Upcoming events – Sage targets depression and Biogen aims for lupus

Sage’s big depression readout looms, while Biogen hopes for a mid-stage hit in lupus.

With a win in postpartum depression in the bag Sage Therapeutics’ attention with its oral GABA-A modulator SAGE-217 now turns to the big one: major depressive disorder (MDD). Data from the phase III Mountain trial are due in the fourth quarter, although this could slip into early next year.
The company needs a hit to help justify its $7bn valuation. It already sells the intravenous post-partum depression therapy Zulresso, but SAGE-217 is expected to be its biggest growth driver, with 2024 sales forecast to reach $1.8bn, according to EvaluatePharma sellside consensus. The oral project has a risk-adjusted NPV of $4.7bn.
Hopes are high going into the Mountain readout, but depression trials are notoriously tricky. The study tests two weeks’ SAGE-217 at 20mg or 30mg versus placebo, with four weeks’ follow-up. The primary endpoint is change from baseline in the 17-item Hamilton rating scale for depression (HAM-D) total score at 15 days; a higher score indicates more severe depression.
Sage bulls will point to the fact that the phase IIb trial of SAGE-217 in MDD met its primary endpoint, showing a seven-point improvement in HAM-D versus placebo at 15 days; in addition 64% of SAGE-217-treated patients achieved remission, compared with 23% of placebo recipients.
More recently, SAGE-217 prevailed in a phase III study in postpartum depression (JP Morgan 2019 – development shortcuts pay off for Sage, January 8, 2019). However, data from the single-arm Archway trial in bipolar depression disappointed, and Sage has chosen not to continue in this indication.
Safety will also be closely watched, as there have been reports of fainting with Zulresso, which has a similar chemical structure to SAGE-217. This would be particularly problematic for the oral drug, which would be given in an outpatient setting, whereas Zulresso is administered by a continuous intravenous infusion over 60 hours. Still, there have been no reports so far of fainting with SAGE-217.
Two further phase III trials of the oral project are looking at retreatment in MDD: Shoreline evaluates SAGE-217 on an as-needed basis, while Redwood will assess long-term dosing. Meanwhile the Rainforest study, in comorbid depression and insomnia, is also under way.

Climbing the Mountain: selected trials of SAGE-217
Study	Details	Trial ID	Placebo adjusted change on HAM-D after treatment	Share price reaction
Robin	Phase III PPD	NCT02978326	4 points, p=0.0029	43%
–	Phase IIb MDD	NCT03000530	7 points, p=<0.0001	70%
Mountain	Phase III MDD	NCT03672175	–	–
MDD: major depressive disorder; PPD: postpartum depression. Source: Clinicaltrials.gov, company releases.

Homo homini lupus
Pipeline concerns have been laying Biogen low for some time now – the company’s R&D head of three years quit this week – so any signal of efficacy from BIIB059, a mid-stage lupus candidate, would give the beleaguered biotech a much-needed boost. Phase II results are due before the end of the year, and the trial looks rigorous enough to provide some fairly reliable pointers of activity.
BIIB059 binds BDCA2, a receptor found on plasmacytoid dendritic cells, immune cells that produce large amounts of type I interferon, a key driver of lupus. Plasmacytoid dendritic cells have been shown to accumulate in the skin, and it is hoped BIIB059 will have a particularly marked impact on the rashes seen in many lupus patients.
Data from a phase I study published earlier this year found significant reductions in interferon-related gene and protein expression in patients who received BIIB059, as well as improvements in skin-related disease activity.
The phase II, double-blind, placebo-controlled trial, Lilac, has enrolled distinct lupus populations into two separate cohorts, 264 in total.
Part A assesses a 450mg dose in subjects with systemic lupus erythematosus who suffer from lupus rash and painful joints. The primary measure is change on a joint pain assessment, incorporating 28 different joints, measured over 24 weeks.
Part B tests patients with various forms of lupus skin disease, including cutaneous lupus and discoid lupus, who may or may not have systemic disease. Three different doses are being used in this cohort – 50mg, 150mg and 450mg – and the primary endpoint is an activity score used in lupus skin diseases called CLASI-A. Change in baseline is measured over 16 weeks.
Lupus has proven a very difficult field for drug developers, so any positive signals from Lilac will need to be confirmed in a much larger study. Still, the recent surprise success with Astrazeneca’s anifrolumab suggests that progress is being made (Second time lucky for Astra in lupus, August 29, 2019).
Anifrolumab also targets INF-1, binding to receptors on the interferon; by turning off INF-1 at the source BIIB059 theoretically works earlier. Whether this makes any difference should soon begin to be answered.
https://www.evaluate.com/vantage/articles/events/upcoming-events/upcoming-events-sage-targets-depression-and-biogen-aims

Japanese drugmakers stand out at the nine-month mark

Daiichi Sankyo’s incredible stock market performance stands out amid the usual mixed bag of fallers and risers among biopharma’s mid- and small caps.

