Rare diseases

Regulators have signaled for the last few years that they’ll be keeping a closer eye on M&A in pharma — and the Federal Trade Commission’s move in December to block Sanofi’s acquisition of Maze Therapeutics’ clinical program for Pompe disease offers a look at how this fresh scrutiny could play out.

The FTC’s decision was still unusual, and not only because it interfered with a licensing deal, according to Laksheeta Johari, a consultant with Lifescience Dynamics.

“What the FTC statement failed to take into account were the challenges that are associated with developing therapies for rare diseases,” Johari added.

The FTC regularly weighs in on M&A and recently highlighted its work to lower drug prices and encourage competition. For instance, it touted a proposed consent order for Amgen’s $27.8 billion acquisition of Horizon Therapeutics that would prohibit Amgen from leveraging its drug portfolio to disadvantage rivals and require the company to seek prior approval before acquiring related products.

However, the announcement a few days later that the FTC would block Sanofi’s acquisition of Maze’s glycogen synthase 1 inhibitor MZE001 came as a surprise.

“This is unprecedented,” Maze CEO Jason Coloma told Biotech TV earlier this year. “As far as we’re aware, this is the first time that a licensing project or a licensing deal has been blocked by the FTC.”

While the commission has an important role to play in ensuring a “healthy spirit of competition,” Johari believes there should be an extra layer of consideration for rare diseases.

“We can’t compare the rare disease space with some of the more established therapeutic areas … I think that’s one nuance every aspect of the industry does need to keep in mind,” she said. “Whether it’s from a clinical development perspective, a commercialization perspective or even an access and reimbursement perspective, it’s not going to be an apples-to-apples comparison when we’re looking at rare diseases.”

A deal abandoned

Sanofi’s deal with Maze brimmed with optimism when it was announced in May 2023.

“People with Pompe disease continue to need additional treatment options for this life-threatening condition,” Coloma said in a statement. “Sanofi is a leading global healthcare company with deep experience working with this community and the ideal partner to continue the advancement of MZE001.”

Indeed, treatment options for Pompe disease, a rare genetic disease that causes progressive weakness, are limited and come from just two companies, Sanofi and Amicus Therapeutics, the latter of which scored an approval for its two-component therapy in September. In addition, the current treatments are infusions. If MZE001 makes it to market, it could be the first oral medication available for Pompe disease patients.

The Sanofi-Maze deal followed a familiar pharma strategy. Maze is a smaller, clinical-stage company, and Sanofi is a major player that already has three approved drugs for Pompe disease. The licensing deal meant Pompe disease patients would potentially get a new treatment faster because the development would be in the hands of a company with vast resources and established experience in that indication.

But the FTC disagreed, and the very factors that made this deal favorable for the companies — and potentially patients — is what sunk it in the end. The FTC called Sanofi “a monopoly supplier” of Pompe treatments and said Sanofi could use the acquisition to squash competition and delay development of the new drug.

According to Sanofi, “The exact opposite is true.”

“Sanofi had no intention of shelving or killing the program. Sanofi executed the license agreement with Maze because Sanofi believed that it could bring its resources, experience, and expertise in Pompe disease to accelerate the development of MZE001 and potentially bring it to Pompe patients around the world, as Sanofi has done with substrate reduction therapies for other rare diseases,” a Sanofi spokesperson told PharmaVoice via email. 

Ultimately, Sanofi decided to abandon the deal.

Another rare disease roadblock

Rare disease drug development is already lengthy and filled with significant and unique roadblocks. When a disease is poorly understood and the patient population is small, it can be a challenge to design trials with endpoints with known clinical benefits. It can also be difficult to find experts in rare disease indications and to recruit for trials among a geographically scattered patient population.

Incentives like the Orphan Drug Act exist to encourage companies to develop drugs for rare diseases in the face of such obstacles, and the FDA granted Maze’s MZE001 an orphan drug designation in 2022.

Those challenges are also why smaller companies developing rare disease treatments partner with larger ones that have the resources and experience needed to develop drugs more quickly and efficiently.

Pompe is a life-threatening genetic condition that affects about one in 40,000 people. Sanofi has decades of experience in the field and established relationships with healthcare providers and patient groups, and has designed successful Pompe disease clinical trials.

“In this case, you had a company that had over 20, 25 years of experience working with that community,” Coloma told Biotech TV. “They were in a very strong position to think about the best way and the most rapid way to develop this for patients, and that’s, in part, one of the major reasons we wanted to work with them.”

Rather than starting from scratch, Sanofi would have been able to apply existing resources and years of experience to developing MZE001.

