Medical Innovation Exchange

Nick Paul

Roivant decants another Vant armed with Eisai blood cancer drug and plans to start phase 1/2 soon

Roivant Sciences has spawned another Vant. The latest addition to the clan is Hemavant, a biotech that starts life with a former Eisai drug and plans to start a study in patients with myelodysplastic syndromes (MDS) this year.Hemavant is developing RVT-2001, the small-molecule modulator of splicing factor 3B subunit 1 that Roivant licensed from Eisai late last year. Eisai, working with its H3 Biomedicine subsidiary, took the oral candidate into a phase 1 clinical trial in 2016 but saw no complete or partial responses in the first 84 patients enrolled in the study of patients with MDS and other blood cancers.
Work stalled on the candidate after the 2019 data drop, with Roivant saying in January that the number of subjects treated with RVT-2001 still stands at “over 80.” Yet, Roivant sees promise in some of the data generated by Eisai, leading it to license the asset and narrow the focus of the program.

Eisai enrolled patients with acute myeloid leukemia, chronic myelomonocytic leukemia and lower- and higher-risk MDS in its phase 1 study. In that population, the lack of responses was a blow, but Roivant has zeroed in on another endpoint that suggests RVT-2001 may have a future in lower-risk, transfusion-dependent MDS patients. 
RELATED: Roivant ditches plan to reacquire Immunovant, invests $200M
Thirty percent of the 19 lower-risk MDS patients treated with RVT-2001, formerly known as H3B 8800, gained red blood cell transfusion independence. Most of the patients had previously received Bristol Myers Squibb’s Revlimid, hypomethylating agents or both therapies. 
Based on the signal, Hemavant is developing RVT-2001 as an oral therapy for transfusion-dependent anemia in patients with lower-risk MDS. A phase 1/2 clinical trial is set to start in the first half of the year. 
Roivant has paid Eisai $8 million in cash and $7 million in stock for the global rights to the candidate. As RVT-2001 advances, Roivant will pay up to $65 million in development and regulatory milestones in the first indication plus up to $18 million in additional indications. The deal also features up to $295 million in commercial milestones and a tiered high single-digit to sub-teens royalty.

FDA fingers tox assessment as cause of Denali clinical hold, leaving biotech with a to-do list to regain momentum

Denali Therapeutics now knows what it needs to do to get its Alzheimer’s disease drug DNL919 back on track. Almost one month after the FDA informed Denali of a clinical hold via email, the agency has sent a formal letter setting out what needs to happen before it OKs a study of the Takeda-partnered prospect.

San Francisco-based Denali shared a brief notice about the FDA’s clinical hold Jan. 13, precipitating a double-digit drop in its share price. At that time, little information was available publicly, with Denali only disclosing the FDA’s action and promising to provide additional updates after talking to the agency.
Today, with the FDA nearing the end of the 30-day window it had to send an official clinical hold letter, Denali revealed it has received the formal notice from the agency. Denali shared details of what the FDA said and what it will take to get clearance to run the study of the antibody transport vehicle, which is designed to activate the TREM2 receptor found on certain immune cells in the central nervous system.   

The FDA’s observations related to the preclinical toxicology assessment, Denali said. Denali is working to provide the FDA with the information needed to start the study, which include proposed changes to the clinical trial protocol, the informed consent form and the investigator brochure.
RELATED: FDA denies Denali’s Takeda-partnered Alzheimer’s drug from entering clinic
It is unclear how long it will take Denali to get the FDA to lift the clinical hold. Denali is yet to share a  timeline but plans to post an update on the program “once a clear path forward has been established.” 
The delay affects a study that Denali identified as one of three trials that were supposed to post clinical data with “high impact potential” this year. Shortly before being hit with the clinical hold, Denali listed the delivery of first-in-human data that could confirm pathway engagement and validate its antibody transport vehicle as one of the highlights of 2022. Those data could now slip into 2023. 


Hunting for cutting-edge biotech, Fujifilm sets up early-stage VC fund

Fujifilm is pushing deeper into early-stage biotech venture capital, providing fresh funding for a new VC unit and rolling its existing investments in areas such as regenerative medicine and cell therapies up into the group.

