Medical Innovation Exchange


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.” 
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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. 

Vivocore combines InterVivo, Transpharmation to form neuroscience CRO with an interest in psilocybin

InterVivo Solutions and Transpharmation have merged to form a neuroscience-focused preclinical services CRO.The merger, which establishes the firms as “sister companies” with a joint executive team, comes days after InterVivo’s owner Vivocore acquired Transpharmation. The two companies have worked together since 2017 when they established a joint venture to co-market and develop translational research services to help drug firms develop novel treatments for CNS disorders.
The merger will significantly expand the range of assays available to customers in the biopharma and biotech space, according to CEO Mark Duxon, who told us “although we work in complementary therapeutic areas, we have minimal overlap in services.”

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With the new merger, the combined company will have “double the suite” of assays in pain, neurodegenerative disorders and psychiatric disorders. Duxon also suggested customers would benefit from working with a merged CRO with a broader offering, citing reduced contract management and oversight as an example.
“Some of the larger companies especially find it time-consuming to deal with multiple smaller CROs, as there are more contracts to administer and they need to manage assays and services across suppliers and scientific teams,” Duxon said. 
Transpharmation and InterVivo already count top 10 pharma companies, midcap pharma and biotechs in Japan, Europe and the U.S. as customers, according to Duxon, who added that as a result of the merger, “we can now communicate with them across the board.”
InterVivo Solutions is based in Toronto, while Transpharmation has bases in Discovery Park in Kent, the UK and in Olsztyn in Poland.
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The merged firm also plans to expand its current 120-strong scientific team at existing sites in Canada, Ireland, the UK and Poland. One particular interest is in bringing on talent with experience in drugs based on psilocybin, according to Duxon. 
He predicted psilocybin-based products would reach the market within six years, adding, “we’re involved in multiple discussions.”

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. 
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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.

Engineered TCR-T cells by Fred Hutch, San Raffaele-Intellia fend off evasive leukemia, solid tumors

Engineered T-cell therapy has become an important weapon against blood cancers. Aiming to overcome the obstacles that have stalled the utilization of T-cell immunotherapies in acute myeloid leukemia, two research teams have concurrently found a promising solution in one protein target—along with the potential to expand into solid tumors.Scientists from the Fred Hutchinson Cancer Research Center and a collaboration between Ospedale San Raffaele Scientific Institute in Italy and U.S. biotech Intellia Therapeutics have designed T-cell receptor (TCR)-based cell therapies targeting the WT1 antigen on leukemia cells. The therapies showed strong antitumor effects in cell cultures and in mice, including against cells from a patient who had developed immune evasion, the teams reported in Science Translational Medicine here and here.
Intellia is already developing a WT1-targeted TCR T-cell therapy dubbed NTLA-5001 in a phase 1/2a AML clinical trial. The Fred Hutch team also suggests that targeting WT1 with a TCR T-cell therapy represents a promising approach to treating AML and possibly even solid tumors.