“Sanofi, given that they have approved assets in Pompe, already has those established relationships, and that could have really benefited Maze with the clinical development of the MZE001 asset,” Johari said.

Now, Maze seems to be going back to the drawing board for MZE001.

“All it does is delay the ability to even test the hypothesis in the clinic,” Coloma told Biotech TV, adding that the company was “exploring our options” and committed to advancing MZE001 to the clinic and to patients.

A chilling effect?

Gaining a partner with experience in a rare disease indication should be a boon for a small company that’s trying to develop an orphan product.

“If you’re looking at rare diseases, it is very important that you have a player that understands the field, that has those relationships,” Johari said.

However, the FTC’s scrutiny and blocking of a par-for-the-course licensing deal could have a chilling effect on other, similar partnerships, she said.

“Across the rare disease industry, it may make players do a double take on who they want as their partner,” Johari said.

It also raises questions about whether the FTC should engage with experts in rare disease as it evaluates future partnerships.

“Maybe there’s a need to have a rare disease expert have a seat at the table to determine what’s an anticompetitive threat or something that can benefit the industry,” Johari said. 

Rare diseases, once a miniscule chapter in the pharma playbook, have become a major focus for even the biggest companies in the world. From 5% of new drugs in the late 1980s to 43% in 2023, rare disease treatments comprise a rapidly growing sector of the overall pipeline.

For pharma giant Johnson & Johnson, the rare disease space is where a large company can have an outsized impact, said Dr. Katie Abouzahr, vice president, autoantibody portfolio and maternal fetal disease area leader at J&J Innovative Medicine. 

Abouzahr heads up the development of nipocalimab, an autoantibody drug that could treat rare diseases like myasthenia gravis or more common ones like rheumatoid arthritis. By dampening a specific receptor and keeping the immune system from attacking a patient’s healthy cells, the drug could play a part in several areas of unmet need, she said.

Last month, J&J announced positive results from a late-stage study in the rare muscle disease myasthenia gravis as well as from a mid-stage trial in the inflammatory Sjögren’s disease, which currently has no approved treatments that address the underlying cause.

Here, we spoke with Abouzahr about pharma’s growing focus on rare diseases, the development of nipocalimab and what’s next in the autoantibody space.

This interview has been edited for brevity and style.

PHARMAVOICE: What makes rare disease a growing interest for J&J and Big Pharma in general?

KATIE ABOUZAHR: The way we think about anything is: What are the unmet needs? What impact can we have? And one of the things I find fascinating is that, yes, each individual disease is rare, but when you add them all up, the burden is absolutely immense — 300 million people with 7,000 rare diseases. And yet, because each disease is smaller, they perhaps haven’t had the focus or investment or awareness, or even just the innovative approaches to address that unmet need. It’s a double whammy of patients feeling a bit isolated even though there are so many of them. I hope we always go where the unmet need is and where there’s an ability to do something scientifically.

In your own career, how has the approach to rare disease changed over time?

There is greater awareness and understanding, and then often, the scientific tools and approaches that allow us to realize there is a path forward to do something about that medical need — those two things coming together intersect in rare disease. Also, regulators are thinking increasingly about the path to approval in rare and orphan disease. So increasingly, I think the confluence of awareness, unmet medical need and the ability to impact that creates interest, excitement and anticipation about where we can go.

Can you tell me how the autoantibody field fits into the evolution of rare disease drug development?

Autoantibody-driven diseases overlap with rare diseases — not all of them are rare, but many of them are. And in autoantibody, essentially, you have [immunoglobin G, or IgG] antibodies that attack one’s own body and cause disease, and there are different flavors of them. For example, in myasthenia gravis, they attach the acetylcholine receptor. In [hemolytic disease of the fetus and newborn, or HDFN], they attack a baby’s red blood cells. And so in the autoantibody program, nipocalimab binds to a receptor and prevents it from recycling these antibodies, and so they reduce out. And importantly, it prevents them from crossing the placenta. So that one approach, that one treatment, could potentially have input in all diseases caused by IgG pathogenic antibodies.

There are so many of these diseases that we think about them in three segments: those caused by a pathogenic autoantibody, those that affect pregnancy with what we call alloantibodies and then prevalent rheumatology diseases caused by autoantibodies. We are the only one developing in all three segments with nipocalimab, and the golden thread through all of this is unmet need.

Your myasthenia gravis program is furthest along. What can we expect to see there?

