Alnylam Advancing From Platform Buzz To Late-Stage Clinical Work

RNAi pioneer is getting closer to market with NDA filing in amyloidosis expected in 2017, but ample competition is coming along, albeit far behind.

The leader in a field others have abandoned, Alnylam Pharmaceuticals Inc., has been working hard to make the case that its RNA-interference technology is moving beyond buzz-worthy platform status into a near-proven modality that is producing late-stage clinical candidates, with its first NDA filing expected in 2017.

With seven candidates in clinical development, expected to reach nine by year's end, the Cambridge, Mass., firm has met its "5 X 15" goals and now is moving on to its 2020 aspirations to have three marketed products, 10 clinical programs and four late-stage programs across three strategic therapeutic areas (which it calls STArs): genetic medicines, cardio-metabolic disease and hepatic infectious disease (Also see "How And Why Genzyme And Alnylam Expanded Their Alliance" - Pink Sheet, 20 Jan, 2014.).

That progress has been highlighted at a series of recent events, including presentations at the American Society of Hematology and the Oligonucleotides Therapeutic Society and a Dec. 10 investor day.

Following the investor day, Wall Street analysts widely praised Alnylam's execution, giving its stock ratings of "outperform" (Leerink Partners, Dec. 11), "market outperform" (JMP Securities, Dec. 10), and "buy" (Jefferies Equity Research, Dec. 10). At the event in New York, Alnylam laid out a strategy for taking on Alexion Pharmaceuticals Inc. and its high-priced blockbuster Soliris (eculizumab) in paroxysmal nocturnal hemoglobinuria (PNH) and other complement-mediated disorders and to best Roche and its investigational bispecific monoclonal antibody ACE910 in offering a game-changing therapeutic improvement to hemophilia patients (Also see "Alnylam Going After Alexion's Soliris In PNH, Eyes Roche In Hemophilia" - Pink Sheet, 10 Dec, 2015.).

In the process, Alnylam has transitioned in status from being largely an "ambassador," as Morningstar analyst Stefan Quenneville phrased it, for a once ultra-hot technology space to a respected company that has executed on a strategy of pursuing validated targets – liver-expressed proteins – with biomarkers for demonstrating proof-of-concept in Phase I studies and a well-defined path to market.

Alnylam once struggled to rebound from the termination of collaborations with Roche [See Deal], Novartis AG[See Deal], Merck & Co. Inc.[See Deal]and Cubist Pharmaceuticals Inc.[See Deal]. However, the company has moved beyond those dark days, Quenneville said in an interview.

"I think they were seen as a science experiment that hadn't been working out and they obviously had to demonstrate to a lot of skeptical people that there were positive things going on when the headlines were about big pharmas getting out of the space," Quenneville said. "I think they did everything they could to be ambassadors for the technology in general and they had to convince a lot of very skeptical people. That was just the reality. I think they're past that point now."

Dominant IP Position Bolsters Alnylam

Alnylam is far from alone in the RNAi space, but holds a clear-cut lead position. Its joint-venture partner Isis Pharmaceuticals Inc. (newly renamed Ionis Pharmaceuticals) is advancing clinical candidates with a different gene-silencing technology called antisense, and the two got together in 2007 to found Regulus Therapeutics Inc. to focus on microRNA-targeted therapies [See Deal].

Other RNAi firms that have moved into clinical development – sometimes with intellectual property that originated at Alnylam – include Arrowhead Research Corp., Dicerna Pharmaceuticals Inc., Moderna Therapeutics LLC, ProQR Therapeutics BVand Arbutus Biopharma Corp.(See boxes for details on these companies, including their connections to Alnylam.)

"The thing with Alnylam is that they own the very key IP," Quenneville said. "Alnylam and Isis are the big players. They've signed agreements to cross-license the key IP, so they have freedom to operate with slightly different technologies" [See Deal].