WT1 has been linked to tumor initiation and proliferation in AML, and it’s highly expressed in leukemia cells compared with healthy cells. But it’s not just any part of WT1 the two teams have identified—both teams zeroed in on a specific site on the protein called WT1 37-45.
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The Fred Hutch scientists previously devised an engineered WT1 TCR T-cell candidate called TTCR-C4, which targeted the WT1 126-134 site. But a young AML patient developed recurrent disease after receiving the therapy even though functional T cells targeting WT1 persisted during relapse and WT1 was still expressed by the patient’s AML cells.
After investigation, the scientists uncovered a novel mechanism of escape of cancer cells from immunologic targeting. Leukemia cells evaded detection by expressing less of the immunoproteasome, which is required for the presentation of WT1 126-134 to immune cells.
The Fred Hutch team set out to identify alternative WT1s that don’t require a specific type of proteasome. Their screen pinpointed WT1 37-45. Updated TCR-T cells engineered to recognize the new WT1 site successfully killed leukemia cells from the relapsed patient in lab dishes but also reduced the growth of solid tumor cells lines of WT1-expressing pancreatic cancer and breast cancer.
In a mouse model of pancreatic cancer that lacked an immunoproteasome component, the WT1 37-45 TCR-T cells—but not the TTCR-C4 candidate—reduced the tumor burden, the team reported.
As for the San Raffaele-Intellia team, the researchers isolated 19 TCRs for WT1 from healthy donors. A WT1 37-45 TCR showed the strongest binding activity with antigen-presenting elements for T cells. The final TCR T-cell product, perfected with CRISPR-Cas9 gene-editing tools, showed antigen-specific responses and killed AML cells, acute lymphoblastic leukemia cells and brain tumor cells in lab dishes and in mice.
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The two studies on WT1 represent the latest efforts toward constructing engineered immune cell therapy to fight AML. California biotech Senti Bio has made a logic-gated CAR-NK cell therapy that aim to more thoroughly kill off AML by recognizing cancer cells expressing either FLT3 or CD33 but avoid potential side effects by steering the therapy away from healthy cells with the endomucin protein. The therapy recently reported promising results in mouse models.
Both the Fred Hutch and the San Raffaele-Intellia teams believe WT1 37-45 represents an attractive target for the development of cell therapies for AML. Because WT1 is expressed inside leukemia cells, it’s beyond the reach of CAR-T cells, which can only recognize cell surface antigens. Besides, TCR signaling promotes T-cell survival, leading to long-term immune memory, necessary for preventing tumor relapse, the San Raffaele-Intellia researchers said in their study.
WT1 is also expressed across several solid tumors, and a lack of immunoproteasome is a feature of limited response to immunotherapy in solid tumors. A WT1 37-45 TCR-T cell therapy could therefore potentially treat those solid tumors as well, the two teams said.

Rivus throws down mid-stage liver fat data on quest to climb NASH mountain

Considering NASH drug development has stumped companies big and small, can newcomer Rivus Pharmaceuticals move the needle?The Charlottesville, Va.-based company hopes so, and is out today with data on its lead candidate showing a reduction in liver fat, a key hallmark of NASH, or non-alcoholic steatohepatitis. The results also provided some evidence that suggests improvements in metabolic parameters related to Type 2 diabetes, a type of heart failure and the tricky liver disease NASH.
The drug prospect, called HU6, met the primary endpoint of reducing liver fat in a phase 2a study of patients who were obese with elevated liver fat. Secondary goals included different measures of fat loss. The endpoints were achieved while conserving skeletal muscle mass. Patients also saw improvements in markers of insulin resistance and inflammation, according to Rivus.

The company believes that HU6 could help address the root causes of metabolic diseases by reducing liver fat, especially since the results occurred in a relatively short timeframe of eight weeks.
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Rivus said that the therapy achieved reductions in liver fat ranging from 33% to 40% depending on the dose. Participants lost an average of six pounds during the study, but participants who had elevated blood glucose saw even greater reductions in weight and fat. These patients lost an average of 10 pounds.
As for safety, HU6 was well tolerated with no serious adverse events recorded. One patient in the low-dose group discontinued due to diarrhea, but no discontinuations were seen in the high-dose group.
With the results in hand, the company can now consider whether reducing visceral and organ fat can benefit patients with cardiometabolic diseases, Rivus’ Chief Scientific Officer Shaharyar Khan, Ph.D., said.
The biotech plans to continue with the HU6 clinical program through the first half of the year, including a phase 2a study in heart failure with preserved ejection fracture. A phase 2b study in type 2 diabetes and NASH will come next.
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NASH has stymied some of the top drugmakers in the world. Bristol Myers Squibb in November shelved a mid-stage asset in the disease after lackluster results. But Big Pharma still wants in on this potentially lucrative market. GlaxoSmithKline just put up to $1 billion on the line in a pact with Arrowhead Pharmaceuticals to develop the NASH candidate ARO-HSD.
A couple small biotechs have kept the lights on in NASH. Madrigal and 89bio both reported some success with their candidates in January. To join that group, Rivus will need to see that phase 2b through.
Rivus emerged in July of last year with a $35 million series A to tackle a host of metabolic disorders. 

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.
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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.