Why Policymakers and Investors Should Be Wary of Gene Therapy Hype

If anyone needs evidence of the vast gulf that exists between the hype and the reality of gene therapy, he can find it in the contrasting fortunes of Neurogene and Sangamo, two companies at the forefront of this sector.

The former, established just a year ago, has just closed a Series A Bond sale worth nearly $70 billion to support the therapies it is creating for neurological diseases.  The latter, which has been doing its own research for 20 years, has just lost a third of its stock market value — because it still can't find a winning formula.

Progress is certainly being made in gene therapy.  Sangamo's latest clinical trials may have prompted the brutal sell-off on Wall Street.  But they also suggest that the company has broken new ground by achieving "in-body" gene-editing, news that would cheer researchers everywhere.

The FDA, which recently approved a string of gene therapy treatments, is certainly on board.  It says we are approaching a "turning point" and predicts that it will soon be approving twenty new therapies a year.

At the moment, the facts tell a different story.  The promise of gene therapy — a single-shot panacea, one that's quick enough to catch childhood diseases with far fewer complications than traditional drug-based courses — is yet to be matched by actual advances in the laboratory.  While it's easy to see why regulators, and venture capitalists, are so enthused, that enthusiasm could be dangerous unless kept in check.

Concerns about the viability of gene therapy have, until now, largely focused on safety.  Yet an even bigger worry is the apparent ineffectiveness of many experimental therapies.  While many of the latest trials report strong gains on safety, with patients reporting few if any adverse effects, they also show precious little evidence of positive change.

Various tests over the past few weeks, addressing a range of conditions, have shown the therapies to be little or no better than the placebos they were measured against.  Although there is plenty of positive spin from the researchers' P.R. teams about the "encouraging" strides they are making, the quest for a clear breakthrough, proving the credentials of gene therapy, continues.

In this context, Sangamo's recent in vivo trials, performed on a group of men whose condition prevents their bodies from breaking down certain sugars, are fairly typical.  The company has tried two variants of its core therapy, which sends zinc finger proteins combined with DNA-cutting enzymes to slice cells open and insert a corrected version of the necessary gene.

Both variants have been granted fast-track status by the FDA, designed to speed up their regulatory passage.  Yet neither of the two trials showed any significant increase in the key enzyme required.  Even Sangamo's own CEO admitted that the gains seen during the trial were "not sufficient for a clinical benefit."  Wall Street's frenzied sell-off shows that the regulators' optimism is not shared by investors.

Even where therapies are racing toward approval, serious concerns remain about their long-term performance.  Zolgensma, a treatment developed by Avexis  (acquired by Novartis) for the treatment of spinal muscular atrophy (SMA), might get a green light from the FDA in May.  This new therapy, a one-dose drug, is expected to cost $4–5 million.

Yet according to a preliminary Draft Evidence Report from the Institute for Clinical and Economic Review, there is little clinical evidence to vouch for the long-term efficacy of the treatment.  The watchdog adds that, based on current projections, it is unlikely to be cost-effective.

Furthermore, the Phase 1 trial for the AveXis drug involved only 15 infants; the Phase 3 trial involved 20.  With such limited clinical research, there seems to be little value in fast-tracking a relatively untested drug, especially given the lack of clarity around its long-term consequences for patient health.

Despite this litany of failures, disappointments, and concerns, the scientific community is championing gene therapy in ever more areas.  The latest example is Angelman syndrome, a nervous system disorder discovered in the 1960s.  The disorder typically occurs early in life and shares many of the same features as autism.  Because the syndrome is caused by the dysfunction of a single gene, many scientists hope it can be cured through the insertion of a healthy copy into a patient's neurons.

However, as the charity Spectrum has pointed out, studies on mice have shown that alteration of this specific gene can exacerbate seizures.  What's more, the risks of drug dosing are far higher in children than they are in adults, a particularly significant facto,r given that Angelman syndrome typically affects children.

Indeed, policymakers would be well advised to pay particularly close attention to gene therapy over the months and years ahead.  The FDA's enthusiasm, shown by its willingness to fast-track therapies despite some worryingly flimsy evidence, needs to be watched — and, if necessary, overruled.  Gene therapy could, one day, be a genuinely transformative panacea, with application across the medical spectrum.  But that doesn't mean we should wave it through without proper diligence.

Peter Ferrara is the Dunn Liberty Fellow in Economics at the King's College in New York and senior policy adviser at the National Tax Limitation Foundation.  He served in the White House Domestic Policy Council office for President Reagan and as associate deputy attorney general of the United States under President George H.W. Bush.

