KOLs: Orphan Drugs in Oncology

Expert Profile

Section 1: Current Orphan Drug Therapy

1.1. How would you describe the current orphan drug patient journey?

So, my clinical background is both in internal medicine and dermatology. So, I focus on the management of patients with complex medical dermatologic diseases, as well as skin cancers and particularly rare skin cancers and the side effects of cancer chemotherapies. So, in those arenas, I have the opportunity to take care of a number of individuals with quite rare conditions, both several skin diseases that are quite rare, as well as patients with rare forms of cancer who develop side effects from their meds. I’ve had a broad range of experience, both being the prescriber for these medicines, as well as someone involved in the care of individuals who have received these meds and can speak to it from a couple of different angles.

I would say that it is often not particularly difficult to identify the need for a drug. I have had the experience of taking care of multiple individuals who have come to see me with a clinical condition for which there may not even be a single say, FDA approved treatment dedicated to that condition and really identifying the need for a specific treatment or a treatment that has demonstrated specific efficacy in their condition is quite apparent from the onset. One example I can point to for this that has evolved over the last decade or so would be Merkel cell carcinoma. Merkel cell carcinoma is a very rare skin cancer. When we think of skin cancers, most people think of melanoma as a particularly well-known and severe skin cancer, and then much more commonly basal cell carcinoma and squamous cell carcinoma. Merkel cell represents probably less than 1% of all skin cancers, but it may be the most aggressive or among the most aggressive, even likely more aggressive than melanoma, typically.

A decade ago, there was not a single FDA approved treatment for the management of Merkel cell carcinoma. There were multiple treatment strategies essentially using various forms of chemotherapy, radiation, surgery, a multimodal management for patients with Merkel cell carcinoma. However, there was no chemotherapeutic agent that was specifically approved for the management of Merkel cell carcinoma in and of itself. That changed over the last decade when the first agent that was ever FDA approved specifically for Merkel cell carcinoma was approved by the FDA, avelumab. This was really harnessing the development of immunotherapy for the management of solid tumors has been a profound treatment revolutionizing the management of several cancers, including Merkel cell carcinoma.

Then following that up, a second agent that was already on the market for other indications with pembrolizumab, another immunotherapy was also approved for the management of advanced metastatic Merkel cell carcinoma. So, within just the span of a couple of years, going from zero approved indication specifically for this rare skin condition to multiple agents, really shows the spectrum of what can happen in the orphan disease space.

There are of course other treatments besides orphan drugs for these diseases. As I was mentioning, prior to the approval of these agents for the management of Merkel cell carcinoma, there were still many patients who were diagnosed with it who were treated typically in large cancer centers and where I practice. I’m in an academic medical center affiliated with a national comprehensive cancer center so there are both accepted local as well as national protocols for the management of Merkel cell carcinoma. However, the chemotherapeutic agents that were used, none of them were specifically approved in there. If you look on their FDA labeling, what is their approved indication for? None of them were specifically approved for the management of Merkel cell carcinoma. Essentially the treatment protocols for the management were derived from prior clinical experiences with these agents. Sometimes in the setting of Merkel cell carcinoma, sometimes in the setting of other carcinomas; but not from a defined indication that this was the outside goal to be a therapy for Merkel cell carcinoma specifically.

In terms of the orphan drugs I currently administer, there’s a mix I’d say across the board from oral agents to self-administered injectables like subcutaneous to IV infusions and it really is varied.

1.2. What are the main bottlenecks in using orphan drugs for the patient therapeutic journey?

The main bottlenecks can be from the fact they’re not covered under certain insurance schemes or because they maybe are not in the immediate hospital formulary and you have to wait for these orphan drugs to arrive before you can begin administering them.

I think both of those roadblocks or hurdles are real in that there are challenges sometimes. That even if I want to prescribe the medication for the patient to be able to obtain the medication, just as you said. If they’re costs are quite significant than perhaps depending on their insurance status or uninsurance status the ability to obtain the medication may be cost prohibitive or challenging in that sense. If it’s a medication that would be administered in the hospital, then the approval process for the hospital formulary, the pharmacy and therapeutics boards of the individual institution needing to approve the use of the new treatment and stocking it and making sure that it is something that we can make available to our patients is something that I’ve run into.

Occasionally, one other challenge that may present itself is that sometimes patients are a little bit wary of a new medication, even if it is for the condition that they have been diagnosed with. If there is not a long standing or proven safety record, say for a newly approved medication in an orphan drug status. Patients may be somewhat hesitant to try something that’s entirely brand new or a new agent or a new class for their condition, just based on not knowing what the long-term safety profile of that medication may be.

In the case of Merkel cell Carcinoma, patient take up can be quite variable. It would really depend on a number of factors related to that patient. What I will say is now we’re in an era where since that drug has that FDA approved indication, we as physicians have a much stronger bargaining point to make a much stronger case that that medication should be used for that individual that carries that diagnosis and I think the barriers to obtaining it drop significantly.

Another challenge can also be the mode of administration of the drug. That is definitely a hurdle for some individuals to be able to get to a site of administration. I think we’re always hopeful or excited about a new oral medication, if possible, just to be able to deliver care for patients at home and really make it more accessible to larger numbers of patients. I think when something is in an IV infusion, it becomes obviously much more resource intensive. there are over the last several years, more and more infusion agencies or companies that have increasing comfort or a familiarity with the administration, the home administration of particular medications.

I use these services for my patients on therapies like IVIg intravenous immunoglobulin where they are receiving an infusion, let’s say once a month or so. It’s not technically an orphan drug per se, but I think that model of delivering more care at home, even if it is more complex care, maybe adaptable or evolving for further medications as we get more comfortable with them.