Tokyo-based Fujifilm is starting small by the recent standards of biotech VC. Initially, Fujifilm is investing around $60 million, money that its newly established Life Sciences Corporate Venture Capital (LS-CVC) group will use to target “cutting-edge biotechnology primarily through partnerships with early-stage companies around the world.” 
The creation of LS-CVC and the associated life sciences strategic investment fund are the latest in a series of steps intended to support Fujifilm’s growth. Fujifilm set up a life sciences strategy headquarters last year to accelerate its growth in areas such as cell-derived products for drug and discovery research and has also placed bets on early-stage biotechs.

LS-CVC represents the continuation and formalization of Fujifilm’s life science investment plan. The new group will take over the management of Fujifilm’s existing investments and hunt out new opportunities. 
RELATED: Bayer powers Versant cell therapy startup to $250M round
“In many cases, early-stage companies are the first to develop cutting-edge technologies and innovative business models. I believe LS-CVC activities will enable us to speedily develop new partnerships with such promising companies, and to deliver value to society through innovative products,” Takatoshi Ishikawa, general manager of Fujifilm’s life sciences strategy headquarters, said in a statement.
Ishikawa’s operation will receive support from Fujifilm’s existing life science strategic business offices in Massachusetts and Germany. The plan is for the teams in Cambridge and Dusseldorf to play a significant role in approaching early-stage biotechs, setting the stage for the subsequent formation of funding deals that support the development of biotechnologies of interest to Fujifilm.  
There is potential for the deals to diverge from the standard VC playbook, with Fujifilm saying it “is considering a wide range of new and innovative business constructs in order to cultivate and foster relationships with emerging biotechs to create new, and strengthen existing, businesses.”


With approval in sight, ObsEva sells regional rights to women’s health drug for tiny upfront

ObsEva has found a taker for its near-approval uterine fibroid treatment linzagolix. With the oral GnRH antagonist on the cusp of approval on both sides of the Atlantic, ObsEva has sold rights to the drug in Europe and certain other territories to Theramex.The deal grants Theramex rights to the drug outside of the U.S., Canada and Asia, positioning it to deploy its sales representatives in Europe, Brazil and Australia and third-party distributors in 60 countries to try to turn the treatment into a commercial success. Theramex will pay €5 million ($5.7 million) upon signing the agreement as part of a deal that could be worth €72.8 million if all milestones are hit.
Most of the money, €54 million, is tied to sales, with the rest linked to development and commercial milestones. As such, the near-term cost of the deal to Theramex is likely to be small, particularly in light of the advanced position of linzagolix in the pipeline. The bigger paydays will arrive if linzagolix racks up significant sales, with ObsEva securing around 35% royalties on commercial sales. 

A European Medicines Agency committee recommended the approval of linzagolix in the treatment of symptoms of uterine fibroids late last year, suggesting the authorization of the product should now be a formality. Yet, last week ObsEva said “further questions on the marketing authorisation application for linzagolix may be forthcoming, thereby extending the application timeline.” 
RELATED: Merck spinout Organon bags preterm labor drug ahead of phase 3
If approved, linzagolix will face competition. The European Commission approved oral GnRH receptor antagonist Ryeqo in the treatment of moderate-to-severe symptoms of uterine fibroids last summer, positioning Gedeon Richter, which has rights to the drug through a deal with Myovant Sciences, to target the market. 
AbbVie also has an oral GnRH antagonist, Orilissa, on the market in the U.S. The FDA is set to decide whether to approve linzagolix in September. ObsEva is working with Syneos Health on commercialization in the U.S. 

FDA denies Ardelyx’s appeal against kidney drug rejection, hammering another nail in tenapanor’s coffin

The FDA has deflated Ardelyx’s attempt to recover quickly from a complete response letter. With Ardelyx looking to sidestep a request for another trial, the FDA held its ground and denied the appeal—leaving the biotech looking to a Hail Mary pass to overturn the decision.

Ardelyx’s woes date back to last summer, when the FDA raised concerns with the evidence submitted to support approval of chronic kidney disease (CKD) drug tenapanor. The FDA agreed Ardelyx had found the drug, which inhibits the sodium-proton exchanger NHE3, reduces serum phosphorus in CKD patients on dialysis, but deemed the treatment effect to be “small and of unclear clinical significance.”
Facing a request for an additional “adequate and well-controlled trial,” Ardelyx laid off 65% of its staff and filed a Formal Dispute Resolution Request with the Office of Cardiology, Hematology, Endocrinology and Nephrology (OCHEN). The FDA office responded with an appeal denied letter (ADL).

