Vertex builds in gene editing yet again, with $1.2bn Arbor deal

 Vertex Pharma has ramped up its involvement in gene-editing medicines for the third time in a matter of months, agreeing a partnership with CRISPR specialist Arbor Biotechnologies that could be worth up to $1.2 billion.

The latest deal allows Vertex to tap into Arbor’s technology platform to develop cell therapies for diseases like type 1 diabetes and blood disorders sickle cell disease (SCD) and beta thalassaemia. It will focus on ‘ex vivo’ therapies, which involves harvesting cells from patients, modifying them and then infusing then back into the body.

It seems likely that the type 1 diabetes programme will be focused on developing cells that can secrete insulin in response to blood glucose levels – acting as a replacement for pancreatic beta cells that are destroyed in the autoimmune disease – which is already a focus of Vertex’ research.

The latest partnership follows an alliance with Obsidian Therapeutics and a reworked deal with CRISPR Therapeutics, both signed in April, and broadens Vertex’ position in therapies that promise to provide one-shot cures for a range of disorders.

According to the terms of the agreement, Arbor is in line for an undisclosed upfront payment and equity investment, plus milestone payments tied to a maximum of seven programmes and royalties on sales if any reach the market.

It’s not the first time Vertex and Arbor have worked together – in 2018, they collaborated on a project focused on genetic diseases, including cystic fibrosis, Vertex’s core therapeutic focus with four approved therapies that treat around 90% of CF patients.

Arbor’s in-house pipeline meanwhile is concentrating initially on liver diseases, including primary hyperoxaluria, although much of its work to date has gone towards extending its gene-editing tools, such as proprietary gene editor enzymes.

“This new collaboration further expands our toolkit in cell and genetic therapies,” said Bastiano Sanna, Vertex’s chief of cell and genetic therapies. Bringing the two companies’ technologies together will create “improved cell replacement therapies for broad populations of patients”, he added.

Vertex’s lead gene-editing candidate is CRISPR Therapeutics-partnered CTX001 for SCD and transfusion-dependent thalassaemia (TDT), which generated impressive results at last year’s American Society of Hematology (ASH) annual meeting.

The company says it should have completed enrolment in its pivotal trials of CTX001 in the third quarter, with filings expected within the next two years. If approved, it could mount a challenge to bluebird bio’s gene therapy Zynteglo, which is already approved in Europe.

https://pharmaphorum.com/news/vertex-builds-in-gene-editing-yet-again-with-1-2bn-arbor-deal/

Whistleblower is the next problem for Cassava

 Speculative biotech plays don’t come much flakier than Cassava, a former penny stock that was catapulted to stardom and a $4.7bn valuation on the back of a wave of investor enthusiasm over Alzheimer’s disease. Now the company, which fell 24% in July on open-label data with simufilam, faces the problem of a citizen’s petition claiming serious misconduct and asking the FDA to halt simufilam’s two ongoing clinical trials. The basis for this request, made by the law firm Labaton Sucharow on behalf of a whistleblower, is that Cassava’s claim that simufilam blocks amyloid-beta’s toxic signalling by restoring the normal shape of filamin A is bogus. “No other lab has [connected] filamin A to Alzheimer’s disease,” the petition claims, alleging that Western blots going back 15 years, some appearing with very sharp edges, had been manipulated and “pieced together from multiple sources”. This morning, with shares off 20%, Cassava called the claims “false and misleading”, saying Western blot bands were “supposed to look sharp”, and that “proteins can and do stick to the side of a lane and migrate that way”. 12-month readout of uncontrolled simufilam data are expected soon, and the two studies are continuing for now.

Simufilam's active clinical trials
Study	Design	Primary endpoint(s)	Data
NCT04388254	200 mild-to-moderate Alzheimer's patients, placebo	Safety, chg in biomarkers, chg in Adas-Cog11 at <12mth (open-label) & 12-18mth (blinded randomised withdrawal)	Open-label data in 50 patients showed mean 3-point Adas-Cog11 improvement
Rethink-Alz (ph3)	750 mild-to-moderate Alzheimer's patients, vs placebo	52wk chg in Adas-Cog12 & ADCS-ADL	Completion Oct 2023
Source: clinicaltrials.gov. https://www.evaluate.com/vantage/articles/news/snippets/whistleblower-next-problem-cassava

Roche's gene therapy plans take Shape with $3B-plus biobucks deal

 Roche may market the first FDA-approved in vivo gene therapy, but the company isn’t resting on its laurels. The Swiss pharma is teaming up with Shape Therapeutics on next-generation gene therapies for Alzheimer’s, Parkinson’s and rare diseases in a deal that could exceed $3 billion.