Arbutus Biopharma Corp., Burnaby, BC, Canada

• Formed by 2015 merger of Tekmira Pharmaceuticals and OnCore Biopharma to focus on hepatitis B therapies [See Deal].
• Has ARB 1467 and ARB 1468 in Phase I for HBV, along with preclinical candidates, a covalently closed circular DNA (cccDNA) formation inhibitor and a core protein inhibitor (also known as capsid assembly inhibitor).
• Holds a 5% royalty position in Alnylam/The Medicines Co.'s ALN-PCSsc for cholesterolemia, which was originally developed by Alnylam utilizing Tekmira's lipid nanoparticle (LNP) platform. In November 2012, Alnylam and Tekmira reached a legal settlement to restructure their existing partnership, agreeing to consolidate certain IP elements related to LNP technology for the systemic delivery of RNAi therapeutic products. Alnylam paid $30m to Tekmira for rights to manufacture its own LNP-based products going forward, either itself or through a third-party contractor (Also see "Alnylam Sheds Legal Trouble But Picks Up Manufacturing Challenge In Tekmira Settlement" - Pink Sheet, 13 Nov, 2012.).

"For the most part, everybody [in the space] has some sort of [connection with Alnylam]," he continued. "Arrowhead has the former Roche IP that was acquired from Alnylam, so they're based on that [See Deal]. Alnylam wets its beak in different companies because it has IP agreements and is getting some sort of royalty on a lot of products that are being developed. They're competing, certainly, but they're also going to benefit if something [at another RNAi firm] ends up working. … It's hard to gauge because it's relatively opaque, but they have a pretty dominant IP position in the space."

Alnylam gained further control of RNAi intellectual property in 2014 by buying out Merck's IP estate, acquired in its purchase of Sirna Therapeutics Inc. in 2006 [See Deal]. The big pharma got $186m in cash and equity to cede its portion of the RNAi space to Alnylam, having paid roughly $1.1bn to acquire Sirna eight years prior [See Deal].

After an initial splash about a decade ago on the promise of RNAi, Alnylam suffered when the practicality of advancing the idea into the clinic proved troublesome. Among the issues was drug delivery, which Alnylam thinks it has conquered with its enhanced stabilization chemistry-GalNAc (N-acetylgalactosamine) conjugate technology, which enables targeted delivery of an RNAi therapeutic to hepatocytes via uptake on the asialoglycoprotein receptor.

Arrowhead Research Corp., Pasadena, Calif.

• Took over RNAi programs and IP licensed by Alnylam to Roche [See Deal]. Later completed IP swap with Alnylam [See Deal], and acquired Novartis' RNAi pipeline [See Deal].
• Has Phase IIb candidate ARC-520 in hepatitis B, licensed from Alnylam in 2012. ARC-520 is an intravenous drug based on a formulation of Dynamic Polyconjugate siRNA delivery vehicle and two siRNA sequences that target different regions of the viral genome.
• ARC-AAT, in Phase I for liver failure/cirrhosis, is an unlocked nucleobase analog (UNA)-containing RNAi molecule designed for systemic delivery using the Dynamic Polyconjugate delivery system that knocks down the Alpha-1 antitrypsin (AAT) gene transcript and reducing the hepatic production of mutant AAT protein.

Alnylam says this technology enables subcutaneous dosing with increased potency and durability, and a wide therapeutic index (Also see "Alnylam Validates Subcutaneous Delivery Technology With Strong Phase I Results" - Pink Sheet, 11 Jul, 2013.). For some of its initial late-stage candidates, Alnylam is depending partly on a convenience advantage as its method of administration might be less frequent than competing therapies, and also more convenient than intravenous infusion products such as Soliris.

Near Future Hinges On Sanofi Partnership

A significant portion of Alnylam's near-term hopes are tied to a partnership with Sanofi's rare disease division Genzyme Corp. – the collaboration on therapies targeting the transthyretin (TTR) gene was signed in 2012 and expanded in 2014 . Under those arrangements, the companies are partnered on patisiran for TTR-mediated amyloidosis indications, currently in the Phase III APOLLO study with an NDA filing slated for 2017. Another candidate for those indications, revusiran, is also in Phase III.