Ardelyx plans to respond to the denial by escalating the matter. Having failed to persuade OCHEN of the merits of its case, Ardelyx is preparing to appeal the ADL to the Office of New Drugs (OND). The FDA’s appeal process allows companies to go up the chain of command step by step, culminating in a request for the commissioner to review the matter.
RELATED: Ardelyx’s FDA rejection points to long path back for CKD drug
The next milestone for Ardelyx is penciled in for April, when it expects to learn OND’s decision about its latest appeal. If successful, Ardelyx could refile for approval without running an additional study. Ardelyx is proposing to include new analyses of existing phase 3 results, as well as an assessment of the benefits and risks of tenapanor and a proposal for how to label the drug.
Another rejection will leave Ardelyx in a sticky situation. Ardelyx ended September with $142 million in the bank, a sum it sought to eke out by laying off 65% of its staff. The biotech burned through $47 million over the first nine months of last year. 


AstraZeneca dumps late-phase, next-gen COVID-19 vaccine, calling time on a beta player in an omicron world

Events have overtaken AstraZeneca’s next-generation beta variant COVID-19 vaccine. After moving the prospect into phase 2/3 last year, AstraZeneca saw beta fall down the list of the most worrying variants, culminating in today’s decision to dump the AZD2816 vaccine candidate.The removal (PDF) of AZD2816 from the pipeline follows the conclusion of work that persuaded AstraZeneca to stick with Vaxzevria, its first-generation vaccine, rather than push ahead with plans to seek authorization for its beta-specific sibling. AstraZeneca’s decision is underpinned by AZD2816’s lack of differentiation against the now-dominant omicron.
“Vaxzevria was exactly the same—there was no meaningful difference between immunogenicity of 2816 and Vaxzevria. It meant there was no need to switch from one to the other because obviously switching vaccines at this stage is not an easy thing, from a manufacturing perspective, capacity perspective. It would have to be really considerably better to make that switch,” Mene Pangalos, EVP biopharmaceuticals R&D at AstraZeneca, said.

When beta was identified in October 2020, it represented the most worrying COVID-19 variant yet from an immune escape perspective. The virus has 10 changes across the spike protein and was soon shown to render first-generation vaccines less effective, with the efficacy of Novavax’s vaccine falling from 89% in the U.K. to 49% in beta-dominated South Africa. 
RELATED: AstraZeneca kick-starts new COVID variant-busting vaccine test
AstraZeneca responded by tweaking its Vaxzevria in light of the small genetic differences between beta and the original SARS-CoV-2. At one point, the development of a beta-specific vaccine looked like a prudent move. Beta established itself in South Africa and was making inroads into some European countries around the time that AstraZeneca began its AZD2816 trial. However, first delta and then omicron swept beta away around the world, significantly reducing the need for a vaccine specifically against the once-worrisome variant. 
AstraZeneca dosed the first subjects in the phase 2/3 clinical trial in June, marking the start of a study that ultimately enrolled more than 2,800 people to evaluate the effect of its beta vaccine and its original Vaxzevria product in multiple different contexts. Investigators gave AZD2816 to unvaccinated individuals and to people who had previously received either Vaxzevria or an mRNA vaccine against COVID-19.
The rise and fall of AZD2816 offers a cautionary tale for Moderna and Pfizer, which have recently moved omicron-specific vaccines into clinical development. While omicron is far more prevalent than beta ever was, the pace with which it displaced delta, and the fact it differs so much from that formerly dominant variant, shows any jab against a specific form of SARS-CoV-2 could be rendered obsolete before it gets to market.
AstraZeneca disclosed the termination of AZD2816 in a quarterly update that also saw it remove a clutch of earlier-stage programs from its pipeline. The Big Pharma disclosed the divestitures of cholesterol drug MEDI5884, which it recently offloaded to Regio Biosciences, and an antibody for preventing pneumonia caused by Staphylococcus aureus. Both assets were in phase 2. Another phase 2 project, solid tumor candidate AZD2811, got the chop, as did three phase 1 programs, including the push to develop inhaled JAK inhibitor AZD0449 for use in patients with asthma.

