Prothena president and CEO Gene G. Kinney, PhD

No sooner did Prothena announce positive Phase I data for its transthyretin amyloidosis (ATTR) candidate PRX004 than the company began hearing from several other companies interested in developing the humanized monoclonal antibody.

One of those companies was Novo Nordisk—which over recent months backed up its interest in the drug with cash and commitments, working out a deal to acquire the Phase II-ready PRX004 from Prothena for up to $1.2 billion.

The deal, announced last week, gives Prothena $60 million in upfront cash and potentially up to $1.17 billion tied to achieving development, commercialization and net sales-based milestones, starting with $40 million if the anti-amyloid immunotherapy advances to Phase II—while committing Novo Nordisk to overseeing that Phase II development, and paying out hundreds of millions of dollars more in later development and sales milestones.

Prothena president and CEO Gene G. Kinney, PhD, and Chief Business Officer Brandon Smith discussed the Novo Nordisk deal and the development to date of PRX004 in interviews with GEN Edge.

When patients are diagnosed with ATTR, affected organs contain extracellular amyloid deposits that cause organ dysfunction. PRX004 is designed to deplete the amyloid deposits that are associated with the disease pathology that underlies both hereditary ATTR amyloidosis (hATTR) and wild type ATTR amyloidosis (wtATTR)—without affecting the native or normal tetrameric form of the protein.

Prothena estimates the potential patient population for PRX004 at 400,000 patients worldwide with wtATTR amyloidosis and 50,000 patients worldwide with hATTR amyloidosis.

“With a relatively broad cardiovascular patient population here, we think this approach, with Novo’s expertise, is really an opportunity to potentially accelerate the overall movement of this molecule towards patients, and that’s what’s key and most important for most of us, if not all of us, working in this industry,” Kinney told GEN Edge.

PRX004 showed itself in preclinical studies to promote clearance of insoluble amyloid fibrils through antibody-mediated phagocytosis and inhibit amyloid formation. This depleter mechanism of action, Prothena reasons, could benefit ATTR patients at high risk for early mortality due to amyloid deposits in vital organs.

Kinney uses the analogy of a bathtub full of water. Current treatments—whether silencers designed to reduce new protein production, or stabilizers designed to slow the breakdown of the normal tetrameric protein form—turn off the proverbial faucet.

Draining the “bathtub”

“Where PRX004 is differentiated is, it’s designed to drain the bathtub,” Kinney said.

PRX004 is designed to leave the normal tetrameric form of the protein intact. The antibody binds to a section of transthyretin that, when assembled into the normal tetramer, is hidden from PRX004. But when that protein breaks down and becomes dysregulated into an abnormal or dysregulated conformation, Kinney said, the area targeted by PRX004 is exposed.

“Based on our preclinical studies, PRX004 prevents further aggregation at that point. And second, very importantly for material that’s already deposited in various tissue—for example, the heart—it’s designed to tag that for removal and clear the material that’s already there and already causing dysfunction for patients.”

Last December, Prothena concluded that PRX004’s depleter mechanism of action can benefit both neuropathy and cardiac function, based on positive data from a Phase I dose-escalation study (NCT03336580). That data showed PRX004 to have slowed the progression of neuropathy for all seven evaluable patients at nine months, including improvement in neuropathy in three of the patients, and improved cardiac systolic function for all seven patients.

For all evaluable patients, slowing of neuropathy progression was shown by a mean change from baseline in Neuropathy Impairment Score (NIS) of +1.29 points at nine months—compared with +9.2 points in untreated and placebo-treated patients with hereditary ATTR peripheral neuropathy (hATTR-PN), based on analysis of published historical data. Three of the seven evaluable patients showed improvement in neuropathy with a mean change in NIS of –3.33 points at nine months.

In addition, PRX004 also showed improvement in cardiac systolic function in each of the seven evaluable patients, with a mean change in global longitudinal strain (GLS) of –1.21% at nine months (centrally read). For the three patients who showed NIS improvement, the resulting GLS improvement was more evident, with a mean change of –1.51% at nine months.

Resonating with would-be partners

Prothena’s data didn’t seem to wow investors; the day of the Phase I announcement, the company’s stock closed December 9 at $11.47, down 9 cents from the previous day—before shares climbed into the $50s, where they have fluctuated since June 30.

But the Phase I readout did resonate with the companies that sent Prothena unsolicited expressions of development interest in PRX004.

Prothena chief business officer Brandon Smith

“Novo’s ability to drive it forward quickly, it was certainly something that was interesting to us,” Smith recalled of Novo Nordisk. “We were certainly very excited about their strong interest. They did their market research, they did their due diligence, they were very, very focused on this and strategically, it seemed like a great fit.”

