New insight into how Biogen’s Tecfidera works may lead to better MS therapies

Biogen’s top-selling Tecfidera (dimethyl fumarate) has proven to be an effective treatment for multiple sclerosis, bringing in $4.27 billion in sales in 2018, but its exact mechanism of action remains a mystery. Now scientists from the City University of New York and the Icahn School of Medicine at Mount Sinai have identified a possible mechanism of action, providing information that they believe could lead to better drugs for MS and other autoimmune diseases.

MS happens when brain-homing T cells mistakenly attack the central nervous system. In their paper, which is featured on the March cover of the journal Brain, the CUNY-Mount Sinai team suggested that Tecfidera—after it is metabolized by the body—works via a particular DNA region to reduce the development of these harmful immune cells.

During the study, the researchers analyzed 35 patients who were given Tecfidera and 16 who were treated with Teva’s Copaxone. They collected blood samples from all the participants and measured their levels of brain-homing T cells by looking at the cytokine receptors CCR4 and CCR6, which are important for T-cell trafficking and have been implicated in MS development.

In patients on Tecfidera, the researchers recorded lower levels of brain-homing T cells compared with other groups. They then analyzed how the drug achieved that immuno-modulating effect on the epigenetic level, meaning they studied how Tecfidera alters gene expression of T cells without changing the underlying DNA sequence.

They found that Tecfidera hyper-“methylates” a genomic site in CD4 T cells that encodes miR-21, a microRNA that is believed to be critical for producing MS-related T cells. Methylation is an epigenetic process whereby DNA’s structure—and hence its activity—is changed. The researchers treated CD4 T cells in vitro and observed DNA methylation at miR-21 that was dose-dependent.

The CUNY-Mount Sinai team believes their findings offer “useful insight into how we might leverage the metabolic-epigenetic interplay between cells and their environment to create new immune-modulating therapies for diseases like MS,” Patrizia Casaccia, M.D. Ph.D., the study’s senior author, said in a statement.

Figuring out why some T cells turn on the body is a priority for researchers studying MS and other autoimmune diseases. Researchers at the Georgia Institute of Technology, for example, said last year that they discovered a mechanism in the body that prevents precursor cells from maturing into harmful T cells—a signaling process that could be a potential target for autoimmune diseases.

The new insight into Tecfidera may benefit more than just MS research, the CUNY-Mount Sinai scientists argue. It could boost efforts to find new therapies for other immune-mediated diseases that are dependent on miR-21 overexpression. The authors noted in the study that psoriasis, systemic lupus erythematosus and inflammatory bowel disease have all been linked to miR-21.

https://www.fiercebiotech.com/research/new-insight-into-how-tecfidera-works-may-lead-to-better-ms-therapies

Gilead’s Kite in 10-target CAR-T tech deal with MaxCyte

Gilead’s Kite Pharma has expanded its CAR-T agreement with MaxCyte. The revised deal gives Kite the chance to apply MaxCyte’s transfection technology to up to 10 targets.

Kite first struck a deal to use MaxCyte’s technology, dubbed Flow Electroporation, in November. Now, Kite has significantly expanded the deal by securing the right to use the technology in the nonviral engineering of CAR-T therapies against up to 10 targets. MaxCyte granted Kite nonexclusive access to the technology in return for a financial package featuring development and approval milestones.

“We’re excited to take our relationship with Kite further into product development, providing the company the ability to leverage MaxCyte’s versatile cell engineering platform to enable the power of gene-editing for clinical and commercial development of critical new CAR-T therapeutics,” MaxCyte CEO Doug Doerfler said in a statement.

The quick decision to expand the agreement suggests Kite, like other companies before it, was won over by the technology. MaxCyte’s platform uses an electrical field to reverse the permeability of cell membranes and enable molecules to pass into the cell, eliminating the use of chemicals or viruses.

Applied to autologous CAR-T therapies, MaxCyte thinks the technology will shorten and simplify the production process, enabling companies to get drugs to cancer patients sooner and for less money. If MaxCyte’s technology lives up to that billing, it could lessen two of the big shortcomings of existing CAR-Ts, namely the cost of making them and the lag between prescription and treatment.

MaxCyte is working on its own CAR-T candidates while licensing its technology to other companies. For its in-house pipeline, MaxCyte has used the technology to create autologous CAR-Ts using human mRNA.

https://www.fiercebiotech.com/biotech/gilead-s-kite-pens-10-target-car-t-tech-deal-maxcyte

Tonix says FDA rescinds Breakthrough Therapy designation for Tonmya

Tonix Pharmaceuticals Holding Corp. announced program updates related to the development of Tonmya, which is in Phase 3 development for the treatment of posttraumatic stress disorder, or PTSD. The FDA notified the company that the Breakthrough Therapy designation, or BTD, granted for Tonmya for PTSD in December 2016 has been rescinded because interim analysis data on Tonmya from the HONOR study do not support the continuation of the BTD. The BTD granted to Tonmya was based on retrospective analysis of the effect of Tonmya 5.6 mg in the Phase 2 AtEase study in military-related PTSD, that shows a substantial improvement over existing therapies in military-related PTSD. Tonix CEO Seth Lederman commented, “The rescission of Breakthrough Therapy designation of Tonmya for PTSD does not alter our NDA plan and will have minimum impact on our future interactions with the FDA. We are on track to start imminently the Phase 3 RECOVERY trial in civilian and military-related PTSD. We are grateful for the guidance and continued support received from the FDA. We remain committed to expedite the development of Tonmya for PTSD, especially military-related PTSD.”

https://thefly.com/landingPageNews.php?id=2873352

Novartis’ shift to superpricey cell and gene therapies draws investor ire

It’s not unusual for critics to challenge top drugmakers for price hikes on old drugs, but Novartis is contending with a different kind of pricing pressure from a Swiss shareholder activist group.