Chasing Novartis and Roche, Ventus banks $140M to take inflammatory disease drug into the clinic

The money keeps flowing into Ventus Therapeutics. Just 10 months after raising one mega-round, the undruggable target specialist has banked a further $140 million as it prepares to file three INDs next year.Ventus is developing two molecules, one of which penetrates the brain, against NLRP3, a target that has attracted the interest of companies including Bristol Myers Squibb, Novartis and Roche. The third asset that is barrelling toward the clinic targets cGAS, a regulator of the STING pathway. Again, the drug is in an area that a who’s who of biopharma companies have targeted, and in some cases left, in recent years.  
Investors including SoftBank Vision Fund and RA Capital Management, the co-leads of the series C, have backed Ventus in the belief its platform can deliver differentiated drug candidates. Ventus’ platform is designed to shed light on previously unknown or poorly understood binding pockets for small molecules.

Tests of whether the platform can enable Ventus to overcome problems faced by other companies are on the horizon. Ventus’ pipeline is led by its peripherally restricted inhibitor of NLRP3. Years ago, Pfizer tested an NLRP3 inhibitor, only for safety issues to curtail the program. Later research ignited interest in the target, leading to deals such as Roche’s €380 million ($435 million) bet on Inflazome and hopes that NLRP3 is the key to treating a wide range of diseases driven by inflammation.
RELATED: Ventus raises $100M to pursue NLRP3, crack undruggable targets
Ventus is trailing the frontrunners in NLRP3 but has expressed confidence in its chances of coming from behind in the past, with CEO Marcelo Bigal arguing that rival molecules are based on Pfizer’s failed drug candidate and lack meaningful differentiation. Ventus’ molecules are “completely structurally distinct,” Bigal said last year, notably because they lack the pro-fibrotic areas linked to Pfizer’s safety problems.
IND filings for Ventus’ peripherally restricted and brain-penetrant NLRP3 inhibitors, which are scheduled for next year, will mark the start of efforts to show the molecules’ features translate into better clinical outcomes. Ventus also plans to file an IND for its cGAS program next year. 

GSK kills one of Barron’s early darlings, axing two synthetic lethal programs and Epizyme pact

Shortly after becoming GlaxoSmithKline’s chief scientific officer, Hal Barron highlighted (PDF) GSK3326595 as one of four early-stage cancer programs to watch. Today, with Barron’s time at the company nearing its end, GSK axed (PDF) the PRMT5 inhibitor and sibling molecule GSK3368715 from its pipeline. Evidence that GSK was rethinking plans for PRMT1 inhibitor GSK3368715 emerged last year, when the company wrapped up an early-phase study in solid tumor and diffuse large B-cell lymphoma patients 15 months ahead of schedule. The trial enrolled 31 subjects, well down on the 215 patients GSK originally planned to recruit.
A trial of GSK3326595 in myelodysplastic syndrome and acute myeloid leukemia patients continued after GSK closed up the study of its sibling molecule. But GSK recently stopped recruiting in that clinical trial, too, having enrolled just 10% of the 302 subjects it planned to recruit at the start of the study.

GSK confirmed the removal of the programs from its phase 1 pipeline as part of its fourth-quarter results earning release. In a brief statement, GSK attributed its actions to prioritization within the synthetic lethal portfolio, adding that it will end the in-license agreement with Epizyme covering the molecules next month.
RELATED: Barron quits GSK to take CEO post at $3B biotech startup
Epizyme landed the deal with GSK in 2011. At that time, the plan was to work on small molecule HMT inhibitors against three targets. GSK dumped the third target in 2017 but forged ahead with the PRMT5 and PRMT1 programs, moving both candidates into the clinic the following year. 
Along the way, Epizyme received $89 million from GSK but the big paydays were still to come. As of the end of September, Epizyme was in line to receive up to $50 million in clinical development milestones, $197 million in regulatory payments and $128 million in sales-based paydays. 

Ovid pens deal to offload twice-failed former lead program, positioning Healx to write new chapter in fragile X

Ovid Therapeutics has found a potential buyer for its onetime lead program. A little more than one year after gaboxadol’s value-crushing phase 3 flop, Healx has stepped in to see whether it can write another chapter in the long, failure-strewn history of the neurological disease drug. 