We’ve completed our pivotal phase 3, and the next step is to engage with regulators to bring that medicine to patients. If you think about myasthenia gravis, it’s a chronic disease, and one of the features is that you don’t stop making the autoantibodies — they are always causing disease. A lot of these diseases really need sustained chronic treatments so that the patient’s symptoms are as minimal as possible or ideally gone as opposed to having any kind of fluctuations. There are advanced therapies that have been recently approved, but … this would be the first indication for nipocalimab and the beginning of our journey there.

We hope to significantly contribute to the collective understanding of what the underlying cause of these diseases is, and what the available therapeutic approaches are to develop medicines in them. Even just in the last couple years, we’ve shown data we hope contributes to everyone’s understanding of these diseases and we’re taking steps forward toward treatment options for patients that allow them to reclaim their lives.

What’s next for J&J in the autoantibody programs?

Myasthenia gravis is of course one that we’re obviously excited about first, but we’re also in a program in autoimmune hemolytic anemia where there are no approved advanced therapies and very high unmet needs. In maternal-fetal we’re moving into a phase 3 program in HDFN, and we’re continuing to progress in rheumatology.

In approaching rare diseases, clinical trials can be a real challenge. How do you take that into consideration as you develop these treatments?

A feature of rare diseases is that they’re rare, so there are few patients and in some of them, there are often competitors. Regardless, the No. 1 thing we try to do is listen to patients. Because if you listen, they will tell you what they need, not only as you develop your program or what you’re trying to solve for them, but also what’s important to them as they think about entering clinical studies. We do a lot of work with advocacy groups, as well, because they’re such important sources of understanding and knowledge, and we consider them partners.

We have the good fortune of being a very large company, and so we’re able to go where the patients are. In rare disease, you might use data sciences to go where they are as opposed to hoping they will come to you. So we think very carefully about where we’re going to run our programs.

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The most common challenges in clinical trials have remained the same for many years – the costs of trials soar due to difficulty recruiting patients and high dropout rates or lack of patient retention. Up to 50% of sites fail to recruit enough patients and an average of 20% of patients drop out of clinical trials.  There are solutions that have existed for decades that are still seeing slow adoption rates that can create more convenient trials for patients and those that have onboarded these patient-centric approaches have reaped the benefits of accelerated timelines. 

Improving recruitment and retention can be accomplished by providing patients greater access to trials and making participation easier, bringing the trial to the patient’s own community. For instance, MRN has seen a consistent 95% retention rate for patients using their Home Trial Support solution. Impactful results like these can be achieved by including in-home clinical visit delivery in the trial protocol, bringing visits to the patient, alleviating much of their participation burden.  The impact is compounded when paired with a global network of research ready sites able to provide patients in new communities the opportunity to participate, bringing the trial site closer to the patient. 

In-home trial delivery – Supporting participant success

Home Trial Support brings selected clinical trial visits to the patient’s own home or alternative location that is not the site.  Participants have identified travel and logistics to be highly burdensome when participating in and staying in a clinical trial, challenges that can be exacerbated for a patient with rare disease, mobility limitations or cognitive decline. By removing these barriers, bringing trials to patients where they live, we can expand the geographical reach of clinical research across the globe allowing more patients to participate. This patient-centric delivery means added convenience and comfort working the schedule of the trial around the schedule of the patient and their family, not the other way around. This approach provides important access to medical care for many, enhances the inclusivity of clinical trials and serves as a powerful recruitment and retention tool. 

A global site network – Supporting site success

A site network should collaborate with sites and provide a positive clinical trial experience for them.  MRN now has an established global site network of research ready sites, many of them trial naïve.   This means, the industry now has a vehicle for getting to more patients in more communities while engaging new sites and researchers.  By allowing new sites to participate, the right patients can be onboarded, reducing the need for Sponsors to find more sites later in the trial – a costly task. By listening and collaborating with sites, MRN can further this support by placing the right resources and the right training for more sites to be research-ready and achieve faster patient identification and recruitment. 

Conclusion

As the clinical trial community strives to create more accessible options for patient participation, in-home delivery and site networks have become a powerful strategy with a positive impact.  Thanks to the benefits created for patients and sites, drug developers are also seeing benefits through increased patient enrollment, engagement and retention leading to a shortened timeline to market.

Learn more about these solutions and their return on investment here.

After years of under-performance and stagnant share prices, the pharma industry is starting to find its feet again as evidenced by a steady pickup in M&A. But the battle isn’t over, and companies looking to keep their heads above water need to think long and hard about their focus, their risk and their reputation among shareholders, according to analysts.

