On February 7, 2020 BMS reported completed its merger with Celgene in November, enough time to help its revenues rise 33% to $7.95bn for the period, up from just under $6bn a year earlier, thanks to the contribution of drugs like blockbuster blood cancer drug Revlimid (lenalidomide) (Press release, Celgene, FEB 7, 2020, View Source,_but_opdivo_stalls_1324495 [SID1234554064]).

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Investors responded warmly to the figures, sending BMS’ share price up 3%, though it would likely have been a different story if the Celgene deal hadn’t come through in time.

Opdivo (nivolumab) grew modestly for the full-year, but declined 2% in the fourth quarter to $1.76bn after a slowdown throughout the year that BMS said stemmed largely from reduced sales in second-line non-small lung cancer (NSCLC).

The reason? First-line use of rival checkpoint inhibitors – mainly Merck & Co’s Keytruda (pembrolizumab) – have reduced the opportunity for later-line chemotherapies in this form of cancer, as well as some other tumours like small cell lung cancer and head and neck cancer.

BMS chief executive Giovanni Caforio said on a conference call that he expects Opdivo to return to growth in 2020, providing it gets additional launches in new indications, including first-line NSCLC.

That hinges on two studies – CheckMate-227 and CheckMate-9LA – which involved a combination of Opdivo with low-dose Yervoy (ipilimumab), its CTLA4 inhibitor.

BMS was forced to withdraw its filing in the EU based on the CheckMate-227 trial after the EMA said protocol changes had made the data uninterpretable, but its still under review in the US with an FDA verdict due in May.

Full data from CheckMate-9LA is due for presentation later this year, but BMS said in October it had met its main objective of improving overall survival.

"While we’re disappointed by the position taken by the CHMP, we continue to view the combination of Opdivo and Yervoy as a differentiated regimen with the potential for long-term survival and one that should be available to patients globally," said Caforio on the call.

Revlimid brought in almost $1.3bn between 20 November – when the takeover completed – and the end of the year, but it is facing the loss of patent protection in the US in 2023 and generics are already being launched in Europe.

Thankfully for BMS, it wasn’t only Celgene’s drugs that caused the revenue surge. BMS’ well-established anticoagulant Eliquis (apixaban) had another strong quarter with a 19% rise to just over $2bn, while multiple myeloma drug Empliciti (elotuzumab) grew by more than a third to $94m.

Meanwhile, Caforio is confident that Opdivo’s expected return to growth – plus a series of upcoming launches like multiple sclerosis drug ozanimod, Reblozyl (luspatercept) in myelodysplastic syndrome (MDS) and its CAR-T therapy franchise headed by liso-cel for B-cell lymphomas – sets the company up well for the future.

"The company is in a strong position and this is reflected in the performance of our business and the outlook we are providing today," he said. The company is predicting that full-year 2020 revenues will be between $40.5bn and $42.5bn.

On February 7, 2020 Researchers with the Abramson Cancer Center of the University of Pennsylvania, led by Carl June, reported that results from the first U.S. Phase I trial of CRISPR-Cas9-edited T-cells in humans with advanced cancer. The data was published in the journal Science (Press release, University of Pennsylvania, FEB 7, 2020, View Source [SID1234554028]).

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The trial involved three patients with refractory cancer, two women and one man, all in their 60s. One of the patients had sarcoma and two had multiple myeloma. The approach was similar to that seen in CAR-T therapy, where the patient’s own T-cells are recovered, engineered to express a specific receptor that can detect and kill cancer cells, then reinfused into the patient.

In the case of this trial, instead of engineering the T-cells with a receptor to a protein like CD19, they used CRISPR to remove three genes from the T-cells. Two edits removed the T-cell’s natural receptors, which could then be reprogrammed to express a synthetic T-cell receptor called NY-ESO-1. The third edit eliminated PD-1, a checkpoint receptor that allows cancer cells to hide from T-cells.

The researchers are presenting the data as a positive because it appears to be safe. June told Genetic Engineering & Biotechnology News, "CRISPR technology has proven safe in patients with advanced refractory and metastatic cancer. Our results demonstrate the ability to precisely edit the DNA code at three different genes."

In an accompanying article, Jennifer Hamilton and CRISPR pioneer Jennifer Doudna wrote, "These findings provide a guide for the safe production and non-immunogenic administration of gene-edited somatic cells. The clinically validated long-term safety of CRISPR-Cas9 gene-edited cells reported [here] paves the way for next-generation cell-based therapies."

Before getting overly excited about this, it was also reported that one of the patients has since died and the disease became worse in the other two. June indicated the goal of the study wasn’t to cure cancer, but to show that the CRISPR technique was feasible and safe.