The third quarter of 2019 is unlikely to be a period remembered fondly by biotech investors. Not in the US anyway: the closely watched Nasdaq Biotechnology Index faded over the three months, eventually hitting a low for the year. Which means kudos must go to those US companies that have managed to remain in positive territory: Seattle Genetics and The Medicines Company stand out in Vantage’s quarterly look at biopharma share prices.
However it is Japanese groups that top both the mid- and small cap tables, with Daiichi Sankyo’s remarkable advance this year particularly notable. Its stock has almost doubled in value, pushing Daiichi’s market cap to $44bn, and well into the league of the sector’s bigger beasts. For example, the company is now worth considerably more than Regeneron and is on par with Biogen, two US biotechs that have been having a torrid time.
A licensing deal with Astrazeneca over Daiichi’s Her2 antibody-drug conjugate, DSD-8201, is largely behind the move; the project will be filed in the US later this year. Last month the Tokyo-based firm also won FDA approval for Turalio, a CSF1R-targeted kinase inhibitor, for a very rare cancer of the joints, and it is clear that investors have sat up and taken notice of the company’s progress.

Mid-cap ($5-25bn): top risers and fallers in first nine months of 2019
	Share price	Market capitalisation ($bn)
Top 5 risers	9-mth change (local currency)	30 September 2019	9-mth change ($bn)
Daiichi Sankyo	94%	44.6	22.5
Galapagos	74%	9.7	4.7
Sino Biopharmaceutical	70%	16.1	7.8
Seattle Genetics	51%	13.8	4.7
Vifor Pharma	49%	10.5	3.5
Top 5 fallers
Teva Pharmaceutical	(55%)	7.5	(9.3)
Sumitomo Dainippon	(49%)	6.5	(5.8)
Nektar Therapeutics	(45%)	3.2	(2.5)
Eisai	(35%)	15.1	(7.3)
Piramal Enterprises	(31%)	4.7	(1.2)

Another Japanese group, Sosei, tops the risers among the small caps, below. This is something of a recovery story – the company has suffered pipeline setbacks over the past couple of years, but recent progress with Novartis’s respiratory franchise, upon which Sosei will receive royalties, has provided a boost. A couple of big research collaborations with Takeda and Genentech also helped.
It is not all good news for Japanese drug makers, however. Sumitomo Dainippon remains one of the mid-cap laggards, and the company’s remarkable decision to hand over $3bn to Roivant for an eclectic mix of assets has not made up for a string of pipeline blow-ups and a looming patent cliff (Sumitomo bets on Roivant to solve its patent expiry woes, September 6, 2019).
Eisai, meanwhile, has been dragged down by disappointments in Alzheimer’s disease – the company was partnered with Biogen on the amyloid project aducanumab and the Bace inhibitor elenbecestat, both of which flunked phase III this year. The two companies are still working on another amyloid-targeting agent, BAN2401, but hopes are not high.
Europe is also well-represented among the mid-cap risers, with both Galapagos and Vifor notching up respectable gains. The former has benefitted from rising hopes for its Gilead-partnered Jak inhibitor, filgotinib, which could reach the market late next year and has been widely pegged as a future blockbuster. A huge research collaboration, forged between the two partners in July, also gave the Belgium company’s stock a boost.
Vifor Pharma, which sells products for iron deficiency and kidney disorders, has been a beat-and-raise story this year, with strong financial results driving share price gains. Hong Kong-based Sino Biopharmaceutical has also been delivering strong sales growth on a raft of new product launches, most notably the anti-VEGF kinase inhibitor anlotinib, which has been swiftly adding indications to its label.
The only US company to make it into the top five mid-cap risers is Seattle Genetics, which is riding high on the prospects for enfortumab vedotin in bladder cancer. The project is filed in a second-line setting, and encouraging data in first-line patients at Esmo this week gave the company a $2bn boost to its market cap.
Notable decliners among the mid-caps include Teva; the Israeli generics giant has yet to solve its myriad of financial woes. Meanwhile Nektar’s concerns are clinical: efficacy of its lead project, bempegaldesleukin, appears to be waning, and investors have declined to swallow the company’s explanations.