Novo Nordisk concluded PRX004 was a great fit based on its desire to broaden its commercial portfolio, now largely centered around products to treat diabetes and obesity, as well as its Biopharm business which encompasses hemophilia and growth hormone deficiency.

Novo Nordisk said it will initially focus its clinical development of PRX004 on ATTR cardiomyopathy—an under diagnosed and potentially fatal form of ATTR amyloidosis characterized by build-up of amyloid deposits in cardiac tissue.

“One of our strategic aspirations for 2025 is to establish a presence in other serious chronic disease, focusing on cardiovascular disease, non-alcoholic steatohepatitis (NASH), and chronic kidney disease,” Novo Nordisk spokesman Michael Bachner told GEN. “The deal with Prothena is a continuation of our strategy in cardiovascular disease that provides us with the opportunity to accelerate the build-up of our CVD pipeline, and it gives us access to an innovative clinical asset for the treatment of ATTR cardiomyopathy, a disease area within cardiovascular disease with significant unmet need.”

Jefferies analyst Michael Yee wrote July 12 that Novo Nordisk’s acquisition of PRX004 aligned with efforts in recent years to grow its CV portfolio—most notably the company acquiring Corvidia Therapeutics last year for up to $2.1 billion (of which $725 million was upfront). That deal expanded Novo’s pipeline with the anti-IL-6 antibody ziltivekimab, designed to reduce the risk of major adverse cardiovascular events in chronic kidney disease (CKD) patients with atherosclerotic cardiovascular disease (ASCVD) and inflammation.

Novo Nordisk is also partnering with Staten Biotechnology of The Netherlands to develop Staten’s lead pipeline candidate STT-5058, a monoclonal antibody designed to treat dyslipidaemia by targeting the lipoprotein ApoC3. A first-in-human Phase I trial (NCT04419688) began last year. Novo Nordisk is providing funding and support to Staten to develop STT-5058 for dyslipidemia, under a collaboration and exclusive option agreement of undisclosed value inked in 2018.

“Novo is well positioned as a global [company] to run a Phase II/III and to commercialize [PRX004] w/ their cardio-metabolic presence in diabetes and CV,” Yee concluded.

Making commercial sense

Smith said the sale of PRX004 also made sense for Prothena from a commercial standpoint.

“Quite frankly, long term cardiovascular is quite a large commercial presence requirement. And without additional cardiovascular programs in our pipeline, we thought it made more sense for a company like Novo to take it forward, because they will have the broader presence commercially.,” Smith explained.

“Put all those things together, and the fact that any big pharma likes to run clinical trials their own way,” Smith added, “and we thought it made sense for us to take a step back and allow Novo to drive the program forward for patients.”

Novo Nordisk will initially focus its clinical development of PRX004 on ATTR cardiomyopathy. Driving that program will entail advancing PRX004 into Phase II studies. “A Phase II clinical trial for PRX004 is expected to be initiated in 2022” Novo spokesman Michael Bachner said. [Novo Nordisk]
Driving that program will entail advancing PRX004 into Phase II studies. “A Phase II clinical trial for PRX004 is expected to be initiated in 2022” Bachner said. “This is expected to be followed by a Phase III cardiovascular outcomes trial (CVOT).”

The timing of the Phase II trial has been pushed back from earlier plans. According to Prothena’s Form 10-Q for the first quarter, filed May 11, a Phase II/III trial of PRX004 was “expected to initiate in the fourth quarter of 2021.”

Through its deal with Prothena, Novo Nordisk acquired a wholly-owned subsidiary of Prothena and gained full worldwide rights to the intellectual property and related rights of Prothena’s ATTR amyloidosis business and pipeline.

Novo Nordisk’s acquisition of PRX004 came barely two weeks after researchers from Intellia Therapeutics, Regeneron Pharmaceuticals, and partners reported that its in vivo CRISPR genome editing therapy NTLA-2001 generated a dramatic reduction of protein linked to ATTR amyloidosis following a single dose in six patients with hATTR-PN. In publishing June 26 the first-ever clinical data supporting the efficacy of in vivo CRISPR genome editing in humans, Intellia’s president and CEO John Leonard, MD, declared “a new era of medicine.”

The FDA’s approved treatments for wild-type or hereditary ATTR cardiomyopathy include Pfizer’s Vyndamax® and Vyndaqel®, both authorized in 2019 as separate oral formulations of the same drug. Pfizer reports combined revenues for both drugs, which nearly tripled last year to $1.288 billion from $473 million, and nearly doubled year-over-year during Q1 2021, to $453 million from $231 million.