With that goal in mind, it’s safe to say the trial was a success.

"This is a Rubicon that has been decisively crossed," said Fyodor Urnov, a genome editor at the University of California (UC), Berkeley, in a Science article. He noted the trial was the first of its kind in the U.S. and answered "questions that have frankly haunted the field."

The research also suggests what the limitations of the approach are, at least currently.

One of the big concerns in using CRISPR is off-target edits. CRISPR is generally pretty precise, but the human genome is quite larger and even a target of 20 or so specific nucleotides in a gene might be duplicated elsewhere, which could have unintended effects. And, studies of the three patients in the study confirmed that CRISPR had resulted in some off-target edits. There weren’t many and the number of cells affected decreased over time.

There have also been questions on how long gene edits last. In theory, they should last indefinitely, but some research has suggested the body tries to fix the edits and return them to their original state. However, this study showed the CRISPR-edited cells continued at least nine months, which is significant compared to about two months in similar CAR-T therapeutic studies.

So this study, which is significant, is more of a starting point for CRISPR-based therapies, particularly given the modest clinical response.

"It wasn’t like you turned off those genes and those T-cells started doing things that were amazing," Antoni Ribas, a UC Los Angeles oncologist told Science. But it was "a needed start" and going forward, "It’s going to be easier—because they did it first."

On February 7, 2020 Shanghai Junshi Bio reported that invested $1.4 million in Stemirna Therapeutics, a Shanghai company developing mRNA vaccine therapeutics for cancer (Press release, Shanghai Junshi Bioscience, FEB 7, 2020, View Source [SID1234554030]). Junshi, which made the investment as part of an A+ round, acquired an 3% stake in Stemirna. The two companies will jointly develop novel drugs and combination therapies Formed in 2016, Stemirna identifies tumor-specific antigens, loading them onto a single mRNA strand. Junshi, which has 13 molecules in development, was the first China company approved to market a PD-1 candidate in China, Tuoyi.

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On February 7, 2020 CytomX Therapeutics, Inc. (NASDAQ:CTMX), a clinical-stage oncology-focused biopharmaceutical company pioneering a novel class of investigational antibody therapeutics based on its Probody therapeutic technology platform, reported that on February 3, 2020, the Company granted its recently appointed senior vice president and chief medical officer, Alison L. Hannah, M.D., an option to purchase 250,000 shares of the Company’s common stock at an exercise price per share equal to $7.71, which was the closing trading price on February 3, 2020, the date of the grant (Press release, CytomX Therapeutics, FEB 7, 2020, View Source [SID1234554031]). The Company also granted Dr. Hannah a performance option to purchase 50,000 shares of the Company’s common stock at an exercise price per share equal to $7.71. The performance option vests upon the accomplishment of certain clinical trial related goals established by the Company.

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The stock options were granted pursuant to the Company’s 2019 Employment Inducement Incentive Plan, which was approved by the Company’s board of directors in February 2020 under Rule 5635(c)(4) of The Nasdaq Global Market for equity grants to induce new employees to enter into employment with the Company.

On February 7, 2020, Inovio Pharmaceuticals, Inc. (the "Company") reported that it entered into an amendment (the "Amendment") to the At-The-Market Equity Offering Sales Agreement dated May 25, 2018 (as amended, the "Sales Agreement") with Stifel, Nicolaus & Company, Incorporated ("Stifel"), which amendment increases the amount of Company common stock, par value $0.001 per share (the "Common Stock"), that can be sold by the Company through Stifel as its sales agent under the Sales Agreement from an aggregate offering price of up to $100,000,000 to an aggregate offering price of up to $200,000,000 (Filing, 8-K, Inovio, FEB 7, 2020, View Source [SID1234554048]).

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Pursuant to the Sales Agreement, sales of the Common Stock, if any, will be made under the Company’s previously filed and effective Registration Statement on Form S-3 (File No. 333- 225233) and an applicable prospectus supplement, by any method that is deemed to be an "at the market offering" as defined in Rule 415(a)(4) under the Securities Act of 1933, as amended. Since September 30, 2019 the Company has sold approximately $68.3 million of its common stock pursuant to the Agreement and since May 25, 2018 has sold $100 million of its common stock pursuant to the Agreement.

The Sales Agreement is attached or incorporated by reference to this Current Report on Form 8-K as Exhibits 1.1 and 1.2 and is incorporated herein by reference. The foregoing description of the material terms of the Amendment does not purport to be complete and is qualified in its entirety by reference to the exhibits attached hereto.

This Current Report on Form 8-K shall not constitute an offer to sell or the solicitation of an offer to buy the securities discussed herein, nor shall there be any offer, solicitation, or sale of the securities in any state in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state.