New York-based Ovid took gaboxadol, also known as OV101, into a phase 3 clinical trial in patients with the rare genetic disorder Angelman syndrome only to report the drug had failed to beat placebo late in 2020. Ovid responded to the setback by turning its attention to other candidates, but Healx sees a future for the molecule in other indications.
British artificial-intelligence-enabled drug discovery shop Healx has secured an option to license gaboxadol in the belief it may work in fragile X syndrome. Ovid put the drug candidate through a phase 2a trial in the indication, emerging with an initial efficacy signal but ultimately opting against further development.

Healx is looking to improve on the initial efficacy signal seen in phase 2a. Under the agreement, Healx will explore the effects of combination therapies featuring gaboxadol. Healx has already found a possible partner for gaboxadol, the nonsteroidal anti-inflammatory drug HLX-0201, using its AI platform and will evaluate that cocktail and other combinations. 
RELATED: Ovid’s fragile X drug shows promise in phase 2
If Healx exercises its option, Ovid will receive undisclosed clinical, regulatory and commercial milestones, indicating the extent to which the perceived value of the drug candidate has fallen. Ovid will retain the option to co-develop and co-commercialize gaboxadol with Healx but has no plans to run further trials of the molecule. 
The deal creates the possibility of another rebirth for gaboxadol, a molecule that was in development at Lundbeck and Merck 15 years ago. Lundbeck and Merck were developing gaboxadol as a sleeping pill but called time on the program in 2007. The candidate then sat on the shelf until 2015, when Ovid picked up the rights and outlined plans to run midphase trials in Angelman and fragile X. 


Pfizer, in a rare COVID-19 setback, dumps Paxlovid's intravenous sibling to leave ACTIV-3 future in doubt

Add Pfizer to the long list of victims of ACTIV-3. While the Big Pharma has enjoyed unparalleled success in COVID-19, it was unable to buck the trend in the National Institutes of Health (NIH) study of hospitalized patients and has stopped development of Paxlovid’s intravenous sibling PF-07304814.The NIH set up ACTIV-3 to test anti-SARS-CoV-2 monoclonal antibodies and other therapies in patients hospitalized with COVID-19. Brii Biosciences, Eli Lilly, GlaxoSmithKline and Novartis are among the drug developers to contribute candidates to the study. All those candidates failed to move the needle in hospitalized patients with severe COVID-19, resulting in a persistent unmet need even as the broader pandemic armory has gone from strength to strength.
PF-07304814 represented a different answer to the question of how to treat severe COVID-19. Like one of the components of Pfizer’s oral COVID-19 drug Paxlovid, PF-07304814 is a SARS-CoV-2 main protease inhibitor. The idea was to expand into patients with severe COVID-19 through intravenous delivery.

That plan, like others tested by Pfizer’s peers, came unstuck in NIH’s ACTIV-3 trial. Dosing of the intravenous antiviral in the trial has stopped, and Pfizer has discontinued the global clinical development. Pfizer said the decision “was made based on a totality of information, including a careful review of early data and a thorough assessment of the candidate’s potential to successfully fulfill patient needs.”
RELATED: Novartis-partnered DARPin flames out in COVID-19 study
The discontinuation means ACTIV-3 is no longer enrolling patients. In a recent update to the listing on ClinicalTrials.gov, the sponsor changed the status from “recruiting” to “active, not recruiting” and added “Suspended: Participants are not currently being randomized to this intervention” to the description of the PF-07304814 arm. Patients aren’t being randomized into any of the other arms, either.
If that marks the end of ACTIV-3, the study will go down as a rare graveyard for COVID-19 programs. The global vaccine race and push to create therapies for mild to moderate COVID-19 each featured multiple successes. But efforts to improve on Gilead Sciences’ Veklury in hospitalized COVID-19 patients have floundered, potentially because by that point in the disease pathway elements other than the virus are at play.
Pfizer disclosed the discontinuation of PF-07304814 in its quarterly pipeline update. The Big Pharma also used the update to reveal the end of work on PRMT5 inhibitor PF-06939999 in solid tumor patients and PF-07059013 in sickle cell disease. Both programs were in phase 1.