Shape will use its RNA-editing platform to identify development candidates against multiple targets, according to a statement. The deal could also include use of the biotech's adeno-associated virus (AAV) technology as well the creation of tissue-specific vectors to deliver treatments. Roche will pick up development and worldwide commercialization of programs that come out of the pact.

The companies did not break out financial details saying only that the $3 billion includes an upfront payment and milestone payments if development, regulatory and sales goals are met.

After launching in November 2019, Shape raised a major $112 million round in July of this year to bankroll multiple RNA-editing platforms. Rather than treat disease by editing DNA directly, Shape is taking aim at the molecules that carry instructions from the DNA to produce proteins. The company is working on medicines that address defective or toxic proteins that result from disease-causing mutations without making permanent changes to a person’s DNA.

Roche picked up Luxturna, an in vivo gene therapy for an inherited form of blindness, in the $4.8 billion buyout of Spark Therapeutics in 2019. Spark continues to develop gene therapies for diseases of the eye, liver and central nervous system.

The Shape deal follows a collaboration Roche struck with Dyno Therapeutics in October 2020 and a partnership the Spark unit inked with Senti Biosciences in April this year.

With Dyno, the Swiss major is working on treatments for central nervous system disorders and liver disease. Dyno is designing, developing and testing new AAV capsids to deliver gene therapies, while Roche and Spark will bring genetic payloads and advance the development of the treatments.

As for Spark and Senti, the duo is using the latter’s gene circuits technology to overcome hurdles that have dogged the first generation of cell and gene therapies. Adding gene circuits to these treatments allows them to sense and adapt to their environment, treating disease while limiting side effects.

https://www.fiercebiotech.com/biotech/roche-taps-rna-editing-shape-biobucks-deal-worth-up-to-3b

Brii's COVID antibody slashes hospitalization, deaths in late-phase trial, teeis up to take on Regeneron

 Add Brii Biosciences to the list of biotechs that have surged forward because of the COVID-19 pandemic. Brii, which only launched in 2018, now has phase 2/3 clinical trial data showing its antibody cocktail slashes the chances of hospitalization and death in high-risk outpatients with COVID-19 infections. 

The National Institutes of Health-sponsored ACTIV-2 study randomized 837 non-hospitalized COVID-19 patients at high risk of clinical progression to receive placebo or Brii’s antibody cocktail. As of the interim analysis, 12 people in the treatment arm had been hospitalized, compared to 45 of their peers on placebo. One patient on BRII-196/BRII-198 died, compared to nine people on placebo. Brii used the data to calculate that BRII-196/BRII-198 cuts hospitalizations and deaths by 78%.

Brii’s figures compare favorably to phase 3 data on Regeneron’s antibody cocktail. In a larger study of high-risk COVID-19 patients, Regeneron’s treatment reduced coronavirus-related hospitalization and all-cause death by 71%.

Full details on the effects of Brii’s antibodies are yet to emerge. Researchers are still following up with the patients in the study and analyzing questions such as whether the delay between the onset of symptoms and the start of treatment affects outcomes. Brii is also yet to share detailed safety data, saying only that 3.8% of patients on BRII-196/BRII-198 and 13.4% of patients on placebo had grade 3 or worse adverse events. “Few” events were considered to be drug related. 

The efficacy of the cocktail against different variants will be another area of focus. Participants in the study enrolled at sites in the U.S., Brazil, South Africa, Mexico, Argentina and the Philippines between January and July. The timing of the trial and locations of the sites suggests subjects may have been infected with any one of a number of variants, including alpha, beta, gamma and delta. The cocktail retained its activity against those and other variants of concern in in vitro tests.

Efficacy against variants is now essential for anti-SARS-CoV-2 antibodies. After a slow start, sales of Regeneron’s antibody cocktail have taken off in recent months, generating $2.6 billion in the second quarter. In contrast, sales at Eli Lilly crashed after the FDA revoked the authorization of one of its antibodies as a monotherapy. 

Shares in Brii rose 8.8% to 38.95 Hong Kong dollars ($5.00) after the release of the top-line data. Brii went public in Hong Kong earlier this year, securing around $319 million to add to the hundreds of millions it raised as a private company. 

https://www.fiercebiotech.com/biotech/brii-s-covid-19-antibody-slashes-hospitalizations-and-deaths-late-phase-trial-teeing-it-up

Intuitive Surgical responds to FDA notice on unauthorized use of robots in mastectomies

 Two years after the FDA first issued a safety notice outlining the lack of clinical evidence to support the use of robotic-assisted surgery systems in mastectomies, the agency is doubling down.