In this case, it’s the company’s move into ultra-expensive, one-time treatments that has critics riled. At the Swiss drugmakers’ annual meeting Thursday, the investment firm Actares questioned Novartis’ rollout prices on cell and gene therapies and whether they’re sustainable for payers.

The investors say they’ve been questioning drug prices for years, especially in cancer, but Novartis has taken the issue a step further by deciding to specialize in the new wave of treatments, starting with the cell therapy Kymriah it launched in 2017. Novartis believes six- and seven- digit prices for such drugs are “justified,” Actares said in a statement, according to a translation.

Novartis rolled out Kymriah at a list price of $475,000, and the company has said its forthcoming spinal muscular atrophy gene therapy, Zolgensma, would be cost-effective at a price of $4 million to $5 million. The company hasn’t announced a launch price for Zolgensma.

Novartis CEO Vas Narasimhan said at Thursday’s meeting that the company prices drugs based on value and seeks a fair return for more R&D, according to Reuters.

“With respect to pricing in cell and gene therapies, I think what’s often lost in the discussion is the remarkable impact of these medicines,” Narasimhan said at the meeting, as quoted by the news service. “These are true breakthroughs that come from a single infusion of a medicine that don’t require lifelong therapy.”

Narasimhan has made no secret of his enthusiasm for the up-and-coming category. At the J.P. Morgan Healthcare Conference in January, he said Novartis is building out a “game board” of treatments in cell and gene therapy, plus radio-drug conjugates. He said the company’s efforts in the field now will pay off in the long run as the new drug classes, now targeted at rare diseases, expand into broader markets.

For example, Novartis launched Kymriah at $475,000 to treat young adults with acute lymphoblastic leukemia. When the drug won a follow-up approval in diffuse large B-cell lymphoma—which is more common—the company matched Gilead Science’s $373,000 sticker price for Yescarta in that indication.

Ahead of Kymriah’s approval, drug cost activists such as David Mitchell, founder of Patients For Affordable Drugs, raised red flags about their potential prices. Mitchell met with Novartis executives ahead of the approval, but afterward said he was still worried Kymriah would be too expensive. After the pricing decision, he called the cost “excessive.”

Recently, U.S. cost watchdog ICER said Zolgensma should be priced far lower than the $4 million to $5 million Novartis has quoted. The group suggested a max price of $900,000, or $1.5 million using an alternative calculation method. Some analysts say they believe Novartis will set Zolgensma’s price at around $2 million.

https://www.fiercepharma.com/pharma/investors-question-novartis-move-into-superpricey-cell-and-gene-therapies

Can BMS rebels scuttle Celgene buy? Analysts math: so far, votes don’t add up

Bristol-Myers Squibb shareholders panicked on Wednesday when its largest institutional shareholder, Wellington Management, came out against its $74 billion acquisition of Celgene—and activist hedge fund Starboard Value immediately followed suit. Now, BMS is reportedly stepping up its efforts to calm investors’ nerves, meeting with institutional shareholders in New York and Boston this week, according to CNBC sources.

But could Wellington and Starboard really halt the deal, which comes up for an investor vote on April 12?

The answer is no—at least according to a slate of Wall Street analysts who crunched the numbers after Wellington announced its opposition. Sure, the influential investor’s negative opinion could persuade some on-the-fence voters, but Wellington is still facing an uphill battle, they said.

“Wellington, even combined with similarly positioned funds, lacks the votes to sway the deal outcome,” wrote analysts at Atlantic Equities in a Thursday investor note. They did the math in Wellington’s SEC filing and found that even though the firm said it has “investment discretion” over nearly 8% of BMS’ outstanding shares, it has shared voting power over only 1.7% of them.

Dodge & Cox reportedly opposes the deal, too, but it owns just 2.6% of shares. And Starboard Value’s voting power is even more limited, the Atlantic analysts said.

Then there’s another problem that could seriously hamper Wellington’s ability to sway undecided voters: “We see Wellington’s grounds for opposition as raising no specific or credible reasons why the deal should not go through.”

In a statement announcing its opposition on Wednesday, Wellington said it believed the deal requires BMS shareholders to take on too much risk and Celgene shareholders to accept BMS shares “at a price well below implied asset value.” Wellington also contended that making the merger a success will be more difficult than BMS’ executives have suggested it will be.

