Like its namesake star twinkling 25 light-years from Earth, Vega Therapeutics hopes to shine as brightly in treating rare blood disorders, starting with a therapy for von Willebrand disease (VWD) that the company plans to advance into the clinic in the new year.

Vega launched earlier this month as the second star-themed spinout of Star Therapeutics, which is building a portfolio of spinouts, each focused on a family of rare diseases. Star joined with a group of new and existing investors to finance the launch with $40 million.

“We view these thousands of rare diseases like stars in the night sky,” Adam Rosenthal, PhD, CEO and co-founder of Vega, told GEN Edge. “If you start to group the stars together or the diseases together like in constellations, you find diseases that share a common path of biology that can potentially be treated in the same way. That’s really the basis behind the theme and the analogy.”

Rosenthal said spinning out Vega—rather than simply expanding Star’s operations to include Vega’s work in VWD—offered the same two advantages Star found when it launched its first spinout in February 2022 with $84 million in Series B financing.

“One advantage is focus. It allows us to build each company, and go very deep into that biology, and build the capabilities in the team to allow us to really prioritize and take a big swing in a new area biology. It really helps us focus the efforts on the programs, so we don’t have to make prioritizations across unrelated programs. Each company is solely focused on that area of biology,” said Rosenthal, who is also CEO and founder of Star.

“The second advantage is flexibility,” he added. “It allows us to pursue a range of options when it comes to partnering discussions or financing options, and each company can do that independently of one another. That’s been a really big help.”

Star’s first spinout, Electra Therapeutics, is developing a pipeline led by the Phase I antibody ELA026 for secondary hemophagocytic lymphohistiocytosis (sHLH), with undisclosed preclinical candidates in immunology and immuno-oncology. ELA026 targets the Signal Regulatory Protein (SIRP) family of cell surface receptors, which consists of several proteins with differing roles across various immune cell types.

Vega’s first order of business is to develop VGA039, a monoclonal antibody designed to fight VWD by targeting human Protein S. Vega aims to position VGA039 as an easier-to-use alternative to factor replacement therapies, which require IV infusions several times a week.

Changing the game

Vega aims to revolutionize treatment of VWD much as Roche and its Genentech subsidiary reshaped the landscape of hemophilia treatment in 2017 by bringing to market Hemlibra® (emicizumab-kxwh), a bispecific monoclonal antibody treatment for hemophilia A that enables coagulation by bridging factor IXa and factor X. Hemlibra is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children with hemophilia A, with or without factor VIII inhibitors.

“Hemlibra really changed the game for people living with hemophilia. So, we thought it would be possible to take a similar approach for other bleeding disorders,” Rosenthal said.

Hemlibra’s antibody approach has also proven to be a blockbuster for Roche. During the first nine months of 2022, Hemlibra was Roche’s third highest-selling treatment, generating CHF 2.778 billion ($2.977 billion), up 28% from Q1–Q3 2021. Most of the sales—CHF 1.684 billion ($1.804 billion)—were generated in the United States, where Hemlibra grew 22% year-over-year.

For all of 2021, Hemlibra was No. 6 among Roche’s top sellers with sales of CHF 3.022 billion ($3.238 billion), up 41% from 2020.

“We’re trying to do a similar thing, but almost [with] both steps in parallel here, where we’re trying to raise awareness for the severity of the disease, and at the same time bring a convenient therapy,” Rosenthal said. “I think what we saw with Hemlibra is that once there is a more patient-friendly therapy, the awareness ramps up, and the uptake in terms of chronic prophylaxis also ramps up quite a bit. We’re hoping that something similar happens here as we continue to develop VGA039.”

He added, however, that Vega has no plans to expand into hemophilia drug development, since that specialty is much more crowded with approved therapies—the most recent of which is a one-time gene therapy for hemophilia B, CSL Behring’s Hemgenix® (etranacogene dezaparvovec-drlb), which won FDA approval last month. At a list price of $3.5 million, Hemgenix is the costliest drug approved for any indication anywhere in the world. The company defends the list price by citing strong efficacy results that include pivotal data released last year and showing statistical superiority over current standard-of-care treatment 18 months after infusion.