An updated safety notice published this month takes an even firmer stance on the matter, noting that surgical robots still have yet to be proven to be a safe and effective tool to perform mastectomies and other procedures to prevent and treat breast cancer.

Even so, the FDA said that it’s aware of ongoing clinical studies that are allegedly using robotic technology to perform those procedures “without the FDA oversight required for such significant risk studies.” Those requirements include, first and foremost, submitting an investigational device exemption application for the robotic-assisted surgery system in question before the study starts.

Additionally, while the agency has cleared the use of robotics in some surgical procedures that are often performed on cancer patients—such as hysterectomies, prostatectomies and colectomies—those clearances have largely been based on the 30-day complication rate of each procedure, rather than their long-term abilities to prevent or treat cancer.

In the initial 2019 safety notice, the FDA suggested that in order to obtain clearance for surgical robots to perform mastectomies and other procedures billed as cancer prevention tools, the developers of the devices would need to submit clinical data demonstrating the robots’ positive impact on factors like “local cancer recurrence, disease-free survival or overall survival at time periods much longer than 30 days.”

Though the agency didn’t name names, its updated safety communication came about a month after a Medscape report listed several ongoing clinical studies of robotically assisted mastectomies in the U.S.—all of which are reportedly focusing only on short-term survival and complication rates, rather than the longer-term outcomes that the FDA previously suggested would be necessary to gain clearance.

The largest of these studies is a five-center trial backed by Intuitive Surgical, which has led the surgical robotics industry with its da Vinci system for the past two decades.

In response to the FDA’s safety notice, Intuitive issued a statement of its own, confirming that “Intuitive’s ongoing U.S. clinical investigation on the safety and effectiveness of robotic-assisted surgery in prophylactic nipple-sparing mastectomy has been approved by the FDA under an investigational device exemption.”

The company also reiterated that the FDA has not yet cleared any robotic devices based on long-term, cancer-related outcomes, but stopped short of confirming whether its own ongoing study would evaluate its surgical robots based on those endpoints.

With these clinical parameters—and the continued lack of any robotic systems cleared for use in procedures to prevent or treat breast cancer—in mind, the agency recommends that healthcare providers who choose to use surgical robots in these operations anyways speak openly with patients about the risks and lack of clinical evidence associated with the devices.

Patients are also recommended to question surgeons about their training and experience with robotic-assisted surgery systems and discuss other treatment options. Any individuals who have experienced complications after being treated for breast or any other cancers with robotics are encouraged to file a report with the FDA’s MedWatch adverse event database.

https://www.fiercebiotech.com/medtech/fda-warns-against-unauthorized-use-surgical-robots-mastectomy-procedures

Anixa Covid-19 Compounds Expected to be Effective Against Delta Variant

  Anixa Biosciences, Inc. (NASDAQ: ANIX), a biotechnology company focused on the treatment and prevention of cancer and infectious diseases, announced today that a genomic variant analysis indicates that its potential compounds may be even more effective against the Delta variant than the original wild type SARS-CoV-2. 

While vaccination has proven to be an effective strategy to prevent Covid-19, the need exists for inexpensive, room-temperature stable, and orally bioavailable therapeutics for COVID-19.  Reasons for this need include the large percentage of individuals that have chosen to remain unvaccinated, the logistics and expense of distributing the vaccines worldwide, the reduction in efficacy that is seen for certain variants, and the expected need to continuously require booster shots due to waning immunity.

Anixa's program in collaboration with European partner MolGenie, focuses on identifying novel, small molecule inhibitors of Mpro, the main protease of the virus. The current compounds that Anixa is synthesizing and evaluating have demonstrated their ability to inhibit the function of this protein, which the virus needs to replicate. 

A key attribute of a successful therapeutic is the need to be effective against the prevailing variants that are circulating, especially if such emerging variants are more infectious.  Since the authorized vaccines target a surface protein of the SARS-CoV-2, known as the spike protein, variants demonstrating variability in evading the vaccines are characterized by mutations in this protein.  The prevailing variant of concern is known as the Delta variant.  