Despite hints of a rebound, leaders across sectors are still wallowing in doubt about the future — 45% of CEOs surveyed by professional services and accounting firm PwC said they felt their company would not be viable a decade from now, up from 40% the year before. And with the pharma industry trailing behind the S&P 500 by 10 percentage points in the last five years, the sting is even more acute, said Greg Rotz, U.S. pharma & life sciences advisory leader at PwC.

There are many reasons for that, but near-term earnings growth isn’t one of them, Rotz said.

“While our sector has returned single digits and total shareholder returns, it's actually been driving double-digit earnings growth,” Rotz said, pointing out that long-term investment has not been in step with near-term earnings. “Investors are losing faith in the confidence of the pharmaceutical business model, looking out into time.”

This declining investor confidence in the future performance of pharma companies comes down in part to the competitive saturation of the market, Rotz said, pointing out that “great science alone is not enough to create outperformance.”

As pharmas navigate the next steps of a potential economic upswing, they need to make the right kinds of deals to secure new market “white spaces” — however risky it is to explore the unknown — to bring investors back into the fold, Rotz said.

‘Fundamental economics’

For Rotz, the answer comes back to the “fundamental economics” of pursuing not only the most promising science, but doing so in areas where no one else has arrived first.

“There are so many products chasing the same spaces, driving up competition, and we know from the basics of economics that anytime you have increased competition, you generally have lower returns,” Rotz said. “We know that great science is generally going towards smaller patient populations, as we have gotten better at precision medicine — even the best science put into that environment, compared to the environment of five or 10 years ago, is going to struggle to generate the same level of returns.”

Pharma R&D expenditure grew almost 50% between 2018 and 2023 to a record $161 billion, according to an IQVIA report. That’s good news for patients, but with so many companies scrambling for the same targets, it can be tough to stand out, Rotz said.

“In this environment of increased scientific inquiry and more trials, it's important to step back and say: How many of those are chasing validated pathways that already exist?” Rotz said. “How many of those are chasing therapeutic categories where there are already breakthrough standards of care, versus how many of those are going into the next frontiers of neuroscience or the next frontiers of fighting resistant bacteria, and so on.”

Introducing more risk into the portfolio could help pharmas see better returns, despite the potential for failure, Rotz said.

“It feels safer to go after validated pathways in the moment when you think about scientific risk, but do these models have enough risk in them?” Rotz said. “Are we tied into all the leading edge science coming out of academia and in a position to know where those next frontiers are really going to be so that we can get on them even faster?”

And while diversification can be tempting for the sake of spreading failures thin, companies with a sharper focus tend to be more appealing to investors, said Nicole Daley, a life sciences and M&A partner at law firm Allen & Overy.

“With companies that are more honed in and focused, there's also the risk that the thing you're most focused on then maybe doesn't work or maybe doesn't rise to best in class. But being more focused as opposed to more diverse in terms of what prospects you're thinking about seems to be the more appealing route,” Daley said.

Additive dealmaking

As M&A picks up after the pandemic lull, how can executives make the right kinds of deals to launch them into a more focussed approach that embraces risk and new frontiers?

“We think of M&A as a means to accelerate strategy, but M&A isn’t an end in itself,” Rotz said. “Executives at today’s pharmaceutical companies need to find the fundamental narrative of their strategy to differentiate themselves — once that’s clear, we expect to see M&A playing a big role in helping accelerate those strategies and fill in the products and portfolio underneath that strategy.”

A trend many large drugmakers have taken particularly seriously is divesting business arms to focus more wholly on innovation. J&J, Pfizer, Merck & Co. and more have sold off sizable branches in the last several years to put greater emphasis on more groundbreaking areas. It’s a strategy that pays off down the road, Rotz said.

“The more you can create coherence between your capabilities, your strategy in the market and the products and portfolio you have, the faster you can go and the more value you can create,” Rotz said. “That's the calculus that has been happening, and it’s a good ongoing exercise for management teams to be undertaking.”

But as companies whittle themselves down to become sleeker R&D machines, they need to build up in the spaces where they’ve chosen to focus, Rotz said. And that has changed the face of today’s dealmaking strategies.

“The deals are strategic and trying to help companies solve an issue — we haven’t seen the kind of large-scale megamergers of the past, and I think in today's environments, and specifically in today's regulatory environment, those deals are harder to come by,” Rotz said. “But the need still exists to build out portfolios and maintain access to great science, with a more surgical basis. We see a lot of companies saying their No. 1 priority is to execute deals to solve specific problems.”