Small cap ($250m-$5bn): top risers and fallers in first nine months of 2019
	Share price	Market capitalisation ($m)
Top 5 risers	9-mth change (local currency)	30 September 2019	9-mth change ($m)
Sosei	203%	1,723	1,182
Eidos Therapeutics	161%	1,347	841
The Medicines Company	161%	3,968	2,554
Arqule	159%	862	560
Spark Therapeutics	148%	3,732	2,255
Top 5 fallers
Inflarx	(94%)	64	(879)
Novavax	(86%)	120	(584)
Kezar Life Sciences	(86%)	63	(388)
Mallinckrodt	(85%)	202	(1,114)
Aclaris Therapeutics	(85%)	45	(258)

Among the small cap risers, both Eidos and Spark have been the recipients of takeover offers. Eidos’s majority shareholder Bridgebio has been trying to buy the remaining stake in the company, attracted by a that group’s amyloidosis project, but its overtures have been rejected so far. Meanwhile Spark looks likely to fall to an offer from Roche, though drawn out scrutiny by competition watchdogs in both the US and Europe mean this cannot be considered a done deal.
Clinical successes have driven The Medicines Company and Arqule, the former with a novel cholesterol lowering therapy, and the latter in the field of haematological cancers.
Among the small cap fallers, it is mostly clinical failures that have demolished the companies. For Novavax, it was a second phase III failure for its RSV vaccine, Resvax; a post-hoc data dredge failed to convince Inflarx investors that a phase II study of IFX-1 was actually a success; Aclaris’s Jak posted ostensibly positive results but looks unlikely to live up to the competition; while mid-stage data on Kezar’s lupus project, KZR-616, raised safety concerns.
Finally, Mallinckrodt has been taken down by the opioid selling scandal. With the lawsuits claiming compensation far from concluded, the outlook for this company could still worsen.
https://www.evaluate.com/vantage/articles/data-insights/quarterly-shareprice-performance/japanese-drugmakers-stand-out-nine

Keytruda on path to become world’s no. 1 selling drug: research firm

Merck’s (NYSE:MRK) Keytruda cancer drug will be the world’s best selling drug by 2025, with projected annual sales of $22.5B, according to a new report from the GlobalData research firm.

Keytruda already has received 22 approvals for oncology indications by the Food and Drug Administration, and the drug is involved in more than 1,000 clinical trials; if only 10% of those trials hit, approvals for Keytruda will climb exponentially.

While AbbVie’s (NYSE:ABBV) Humira will lose its current top spot for global revenue, it will remain in the top 10 of best-sellers, with GlobalData ranking the drug in 6th place by 2025.

Following Keytruda, Bristol-Myers Squibb (NYSE:BMY) and Pfizer’s (NYSE:PFE) Eliquis is forecast as the second best selling drug, with annual sales of $18.7B by 2025.

Celgene’s (NASDAQ:CELG) – and soon to be BMY’s because of their merger – Revlimid is predicted to take third place, although its worldwide sales will be affected by generic versions, which are set to hit the U.S. market in 2022.

GlobalData sees BMY’s Opdivo, a rival checkpoint inhibitor to Keytruda, coming in fourth place for global revenue, with AbbVie and Janssen’s (NYSE:JNJ) Imbruvica in fifth position.

Rounding out the top 10: Gilead’s (NASDAQ:GILD) HIV drug Biktarvy, Pfizer’s Ibrance, J&J and Mistubishi Tanabe’s Stelara, and Eli Lilly’s (NYSE:LLY) Trulicity.

https://seekingalpha.com/news/3504108-keytruda-path-become-worlds-1-selling-drug-research-firm-says

Altria turns to iQOS in U.S.

Altria (MO +1.1%) is launching its iQOS product in the U.S. with an initial introduction at about 500 stores in the Atlanta area. The company has the rights to sell the product under a licensing agreement with Philip Morris International (PM +1.1%).

Altria hasn’t stated when iQOS will be rolled out across the U.S.

The iQOS device, which heats tobacco but doesn’t burn it, hits the U.S. market with vaping companies like Juul Labs (JUUL) under increasing regulatory scrutiny.

“It’s perfect timing,” notes Piper Jaffray analyst Michael Lavery. “I don’t think they would have expected some consumer uncertainty around vapor coinciding with the launch of Iqos in the U.S.,” he adds.