If anyone needs evidence of the vast gulf that exists between the hype and the reality of gene therapy, he can find it in the contrasting fortunes of Neurogene and Sangamo, two companies at the forefront of this sector.

The former, established just a year ago, has just closed a Series A Bond sale worth nearly $70 billion to support the therapies it is creating for neurological diseases.  The latter, which has been doing its own research for 20 years, has just lost a third of its stock market value — because it still can't find a winning formula.

Progress is certainly being made in gene therapy.  Sangamo's latest clinical trials may have prompted the brutal sell-off on Wall Street.  But they also suggest that the company has broken new ground by achieving "in-body" gene-editing, news that would cheer researchers everywhere.

The FDA, which recently approved a string of gene therapy treatments, is certainly on board.  It says we are approaching a "turning point" and predicts that it will soon be approving twenty new therapies a year.

At the moment, the facts tell a different story.  The promise of gene therapy — a single-shot panacea, one that's quick enough to catch childhood diseases with far fewer complications than traditional drug-based courses — is yet to be matched by actual advances in the laboratory.  While it's easy to see why regulators, and venture capitalists, are so enthused, that enthusiasm could be dangerous unless kept in check.

Concerns about the viability of gene therapy have, until now, largely focused on safety.  Yet an even bigger worry is the apparent ineffectiveness of many experimental therapies.  While many of the latest trials report strong gains on safety, with patients reporting few if any adverse effects, they also show precious little evidence of positive change.

Various tests over the past few weeks, addressing a range of conditions, have shown the therapies to be little or no better than the placebos they were measured against.  Although there is plenty of positive spin from the researchers' P.R. teams about the "encouraging" strides they are making, the quest for a clear breakthrough, proving the credentials of gene therapy, continues.

In this context, Sangamo's recent in vivo trials, performed on a group of men whose condition prevents their bodies from breaking down certain sugars, are fairly typical.  The company has tried two variants of its core therapy, which sends zinc finger proteins combined with DNA-cutting enzymes to slice cells open and insert a corrected version of the necessary gene.

Both variants have been granted fast-track status by the FDA, designed to speed up their regulatory passage.  Yet neither of the two trials showed any significant increase in the key enzyme required.  Even Sangamo's own CEO admitted that the gains seen during the trial were "not sufficient for a clinical benefit."  Wall Street's frenzied sell-off shows that the regulators' optimism is not shared by investors.

Even where therapies are racing toward approval, serious concerns remain about their long-term performance.  Zolgensma, a treatment developed by Avexis  (acquired by Novartis) for the treatment of spinal muscular atrophy (SMA), might get a green light from the FDA in May.  This new therapy, a one-dose drug, is expected to cost $4–5 million.

Yet according to a preliminary Draft Evidence Report from the Institute for Clinical and Economic Review, there is little clinical evidence to vouch for the long-term efficacy of the treatment.  The watchdog adds that, based on current projections, it is unlikely to be cost-effective.

Furthermore, the Phase 1 trial for the AveXis drug involved only 15 infants; the Phase 3 trial involved 20.  With such limited clinical research, there seems to be little value in fast-tracking a relatively untested drug, especially given the lack of clarity around its long-term consequences for patient health.

Despite this litany of failures, disappointments, and concerns, the scientific community is championing gene therapy in ever more areas.  The latest example is Angelman syndrome, a nervous system disorder discovered in the 1960s.  The disorder typically occurs early in life and shares many of the same features as autism.  Because the syndrome is caused by the dysfunction of a single gene, many scientists hope it can be cured through the insertion of a healthy copy into a patient's neurons.

However, as the charity Spectrum has pointed out, studies on mice have shown that alteration of this specific gene can exacerbate seizures.  What's more, the risks of drug dosing are far higher in children than they are in adults, a particularly significant facto,r given that Angelman syndrome typically affects children.

Indeed, policymakers would be well advised to pay particularly close attention to gene therapy over the months and years ahead.  The FDA's enthusiasm, shown by its willingness to fast-track therapies despite some worryingly flimsy evidence, needs to be watched — and, if necessary, overruled.  Gene therapy could, one day, be a genuinely transformative panacea, with application across the medical spectrum.  But that doesn't mean we should wave it through without proper diligence.

Peter Ferrara is the Dunn Liberty Fellow in Economics at the King's College in New York and senior policy adviser at the National Tax Limitation Foundation.  He served in the White House Domestic Policy Council office for President Reagan and as associate deputy attorney general of the United States under President George H.W. Bush.