Sanofi also holds options on other Alnylam programs, as well as an ownership stake in the biotech (roughly 12% as of January, making it the third largest shareholder), but Quenneville does not see M&A in the collaboration's future. He thinks Sanofi sees the relationship more like its one with Regeneron Pharmaceuticals Inc. around PCSK9 inhibitor Praluent (alirocumab), an agreement that has been built upon and rearranged over time [See Deal].

"I think they're looking at [the partnership with Alnylam] like they did with Regeneron, where they keep an equity piece and they're the co-promotional partner, and it's a way of getting access to the technology to fill their pipeline and co-develop drugs," the analyst said. "I don't know that they don't want to take out Alnylam, but they seem to want to partner with them long-term while keeping an equity stake."

Moderna Therapeutics LLC, Cambridge, Mass.

• Has two preclinical messenger RNA candidates, MT-004 for cancer and MT-026 for hemophilia A, which is partnered with AstraZeneca [See Deal].
• Agreed in January 2015 to collaboration with Merck to design and synthesize up to five candidates against four undisclosed viruses [See Deal].

He noted that former Sanofi CEO Christopher Viehbacher had opined multiple times that when pharmas acquire and absorb biotechs, the acquired firms become less productive and less innovative. But Quenneville isn't sure current Sanofi management views a partner like Alnylam in the same way that Viehbacher did.

At the same time, however, Alnylam is not ideally positioned to become a standalone big biotech, like Amgen Inc. or Celgene Corp., the analyst said. Beyond the Sanofi/Genzyme tie-up, Alnylam is also partnered on another late-stage candidate – potential Praluent rival ALN-PCSsc, now in Phase I – with The Medicines Co. (Also see "The Medicines Co. Enters PCSK9 Race With Alnylam Deal" - Pink Sheet, 4 Feb, 2013.).

"Ultimately, for a company to make it big, they typically have to be selling their own products, not having partnered everything," Quenneville said. "They [need to] get to a stage where they can bring something to market by themselves and then keep the profits for themselves and keep reinvesting in their pipeline."

"The PCSK9 inhibitor is partnered, but they have some preclinical assets that maybe they'll want to build up," he continued. "The rare disease stuff is the most advanced and a lot of that is partnered, but it looks like Alnylam is going to co-market some of that with Genzyme, so they're probably going to build their own sales force in North America and Europe in the rare disease space, which makes a lot of sense." Rare diseases offer an attractive business model for biotech because of the limited overhead needed versus other therapeutic areas, he noted.

"I think they have the potential but at the same time, I think they're thinking about how many products they can advance and how many they can do on their own or whether it's better to leverage other people to develop [some of] it, because they do have a bit of a discovery engine. Once they identify the gene they want to silence, I think they're pretty efficient at developing an oligonucleotide to do that," Quenneville added. "It seems to me that it might be more efficient to partner with the right people and advance things that way too. I think they've been pretty rational, to be honest."

Amyloidosis Candidate Likely First To File

Alnylam's most advanced clinical candidate is patisiran, now in the Phase III APOLLO trial for familial amyloidotic polyneuropathy (FAP). Earlier in Phase III is revusiran for TTR-mediated familial amyloidotic cardiomyopathy (FAC). Together known as transthyretin-mediated amyloidosis (ATTR), these indications claim about 50,000 patients worldwide and prove fatal within two to 15 years after onset. TTR stabilizers currently provide a modest benefit to these patients and some sicker patients get liver transplants, Alnylam Chief Medical Officer Akshay Vaishnaw said during the investor day, but a therapy to halt disease progression remains an unmet medical need.

The APOLLO trial is ongoing and is expected to complete enrollment early in 2016 and report out data in 2017, potentially leading to Alnylam's first NDA filing. The company also anticipates two-year data from a Phase II open-label extension study of the drug in 2016. While patisiran could be Alnylam's first drug to market, however, it doesn't use the GalNAc delivery technology and is administered intravenously.

