percent of BRCA mutations in those of self-reported Ashkenazi Jewish descent because it doesn’t test for them.

The results of the study, which looked at data from almost 125,000 de-identified individivuals who had been referred to Invitae for diagnostic testing with one of the firm’s cancer risk tests, was presented yesterday at the American College of Medical Genetics and Genomics annual meeting by Edward Esplin, a clinical geneticist at Invitae.

Esplin told GenomeWeb that the study, which did not mention 23andMe by name, was meant to criticize a screening strategy with an FDA-authorized DTC test that appears to have limited clinical utility rather than to criticize 23andMe for offering the test.

In his presentation, he pointed out that the FDA’s authorization for the test last year “sounds more like a warning than an approval.” FDA cautioned that the test, which examines three founder mutations in the BRCA genes that are common in the Ashkenazi Jewish population, does not assess more than 1,000 other known BRCA mutations, so a negative result does not rule out someone is a mutation carrier. It also advises that positive test results should not be used to determine any treatments without confirmatory testing and genetic counseling.

23andMe has been widely criticized for offering the test, and many experts have said that customers receiving a negative result may falsely assume they do not have an elevated breast or ovarian cancer genetic risk. The company has countered that it believes its customers do understand the limitations of the test and that many who receive a positive result may not have learned about it otherwise.

However, Esplin said, up until now, there has been no data available on the implications of a DTC strategy for breast and ovarian cancer risk testing that is limited to only three mutations.

For their ongoing study, which involves clinical collaborators from the Dana-Farber Cancer Institute, Yale University, and Georgetown University, the researchers are planning to analyze data from more than 200,000 de-identified individuals tested by Invitae and to include clinical vignettes of patients they have seen. Yesterday, Esplin presented preliminary results from three cohorts totaling almost 125,000 de-identified persons who had undergone diagnostic cancer risk testing at Invitae for different reasons.

Of these, 119,300 were referred for diagnostic hereditary breast and ovarian cancer genetic testing because of a personal or family history of cancer. The company offers a variety of cancer risk panels of different sizes that include the BRCA genes, and Esplin did not specify which of these panels were used in testing patients.

Another 5,200 patients had undergone Invitae testing without a reported personal or family history of cancer because they had sought genetic testing to inform their own health. These included patients who had taken one of Invitae’s proactive health genetic tests, such as the Cancer Screen or the Genetic Health Screen.

A third cohort consisted of 100 patients who were referred to Invitae for confirmatory testing after receiving a positive result on a DTC test from 23andMe and others.

In the indication-based cohort, Invitae found that 11 percent had a pathogenic or likely pathogenic mutation in a hereditary cancer syndrome-associated gene, while 89 percent had a negative result.

Of the more than 4,700 patients in whom Invitae found a pathogenic or likely pathogenic mutation in BRCA1 or BRCA2, only 12 percent had one of the three Ashkenazi Jewish founder mutations, while 88 percent had a different mutation. Those patients would not have obtained a positive result had they taken the limited 23andMe test, which is “clearly very concerning,” Esplin said.

Within the BRCA-positive group, 94 percent of those who said they were not of Ashkenazi Jewish descent had a mutation that was not included in the 23andMe test.

Even within some self-reported Ashkenazi Jewish individuals with a BRCA mutation, 23andMe would have delivered a negative result: 19 percent of them had a mutation other than the three founder mutations.

Among the 5,000 or so “healthy” patients who underwent Invitae testing without a reported family or personal history of cancer – a group that might be more representative of the type of person seeking out 23andMe’s BRCA test because they would not be covered by current screening guidelines – the results were no different: only 12 percent of those who were found to have a mutation in BRCA1 or BRCA2 had one of the three mutations tested by 23andMe, and 88 percent had a different mutation.

Finally, Invitae was only able to confirm a positive DTC result – many of them in BRCA1 or BRCA2 – for half of the 100 individuals who were referred to it for confirmatory testing. Esplin said this result is consistent with other data published last year and points to the potential for false-positive results from a DTC screening strategy. Not all of the 100 had their DTC test from 23andMe, he said, and about a third had obtained their positive result not directly from the test provider but by submitting their raw data to a third party for analysis.

Overall, Esplin said, the data confirms the caveats contained in the FDA’s authorization of 23andMe’s BRCA test and suggests that confirmatory testing is needed for those with a positive result as well as those with a negative result from limited DTC testing. “Both of these types of individuals should receive clinical genetic testing,” he said.