The first FDA-approved therapy for a form of polyneuropathy caused by hATTR in adults is Onpattro® (patisiran), a first-in-class small interfering ribonucleic acid (siRNA) treatment authorized in August 2018. Onpattro generated $306 million in global net product revenues last year, up 84% from 2019—and $102 million in the first quarter of 2021, up 53% from Q1 2020.

Expanded label

Alnylam is pursuing an expanded label for Onpattro. In June, Alnylam completed enrollment in the Phase III APOLLO-B trial (NCT03997383), designed to evaluate Onpattro for cardiomyopathy in patients with ATTR amyloidosis. The estimated primary completion date for the 360-patient study is June 2022.

Two months after Onpattro’s approval, the FDA authorized a second drug for polyneuropathy of hATTR in adults—Tegsedi® marketed by Akcea Therapeutics, a majority-owned affiliate of Ionis Pharmaceuticals, as the first and only subcutaneous RNA-targeting drug designed to reduce the production of human TTR protein. As of the second quarter, Tegsedi is being distributed in the U.S. by Swedish Orphan Biovitrum (Sobi™).

Ionis reports Tegsedi revenue combined with another marketed drug for a rare disease indication, Waylivra® for familial chylomicronaemia syndrome. During the first quarter, the drugs generated $19.8 million in combined revenue, up 30% from $15.2 million in Q1 2020.

“We know there are other groups working on new medicines to treat ATTR cardiomyopathy. However, we truly believe that PRX004 represents a differentiated and competitive approach with an innovative mode-of-action,” Bachner said.

While current treatments prevent further build-up of myocardial amyloid, he asserted, PRX004 offers the advantage of removing myocardial amyloid, reversing ATTR cardiomyopathy, and preventing further aggregation of amyloid deposits: “PRX004 represents a novel class of investigational drugs that work by a depleter mechanism of action and has the potential to provide benefit for ATTR patients at high risk for early mortality due to amyloid deposition in vital organs.”

Not covered by Prothena’s agreement with Novo Nordisk—and thus still under Prothena’s sole control—is development of its monoclonal antibody for AL (Light Chain) amyloidosis, birtamimab (formerly NEOD001). Earlier this year, Prothena initiated a confirmatory Phase III trial, AFFIRM-AL, designed to assess birtamimab in Mayo Stage IV patients with AL amyloidosis, having the poorest prognoses for disease survival—a potential population estimated at between 60,000 and 120,000 patients. AFFIRM-AL is being conducted under a Special Protocol Assessment agreement with the FDA, with a primary endpoint of all-cause mortality at p≤0.10.

Through AFFIRM-AL, Prothena is resurrecting a clinical program that it ended in 2018 after it failed the Phase IIb PRONTO trial (NCT02632786), and appeared headed for another failure in the Phase III VITAL trial (NCT02312206). The termination led to a 63% plunge in Prothena’s stock price.

According to Prothena, a post hoc analysis of data from the 260-patient VITAL trial showed that of 77 patients who were diagnosed as Mayo Stage IV with AL amyloidosis, 74% of patients treated with birtamimab were still alive nine months after treatment, vs. 49% of placebo-treated patients. At a hazard ratio of 0.413, nearly 59% of patients treated with birtamimab were likely to die than patients in the placebo control group.

Beyond amyloidosis, Prothena’s pipeline includes candidates for:

  • ALS—the discovery-phase TDP-43, whose modality is undisclosed, partnered with Bristol Myers Squibb (BMS).
  • Neurodegeneration—A discovery phase monoclonal antibody partnered with BMS.
  • Parkinson’s disease—Prasinezumab, being co-developed with Roche
  • Alzheimer’s disease—including preclinical monoclonal antibody candidates that target tau (PRX005, partnered with BMS) and amyloid beta (PRX012), as well as a vaccine targeting tau and amyloid beta and a small molecule drug for Alzheimer’s in Down syndrome.

Last month, BMS agreed to pay Prothena $80 million for an exclusive US license to PRX005, which fights tau by targeting an area within the microtubule binding region (MTBR). BMS has a next option for global rights to PRX005 following completion of a Phase I trial that has initiated.

On the amyloid beta front, “We’re expecting to initiate clinical trials for the PRX012 molecule in the early part of next year,” Kinney added.

“We think the Alzheimer’s field is going to move towards the combination treatment by targeting both amyloid beta and tau proteins,” Kinney said. “Second, we see a shift ultimately from treating patients, particularly early in their disease process, to starting to think about prevention trials, starting with secondary prevention trials. And obviously with success there, you can start to think about primary prevention. So, a vaccine becomes a very important component in that.”

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