Revusiran is the biotech's most advanced subcutaneous injectable candidate. Its ongoing 200-patient Phase III ENDEAVOUR study will measure improvement from baseline in the six-minute walk test and knockdown of TTR at 18 months.

Morningstar's Quenneville thinks these lead candidates bode well for the company. "I do like their pipeline," the analyst said. "They're in some attractive therapeutic areas. The amyloidosis drugs, those are big rare disease markets where they're going to have strong pricing power. I think both of those are very attractive opportunities for them. The results there look good and very encouraging."

Dicerna Pharmaceuticals Inc., Watertown, Mass.

• Developer of RNAi drugs targeting unmet needs in cancer. Dicerna’s therapeutic approach utilizes its patented Dicer Substrate siRNA (DsiRNA) molecules and EnCore drug delivery technologies to silence previously undruggable disease targets, offering a potential new treatment option for oncology patients.
• Lead candidate DCR-MYC is short interfering RNA targeting the MYC oncogene. In Phase I/II in hepatocellular carcinoma including secondary metastases, Phase I in solid tumors.
• Raised $96.3m in IPO in January 2014 [See Deal].

Alnylam's only clinical candidate in its cardio-metabolic disease STAr, ALN-PCSsc for hypercholesterolemia, will be tested in a Phase II study as a quarterly subcutaneous injection to lower LDL cholesterol. Quenneville is less impressed with Alnylam's prospects in the cholesterolemia space, because its candidate will be such a late entrant in the PCSK9 inhibitor class.

"I think the PCSK9 inhibitor also looks good, but I'm a little more skeptical just because you're probably already going to have three players in the market when they get there," he explained. "Regeneron and Amgen [with Praluent and Repatha (evolocumab), respectively] are going to have monthly doses, so [dosing] every three months or six months would definitely be more convenient, but I don't know that it would be a dramatic game-changer."

Six of the firm's seven clinical candidates fall into the genetic disease category – Alnylam has no hepatic infectious disease candidates in the clinic, with ALN-HBV for hepatitis B being the furthest along in preclinical development.

CEO John Maraganore told the investor day crowd that Alnylam anticipates advancing five candidates into Phase III development by 2016, with the patisiran results expected in 2017 as the company's first Phase III readout. All told, the firm expects 10 significant clinical data readouts in 2016, he said.

Process For Quick Drug Development

Driving the quick progress of the pipeline, the exec said, will be a reproducible, modular drug-development methodology.

"This is a platform that creates an important framework for how we think every single drug we put into development can be developed," Maraganore explained. "Number one, we are focusing on liver-expressed disease genes because we have robust delivery to the liver, we've solved that problem. All of the target genes that we've worked on are genetically validated, they're either human gain-of-function mutations or human loss-of-function mutations that fundamentally de-risk the target as we think about employing these targets in our drug development programs."

A biomarker that can be measured in the first clinical studies for each candidate is another key part of the process, he said, allowing Alnylam to confirm that the candidate is active in human subjects and to determine the proper dose and dosing regimen very early in development.

"And then finally … we have definable paths for market approval through regulatory authorities and we have a definable path to value creation as it relates to reimbursement," Maraganore said.

Alnylam's R&D engine enables it to proceed from idea to developmental candidate in roughly six months, he added.

"But not only is time important here, the other feature that's important here is our success rate," he said. "There has never been a liver-expressed disease gene that we have not been able to generate a potent development candidate toward. We have 100% success at that stage. And there's never been a development candidate that has not gone through tox programs to basically clear toxicology. We're 100% at that stage. And to date … there's not a single clinical program that we've put in man that has not read out with positive pharmacology in humans."

Alnylam's Next Wave

At ASH in early December, Alnylam presented early data on its candidates for hemophilia, ALN-AT3, and for complement-mediated disorders, including PNH, ALN-CC5. Maraganore told "The Pink Sheet" that these programs mean Alnylam is "poised to be a significant competitor in what are the two largest orphan disease markets." Both candidates, currently in Phase I, could be "truly game-changing for patients," he asserted.