This, Esplin and his colleagues wrote in their conference abstract, “begs the question of what role, if any, does DTC testing for these three mutations really play in the healthcare of individuals who either have an indication for testing or are seeking to know their risks.”

https://www.genomeweb.com/molecular-diagnostics/23andme-dtc-breast-and-ovarian-cancer-risk-test-misses-almost-90-percent-brca#.XKeNJNJKjIU

Soliton Initiated Clinical Trials for Treatment of Cellulite in Humans

Soliton, Inc., (NASDAQ: SOLY) (“Soliton” or the “Company”), a medical device company with a novel and proprietary platform technology licensed from The University of Texas on behalf of the MD Anderson Cancer Center (“MD Anderson”), today summarized its efforts to conduct a proof of concept clinical trial for the treatment of cellulite based on Institutional Review Board (“IRB”) approval of the study.  The study was initiated after positive results in animal studies indicated the potential for a higher-energy version of its acoustic shockwave technology to affect the factors contributing to the formation of cellulite.

The study treated each thigh of five patients (n=10) with a higher-energy version of Soliton’s acoustic shockwave device with the intent to evaluate safety and efficacy in the treatment of cellulite.  The study is designed to evaluate results at both the 12-week and 26-week timepoints from initial treatment in order to assess both near-term and long-term effects.

“Our preclinical data led us to believe we could have a significant impact on the reduction of cellulite,” commented Dr. Chris Capelli, Soliton’s President and CEO.  “This is especially significant since our technology should represent a non-invasive, pain free treatment that requires no anesthesia and involves no bruising, discomfort or downtime.  If we are right, we believe this could be a major breakthrough in the treatment of cellulite.”

Soliton, Inc. is a medical device company with a novel and proprietary platform technology licensed from MD Anderson. The Company’s first planned commercial product is designed to use rapid pulses of designed acoustic shockwaves in conjunction with existing lasers to accelerate the removal of unwanted tattoos (RAP device). In addition, higher energy versions of acoustic pulse devices are in early stages of development for potential stand-alone treatment of cellulite and other indications. Both products are investigational and are not available for sale in the United States.

https://www.prnewswire.com/news-releases/soliton-initiated-clinical-trials-for-treatment-of-cellulite-in-humans-300821569.html

Clues to what causes immuno-oncology drug resistance

Checkpoint-inhibiting drugs have revolutionized the treatment of melanoma and other cancers by freeing up the immune system to attack tumors. But the medicines don’t work for as many as half of patients, even when they’re combined with other cancer treatments.

Now, two separate research groups have uncovered different mechanisms of immuno-oncology drug resistance. One involves the gut microbiome, while the other is related to vesicles that are produced by cancer cells.

First, a worldwide consortium of 40 scientists led by Sanford Burnham Prebys released a study demonstrating that the gut microbiome orchestrates the immune system’s response to cancer. They published their observations in the journal Nature Communications.

The Sanford Burnham Prebys-led team made the discovery by working with mice engineered to lack RING finger protein 5 (RNF5), a gene that normally works to clear damaged proteins from cells. These mice mounted a strong immune response to melanoma, so the researchers used bioinformatics technology to identify 11 bacterial strains that were plentiful in the animals’ guts. They then transferred the bacteria to normal mice and found it also induced a strong immune response to melanoma in those animals.

The researchers mapped out the immune components that were active in the gut, and they discovered that a signaling pathway called the unfolded protein response (UPR) was reduced when immune cells were activated. Then they studied tumor samples from people who had received checkpoint inhibitors, and they found reduced UPR expression correlated with a good response to treatment.

The findings “identify a collection of bacterial strains that could turn on anti-tumor immunity and biomarkers that could be used to stratify people with melanoma for treatment with select checkpoint inhibitors,” said senior author and Sanford Burnham Prebys professor Ze’ev Ronai, Ph.D., in a statement.

The second study, from a team at the University of California, San Francisco (UCSF), focused on the protein PD-L1, the target of some checkpoint-inhibiting drugs. Normally, checkpoint inhibitors work by recognizing PD-L1 on the surface of cancer cells and then interfering either with it or the related protein PD-1. The UCSF researchers discovered that in some patients, PD-L1 travels throughout the body, inhibiting immune cells before they can reach the cancer.

In those patients, the PD-L1 ends up in exosomes, which are vesicles that come from cancer cells and travel in the bloodstream to the lymph nodes, the UCSF team discovered. While there, they “disarm” the immune cells, so they’re unable to launch an attack against the cancer. They published their findings in the journal Cell.

The prevailing view of why patients sometimes don’t respond to PD-L1 inhibitors is that their cancers are not making enough of the protein. But the UCSF researchers showed “the protein was in fact being made at some point, and that it wasn’t being degraded,” senior author Robert Blelloch, M.D,. Ph.D., professor of urology at UCSF, said in a statement. “That’s when we looked at exosomes and found the missing PD-L1.”