A team of Vega researchers reported positive preclinical activity for VGA039 in a paper published recently in Blood, and presented at the recent 64th American Society of Hematology (ASH) Annual Meeting & Exposition in New Orleans.

The researchers found that VGA039 inhibits Protein S cofactor activity for tissue factor pathway inhibitor alpha (TFPIα) and activated protein C (aPC). That, in turn, enhances the production of thrombin—an enzyme in blood plasma that causes the clotting of blood by converting fibrinogen to fibrin—by acting on both the initiation and propagation phases of coagulation.

“It really helps to augment and restore thrombin generation,” Rosenthal said. “Thrombin is essentially what pushes it more to a [coagulation] state. It’s like a seesaw between bleeding and coagulation. So, pushing it on the thrombin side helps to really push it more to a balanced hemostatic state, away from the bleeding disorders under the spectrum.”

The researchers reason that since deletion of Protein S had been shown in the past to restore hemostasis in a hemophilia A mouse model, Protein S inhibition may also be a viable approach to treating various other bleeding disorders, starting with VWD.

Long half-life

One potential advantage to VGA039, according to Vega, is its relatively long half-life—shown in the preclinical study to be 21 days when administered via IV, and 12 days when administered subcutaneously at 1 mg/kg. “We think that it would be a patient-friendly dosing profile that could be given [subcutaneously] with an infrequent dose,” Rosenthal observed.

“We believe it can lead to the basis of a universal hemostatic therapy across a range of bleeding disorders, including von Willebrand Disease,” Rosenthal said.

VGA039 was selected for study based on its cross-reactivity with human and non-human primate (NHP) Protein S and the reversal of aPC and TFPIα anticoagulant activities. VGA039 was found to bind to human and NHP Protein S, but not to Protein S of pigs, dogs, or rodents. Thrombin generation assays conducted in vitro showed VGA039 to increase thrombin generation in aPC-treated normal human and NHP plasma with an EC50 of ~10 µg/mL. [EC50 is the concentration of a drug that is necessary to cause half of its maximum possible effect.]

Similarly, in pooled normal human plasma containing exogenous recombinant human TFPIα (rTFPIα), VGA039 enhanced tissue factor induced thrombin generation in a concentration-dependent manner with an EC50 of ~10 µg/mL.

“Due to its mechanism of action, subcutaneous bioavailability, and long half-life, VGA039 has the potential to be a universal pro-hemostatic agent that can ease the treatment burden for patients on factor replacement therapy,” the researchers concluded.

If VGA039 fulfills or exceeds that potential, it can expand a market for von Willebrand disease drugs that according to Verified Market Research stood at $561.58 million in 2022, and will nearly double to $963.25 million by 2030, by growing at a compound annual growth rate (CAGR) of 5.76% from 2023 to 2030.

According to the National Hemophilia Foundation, VWD is the most common bleeding disorder, affecting up to 1% of the U.S. population, or approximately 1 in every 100 people. About 60–80% of people with VWD have the mildest form or type 1, with levels of von Willebrand factor that are 20–50% of normal. Type 2 (15–30% of those with VWD) have normal levels of Willebrand factor, but it doesn’t function as it should. Type 3 (5–10% of patients) have low levels or no factor in their blood.

“Most of the preclinical work has finished,” Rosenthal said. “There are some lingering things, but right now the focus is going to be all about the clinic, and we’ll be starting the Phase I study early next year in healthy volunteers, and then it’ll progress into patients after that.”

A data readout from the Phase I study, and its progression into patients, are both expected to occur later in 2023.