Some of the more high-profile deals that embody this strategy include Amgen’s $28 billion purchase of rare disease drugmaker Horizon Therapeutics in October, and Pfizer’s $43 billion acquisition of antibody-drug conjugate specialist Seagen earlier in 2023.

Daley points to Bristol Myers Squibb’s $14 billion purchase of neuroscience biotech Karuna Therapeutics in December as another example of this kind of additive dealmaking.

“If you’ve got a really promising therapy that seems like it’s going to continue to drive things …  that momentum is important to keep going,” Daley said. “And after a couple of years of there not being a whole lot [of deals], it really doesn’t seem to be slowing down.”

As for building and maintaining trust among investors that these deals will fuel growth, Rotz has fundamental advice for executives: Be real.

“It's in everyday actions, when the pressure is on, that we see companies either enhancing and building trust or losing trust very quickly, and leaders need to … know that [pharma’s] trust generally [from] society is declining,” Rotz said. “So you don't get the benefit of the doubt, and your authentic engagement with stakeholders is critical.”

In focus with: Peter Flynn, president and CEO, Arialys Therapeutics 

The company’s vision: Arialys Therapeutics is a preclinical company developing a treatment for a rare and potentially lethal autoimmune disease called anti-NMDA receptor encephalitis (ANRE). It’s often misdiagnosed because it presents with psychiatric symptoms. Arialys’ lead candidate, ART5803, blocks disease-causing autoantibodies rather than suppressing the immune system overall, which is the current standard of care.

ANRE was made famous by the bestselling memoir, Brain on Fire, by a journalist whose sudden seizures, hallucinations and other symptoms led to a “month of madness” and misdiagnoses ranging from schizophrenia to alcohol withdrawal.

Arialys Therapeutics launched in September 2023 with $58 million in seed financing after purchasing ART5803 from Astellas Pharma. In addition, ART5803’s lead developer, Mitsuyuki Matsumoto, joined Arialys as scientific founder and chief scientific officer after previously serving as head of the neuroscience research unit at Astellas.

The drug works by competitively inhibiting the antibodies responsible for ANRE.

“The actual product is elegantly simple,” said Flynn, who joined the company in June. “We’re not really impacting the immune system of the patients. We’re taking what is making these patients sick … and [blocking] that using another antibody.”

Why it matters: When people think of autoimmune conditions like rheumatoid arthritis, lupus and multiple sclerosis, they think of familiar symptoms like fatigue and joint pain. But far less known and understood are autoimmune conditions that target the brain, where certain autoantibodies trigger psychosis and lead to a “terrifying descent” into sudden psychiatric symptoms, Flynn said.

“The challenge with this disease is that you have patients with no history of neuropsychiatric disease. Then they’ll descend through the symptomology very rapidly,” Flynn said. “Tragically, some of these patients end up in psychiatric wards when they’re not a traditional psychiatric patient — they’re an autoimmune patient.”

There’s also growing evidence to suggest that autoimmune conditions of the brain may be far more prevalent than is currently known.

“It may well be that certain patients who are diagnosed with schizophrenia or other forms of psychosis may actually have an autoimmune component to their disease,” Flynn said. “Numbers in academia are being suggested that between 5% and 10% of psychosis patients may have these autoantibodies.”

The challenge: Since ANRE was first identified in 2007, an increasing number of autoimmune diseases and antibodies have been identified and associated with the brain.

“This is a fairly new area of science,” Flynn said. ANRE is “currently diagnosed at a prevalence of about 2,000 patients in the U.S., but as we’ve described, it may be chronically underdiagnosed.”

Underdiagnosis and misdiagnosis mean these patients are often treated for psychiatric symptoms rather than the underlying autoimmune disorder. That’s why in addition to developing ART5803, Arialys is also developing an assay that detects antibodies in cerebrospinal fluid and serum and is more sensitive than current tests, Flynn said. While Arialys isn’t currently developing the assay as a companion diagnostic, they plan to use it to better understand the disease’s true prevalence.

“It’s rare, but on a global scale we still think there is a market there,” Flynn said. “We’ll see, ultimately, where the population falls for this.”

Another challenge is that an estimated 45% of these patients are pediatric, which is why they need a treatment that works quickly. Flynn said preclinical research has shown that ART5803 works in days or weeks, rather than months

“We believe a rapid, acute therapy is going to be really important in this space,” Flynn said. “The standard of care is immunosuppression, and patients do recover. But I think it’s all about the timing of their recovery. Especially if you think about pediatric patients. You want them to get back on the road to recovery as quickly as possible because … there could be long term cognitive effects.”