In a second experiment, the UCSF team used the gene-editing technology CRISPR to delete two genes necessary for exosome production from cancer cells. Mice that received those cells had more activated immune cells in their lymph nodes than did animals that got unedited cancer cells.

They then treated a mouse model of colorectal cancer with a combination of a PD-L1 inhibitor and a drug that prevents exosomes from forming. Those mice survived longer than animals treated with either drug alone did.

Blelloch’s team plans to conduct further studies, with the ultimate goal of developing a “tumor cell vaccine” to help patients who don’t currently respond to checkpoint inhibitors.

https://www.fiercebiotech.com/research/new-pathways-towards-improving-immuno-oncology-drugs

U.S. forces Chinese divestiture in health data startup PatientsLikeMe

Real-world data gatherer PatientsLikeMe has to shop for a new buyer—and quickly—after the Trump administration ordered a Chinese company to divest its majority stake, according to a report from CNBC.

In 2017, PatientsLikeMe partnered with the Shenzhen, China-based iCarbonX—a genomics data firm supported by the conglomerate Tencent—and raised more than $100 million in a series C round with iCarbonX serving as lead investor.

iCarbonX agreed to provide multi-omics sequencing services, while PatientsLikeMe would serve as “a cornerstone” of its health technology collaboration, which aimed to merge and analyze biological and patient-generated information using artificial intelligence.

The Cambridge, Massachusetts-based PatientsLikeMe links together about 700,000 people with those who have similar conditions to share health experiences and gather data for research studies. Other companies participating in iCarbonX’s alliance included SomaLogic, HealthTell, AOBiome, GALT, Imagu and Robustnique, according to a release.

However, the Treasury Department’s Committee on Foreign Investment in the United States (CFIUS) has been scrutinizing Chinese investments in American companies.

CFIUS ordered the divestiture under a 2008 statute that allows the president to review and block any merger that could result in a foreign person or company controlling a U.S. company. That was expanded last year to include foreign investments and minority stakes, in addition to takeovers, the article said.

While CFIUS previously focused on multibillion-dollar international acquisitions, the actions singling out a small company could have harsh effects on the startup sphere by chilling international investment.

CNBC reported that Chinese expenditures in U.S. businesses have dropped 90% in the past two years, from $46 billion in 2016 to $4.8 billion in 2018, according to data from the Rhodium Group, which said another $20 billion in divestitures is still pending.

https://www.fiercebiotech.com/medtech/u-s-government-forces-chinese-divestiture-health-data-startup-patientslikeme

FDA declares 40 generics free of carcinogens as ‘sartan’ recalls continue

As recalls on blood pressure drugs continue to plague drugmakers, the FDA declared a slate of 40 generic pills safe to use.

On Thursday, the agency released a list of 40 generic angiotensin II receptor blockers (ARBs) that are free of three potentially carcinogenic compounds linked to various “sartan” drugs, including valsartan and losartan.

The FDA launched a global recall in 2018 after a U.S. drug manufacturer found high levels of N-nitrosodimethylamine (NDMA) in the valsartan active ingredient it had bought from a Chinese supplier. Since then, the FDA discovered that NDMA, N-Nitroso-N-methyl-4-aminobutyric acid (NMBA) and NDEA—all considered unsafe at certain levels—can be created during sartan drug manufacturing under certain conditions.

The first global recall included all non-expired generic valsartan sold by Major Pharmaceuticals, Teva and Huahai’s U.S. subsidiary, Solco Healthcare, as well as valsartan/hydrochlorothiazide (HCTZ) made by Teva and Solco.

The recall later expanded to other “sartan” products as impurities turned up in the irbesartan API produced by India’s Aurobindo and in losartan products made using an API from China’s Zhejiang Huahai Pharmaceuticals.

With an investigation underway, the FDA’s top two drug officials reiterated in a joint statement that generics with carcinogen levels higher than the accepted limit would be temporarily distributed to prevent a shortage of losartan, which is used to treat high blood pressure and prevent heart failure.

Outgoing FDA Commissioner Scott Gottlieb and Janet Woodcock, director of the Center for Drug Evaluation and Research, said agency scientists believe using the tainted drugs temporarily wouldn’t raise cancer risks in a “meaningful” way. “After careful evaluation of safety data and consideration of the benefits and risks to patients, we think it’s critical that patients have access to these drugs while impurity-free losartan is manufactured,” the Thursday statement said.

Gottlieb and Woodcock said they expected carcinogen-free products to replenish the U.S. supply of losartan within six months.

“We want to reassure patients that we strongly believe the risks, such as stroke, of abruptly discontinuing these important medicines far outweighs the low risk associated with continuing the medications with these impurities,” they said.