ProQR Therapeutics BV, Leiden, Netherlands

• Engaged in the discovery and development of RNA-based therapeutics for the treatment of severe genetic disorders, with an initial focus on cystic fibrosis.
• QR-010 is a Phase I RNA-based oligonucleotide designed to address the underlying cause of CF by repairing the mRNA defect encoded by the delta-F508 mutation in the CFTR gene. Designed to be delivered through a small, handheld aerosol delivery device, or nebulizer, in the form of a mist inhaled into the lungs.

ALN-AT3, now known as fitusiran, has a mechanism that works across the whole spectrum of bleeding disorders, including hemophilia A, hemophilia B and other rare bleeding indications that Alnylam plans to investigate later on, Maraganore said. Fitusiran is designed to lower levels of antithrombin, with the goal of promoting increases in thrombin generation to restore hemostasis and thereby prevent bleeding in patients with severe hemophilia, he explained.

The drug has shown an ability to reduce annual bleeding events by about 85% with a monthly subcutaneous injection. Patients currently need I.V. infusions two or three times a week. Fitusiran is viewed as a preventive therapy, the CEO said, but it has not demonstrated a quick enough onset of action to be considered ideal for acute therapy.

Alnylam plans to move from the current Phase I/II study in 2016 to a pair of Phase III trials, one in about 100 to 150 hemophilia A and hemophilia B patients who currently are treated on-demand with replacement factor therapies. A second Phase III study will test fitusiran in approximately 50 "inhibitor" patients, who have pre-existing antibodies against existing therapies like Factor VIII and Factor IX. These studies could wrap up in time for an NDA filing in 2018, Maraganore said.

The inhibitor patients in particular are an unmet need, he added. "These patients have nothing they can use for prophylaxis, and what they do is treat themselves every time they bleed with so-called bypass agents, like Factor VII, NovoSeven (recombinant human coagulation Factor VIIa) sold by Novo Nordisk AS, or a drug called Feiba (Factor Eight Inhibitor Bypassing Activity) sold by Baxalta Inc. And that's a poor standard of care for these patients because they have these 20 or 30 bleeds a year and have to treat themselves acutely every time they start bleeding."

Quenneville calls fitusiran "the drug I like a lot" within Alnylam's pipeline, describing it as a potentially disruptive therapy in a space that has not seen a lot of innovation recently (Also see "Hemophilia Market Snapshot: Is There Enough Innovation For Patients To Switch?" - Pink Sheet, 30 Jun, 2014.). Hemophilia currently is about a $10bn market opportunity, according to data compiled by the World Federation of Hemophilia and Baxalta, and is projected to grow to about $13bn in 2020. A drug to treat both hemophilia A and B is a nice advantage for Alnylam, Quenneville said, but he pointed out that hemophilia A is the primary opportunity, comprising about 80%-85% of the worldwide patient population.

The analyst is less optimistic about Alnylam's chances of competing with Alexion's well-established Soliris in complement-mediated disorders. Maraganore said his firm will stake its hopes mainly on convenience, with a subcutaneous drug that might only need to be administered monthly or even less frequently, compared to I.V. infusion of Soliris every two weeks. ALN-CC5 likely will have a similar safety profile to Soliris, he said, although less-frequent dosing could reduce the number of injection-site infections.

In testing so far, ALN-CC5 has shown an ability to knock down C5 protein to levels of about 1 mcg per million, comparable to the effect seen with Soliris, the exec noted. Alnylam isn't ruling out the possibility of an efficacy advantage, although Maraganore admitted it would need head-to-head study data to make such a claim.