https://seekingalpha.com/news/3504036-altria-turns-iqos-u-s

DC hospital goes 1 week without running water amid Legionnaires’ threat

Washington, D.C.-based St. Elizabeths Hospital has been without safe water for more than seven days after the discovery of bacterial contamination that could cause Legionnaires’ disease, according to The Washington Post.
During routine water testing, both Pseudomonas and Legionella bacteria were found Sept. 26, forcing the facility shut off all water. The hospital’s patients and staff are currently using bottled water, hand sanitizer and portable showers. As of Oct. 3, none of the state-run facility’s 273 patients have symptoms of Legionnaires’ disease.
“As with any water outage, infectious disease control staff are monitoring closely to address any potential infection risks,” Phyllis Jones, chief of staff of the district’s Department of Behavioral Health, said in a statement to The Washington Post.
Patients are “very distressed” by the situation, especially with flu season approaching, according to Andrea Procaccino, an attorney at the patient advocacy group Disability Rights DC.
“If you’re not able to wash your hands after you go to the bathroom or there’s no running water, it makes it hard to have proper hygiene and sanitation,” she told The Washington Post. “People haven’t taken showers in four or five days.”
The psychiatric hospital will continue to accept patients but lacks a clear timeline of when water will be restored.
https://www.beckershospitalreview.com/quality/dc-hospital-goes-1-week-without-running-water-amid-legionnaires-threat.html

FDA strengthens warning on vaping THC products

The U.S. Food and Drug Administration warns consumers not to use vaping products that include THC, the primary psychoactive ingredient in pot, in an updated consumer alert.

Also warns people not to modify vaping products by adding any substances and tells them not to purchase any vaping products off the street or from other illicit channels.

“At this time, the FDA does not have enough data to identify the cause, or causes, of the lung injuries in these cases,” it said in the statement.

While no one compound or ingredient has emerged as the culprit in the string of lung injuries, “we do know that THC is present in most of the samples being tested,” the FDA said.

The Centers for Disease Control reports 1,080 lung injury cases and 18 deaths associated with using e-cigarette, or vaping products, from 48 states and 1 U.S. territory as of Oct. 1.

Related stocks: Altria (MO +1.3%), Philip Morris (PM +1.3%), British American Tobacco (BTI -0.2%), Gilla (OTCPK:GLLA -12.1%), Vape Holdings (OTCPK:VAPE -25%), Vector Group (VGR +1.7%), Imperial Brands (OTCQX:IMBBY -1.5%), and privately owned Juul (JUUL)

https://seekingalpha.com/news/3504058-fda-strengthens-warning-vaping-thc-products

Gene therapy stocks have taken a beating. Their recovery may be slow

The honeymoon period for gene therapy developers was short-lived. Shares of at least 26 are trading lower now than they were a year ago, amounting to roughly $18 billion in lost market value.
Relief may not come soon, either. Analysts suspect investors aren’t just looking for promising safety and efficacy data anymore; they want to know how companies intend to make money off these treatments. Most don’t have answers to that question yet.
“There’s this phase, not just in gene therapy, but in most companies or technologies, where it’s all exuberance and development,” said Tyler Van Buren, an analyst at Piper Jaffray. “A lot of that can end once rubber hits the road and you have to launch a product.”

Bluebird bio is having this problem. The Boston biotech’s share price is down 41% from a year ago and 26% since mid-June, when executives said the European launch of its Zynteglo gene therapy would be pushed back from 2019 to 2020.
Mani Faroohar of investment bank SVB Leerink argues the delay has dimmed investor confidence in smaller biotechs working on “transplant” gene therapies like Zynteglo, which treats a blood disorder known as beta-thalassemia by harvesting a patient’s stem cells, engineering them to produce a form of hemoglobin, and infusing them back into patients.
“If the bellwether can’t launch a product that they’ve been spending billions of dollars on over the course of 10 years, how is a $400 million company somewhere going to do it?” Faroohar told BioPharma Dive.
Bluebird isn’t the only gene therapy leader to get knocked recently.
Swiss pharma giant Novartis remains on damage control following a data scandal that, to some extent, tarnished the approval of its Zolgensma gene therapy. Roche’s acquisition of Spark Therapeutics, meanwhile, is taking longer than expected because of antitrust concerns.
Delays to the Spark deal may be having a particularly outsized effect on gene therapy stocks. Signs that the Federal Trade Commission took issue with the pairing, which many analysts assumed would be a sort of “check-the-boxes” acquisition, started to show up in early April.
No gene therapy acquisitions have been announced since, and Faroohar doesn’t expect that to change until buyers have more clarity on what’s holding up Roche. With the deal’s timeline already extended by months, shareholders of other companies might not be willing to wait around for a resolution.
“If you paralyze the acquirers, that makes it very difficult to make a compelling case for a lot of these companies that certainly wouldn’t be able to commercialize their own products without raising a lot of diluted capital,” Faroohar said.
Van Buren sees the Spark deal as a more minor issue, given that gene therapy continues to be one of the hottest areas in drug development. Even so, he acknowledged that it could discourage “natural bidders” from coming to the table, which lowers the probability of certain acquisitions.