The road ahead: ART5803 has received orphan drug designation from the FDA and in preclinical, nonhuman primate models has been shown to block NMDA receptor autoantibodies and reverse encephalitis and behavioral symptoms.

Flynn said the company recently made its first regulatory filing and anticipates being in the clinic for a study in healthy volunteers later this year.

He also called ART5803 a “pipeline within an asset” because of other possible indications where “elegant competitive inhibition approaches to autoimmune neuropsychiatric disease” could be applied. 

Ultimately, identifying patients and understanding the disease’s true prevalence will be key.

“In the academic community, I think there’s an absolute understanding and acceptance that we’re almost at the start of this journey of understanding how autoimmune disease actually impacts neuropsychiatric disorders,” Flynn said.

When Luxturna was approved in 2017 to treat a rare form of inherited vision loss, it became the first one-and-done therapy targeting a disease caused by mutations in a specific gene. Despite the historical achievement, there was a problem. The patient population was tiny, topping out at around 2,000 in the US., and the drug had become the priciest therapy on the market costing $425,000 per eye.

Although gene therapy holds promise for rare diseases, current therapies target small patient populations. But a Pennsylvania-based biotech company Ocugen is hoping to change that paradigm by working on therapies that it calls “gene agnostic,” using a first-in-class modifier gene therapy platform with the potential to treat a range of genetically diverse inherited retinal diseases.

“It’s not gene specific like CRISPR or traditional gene therapy,” said Shankar Musunuri, CEO and co-founder of Ocugen. “We are embarking on something really big that nobody has done before.”

Reaching a larger patient population

Although Luxturna’s approval paved the way for other gene therapies, it also only treats patients with a mutation of RPE65. However, there are hundreds of genes that cause inherited retinal diseases.

For example, people with the RPE65 gene mutation represent just 0.3%–1% of all cases of retinitis pigmentosa, the most common type of inherited retinal dystrophy, according to a 2023 article in the journal Pharmaceutics

“There are more than 100 genes which can cause RP. There are about 100,000 patients in the U.S. alone, about 1.6 million globally,” Musunuri said.

Ocugen’s lead candidate is OCU400, a modifier gene therapy targeting two families of inherited retinal diseases: RP and Leber congenital amaurosis. It works by delivering a functional copy of a nuclear hormone receptor gene called NR2E3 to target cells in the retina, resetting “retinal homeostasis, potentially stabilizing cells and rescuing photoreceptor degeneration,” the company said.

“If we can reset the homeostasis, restore the function and also create a healthy environment, that’s important for long-term vision restoration. It’s not just fixing one gene,” Musunuri said.

Earlier this month, the FDA cleared Ocugen to initiate a phase 3 clinical trial of OCU400, which also received orphan drug and regenerative medicine advanced therapy designations from the FDA. The company is targeting a 2026 approval.

Ocugen has other gene therapies in development as well, including a candidate for dry age-related macular degeneration and another for Stargardt disease, both of which are in phase 1/2.

Beyond gene therapy

In addition to its specialty in gene therapy, Ocugen is investigating how its platform could be used in other therapeutic arenas.

“Our focus is primarily gene therapy, but these other technology platforms can do a lot of good for patients,” Musunuri said. “We’re focused on unmet medical needs. All the areas we’re working on have significant unmet medical needs.”

One of its most developed assets is on the cell therapy side. Called NeoCart, the therapy treats articular cartilage defects in the knee and was picked up through a reverse merger with Histogenics in 2019. The phase 3-ready candidate is made from a three-dimensional disc of new cartilage grown from patient-derived cells..

Ocugen also has three vaccines in early development for COVID-19, the flu and one being developed as a combination for both. The National Institute of Allergy and Infectious Diseases will study the covid candidate, OCU500, in a trial comparing administration via inhalation into the lungs and as a nasal spray.

The inhaled vaccines are based on a novel ChAd platform designed to reduce transmission and protect against new variants with long-term durability.

“If you look at the COVID landscape, the current vaccines are not durable,” Musunuri said.

An inhaled, rather than an injectable vaccine, could boost uptake among patients.

“Those are all the salient features which are required for people to be more compliant to take vaccinations,” he said.

A global scope

Musunuri’s career spans from small biotechs to big pharma, including nearly 15 years at Pfizer, where he was global operations team leader for the launch of the blockbuster pneumonia vaccine Prevnar 13.

In the world of Big Pharma, “you do so much, from start to finish,” he said, learning “how to take a product from inception all the way to the market, not just in the U.S. but global.”

He has global ambitions for Ocugen, too.