On the market

VGA039 would, if approved, join several drugs on the market as treatment options for VWD patients. They include:

  • Grifols’ Alphanate® (antihemophilic factor/von Willebrand factor complex [human])
  • Ferring Pharmaceuticals’ DDAVP® (desmopressin), a man-made form of vasopressin available in generic versions
  • CSL Behring’s Humate-P® (Antihemophilic Factor/von Willebrand Factor Complex [human])
  • Octapharma’s Wilate® (von Willebrand Factor/Coagulation Factor VIII Complex [human])
  • Takeda Pharmaceutical’s Vonvendi® (von Willebrand Factor [recombinant])

Vonvendi entered the market in 2015 after the FDA granted Shire authorization for treating bleeding episodes in patients with VWD. Three years later, the agency expanded Vonvendi’s approval to include perioperative management of bleeding in adults with VWD. Takeda—which acquired Shire in 2019 for £46 billion ($55 billion)—won FDA approval in January 2022 for Vonvendi’s use in routine prophylaxis, to reduce the frequency of bleeding episodes in patients with severe Type 3 VWD receiving on-demand therapy.

Wilate won FDA approval in 2009 and was launched in the United States the following year as the first replacement therapy authorized for VWD. Earlier this month at the 64th American Society of Hematology (ASH) Meeting, Octaphara presented data from the Phase III WIL-31 trial (NCT04052698) showing that prophylaxis with Wilate resulted in an 84% reduction in annualized bleeding rate (ABR) compared with on-demand treatment during the prior run-in study, and a 95% reduction in the median spontaneous ABR.

Alphanate and DDAVP were both approved by the FDA in 1978, followed in 1986 by the agency’s authorization of Humate-P.

“The fact that there are only these factor replacements that are quite burdensome,” Rosenthal said. “VWD is just a disease that’s been quite overlooked. So that’s definitely the reason why we’re focused there.”

Rosenthal said he and several colleagues at Star became interested in rare blood diseases while they worked at True North Therapeutics, a drug developer acquired in 2017 for up to $825 million by Bioverativ, which in turn was bought out by Sanofi for $11.6 billion the following year.

“Rare hematologic diseases represented a natural starting point for us to follow the biology to find nodes for treating multiple diseases. From our time at True North, we understood the principal biological processes, the clinical development path, and, importantly, many of the key opinion leaders who could be sounding boards for our ideas,” Rosenthal told Inside Precision Medicine, a sister publication of GEN also published by Mary Ann Liebert, Inc., publishers. “We compiled a list of rare diseases in hematology and went to work evaluating these diseases one at a time to identify the mechanisms driving each. We dug into the literature and had discussions with experts about what we found.”

Vega said the financing is helping it advance VGA039 into clinical phases, further study the biology of Protein S in bleeding disorders, and over time develop antibody treatments for blood disorders. The company also plans to focus future growth on its clinical programs, which is expected to add to Vega’s headcount of 15 full-time equivalents (part of Star’s total workforce in the high-40s).

Vega’s $40 million financing comes from Star and its investors—a group that includes Westlake Village BioPartners, OrbiMed, Redmile Group, RA Capital, Cowen Healthcare Investments, Cormorant Asset Management, and New Leaf Venture Partners.

“We’re very sensitive to the current market environment, and we’re always exploring multiple sources of funding and having partnering discussions,” Rosenthal said. “Given the strong syndicate that we have—we’ve got seven top-tier investors, VCs, and crossovers through Star that have supported us along the way, and we’ve been quite efficient in taking this from an idea to the clinic with efficient resources. So, we’re in a good place right now, and we’re always open to different sources of funding going forward, be it financing or partnering discussions.”

“We’re building Vega to go it alone. But at the same time, we’re having these conversations, so if we did find the right partner along the way, we’d be open to that and start to build for either additional candidates or additional indications for VGA039,” Rosenthal added. “Given the nature of it being a universal, hemostatic therapy, we could go into other diseases outside of VWD. So, whether in addition to VGA039, we continue to build up the pipeline, that’s something that we’ll be open to, based on following the science.”

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