Two pioneers of genetic medicine shared histories and insights on current developments within the field in keynote talks during Chardan’s 6th Annual Genetic Medicines Conference, held recently in New York City.

John Maraganore, PhD, Alnylam Pharmaceuticals’ founding CEO who stepped down at the end of 2021, told attendees he attributed the company’s success to a culture that allowed it to outcompete pharma giants and survive a tragic clinical setback.

“We had a 24/7 mentality that at times some people thought was too much and didn’t want to stick with it. But we really did have a very passionate urgent approach to how we operated as a company,” said Maraganore, who remains busy in biotech as a Venture Partner at ARCH Venture Partners, a Venture Advisor at Atlas Ventures, and an Executive Partner at RTW Investments.

“We were innovation pioneers together. We all had a sense of purpose around making drugs out of RNA interference, and we felt in some ways like pioneers in a new frontier, trying to solve that major medical problem.

“We were very patient focused in what we did, we always kept the patient front and center. And finally, we were persevering. We had our ups and downs. We didn’t let it kill us. We learned from it. We got stronger,” Maraganore asserted.

He cited how Alnylam bounced back from its halting development of revusiran in 2016 following the deaths of 18 patients in the Phase III ENDEAVOUR trial (NCT02319005) assessing the RNA interference (RNAi) candidate in hereditary transthyretin-related amyloidosis (hATTR) with cardiomyopathy (hATTR-CM).

Maraganore said corporate culture also enabled the company to withstand an earlier commercial challenge—Merck & Co.’s $1.1 billion acquisition of an Alnylam rival, RNA interference drug developer Sirna Therapeutics, in 2006.

In the eight years that followed, Merck-Sirna filed no INDs for RNAi drugs, and eventually sold their assets to Alnylam for $175 million. Over the same period, Alnylam filed eight INDs, of which three today are market products that according to Maraganore have generated a combined $4 billion in value since then.

“It’s not that we were smarter than Merck, because we all know that nobody is smarter than a Merck scientist, right?” Maraganore, eliciting chuckles from the audience while delivering a lunchtime address.

“I can also assure you that we did not outspend Merck. In fact, they outspent us 2-to-1 over that period. The difference really was as simple as culture,” Maraganore said. “It was the ability of the team at Alnylam to be willing to take risks, and to advance programs safely into the clinic, and maybe learn from those programs and cycle back into discovery.”

There was also a fear of mortality at Alnylam, whose life or death depended on its success. “At Merck, there was no fear of mortality around RNA interference, because they could have easily failed in that effort and gone on to do other things without blinking an eye at the end of the day,” he said.

Maraganore cited Merck’s successful development of cancer immunotherapy blockbuster Keytruda, which racked up sales of more than $10 billion during the first half of this year, up about 25% from $8.07 billion a year earlier.

“Management consultant Peter Drucker is quoted as saying that culture eats strategy for lunch. And I personally believe it eats strategy for breakfast, lunch, and dinner,” Maraganore observed. “It is by far the most powerful element of building a great powerful company—people and culture together, but culture really is powerful.”

In addition to his VC roles, Maraganore chairs the boards of Orbital Therapeutics and Hemab Therapeutics; serves as a strategic advisor to SQZ Biotechnologies and GNS Healthcare; and holds seats on the boards of Agios Pharmaceuticals, Beam Therapeutics, Kymera Therapeutics, and the Biotechnology Innovation Organization (BIO), where he served as Chair from 2017-2019.

Investors and biomarkers

Delivering the conference’s second-day keynote address, gene therapy pioneer James M. Wilson, MD, PhD, contrasted the research and clinical progress made by investigators of new genome editing treatments, with the skittishness of many investors to embrace companies applying those discoveries.

“The disconnect for me is the excitement that I see with respect to the scientific development of the field versus the way that many investors have approached the field,” said Wilson, Director of the University of Pennsylvania’s Gene Therapy Program (GTP). “I haven’t been more excited about the potential for in vivo gene therapy and now gene editing than I’ve ever been previously. And there were many years where we had nothing to talk about.”

That is not the case today, Wilson asserted.

One example Wilson cited was REGENXBIO (of which Wilson is a scientific founder), which over the summer announced positive interim data from its Phase I/II CAMPSIITE™ trial (NCT03566043) assessing the company’s RGX-121 for the treatment of patients up to 5 years old diagnosed with Mucopolysaccharidosis Type II (MPS II), also known as Hunter Syndrome.

RGX-121 is a one-time gene therapy designed to use the adeno-associated virus, serotype 9 (AAV9) vector to deliver to the central nervous system (CNS) the human iduronate-2-sulfatase gene (IDS) which encodes the iduronate-2-sulfatase (I2S) enzyme.

While the study’s primary endpoint is the safety of RGX-121, secondary and exploratory endpoints include several examples of biomarkers. They include cerebral spinal fluid (CSF) glycosaminoglycans (GAGs)—namely heparan sulfate (HS) and D2S6, a component of HS closely correlated with severe MPS II. Both are key biomarkers of I2S enzyme activity being measured in the CSF both at baseline and after administration of RGX-121.

“I view that as really a landmark,” Wilson said. “For rare diseases, we need to begin to look at novel ways to think about approving our drugs. And people have talked about biomarkers, and there has to be some relationship between the biomarker and the potential for benefit.”

A majority of the trial’s 14 participants in all three dosing cohorts showed reductions of HS in the CSF up to 48 weeks following one-time administration of RGX-121. At week 48, median reduction of CSF HS from baseline was 33.5% in Cohort 1, 52.9% in Cohort 2 and 62.5% in Cohort 3.

Dose-dependent reductions of CSF HS D2S6 were seen in most patients treated with RGX-121, with some patients approaching normal levels at 48 weeks. The Cohort 3 dosage of 2.9 x 1011 GC/g of brain mass will be advanced into a pivotal program, REGENXBIO said.

According to the company, GAGs in the CSF could be considered surrogate biomarkers reasonably likely to predict clinical benefit in MPS II under the trial’s accelerated approval pathway, since the buildup of GAGs in the CSF of MPS II patients correlates with clinical manifestations that include neurodevelopmental deficits.

Wilson credited the FDA with working alongside REGENXBIO to develop an accelerated approval pathway that he predicted could serve as a model for the field: “I think others will look at that as well.”

REGENXBIO reasons that delivery of the IDS gene within cells in the CNS could offer a permanent source of secreted I2S beyond the blood-brain barrier, allowing for long-term cross correction of cells throughout the CNS.

Roberto Giugliani, MD, PhD, of UFRGS (Universidade Federal do Rio Grande do Sul) in Brazil, presented data from CAMPSITE at the recent Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium, held in Freiburg, Germany.

REGENXBIO was formed in 2008 to commercialize an AAV-based gene therapy platform discovered at Wilson’s lab at Penn. The company’s NAV Technology Platform consists of exclusive rights to more than 100 novel AAV vectors, including AAV7, AAV8, AAV9 and AAVrh10.