“Our mission is not just to take these cutting-edge technologies to market. We’re going to work even harder,” he said. “We really want to create market access to patients globally.”

Life sciences companies are leaning into the rare disease space, with the market expected to grow at a compound annual growth rate of 12.8% between now and 2030. Still, more than 90% of the 7,000 known rare diseases lack a treatment option.

And, as the industry is all too aware, there’s no silver bullet for filling these gaps. Despite the increased investment, numerous roadblocks along the drug development pipeline continue to hamper efforts to bring therapies to patients.

In a recent PharmaVoice poll, industry leaders were divided over where the biggest barrier to rare disease drug development lies — designing and enrolling patients in clinical trials, pushing treatments through regulatory approvals or launching the drug into the market.

Recently, regulatory and research advancements spurred by COVID-19 have helped overcome some of the most glaring obstacles to rare disease drug development.

Clinical trial concerns

With restrictions on in-person clinic visits during the pandemic, pharma companies were forced to think outside the box and utilize decentralized trial approaches and real-world evidence to keep research flowing. Once the infrastructure kinks can be worked out, these new techniques could provide a more effective framework for designing rare disease clinical trials with small patient populations

According to Hassan Kadhim, senior director and head of clinical trial business capabilities at Bristol Myers Squibb, DCTs could allow companies to recruit more patients in trials because “they don’t have to be geographically located with the different sites.”

Similarly, Will Maier, the vice president of rare disease at ICON, told us in August that real-world evidence can be used to supplement the small patient cohorts that participate in rare disease trials.

“In rare disease, where you might not have much in the way of patient numbers or where diagnosis might be quite difficult, we often will just look at medical records to figure out who the patients are,” Maier said. “Sometimes those registries evolve into a post-approval safety study that is used as part of the condition of approval.”

Regulatory requirements

Operation Warp Speed allowed the federal government to accelerate the development of needed vaccines and therapeutics at the onset of the COVID-19 crisis. The same tactics implemented through that initiative could soon be applied to expedite the approval of rare disease medications, Dr. Peter Marks, the director of the FDA’s Center for Biologics Evaluation and Research, told attendees of the 2023 Biopharma Congress.

Among the regulatory challenges drug developers face in the rare disease space is collecting enough evidence in small population clinical trials to show efficacy and safety, and then communicating the information quickly with regulators.

In October, the FDA announced a pilot program to help sponsors address these problems and better determine endpoints to assess the efficacy of a drug. Under the Rare Disease Endpoint Advancement (RDEA) Pilot Program, the FDA will accept one proposal for an active pre-IND or IND for a rare disease and will conduct ongoing meetings with the sponsor to evaluate the endpoint. Eventually, findings from the program could be used in an agency guidance document or workshop to improve the industry’s overall understanding of rare disease endpoints.

Additionally, Marks said the FDA hopes soon to “allow the clinical development (of rare disease drugs) to happen in constant communication and sharing of potential results before a submission of an NDA or BLA. That’s the idea — to move things as fast as possible.”

Market viability

Rare disease treatments that make it to launch often come with a hefty price tag. For instance, CSL Behring’s gene therapy Hemgenix for hemophilia B was approved in November and given a $3.5 million price tag.

While the high list prices aren’t likely to change, companies and governments are searching for better financing mechanisms to reduce out-of-pocket costs for these types of medications. Some of the innovative methods include voucher programs, value-based pricing, public-private partnerships, patient assistance programs and targeted grants. In the case of Bluebird Bio’s Zynteglo for the blood disorder beta thalassemia, which entered the market last year with a list price of $2.8 million per treatment, the biotech opted for an outcomes-based pricing approach, meaning it will refund up to 80% of the drug’s cost if it is not effective for the patient.

Still, as patient healthcare costs rise, developing new financing models to improve patient access to rare diseases is likely to become more important for both governments and private entities. 

When Tamar Thompson’s husband was diagnosed with prostate cancer, she knew better than most what kinds of testing and care he’d need. As vice president and head of corporate affairs at Alexion, AstraZeneca Rare Disease, Thompson is intimately familiar with the healthcare world. And as a decorated officer in the United States Air Force, her husband should have received the best, most cutting-edge care.

Despite all these advantages, Thompson still struggled to get her husband the genetic testing she knew was available.

“I had to fight for that. It wasn't offered right up front,” she said. “I don't know that it would have been (like) for someone who was non-African American. But I know that for him, I had to fight for a number of things. And thank goodness I work in the space to know what to ask for. But I saw the misses along the way.”

Thompson even pulled her husband out of their local health system for fear that he wouldn’t get adequate care as a Black man.

