Rare Diseases, Rare Opportunities

Posted March 4th, 2015 by Tom Hughes, in From The Trenches, Rare Diseases

Last week on February 28th – as I sat down to write this short blog– was Rare Disease Day 2015.

Rare diseases, and there are estimated to be 7000 of them, impact almost 30 million people in the US alone, according to the National Organization for Rare Disorders (NORD). These diseases – such as Spinal Muscular Atrophy, Fabry Disease, Duchenne Muscular Dystrophy, obviously weigh heavily on the patients and families impacted, and on the healthcare system as a whole. It’s hard for many of us to appreciate the impact of having a child born with a debilitating or life-limiting disorder, to struggle with having a poorly understood condition, to be studied as a patient with an unusual and challenging condition, or to agonize with being misunderstood while seeking an accurate diagnosis or treatment approach. It’s tough to ponder. We have a long way to go in medicine.

One patient’s journey through a rare disease experience can be found in an incredible book titled “Brain on Fire” written by Susannah Cahalan. The book details her experience with anti-NMDA receptor encephalitis, which temporarily robbed her of her sanity, nearly destroyed her life, and for which treatment cost more than a million dollars over the course of less than a year. Devastating? Yes. Rare?   Certainly. Worthy of focus from our industry? Definitely, although existing medications and a gifted physician did save her life. The disease nearly robbed us of an incredibly talented journalist, and worse still, could have led her to be institutionalized and labeled as ‘insane’.

Until the Orphan Drug Act was authorized in 1983, many rare diseases remained unaddressed – in truth, orphaned by the industry due to complex biology, challenges with diagnosis, difficult patient identification, and other issues including navigating market access hurdles across multiple geographies.

Our company Zafgen is dedicated to significantly improving the health and well-being of patients affected by obesity and complex metabolic disorders. Through an interesting series of confluent events, we launched efforts in two rare disorders (Prader-Willi syndrome and hypothalamic injury-associated obesity) with our lead molecule over the past few years. I have to say, coming from a 21 year career at a major pharma company spent discovering drugs and tackling the highly complex and expensive development of drugs for common diseases like dyslipidemia and type 2 diabetes, it has been eye-opening.

This rare disease path has had very concrete impacts on our strategy, our ability to access funds and non-financial resources, and on our momentum as a team. Working on rare diseases with our first drug candidate helps us stabilize our company and sets us up well for our broader approach – to tackle the massive and prevalent indications of obesity in the general population and fatty liver disease with our second generation drugs. As a drug hunter, it is a privilege to serve patients with high unmet need.

Rare diseases, providing the technology fits, make excellent starting points for small early stage biotech companies. You don’t need large firms to support your development or commercial efforts – you can fully develop and commercialize a drug with a relatively small team.

Your scientific and medical marketing efforts become more streamlined – the disorder is generally clear enough – it’s an issue of genetics, or a clear disease pathway, to be communicated. How your drug works becomes almost secondary to the point that it can provide much needed relief to the patients. People – and their families and physicians – need little or no convincing. You’re in a very unique position, by working on a potentially meaningful new therapeutic approach, to offer them hope for a better tomorrow.

If the condition is well-characterized, you’re likely to benefit from (well established) built-in advocacy – in our case the Foundation for Prader-Willi Research and Prader-Willi Syndrome Association are comprised of incredible people focused on providing support and guidance to their affected families, to sponsoring needed research, and to building awareness within the medical care community, regulatory agencies, and physician community about the disorder. These are amazing, driven, constructive, and dedicated people. Just wow. Unfortunately, the reality is that the majority of rare diseases do not have organized advocacy groups. One key role that companies can play is to connect patients with rare diseases and enable them to get organized.

As a small company working on one of the estimated 7000 rare conditions, you’re likely to face reduced competitive pressure. This provides you with some breathing room as you run your program. That’s good too, although competition can be good for patients who otherwise have no options.

Regulators appreciate the dire need for new treatments affecting rare disorders. That helps, and one can only imagine it provides them with a greatly deserved look at more interesting and less-trodden biology, trial strategy, and path to generation of medically relevant evidence.

Lastly, and importantly to small companies, investors inherently get the merits of working in the rare disease / orphan drug space. It’s efficient, understandable, and much easier to model potential returns on investment than if you are working in a crowded space with competitive pressure and narrow margins. It’s really been critical to our success in raising money and remaining capital-efficient.

That isn’t to say that discovering drugs for rare conditions is easier. It’s not. Drugs need to be potent, selective, effective, and have a safety profile that is appropriate to the patient population. The pitfalls that apply to development of drugs for major indications apply in full force to rare disorders. Drugs fail for myriad reasons, and finding a drug that works for a rare disease is still an amazing feat. That’s just how it is. Our work is fiendishly difficult, complex, and fraught with challenges.

Finding and accessing patients becomes a work stream of its own and, as our Chief Commercial Officer Alicia Secor says, is “an enduring pillar of the rare disease business model”. You likely will need to set up a patient registry, educate physicians, change the paradigm for differential diagnosis and screening to diagnose patients earlier in the cycle of their disease, and more. You likely will need to help to establish a patient service model that is customized to the nuances of the disease and provide services post-launch that promote adherence, since these therapies are for chronic conditions. You’ll also need to help ensure support through a patient services model to streamline and ensure access to your drug.

Trials are challenging and expensive on a per patient basis. Running your trial may require that you conduct elaborate physical and biochemical exams, implement new tests with previously un-validated endpoints, and support travel costs your patients will incur throughout the trial. You may need to provide support for genetic confirmation of the disease state and to characterize your potential trial participants fully to establish their eligibility for your trials.

Your drug will be put to rigorous tests to be approved, too. Severe conditions need highly effective therapies – the efficacy bar is set high. This makes sense, but if the drug is well-matched to the underlying problem affecting the patients, you’ll likely benefit from the more homogeneous etiology of the disease, meaning you’ll get tighter data and need fewer patients to show effects.

You’re likely walking untrodden ground, since the problem won’t be worth fixing if existing therapies already work well. Any new drug approach brings with it greater unknowns, and this makes for interesting days and challenging science, for sure.

Beyond all of this, though, Rare Diseases become deeply personal. I think none of us at Zafgen expected to experience the attachment we would feel to the patients when we first started working in the rare disease space. In my old job, working in mass market disease areas like type 2 diabetes, you knew up front that you’d be happy with a few percentage points of market penetration. You’d likely never meet a patient who would take your drug.

What’s been striking about our efforts, for example, in Prader-Willi syndrome, is that we realized quickly that every single patient we met could eventually end up taking our drug. You don’t meet a child with the condition, or their parents, without thinking that you could be impacting their lives in a meaningful way. It’s a special bond. In our team, we wear PWS bracelets to remind ourselves – every day, every moment – that we are working to help these people. It’s a humbling reminder that we need to do our jobs well – and as quickly as possible.

Every day, for those of us in the business, is Rare Disease day.

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