In an attempt to evaluate whether the compounds Anixa is developing might be effective against the Delta variant, Anixa undertook an analysis of the corresponding Mpro enzyme mutations in the Delta variant.  While mutations in the spike protein do not necessarily force a mutation in other functional proteins like Mpro, Anixa's analysis and published work demonstrate that a key mutation in Mpro does exist for the Delta variant.  Sequence analysis of several Delta variant samples demonstrate that the Mpro enzyme often has a mutation that replaces an asparagine (an amino acid) with leucine (another amino acid) at position 142, near the binding site.  This change makes the binding pocket of Mpro more hydrophobic.  By virtue of this change, the analysis indicates that Anixa's novel compounds will be stronger inhibitors of the variant Mpro than the wild-type (original).

"This analysis and conclusion is a theoretical study, but we are pleased that this analysis indicates that our compounds should be effective against the Delta variant," stated Dr. Amit Kumar, President and CEO of Anixa Biosciences.  "While this program is relatively early-stage in development, we have already received inbound calls from pharmaceutical companies and funding agencies interested in collaborating at the right time," continued Dr. Kumar.

Dr. Lutz Weber, President and CEO of MolGenie, stated, "We continue to synthesize several candidate compounds to identify the most potent drug candidate which we will take into pre-clinical drug development." 

https://www.prnewswire.com/news-releases/anixa-biosciences-covid-19-compounds-expected-to-be-effective-against-the-delta-variant-301362160.html

Covid protection for the fully vaccinated is waning: UK study

 Protection against the coronavirus is waning among those who have received both shots of the AstraZeneca and Pfizer vaccines, a new U.K. study has found. 

An analysis from the U.K.’s ZOE Covid app study of over 400,000 people who had received both shots of the Pfizer-BioNTech vaccine, showed that it was 88% effective in protecting against the coronavirus a month after receiving both shots. However, its effectiveness fell to 74% five or six months after receiving both doses of the Pfizer vaccine. 

In the same study, an analysis of over 700,000 people who had received both doses of the Oxford-AstraZeneca vaccine showed its effectiveness fell from 77% after a month to 67% at the four to five month mark. 

The data was collected after May 26, when the delta variant became the dominant strain, said Tim Spector, who is running the ongoing ZOE Covid app study. 

Spector, a professor of genetic epidemiology at King’s College London, presented this latest data during a webinar on Tuesday and said that the findings showed a “reduced benefit” of protection from both of these vaccines as the months progress. 

Nearly 42 million people in the U.K., 77% of the population aged over 16, have received two doses of a Covid vaccine, according to government data last updated on Tuesday. The daily data showed 30,838 Covid-19 infections had been recorded on Tuesday, while 174 people had died within 28 days of testing positive for the virus. 

Alexander Hammers, a professor of imaging and neuroscience at King’s College London, said on the webinar it was already known from other coronaviruses that immunity against the disease didn’t tend to be lifelong. 

“So we knew there was going to be some levelling off and the way I look at this is the levelling off is actually a little slower than I would have expected,” he said. 

And even though the data did show a “waning” in the effectiveness of the vaccines over time, Hammers said that people were “still probably at least 50% protected.” 

“Remember when the vaccines were first developed it was hoped that they were to have 60%-70% efficacy and everybody was pleasantly surprised that they came in well over 80%, sometimes well over 90,” he added. 

Nevertheless, Spector said he was still “a bit worried” by coronavirus data coming out of Israel, which had one of the fastest vaccination programs in the world and was ahead of the U.K. 

He pointed out that Israel was starting to see increased hospitalizations and deaths from the coronavirus, despite a large proportion of its population being vaccinated.  

Data published by Israel in July, showed that the Pfizer vaccine was just 16% effective against symptomatic infection for those individuals who received two doses in January. 

Comparing results is tricky, however, given differences in the nature of the vaccination programs in different countries, as well as differences in study dates, age groups and Covid testing regimes. 

Two U.S. studies published Tuesday by the Centers for Disease Control and Prevention showed waning immunity against Covid among those who were fully vaccinated, one of which was focused on front-line workers. 

The ZOE Covid study webinar panelists also discussed whether the waning effectiveness of the vaccines would bolster the need for booster Covid vaccine shots in the future. Spector pointed to the fact that Israel had already started planning to give out booster shots.

Anna Goodman, a consultant in infectious diseases and general medicine at London’s Guy’s and St Thomas’ NHS foundation trust, who is working on Covid vaccine booster trials said she imagined that “in time boosters will be needed but I’d like that time to be once everybody in the world is vaccinated.”

https://www.cnbc.com/2021/08/25/covid-protection-for-the-fully-vaccinated-is-waning-uk-study-finds.html