A spokesperson for BMS did not comment to FiercePharma on reports that it’s stepping up meetings with investors. In a statement issued late Thursday, Bristol-Myers said its Celgene merger “is consistent with our strategy and is the natural next step” in the company’s evolution.

Reiterating its initial justification for the deal, BMS touted six potential drug launches—including five from Celgene—that together represent more than $15 billion in potential sales. The combo will also “enhance our leadership positions across our portfolio, including in oncology, immunology and inflammation and cardiovascular,” the company said.

Counting potential votes

It’s not just the rebel investors’ voting power that matters here, some analysts have pointed out. It’s also the outsized influence of investors who own shares in both companies. Credit Suisse analysts did that math and found that, as of the end of December, there was a roughly 58% overlap in the shareholder base of the two companies.

That could “shore up support for the deal, as these shareholders would benefit from the takeout of Celgene,” they wrote in a note to investors on Friday.

Wolfe Research analyst Tim Anderson surveyed more than 100 Bristol-Myers and Celgene shareholders and predicted in an investor note this week that the majority of them would favor the deal. Only “aggressive shareholder activism” could derail the merger, he said—and that would most likely have to come in the form of a bidder swooping in to take out Bristol-Myers before the Celgene deal wraps up.

That scenario has come up many times since BMS announced the Celgene buy earlier this year. Bristol-Myers has been under pressure from investors unhappy that its immuno-oncology blockbuster, PD-1 inhibitor Opdivo, has been losing ground to Merck & Co.’s Keytruda. And the hits just keep coming for Opdivo. Earlier this month, for example, Merck released data from a key kidney cancer trial showing that a combo of Keytruda and Pfizer’s Inlyta cut the risk of death nearly in half.

Anderson said his investor poll placed the odds of another pharma company picking off BMS at no more than 20%. “This is where we place odds as well,” Anderson said, adding that acquiring BMS would only make sense for companies that “missed the PD-1 boat” and would be satisfied being the number-two player in that market. The only company he named that might qualify, however, was Amgen.

Barclays analysts predict that other funds will step forward to oppose the BMS-Celgene combo. But ultimately, they say, the majority of shareholders will support it on April 12. “Beyond the lack of realistic, potential alternatives that could collectively provide a similar level of upside, we continue to see strong rationale for the acquisition,” Barclays said in a note to investors.

That said, Wellington shouldn’t be counted out, other analysts warn. “Wellington in and of itself is huge in the bio-pharmaceutical space. They’re a major voice in terms of long-term shareholders,” said Robert W. Baird analyst Brian Skorney in an interview with CNBC. “Now the question is, does [Wellington’s opposition] bring more shareholders away who would otherwise vote with Bristol?”

https://www.fiercepharma.com/pharma/bms-stakeholder-wellington-unlikely-to-garner-votes-to-crater-celgene-deal-analysts

Pfizer blockbuster safety issue jumps Atlantic: EMA launches review of Xeljanz

Pfizer’s Xeljanz woes have spread to Europe.

After the FDA announced earlier this week that it is investigating the increased risk of blood clots and death linked to their blockbuster JAK inhibitor seen in a post-marketing study, the EMA says they’ll now make their own assessment on the safety of the drug.

“EMA is assessing the results of the study and will consider what regulatory action is needed,” the agency said in a statement sent to Endpoints News. The EMA added that patients should consult a doctor if they have any questions.

European regulators had proved much tougher than the FDA on Xeljanz, waiting until 2017 to approve the drug for rheumatoid arthritis after delaying the rollout for more safety data — 6 years after the FDA OK.

The drug entered the market with a black box warning of a higher risk of infections, but the pharma giant set off alarm bells when researchers said they were taking people off the 10 mg dose used in their assessment of the drug’s safety among patients with an added cardio risk after the trial monitors concluded that the drug was associated with higher rates of blood clots and death.

Both the FDA and EMA note that the recommended dose for Xeljanz in RA is 5 mg twice a day, but the drug is approved at 10 mg for ulcerative colitis. Eli Lilly also faced its own challenges after the FDA initially rejected its JAK inhibitor baricitinib, finally approving it as Olumiant last year at a lower dose than it had sought.

The new safety alert comes at a bad time for Pfizer, which is depending on rising sales of its blockbuster drug at a time when US lawmakers have been hammering hard against annual price hikes. Other JAKs are in the late-stage pipeline with their own claims on safety and efficacy that will now face further scrutiny.

On the other hand, any new RA therapy entering the field with a better safety profile will be looking at a seriously disrupted market.

https://endpts.com/pfizers-blockbuster-safety-issue-jumps-the-atlantic-as-ema-launches-its-own-review-of-xeljanz/

Intrexon hit after ‘going concern’ disclosure

Alongside Q4 results, the company said it expects to include a “going concern” statement in its annual report.

That’s enough for Northland bull Robert Breza to throw in the towel, downgrading to Market Perform from Outperform. The disclosure, he says, will have investors taking a “wait and see attitude” until a way forward becomes clearer.

10-K is here

Previously: Intrexon beats by $0.13, beats on revenue (Feb. 28)

https://seekingalpha.com/news/3439143-intrexon-plunges-nearly-30-percent-going-concern-disclosure