Gene therapy co.	Lead therapeutic focus	Stock change, past 52 weeks through Oct. 1
BioMarin Pharmaceutical	Hemophilia	-36% ▼
Sarepta Therapeutics	Duchenne muscular dystrophy	-49% ▼
Bluebird bio	Beta-thalassemia, sickle cell, CALD	-38% ▼
Spark Therapeutics	Eye disease, hemophilia	+80% ▲
Ultragenyx	Rare disease	-45% ▼
CRISPR Therapeutics	Beta-thalassemia, sickle cell	-9% ▼
PTC Therapeutics	AADC deficiency	-31% ▼
Amicus Therapeutics	Batten diesease, CNS	-37% ▼
UniQure	Hemophilia, Huntington’s	+9% ▲
Regenxbio	Retinal diseases, Hunter and Hurler syndromes	-53% ▼
Audentes Therapeutics	Enzyme disorders	-25% ▼
Editas Medicine	Eye disease, beta-thalassemia, sicke cell	-29% ▼
Sangamo Therapeutics	Hemophilia, Fabry, beta-thalassemia, sicke cell	-48% ▼
Homology Medicines	Enzyme, lysosomal disorders	-23% ▼
Intellia Therapeutics	Amyloidosis, AAT deficiency	-56% ▼
Voyager Therapeutics	Parkinson’s, Huntington’s, ALS	-13% ▼
Krystal	Rare skin diseases	+95% ▲
MeiraGTx	Eye disease, Parkinson’s	+16% ▲
Rocket Pharmaceuticals	Danon disease, Fanconi anemia	-52% ▼
Solid Biosciences	Duchenne muscular dystrophy	-79% ▼
Avrobio	Fabry, Gaucher	-46% ▼
Cellectis	Blood cancers	-69% ▼
Prevail Therapeutics	Parkinson’s Gaucher disease	N/A
Adverum Biotechnologies	Eye diseases	-8% ▼
LogicBio Therapeutics	Hemophilia, liver disease	N/A
Axovant	Parkinson’s disease, gangliosidosis	-68% ▼
Mustang Bio	SCID	-43% ▼
Abeona Therapeutics	Skin disease, Sanfilippo syndromes	-82% ▼
AGTC	Eye diseases	-40% ▼
Catalyst Biosciences	Hemophilia B	-57% ▼
Iveric Bio	Eye diseases	-54% ▼
Fibrocell	Skin diseases	+34% ▲
Tocagen	Brain cancer	-96% ▼

A strategy beyond positive readouts

The gene therapy field evolved rapidly over the last decade and, by 2025, the Food and Drug Administration expects to clear for market 10 to 20 cell or gene therapy products annually.
Investor sentiment is shifting with the times. As Bluebird, Novartis and Spark Therapeutics proved these treatments can move through the clinic and gain regulatory approval, investors became increasingly interested in marketing and manufacturing strategies — even for drugs in early development.
“For so long, [gene therapy companies] didn’t really trade on, ‘What’s my margin structure going to be? What’s my distribution method? How do I realize attractive pricing in Europe versus Japan versus the U.S.?'” Faroohar said.
Now, investor awareness “about some of these very nuanced commercial questions is catching up.”
One of their biggest commercial concerns revolves around insurance coverage, since the U.S. insurance system wasn’t designed to handle incredibly expensive, potentially one-time treatments like Zolgensma, which Novartis offers at $2.1 million through a five-year installment plan.
Another commercial sticking point has been manufacturing. Bluebird, for example, pinned Zynteglo’s slower launch on tweaks the company was making to the therapy’s production process.
Ensuring consistent and quality manufacturing will likely be a challenge for others too. PwC proposes in a new report that the growing interest in gene therapy will lead to greater competition for the time and resources of contract manufacturers working in the space. The competition could, in turn, result in higher costs or supply constraints, and may force companies to invest more in their own manufacturing — a development seen with projects begun by Novartis, Pfizer, Sarepta and Bluebird.
“The days of 100% outsourcing and letting somebody else deal with it — I don’t see that being the standard model,” said Karen Young, U.S. Pharmaceutical and Life Sciences Leader at PwC.
The industry, however, is still getting acclimated to the small-scale, highly personalized, logistically daunting processes required for cell and gene therapy production. Building in-house capabilities and a team with the technical know-how to run them would likely be an expensive, time-consuming endeavor.
These challenges are, of course, predicated on a gene therapy having positive clinical data. On that measure, analysts have observed investors becoming harder to impress.
https://www.biopharmadive.com/news/gene-therapy-stocks-investor-concerns-marketing-manufacturing/564112/