After the recalls, a suite of lawsuits were filed against drugmakers cited by the FDA, including Indian drugmaker Aurobindo and Huahai.

In October, Huahai told the Shanghai Stock Exchange that it faced lawsuits in four states over its production of tainted valsartan.

In a federal suit in Florida, consumers accused Walmart, Aurobindo, U.S. drugmaker ScieGen Pharmaceuticals and distributor Westminster Pharmaceuticals of producing and selling tainted irbesartan that may have exacerbated health conditions.

In an attempt to begin cleaning up the valsartan market, the FDA hustled through a new valsartan generic from India’s Alkem Laboratories last month. The agency said Alkem’s Diovan copy was free from NDMA and NDEA.

https://www.fiercepharma.com/pharma/fda-names-40-generics-free-carcinogens-as-sartan-recalls-continue

Why your doctor might ignore your DNR — and it’s perfectly legal

While seated in the waiting room of a Florida outpatient surgery center, an 82-year-old patient received a nasty surprise. The receptionist asked him to sign a form stipulating that the facility would disregard his properly executed DNR [do-not-resuscitate] order.

Specifically, the form stated that the center would ignore his end-of-life wishes “regardless of the contents of any advance directives/living wills.” The patient was angry and confused.

There’s a business rationale for health care facilities to proclaim their indifference to a patient’s wishes. By keeping people alive at all cost, they avoid potential liability for a mishap before, during or after a medical procedure.

But are they allowed to ask a patient awaiting surgery to sign such a form?

“It is legal but it may not be ethical,” said Craig Klugman, a professor of bioethics at DePaul University in Chicago. “It is done out of fear of harming patients and the liability.”

He notes that several medical associations have concluded that asking patients to sign blanket DNR overrides is not appropriate. Instead, the provider should confer with the patient beforehand and hash out a plan if things go awry.

In practice, however, such conversations rarely occur. In the run-up to surgery, harried providers may lack the time or inclination to raise this sensitive issue. And patients might assume that as long as they’ve completed their advance directives and their doctor has signed their DNR order, there’s nothing further to discuss.

There’s an understandable medical reason why some facilities disregard DNRs. Say a procedure involves anesthesia and temporary cardiac abnormalities or other serious problems arise. Anesthesiologists and surgeons can in many cases “pretty easily reverse” such adverse events, Klugman says, thus bringing you back to life before you know it.

“You might have an interaction with the anesthesia drug,” he said. “It can have nothing to do with your underlying disease,” and resuscitating you poses a manageable risk. So it’s no wonder facilities want you to acknowledge in advance that they can intervene in such instances.

Always ask ahead of time if a hospital, outpatient surgical center or other provider will honor your DNR order. Know their policy in advance so that you’re not caught off guard when they ask you to sign something just before they wheel you into the operating room.

“You have to be willing to negotiate,” Klugman said. “When I’m handed an informed consent form, I cross things out and add things in,” such as limiting the institution’s ability to share his medical information with third parties without his permission.

It’s also important to understand what documents you need to convey your end-of-life wishes. Laws and protocols vary by state.

Terms such as “advance directive,” “living will” and “health care power of attorney” can have subtle differences depending on where you live. In addition, about two-thirds of states have some version of a “POLST” form that indicates what medical treatments you want (or don’t want) in an emergency, Klugman says. In some states, physicians and other providers must honor a valid advance directive or face disciplinary action.

Because you cannot anticipate every conceivable scenario when you might get resuscitated or receive life-altering care, think ahead. Write an expansive letter describing under what conditions you want to be kept alive (to play with your grandkids?, eat and drink on your own?, cheer your favorite sports team? etc.).

Use the letter as an opportunity to share your values and end-of-life philosophy. For instance, consider whether you prioritize pain management over mental clarity (or vice versa) if battling a major illness. Sign and date the letter and share it with your family, medical providers and anyone else involved in your care.

“Be as clear as you can be with your written documents and with your loved ones so that your health care agent can express your wishes on your behalf,” said Robyn Shapiro, an attorney and founder of the Health Sciences Law Group in Fox Point, Wis. “Be clear with your doctor as well.”

An often-overlooked step involves completing a psychiatric advance directive, especially if you have a mental illness. Otherwise, a crisis can leave you dependent on others to make life-or-death decisions for you.

“A psychiatric advance directive can be a different form or part of standard advance directives,” Shapiro said. “If you have a history of mental illness, you can say if you want a loved one to enter you in a clinical [drug] trial or get electroshock therapy.”

https://www.marketwatch.com/story/if-you-dont-declare-your-end-of-life-wishes-and-even-if-you-do-medical-providers-might-ignore-them-2019-04-05?siteid=rss&rss=1