Regulus Therapeutics Inc., San Diego

• Joint venture formed in September 2007 by Alnylam and Isis (Also see "Alnylam, Isis JV Regulus to Tackle MicroRNA" - Scrip, 1 Oct, 2007.). Regulus benefits substantially from the collective therapeutic RNA expertise of its founding companies, including established proprietary oligonucleotide-based technologies, and broad and dominant IP estates specific to chemically modified oligonucleotides.
• Lead candidate is Phase II RG-101 for hepatitis C, a GalNAc-conjugated microRNA antagonist (anti-miR) that targets microRNA-122 (miR-122). In February 2010, Regulus announced a collaboration with GlaxoSmithKline to develop and commercialize microRNA therapeutics targeting microRNA-122 in all fields with HCV as the lead indication [See Deal]. In June 2013, the agreement with GSK was amended to clarify that RG-101, and other formulations thereof, will be developed by Regulus independently of the alliance with GSK for HCV.
• A second clinical candidate is RG-012, in Phase I for the fibrotic disorder Alport syndrome. The candidate targets microRNA-21 (miR-21), which is upregulated in fibrotic tissues of humans. Preclinical studies have shown that anti-miR-21 can impact fibrosis by reducing expression of extracellular matrix proteins, as well as significantly improve organ function in multiple models of fibrosis including heart and kidney.

"Because we're achieving this very clamped knockdown of C5, essentially knocking it down to the floor and keeping it there … something we'll have to prove out with more advanced studies – we think we might even have potential efficacy advantages because of the fact that with eculizumab, you're mopping up all the C5 in the blood and a lot of times you have a breakthrough, the C5 levels are increased in patients and you don't have enough eculizumab in the blood to mop it up," he explained.

In all, Alnylam sees ALN-CC5 as a potential therapy in a wide range of complement-mediated disorders, including hemolytic diseases such as aHUS, for which Soliris also is approved. Other potential indications include a host of inflammatory diseases, such as myasthenia gravis and neuromyelitis optica, Maraganore said.

A Wave Beyond The Next Wave

At the Oligonucleotide Therapeutics Society annual meeting in mid-October in the Netherlands, Alnylam unveiled a pair of preclinical initiatives: BIS-RNAi, a process by which one therapeutic can knock down two genes simultaneously, and Reversir, a method to halt an RNAi drug's therapeutic process after it has occurred. Clinical plans will be revealed in 2016.

BIS-RNAi involves using a GalNAc conjugate to deliver two or possibly more small-interfering RNAs (siRNA) into hepatocytes, Maraganore explained. "We can imagine many indications where this could be of interest," he said. "This would include for example in the cardio-metabolic space, many diseases, such as metabolic syndrome, NASH, diabetes, etc., where there are known features of the disease pathophysiology where not just one target would be of interest but potentially two targets would be of interest."

Alnylam expects to unveil its first candidate using this technology in 2016. Maraganore said another setting where the technology could be useful is in hepatic infectious diseases.

"We have a very active program in HBV infection," he pointed out. "Obviously, there are interesting combinations that could be considered, for example targeting the genome of the virus and maybe at the same time targeting immune mechanisms in the liver that are involved in escaping immune detection."

Reversir represents a potential advance in precision medicine, the exec added. "It's a feature that we think really allows for an enhanced way to look at RNAi therapeutics," he said. "It's not just about drugs that work and that are given monthly or quarterly, for example, but drugs that also can be turned off if you want to turn them off. It's all about precision medicine really."

In preeclampsia, for example, the technology could be used to turn off an effective therapy after a pregnancy ends and the therapeutic effect no longer is needed. Alnylam has a preclinical candidate for preeclampsia that targets angiotensinogen, Maraganore said.

"You want to target angiotensinogen in the mother when she's pregnant and you might want to turn it off after the baby is born but they no longer need the drug to be there," he said. "It's not that the drug is doing anything wrong; you just want to be able to tailor the pharmacology so that the drug is there when you want it to be there, and not there when you don't want it to be there, plain and simple."

Between new candidates coming along and pivotal trials progressing for its front wave of contenders, 2016 stands to be a year of significant catalytic events for Alnylam. The firm expects 10 major clinical data readouts during the year, which will be the first evidence of whether Alnylam's focus will pay off, and of how worthy of buzz RNA interference really is.

Alnylam Development Pipeline

Source: Alnylam