1.3. What are the greatest unmet needs around clinical use of orphan drugs?

I would say the biggest barrier is often just access. Like I said, once the medication is approved, it’s getting it into people or getting it to people is really the biggest hurdle. As a physician, it can be very frustrating if there’s an insurance coverage issue or just not being able to obtain the medication, that’s the biggest challenge. Typically, these orphan drugs can be funded on the Medicare and Medicaid programs. There may be a lag time depending on the specific medication and things of that nature, but often they will end up getting covered by the government insurance agencies.

Section 2: Future of Orphan Drug Therapy

2.1. How will the patient journey for orphan drugs change in the future?

I do see that evolving. I think the case to be made for the use of the medications gets stronger and stronger each year with more data on the effectiveness of these medications in real-world practice. The more that that is evident and justifiable and not solely a finding that is present in clinical trials, but really based on real world experience and the numbers can grow exponentially. You’ll see it evolve into more of a standard of care approach for the management of patients with rare diseases. It becomes something that is more accessible, more easily approved and more easily obtained for our patients. So, I do think getting an orphan drug approved is the first step in the journey, not really the last step in the journey. Some people view that as, “Oh, now that we have the medication we’re done”. But it’s not really the end of the journey, if you will. It’s a very important milestone on the route, but it’s not the final destination.

2.2. What oncology indications will see future orphan drug treatment?

I can think of a couple diseases just based on conditions that I treat. So, one of them is acute cutaneous lupus. Lupus is a quite common auto immune disease that most people may be familiar with or may have heard about such as systemic lupus, where you have internal organ involvement. There are a large number of people that have solely skin limited disease and we call that cutaneous lupus. They don’t have internal organ involvement and yet medications that are approved for the management of lupus are all approved for systemic lupus disease. Now one of the reasons you may ask, well if it’s only skin disease, that seems like it might almost be easier to find a medication or get something approved for? But one of the challenges is in actually defining skin lupus. There haven’t been as many validated clinical endpoints and that has really stymied clinical trials for the development of new therapeutics. That’s something that I’ve worked on with colleagues of mine is to better identify, better categorize or characterize what are the variables of interest for skin lupus.

Another example that falls into that category is a condition known as dermatomyositis. It’s another auto-immune disease. It typically involves some form of auto antibody production that’s attacking both the skin and the muscles. So individuals present not only with a diffuse rash, but often with muscle weakness as well and it can be quite devastating for individuals in that they can develop weakness, inability to stand up from the chair or comb their hair or things that are very basic routine functions if this condition is not treated. Traditionally, the management of this condition is essentially with general immunosuppressives, there’s not a single medication that is the go-to dermatomyositis anti-inflammatory medication. That’s something that can make the initial management or the initial approach challenging for patients because we don’t have something that we automatically can say, “This is here, the standard of care for this medication that’s approved for this condition”. We’re using medications that are more short of general immunosuppressive or immunomodulatory medications to treat this autoimmune condition.

As part of my work, especially being at a large cancer center, I see many patients that are on clinical trials with drugs that we would be considered orphan drugs for these rare indications. I think that’s probably reflective of just the environment that I find myself and if I were trying to run a clinical trial in a less highly tertiary or quaternary care setting, it probably would be very difficult to run trials or recruit patients for these very rare indications.

I think you see these large cancer centers; you see places like the NIH, really being hubs for clinical trial activity for these rare disease indications. Then you can see much more commonly widespread clinical trials all over the country for very common conditions. In dermatology, we see clinical trials for things like acne and psoriasis, being able to enroll hundreds, if not thousands of patients, and to be able to recruit from all over the country. If you’re studying something like Merkel cell and looking at a new orphan drug, there’s only going to be very few, maybe a handful of select centers across the country that might be able to enroll a large number of patients for the trial.

2.3. How could patient access to orphan drugs be improved?

I think there’s a large number of factors at play. One thing that is very powerful are our patient organizations and patient advocacy groups for helping spread the word about rare diseases. Some of the groups that I’ve worked with for either various genetic diseases or skin diseases are very, very close-knit communities. So really reaching out to patients through such organized advocacy groups can be a very powerful tool to spread the word about, a new clinical trial is recruiting and we’re looking for participants. Or, these are new medications that are being explored for this condition. Or, we’re in need of participants to help us better understand the genetic or proteomic or other signatures of this disease, which is maybe a first step to thinking about a therapy down the road. So, I think that’s one very powerful arm of working with individuals who have orphan diseases or rare diseases to really engage them directly to better understand how we’re going to be able to treat them.

I would say the way that I see that playing out is not necessarily that there are more patients with the specific disease for which the drug was approved, but rather the pharmaceutical companies and physicians in concert are able to identify new indications for those approved medications. So once the drug has been approved for an orphan indication, thinking about, well now we have this FDA approved medication, what are the other diseases that we might be able to explore this agent for? I think that’s actually a powerful tool to advance the progress of medicine and maybe give us insights into new drugs for diseases that are still as yet unmet in their treatments.

2.4. What can pharmaceutical companies do to improve orphan drug access?

Not off the top of my head, I would say that they do a really good job, especially once medications are approved in marketing them quite aggressively. I think they have an incentive to do so as well and so that really aligns with their goal, and once something is approved to really get it out there, get it used, get it to be up taken by patients through their physicians. I think they do that element extraordinarily well and they’re highly motivated to do so.

I think on the upstream development side, every industry, every sector has its own motivations for the medications that it chooses to pursue. Maybe based on their expertise or their portfolio or their pipeline of medications that they’re exploring, or the compounds that they’re exploring. I think something like the incentives that have been put into place for orphan drugs have stimulated the growth and development of treatments for these conditions that may not otherwise have been developed over the last few decades.