These challenges — including lack of access, missed care and subpar treatment at small or rural hospitals — are common healthcare experiences for people of color.

They’re also common for rare disease patients, and Thompson sees those parallels every day.

For instance, some rare disease patients live in rural communities without access to an academic medical center, she said, and that’s true for minority patients, too.

“Black and brown patients generally can't travel more than a 50-to-75-mile radius from their home,” she said.

They often face similar financial hurdles, too.

“Rare disease patients may live on one income, often because one person has had to give up a job to be a caregiver. And that's very similar to some of the challenges you see in the minority communities as well,” she said.

Those parallels are some of the reasons why Thompson was drawn to working with the rare disease patient population at Alexion.

An unconventional path

A rare disease biopharma company that was acquired by AstraZeneca in July 2021, Alexion has five approved medications for seven rare diseases, including the blockbuster first-in-class C5 complement inhibitor Soliris (which was, at one time, the most expensive drug in the U.S.), and the second-generation C5 complement inhibitor Ultomiris. Its pipeline also consists of potential medicines for more than a half dozen rare therapeutic areas, including hematology, neurology, cardiology, nephrology, bone metabolism, metabolics and ophthalmology. 

Thompson leads the government affairs and policy and communications functions for the company, working to amplify the voices and experiences of rare disease patients, advocate for needed policy changes, create access opportunities for patients and partner with rare disease organizations.

Prior to joining Alexion in 2019, she worked as the head of federal executive branch strategy and state government affairs for Bristol Myers Squibb. However, her path to healthcare policy was much more unconventional.

At first, Thompson studied nursing, but soon realized that she wasn’t quite suited for it. Sticking a needle in someone’s arm and telling them, “Suck it up, buttercup? That probably isn't the best bedside manner,” she laughed.

Instead, she shifted her focus to healthcare administration and the revenue cycle side of healthcare, eventually pivoting to the life sciences and policy advocacy. But it was working at Bristol Myers Squibb that first exposed her to the rare disease community and opened her eyes to the parallels between the experiences of rare disease patients and the healthcare inequities that minority communities face.

For instance, she notes that it often takes rare disease patients roughly five years to get a diagnosis, and that missed or delayed diagnoses are also common among ethnic minorities. Such diagnostic disparities are well documented in academic research, from dementia, to autism spectrum disorder, to appendicitis, to breast cancer and many other conditions.

Too often, health complaints of people in the Black community — especially Black women — are dismissed, Thompson said. In fact, she had a close family member who died from a disease because they didn’t get a diagnosis until it was too late.

That’s why, when she had the opportunity to move to Alexion and advocate on behalf of the rare disease community, she took it.

“It felt really aligned and parallel with my family journey, with what I've seen in my community, so I was drawn to it,” she said. “I've never looked back. I'm still loving every minute of it and appreciating the opportunity and the privilege that I get to come in every day and search for disease patients.”

Rare disease progress

Now, as the U.S. commemorates the 40th anniversary of the Orphan Drug Act, as well as Rare Disease Day later this month, Thompson is reflecting on how far rare disease treatment has come — and how far it still needs to go.

“We can point to more than 500 unique therapies that have come through the pathways under the Orphan Drug Act,” she said. “I think the Orphan Drug Act is really an example of when you get policy right, it can be a motivator and a simulator for innovation, and it's good for patients at large.”

However, she expressed concern that certain provisions within the new Inflation Reduction Act (IRA) could inhibit future progress in rare disease research.

Although the National Organization for Rare Disorders called the IRA “a significant step forward in helping ensure that individuals and families with rare diseases have access to the comprehensive health care they need to survive and thrive,” Thompson said provisions within it undermine part of the Orphan Drug Act.

Part of the IRA allows the CMS to negotiate the prices of certain Medicare and Medicaid covered pharmaceuticals and biologics. However, orphan drugs that are indicated for “only one rare disease or condition,” are exempt from price setting, which could discourage companies from studying products for secondary or tertiary conditions. 

“We have drugs that are useful for multiple disease states: One therapy, but useful for multiple rare diseases. We wouldn’t fall under the exemption for that under IRA,” Thompson said.

Still, she remains hopeful about the future of rare disease treatments and health equity for all patients.

“If you look across industry at what's in development, 40% of that is rare by some definition. So that’s promising for a community with more than 7,000 unique rare diseases and roughly 5% (that have) approved treatment options,” she said. “If you're telling me that 40% of the pipeline in development is touching that, that is a call for excitement and enthusiasm within itself. That means hope and promise.”